Methods for treating joint or bone canal disorders

Abstract

The present invention relates to the treatment of patients requiring treatment for joint or bone canal pathologies. In particular, the present invention relates to the injection of a sustained-release biodegradable depot comprising a hydrogel and a tyrosine kinase inhibitor.

Description

[Technical Field]

[0001] Cross-reference of related applications This invention claims priority to U.S. Provisional Application No. 63 / 472,162, filed on 9 June 2023, which is incorporated herein by reference.

[0002] The present invention relates to the treatment of joint conditions such as arthritis, or bone canal conditions. According to the present invention, such conditions are treated by administering by injection a biodegradable depot that provides sustained release of a tyrosine kinase inhibitor, particularly axitinib. The present invention further relates to an injectable pharmaceutical preparation comprising such a depot suspended as particles in a liquid carrier, the carrier being an aqueous or non-aqueous fluid suitable for injection. [Background technology]

[0003] Common problems include joint conditions such as joint pain, and bone canal conditions, which cause limitations in mobility and, consequently, prevent individuals from actively participating in daily life. Arthritis, one of the most common causes of joint pain, is generally described as one of over 100 conditions affecting joints and connective tissue. It involves inflammation of the joints and can affect one or more joints. In addition to pain, the main symptoms of arthritis include redness, heat, swelling, stiffness, and reduced range of motion in the affected joint(s). Symptoms of arthritis usually develop over time, but can also appear suddenly. They can change from week to week and even from day to day. Many types of arthritis are long-term conditions. The causes of arthritis are not fully understood. Most types of arthritis, such as rheumatoid arthritis, are thought to be caused by a malfunction of the immune system that causes the body to attack its own tissues. Other types of arthritis originate from metabolic conditions such as gout. Furthermore, environmental factors such as obesity, age, repetitive activity, or injury may contribute to the development of certain types of arthritis, including osteoarthritis.

[0004] Osteoarthritis (OA), also known as "wear and tear" arthritis, is the most common type of arthritis, affecting approximately 250 million people worldwide (Hunter et al., Osteoarthitis. Lancet 2019, 393, 1745-1759). Knee OA accounts for approximately 85% of the disease burden of osteoarthritis, preceding gluteal and hand OA, and the prevalence of knee OA in adults over 60 years of age is estimated to be about 10% in men and 13% in women (Zhang et al., Epidemiology of Osteoarthritis. Clin. Geriatr. Med. 2010, 26, 355-369). OA is characterized by slow, progressive degeneration of articular cartilage, dysregulation of subchondral bone remodeling, and inflammation of the synovial membrane, ultimately leading to loss of joint function and chronic pain. As cracks develop in the articular cartilage and it gradually wears down, the joint attempts to heal naturally by forming bone growths (osteophytes) on the sides of the joint. OA is generally described as a non-inflammatory disease to distinguish it from "inflammatory arthritis" such as rheumatoid arthritis (RA). Nevertheless, inflammation is increasingly recognized as contributing to the symptoms and progression of OA (Conrozier et al., Increased serum C-reactive protein levels by immunonephelometry in patients with rapidly destructive hip osteoarthritis. Rev Rhum Engl Ed 1998, 65:759-65). Furthermore, angiogenesis, the generation of new blood vessels from existing blood vessels within the affected joint, is also attributable to the progression of OA.

[0005] Angiogenesis and inflammation are closely integrated processes. Inflammation can promote angiogenesis directly through the release of growth factors from cells such as macrophages, and also through the stimulation or sensitization of other cells such as chondrocytes, nerves, and osteoblasts, which release further angiogenic factors. Angiogenesis at the osteochondral junction leads to ossification and osteophyte formation within the cartilage, further exacerbating inflammation. Angiogenesis can also lead to nerve innervation of articular cartilage, which can be a cause of pain in osteoarthritis (OA). Therefore, angiogenesis and inflammation are important processes in the pathophysiology of OA (Bonnet et al., Osteoarthritis, angiogenesis and inflammation. Rheumatology 2005, 44(1):7-16). Regarding this pathophysiology, accumulating evidence suggests the pathological involvement of vascular endothelial growth factor (VEGF) and its analogous receptors, VEGFR-1 and VEGFR-2, in the progression of osteoarthritis and associated joint pain (Hamilton et al., Targeting VEGF and Its Receptors for the Treatment of Osteoarthritis and Associated Pain. J Bone Miner Res. 2016, 31(5):911-24).

[0006] Vascular endothelial growth factor receptors (VEGFRs) belong to the receptor tyrosine kinase supergene family and consist of a ligand-binding domain containing seven immunoglobulin-like domains, a transmembrane domain, and a tyrosine kinase domain containing a long kinase insert. Upon ligand binding, various intracellular signals and mediators are activated, through which the vascular endothelial growth factor signaling pathway exerts its effects. VEGFRs are generally responsible for binding to their ligand, VEGF, and promote angiogenesis during development, wound healing, and ossification within cartilage. There are three subtypes of VEGF receptors, VEGFR-1, VEGFR-2, and VEGFR-3, which can be activated by various structurally related VEGFs. The glycoprotein VEGF family consists of VEGF-A, VEGF-B, VEGF-C, VEGF-D, and placental growth factor (PlGF), and VEGF-A, whose name is included in the VEGF family, is classically and herein referred to as VEGF. Even though VEGF is the most widely studied and targeted anaerobic pathogen (OA) pathway, all VEGFRs appear to be highly expressed in OA chondrocytes (Shakibaei et al. M, Expression of the VEGF receptor-3 in osteoarthritic chondrocytes: stimulation by interleukin-1 beta and association with beta1-integrins. Histochem Cell Biol 2003, 120:235-41). VEGF expression has been shown to increase in articular cartilage, synovial membrane, synovial fluid, subchondral bone, and serum during the later stages of OA in affected patients.Evaluation of VEGF as a biomarker in OA patients has shown that increased synovial VEGF correlates not only with the severity grade of OA but also with the degree of OA pain (Gaballah et al., Correlation between synovial vascular endothelial growth factor, clinical, functional and radiological manifestations in knee osteoarthritis. The Egyptian Rheumatologist). Consistent with this, bevacizumab, a monoclonal anti-VEGF antibody, reduced OA pain in a rabbit model of OA, and further reduced articular cartilage degeneration, osteophyte formation, and synovitis (Nagai et al., Bevacizumab, an anti-vascular endothelial growth factor antibody, inhibits osteoarthritis. Arthritis Research & Therapy 2014, 16(5):427).

[0007] OA is a highly debilitating disease, resulting in significant personal and socioeconomic burdens. Currently, there are no available treatments that can effectively halt the structural deterioration of cartilage and bone, successfully correct any existing structural defects, and provide long-term symptom relief. Therefore, approximately 30–50% of patients eventually require articular prostheses to cope with progressive OA, which is currently the most effective measure to improve pain perception and quality of life. Therapeutic and non-surgical approaches primarily aim to alleviate symptoms and modify / improve the structural characteristics of the affected joint tissue. For example, while several oral medications are prescribed to primarily address pain issues for the treatment of OA, other treatments, particularly intra-articular treatments, target inflammatory processes or degeneration of articular cartilage.

[0008] A typical approach to osteoarthritis (OA) therapy is initiated as first-line treatment with symptomatic agents, including acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs), adopted in 50–60% of cases. Acetaminophen is commonly used to treat knee OA, but is inferior to NSAIDs (Towheed et al., Acetaminophen for osteoarthritis. Cochrane Database Syst Rev 2006;1:CD004257). NSAIDs should be considered only as short-term treatments for managing symptomatic knee OA, given their side effect profile. Other symptomatic agents for first-line OA treatment may include COX-2 inhibitors such as celecoxib, duloxetine, and opioid analgesics. Second-line OA treatment in the form of intra-articular corticosteroid injections, e.g., triamcinolone acetonide, available as KENALOG®, is usually tried at least once in most OA cases and adopted in 15–20% of cases. Intra-articular corticosteroid injections are routinely administered in moderate to severe cases to reduce acute inflammation and alleviate pain in the short term, but they are not a good treatment option for the long-term management of knee osteoarthritis due to the associated cartilage destruction (Bannuru et al., Therapeutic trajectory of hyaluronic acid versus corticosteroids in the treatment of knee osteoarthritis: a systematic review and meta-analysis. Arthritis Rheum 2009, 61:1704-1711). Alternatively or additionally, intra-articular hyaluronic acid injections can be administered as a third-line treatment for major joint osteoarthritis, such as knee osteoarthritis, and are most effective in early stages of the disease, being used in 8-10% of cases.The favorable safety profile of hyaluronic acid injections makes them an attractive treatment for long-term use compared to NSAIDs, and the absence of known drug interactions makes them a good option for patients receiving multiple medications (Fibel et al., State-of-the-Art management of knee osteoarthritis. World J Clin Cases 2015,16,3(2):89-101). Finally, the fourth and last line of treatment for preoperative OA includes platelet-rich plasma (PRP) therapy. PRP is obtained by centrifugating whole blood to obtain platelet concentrations above baseline, and growth factors including platelet-derived growth factor, insulin growth factor, transforming growth factor beta-1, and VEGF are considered important components of PRP for structural repair. However, PRP therapy is used only in severe cases of disease resistant to other therapies and is employed in 1-2% of cases.

[0009] Furthermore, in recent years, a new concept has emerged that views osteoarthritis (OA) as a multifaceted disease involving the entire joint, not just the cartilage or synovial membrane. This provides new options for identifying and developing novel therapeutic agents and for reprofiling candidate drugs (Grassel et al., Recent advances in the treatment of osteoarthritis. F1000Res.2020,9:F1000 Faculty Rev-325). For example, SPRIFERMIN®, a truncated form of human FGF18 that induces chondrocyte proliferation and cartilage matrix production, showed improvement in total femorotibial joint cartilage thickness (Karsdal et al., Disease-modifying treatments for osteoarthritis (DMOADs) of the knee and hip Lessons learned from failures and opportunities for the future. Osteoarthritis Cartilage 2016, 24(12):2013-21). CNTX-4975®, an ultrapure synthetic form of transcapsaicin targeting transient receptor potential vanilloid 1 (TRPV1), reduced pain in patients with moderate to severe knee osteoarthritis after direct injection into the pain site (Stevens et al., Randomized, Double-Blind, Placebo-Controlled Trial of Intraarticular Trans-Capsaicin for Pain Associated With Osteoarthritis of the Knee. Arthritis Rheumatol. 2019, 71(9):1524-1533).Furthermore, the limitations of the efficacy of conventional intra-articular corticosteroid preparations and the systemic side effects associated with corticosteroids have been addressed by formulating triamcinolone acetonide into extended-release poly(lactic acid-coglycolic acid) microspheres, which are available as ZILRETTA® (Paik et al., Triamcinolone Acetonide Extended-Release: A Review in Osteoarthritis Pain of the Knee. Drugs 2019 79(4):455-462).

[0010] However, despite these advances, there are limitations to the treatment of osteoarthritis (OA). Most injection therapies target only knee OA or OA of larger joints, leaving smaller joints such as finger joints untreated. Furthermore, patients typically require multiple injections for the rest of their lives (e.g., monthly) because the steroids are rapidly expelled from the joints. In addition, while KENALOG® corticosteroid injections remain the current standard of care for OA joint pain, prolonged exposure and repeated administration have been reported to cause cartilage destruction (Testa et al., Intra-Articular Injections in Knee Osteoarthritis: A Review of Literature. Journal of Functional Morphology and Kinesiology 2021 6(1),15). Therefore, corticosteroid injections are generally limited to at least 3 months between repeated injections, but the effective pain relief period is only 2-6 weeks, and for the remainder of the 3-month period, patients remain unable to control their pain.

[0011] Therefore, there is an urgent need for improved treatment of osteoarthritis (OA) throughout the entire body's joints. In particular, given the shortcomings and challenges experienced with currently available treatments, novel therapies that effectively alleviate pain and provide sustained pain relief lasting 3-6 months would benefit patients. Furthermore, recognizing the complex pathophysiology of OA progression, novel therapies that target not only OA-related pain but also signaling pathways involved in inflammation and angiogenesis, such as the VEGF signaling pathway, are highly desirable. [Overview of the project]

[0012] The objective of certain embodiments of the present invention is to provide a treatment for joint conditions such as (osseous) arthritis, or for bone canal conditions such as carpal tunnel syndrome or spinal stenosis.

[0013] Another object of certain embodiments of the present invention is to provide a long-term treatment method suitable for joint conditions such as (osseous) arthritis, or for bone canal conditions such as carpal tunnel syndrome or spinal stenosis.

[0014] Another object of certain embodiments of the present invention is to provide a treatment for relieving pain, such as joint pain, in joint conditions such as (osseous) arthritis or bone canal conditions such as carpal tunnel syndrome or spinal stenosis.

[0015] Another object of certain embodiments of the present invention is to provide a treatment for alleviating pain in the early stages, particularly within 48 hours, of joint conditions such as (osseous) arthritis, or bone canal conditions such as carpal tunnel syndrome or spinal stenosis.

[0016] Another object of certain embodiments of the present invention is to provide a treatment that results in an extension of the period of pain relief, particularly by at least three months, for joint conditions such as (osseous) arthritis, or for bone canal conditions such as carpal tunnel syndrome or spinal stenosis.

[0017] Another object of certain embodiments of the present invention is to provide a treatment for reducing inflammation in joint conditions such as (osseous) arthritis, or in bone canal conditions such as carpal tunnel syndrome or spinal stenosis.

[0018] Another object of certain embodiments of the present invention is to provide a therapy that reduces the expression of at least one inflammatory marker, such as cytokines, in joint conditions such as (osteotic) arthritis, or in bone canal conditions such as carpal tunnel syndrome or spinal stenosis.

[0019] Another object of certain embodiments of the present invention is to provide a treatment for reducing hypervascularity in joint pathologies such as (osseous) arthritis.

[0020] Another object of certain embodiments of the present invention is to provide a treatment for delaying, halting, or improving progressive structural tissue damage in joint pathologies such as (osseous) arthritis.

[0021] Another object of certain embodiments of the present invention is to provide a treatment that delays, halts, or improves the loss of joint function in joint pathologies such as (osseous) arthritis.

[0022] Another object of certain embodiments of the present invention is to provide a treatment for improving joint function in joint pathologies such as (osseous) arthritis.

[0023] Another object of a particular embodiment of the present invention is to provide a treatment method that is not limited to major joints throughout the body for joint pathologies such as (osseous) arthritis.

[0024] Another object of a particular embodiment of the present invention is to provide a treatment applicable to joint pathologies such as (osseous) arthritis, including knee OA, gluteal OA, and / or finger joint OA.

[0025] Another object of certain embodiments of the present invention is to provide a treatment for delaying, stopping, or improving stenosis of the bone canal in bone canal pathologies such as carpal tunnel syndrome or spinal stenosis.

[0026] Another object of certain embodiments of the present invention is to provide a treatment for delaying, cessating, or improving stabbing pain, weakness, or numbness in the limb joints of bone canal pathologies such as carpal tunnel syndrome or spinal stenosis.

[0027] Another object of certain embodiments of the present invention is to provide a treatment that reduces compression of nerve tissue in bone canal pathologies such as carpal tunnel syndrome or spinal stenosis.

[0028] Another object of certain embodiments of the present invention is to provide a treatment that is safe and well-tolerated for joint conditions such as (osseous) arthritis, or for bone canal conditions such as carpal tunnel syndrome or spinal stenosis.

[0029] Another object of a particular embodiment of the present invention is to provide a treatment that is suitable for repeated administration without the need for drug-free periods for joint conditions such as (osseous) arthritis, or for bone canal conditions such as carpal tunnel syndrome or spinal stenosis.

[0030] Another object of certain embodiments of the present invention is to provide a therapy that targets the VEGF signaling pathway for joint conditions such as (osseous) arthritis, or bone canal conditions such as carpal tunnel syndrome or spinal stenosis.

[0031] Another object of certain embodiments of the present invention is to provide a therapeutic method, including the administration of a biodegradable depot, such as in-articular administration, that provides sustained release of an activator that targets the VEGF signaling pathway in joint conditions such as (osteotic) arthritis, or in bone canal conditions such as carpal tunnel syndrome or spinal stenosis.

[0032] Another object of certain embodiments of the present invention is to provide a treatment method, including the administration of a biodegradable depot, for example, in the joint, that provides sustained release for a period of one month or more for joint conditions such as (osseous) arthritis, or for bone duct conditions such as carpal tunnel syndrome or spinal stenosis.

[0033] Another object of certain embodiments of the present invention is to provide a treatment that withstands mechanical loads in the joint or bone canal for joint conditions such as (osseous) arthritis, or for bone canal conditions such as carpal tunnel syndrome or spinal stenosis, including the administration of a sustained-release biodegradable depot, for example, in the joint.

[0034] Another object of certain embodiments of the present invention is to provide a treatment method, including the administration of a sustained-release biodegradable depot, for example, in the joint, that is tolerable to discharge from the joint or bone canal in joint conditions such as (osseous) arthritis, or bone canal conditions such as carpal tunnel syndrome or spinal stenosis.

[0035] Another object of certain embodiments of the present invention is to provide a treatment that increases joint residence or bone canal residence for joint conditions such as (osseous) arthritis, or bone canal conditions such as carpal tunnel syndrome or spinal stenosis, including the administration of a sustained-release biodegradable depot, for example, by joint administration.

[0036] Another object of certain embodiments of the present invention is to provide a treatment method, including the administration of a sustained-release biodegradable depot, for example, in the joint, which is safe and well-tolerated for joint conditions such as (osseous) arthritis, or bone canal conditions such as carpal tunnel syndrome or spinal stenosis.

[0037] Another object of a particular embodiment of the present invention is to provide a treatment for joint conditions such as (osseous) arthritis, or bone duct conditions such as carpal tunnel syndrome or spinal stenosis, comprising the administration of a biodegradable, low- or non-immunogenic, sustained-release biodegradable depot, for example, joint administration, by a particular embodiment of a depot free of animal or human-derived components.

[0038] Another object of certain embodiments of the present invention is to provide a treatment method, including the administration of a sustained-release biodegradable depot, such as in articular administration, that does not cause severe side effects of joint conditions such as (osteotic) arthritis, or bone duct conditions such as carpal tunnel syndrome or spinal stenosis.

[0039] Another object of certain embodiments of the present invention is to provide a treatment method for joint conditions such as (osseous) arthritis, or bone canal conditions such as carpal tunnel syndrome or spinal stenosis, which does not involve chondrotoxicity, including the administration of a sustained-release biodegradable depot, for example, by joint administration.

[0040] Another object of certain embodiments of the present invention is to provide a treatment for joint conditions such as (osseous) arthritis, or bone canal conditions such as carpal tunnel syndrome or spinal stenosis, including the administration of a sustained-release biodegradable depot that is non-destructive to the joint, cartilage, bone canal, or nerve, for example, by joint administration.

[0041] Another object of a particular embodiment of the present invention is to provide a pharmaceutical composition comprising a biodegradable depot that provides sustained release of an activator for targeting the VEGF signaling pathway.

[0042] Another object of certain embodiments of the present invention is to provide a pharmaceutical composition that enables injection, for example, intra-articular injection.

[0043] Another object of certain embodiments of the present invention is to provide a pharmaceutical composition comprising an activator for targeting a VEGF signaling pathway, which can be safely injected via a small-gauge needle.

[0044] Another object of certain embodiments of the present invention is to provide a method for producing a pharmaceutical composition comprising a biodegradable depot that results in the sustained release of an activator for targeting the VEGF signaling pathway.

[0045] Another object of a particular embodiment of the present invention is to provide a kit comprising one or more pharmaceutical preparations for injection, for example, intra-articular injection.

[0046] One or more of these objectives of the present invention, and others, are addressed by one or more embodiments disclosed and claimed herein.

[0047] In certain embodiments, the present invention enables effective long-term treatment of signs and symptoms of joint conditions such as (osteogenic) arthritis, or bone canal conditions such as carpal tunnel syndrome or spinal stenosis, by injection of a tyrosine kinase inhibitor (such as axitinib) via a sustained-release biodegradable depot. In some embodiments, one dose of the tyrosine kinase inhibitor (such as axitinib) is contained in one or more sustained-release biodegradable fibers. In other embodiments, one dose of the tyrosine kinase inhibitor (such as axitinib) is contained in multiple sustained-release biodegradable beads.

[0048] While we do not wish to be bound by theory, as used herein, tyrosine kinase inhibitors (such as axitinib) may reduce OA-related pain and decrease inflammation and hypervascularity in OA by inhibiting VEGFR-1 and VEGFR-2 activity, respectively. Similarly, as used herein, tyrosine kinase inhibitors (such as axitinib) may reduce pain associated with carpal tunnel syndrome or spinal stenosis and decrease compression and inflammation within the carpal tunnel or spinal canal.

[0049] Individual aspects of the present invention are disclosed herein and claimed in independent claims. Dependent claims, on the other hand, claim specific embodiments and variations of these aspects of the present invention. Details of various aspects of the present invention are shown in the following embodiments for carrying out the invention. [Brief explanation of the drawing]

[0050] [Figure 1] The time-dependent release of axitinib from 4a20kPEG-SG fibers in vitro (in PBS at 37°C and pH 7.4) according to embodiments of the present invention containing 7.7 μg, 15.4 μg, and 30.8 μg of axitinib is shown. [Figure 2] The time-dependent release of axitinib from 4a20kPEG-SG and 4a20kPEG-SAZ fibers in vitro (in PBS at 37°C and pH 7.4) according to embodiments of the present invention containing 32.94 μg or 56.30 μg of axitinib is shown. [Figure 3] This shows the time-dependent release of axitinib from 4a20kPEG-SAZ fibers in vitro (in PBS at 37°C and pH 7.4) according to embodiments of the present invention containing 421.6 μg and 103.6 μg of axitinib. [Figure 4] This shows the time-dependent release of axitinib from 4a20kPEG-SAZ beads in vitro (in PBS at 37°C and pH 7.4) according to an embodiment of the present invention. [Figure 5] This shows the relative in vivo release of axitinib from 4a20kPEG-SG and 4a20kPEG-SAZ fibers according to embodiments of the present invention containing 32.94 μg or 56.30 μg of axitinib, respectively. [Figure 6] This shows relative in vivo axitinib release from 4a20kPEG-SAZ fibers according to embodiments of the present invention containing 421.6 μg and 103.6 μg of axitinib. [Figure 7] This study demonstrates the effects of 4a20kPEG-SG fibers according to embodiments of the present invention, containing 7.7 μg, 15.4 μg, and 30.8 μg of axitinib, on MIA-induced hyperalgesia in rats. [Figure 8] The effects of 4a20kPEG-SG and 4a20kPEG-SAZ fibers on MIA-induced hyperalgesia in rats, according to embodiments of the present invention containing 32.94 μg or 56.30 μg of axitinib, respectively, are shown. [Figure 9] This document demonstrates the effects of 4a20kPEG-SG fibers according to embodiments of the present invention, containing 7.7 μg, 15.4 μg, and 30.8 μg of axitinib, on inflammation in the knees of rats with MIA-induced osteoarthritis. [Figure 10] This document demonstrates the effects of 4a20kPEG-SG fibers according to embodiments of the present invention, containing 7.7 μg, 15.4 μg, and 30.8 μg of axitinib, on the pannus of the knee in rats with MIA-induced osteoarthritis. [Figure 11]This study demonstrates the effects of 4a20kPEG-SG fibers according to embodiments of the present invention, containing 7.7 μg, 15.4 μg, and 30.8 μg of axitinib, on cartilage degeneration in the knee of rats with MIA-induced osteoarthritis. [Figure 12] This study demonstrates the effects of 4a20kPEG-SG fibers according to embodiments of the present invention, containing 7.7 μg, 15.4 μg, and 30.8 μg of axitinib, on bone resorption in the knee of rats with MIA-induced osteoarthritis. [Figure 13] The effects of 4a20kPEG-SG fibers according to embodiments of the present invention, containing 7.7 μg, 15.4 μg, and 30.8 μg of axitinib, on IFN-γ expression 14 days (left) or 42 days (right) after administration are shown. [Figure 14] The effects of 4a20kPEG-SG fibers according to embodiments of the present invention, containing 7.7 μg, 15.4 μg, and 30.8 μg of axitinib, on IL-10 expression 14 days (left) or 42 days (right) after administration are shown. [Figure 15] The effects of 4a20kPEG-SG fibers according to embodiments of the present invention, containing 7.7 μg, 15.4 μg, and 30.8 μg of axitinib, on IL-1β expression 14 days (left) or 42 days (right) after administration are shown. [Figure 16] The effects of 4a20kPEG-SG fibers according to embodiments of the present invention, containing 7.7 μg, 15.4 μg, and 30.8 μg of axitinib, on IL-4 expression 14 days (left) or 42 days (right) after administration are shown. [Figure 17] This shows the effect of 4a20kPEG-SG fibers according to embodiments of the present invention, containing 7.7 μg, 15.4 μg, and 30.8 μg of axitinib, on IL-5 expression 42 days after administration. [Figure 18] The effects of 4a20kPEG-SG fibers according to embodiments of the present invention, containing 7.7 μg, 15.4 μg, and 30.8 μg of axitinib, on KC / GRO expression 14 days (left) or 42 days (right) after administration are shown.

[0051] definition The term “articular pathology,” also known as “articular conditions,” broadly refers, as used herein, to any disease, disorder, or discomfort affecting or involving a joint. In this context, the term “joint” is understood to mean the junction between two or more bones, including the surrounding soft tissues such as cartilage, tendons, muscles, and ligaments. Articular pathologies may be inflammatory, i.e., they may involve inflammation of the bone or associated tissues. In certain embodiments, the inflammation is related to arthritis. In other embodiments, the inflammation is not related to arthritis.

[0052] As used herein, the term “pathology of the bone canal” broadly refers to any disease, disorder, or discomfort associated with the bone canal(s). In this context, the term “bone canal” is understood to mean a cavity formed by the involvement of at least bone(s) and associated soft tissues. This includes, for example, the carpal tunnel, i.e., the structure between the anterior forearm and the hand, particularly the palmar-located fibrous canal that serves as a passage for the median nerve. In some circumstances, narrowing of the carpal tunnel can restrict / compress the median nerve, which can cause a common condition known as carpal tunnel syndrome, characterized by numbness, tingling, and weakness in the thumb and fingers. Another exemplary pathology of the bone canal is spinal stenosis, i.e., narrowing of the spinal canal and nerve root canal, which are elongated cavities enclosed within the dorsal bone arch of the spine, including, particularly the spinal cord and vertebral roots. Spinal stenosis can compress either the spinal cord or the nerve roots extending from the neck to the lower back. It generally occurs in the cervical and lumbar regions of the spine. Some people have spinal stenosis without experiencing any symptoms, but many people experience pain, numbness, tingling, and muscle weakness, all of which can worsen over time if left untreated. "Pathophysiology of the spinal canal" can be associated with or caused by arthritis.

[0053] As used herein, the term “angiogenesis” refers to the growth of new capillaries from existing vascular structures during essential, normal physiological processes, but it can also contribute to various pathological conditions, such as undesirable vascular growth in chronic inflammatory diseases. Angiogenesis is a complex, multi-step process regulated by a wide range of positive and negative regulators, including VEGFs. Conversely, hypervascularization, i.e., an increase in the number or concentration of blood vessels, can result from dysregulation of these factors.

[0054] As used herein, the term “arthritis” refers to a disease of the joints, i.e., a particular abnormal condition affecting the structure or function of all or some of the joints, i.e., not immediately caused by any external injury. “Arthritis” is a form of arthritis involving inflammation of one or more joints. Arthritis may be infectious, i.e., caused by an infection of bacteria, viruses, or fungi spreading from another part of the body, or it may be non-infectious, i.e., caused by other factors.

[0055] As used herein, the phrase “mediated by” is understood to include “stimulated and / or inhibited by,” as well as “related to,” for example, a joint pathology may be a joint disorder related to at least one receptor tyrosine kinase (RTK).

[0056] As used herein, the term “joint pain,” also called arthralgia, refers to discomfort, throbbing, or pain in any of the body’s joints. The pain may be constant or intermittent. It may be the result of disease or injury. However, it may also be caused by other conditions or factors. In this context, a joint is understood to be a pivotal structure of the articular system, which can be seen as a discontinuity within the skeleton that allows for controlled mobility, and which can have different structures depending on its functional requirements. Furthermore, a “synovial joint,” also known as a movable joint, is understood to mean a negative-pressure enclosed space where the ends of bones (articular surfaces) that move relative to each other are covered with articular cartilage. This is composed of proteoglycans and collagen, combined in a way that allows it to absorb large pressures like a buffer, while providing a glossy surface for smooth, low-friction movement. A healthy synovial joint is lubricated by a small amount of synovial fluid (0–4 mL), which is the ultrafiltered form of plasma containing further components secreted by the synovial membrane. The cartilage and synovial fluid together maintain a coefficient of friction of less than 0.02. The fibrous joint capsule surrounds the movable joint and connects the articular bones. It consists of two layers: an outer fibrous membrane that may contain ligaments and an inner synovial membrane that secretes synovial fluid for lubrication, shock absorption, and joint nutrition. In certain embodiments, joint pain is associated with arthritis. In other embodiments, joint pain is not associated with arthritis.

[0057] As used herein, the term "chondrotoxicity" refers to cytotoxicity relating to chondrocytes, i.e., toxicity to cartilaginous tissue.

[0058] In this specification, a particular administration or injection is performed "concurrently with" the administration or injection of a depot according to the present invention, also known as "simultaneously to" or "at the same time as," meaning that either two or more depot injections or one or more depot injections are typically performed at very short intervals, for example, simultaneously, successively, i.e., without significant delay, together with the administration or injection of at least one other drug disclosed herein. If at least one other drug is administered by intravenous injection, this injection is also typically intended to be performed immediately before or after the intravenous injection of one or more depots according to the present invention (as disclosed above), for example, during a single treatment session. Alternatively, at least one drug may be administered by intravenous injection together with one or more depots, i.e., by the same subcutaneous injection needle. Even if at least one other drug is administered concurrently with one or more depots of the present invention (disclosed herein), the other drug does not need to have the same re-dosing frequency as the depots of the present invention. Furthermore, the treatment of joint pathologies according to the disclosed embodiments of the present invention may be combined with one or more other treatments for the same or different joint pathologies. The duration and / or interval of such other treatments may correlate with, overlap with, or differ from the duration and / or interval of the depots of the present invention. The other treatments may be administered by any suitable route, not limited to oral, topical, or by injection, e.g., intravenous, intramuscular, intra-articular, or any other type of injection.

[0059] As used herein, terms such as “administer,” “administer,” or “administered” in the context of the depot of the present invention refer to the process of inserting a depot(s) into a joint, particularly one affected by a joint pathology. Therefore, “administering a depot” or similar terms refer to the insertion of a depot into the joint cavity or surrounding tissue. Terms such as “insertion,” “insertion,” or “inserted” in the context of the depot of the present invention also refer to the process of inserting a depot into a joint by a hypodermic (hypo-) needle and are therefore used interchangeably herein with the terms “administer,” “administer,” or “administered.” In contrast, terms such as “administer,” “administer,” or “administered” in the context of other drugs (which are not the subject of this invention) may also refer to the oral or topical application of these drugs.

[0060] As used herein, the term “articular injection” refers to administration / insertion into an intra-articular cavity, including the joint cavity and surrounding tissues, by injection. In this context, the term “articular” generally refers to joints. The terms “intra-articular” and “peri-articular” are understood in the context of this invention to mean within the joint cavity or peri-articular, i.e., within the surrounding tissues. Regardless of whether the injection is performed intra-articular or peri-articular, the depot can change its position on its own to be located intra-articular or peri-articular.

[0061] As used herein, the term “injection into or near the bone canal” refers to administration / insertion into the bone canal or into the bone canal, including the surrounding (soft) tissue, such as the carpal tunnel or spinal canal. In this context, injection into the spinal canal is also referred to as “epidural injection.”

[0062] As used herein, the term “treatment period” means that the therapeutic effect of the depot of the present invention at the time of administration is maintained or essentially maintained over that period.

[0063] As used herein, the term “depot” refers to an object containing an activator, in particular a tyrosine kinase inhibitor (TKI), e.g., axitinib, and other compounds disclosed herein, which is administered into the body of a human or animal, e.g., into the joint capsule of a synovial joint, where it remains for a specific period of time while simultaneously releasing the activator into the surrounding environment. A depot may have any predetermined shape before insertion, and its general shape may be maintained to some extent once the depot is placed in the desired position, although the dimensions of the depot (e.g., length and / or diameter) may change after administration due to hydration, as further disclosed herein. A depot according to the present invention may exist as a single unit or may consist of two or more units. In certain embodiments, the unit(s) may be in the form of a fiber(s) or beads. One dose of a TKI may be contained in a single unit (e.g., one fiber disclosed herein) or in two or more units (e.g., multiple beads disclosed herein) administered simultaneously in a single injection, e.g. Whenever the amount of activator contained in a depot is mentioned, it should be understood that this refers to the total amount of activator contained in the entirety of the units contained in the depot. The units may be the same or different. In certain embodiments, what is administered intraarticular is a pre-formed, consistent object. Thus, the depot is fully formed (pre-formed as a fiber) before administration, for example by the method disclosed herein. In alternative embodiments, the depot may occur in situ, i.e., a solution or suspension is administered intraarticular, and the depot is formed after injection in an aqueous environment at the desired site. Over time, the depot inserted in certain embodiments may biodegrade (as disclosed herein), thereby changing its shape (e.g., its diameter may increase and its length may optionally decrease) until it is completely dissolved / absorbed.In this specification, the term “depot” is used to refer to both the hydrated state (also referred to herein as “wet”) after the depot has been administered to a joint and hydrated or rehydrated, or after being immersed in an aqueous environment (e.g., in vitro), and the state in which the depot is produced, dried, or immediately before it is administered as disclosed herein, after it has been manufactured in a dry state without requiring dehydration. In the art, in a dry state, a “hydrogel” (e.g., a hydrogel contained in the depot of the present invention) may also be referred to as a “xerogel.” Therefore, in certain embodiments, in the context of the present invention, the depot in its dry / dry state may contain about 0.01% to about 10% by weight of water, or about 0.1% to about 7% by weight of water, or about 0.25% to about 5% by weight of water, or about 1% by weight or less of water. The moisture content of a dry / free-state depot can be measured, for example, by Karl Fischer coulometry. Whenever the dimensions of a depot (i.e., length, diameter, or volume) are reported in the hydrated state, these dimensions are measured after the depot has been immersed in phosphate-buffered saline at 37°C and pH 7.2 for 24 hours. When the dimensions of a depot are reported in the dry state, these dimensions are measured after the depot has been completely dried (and therefore, in certain embodiments, containing about 1% by weight or less of water). In certain embodiments, the depot is maintained in a glove box in an inert atmosphere containing less than 20 ppm of both oxygen and moisture for at least about 7 days.

[0064] In certain embodiments of the present invention, the term “fiber” (as used herein interchangeably with the term “rod”) refers to an object generally having an elongated shape (i.e., in this case, a depot according to a particular embodiment of the present invention). The specific dimensions of the depot according to the present invention are disclosed herein. The depot or unit of depot may have a cylindrical or essentially cylindrical shape, or a non-cylindrical shape. The cross-sectional area of ​​the fiber or depot may be circular or essentially circular, but in certain embodiments it may be elliptical or oblong, or in other embodiments it may have a different shape, such as cruciform, star-shaped, or any other shape disclosed herein.

[0065] Where used in other specific embodiments of the present invention, the term “beads” generally refers to objects having a spherical shape (i.e., in this case, depots according to specific embodiments of the present invention). Depots or units of depots may have a spherical or essentially spherical shape, or a non-spherical shape. The cross-sectional area of ​​a bead or depot may be circular or essentially circular, but in specific embodiments, it may be elliptical or oval. Beads may be uniform, i.e., have a regular surface, or they may be irregular. The particle size of the beads can be selected with respect to the needle gauge intended to be used for dosing, the carrier used (aqueous vs. non-aqueous), and the control of release kinetics as a function of the hydrated bead diameter. In specific embodiments, they may have a narrow particle size distribution, i.e., all beads constituting a depot may have substantially similar sizes. For example, beads in a dry state may have a D90 of less than about 220 μm, or a D90 of less than about 300 μm. The "D90" value means that at least 90 volume percent of all particles in the measured bulk material (with a specific particle size distribution) have a particle size below the indicated value. For example, a D90 particle size of less than approximately 220 μm means that at least 90 volume percent of the particles in the measured bulk material have a particle size of less than approximately 220 μm. The corresponding definition also applies to other "D" values ​​such as "D50" or "D100". The particle size distribution can be measured by methods known in the art (including sieving, laser diffraction, or dynamic light scattering). In embodiments in which a tyrosine kinase inhibitor other than axitinib is used in the present invention, the same particle size as disclosed for axitinib may apply.

[0066] For the purposes of the present invention, the term “sustained-release” is generally defined to refer to a pharmaceutical dosage form or product (in the present invention, these products are depots) formulated to make an activator (e.g., a tyrosine kinase inhibitor according to the present invention, specifically, but not limited to axitinib) available for an extended period after administration (e.g., more than one month), thereby reducing the frequency of administration compared to an immediate-release dosage form, such as a solution of a tyrosine kinase inhibitor applied topically to a joint. Other terms that may be used interchangeably with “sustained-release” herein include “sustained-release” or “controlled-release.” Therefore, “sustained-release” is characterized by the release of the API contained in the depot according to the present invention, in particular, a tyrosine kinase inhibitor, e.g., axitinib. The term “sustained-release” is not in itself associated with or limited to a particular (in vitro or in vivo) release rate, however, in certain embodiments of the present invention, the depot may be characterized by a particular average (in vitro or in vivo) release rate or a particular release profile disclosed herein. Within the specific meaning of the present invention, the term “sustained release” also includes a period of release of tyrosine kinase that is constant or substantially constant per day (i.e., above a certain level), followed by a tapering period of tyrosine kinase release. In such specific cases, the overall sustained release provided by the depot of the present invention (as defined above) may mean that the release rate is not necessarily constant or essentially constant throughout the entire period of TKI release, but may change over time (i.e., to a constant or essentially constant initial period, i.e., sustained release, followed by a tapering release period) as described above. Within the meaning of the present invention, the terms “tapering” or “to tapering” refer to the decrease over time of release of a tyrosine kinase inhibitor, e.g., axitinib, until the tyrosine kinase inhibitor is completely released. In some specific cases, the release profile may also exhibit an initial drug burst and / or a late drug burst, indicated by a short-term increase in the respective release rates (in vitro or in vivo).

[0067] As used herein, the term “biodegradable” refers to a material or object that decomposes in vivo, i.e., when placed in the body of a human or animal (e.g., a depot according to the present invention). In the context of the present invention, a depot comprising a hydrogel in which particles of a tyrosine kinase inhibitor, e.g., axitinib particles, are dispersed, is slowly biodegraded over time after being placed in a joint, e.g., in the joint capsule. In certain embodiments, the biodegradation occurs at least partially via ester hydrolysis in an aqueous environment provided by synovial fluid. In certain embodiments, the depot of the present invention gradually softens and liquefies and is eventually removed from the joint (excreted / leached out).

[0068] A "hydrogel" is a three-dimensional network of one or more hydrophilic natural or synthetic polymers (as disclosed herein), optionally including hydrophobic domains, which swell in water to retain a certain amount of water, and whose structure can be maintained or substantially maintained, for example, by chemical or physical crosslinking of individual polymer chains. Hydrogels are soft and flexible due to their high water content and are therefore very similar to natural tissues. In the present invention, the term "hydrogel" is used to refer to both the hydrated / wet hydrogel when it contains water (for example, after the hydrogel is formed in an aqueous solution, or after the hydrogel is hydrated or rehydrated when it is inserted into a joint or immersed in an aqueous environment by other means), and the dry (dry / dehydrated) hydrogel when it has been dried to a low water content of 1% by weight or less, for example, as disclosed herein. The dry form of a hydrogel is sometimes called a "xerogel" in the art, which is a dry hydrogel that can be converted into a hydrogel upon exposure to and absorption of water. The drying process for forming xerogels can be achieved in several ways, resulting in varying degrees of shrinkage and porosity. The choice of process to achieve a particular degree of shrinkage and porosity depends on the desired balance of these properties. In some cases, a smaller size is advantageous, for example, to fit a small needle diameter. In some cases, a faster rehydration rate is advantageous, which is promoted by higher porosity. In the present invention, if the active ingredient is contained within the hydrogel (e.g., dispersed), the hydrogel may also be called the "matrix".

[0069] As used herein, the term “polymer network” refers to a structure formed from polymer chains that are crosslinked with each other (of the same or different molecular structures and of the same or different average molecular weights). Types of polymers suitable for the purposes of the present invention are disclosed herein. Polymer networks may be formed using crosslinking agents also disclosed herein.

[0070] The term "amorphous" refers to polymers, polymer networks, or other chemical substances or entities that do not exhibit a crystalline structure in X-ray or electron scattering experiments.

[0071] The term "semi-crystalline" refers to a polymer, polymer network, or other chemical substance or entity that possesses some crystalline properties, i.e., exhibits some crystalline properties in X-ray or electron scattering experiments.

[0072] The term "crystalline" refers to a polymer or polymer network or other chemical substance or entity that possesses crystalline properties as demonstrated by X-ray or electron scattering experiments.

[0073] In this specification, the terms “precursor” or “polymer precursor” or, in particular, “PEG precursor” refer to molecules or compounds that react with each other and are therefore linked via crosslinking to form a polymer network, and thus a hydrogel matrix. Other substances, such as activators, visualizers, or buffers, may be present in the hydrogel, but they are not referred to as “precursors.” The molecular weight of polymer precursors used for the purposes of the present invention and disclosed herein can be determined by analytical methods known in the art. For example, the molecular weight of polyethylene glycol can be determined by any method known in the art, including gel electrophoresis, e.g., SDS-PAGE (sodium dodecyl sulfate-polyacrylamide gel electrophoresis), gel permeation chromatography (GPC) (including GPC with dynamic light scattering (DLS)), liquid chromatography (LC), and mass spectrometry (e.g., matrix-assisted laser desorption / ionization time-of-flight (MALDI-TOF) spectroscopy or electrospray ionization (ESI) mass spectrometry). The molecular weight of polymers containing polyethylene glycol precursors disclosed herein is the average molecular weight (based on the molecular weight distribution of the polymer) and can therefore be expressed by various average values, including weight-average molecular weight (Mw) and number-average molecular weight (Mn). Any such average value can generally be used in the context of the present invention. In the context of the present invention, the average molecular weight of polyethylene glycol units or other precursors or units disclosed herein is the number-average molecular weight (Mn) and is expressed in "Dalton" units. The portion of precursor molecules still present in the final polymer network is also referred to herein as a "unit." Thus, a "unit" is a building block or component of a polymer network that forms a hydrogel. For example, a polymer network suitable for use in the present invention may contain identical or different polyethylene glycol units, as further disclosed herein.

[0074] As used herein, the terms “crosslinking agent” or “crosslinker” refer to any molecule suitable for linking precursors via crosslinking to form a polymer network, and by extension, a hydrogel matrix. In certain embodiments, the crosslinking agent may be a low molecular weight compound or one of the polymer compounds disclosed herein.

[0075] As used herein, the term “visualizer” refers to a molecule or composition that may be contained within a depot of the present invention and, when the depot is located in a joint, provides the possibility of easily visualizing the depot in a non-invasive manner. The visualizer may be a fluorophore, such as fluorescein, rhodamine, coumarin, and cyanine, or other suitable agents disclosed herein. In certain embodiments, the visualizer is fluorescein or comprises a fluorescein moiety.

[0076] The terms “API,” “active (pharmaceutical) ingredient,” “active (pharmaceutical) agent,” “effective (pharmaceutical) ingredient,” “(effective) therapeutic agent,” “active substance,” and “drug” are used interchangeably herein and refer to substances used in a final product (FPP) of a pharmaceutical product that imparts pharmacological activity or otherwise directly affects the diagnosis, cure, alleviation, treatment, or prevention of a disease or directly affects the restoration, correction, or modification of a patient’s physiological function, and substances used in the preparation of such a final product of a pharmaceutical product. The API used in this invention is a tyrosine kinase inhibitor, for example, axitinib.

[0077] Tyrosine kinase inhibitors were developed as chemotherapeutic agents that inhibit signaling of receptor tyrosine kinases (RTKs), a family of tyrosine protein kinases. RTKs extend across the cell membrane in both intracellular (internal) and extracellular (external) portions. When a ligand binds to the extracellular portion, the receptor tyrosine kinase dimerizes and initiates an intracellular signaling cascade driven by autophosphorylation using the coenzyme messenger adenosine triphosphate (ATP). Many RTK ligands are growth factors such as VEGF. In certain embodiments, the TKI used in this invention is axitinib. Axitinib is the active ingredient in INLYTA® (Pfizer, NY), which is indicated for the treatment of advanced renal cell carcinoma. It is a small molecule (386.47 daltons) synthetic tyrosine kinase inhibitor. The primary mechanism of action is the inhibition of angiogenesis (formation of new blood vessels) mainly by the inhibition of the following receptor tyrosine kinases: VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-β, and c-Kit (Retina, 32(8):1652-63) (these are involved in pathological angiogenesis, tumor growth, and cancer progression). Therefore, axitinib is a multi-target inhibitor that inhibits both the VEGF and PDGF pathways. The molecular formula of axitinib is C 22 H 18 N4OS has the IUPAC name N-methyl-2-[3-((E)-2-pyridine-2-yl-vinyl)-1H-indazole-6-ylsulfanil]-benzamide. It has the following chemical structure: [ka] The solubility of axitinib in bio-related media (e.g., 37°C, PBS, pH 7.2) has been confirmed to be low, e.g., 0.2–0.5 μg / mL. Its partition coefficient (n-octanol / water) is 4.2 (logP; see DrugBank entry "axitinib"). In certain embodiments, any tyrosine kinase inhibitor used in the present invention, including axitinib, may be used with a particle size of about 100 μm or less, or about 75 μm or less, or about 50 μm or less (e.g., expressed as a D90 value). In certain embodiments of the present invention, axitinib may be used in the form of finely ground particles, with a D90 particle size of about 100 μm or less, or about 75 μm or less, or about 50 μm or less, or about 20 μm or less, or about 10 μm or less, or about 5 μm or less. In these embodiments and other embodiments, the D100 particle size of micronized axitinib may be about 100 μm or less, or about 75 μm or less, or about 50 μm or less, or about 20 μm or less, or about 10 μm or less, or about 5 μm or less. In certain embodiments of the present invention, micronized axitinib has a D90 particle size of about 10 μm or less and a d100 particle size of less than about 20 μm. The particle size distribution of micronized (axitinib) particles can be measured by methods known in the art (including sieving, laser diffraction, or dynamic light scattering). In embodiments in which another tyrosine kinase inhibitor other than axitinib is used in the present invention, the same particle sizes as disclosed for axitinib may be applied.

[0078] For the purposes of the present invention, the activator (including axitinib) may be used in any possible form, including any polymorph of the activator, or any pharmaceutically acceptable salt, anhydride, hydrate, other solvate, prodrug, or derivative of the activator, e.g., axitinib. In this description or claims, whenever the activator is referred to by a name such as "axitinib," it also refers to any such polymorph, pharmaceutically acceptable salt, anhydride, solvate (including hydrate), or derivative of the activator, even if not expressly stated. In particular, the term "axitinib" refers to axitinib and its pharmaceutically acceptable salts, all of which may be used for the purposes of the present invention. As used herein, the term "polymorph" refers to any crystalline form of the activator, e.g., axitinib. Often, activators, which are solid at room temperature, exist in various different crystalline forms, i.e., polymorphs, one polymorph being the most thermodynamically stable at a given temperature and pressure. Regarding axitinib, its solid forms and polymorphs, including its anhydrous form and solvate, are disclosed in scientific literature, such as AMCampeta et al., Journal of Pharmaceutical Sciences, Vol.99, No.9, September 2010, 3874-3886; BPChekal et al., Organic Process Research & Development 2009, 13, 1327-1337, and patent documents including, but not limited to, US8,791,140B2, US2006 / 0094763A1, and WO2016 / 178150A1. The thermodynamically most stable polymorph of axitinib is referred to as the XLI form in, for example, US8,791,140B2. XLI is the anhydrous crystalline form of axitinib. In addition to the anhydrous form, numerous solvates of axitinib with various solvents exist, as described in the cited art, all of which can be used to prepare the depot according to the present invention. Any of the axitinib polymorphs known in the art and disclosed in the art, in particular (but not limited to), in the references cited herein, can generally be used in the present invention (unless a particular aspect of the present invention requires a specific solubility, as described above, then only axitinib polymorphs that satisfy this requirement may be used). In a particular embodiment of the present invention, the axitinib used to prepare the depot according to the present invention is the anhydrous crystalline form XLI. In other embodiments, the axitinib used to prepare the depot according to the present invention is the anhydrous crystalline form IV. In certain other embodiments, suitable crystalline anhydrous forms of axitinib for use in the depot of the present invention include (but are not limited to) polymorphs I, VI, and XXV. These forms are disclosed in Campeta et al. in the references cited above.

[0079] In certain aspects and embodiments of the present invention, the non-solvated crystalline form of axitinib SAB-I disclosed in WO2016 / 178150 may be used to prepare a depot according to the present invention. This includes an XRD pattern containing at least three, or at least four, or at least five characteristic 2θ° peaks selected from 2θ° at 8.3, 15.6, 16.5, 18.6, 21.0, 23.1, 24.1, and 26.0 (all values ​​±0.3), and / or chemical shifts in DMSO solvent containing 26.1, 114.7, 154.8, and 167.8, each shift ±0.2 ppm. 13 13C NMR and / or chemical shifts of 171.1, 153.2, 142.6, 139.5, 131.2, 128.1, and 126.3, each with a range of ±0.2 ppm. 13 Characterized by 13C solid-state NMR and / or by DSC isotherms containing two endothermic peaks between 213°C–217°C (peak 1) and 219°C–224°C (peak 2).

[0080] In certain embodiments of the present invention, a tyrosine kinase inhibitor such as axitinib is used to prepare a depot according to the present invention having a solubility greater than 0.3 μg / mL, measured after incubation for 5 days at 37°C in phosphate-buffered saline (PBS) at pH 7.2–7.4. Axitinib polymorph IV is a particularly preferred polymorph of axitinib. Polymorph IV is disclosed, for example, in US2006 / 0094763A1. Therefore, axitinib polymorph IV can be used in embodiments of all aspects of the present invention. The solubility of axitinib polymorph IV is, for example, about twice that of axitinib polymorph SAB-I, and has been confirmed to be greater than 0.3 μg / mL, and at least 0.4 μg / mL, after incubation for 5 days at 37°C in PBS at pH 7.2–7.4 (or pH 7.2).

[0081] In certain specific embodiments, axitinib contained in or used for the preparation of a depot according to the present invention alternatively features a powder X-ray diffraction pattern including at least two, for example, at least three, or at least four, or at least five peaks among diffraction angles (2θ) of 8.90, 9.40, 9.50, 12.0, 14.60, 15.25, 15.75, 17.80, 19.30, 20.65, 24.95, and 26.10 (all values ​​±0.2). In particular, axitinib used to prepare a depot according to this embodiment of the present invention may be characterized by a powder X-ray diffraction pattern including peaks at diffraction angles (2θ) of 8.90, 12.0, 14.60, 15.75, and 19.30 (all ±0.2), and / or by a DSC peak at approximately 221°C with a scanning speed of 5°C / min (over a range of 25–300°C).

[0082] In addition to axitinib polymorph IV, any other preferred form of axitinib having a solubility greater than 0.3 μg / mL, measured after incubation for 5 days at 37°C in phosphate-buffered saline (PBS) at pH 7.2–7.4, may be used in all embodiments of the present invention to prepare the depots of the present invention. Such forms include, but are not limited to, cocrystals of axitinib and a prodrug or derivative of axitinib.

[0083] Axitinib cocrystals with carboxylic acids, including but not limited to one or more of the following as co-formations: citric acid, fumaric acid, (+)-L- or (-)-D tartaric acid, glutaric acid, (trans- or cis) cinnamic acid, suberic acid, succinic acid, adipic acid, pimelic acid, and salicylic acid, are particularly suitable for use in the present invention. Cocrystals of axitinib are disclosed, for example, in BY Ren et al., Cryst Eng Comm. 2021, 23, 5504-5515. Suitable axitinib cocrystals for use in depots according to the present invention, as well as their synthesis and properties, are also disclosed, for example, in concurrently pending U.S. Provisional Application No. 63 / 458,558, filed April 11, 2023. All axitinib cocrystals disclosed in any of these references, but not limited to these, are generally suitable for use in the present invention.

[0084] In certain embodiments, axitinib cocrystals have a solubility greater than 0.3 μg / mL when measured in phosphate-buffered saline (PBS) after incubation for 5 days at pH 7.2-7.4 and 37°C.

[0085] In certain embodiments, the axitinib cocrystal may have a solubility at least twice, at least five times, at least ten times, at least 25 times, at least 50 times, at least 75 times, or at least 100 times greater than the solubility of the free base of axitinib.

[0086] In certain embodiments, axitinib cocrystals have a solubility of at least 10 μg / mL, for example, at least 12 μg / mL, at least 15 μg / mL, or at least 18 μg / mL, in PBS at pH 7.4 after 24 hours at 37°C. Axitinib cocrystals containing citric acid have an average solubility of about 19 μg / mL in PBS at pH 7.4 after 24 hours at 37°C, axitinib cocrystals containing fumaric acid have an average solubility of about 12 μg / mL in PBS at pH 7.4 after 24 hours at 37°C, and axitinib cocrystals containing (+)-L-tartaric acid have an average solubility of about 19-20 μg / mL in PBS at pH 7.4 after 24 hours at 37°C.

[0087] The axitinib prodrugs suitable for depot use according to the present invention, as well as their synthesis and characterization, are disclosed in concurrently pending U.S. Provisional Application US63 / 416,292 and concurrently pending International Application PCT / US2022 / 046750. Further axitinib prodrugs suitable for depot use according to the present invention are disclosed in US2021 / 0078970. All axitinib prodrugs disclosed in any of these references, but not limited to these, are generally suitable for use in the present invention.

[0088] In the present invention, examples of particularly preferred prodrugs of axitinib are those in which the axitinib molecule is functionalized at one or more of the nitrogen atoms of the free base of axitinib. For example, in a prodrug of axitinib for use according to the present invention, one or more of the nitrogen atoms of the free base of axitinib can be independently substituted with one or more of the following groups: acyl, alkylcarbonyl, arylcarbonyl, alkylthiocarbonyl, arylthiocarbonyl, alkylcarbamoyl, arylcarbamoyl, substituted or unsubstituted acetyl, substituted or unsubstituted aminoalkanoyl, substituted or unsubstituted α-aminoalkanoyl, an acyl group obtained from a natural or unnatural amino acid with or without a substituent, an acyl group of a peptide residue, phosphonyl, phosphinyl, aminophosphinyl, alkylaminophosphinyl, sulfonyl, cycloalkane-carbonyl, heterocycloalkane-carbonyl, alkoxycarbonyl, aryloxycarbonyl, heteroalkoxycarbonyl, heteroaryloxycarbonyl, and an O-substituted hydroxymethyl group with or without a substituent.

[0089] In certain embodiments, a prodrug of axitinib for use in the present invention is a compound of general formula (I) shown below, or a salt or solvate thereof:

Chemical formula

[0090] In certain other embodiments, in the above general formula (I), Y 1 , Y 2 , and Y 3 These are independently -(CH2)p 1OCO(O(CH2)p 2 )n 1 OM, or -(CH2)p 1a OCO((CH2)p 2 O)n 1 (CH2)Z, or -(CH2)p 1 OCO(CH2)q 1 COOH, selected from p 1 , p 1a , and p 2 are independently selected from integers from 1 to 4, q 1 are independently selected from integers from 0 to 4, and other meanings are as defined above for formula (I).

[0091] In certain embodiments, the following prodrugs are suitable for the present invention, and in the above formula (I), X 1 is N + Y 1 and X 2 is NH, X 3 is NH, Y 1 is -CH2OCO(CH2CH2O)n 1a Z 1 or -CH2OCO(CH2)n 1b COOH, or X 1 is N, X 2 is NY 2 and X 3 is NH, Y 2 is -CH2OCO(CH2CH2O)n 2a Z 2 or -CH2OCO(CH2)n 2b COOH, or X 1 is N, X 2 is NH, X 3 is NY 3 and Y 3 is -CH2OCO(CH2CH2O)n 3a Z 3 or -CH2OCO(CH2)n 3b COOH.

[0092] In certain embodiments, in the above formula (I), n 1 is 0, 1, 2, 3, 4, 5, 6, 7, or 8, or is 1 - 3 or 4 - 6 or 7 - 8, n 2 is 0, 1, 2, 3, 4, 5, 6, 7, or 8, or is 1 - 3 or 4 - 6 or 7 - 8, n 3 is 0, 1, 2, 3, 4, 5, 6, 7, or 8, or is 1 - 3 or 4 - 6 or 7 - 8, n 1a is 0, 1, 2, 3, 4, 5, 6, 7, or 8, or is 1 - 3 or 4 - 6 or 7 - 8, n 2a is 0, 1, 2, 3, 4, 5, 6, 7, or 8, or is 1 - 3 or 4 - 6 or 7 - 8, n 3a is 0, 1, 2, 3, 4, 5, 6, 7, or 8, or is 1 - 3 or 4 - 6 or 7 - 8, n 1b is 0, 1, 2, 3, 4, 5, 6, 7, or 8, or is 1 - 3 or 4 - 6 or 7 - 8, n 2b is 0, 1, 2, 3, 4, 5, 6, 7, or 8, or is 1 - 3 or 4 - 6 or 7 - 8, n 3b is 0, 1, 2, 3, 4, 5, 6, 7, or 8, or is 1 - 3 or 4 - 6 or 7 - 8.

[0093] In certain embodiments, in the above formula (I), M 1 is methyl, ethyl, propyl, or phenyl, M 2 is methyl, ethyl, propyl, or phenyl, M 3 is methyl, ethyl, propyl, or phenyl, Z 1These are methyl, ethyl, propyl, or phenyl. Z 2 These are methyl, ethyl, propyl, or phenyl. Z 3 These are methyl, ethyl, propyl, or phenyl.

[0094] In certain further embodiments, n 1 , n 2 , or n 3 is 2, 3, or 4, and / or n 1a , n 2a , or n 3a is 2, 3, or 4, and / or n 1b , n 2b , or n 3b The answer is 2, 3, or 4.

[0095] In certain specific embodiments, the axitinib prodrug used in the implant according to the present invention is selected from: axitinib-N-succinoyloxymethyl prodrug, axitinib-N-mPEG-oxymethyl prodrugs comprising axitinib-Nm(PEG)1-oxymethyl, axitinib-Nm(PEG)2-oxymethyl, axitinib-Nm(PEG)3-oxymethyl, axitinib-Nm(PEG)4-oxymethyl, or salts or solvates thereof as shown below.

[0096] Axitinib prodrugs, particularly those having hydrophilic substituents as disclosed herein, may exhibit higher solubility than the free base of axitinib. Such prodrugs may have solubility at least 2 times, at least 5 times, at least 10 times, at least 25 times, at least 50 times, at least 75 times, at least 100 times, at least 150 times, at least 200 times, at least 250 times, or at least 500 times, or at least 1000 times, that of the free base of axitinib.

[0097] The axitinib prodrug for use in the implant of the present invention may have a solubility of at least 50 μg / mL, or at least 90 μg / mL, or at least 150 μg / mL, or at least 200 μg / mL after 24 hours at 22°C in PBS at pH 7.4.

[0098] The following are exemplary axitinib prodrugs used in the implants of the present invention: [ka] Axitinib-N-succinoyloxymethyl prodrug (Total Mw: 516.57) Solubility after incubation in PBS at pH 7.2-7.4 at 22°C for 24 hours: 217.4 μg / mL [ka] [ka] [ka] [ka]

[0099] As used herein, the term “therapeutically effective” refers to the amount of drug or activator necessary to produce a desired therapeutic outcome after administration. For example, in the context of this invention, one desired therapeutic outcome is the reduction of pain in a patient suffering from pain. In connection with this invention, the “therapeutically effective” amount of activator also refers to the IC that this activator produces for a particular substrate. 50 Multiples of, for example, IC 50 It could be more than 50 times that amount.

[0100] In this specification, the term “patient” includes both human and animal patients. The depot according to the present invention is generally suitable for human or veterinary medical use. Patients are sometimes referred to as “subjects.” Generally, a “subject” is an individual (human or animal) to which the depot according to the present invention is administered, for example, during a clinical trial. A “patient” is a subject that requires treatment due to a particular physiological or pathological condition.

[0101] As used herein, the term “room temperature” refers to the unaltered temperature found in the laboratory where the experiment is conducted, which is typically in the range of about 15 to 35°C, preferably about 18 to 25°C.

[0102] As used herein, the term "body temperature" typically refers to a human body temperature in the range of 36.5 to 37.5°C, with approximately 37°C being preferred.

[0103] As used herein, the term “carrier” refers to an accompanying medium that may be administered with the depot (and, in certain embodiments, a suspension of the depot such as beads). The carrier may be non-aqueous and therefore have the properties of a liquid other than water. The (non-aqueous) carrier may be (but not limited to) an oily carrier, that is, it may be based on a pharmaceutically acceptable (vegetable) oil, particularly in a diluted form. In this context, “pharmaceutically acceptable” material is understood to be biologically or pharmacologically suitable for in vivo use in human or animal species.

[0104] As used herein, the term “mean” refers to the central or representative value within a set of data (points), calculated by dividing the sum of the data (points) in the set by that number (i.e., the mean of the dataset).

[0105] As used herein, the term “approximately” in relation to a measured quantity refers to the normal variation of the measured quantity that a person skilled in the art would expect in performing a measurement and exercising a level of care equal to the purpose of the measurement and the precision of the measuring instrument.

[0106] As used herein, the term “at least about” in relation to a measured quantity means the normal variability of the measured quantity and any amount higher than that expected by a person skilled in the art in performing the measurement and exercising a level of care equal to the purpose of the measurement and the precision of the measuring instrument.

[0107] In this book, the singular forms "a," "an," and "the" also refer to multiple objects unless otherwise specified by the context.

[0108] In this specification, the term "and / or" as used in expressions such as "A and / or B" is intended to include both "A and B" and "A or B".

[0109] As used herein, open terms such as “include,” “including,” “contain,” and “containing” mean “comprising” and are intended to refer to an open-ended list or enumeration of elements, method steps, etc., and are therefore intended to include additional undescribed elements, method steps, etc., rather than being limited to those described.

[0110] Where used herein with a specific value or number, the term “maximum” means including that value or number. For example, the term “maximum 14 days” means “maximum 14 days and including 14.”

[0111] As used herein, the abbreviation "PBS" means phosphate-buffered saline.

[0112] As used herein, the abbreviation "PEG" refers to polyethylene glycol.

[0113] All references disclosed herein are incorporated herein by reference in their entirety for all purposes (in case of any inconsistency, this specification shall prevail). [Modes for carrying out the invention]

[0114] I. Therapy The present invention generally relates to methods for treating pathological conditions, and more particularly to methods for treating joint or bone canal conditions in patients requiring treatment using a sustained-release biodegradable depot comprising a hydrogel and a tyrosine kinase inhibitor. One particular tyrosine kinase inhibitor for use in all embodiments of the present invention is axitinib. Details regarding axitinib, its chemical structure, and its properties such as solubility are disclosed in the definitions section herein.

[0115] In one embodiment, the present invention also relates to a sustained-release biodegradable depot comprising a hydrogel and a tyrosine kinase inhibitor for use in treating pathological conditions, particularly for use in treating joint pathological conditions in patients requiring treatment, or for use in treating bone canal pathological conditions.

[0116] In one embodiment, the present invention also relates to the use of a sustained-release biodegradable depot comprising a hydrogel and a tyrosine kinase inhibitor for the preparation of pharmaceuticals for treating pathological conditions, particularly for the preparation of pharmaceuticals for treating joint conditions in patients requiring treatment, or for the preparation of pharmaceuticals for treating bone canal conditions.

[0117] In one embodiment, the present invention relates to a method for treating patients who generally require treatment for joint pathologies (such as arthritis), the method comprising administering to the patient at least one sustained-release biodegradable fiber comprising a hydrogel and a tyrosine kinase inhibitor, wherein the at least one fiber is administered by joint injection.

[0118] In another embodiment, the present invention relates to a method for treating patients who require treatment for joint pathologies (such as arthritis), the method comprising administering to the patient a plurality of sustained-release biodegradable beads, each containing a hydrogel and a tyrosine kinase inhibitor, the plurality of beads being administered by joint injection.

[0119] In yet another embodiment, the present invention relates to a method for treating patients who require treatment for joint conditions (such as arthritis), the method comprising administering to the patient a therapeutically effective amount of an injectable pharmaceutical preparation comprising a sustained-release biodegradable depot and carrier as further disclosed below, or prepared according to a method further disclosed below, wherein the pharmaceutical preparation is administered by joint injection.

[0120] In a further embodiment, the present invention relates to a method for treating patients who require treatment for a pathological condition of the bone canal (such as carpal tunnel syndrome or spinal stenosis), the method comprising administering to the patient at least one sustained-release biodegradable fiber comprising a hydrogel and a tyrosine kinase inhibitor, wherein at least one fiber is administered by injection into or near the bone canal.

[0121] In another embodiment, the present invention relates to a method for treating patients who require treatment for a pathological condition of the bone canal (such as carpal tunnel syndrome or spinal stenosis), the method comprising administering to the patient a plurality of sustained-release biodegradable beads, each containing a hydrogel and a tyrosine kinase inhibitor, wherein the plurality of beads are administered by injection into or near the bone canal.

[0122] In yet another embodiment, the present invention relates to a method for treating patients who require treatment for a pathological condition of the bone canal (such as carpal tunnel syndrome or spinal stenosis), the method comprising administering to the patient a therapeutically effective amount of an injectable pharmaceutical preparation comprising a sustained-release biodegradable depot and carrier as further disclosed below, or prepared according to a method further disclosed below, wherein the pharmaceutical preparation is administered by injection into or near the bone canal.

[0123] In all these embodiments, the specific tyrosine kinase inhibitor for use in the present invention is axitinib.

[0124] In all these embodiments, the joint pathology in the particular embodiment of the present invention may be arthritis (infectious or non-infectious).

[0125] In all these embodiments, the pathological condition of the bone canal in the particular embodiment of the present invention may be carpal tunnel syndrome or spinal stenosis.

[0126] The fibers and beads may be used separately or in combination in the therapeutic method according to the present invention. They may be present separately or in combination in an injectable pharmaceutical preparation further comprising a carrier.

[0127] In one particular embodiment, the present invention relates to a method for reducing pain, particularly joint pain, in patients in general, the method comprising administering to the patient a therapeutically effective amount of an injectable pharmaceutical preparation comprising a sustained-release biodegradable depot and carrier as further disclosed below, or manufactured according to a method further disclosed below, wherein the pharmaceutical preparation is administered by injection, particularly by joint injection.

[0128] In another specific embodiment, the present invention relates to a method for reducing inflammation, particularly inflammation associated with arthropathy, in general, in patients, the method comprising administering to the patient a therapeutically effective amount of an injectable pharmaceutical preparation comprising a sustained-release biodegradable depot and carrier further disclosed below, or manufactured according to a method further disclosed below, wherein the pharmaceutical preparation is administered by injection, particularly by articular injection.

[0129] In another specific embodiment, the present invention relates to a method for reducing hypervascularity associated with arthritis in patients, the method comprising administering to the patient a therapeutically effective amount of an injectable pharmaceutical preparation comprising a sustained-release biodegradable depot and carrier as further disclosed below, or prepared according to a method further disclosed below, the pharmaceutical preparation being administered by joint injection.

[0130] In another particular embodiment, the present invention relates to a method for a patient who generally needs to delay, halt, or improve progressive structural tissue damage associated with arthritis, the method comprising administering to the patient a therapeutically effective dose of an injectable pharmaceutical preparation comprising a sustained-release biodegradable depot and carrier as further disclosed below, or prepared in accordance with a method as further disclosed below, the pharmaceutical preparation being administered by joint injection.

[0131] In another particular embodiment, the present invention relates to a method for a patient who generally needs to delay, halt, or improve joint function loss associated with arthritis, the method comprising administering to the patient a therapeutically effective amount of an injectable pharmaceutical preparation comprising a sustained-release biodegradable depot and carrier as further disclosed below, or prepared in accordance with a method as further disclosed below, the pharmaceutical preparation being administered by intra-articular or peri-articular injection.

[0132] In another specific embodiment, the present invention relates to a method for improving joint function in patients generally in relation to arthritis, the method comprising administering to the patient a therapeutically effective amount of an injectable pharmaceutical preparation comprising a sustained-release biodegradable depot and carrier further disclosed below, or prepared in accordance with a method further disclosed below, wherein the pharmaceutical preparation is administered by intra-articular or peri-articular injection.

[0133] In another particular embodiment, the present invention relates to a method for a patient who generally needs to delay, cessate, or improve tingling, weakness, or numbness in the limbs, particularly in the fingers associated with carpal tunnel syndrome or in the arms or legs associated with spinal stenosis, the method comprising administering to the patient a therapeutically effective dose of an injectable pharmaceutical preparation comprising a sustained-release biodegradable depot and carrier as further disclosed below, or prepared in accordance with the method further disclosed below, the pharmaceutical preparation being administered by injection into or near the bone canal or by epidural injection.

[0134] In another particular embodiment, the present invention relates to a method for a patient who generally needs to reduce compression of nerve tissue, particularly of the median nerve associated with carpal tunnel syndrome, or of the spinal cord or nerve root associated with spinal stenosis, the method comprising administering to the patient a therapeutically effective amount of an injectable pharmaceutical preparation comprising a sustained-release biodegradable depot and carrier as further disclosed below, or prepared according to a method further disclosed below, the pharmaceutical preparation being administered by injection into or near the bone canal, or by epidural injection.

[0135] Patients treated by all aspects of the present invention may be human or animal subjects suffering from joint or bone canal pathologies. In particular, patients treated may be human or animal subjects requiring arthritis treatment, such as treatment for osteoarthritis of the hip or knee. Alternatively, patients treated may be human or animal subjects requiring treatment for carpal tunnel syndrome or spinal stenosis. Therefore, in some embodiments, a method for treating joint pathologies is a method for treating human patients. Alternatively, a method for treating joint pathologies is a method for treating animal subjects such as livestock (e.g., horses including racing horses, cattle, pigs) or companion animals (e.g., dogs, cats, or rodents).

[0136] Specific embodiments and features of the method for treating a pathological condition according to the present invention are disclosed below.

[0137] Treatment method Joint pathology The joint pathology being treated may be a disease, disorder, or discomfort in any joint. In certain embodiments, the joint pathology affects at least one joint. In some embodiments, the joint pathology affects at least one single joint. In other embodiments, the joint pathology affects two or more joints. The joint pathology may further affect the adjacent tissues surrounding the joint(s).

[0138] In certain embodiments, the joint pathology is an inflammatory joint pathology. Inflammatory joint pathologies can be caused by injury, infection, or irritation. Injury to the joint typically causes local inflammation. In some embodiments, inflammatory joint pathologies may include synovitis, bursitis, or tendinitis.

[0139] In certain embodiments, joint pathologies are accompanied by angiogenesis. Angiogenesis can be stimulated by at least one angiogenesis regulator, such as angiogenin, angiopoietin-1, angiotensin II, bradykinin, connective tissue growth factor, endoglin, endothelial cell-stimulated growth factor, epidermal growth factor, fractalkine, hepatocyte growth factor, histamine, hyaluronic acid (low molecular weight), IL-1, IL-4, IL-8, IL-18, nitric oxide, platelet-derived (endothelial) growth factor, pleiotrophin, soluble E-selectin, stem cell-inducing factor-1, thrombospondin, vascular cell adhesion molecule 1, or VEGF. In some embodiments, angiogenesis may be associated with inflammation.

[0140] In certain embodiments, the joint pathology is arthropathy. In some embodiments, the joint pathology is reactive arthropathy (i.e., caused by infection), enteric arthropathy (i.e., caused by colitis and related conditions), or diabetic arthropathy (i.e., caused by diabetes). In other embodiments, the joint pathology is neuropathic arthropathy, i.e., associated with loss of sensation. According to one embodiment, the joint pathology can be spondyloarthropathy, i.e., any form of arthropathy of the spine.

[0141] In certain specific embodiments, the joint pathology is arthritis. Arthritis can be infectious or non-infectious. In some embodiments, the joint pathology is rheumatoid arthritis (RA), i.e., a long-term autoimmune disorder that primarily affects the joints; juvenile arthritis (JA), i.e., an autoimmune non-infectious inflammatory joint disease (PsA) that develops before the age of 16; or psoriatic arthritis (PsA), a long-term inflammatory arthritis caused by psoriasis. In other embodiments, the joint pathology may be gouty or pseudogouty arthritis, i.e., a form of inflammatory arthritis caused by needle-shaped crystals of uric acid known as monosodium urate crystals, or calcium pyrophosphate dehydrate crystals, respectively. In further embodiments, the joint pathology may be systemic lupus erythematosus (SLE), i.e., an autoimmune pathology that can affect many different organs and tissues of the body; or ankylosing spondylitis (AS), i.e., a long-term inflammatory pathology that primarily affects the bones, muscles, and ligaments of the spine.

[0142] In one particular embodiment of the present invention, arthritis is osteoarthritis (OA). Osteoarthritis may be selected from hip osteoarthritis, knee osteoarthritis, foot osteoarthritis, or finger joint osteoarthritis.

[0143] Pathological models of osteoarthritis (OA) include intra-articular injection of monosodium iodoacetate (MIA) into the femoro-tibial joint cavity of rats, which elicits significant pain-related behaviors (Bove et al., Weight bearing as a measure of disease progression and efficacy of induced osteoarthritis. Osteoarthritis Cartilage 2003, 11:821-830; Combe et al., The monosodium iodoacetate model of osteoarthritis: a model of chronic nociceptive pain in rats? Neurosi Lett 2004, 370:236-240), as well as the production of several cytokines following local inflammation (Smith et al., Synovial membrane inflammation and cytokine production in patients with early osteoarthritis. Rheumatol 1997, 24:365-371; Fiorito et al., Inflammatory status and cartilage regenerative potential of synovial fibroblasts from patients with osteoarthritis and Chondropathy. Rheumatology (Oxford) 2005, 44:164-171; Pearle et al., Elevated high-sensitivity C-reactive protein levels are associated with local inflammatory findings in patients with osteoarthritis. Osteoarthritis Cartilage 2007, 15:516-523) have been reported.The onset of the above pathological signs in this animal model is considered clinically relevant, as it reflects the symptoms exhibited by patients with chronic inflammatory pain associated with underlying conditions such as OA or RA (Fernihough et al., Pain related behaviour in two models of osteoarthritis in the rat knee. Pain 2004, 112(1-2):83-93). The effect of the therapeutic method according to the present invention on rats with MIA-induced OA is described in Example 4.

[0144] In certain embodiments, the joint pathology is a joint disorder mediated by at least one receptor tyrosine kinase (RTK). The at least one receptor tyrosine kinase (RTK) may be VEGFR-1, or it may be VEGFR-2. In some embodiments, the joint pathology is a joint disorder mediated by VEGFR-1 and VEGFR-2. VEGFR-1 and / or VEGFR-2 activity may be affected by at least one tyrosine kinase inhibitor, such as axitinib.

[0145] In certain embodiments, the pathology of the joint is associated with the expression of TRPV1, i.e., the expression of vanilloid receptor 1, also known as the capsaicin receptor.

[0146] In certain embodiments, the joint pathology is joint pain. Joint pain can be chronic and may last for at least 3 to 6 months. It may be related to a problem with the bones of the joint or in its vicinity, or it may be related to a problem with the tendons, ligaments, or muscles around the joint. In some embodiments, joint pain may be analgesic pain. In other embodiments, joint pain may be neuropathic pain. In some specific embodiments, the joint pathology is joint pain caused by arthritis, such as osteoarthritis.

[0147] In certain embodiments, the method for treating joint pathologies according to the present invention may be provided without or with reduced cartilage destruction, i.e., without chondrotoxicity or with reduced chondrotoxicity. As demonstrated in Example 5, when the treatment method according to the present invention was administered by intra-articular administration of a sustained-release biodegradable depot of axitinib, no histopathological evidence of chondrotoxicity was detected. In certain embodiments, the method according to the present invention does not impair the viability of human chondrocytes. In particular, chondrotoxicity in human chondrocytes is less than 10%, less than 8%, or less than 5% during the administration period.

[0148] In certain embodiments, only mild or moderate adverse events are observed throughout the treatment period. In certain embodiments, no serious joint adverse events are observed during the treatment period, and no serious treatment-related joint adverse events are observed.

[0149] Pathophysiology of the bone canal The osteocanthal pathology being treated may be any disease, disorder, or discomfort related to the osteocanth. In certain embodiments, the osteocanthal pathology affects at least one osteocanth. In some embodiments, the osteocanthal pathology affects a single osteocanth. In other embodiments, a single osteocanthal pathology affects two or more osteocanths. The osteocanthal pathology may further affect the adjacent tissues surrounding the osteocanth(s).

[0150] In certain embodiments, the pathology of the bone canal is an inflammatory pathology of the bone canal. Inflammatory pathologies of the bone canal can be caused by injury, infection, or irritation. Injury to the bone canal typically causes localized inflammation. In some embodiments, the (inflammatory) pathology of the bone canal may be related to arthritis.

[0151] In certain embodiments, the pathophysiology of the bone canal is accompanied by angiogenesis. Angiogenesis can be stimulated by at least one angiogenic regulator, such as angiogenin, angiopoietin-1, angiotensin II, bradykinin, connective tissue growth factor, endoglin, endothelial cell-stimulated growth factor, epidermal growth factor, fractalkine, hepatocyte growth factor, histamine, hyaluronic acid (low molecular weight), IL-1, IL-4, IL-8, IL-18, nitric oxide, platelet-derived (endothelial) growth factor, pleiotrophin, soluble E-selectin, stem cell induction factor-1, thrombospondin, vascular cell adhesion molecule-1, or VEGF. In some embodiments, angiogenesis may be associated with inflammation.

[0152] In certain embodiments, the pathology of the bone canal is related to narrowing of the bone canal, such as the carpal tunnel or the (cervical or lumbar) spinal canal, i.e., stenosis.

[0153] In certain embodiments, the pathology of the bone canal involves compression of nerve tissue, particularly compression of the median nerve, known to be associated with carpal tunnel syndrome, or compression of the spinal cord or nerve roots, known to be associated with spinal stenosis.

[0154] In certain specific embodiments, the pathology of the bone canal is carpal tunnel syndrome. In certain other specific embodiments, the pathology of the bone canal is spinal stenosis, in particular cervical spinal stenosis or lumbar spinal stenosis.

[0155] In certain embodiments, the osteopathology is a disease of the osteodosteum mediated by at least one receptor tyrosine kinase (RTK). The at least one receptor tyrosine kinase (RTK) may be VEGFR-1. Alternatively, the at least one receptor tyrosine kinase (RKT) may be VEGFR-2. In some embodiments, the osteopathology is a disease of the osteodosteum mediated by VEGFR-1 and VEGFR-2. VEGFR-1 and / or VEGFR-2 activity may be affected by at least one tyrosine kinase inhibitor, such as axitinib.

[0156] In certain embodiments, the pathology of the bone canal is associated with the expression of TRPV1, i.e., the expression of vanilloid receptor 1, also known as the capsaicin receptor.

[0157] In certain embodiments, the osteopathy of the osteopathy is pain within or around the osteopathy. The pain may be chronic and may last for at least 3 to 6 months. It may be related to a problem with the structure of the osteopathy or its vicinity, or it may be related to a problem with the tendons, ligaments, or muscles around the osteopathy. In some embodiments, the pain may be analgesic pain. In other embodiments, the pain may be neuropathic pain. In some specific embodiments, the osteopathy of the osteopathy is pain caused by carpal tunnel syndrome or pain caused by spinal stenosis.

[0158] In certain embodiments, the method according to the present invention does not impair the viability of human chondrocytes. In particular, chondrogenicity in human chondrocytes is less than 10%, less than 8%, or less than 5% during the administration period.

[0159] In certain embodiments, only mild or moderate adverse events are observed throughout the treatment period. In certain embodiments, no serious joint adverse events are observed during the treatment period, and no serious treatment-related joint adverse events are observed.

[0160] Effectiveness The effectiveness of the method for treating the conditions according to the present invention in specific embodiments is shown in the Examples section (Example 4). While these embodiments are illustrated with respect to the treatment of osteoarthritis, it should not be assumed that the invention is for these uses only. Rather, embodiments of the invention are intended to be useful for treating other forms of joint conditions by joint injection of a sustained-release biodegradable depot or pharmaceutical preparation. Furthermore, embodiments of the invention are intended to be useful for treating carpal tunnel conditions, such as spinal stenosis, by injection of a sustained-release biodegradable depot or pharmaceutical preparation into or near the carpal tunnel, or by epidural injection.

[0161] In certain embodiments, the treatment is effective in reducing pain, particularly joint pain. (Joint) pain may be reduced for at least one month, at least two months, at least three months, or at least six months. In certain embodiments, the treatment may be effective in reducing (joint) pain. In certain embodiments, the treatment may be effective in eliminating (joint) pain.

[0162] In certain embodiments, the treatment is effective in reducing inflammation, particularly inflammation associated with arthropathy, i.e., inflammation in joint diseases or bone duct diseases. In particular, the treatment may be effective in reducing the expression of at least one inflammatory marker. In some embodiments, the treatment is effective in reducing the expression of at least one cytokine. The at least one cytokine may be selected from at least one interferon (IFN), interleukin (IL), and / or chemokine of the CXC family. The at least one cytokine may be selected from IFN-γ, IL-1β, IL-4, IL-5, IL-10, or CXCL1. CYCL1 is also known as KC / GRO (keratinocyte chemotactic factor / human growth-regulating oncogene). In certain embodiments, the expression of at least one inflammatory marker may be reduced by at least 10%, at least 20%, or at least 25% within a 14-day period, or a 1-month period, or a 2-month period after administration.

[0163] In certain embodiments, the treatment is effective in reducing hypervascularity associated with arthritis.

[0164] The method for treating joint pathologies according to the present invention may be effective when one or more signs or symptoms associated with joint pathologies such as arthritis, particularly osteoarthritis, are reduced, suppressed, or do not progress further, i.e., do not worsen. In certain embodiments, the treatment is effective in delaying, halting, or improving progressive structural tissue damage associated with arthritis, such as osteoarthritis. In certain embodiments, the treatment is effective in delaying, halting, or improving loss of joint function associated with arthritis, such as osteoarthritis. Furthermore, the treatment may also be effective in improving joint function associated with arthritis, such as osteoarthritis.

[0165] In certain embodiments, a method for treating joint pathologies is effective in reducing at least one sign or symptom associated with arthritis, such as pain, joint stiffness, limited range of motion, periarticular swelling, muscle weakness, or joint instability.

[0166] In certain embodiments, the treatment is effective in reducing compression of nerve tissue associated with narrowing of the bone canal, such as in carpal tunnel syndrome or spinal stenosis.

[0167] The method for treating osteopathic conditions of the bone canal according to the present invention may be effective when one or more signs or symptoms associated with osteopathic conditions of the bone canal, such as carpal tunnel syndrome or spinal stenosis, are alleviated, reduced, suppressed, or do not progress further, i.e., do not worsen further. In certain embodiments, the treatment is effective in stopping or improving tingling, weakness, or numbness in the limbs, such as the fingers associated with carpal tunnel syndrome, or the arms or legs associated with spinal stenosis.

[0168] In certain embodiments, methods for treating conditions of the bone canal are effective in reducing at least one sign or symptom associated with carpal tunnel syndrome or spinal stenosis, such as pain, limited range of motion, swelling of the bone canal, muscle weakness, or compression of nerve tissue.

[0169] Administration injection: In certain embodiments of the method for treating joint pathologies according to the present invention, the depot is administered by joint injection. In some embodiments, the depot is administered by intra-articular injection. In other embodiments, the depot is administered by peri-articular injection.

[0170] In certain specific embodiments, the depot is administered into the patient's synovial joints, such as the hip joints, knee joints, ankle joints, or finger joints. In some embodiments, the depot is administered into the patient's synovial joint cavity. In other embodiments, the depot may be administered into the tissue surrounding the patient's synovial joint cavity, such as the synovium.

[0171] The depot may be administered to the patient's knee, elbow, fingers, buttocks, shoulder, wrist, ankle, or to the foot, hand, shoulder girdle, rotator cuff, pelvis, spine (including all areas of the spine such as the cervical, thoracic, lumbar, sacral, or coccyx), or to the temporomandibular joint. In one embodiment, the depot is administered to the patient's knee, for example, into the synovial joint cavity of the patient's knee.

[0172] In certain embodiments, the depot is administered to the patient's tibiofemoral joint, patellofemoral joint, humeroulnar joint, humerorar joint, proximal radioulnar joint, pelvic femoral joint, glenohumeral joint, acromioclavicular joint, distal radioulnar joint, radiocarpal joint, intercarpal joints, metacarpal joints, carpometacarpal joints, intermetacarpal joints, talocrural joint, subtalar joint, tibiofibular joint, talonavicular joint, calcaneocuboid joint, metatarsophalangeal joints, interphalangeal joints of the foot or hand, metacarpophalangeal joints, sternoclavicular joint, costochondral joint, atlantooccipital joint, atlantoaxial joint, costovertebral joint, costotransverse joint, articular joint, sacroiliac joint, or temporomandibular joint. In certain specific embodiments, the depot is administered to the patient's tibiofemoral joint, i.e., the knee joint; the iliofemoral joint, i.e., the hip joint; the talocrural joint; the subtalar joint, i.e., the ankle / foot joint; the metatarsophalangeal joint, i.e., the ankle / foot joint; the interphalangeal joint of the ankle / foot; the atlantoaxial joint, i.e., the cervical joint; or the articular joint, i.e., the lumbar joint. In one embodiment, the depot is administered into the patient's tibiofemoral joint cavity.

[0173] In certain embodiments of the method for treating a pathological condition of the bone canal according to the present invention, the depot is administered by injection into or near the bone canal of the patient. In some embodiments, the depot is administered by epidural injection.

[0174] In certain specific embodiments, the depot is administered into or near the patient's carpal tunnel. In certain other specific embodiments, the depot is administered into or near the patient's spinal canal, in particular, into or near the patient's cervical spinal canal, or into or near the patient's lumbar spinal canal. In some embodiments, the depot is administered into the patient's bone canal. In other embodiments, the depot may be administered into the tissue surrounding or within the patient's bone canal.

[0175] In certain embodiments, the depot is administered via a subcutaneous injection needle, such as an 18-30 gauge needle. The subcutaneous injection needle may be a 20-27 gauge needle, or a smaller gauge needle, depending particularly on the injection site. For example, a 21 gauge needle may be used for injections in the buttocks, a 22 gauge needle for injections in the knee, and a 25 gauge needle for injections in the finger.

[0176] In certain embodiments, the dry depot is filled into a subcutaneous injection needle, such as a 21-gauge, 22-gauge, or 25-gauge needle, for injection, and administered through this needle into the joint, i.e., the joint cavity or surrounding tissue. In one embodiment, a subcutaneous injection needle used for injecting the depot into the joint and optionally an injection device are provided in the kit with the depot, as further described below.

[0177] Treatment duration and dosage: In certain embodiments of the method for treating joint pathologies according to the present invention, the depot is administered once during a specific treatment period. In some embodiments, the treatment period is at least one month. In other embodiments, the treatment period is at least two months, at least three months, at least six months, at least nine months, or at least twelve months. In certain embodiments, the treatment period is at least three months, at least six months, or at least nine months. In certain embodiments, the treatment period may also be longer, for example, up to about fifteen months.

[0178] A dose administered once during the treatment period may be contained in one or more depots. In embodiments in which two or more depots are administered, the depots containing the dose are administered simultaneously / in combination. The simultaneously administered depots may be the same or different. For example, if administration is not possible during the same period due to complications of administration or patient-related reasons, two or more consecutive administrations over different periods may be administered, for example, two depots administered 7 days apart. This may still be considered “simultaneous” administration in the context of the present invention.

[0179] In some embodiments, a single dose administered during the treatment period is contained in one depot containing one unit. Examples of such depots containing the total dose administered in one unit are depots A-G, which are manufactured exemplary in the Examples section (Examples 1 and 2). In other embodiments, a single dose administered during the treatment period is contained in one depot containing two or more units, for example, multiple units. In such embodiments, a single dose administered during the treatment period may be contained in two or more fibers, or a single dose administered during the treatment period may be contained in two or more beads, in particular multiple beads.

[0180] According to the present invention, a single dose of axitinib administered during the treatment period (when the TKI is axitinib) provides a therapeutic local tissue concentration, but the dose does not exceed a safe tissue concentration in tissues proximal or distal to the implantation site or in systemic tissues. Generally, the local drug excretion rate constant (k) eLocal distribution volume ( from depot (R) accompanied by Vd The daily drug dissolution rate to the local tissue is equal to the steady-state tissue concentration (C) ss ) brings about.

number

[0181] The dose per joint or bone administered once during a given treatment period may be at least about 0.1 mg, at least about 0.2 mg, or at least about 0.4 mg of the tyrosine kinase inhibitor. In certain embodiments, the dose per joint or bone administered once during a treatment period is about 0.5 mg to about 120 mg of the tyrosine kinase inhibitor, specifically axitinib, depending on the injection site. In some embodiments, the dose per joint or bone administered once during a treatment period is about 1 mg to about 50 mg of the tyrosine kinase inhibitor, specifically axitinib. In certain embodiments, the dose per joint or bone administered once during a treatment period of at least 3 months is about 1 mg to about 50 mg, about 5 mg to about 40 mg, or about 10 mg to about 30 mg of the tyrosine kinase inhibitor, specifically axitinib.

[0182] In certain embodiments, the single dose per knee administered during the treatment period is approximately 1 mg to approximately 70 mg of a tyrosine kinase inhibitor, specifically axitinib. In some embodiments, the single dose per knee administered during the treatment period is approximately 2.5 mg to approximately 60 mg of a tyrosine kinase inhibitor, particularly axitinib, or the single dose per knee administered during the treatment period is approximately 3 mg to approximately 45 mg of a tyrosine kinase inhibitor, specifically axitinib. In certain embodiments, the single dose per knee administered during a treatment period of at least 3 months is approximately 3 mg to approximately 45 mg, approximately 5 mg to approximately 30 mg, or approximately 10 mg to approximately 25 mg of a tyrosine kinase inhibitor, specifically axitinib. In one embodiment, the single dose per knee administered during a treatment period of at least 3 months is approximately 15 mg of a tyrosine kinase inhibitor, specifically axitinib. In another embodiment, the dose per knee, administered once during a treatment period of at least three months, is approximately 20 mg of a tyrosine kinase inhibitor, specifically axitinib.

[0183] In certain embodiments, the dose per buttock administered once during the treatment period is approximately 0.5 mg to approximately 50 mg of a tyrosine kinase inhibitor, specifically axitinib. In some embodiments, the dose per knee administered once during the treatment period is approximately 1 mg to approximately 35 mg of a tyrosine kinase inhibitor, particularly axitinib, or approximately 1.5 mg to approximately 25 mg of a tyrosine kinase inhibitor, specifically axitinib. In certain embodiments, the dose per knee administered once during a treatment period of at least 3 months is approximately 1.5 mg to approximately 25 mg, approximately 2.5 mg to approximately 20 mg, or approximately 5 mg to approximately 15 mg of a tyrosine kinase inhibitor, specifically axitinib. In one embodiment, the dose per knee administered once during a treatment period of at least 3 months is approximately 10 mg of a tyrosine kinase inhibitor, specifically axitinib. In another embodiment, the dose per knee, administered once during a treatment period of at least three months, is approximately 12.5 mg of a tyrosine kinase inhibitor, specifically axitinib.

[0184] In certain embodiments, the single dose per finger administered during the treatment period is approximately 0.1 mg to approximately 20 mg of a tyrosine kinase inhibitor, specifically axitinib. In some embodiments, the single dose per knee administered during the treatment period is approximately 0.2 mg to approximately 15 mg of a tyrosine kinase inhibitor, particularly axitinib, or approximately 0.4 mg to approximately 12 mg of a tyrosine kinase inhibitor, specifically axitinib. In certain embodiments, the single dose per knee administered during a treatment period of at least 3 months is approximately 0.4 mg to approximately 12 mg, approximately 0.5 mg to approximately 10 mg, or approximately 1 mg to approximately 8 mg of a tyrosine kinase inhibitor, specifically axitinib. In one embodiment, the single dose per knee administered during a treatment period of at least 3 months is approximately 3 mg of a tyrosine kinase inhibitor, specifically axitinib. In another embodiment, the dose per knee, administered once during a treatment period of at least three months, is approximately 5 mg of a tyrosine kinase inhibitor, specifically axitinib.

[0185] In certain very specific embodiments, the dose of a tyrosine kinase inhibitor, particularly axitinib, administered once per joint or bone canal during the treatment period is approximately 15 μg, or approximately 35 μg, or approximately 55 μg, or approximately 100 μg, approximately 150 μg, approximately 200 μg, approximately 300 μg, or approximately 420 μg in multiple doses. In some embodiments, the dose of a tyrosine kinase inhibitor, particularly axitinib, administered once per joint or bone canal, such as the knee, during the treatment period is approximately 420 μg in multiple doses. If the dose of a tyrosine kinase inhibitor, particularly axitinib, administered once during the treatment period is contained in two or more depot units, each unit contains, in a particular embodiment, about 15 μgm, or about 35 μg, or about 55 μg, or about 100 μg, about 150 μg, about 200 μg, about 300 μg, or about 420 μg of axitinib, particularly about 420 μg. The amount of axitinib contained in a single unit may be adjusted as appropriate depending on the administration site and the patient (human or animal).

[0186] Simultaneous administration: The methods for treating a condition by depot injection disclosed herein may be combined with the administration of at least one other drug known to treat each condition or another condition. In particular embodiments, the joint condition may be osteoarthritis, and the method for treating osteoarthritis may be combined with the administration of at least one other drug known to treat osteoarthritis. Other known drugs for osteoarthritis may be selected from analgesics, i.e., pain relievers including acetaminophen and opioids; NSAIDs including aspirin, ibuprofen, naproxen, and celecoxib; anti-stimulants including components such as capsaicin, menthol, or lidocaine; corticosteroids such as triamcinolone acetonide (KENALOG®); platelet-rich plasma; or other drugs including hyaluronic acid, the antidepressant duloxetine (CYMBALTA®), or the anticonvulsant pregabalin (LYRICA®).

[0187] In some embodiments, an anti-VEGF agent is administered to the patient concurrently with treatment with a sustained-release biodegradable depot containing a TKI, or with a sustained-release biodegradable depot containing axitinib according to the present invention. The anti-VEGF agent may be selected from the group consisting of aflibercept, bevacizumab, brolucizumab, falisimab, pegaptanib, and ranibizumab. In certain embodiments, the anti-VEGF agent is administered by intra-articular injection concurrently with the administration of the sustained-release biodegradable depot.

[0188] In certain embodiments of the method for treating joint pathologies according to the present invention, an anti-inflammatory agent is administered simultaneously with the depot. In some embodiments, hyaluronic acid is administered simultaneously with the depot. In other embodiments, at least one corticosteroid is administered simultaneously with the depot. In certain embodiments, the patient has a history of anti-inflammatory treatment, for example, treatment with KENALOG®.

[0189] In some embodiments, at least one other drug is administered orally or topically. In other embodiments, at least one other drug is administered arterially. In one embodiment, at least one other drug may be administered by intra-articular or peri-articular injection, or orally. In such embodiments, at least one other drug may be included in the depot according to the present invention, or may be administered in combination with the depot. In some embodiments, the duration of treatment with the depot according to the present invention may correspond to the duration of treatment with at least one other drug, and may begin and / or end essentially simultaneously (e.g., by administering the depot of the present invention and at least one other drug simultaneously or in close proximity in time). In other embodiments, the duration of treatment with the depot according to the present invention may overlap with the duration of treatment with at least one other drug (e.g., begin earlier or later than that duration). At least one other drug may be a drug administered only once. Alternatively, at least one other drug may be a drug administered repeatedly. The dosing frequency (and / or duration of treatment) of the depot of the present invention and at least one other drug may correspond to each other, essentially correspond to each other, or differ from each other. In certain embodiments, a new depot according to the present invention may be administered at or after the end of the treatment period provided by the depot of the present invention. Such a new depot may be identical to or different from the previously administered depot. For example, when re-administering a depot according to the present invention, the dose of the TKI (such as axitinib) may be adjusted to a higher or lower dose depending on the individual patient's circumstances. The depot according to the present invention may be re-administered multiple times after the end of the treatment period.

[0190] Additional / alternative activators In certain embodiments, the tyrosine kinase inhibitor is administered together with a further non-tyrosine kinase inhibitor or is present in the pharmaceutical composition together with a further non-tyrosine kinase inhibitor. In other embodiments, the administered composition and the pharmaceutical composition contain a non-tyrosine kinase inhibitor but do not contain a tyrosine kinase inhibitor. Exemplary non-kinase inhibitors include, but are not limited to, the following:

[0191] Immunosuppressants include, but are not limited to, cyclosporine, mTOR inhibitors (e.g., rapamycin, tacrilimus, temsirolimus, sirolimus, everolimus, KU-0063794, WYE-354, AZD8055, metformin, or Torin-2), cyclophosphamide, atoposide, thiotepa, methotrexate, azathioprine, mercaptopurine, interferon, infliximab, etanercept, mycophenolate mofetil, 15-deoxyspargarin, thalidomide, glatiramer, leflunomide, vincristine, cytarabine, pharmaceutically acceptable salts thereof, and combinations thereof.

[0192] Nonsteroidal anti-inflammatory compounds (NSAIDs) include inhibitors of cyclooxygenase (COX) enzymes, such as cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) isozymes. A common class of NSAIDs includes salicylates, propionic acid derivatives, acetic acid derivatives, enolic acid derivatives, and anthranilic acid derivatives. Examples of nonsteroidal anti-inflammatory compounds include acetylsalicylic acid, diflunisal, salsalate, ibuprofen, dexiibuprofen, naproxen, fenoprofen, ketoprofen, dexketoprofen, flurbiprofen, oxaprozin, loxoprofen, indomethacin, tolmetine, sulindac, etodolac, ketrolac, diclofenac, aceclofenac, nabumetone, piroxicam, tenoxicam, loroxicam, phenylbutazone, mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid, celecoxib, pharmaceutically acceptable salts thereof, and combinations thereof.

[0193] Anti-inflammatory agents that may be used in the implants and methods of the present invention may include agents that target inflammatory cytokines such as TNFα, IL-1, IL-4, IL-5, or IL-17, or CD20. Such agents may include etanercept, infliximab, adalimumab, daclizumab, rituximab, tocilizumab, certolizumab pegol, golimumab, pharmaceutically acceptable salts thereof, and combinations thereof.

[0194] Analgesics that can be used in the implants and methods of the present invention include acetaminophen, acetaminosarol, aminochlortenoxazine, acetylsalicylic acid 2-amino-4-picolinic acid, acetylsalicylsalicylic acid, anilelysine, benoxaprofen, benzylmorphine, 5-bromosalicylic acid, busetin, buprenorphine, butorphanol, capsaicin, syncophene, silamdol, clomethacin, clonixin, codeine, desomorphine, dezosine, dihydrocodeine, dihydromorphine, dimefeptanol, dipylocetyl, eptazosine, etoxazene, ethylmorphine, eugenol, and f This includes loctaphenine, phosphosal, graphenine, hydrocodone, hydromorphone, hydroxypethidine, ibufenac, p-lactophenetide, levorphanol, meptazinol, metazosin, methopone, morphine, nalbuffine, nicomorphine, norlevorphanol, normorphine, oxycodone, oxymorphone, pentazocine, phenazosin, phenocol, phenoperidine, phenylbutazone, phenylsalicylic acid, phenyllamidol, salicin, salicylamide, thiorphan, tramadol, diaselein, actarit, pharmaceutically acceptable salts thereof, and combinations thereof.

[0195] Steroidal anti-inflammatory agents that can be used in the implants and methods of the present invention include dexamethasone, budesonide, triamcinolone, hydrocortisone, fluocinolone, loteprednol, prednisolone, mometasone, fluticasone, rimexolone, fluorometholone, beclomethasone, flunisolide, pharmaceutically acceptable salts thereof, and combinations thereof.

[0196] Anesthetic agents that can be used in the implants and methods of the present invention include benzocaine, procaine, chloroprocaine, cincocaine, ropivacaine, bupivacaine, lidocaine, mepivacaine, prilocaine, and tetracaine.

[0197] Other agents that can be used in the implants and methods of the present invention include glycosaminoglycans such as hyaluronic acid.

[0198] To achieve the objectives of the present invention, the activators include all possible forms, including free acids, free bases, polymorphs, pharmaceutically acceptable salts, anhydrides, hydrates, other solvates, stereoisomers, crystalline forms, cocrystals, prodrugs, conjugates (e.g., pegylated compounds), complexes, and mixtures thereof.

[0199] depot Hydrogel Hydrogels can be formed from precursors having functional groups that form crosslinks to create polymer networks. These crosslinks between polymer strands or arms can be, in effect, chemical (i.e., covalent) and / or physical (e.g., ionic, hydrophobic association, hydrogen crosslinking, etc.).

[0200] Polymer networks can be prepared from either one type of precursor or two or more types of precursors that can react. The precursors are selected considering the desired properties of the resulting hydrogel. A variety of precursors are available that are suitable for use in the preparation of hydrogels. In general, any pharmaceutically acceptable crosslinkable polymer that forms a hydrogel can be used for the purposes of this invention. The hydrogel and therefore the components incorporated therein (including the polymers used to prepare the polymer network) should be physiologically safe so as not to induce, for example, an immune response or other adverse effects. Hydrogels can be formed from natural polymers, synthetic polymers, or biosynthetic polymers.

[0201] Natural polymers may include glycosaminoglycans, polysaccharides (e.g., dextran), polyamino acids, and proteins, or mixtures or combinations thereof, but this list is not intended to be limiting.

[0202] Synthetic polymers can generally be any polymer synthesized from various raw materials by various types of polymerization (e.g., free radical polymerization, anionic or cationic polymerization, chain growth or addition polymerization, condensation polymerization, ring-opening polymerization, etc.). Polymerization may be initiated by specific initiators, light and / or heat, and may be mediated by catalysts. In certain embodiments, synthetic polymers may be used to reduce the potential for allergies in dosage forms that do not contain any human or animal-derived components.

[0203] In general, for the purposes of the present invention, one or more synthetic polymers from the group comprising one or more units of polyalkylene glycol may be used, in particular, polyethylene glycol (PEG), polypropylene glycol, poly(ethylene glycol)-block-poly(propylene glycol) copolymer, polyalkylene oxides such as polyethylene oxide, polypropylene oxide, polyvinyl alcohol, poly(vinylpyrrolidinone), polylactic acid (PLA), polylactic acid-coglycolic acid, p-dioxanone, trimethylene carbonate, caprolactone, random or block copolymers, or any combination / mixture thereof, but not limited to these, and this list is not intended to be limiting.

[0204] Precursors can be covalently crosslinked to form a polymer network crosslinked by covalent bonds. In certain embodiments, a precursor having at least two reaction centers (for example, in free radical polymerization) can function as a crosslinker, since each reactive group can participate in the formation of different growing polymer chains.

[0205] The precursor may have a first functional group that can react with a second functional group, i.e., a first functional group that can react with a second functional group. The functional groups can react with each other, for example, in an electrophile-nucleophile reaction, or are configured to participate in other polymerization reactions. Nucleophiles that can be used in the present invention may include amines, such as primary amines, hydroxyls, thiols, carboxyls, dibenzocyclooctin, or hydrazides. Electrophiles that can be used in the present invention may include succinimidyl esters, succinimidyl carbonates, nitrophenyl carbonates, aldehydes, ketones, acrylates, acrylamides, maleimides, vinyl sulfones, iodoacetamides, alkenes, alkynes, azides, norbornene, epoxides, mesylates, tosylates, tresyl, cyanurates, orthopyridyl disulfide, or halides.

[0206] In addition to classical electrophilic-nucleophilic condensation reactions, other types of chemical reactions based on electrophiles and nucleophiles can also be used in the present invention. For example, precursors can be crosslinked via so-called click chemistry reactions. Functional groups suitable for click chemistry are those that enable click chemistry reactions, such as strain-promoting alkyne-azide cycloaddition (SPAAC), also known as copper catalyst-free click reactions, or reverse electron-demanding Diels-Alder ligation (IEDDA) type click chemistry coupling reactions. An overview of these types of reactions is presented by reference in HCOlb;MGFinn;KBSharpless (2001). “Click Chemistry: Diverse Chemical Function from a Few Good Reactions”, Angewandte Chemie International Edition, 40(11):2004-2021). The coupling reactions of SPAAC and IEDDA are bioorthogonal reactions with selective and quantitative yields under mild conditions, which can even occur within biological systems without interfering with natural biochemical processes. These click chemistry reactions utilize a pair of functional groups that react mutually and efficiently while remaining inert to naturally occurring functional groups. Suitable functional groups include moieties selected from the group consisting of alkynes, cycloalkynes, e.g., dibenzocyclooctyne (DBCO), or bicyclo[6.1.0]-nonine (BCN), strained or terminal alkenes, e.g., norbornene, or trans-cyclooctene (TCO), azides, or tetrazine (Tz).

[0207] The precursor may have a biologically inert and hydrophilic portion, such as a core. In the case of branched polymers, the core refers to a continuous portion of molecules linked to arms extending from the core, where the arms often have functional groups at the ends of the arms or branches. Multi-armed PEG precursors are examples of such precursors and are used in specific embodiments of the present invention, as further disclosed herein.

[0208] The hydrogels used in the present invention can be prepared, for example, from one multi-arm precursor having a first functional group(s) (or set thereof) and another (e.g., multi-arm) precursor having a second functional group(s) (or set thereof). For example, the multi-arm precursor may have hydrophilic arms (e.g., polyethylene glycol units) terminated with a primary amine (nucleophile) or have activated ester end groups (electrophiles). The polymer network according to the present invention may comprise identical or different polymer units that are crosslinked with each other. In particular, the polymer network according to the present invention comprises one or more (identical or different) arm polymer units that are crosslinked with each other. The precursors may be high molecular weight components (e.g., polymers having functional groups as further disclosed herein) or low molecular weight components (e.g., low molecular weight amines, thiols, esters, etc., also as further disclosed herein).

[0209] Certain functional groups can be made more reactive by using activating groups. Examples of such activating groups include (but are not limited to) carbonyl diimidazole, sulfonyl chloride, aryl halide, sulfosuccinimidyl esters, N-hydroxysuccinimidyl (abbreviated as "NHS") esters, succinimidyl esters, benzotriazolyl esters, thioesters, epoxides, aldehydes, maleimides, imide esters, and acrylates. NHS esters are useful for crosslinking with nucleophilic polymers, such as primary amine-terminated or thiol-terminated polyethylene glycol, or other nucleophilic group-containing agents, such as nucleophilic group-containing crosslinking agents. NHS-amine crosslinking reactions may be carried out in aqueous solution in the presence of a buffer, such as phosphate buffer (pH 5.0-7.5), triethanolamine buffer (pH 7.5-9.0), borate buffer (pH 9.0-12), or sodium bicarbonate buffer (pH 9.0-10.0), or in an organic solvent.

[0210] In certain embodiments, each precursor can contain only nucleophilic functional groups or only electrophilic functional groups, as long as both the nucleophilic precursor and the electrophilic precursor are used in the crosslinking reaction. Thus, for example, if the crosslinker has only nucleophilic functional groups such as amines, the precursor polymer can have electrophilic functional groups such as N-hydroxysuccinimide. On the other hand, if the crosslinker has electrophilic functional groups such as sulfosuccinimide, the functional polymer can have nucleophilic functional groups such as amines or thiols. Thus, functional polymers such as proteins, poly(allylamine), or amine-terminated bifunctional or polyfunctional poly(ethylene glycol) can also be used to prepare the polymer network of the present invention.

[0211] In one embodiment of the present invention, the precursors of the polymer network that form a hydrogel in which a tyrosine kinase inhibitor is dispersed to form a depot that can be used in a method of treating joint pathologies according to the present invention each have from about 2 to about 16 nucleophilic functional groups (referred to as functionality), and in another embodiment, the precursors each have from about 2 to about 16 electrophilic functional groups (referred to as functionality). Reactive (nucleophilic or electrophilic) precursors that are multiples of 4, thus, for example, reactive precursors having 4, 8, and 16 reactive groups, are particularly suitable for the present invention. However, any number of functional groups (for example, when using precursors, including any of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 groups) can allow the precursors to be used in accordance with the present invention while ensuring that the functionality is sufficient to form a well-crosslinked network.

[0212] In certain embodiments of the present invention, the polymer network that forms the hydrogel contains polyethylene glycol (「PEG」) units. PEG is known in the art to form hydrogels when crosslinked, and these PEG hydrogels are suitable for pharmaceutical use, for example, as a matrix for drugs intended to be administered to any part of the human or animal body.

[0213] The polymer network of the hydrogel depot of the present invention may include one or more multi-arm PEG units having 2 to 10 arms, or 4 to 8 arms, or 4, 5, 6, 7, or 8 arms. In certain embodiments, the PEG units used in the hydrogels of the present invention have 4 arms. In certain embodiments, the PEG units used in the hydrogels of the present invention have 8 arms. In certain embodiments, PEG units having 4 arms and PEG units having 8 arms are used in the hydrogels of the present invention. In certain specific embodiments, one or more 4-arm PEGs are utilized. Any combination of multi-arm PEGs may be used. In certain embodiments, only 4-arm PEG units are used (which may be the same or different).

[0214] The number of arms of the PEG(s) used serves to control the flexibility or softness of the resulting hydrogel. For example, a hydrogel formed by crosslinking 4-arm PEG is generally softer and more flexible than one formed from 8-arm PEG of the same molecular weight. In particular, when it is desirable to stretch the hydrogel before drying (or even after drying), as disclosed briefly below in the section regarding the manufacture of fibers, optionally, a more flexible hydrogel (e.g., 4-arm PEG) may be used in combination with another multi-arm PEG, such as the 8-arm PEG disclosed above, or another (different) 4-arm PEG.

[0215] In certain embodiments of the present invention, the average molecular weight (Mn) of polyethylene glycol units used as precursors is in the range of about 2,000 to about 100,000 daltons, or about 10,000 to about 60,000 daltons, or about 15,000 to about 50,000 daltons. In certain specific embodiments, the average molecular weight of polyethylene glycol units is in the range of about 10,000 to about 40,000 daltons, or about 15,000 to about 30,000 daltons, or about 15,000 to about 25,000 daltons. In certain embodiments, the average molecular weight (Mn) of polyethylene glycol units used in the production of hydrogels according to the present invention is about 15,000 daltons. In even more specific embodiments, the average molecular weight (Mn) of polyethylene glycol units used in the production of hydrogels according to the present invention is about 20,000 daltons. Polyethylene glycol precursors with different molecular weights can be combined with each other. In this specification, when referring to a PEG material having a specific average molecular weight (e.g., about 20,000 daltons) (as defined herein), it is intended that a variation of ±10% is included; that is, referring to a material having an average molecular weight of about 20,000 daltons also refers to such materials having an average molecular weight of about 18,000 to about 22,000 daltons. Where used herein, the abbreviation "k" in the context of molecular weight refers to 1,000 daltons; that is, "20k" means 20,000 daltons.

[0216] Furthermore, when referring to PEG precursors having a specific average molecular weight (e.g., 15kPEG or 20kPEG precursors), the indicated average molecular weight (i.e., Mn of 15,000 or 20,000, respectively) refers to the PEG portion of the precursor before the addition of the end group (in this specification, "20k" means 20,000 daltons, and "15k" means 15,000 daltons—the same abbreviations are used herein for PEG precursors of other average molecular weights). In certain embodiments, the Mn of the PEG portion of the precursor is determined by MALDI. The degree of substitution with the end group disclosed herein is after end group functionalization. 1This can be determined by 1H-NMR.

[0217] In 4-arm ("4a") PEG, in certain embodiments, each arm may have an average arm length (or molecular weight) obtained by dividing the total molecular weight of PEG by 4. Therefore, a particularly suitable precursor for use in the present invention, the 4a20kPEG precursor, has four arms with an average molecular weight of approximately 5,000 daltons each and a total molecular weight of 20,000 daltons. Therefore, an 8a20kPEG precursor, which can be used in combination with or as an alternative to the 4a20kPEG precursor in the present invention, has eight arms ("8a"), each with an average molecular weight of 2,500 daltons and a total molecular weight of 20,000 daltons. Longer arms may result in greater flexibility compared to shorter arms. PEGs with longer arms may swell more than PEGs with shorter arms. PEGs with fewer arms may have a higher expansion rate and greater flexibility than PEGs with more arms. In certain specific embodiments, only one or more 4-arm PEG precursors are used in the present invention. In other specific embodiments, the present invention uses combinations of one or more 4-arm PEG precursors and one or more 8-arm PEG precursors. Furthermore, the longer the PEG arms, the higher the melting temperature during drying, which can improve dimensional stability during storage.

[0218] In certain embodiments, the electrophilic end groups for use with the PEG precursor for the preparation of the hydrogel of the present invention are N-hydroxysuccinimidyl (NHS) esters, including, but not limited to, NHS dicarboxylic acid esters (e.g., succinimidylmalonic acid group, succinimidylmaleic acid group, succinimidyl fumarate group), "SAZ" (referring to a succinimidyl azelate end group), "SAP" (referring to a succinimidyl adipate end group), "SG" (referring to a succinimidyl glutarate end group), "SGA" (referring to a succinimidyl glutaramide end group), "SC" (referring to a succinimidyl carboxylic acid), and "SS" (referring to a succinimidyl succinate end group). Examples of active esters other than NHS esters useful in the present invention include (but are not limited to) thioesters, benzotriazolyl esters, and acrylic acid esters.

[0219] In certain embodiments, the nucleophilic terminal group used with the electrophilic PEG precursor for preparing the hydrogel of the present invention is an amine (indicated as "NH2") terminal group. Thiol (-SH) terminal groups or other nucleophilic terminal groups may also be used.

[0220] In certain embodiments of the present invention, a 4-armed PEG having an average molecular weight of about 20,000 daltons and having the electrophilic end groups disclosed above (e.g., SAZ, SAP, SC, SG, and SS end groups, particularly the SG end group) is crosslinked to form a polymer network, and thus a hydrogel according to the present invention. Suitable PEG precursors are available from numerous suppliers, such as Jenkem Technology.

[0221] For example, the reaction between a nucleophilic group-containing crosslinker and an electrophilic group-containing PEG unit, or the reaction between an amine group-containing crosslinker and an activated ester group-containing PEG unit, results in multiple PEG units being formed by formula: [ka] The polymer is crosslinked by a hydrolyzable linker having the formula, where m is an integer from 0 to 10, specifically 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. For a SAZ-terminated group, m is 6; for an SAP-terminated group, m is 3; for an SG-terminated group, m is 2; and for an SS-terminated group, m is 1. In certain embodiments, m is 2. All crosslinks within the polymer network may be the same or different.

[0222] In certain embodiments, the polymer precursor used to form the hydrogel according to the present invention is selected from 4a20kPEG-SAZ, 4a20kPEG-SAP, 4a20kPEG-SG, 4a20kPEG-SS, 8a20kPEG-SAZ, 8a20kPEG-SAP, 8a20kPEG-SG, 8a20kPEG-SS, or a mixture thereof, which may comprise 4a20kPEG-NH2, 8a20kPEG-NH2, and one or more PEG or lysine-based amine groups selected from trilysine, or trilysine salts or derivatives (e.g., trilysine acetate (TLA)).

[0223] In certain embodiments, the SG-terminated group is utilized in the present invention. This terminal group can shorten the time it takes for the hydrogel to biodegrade in aqueous environments such as synovial fluid compared to the use of other terminal groups (e.g., SAZ-terminated group). The SAZ-terminated group has more carbon atoms in the linker and is therefore more hydrophobic, which may make it less susceptible to ester hydrolysis than the SG-terminated group.

[0224] In a specific embodiment, a 20,000 Dalton 4-arm PEG precursor having a SAZ group (as defined above) is crosslinked with a 20,000 Dalton 8-arm PEG precursor having an amine group (as defined above). These PEG precursors are also abbreviated herein as 4a20kPEG-SAZ and 8a20kPEG-NH2, respectively. The schematic chemical structure of 4a20kPEG-SAZ is reproduced below (wherein R represents the pentaerythritol core structure): [ka] The approximate chemical structure of 8a20kPEG-NH2 is reproduced below (where R represents the hexaglycerol core structure): [ka] In the above formula, n is determined by the molecular weight of each PEG arm.

[0225] In another specific embodiment, a 4-arm 20,000 Dalton PEG precursor having SG-terminated groups (as defined above) is crosslinked with a crosslinking agent having one or more reactive amine-terminated groups. This PEG precursor is abbreviated herein as 4a20kPEG-SG. The schematic chemical structure of 4a20kPEG-SG is reproduced below: [ka] In this equation, n is determined by the molecular weight of each PEG arm.

[0226] In certain specific embodiments, the crosslinking agent (also referred to herein as "crosslinker") used is a low molecular weight component containing a nucleophilic end group (e.g., an amine or thiol end group). In certain embodiments, the nucleophilic group-containing crosslinking agent is a low molecular amine having a molecular weight of less than 1,000 Da. In certain embodiments, the nucleophilic group-containing crosslinking agent contains two, three, or more primary aliphatic amine groups. Crosslinking agents suitable for use in the present invention include, but are not limited to, spermine, spermidine, lysine, dilysine, trilysine, tetralysine, polylysine, ethylenediamine, polyethyleneimine, 1,3-diaminopropane, 1,3-diaminopropane, diethylenetriamine, trimethylhexamethylenediamine, 1,1,1-tris(aminoethyl)ethane, their pharmaceutically acceptable salts, hydrates or other solvates, and their derivatives, e.g., conjugates (as long as there are sufficient nucleophilic groups for crosslinking), and mixtures thereof. A particular crosslinking agent used in the present invention is a lysine-based crosslinking agent, e.g., trilysine or a trilysine salt or derivative. A particular nucleophilic crosslinking agent used in the present invention is TLA. Other low molecular weight multi-arm amines can be used as well. The chemical structure of trilysine is reproduced below.

Chemical formula

[0227] In very specific embodiments of the present invention, the 4a20kPEG-SG precursor is reacted with the 4a20kPEG-NH2 precursor to form a polymer network. In other very specific embodiments of the present invention, the 4a20kPEG-SAZ precursor is reacted with the 4a20kPEG-NH2 precursor to form a polymer network. In even more specific embodiments, the 4a20kPEG-SG or 4a20kPEG-SAZ precursor is reacted with trilysine acetate to form a polymer network.

[0228] A polymer precursor may be bound or conjugated with a visualization agent, for example, via a crosslinking agent containing specific reactive (e.g., electrophilic) or nucleophilic groups of the polymer precursor. Fluorophores, such as fluorescein, rhodamine, coumarin, and cyanine, can be used as visualization agents disclosed herein. In certain embodiments of the present invention, fluorescein is used as the visualization agent. The visualization agent may be conjugated with the crosslinking agent, for example, via some of the nucleophilic groups of the crosslinking agent. Since a sufficient amount of nucleophilic groups is required for crosslinking, “conjugated” or “conjugation” generally includes partial conjugation, meaning that only a portion of the nucleophilic groups may be used for conjugation with the visualization agent, for example, about 1% to about 20%, or about 5% to about 10%, or about 8% of the nucleophilic groups of the crosslinking agent may be conjugated with the visualization agent. In certain embodiments, the crosslinking agent is trilysine acetate, which is conjugated with fluorescein.

[0229] In certain embodiments, the molar ratio of nucleophilic and electrophilic end groups reacting with each other is approximately 1:1, i.e., one amine group is provided for each electrophilic group (e.g., SAZ or SG group). In the case of 4a20kPEG-SAZ and 8a20kPEG-NH2, the molar ratio of the two components is approximately 2:1 because the 8-armed PEG contains twice the amount of end groups as the 4-armed PEG. In the case of 4a20kPEG-SAZ and trilysine (acetate), the molar ratio of the two components is approximately 1:1 because trilysine has four primary amine groups that can react with the electrophilic SAZ ester group. However, either electrophilic (e.g., NHS, e.g., SG or SAZ) end group precursors or nucleophilic (e.g., amine) end group precursors may be used in excess. In particular, excess nucleophiles (e.g., amine end group-containing precursors or crosslinking agents) may be used. In certain embodiments, the molar ratio of the electrophilic group-containing precursor to the nucleophilic group-containing crosslinking agent, for example, the molar ratio of 4a20kPEG-SG / 4a20kPEG-SAZ to trilysine acetate, is approximately 1:2 to approximately 2:1.

[0230] The hydrogel may be pre-formed (pre-formed) or formed in situ, i.e., in the joint or bone canal after administration. Pre-formed hydrogels may be in molded or extruded forms such as fibers, rods, beads, or particles. The pre-formed forms can be dried to form a xerogel and packaged for subsequent implantation. Xerogels can also be formed by drying a swollen hydrogel or organic gel, or directly by melting and crosslinking. In embodiments of the present invention, if in-situ gelation is desired, further components (but not limited to) such as viscosity-influencing agents like hyaluronic acid may be used during the production of the hydrogel. In-situ gelation can be achieved by controlling the gelation time after mixing the precursor in solution, so that the operator has sufficient time to mix the components and inject. Alternatively, in-situ gelation can be induced to occur after implantation, in which case the trigger may be exposure to physiological conditions such as moisture, pH, and temperature. Photoactivation is also a gelation trigger known to those skilled in the art.

[0231] The depot of the present invention may contain, in addition to the polymer units and active ingredients that form the polymer network as disclosed above, other further components. Such further components may be, for example, salts derived from the buffer used during the preparation of the hydrogel, e.g., phosphates, borates, bicarbonates, or other buffers, e.g., triethanolamine. In certain embodiments of the present invention, sodium phosphate buffer (specifically, monobasic and dibasic sodium phosphate) is used. Optionally, preservatives may be used in the depot of the present invention. However, in certain embodiments, the depot of the present invention may be free from, or substantially free from, preservatives, e.g., antimicrobial preservatives (including, but not limited to, benzalkonium chloride (BAK), chlorobutanol, sodium perborate, and stabilized oxychloro complex (SOC)).

[0232] Active ingredients: The active ingredient contained in the depot that may be used in a method for treating a pathological condition according to the present invention is a kinase inhibitor, in particular a tyrosine kinase inhibitor (TKI). Examples of suitable kinase inhibitors include (but should not be limited to) axitinib, baricitinib, cabozantinib, fostamatinib, nintedanib, pazopanib, regorafenib, sorafenib, sunitinib, tofacitinib, bororanib, and vandetanib. In a particular embodiment, the TKI used in all aspects of the present invention is axitinib.

[0233] In certain embodiments of the present invention, the tyrosine kinase inhibitor contained in the sustained-release biodegradable depot is axitinib, present in the depot in dose ranges of at least about 0.1 mg, at least about 0.2 mg, at least about 0.4 mg, for example, about 0.5 mg to about 120 mg. Any amount of axitinib within these dose ranges can be used, for example, about 0.2 mg, about 0.4 mg, about 0.6 mg, about 0.8 mg, about 1 mg, about 5 mg, about 10 mg, about 15 mg, about 30 mg, 50 mg, about 100 mg, etc., and all values ​​also include variations of +25% and -20%, or ±10%. In certain specific embodiments of the present invention, the dose of axitinib contained in the depot is as follows: - For administration into any joint or bone canal, in the range of approximately 1 mg to approximately 50 mg, or in the range of approximately 5 mg to approximately 40 mg, or in the range of approximately 10 mg to approximately 30 mg, - For administration to the knee, the range is approximately 3 mg to 45 mg, or approximately 5 mg to 30 mg, or approximately 10 mg to 25 mg, - For administration to the buttocks, the range is approximately 1.5 mg to approximately 25 mg, or approximately 2.5 mg to approximately 20 mg, or approximately 5 mg to approximately 15 mg, - For administration to the finger, the dosage range is approximately 0.4 mg to 12 mg, or approximately 0.5 mg to 10 mg, or approximately 1 mg to 8 mg.

[0234] When a tyrosine kinase inhibitor other than axitinib is used in the sustained-release biodegradable depot according to the present invention, the dose of the other tyrosine kinase inhibitor is included in the depot corresponding to any of the doses and ranges disclosed above for axitinib. The amounts of tyrosine kinase inhibitors, including the variations mentioned, for example axitinib, in this disclosure refer to both the final content of the active ingredient in the depot and the amount of the active ingredient used as a starting ingredient in the manufacture of the depot.

[0235] A tyrosine kinase inhibitor, such as axitinib, is contained in the depot of the present invention, and particles of the tyrosine kinase inhibitor are dispersed or distributed within a hydrogel consisting of a polymer network. In certain embodiments, the tyrosine kinase inhibitor is dispersed within the hydrogel as tyrosine kinase inhibitor particles. In such embodiments, the particles can be uniformly dispersed within the hydrogel. The hydrogel can prevent the particles from aggregating and can provide a matrix of particles that release the drug in a sustained manner upon contact with synovial fluid.

[0236] In one embodiment, tyrosine kinase inhibitor particles, such as axitinib particles, may be small in size and may be micronized particles. In another embodiment, tyrosine kinase inhibitor particles, such as axitinib particles, may not be micronized. Micronization refers to the process of reducing the average diameter of particles in a solid material. Smaller diameter particles may, among other things, have a higher dissolution rate, which improves the bioavailability of the active pharmaceutical ingredient. In the field of composite materials, particle size is known to affect the mechanical properties when combined with a matrix, and smaller particles provide better reinforcement for a given mass fraction. Therefore, a hydrogel matrix in which micronized tyrosine kinase inhibitor particles are dispersed may have improved mechanical properties (e.g., brittleness, strain to fracture, etc.) compared with larger tyrosine kinase inhibitor particles of a similar mass fraction. Such properties are important in depot preparation, during administration, and during degradation. Micronization may also promote a more uniform distribution of the active ingredient in the selected dosage form or matrix. In certain embodiments, any tyrosine kinase inhibitor used in the present invention, including axitinib, may be used with a particle size of about 100 μm or less, or about 75 μm or less, or about 50 μm or less (e.g., represented by a D90 value measured as defined and disclosed herein). In certain embodiments, axitinib may be used in the form of micronized particles, with a D90 particle size of about 100 μm or less, or about 75 μm or less, or about 50 μm or less, or about 20 μm or less, or about 10 μm or less, or about 5 μm or less. In these embodiments and other embodiments, the D98 particle size of micronized axitinib may be about 100 μm or less, or about 75 μm or less, or about 50 μm or less, or about 20 μm or less, or about 10 μm or less, or about 5 μm or less. In certain embodiments of the present invention, the micronized axitinib used in (or used to prepare) the depot of the present invention has a D90 particle size of about 5 μm or less and a D98 particle size of less than about 10 μm. In certain embodiments, the micronized particles have a D90 of less than about 10 μm and a D100 of less than about 20 μm.In embodiments of the present invention in which a tyrosine kinase inhibitor other than axitinib is used, the same particle size as disclosed for axitinib may be applied.

[0237] Formulation: The depot according to the present invention may comprise a tyrosine kinase inhibitor, a polymer network prepared in the form of a hydrogel from one or more polymer precursors disclosed herein above, and optionally, further components remaining in the depot from the production process, such as salts (e.g., phosphates used as buffers). In certain preferred embodiments, the tyrosine kinase inhibitor is axitinib. The depot used in the present invention may be, for example, an implant as disclosed in WO2021 / 195163, which is incorporated herein by reference.

[0238] A dry depot according to the present invention may contain about 5% to about 95% by weight of a tyrosine kinase inhibitor (e.g., axitinib) and about 5% to about 95% by weight of polymer units (e.g., those disclosed above). In certain embodiments, a dry depot according to the present invention may contain about 10% to about 75% by weight of a tyrosine kinase inhibitor (e.g., axitinib) and about 25% to about 80% by weight of polymer units (e.g., those disclosed above). In further embodiments, a dry depot according to the present invention may contain about 25% to about 60% by weight of a tyrosine kinase inhibitor (e.g., axitinib) and about 35% to about 65% by weight of polymer units (e.g., those disclosed above).

[0239] In some embodiments, the depot according to the present invention comprises about 45% to about 55% by weight of a tyrosine kinase inhibitor (e.g., axitinib) and about 40% to about 60% by weight of polymer units (e.g., polyethylene glycol units disclosed above).

[0240] In certain specific embodiments, the dry depot according to the present invention contains about 12% to about 38% by weight of axitinib and about 50% to about 70% by weight of polyethylene glycol units.

[0241] In other specific embodiments, the dry depot according to the present invention contains about 50% by weight of axitinib and about 35% to about 55% by weight of polyethylene glycol units. In such embodiments, the ratio of axitinib to polyethylene glycol is about 50% by weight of axitinib to about 40-50% by weight of polyethylene glycol, with the remainder being phosphate.

[0242] In certain embodiments, the depot according to the present invention may, in a dry state, contain about 0.1% to about 1% by weight of a visualization agent, such as fluorescein or a molecule containing a fluorescein moiety. In certain embodiments, the depot according to the present invention may, in a dry state, contain about 0.5% to about 5% by weight of one or more buffer salts (separately or together). In certain embodiments, the depot in a dry state may contain, for example, about 0.01% to about 2% by weight or about 0.05% to about 0.5% by weight of a surfactant.

[0243] In certain embodiments, the dry residue of the depot (i.e., the residue of the formulation when a TKI (e.g., axitinib) and a polymer hydrogel (e.g., trilyzine crosslinked PEG hydrogel) have already been considered) may be salts remaining from buffers that may be used during the preparation of the depots disclosed herein, or other components used during the preparation of the depots disclosed herein. In certain embodiments, such salts may be phosphates, borates, or (bi)carbonates. In some embodiments, the depot contains phosphates(s) derived from the phosphate buffer used during the preparation of the hydrogel. In one embodiment, the buffer salt is sodium phosphate (monobasic and / or dibasic).

[0244] The amounts of tyrosine kinase inhibitors and polymers may vary, and other amounts of tyrosine kinase inhibitors and polymer hydrogels may also be used to prepare depots that can be used in methods for treating joint pathologies according to the present invention.

[0245] In certain embodiments, the maximum amount (by weight) of drug in the formulation is about twice the amount by weight of the polymer (e.g., PEG), but may be higher in certain cases, provided that a mixture containing, for example, a precursor, buffer, and drug (before the hydrogel has completely gelled) can be uniformly cast into a desired mold or a narrow-diameter tube and / or further successfully processed.

[0246] In one embodiment, the hydrogel after formation and before drying, i.e., in a wet state, contains about 3% to about 20% polyethylene glycol (corresponding to the weight of polyethylene glycol ÷ the weight of the fluid × 100). In one embodiment, the hydrogel in a wet state contains about 7.5% to about 15% polyethylene glycol (corresponding to the weight of polyethylene glycol ÷ the weight of the fluid × 100).

[0247] In certain embodiments, a solid content of about 20% to about 50% (w / v) (where "solid" means the combined weight of the polymer precursor(s), salts, and drugs in the solution, excluding water content) is used to form the hydrogel of the depot according to the present invention.

[0248] In certain embodiments, the water content of the hydrogel in its dry (dehydrated / dried) state may be as low as about 0.01% to about 10% by weight of water, or about 0.1% to about 7% by weight, or about 0.25% to about 5% by weight of water (determined, for example, as disclosed herein). In particular, the water content of the hydrogel in its dry (dehydrated / dried) state is about 1% by weight or less. In certain embodiments, the water content may be lower, perhaps about 0.25% by weight or less, or about 0.1% by weight or less.

[0249] Release of active substances and biodegradation of the depot In one embodiment, a method for treating the condition may include administering a sustained-release biodegradable depot containing a hydrogel and a tyrosine kinase inhibitor, the depot releasing a therapeutically effective amount of the tyrosine kinase inhibitor for at least about one month, at least about two months, at least about three months, up to about six months or longer, for example, up to about nine months, after administration (i.e., after insertion into a joint or bone canal). In certain embodiments, the tyrosine kinase inhibitor is axitinib.

[0250] While we do not wish to be bound by theory, the release of axitinib into the synovial fluid or carpal tunnel or spinal canal fluid is primarily determined by the solubility of axitinib in an aqueous environment. The solubility of axitinib is considered very low in physiological media such as synovial fluid (approximately 0.2 to 0.5 μg / mL in PBS at pH 7.2). When administered to a joint or bone canal, axitinib is released from the depot primarily at the surface more proximal to the fluid.

[0251] In certain embodiments, the activator gradually dissolves and diffuses from the hydrogel into the synovial fluid or the fluid of the carpal tunnel or spinal canal. This begins at the interface between the depot and the fluid on the depot's surface and occurs directionally. The rate of drug dissolution depends on the solubility of the drug in water and the dimensions of the depot; the higher the drug solubility and the larger the surface area, the faster the drug release. The "drug tip" generally moves in a direction receding from the depot surface, i.e., away from the surface, until the activator in the entire depot is eventually depleted.

[0252] Figures 1-4 show exemplary release characteristics of a depot according to an embodiment of the present invention.

[0253] In certain embodiments, the depot according to the present invention provides the release of a tyrosine kinase inhibitor such as axitinib (in a therapeutically effective amount) for a period of about one month or more, for example, about three months or more, for example, at least about three months, or at least about twelve months, after administration to a joint or bone canal.

[0254] In certain embodiments, a depot administered to the articular or osteoidal canal releases a therapeutically effective dose of axitinib over a period of at least about 1 month, at least about 2 months, at least about 3 months, at least about 6 months, at least about 9 months, or at least about 12 months after administration. In certain embodiments, a depot administered to the articular or osteoidal canal releases a therapeutically effective dose of axitinib over a period of at least 3 months. In very specific embodiments, a depot administered to the articular or osteoidal canal releases a therapeutically effective dose of axitinib over a period of at least 6 months.

[0255] In certain embodiments, after administration, the level of activator released per day from the depot, in the case of axitinib, persists and remains constant or essentially constant for a certain period, for example, about one month, or about two months, or about three months (due to limitations on release based on the solubility of the activator). The amount of activator released per day may then be reduced for another period (also called “deceleration”) until all or substantially all of the activator has been released, and the “empty” hydrogel remains in the joint or bone canal until it is completely broken down, liquefied, solubilized, and removed (excreted / flushed). In some cases, the hydrogel may be designed to break down before complete drug release. This may be advantageous in chronic diseases requiring continuous injections. If drug residue remains after the clearance of the hydrogel vehicle, the accumulation of empty vascular material in the joint or bone canal is eliminated. The release of free drug particles provides a “window” of time for administering a second depot before the drug particles released from the first depot are completely depleted.

[0256] In certain embodiments, the depot of the present invention can deliver axitinib at an average release rate of at least about 0.5 mg, at least about 1 mg, for example, about 5 mg to about 20 mg, for example, about 10 mg to about 15 mg per month into the synovial fluid for a period of time during which the release is sustained, constant, or essentially constant, for example, up to about 3 months, up to about 6 months, up to about 9 months, or longer after administration.

[0257] In certain embodiments, axitinib is released into the synovial fluid from the depot after administration at a rate of at least about 0.1 μg / day, or at least about 0.5 μg / day, for example, at an average rate of about 1 μg / day to about 600 μg / day, for example, at an average rate of about 30 μg / day to about 500 μg / day, for example, at an average rate of about 100 μg / day to about 270 μg / day, particularly for at least 3 months. In certain embodiments, axitinib is released from the depot after administration at an average rate of about 165 μg / day, or about 220 μg / day.

[0258] In general, in embodiments of the present invention, the depot according to the present invention may release at least 1 μg per day in vitro in phosphate-buffered saline at 37°C for at least 30 days, for example, about 10 μg to about 1000 μg, or may release about 50 μg to about 750 μg per day in vitro in phosphate-buffered saline at 37°C for at least 30 days.

[0259] In certain embodiments, the depot provides axitinib at an average release rate of approximately 100 μg to approximately 500 μg per day, or approximately 160 μg to approximately 400 μg per day, in vitro at 37°C for 90 days. Alternatively or additionally, the depot may provide axitinib at an average release rate of approximately 150 μg to approximately 600 μg per day, or approximately 200 μg to approximately 450 μg per day, in vitro at 37°C for 30 days.

[0260] In certain embodiments, a depot may provide a cumulative amount of axitinib that releases at least 30 μg, or at least 50 μg, or at least 100 μg, or at least 500 μg, or at least 1 mg, in vitro in phosphate-buffered saline at 37°C, over a period of 30 days, for example, about 3 mg to about 20 mg, or about 4.5 mg to about 18 mg. Additionally or alternatively, a depot may provide a cumulative amount of axitinib that releases about 7 mg to about 36 mg, or about 9 mg to about 33 mg, in vitro in phosphate-buffered saline at 37°C, over a period of 60 days. Furthermore, additionally or alternatively, a depot may provide a cumulative amount of axitinib that releases about 12 mg to about 50 mg, or about 15 mg to about 42 mg, in vitro in phosphate-buffered saline at 37°C, over a period of 90 days.

[0261] In certain embodiments, the depot releases approximately 1% to 15% of the tyrosine kinase inhibitor within 14 days, approximately 5% to 30% within 1 month, approximately 15% to 50% within 2 months, approximately 30% to 80% within 3 months, and approximately 70% to 100% within 6 months in vitro in phosphate-buffered saline at pH 7.2 at 37°C.

[0262] In certain embodiments, the depot releases approximately 9% to 16% of axitinib in vitro in phosphate-buffered saline at pH 7.2 at 37°C within 1 month, approximately 21% to 28% of axitinib within 2 months, approximately 34% to 41% of axitinib within 3 months, approximately 70% to 77% of axitinib within 6 months, and approximately 93% to 100% of axitinib within 9 months, along with the octanol top layer. In some embodiments, the depot releases approximately 9% to 16% of axitinib in vitro in phosphate-buffered saline at pH 7.2 at 37°C within 1 month, approximately 21% to 28% within 2 months, approximately 34% to 41% within 3 months, approximately 70% to 77% within 6 months, and approximately 93% to 100% within 9 months, along with the octanol top layer. Furthermore, in certain embodiments, the depot releases approximately 1% to 5% of axitinib in vitro in phosphate-buffered saline at pH 7.2 at 37°C within 7 days, approximately 3% to 7% within 14 days, approximately 8% to 12% within 28 days, and / or approximately 15% to 19% within 42 days, along with the octanol top layer.

[0263] Generally, in embodiments of the present invention, the depot according to the present invention can provide axitinib concentrations in synovial fluid of at least about 1 ng / mL, at least about 5 ng / mL, at least about 10 ng / mL, for example, about 20 ng / mL to about 800 ng / mL, or can provide axitinib concentrations in synovial fluid of about 30 ng / mL to about 750 ng / mL over at least 14 days.

[0264] In certain embodiments, the depot provides an average axitinib concentration in synovial fluid of approximately 150 ng / mL to approximately 600 ng / mL three days after administration. Additionally or alternatively, the depot may provide an average axitinib concentration in synovial fluid of approximately 350 ng / mL to approximately 750 ng / mL seven days after administration. Additionally or alternatively, the depot may provide an average axitinib concentration in synovial fluid of approximately 35 ng / mL to approximately 200 ng / mL fourteen days after administration. In certain specific embodiments, the depot provides an average axitinib concentration in synovial fluid of approximately 35 ng / mL to approximately 200 ng / mL over 14 days, over 1 month, over 2 months, or over 3 months.

[0265] As the drug is released from the surface of the depot, this region closest to the surface of the hydrogel depot eventually becomes devoid of drug particles and is therefore sometimes called the "clearance zone." In certain embodiments, upon hydration, the clearance zone thus becomes a region of the depot with a lower concentration of the activator than another region of the hydrated hydrogel. An increase in the clearance zone creates a concentration gradient within the depot that can gradually reduce the rate of drug release.

[0266] As the drug diffuses from the hydrogel (and even after the entire amount of drug has diffused from the hydrogel), the hydrogel can be gradually degraded, for example, by ester hydrolysis in the aqueous environment of synovial fluid. As the degradation stage progresses, distortion and erosion of the hydrogel begin to occur. As this occurs, the hydrogel softens and further liquefies (and its shape distorts), and the hydrogel eventually dissolves and is completely absorbed.

[0267] In one embodiment, the persistence of the hydrogel in an aqueous environment within a joint or bone canal depends, in particular, on the structure of the linkers that crosslink the polymer units within the hydrogel, e.g., PEG units. In certain embodiments, the hydrogel is biodegraded within a period of about 2 months, or about 4 months, or about 7 months, or about 10 months, or up to about 15 months after administration. In certain embodiments, the depot is biodegraded within the joint or bone canal before, or almost simultaneously with, the complete solubilization of the tyrosine kinase inhibitor particles contained in the depot.

[0268] In embodiments of the present invention, the hydrogel and, consequently, the depot remain in the joint or bone canal for up to approximately 2 months, or up to approximately 4 months, or up to approximately 7 months, or up to approximately 10 months, or up to approximately 15 months after administration.

[0269] In certain embodiments of the present invention, when the tyrosine kinase inhibitor is axitinib, the entire amount of axitinib may be released before the complete degradation of the hydrogel, and the depot may persist in the joint or bone canal thereafter for up to about 2 months in total, or up to about 4 months, or up to about 7 months, or up to about 10 months, or up to about 15 months, after administration. In certain embodiments, after the complete release of the axitinib load, the depot of the present invention may persist for a further 1 month, or up to 2 months, or up to 3 months, or longer. In other certain embodiments, the hydrogel may be completely biodegradable while the tyrosine kinase inhibitor, such as axitinib, has not yet been completely released from the depot. In other embodiments, the depot may be completely degraded after the release of at least about 50%, or at least about 90%, or at least about 92%, or at least about 95%, or at least about 97% of the tyrosine kinase inhibitor. In certain specific embodiments, the time to complete depot degradation (i.e., dissolution of the hydrogel) essentially corresponds to the time until the complete drug load (i.e., a TKI such as axitinib) from the depot is released. In embodiments, the ratio of the time to complete depot degradation to the time to complete drug release may be less than about 2, or less than about 1.5, for example, about 0.5 to about 1.5, or about 1.8 to about 1.3.

[0270] The administered depot(s) can be visualized by imaging methods known in the art. In particular, visualization can be facilitated by adding adjuvants that help distinguish the depot(s) from the soft tissue surrounding the administration site. For example, a visualization agent such as fluorescein may be conjugated with a polymer precursor or crosslinking agent used to form the hydrogel. Alternatively or additionally, an X-ray contrast agent and / or an MRI contrast agent may be incorporated into the hydrogel.

[0271] unit In particular embodiments of the present invention, when used herein in a method for treating a pathological condition according to the present invention, or in a pharmaceutical preparation further described below, the depot may comprise one or more units, which may be in the form of fibers or beads. The dry units of the depot may have different shapes depending on the method of manufacture, e.g., a mixture comprising a hydrogel precursor containing a tyrosine kinase inhibitor, which is optionally further processed before (or after) complete gelation, and depending on the use of a mold or tube in which it is cast. In one embodiment, the units have an essentially cylindrical shape with an essentially circular cross-section. Such units, generally having a length greater than their diameter, are called “fibers” (this term is interchangeable herein with the term “rod” and having a cylindrical or essentially cylindrical shape). In another embodiment, the units may have an essentially spherical shape. Such essentially spherical units are called “beads.” Further details relating to the fibers and beads according to the present invention are disclosed herein.

[0272] Various shapes of the unit's external form or cross-section can also be used in this invention. For example, instead of a fiber with a circular diameter (i.e., in the case of a cylindrical depot), an oval (or elliptical) diameter fiber may be used. Other cross-sectional shapes such as triangular, cruciate, star-shaped, and square may also be used. Similarly, instead of spherical particles, the beads may be spheroids (also called ellipsoids) or cubes, for example, a cube.

[0273] The polymer network of the hydrogel depot according to a specific embodiment of the present invention, such as the PEG network, may be semi-crystalline in a dry state below room temperature and amorphous in a wet state. The fact that the dry units of the depot may be dimensionally stable below room temperature may be advantageous for loading the depot into the needle and for quality control.

[0274] When a depot in a joint or osteoidal canal is hydrated (which can be simulated in vitro, for example, by immersing the depot in PBS at pH 7.2 at 37°C after 24 hours, which is considered to be the equilibrium state), the dimensions of the depot or its units according to the present invention may change. Generally, the diameter of the unit may increase, but optionally, its length may increase, decrease, or, in certain embodiments, remain the same or substantially the same. The advantage of this dimensional change is that a dry unit is thin enough to be administered and placed in a joint or osteoidal canal, but once placed in a joint or osteoidal canal, it may take on a larger volume due to the release of the activator. Due to the nature of drug diffusion through the hydrogel matrix and release from the depot surface, it should be understood that the duration and rate of drug release are influenced by the final hydrated shape and dimensions.

[0275] In the hydrogel of the present invention, a certain degree of molecular orientation can be imparted by stretching the material and then solidifying it to fix the molecular orientation. Molecular orientation provides one mechanism against anisotropic swelling when the depot is brought into contact with a hydrating medium such as synovial fluid. Upon hydration, the depot of a particular embodiment of the present invention expands in radial dimensions, while its length is either decreased, maintained, or substantially maintained in some cases.

[0276] Another factor influencing the stretchability of the hydrogel and the potential for dimensional changes in the units during hydration is the composition of the polymer network. When PEG precursors are used, those with fewer arms (e.g., 4-arm PEG precursors) contribute to greater flexibility of the hydrogel than those with more arms (e.g., 8-arm PEG precursors). If the hydrogel contains a large amount of less flexible components (e.g., PEG precursors with more arms, e.g., 8-arm PEG units), the hydrogel may become stiffer and less easily stretched without breakage. On the other hand, hydrogels containing more flexible components (e.g., PEG precursors with fewer arms, e.g., 4-arm PEG units) may be more easily stretched and flexible, but also expand more during hydration. Therefore, the behavior and properties of a depot after administration and rehydration can be tuned by altering its structural characteristics and by changing the treatment of the depot after its initial formation.

[0277] The dimensions of the dry depot may depend, in particular, on the amount of tyrosine kinase inhibitor incorporated and the ratio of tyrosine kinase inhibitor to polymer units, and further on on the diameter and shape of the mold or tube in which the hydrogel gels, and / or on the method of further processing the hydrogel before (or after) complete gelation. The diameter of the dry depot, once formed as disclosed herein, may be further controlled by stretching the hydrogel strands (wet or dry). The dry hydrogel strands (after stretching) can be cut into pieces of desired length to form fibers or beads, and thus the length can be selected as needed.

[0278] Fiber: In certain embodiments, the depot is in the form of at least one sustained-release biodegradable fiber. In some embodiments, the depot is in the form of one sustained-release biodegradable fiber, i.e., the depot is one sustained-release biodegradable fiber. In other embodiments, the depot is in the form of two or more sustained-release biodegradable fibers, i.e., the depot consists of two or more units in the form of fibers.

[0279] In one embodiment, the fiber is cylindrical or has an essentially cylindrical shape. Whenever the term “cylindrical” is used herein with respect to the shape of a unit of depot, it always includes “essentially cylindrical.” In this case, the fiber has a circular or essentially circular cross-section. In another embodiment, the fiber is non-cylindrical. The fiber according to the present invention is optionally elongated in its dry state, with the length of the fiber being greater than the width of the fiber, where the width is the maximum cross-sectional dimension substantially perpendicular to the length. In a cylindrical or essentially cylindrical depot, the width is also called the diameter.

[0280] In general, the length and / or diameter of at least one fiber of the present invention may be limited by, for example, the size of each joint cavity or the administration site, such as the needle gauge used for administration. In certain embodiments, at least one fiber of the present invention may have an average length of at least about 1 mm, at least about 5 mm, or at least about 10 mm in a dry state, and / or an average diameter of at least about 0.05 mm, at least about 0.10 mm, or at least about 0.20 mm. In these or other embodiments, at least one fiber of the present invention may have an average length of up to about 5 cm, up to about 1 cm, up to about 0.5 cm, or up to about 0.1 cm in a dry state, and / or an average diameter of up to about 1 mm, up to about 0.8 mm, up to about 0.50 mm, or up to about 0.01 mm. In one embodiment, at least one fiber of the present invention has an average length of about 5 mm to about 15 mm in a dry state, and an average diameter of about 0.10 mm to about 0.50 mm. Such fibers may shorten in length and increase in diameter when hydrated in vitro or in vivo within a joint or bone canal, such as the knee joint. In some embodiments, at least one fiber has an average length of about 6.5 mm to about 14 mm and an average diameter of about 0.15 mm to about 0.45 mm in a dry state. In certain embodiments, at least one fiber has an average length of about 11 mm to about 13.5 mm and an average diameter of about 0.30 mm to about 0.40 mm in a dry state.

[0281] In some embodiments, the fibers according to the present invention may be linear. In other embodiments, the fibers according to the present invention may be coiled, i.e., the fibers employ a three-dimensional arrangement that shortens their final length. Such an arrangement in coil form allows the fibers to contain an increased drug load compared to linear fibers having the same final length.

[0282] In certain embodiments, one fiber contains a tyrosine kinase inhibitor, particularly axitinib, in amounts of at least about 10 μg, or at least 100 μg, or at least 250 μg, or at least 500 μg, or about 10 μg to about 1200 μg. For example, one fiber contains axitinib in amounts of about 15 μg, or about 35 μg, or about 55 μg, or about 100 μg, or about 150 μg, or about 200 μg, or about 300 μg, or about 420 μg (or more). In some embodiments, one fiber contains axitinib in amounts of about 100 μg to about 800 μg. In a particular embodiment, one fiber contains axitinib in amounts of approximately 250 μg to 600 μg, approximately 300 μg to 500 μg, or approximately 380 μg to 460 μg.

[0283] In one particular embodiment, the fiber contains about 420 μg of axitinib and has an average length of about 10 mm to about 15.5 mm and an average diameter of about 0.40 mm to about 0.70 mm.

[0284] In certain embodiments, at least one fiber can be obtained by preparing a mixture containing a hydrogel precursor and a tyrosine kinase inhibitor, such as axitinib; filling the mixture into a tube or mold; and gelling the mixture within the tube or mold to provide the hydrogel in the form of a fiber. In other embodiments, at least one fiber can be obtained by preparing a mixture containing a hydrogel precursor and a tyrosine kinase inhibitor; heating the mixture, melting it, extruding it into a strand, and cutting the strand. Methods and processes for obtaining fibers by thermal melt extrusion are disclosed, for example, in PCT Patent Application PCT / US2022 / 051993, which is incorporated herein by reference.

[0285] Exemplary fibers produced according to the present invention are described and characterized in Examples 1A and 2.

[0286] In one very specific embodiment of the method for treating joint pathologies according to the present invention, the depot is administered intraarticularly to the synovial joint of the patient, and the dose per joint administered once during a treatment period of at least three months is about 0.5 mg to about 120 mg of a tyrosine kinase inhibitor, the hydrogel comprises a polymer network containing one or more crosslinked 4-8 arm polyethylene glycol units, the tyrosine kinase inhibitor is axitinib, and the depot is in the form of one or more sustained-release biodegradable fibers, each of which contains at least 10 μg or at least 50 μg of axitinib, for example, in an amount of about 100 μg to about 800 μg.

[0287] In another very specific embodiment of the method for treating joint pathologies according to the present invention, the depot is administered to the patient's knee, and the dose per knee, administered once during a treatment period of at least three months, is about 10 mg to about 25 mg of a tyrosine kinase inhibitor; the hydrogel comprises a polymer network containing one or more crosslinked 4- to 8-arm polyethylene glycol units; the tyrosine kinase inhibitor is axitinib; and the depot is in the form of one or more sustained-release biodegradable fibers, each of which contains at least 10 μg or at least 50 μg of axitinib, for example, in an amount of about 100 μg to about 800 μg.

[0288] In another very specific embodiment of the method for treating joint pathologies according to the present invention, the depot is administered to the patient's buttocks, and the dose per knee, administered once during a treatment period of at least three months, is about 5 mg to about 15 mg of a tyrosine kinase inhibitor, the hydrogel comprises a polymer network containing one or more crosslinked 4-8 arm polyethylene glycol units, the tyrosine kinase inhibitor is axitinib, and the depot is in the form of one or more sustained-release biodegradable fibers, each of which contains at least 10 μg or at least 50 μg of axitinib, for example, in an amount of about 100 μg to about 800 μg.

[0289] In another very specific embodiment of the method for treating joint pathologies according to the present invention, the depot is administered to the patient's finger, and the dose per knee, administered once during a treatment period of at least three months, is about 1 mg to about 8 mg of a tyrosine kinase inhibitor; the hydrogel comprises a polymer network containing one or more crosslinked 4-8 arm polyethylene glycol units; the tyrosine kinase inhibitor is axitinib; and the depot is in the form of one or more sustained-release biodegradable fibers, each of which contains at least 10 μg or at least 50 μg of axitinib, for example, in an amount of about 100 μg to about 800 μg.

[0290] beads: In certain embodiments, the depot is in the form of a plurality of sustained-release biodegradable beads, i.e., the depot consists of two or more units in the form of beads.

[0291] In one embodiment, the beads are spherical or have the general shape of spherical particles. Whenever the term “spherical” is used herein with respect to the shape of a unit of depot in the specification or claims, this always includes “essentially spherical.” In this case, the beads have a circular or essentially circular cross-section. In other embodiments of the present invention, the beads are non-spherical. The surface of the beads may be regular or irregular.

[0292] The multiple beads constituting the depot used in the method according to the present invention may have a narrow particle size distribution in order for the tyrosine kinase inhibitor to be uniformly released from each bead. In certain embodiments, any type of (dry) bead used in the method according to the present invention may have a particle size of about 300 μm or less, or about 250 μm or less, or about 220 μm or less (e.g., represented by a D50 value measured as defined and disclosed herein). In certain embodiments, the dry beads may have a D50 particle size of about 250 μm or less, or about 220 μm or less, or about 210 μm or less. In these embodiments and other embodiments, the D90 particle size may be about 300 μm or less, or about 280 μm or less, or about 250 μm or less. In certain embodiments of the present invention, the beads constituting the depot of the present invention in a dry state have an average volume particle size of about 50 μm to about 500 μm, about 100 μm to about 300 μm, or about 200 μm, as determined by scanning electron microscopy (SEM) or other suitable method. In these embodiments and other embodiments, the beads constituting the depot of the present invention in a hydrated state have an average volume particle size of about 100 μm to about 1000 μm, about 200 μm to about 600 μm, or about 400 μm, as determined by light microscopy or other suitable method. In one embodiment of the present invention, the beads have an average volume particle diameter of about 200 μm in a dry state and about 400 μm in a hydrated state, as determined by scanning electron microscopy (SEM), light microscopy, or other suitable method.

[0293] In certain embodiments, beads can be obtained by preparing a mixture comprising a hydrogel precursor and a tyrosine kinase inhibitor, such as axitinib, and further processing it to provide a hydrogel in the form of beads containing tyrosine kinase inhibitor particles, for example, by the methods further described below. In one alternative method, the mixture can then be extruded from a static mixer into a tube having a tangential oil flow. In a second alternative method, the mixture can then be filled into a syringe or mold to gel the mixture, and then pushed through at least one mesh screen. In a third alternative embodiment, the mixture can be filled into a mold having microcavities to gel the mixture within the microcavities. In a fourth alternative embodiment, the mixture can be heated and melted and extruded into strands, which can then be cut or pelletized. In a fifth alternative embodiment, the mixture can be heated and extruded into an oil bath. In certain embodiments, the resulting beads can be dried. In these or other embodiments, the resulting beads can be freeze-dried.

[0294] In certain embodiments of the present invention, the tyrosine kinase inhibitor contained in a sustained-release biodegradable depot in the form of multiple beads is present in amounts of about 0.01 μg to about 100 μg or about 50 μg per bead, or about 0.1 μg to about 20 μg per bead, for example, about 1 μg, about 2 μg, about 5 μg, about 10 mg, about 15 μg, etc. In some embodiments, the beads contain the tyrosine kinase inhibitor in amounts of about 0.5 μg to about 12 μg per bead. In certain embodiments, the beads contain axitinib in amounts of about 1 μg to about 8 μg, about 1.5 μg to about 5 μg per bead, or about 2 μg to about 4 μg per bead.

[0295] In certain embodiments, the beads do not aggregate during administration in order to facilitate storage, aspiration, and administration via a subcutaneous injection needle.

[0296] In certain embodiments, multiple beads may be present in a collection medium to hold the beads together during storage, aspiration, and administration. The collection medium may be a fast-degrading polymer network, such as a linear PEG network, which allows the beads to be released into the joint cavity a short time after administration. The polymer network may be obtained, for example, by injection molding, thermal extrusion, or 3D printing.

[0297] In certain embodiments, the beads are suspended in a carrier. The carrier may be a non-aqueous carrier, such as an oily carrier. The carrier simplifies the distribution of the beads administered by joint injection. Thus, in some embodiments, the carrier prevents the beads from agglomerating. Furthermore, with respect to non-aqueous carriers such as oily carriers, swelling of the beads can be prevented, thereby allowing the dry beads to be delivered into the oil phase and funneled through a smaller needle gauge for administration. Once inside the joint, the carrier may diffuse and be replaced by synovial fluid, allowing the beads to take in the aqueous environment, swell to equilibrium, and reach their hydrated diameter.

[0298] In certain embodiments, the beads are suspended in the carrier at a volume ratio of about 45:55 or less (beads:carrier), particularly at volume ratios of about 9:91 to 45:55, about 12:88 to about 32:68, or about 16:84 to about 24:76. In these embodiments or other embodiments, the beads are suspended in the carrier at a bead concentration of about 50% by weight or less, particularly at concentrations of about 10% to about 50% by weight of beads, about 15% to about 40% by weight of beads, or about 20% to about 30% by weight of beads, with the remainder being the carrier. In very specific embodiments, the carrier, such as an oily carrier, is sesame oil or ethyl oleate, or other suitable pharmaceutically acceptable carrier, e.g., one of the carriers disclosed herein in connection with a pharmaceutical preparation. Specifically, the properties of a carrier, including an oily carrier, that can be used in any of the therapeutic methods of the present invention are the same as those disclosed below for carriers in relation to pharmaceutical preparations, or other suitable pharmaceutically acceptable carriers, for example, one of the carriers disclosed below herein in relation to pharmaceutical preparations. Specifically, the properties of a carrier, including an oily carrier, that can be used in any of the therapeutic methods of the present invention are the same as those disclosed below for carriers in relation to pharmaceutical preparations. Therefore, in certain embodiments, beads may be suspended in an oily carrier that is liquid at 15°C or above, such as at room temperature and / or body temperature. Further properties of the oily carrier include, cumulatively or alternatively, a boiling point higher than body temperature, e.g., above 50°C, above 70°C, above 100°C, or above 150°C, and / or a viscosity of less than about 120 mPa·s, less than about 100 mPa·s, or less than about 85 mPa·s at 20°C, and / or about 1.5 g / cm³ 3 Less than approximately 1.0 g / cm³ 3 Less than approximately 0.95 g / cm³ 3 Less than, or approximately 0.92 g / cm³ 3 It may contain densities less than a certain amount.

[0299] Beads manufactured exemplary according to the present invention are described and characterized in Examples 1B and 2. In certain embodiments, beads used as a depot in a therapeutic method according to any aspect of the present invention may be administered in the form of pharmaceutical preparations further disclosed below herein.

[0300] In one very specific embodiment of the method for treating joint pathologies according to the present invention, the depot is administered intraarticularly to the synovial joint of the patient, and the dose per joint, administered once during a treatment period of at least three months, is about 0.5 mg to about 120 mg of a tyrosine kinase inhibitor; the hydrogel comprises a polymer network containing one or more crosslinked 4-8 arm polyethylene glycol units; the tyrosine kinase inhibitor is axitinib; and the depot is in the form of a plurality of sustained-release biodegradable beads, each bead containing at least 0.1 μg or at least 0.5 μg of axitinib per bead, for example, in an amount of 1 μg to about 8 μg.

[0301] In another very specific embodiment of the method for treating joint pathologies according to the present invention, the depot is administered to the patient's knee, and the dose per knee, administered once during a treatment period of at least three months, is about 10 mg to about 25 mg of a tyrosine kinase inhibitor; the hydrogel comprises a polymer network containing one or more crosslinked 4-8 arm polyethylene glycol units; the tyrosine kinase inhibitor is axitinib; and the depot is in the form of a plurality of sustained-release biodegradable beads, each bead containing at least 0.1 μg or at least 0.5 μg of axitinib per bead, for example, in an amount of 1 μg to about 8 μg.

[0302] In another very specific embodiment of the method for treating joint pathologies according to the present invention, the depot is administered to the patient's buttocks, and the dose per knee, administered once during a treatment period of at least 3 months, is about 5 mg to about 15 mg of a tyrosine kinase inhibitor, the hydrogel comprises a polymer network containing one or more crosslinked 4-8 arm polyethylene glycol units, the tyrosine kinase inhibitor is axitinib, and the depot is in the form of a plurality of sustained-release biodegradable beads, the beads containing axitinib in an amount of at least 0.1 μg or at least 0.5 μg per bead, for example, 1 μg to about 8 μg.

[0303] In another very specific embodiment of the method for treating joint pathologies according to the present invention, the depot is administered to the patient's finger, and the dose per knee, administered once during a treatment period of at least three months, is about 1 mg to about 8 mg of a tyrosine kinase inhibitor, the hydrogel comprises a polymer network containing one or more crosslinked 4-8 arm polyethylene glycol units, the tyrosine kinase inhibitor is axitinib, and the depot is in the form of a plurality of sustained-release biodegradable beads, the beads containing axitinib in an amount of at least 0.1 μg or at least 0.5 μg per bead, for example, 1 μg to about 8 μg.

[0304] II. Pharmaceutical preparations In certain embodiments, the present invention also relates to (i) a sustained-release biodegradable depot comprising a hydrogel and a tyrosine kinase inhibitor, and (ii) an injectable pharmaceutical preparation comprising a carrier. In certain preferred embodiments, the tyrosine kinase inhibitor contained in the depot of the pharmaceutical composition according to the present invention in all embodiments is axitinib. If the biodegradable hydrogel is susceptible to hydrolysis, the carrier may be anhydrous, i.e., treated to reduce its water content to a level low enough to provide storage stability to the hydrolyzable hydrogel depot.

[0305] In some embodiments, the depot is in the form of multiple sustained-release biodegradable beads. In particular, the depot may be in the form of spherical or non-spherical particles, as described above for the method of treating joint pathologies according to the present invention. The dry beads, when contained in the pharmaceutical preparation, may have a narrow particle size distribution, in particular having a D50 particle size of about 250 μm or less, or about 220 μm or less, or about 210 μm or less, or a D90 particle size of about 300 μm or less, or about 280 μm or less, or about 250 μm or less. In certain embodiments of the present invention, the dry beads constituting the depot when contained in the pharmaceutical preparation according to the present invention have an average volume particle size of about 50 μm to about 500 μm, about 100 μm to about 300 μm, or about 200 μm, as determined by scanning electron microscopy (SEM) or other suitable method. In these embodiments and other embodiments, the hydrated beads constituting the depot when contained in the pharmaceutical preparation according to the present invention have an average volume particle size of about 100 μm to about 1000 μm, about 200 μm to about 600 μm, or about 400 μm, as determined by a light microscope or other suitable method.

[0306] In certain embodiments, a tyrosine kinase inhibitor such as axitinib contained in a sustained-release biodegradable depot in the form of multiple beads is present in amounts of about 0.01 μg to about 100 μg or about 50 μg per bead, or about 0.1 μg to about 20 μg per bead, for example, about 0.5 μg to 12 μg per bead. In certain embodiments, the beads contain axitinib in amounts of about 1 μg to about 8 μg, about 1.5 μg to about 5 μg per bead, or about 2 μg to about 4 μg per bead.

[0307] Suitable precursors for forming hydrogels of beads in specific embodiments of the present invention are as disclosed above in the section relating to the depot itself. In specific embodiments, the hydrogel may comprise 4a20kPEG units derived from reacting a 4a20kPEG-SG or 4a20kPEG-SAZ precursor with a 4a20kPEG-NH2 precursor or trilysine acetate to form a polymer network.

[0308] In certain embodiments of the pharmaceutical preparation, the beads are suspended in the carrier at a volume ratio of about 45:55 or less (beads:carrier), particularly at about 9:91 to 45:55, about 12:88 to about 32:68, or about 16:84 to about 24:76. In these or other embodiments, the beads are suspended in the carrier at a bead concentration of about 50% by weight or less, for example, at a bead concentration of about 10% to about 50% by weight, with the remainder being the carrier. In some embodiments, the beads are suspended in the carrier at a bead concentration of about 15% to about 40% by weight, with the remainder being the carrier. In certain embodiments, the beads are suspended in the carrier at a bead concentration of about 20% to about 30% by weight, with the remainder being the carrier. The beads may be uniformly suspended in the carrier to ensure a uniform concentration when dispensing the pharmaceutical preparation. The concentration of beads relative to the carrier determines the dose of the tyrosine kinase inhibitor, such as axitinib.

[0309] The injectable pharmaceutical preparation according to the present invention may contain at least about 10 beads, at least about 100 beads, at least about 250 beads, at least about 500 beads, at least about 1000 beads, at least about 2500 beads, or at least about 5000 beads suspended in a carrier (a predetermined amount). In certain embodiments, the injectable pharmaceutical composition according to the present invention contains (i) about 100 to about 400,000 beads suspended in a carrier of about 0.1 mL to about 0.5 mL, or a carrier of about 0.5 mL to about 3 mL. In some embodiments, the pharmaceutical preparation contains (i) about 10,000 to about 100,000 beads suspended in a carrier of about 1 mL. In certain embodiments, the pharmaceutical composition contains (i) about 40,000 to about 70,000 beads suspended in a carrier of about 1 mL, etc.

[0310] In these or other embodiments, the pharmaceutical preparation for injection according to the present invention may contain at least about 0.001 g of beads, at least about 0.003 g of beads, at least about 0.008 g of beads, at least about 0.02 g of beads, at least about 0.03 g of beads, at least about 0.05 g of beads, or at least about 0.08 g of beads suspended in a carrier (a predetermined amount). In some embodiments, the pharmaceutical composition for injection according to the present invention contains (i) about 0.008 g to about 2 g of beads suspended in a carrier, for example, in about 0.1 mL to about 0.5 mL of carrier or about 0.5 mL to about 3 mL of carrier. In some embodiments, the pharmaceutical preparation contains (i) about 0.1 g to about 1 g of beads suspended in a carrier, for example, in about 0.5 mL to about 0.5 mL of carrier or about 0.5 mL to about 3 mL of carrier. In certain embodiments, the pharmaceutical composition comprises (i) about 0.1 g to about 1 g, for example, about 0.2 g to about 0.5 g, suspended in about 1 mL of carrier.

[0311] The carrier contained in the pharmaceutical preparation according to the present invention can be any carrier medium that can suspend multiple depots such as beads without aggregation, does not interact with the hydrogel, and is further tolerable in the patient's body after injection. The specific carrier medium according to the present invention is readily injectable, i.e., is a liquid during injection and in the patient's body, and has low to medium viscosity.

[0312] In certain embodiments, the carrier is a non-aqueous carrier. In certain embodiments, the carrier is an oily carrier, in particular a pharmaceutically acceptable oily carrier. This may include (but is not limited to) pharmaceutically acceptable oils, low-melting-point waxes, fats, lipids, liposomes, and any other pharmaceutically acceptable substances that are lipophilic and substantially insoluble in water. The carrier should be removable by the patient's body's natural processes. The oily carrier may be a natural or synthetic oil, and in particular a natural oil that may include plant oils such as those from vegetables or seeds. In certain embodiments, the carrier, such as an oily carrier, is at least one pharmaceutically acceptable oil, including almond oil, castor oil, coconut oil, corn oil, cottonseed oil, linseed oil, mineral oil, olive oil, palm oil, peanut oil, natto oil, safflower oil, sesame oil, silicone oil, soybean oil, and sunflower oil; at least one pharmaceutically acceptable wax, including beeswax, candelilla wax, carnauba wax, and animal oil; or at least one pharmaceutically acceptable lipid, including fatty acids and esters such as lauric acid, oleic acid, ethyl oleate, triethyl citrate, or acetyl triethyl citrate (ATEC). In a very specific embodiment, the oily carrier is sesame oil. In another very specific embodiment, the oily carrier is ethyl oleate. The tolerability of these oily carriers has been confirmed in the knees of Sprague Dawley rats by histological evaluation and dissection, as well as by blood analysis and complete autopsy (results not shown).

[0313] The properties of oily carriers may include, cumulatively or alternatively, the following: - Boiling points above body temperature, for example, boiling points above 50°C, above 70°C, above 100°C, or above 150°C, and / or Viscosity less than approximately 120 mPa·s, less than approximately 100 mPa·s, or less than approximately 85 mPa·s at -20°C, and / or -About 2.0g / cm 3 Less than, for example, about 1.5 g / cm³ 3 Less than approximately 1.0 g / cm³ 3 Less than approximately 0.95 g / cm³ 3Less than, or approximately 0.92 g / cm³ 3 Density less than.

[0314] In certain embodiments, the oily carrier may be liquid at temperatures above 15°C. In certain embodiments, the oily carrier is liquid at room temperature and body temperature.

[0315] In certain embodiments, the carrier, such as an oily carrier, provides very low solubility of axitinib so that the activator is not released from the depot into the carrier before being administered to the joint or bone canal. In some embodiments, the solubility of axitinib in the carrier is less than about 160 μg / ml. In further embodiments, the solubility of axitinib in the carrier is less than about 100 μg / ml, for example, less than about 50 μg / ml. In certain embodiments, the solubility of axitinib in the carrier is less than about 20 μg / ml. In certain very specific embodiments, axitinib is essentially insoluble in the carrier.

[0316] In certain embodiments, the injectable pharmaceutical preparation according to the present invention further comprises at least one pharmaceutically acceptable excipient. The at least one pharmaceutically acceptable excipient may be selected from the group consisting of antioxidants, free radical scavengers, stabilizers, such as UV stabilizers, and viscosity improvers. Examples of such viscosity improvers include, but are not limited to, oil-soluble and bioabsorbable polymers.

[0317] In one very specific embodiment of the pharmaceutical preparation according to the present invention, the depot is in the form of a plurality of sustained-release biodegradable beads, the hydrogel comprises a polymer network containing one or more crosslinked 4- to 8-arm polyethylene glycol units, the tyrosine kinase inhibitor is axitinib, the beads contain axitinib in an amount of at least 0.1 μg or at least 0.5 μg per bead, for example, 1 μg to about 8 μg, and the carrier is sesame oil or ethyl oleate.

[0318] III. Preparation of Pharmaceutical Products In certain embodiments, the present invention also relates to a method for preparing (i) a sustained-release biodegradable depot comprising a hydrogel and a tyrosine kinase inhibitor, and (ii) a pharmaceutical preparation for injection comprising a carrier. In certain embodiments, the method is I. The steps of forming a hydrogel containing a polymer network (e.g., including PEG units) and tyrosine kinase inhibitor particles dispersed in the hydrogel, and forming the hydrogel into beads, and optionally, II. The step of suspending beads in a carrier.

[0319] In certain preferred embodiments, the tyrosine kinase inhibitor in the method for preparing the injectable pharmaceutical composition according to the present invention in all its embodiments is axitinib. In one embodiment, the tyrosine kinase inhibitor, e.g., axitinib, may be used in a micronized form for preparing a depot. The micronized particles have a D90 of less than about 10 μm and a D100 of less than about 20 μm. In another embodiment, the tyrosine kinase inhibitor, e.g., axitinib, may be used in a non-micronized form for preparing a depot.

[0320] Suitable precursors for forming hydrogels of specific embodiments of the present invention are as disclosed above in the section relating to the depot itself. In certain specific embodiments, the hydrogel is made from a polymer network comprising crosslinked polyethylene glycol (PEG) units disclosed herein. The PEG units in certain embodiments are multi-armed, e.g., 4-armed PEG units having an average molecular weight of about 2,000 to about 100,000 daltons, or about 10,000 to about 60,000 daltons, or about 15,000 to about 50,000 daltons, or 30,000 daltons, or about 20,000 daltons. Suitable PEG precursors having reactive groups such as electrophilic groups disclosed herein are crosslinked to form a polymer network. Crosslinking can be carried out with a crosslinking agent, which is either a low molecular weight compound having reactive groups such as nucleophilic groups or another polymer compound (including another PEG precursor), as also disclosed herein. In certain embodiments, a PEG precursor having electrophilic end groups is reacted with a crosslinking agent (a low-molecular-weight compound or another PEG precursor) having nucleophilic end groups to form a polymer network.

[0321] In a particular embodiment, a method for producing an injectable pharmaceutical preparation includes reacting electrophilic group-containing multi-arm polyethylene glycol, e.g., 4a20kPEG-SG / 4a20kPEG-SAZ with nucleophilic group-containing multi-arm polyethylene glycol, e.g., 8a20kPEG-NH2 or a nucleophilic group-containing crosslinking agent, e.g., trilyzine acetate, in a buffer solution in the presence of axitinib particles (liquid mixture), and gelling the mixture. In another particular embodiment, a method for producing an injectable pharmaceutical preparation includes reacting electrophilic group-containing multi-arm polyethylene glycol, e.g., 4a20kPEG-SG / 4a20kPEG-SAZ with nucleophilic group-containing multi-arm polyethylene glycol, e.g., 8a20kPEG-NH2 powder or a nucleophilic group-containing crosslinking agent, e.g., trilyzine acetate powder, in the presence of axitinib particles (powder mixture), and heating the mixture for the reaction. In certain embodiments, the molar ratio of electrophilic groups in the PEG precursor to nucleophilic groups in other PEG precursors or crosslinking agents is about 1:1, but may be in the range of about 2:1 to about 1:2.

[0322] In certain embodiments, the visualization agents disclosed herein are contained in a mixture forming a hydrogel, and when the depot is administered into the space of synovial articular cartilage or bone canal, the depot can be visualized. For example, the visualization agent may be a fluorophore such as fluorescein or a molecule containing a fluorescein moiety, or another visualization agent disclosed above. In certain embodiments, the visualization agent may be tightly conjugated with one or more components of a polymer network so that the depot always remains in the depot until it is biodegraded. The visualization agent may be conjugated with either a polymer such as a PEG precursor, or a crosslinking agent (polymer or low molecular weight). In certain specific embodiments, during the preparation of the depot of the present invention, a (optionally, buffered) mixture / suspension of a tyrosine kinase inhibitor and a PEG precursor, e.g., axitinib and 4a20kPEG-SAZ, is prepared in water. Next, the tyrosine kinase inhibitor / PEG precursor mixture is combined with a (optionally, buffered) solution containing the PEG precursor and a visualization agent conjugated thereto (e.g., 8a20kPEG-NH2 / fluorescein conjugate). Thus, the resulting combined mixture contains the tyrosine kinase inhibitor, polymer precursor, visualization agent, and (optionally) a buffer.

[0323] In certain embodiments, once a mixture of an electrophilic group-containing polymer precursor, a nucleophilic group-containing polymer precursor, or a crosslinking agent, a tyrosine kinase inhibitor such as axitinib, optionally a visualization agent (optionally conjugated to the polymer precursor or crosslinking agent), and optionally a buffer is prepared (i.e., after these components are combined), the resulting mixture is processed by several manufacturing methods such as gel extrusion, mesh screening, micromolding, melt extrusion, or Vulcan extrusion to obtain hydrogels in bead form. The resulting beads can then be dried and / or lyophilized.

[0324] In some embodiments, a method for producing an injectable pharmaceutical preparation includes extruding a liquid mixture from a static mixer into a tube having a tangential oil flow to obtain beads before complete gelation, and recovering the obtained beads (gel extrusion). In such embodiments, a suspension of a tyrosine kinase inhibitor such as axitinib and an electrophilic multi-arm polyethylene glycol, e.g., 4a20kPEG-SG / 4a20kPEG-SAZ, in a buffer, and a suspension of a nucleophilic multi-arm polyethylene glycol, e.g., 8a20kPEG-NH2, or a nucleophilic crosslinking agent, e.g., trilyzine acetate, in a buffer is mixed / reacted while being extruded from a static mixer. The mixture can be extruded using a 27-30 gauge needle, particularly a 30 gauge needle. In certain embodiments, the mixture is extruded at an extrusion rate of about 0.3 mL / min to about 0.6 mL / min. Furthermore, in certain embodiments, the mixture is extruded at a tangential oil flow rate of about 1 mL / min to about 2 mL / min. The resulting bead size can be controlled by the respective extrusion speed, tangential oil flow rate, or needle gauge.

[0325] In some embodiments, a method for producing an injectable pharmaceutical preparation involves filling a syringe or mold with a liquid mixture before it is completely gelled, and allowing the mixture to gel. In such embodiments, a suspension of tyrosine kinase inhibitor particles, such as axitinib particles, and electrophilic multi-arm polyethylene glycol, e.g., 4a20kPEG-SG / 4a20kPEG-SAZ, in a buffer, and a suspension of nucleophilic multi-arm polyethylene glycol, e.g., 8a20kPEG-NH2, or a nucleophilic crosslinking agent, e.g., trilyzine acetate, in a buffer is mixed / reacted in a syringe to gel the mixture, or the mixture is filled into a syringe or mold before it is (completely) gelled.

[0326] In certain embodiments, the mixture is gelled in a syringe and extruded from the syringe through at least one mesh screen to obtain beads (mesh screening). In certain embodiments, the gel is extruded through one or more mesh screens having different mesh sizes, and the resulting beads are sieved. For example, the gel may be extruded at least once through a 900 μm mesh screen, followed by a 500 μm mesh screen and a 213 μm mesh screen, and the resulting bead size range is corrected by wet sieving of 53 to 500 μm. In other embodiments, the gel is extruded through a 3D printed mesh screen and cut to obtain beads (modified mesh screening). This makes it possible to two-dimensionally constrain the bead size.

[0327] In certain embodiments, a mixture is gelled in a thin sheet mold to obtain a gel sheet, the gel sheet is removed from the mold, and beads are obtained by cutting it using a mesh screen (gel sheet mesh screening). The thickness of the gel sheet may be about 0.4 mm or less, which constrains the bead size in one dimension.

[0328] In certain embodiments, beads are obtained by gelling a mixture in a mold having microcavities (micromolding). This makes it possible to constrain the bead size in all dimensions.

[0329] In certain embodiments, a method for producing an injectable pharmaceutical preparation includes melt-extruding a powder mixture to obtain strands, which are then cut or pelletized to obtain beads (melt extrusion). The particle size of the resulting beads can be controlled by the melt-extrusion diameter, which is particularly 0.4 mm.

[0330] In certain embodiments, a method for producing an injectable pharmaceutical preparation includes mixing and heating a powder mixture under nitrogen in a (Vulcan) ceramic syringe and extruding it into an oil bath to obtain beads (Vulcan extrusion). Heating may be carried out at about 70°C to about 80°C for at least 20 minutes. By initiating a Vulcan wave sequence, the beads are extruded from the Vulcan ceramic syringe.

[0331] Dry and / or freeze-dried beads may be packaged in moisture-proof packaging such as sealed foil pouches. In certain embodiments, the beads are suspended in the carrier at a volume ratio of about 45:55 or less (beads:carrier), particularly at volume ratios of about 9:91 to 45:55, about 12:88 to about 32:68, or about 16:84 to about 24:76. In these or other embodiments, the beads are suspended in the carrier at a bead concentration of about 50% by weight or less, for example, at concentrations of about 10% to about 50% by weight of beads, about 15% to about 40% by weight of beads, or about 20% to about 30% by weight of beads, with the remainder being the carrier. The carrier may be a non-aqueous carrier, such as an oily carrier. The carrier may be at least one pharmaceutically acceptable oil, including almond oil, castor oil, coconut oil, corn oil, cottonseed oil, linseed oil, mineral oil, olive oil, palm oil, peanut oil, nata oil, safflower oil, sesame oil, silicone oil, soybean oil, and sunflower oil; at least one pharmaceutically acceptable wax, including beeswax, candelilla wax, carnauba wax, and animal oil; or at least one pharmaceutically acceptable lipid, including fatty acids and esters such as lauric acid, oleic acid, ethyl oleate, triethyl citrate, or acetyl triethyl citrate (ATEC). In particular, the carrier is sesame oil or ethyl oleate.

[0332] In certain embodiments, optionally, the final prepared beads suspended in a carrier are then loaded into a very fine diameter subcutaneous needle, such as an 18-30 gauge needle. In certain embodiments, the needle is a 20-27 gauge needle, or an even finer gauge needle, e.g., a 30 gauge needle, depending on the diameter of the dry beads and / or the volume of the carrier. If the pharmaceutical preparation is provided for buttock injection, the subcutaneous needle may be a 21 or 22 gauge needle. If the pharmaceutical preparation is provided for knee injection, the subcutaneous needle may be a 25 gauge needle. Generally, the larger the site to which the depot is to be injected, the smaller the needle gauge (i.e., the larger the needle diameter) may be.

[0333] In certain embodiments, subcutaneous injection needles containing pharmaceutical preparations are packaged separately and sterilized, for example, by gamma irradiation.

[0334] IV. Kit In certain embodiments, the present invention further relates to a kit comprising one or more injectable pharmaceutical preparations and one or more subcutaneous injection needles, comprising a sustained-release biodegradable depot and carrier, as disclosed above or manufactured according to the methods disclosed above. If the kit comprises two or more injectable pharmaceutical preparations, these preparations may be identical or different and may comprise identical or different doses of a tyrosine kinase inhibitor, such as axitinib.

[0335] In certain embodiments, at least one sustained-release biodegradable depot (in the form of beads) is present in a kit in a separate container or pouch from the carrier. In such embodiments, at least one sustained-release biodegradable depot needs to be suspended or mixed in the carrier before injection. For example, in some embodiments, the beads may be stored in a separate compartment from the carrier, and the two compartments are separated from each other, for example, by a foil or other separator between the separate compartments. In this case, to prepare the suspension of beads in the carrier, the separator needs to be removed, punctured, or otherwise opened so that the carrier can surround and suspend the beads. In other embodiments, the carrier and beads are provided in individual containers (e.g., individual vials), the carrier is in contact with the beads, and the suspension of beads in the carrier is provided from a separate container immediately before the physician administers the depot into the patient's joint or bone canal. In other embodiments, at least one sustained-release biodegradable depot is included in a kit already suspended in the carrier.

[0336] In certain embodiments, one or more subcutaneous needles are pre-loaded with a sustained-release injectable pharmaceutical preparation (one or more fibers or beads suspended in a carrier, as disclosed herein). These subcutaneous needles are ready for injection.

[0337] The subcutaneous injection needle(s) pre-loaded with the pharmaceutical preparation(s) may be 18-30 gauge needles. In certain embodiments, the subcutaneous injection needle(s) may be 20-27 gauge needles. The needle diameter is selected based on the size of the sustained-release biodegradable depot and / or the volume of the pharmaceutical preparation for injection in a dry state. Furthermore, the diameter of the subcutaneous injection needle may be selected based on the synovial joint into which the pharmaceutical preparation for injection is deployed. In one embodiment, the kit includes one or more 22 gauge subcutaneous injection needles(s). In such embodiments, each of the one or more pharmaceutical preparation(s) may contain about 15 mg or about 20 mg of a tyrosine kinase inhibitor, such as axitinib or another dose disclosed herein. In yet another embodiment, the kit includes one or more 25 gauge subcutaneous injection needle(s).

[0338] The kit may further include an injection device for injecting an injectable pharmaceutical preparation into a patient's synovial joint, particularly the patient's knee. In certain embodiments, the injection device may be provided and / or packaged separately from one or more subcutaneous needles. In such embodiments, the injection device must be connected to one or more subcutaneous needles before injection. In other embodiments, the kit includes one or more injection devices for injecting an injectable pharmaceutical preparation into a patient's synovial joint, particularly the patient's knee, with each injection device pre-connected to a subcutaneous needle pre-loaded with an injectable pharmaceutical preparation or injection fiber. Therefore, in one embodiment, the present invention relates to a pharmaceutical comprising a subcutaneous needle and an injectable pharmaceutical preparation loaded in an injection device, wherein the subcutaneous needle is pre-connected to the injection device.

[0339] In certain embodiments, the injection device includes a push wire or plunger for dispensing an injectable pharmaceutical preparation from a subcutaneous needle, particularly into the synovial joint. The push wire may be made of nitinol or stainless steel / Teflon. The push wire or plunger allows for easier dispensing of the injectable pharmaceutical preparation from the needle.

[0340] In some embodiments, the injection device and / or injection needle may include a stop function to control the depth of injection.

[0341] In some embodiments, the injection device is a modified Hamilton glass syringe.

[0342] The kit may further contain one or more doses of an injectable drug, in particular at least one other drug, such as an anti-inflammatory agent. The anti-inflammatory agent may be selected from the group consisting of hyaluronic acid and corticosteroids, such as triamcinolone acetonide. In some embodiments, the anti-inflammatory agent is hyaluronic acid. In other embodiments, the anti-inflammatory agent is triamcinolone acetonide. The anti-inflammatory agent may be supplied in a separate injection device connected to a needle, or in a sealed vial that can be drawn through a needle into a syringe or other injection device before administration.

[0343] In some embodiments, one or more injectable pharmaceutical preparations are individually packaged for single-dose administration. In some embodiments, one or more injectable pharmaceutical preparations are individually packaged for single-dose administration in airtight vials, such as ampoules, from which the preparations can be drawn into a syringe or other injection device through a subcutaneous needle before administration.

[0344] The kit may also include an operating manual for physicians administering the injectable pharmaceutical preparation(s). The kit may also include a package insert containing product information.

[0345] The present invention relates in particular to the following further items. 1. A method for treating a joint pathology in a patient who requires treatment for the said joint pathology, The method comprises administering to the patient a sustained-release biodegradable depot containing a hydrogel and a tyrosine kinase inhibitor. The method wherein the depot is administered by injection.

[0346] 2. The method according to item 1, wherein the depot is administered by joint injection.

[0347] 3. The method according to item 1 or 2, wherein the depot is administered by intra-articular or peri-articular injection.

[0348] 4. The method according to any one of items 1 to 3, wherein the depot is administered into the synovial joint of the patient.

[0349] 5. The method according to any one of items 1 to 4, wherein the depot is administered into the synovial joint cavity of the patient.

[0350] 6. The method according to any one of items 1 to 5, wherein the depot is administered to the area of ​​the patient's knee, elbow, fingers, buttocks, shoulder, wrist, ankle, or to the area of ​​the foot, hand, shoulder girdle, rotator cuff, pelvis, spine, or jaw.

[0351] 7. The method according to item 6, wherein the depot is administered to the knee of the patient.

[0352] 8. The method according to any one of items 1 to 7, wherein the depot is administered to the patient's tibiofemoral joint, patellofemoral joint, humeroulnar joint, humeral-radial joint, proximal radioulnar joint, pelvic femoral joint, glenohumeral joint, acromioclavicular joint, distal radioulnar joint, radiocarpal joint, intercarpal joint, metacarpal joint, carpometacarpal joint, intermetacarpal joint, talocrural joint, subtalar joint, tibiofibular joint, talonavicular joint, calcaneocuboid joint, metatarsophalangeal joint, interphalangeal joint of the foot or hand, metacarpophalangeal joint, sternoclavicular joint, costochondral joint, atlantooccipital joint, atlantoaxial joint, costovertebral joint, costotransverse joint, articular joint, sacroiliac joint, or temporomandibular joint.

[0353] 9. The method according to item 8, wherein the depot is administered to the patient's tibiofemoral joint, holofemoral joint, talocrural joint, subtalar joint, metatarsophalangeal joint, interphalangeal joint of the foot or hand, atlantoaxial joint, or metaphyseal joint.

[0354] 10. The method according to item 8 or 9, wherein the depot is administered to the tibiofemoral joint of the patient.

[0355] 11. A method for treating a pathological condition of the bone canal in a patient who requires treatment of the said bone canal, The method comprises administering to the patient a sustained-release biodegradable depot containing a hydrogel and a tyrosine kinase inhibitor. The method wherein the depot is administered by injection.

[0356] 12. The method according to item 11, wherein the depot is administered into or near the bone canal of the patient.

[0357] 13. The method according to item 11 or 12, wherein the depot is administered into or near the carpal tunnel of the patient, or into or near the spinal canal of the patient.

[0358] 14. The method according to any one of items 11 to 13, wherein the depot is administered by epidural injection.

[0359] 15. The method described in any one of items 1 to 14, wherein the injection is an ultrasound-guided injection.

[0360] 16. The method according to any one of items 1 to 15, wherein the depot is administered through a subcutaneous injection needle.

[0361] 17. The method according to item 16, wherein the subcutaneous injection needle is a 20-27 gauge needle.

[0362] 18. The method according to item 16 or 17, wherein the subcutaneous injection needle is a 22 or 25 gauge needle.

[0363] 19. The method according to any one of items 1 to 18, wherein the depot is loaded onto the needle in a dry state.

[0364] 20. The method according to any one of items 1 to 19, wherein the depot is administered once during a treatment period of at least one month.

[0365] 21. The method according to item 20, wherein the treatment period is at least 2 months, at least 3 months, at least 6 months, at least 9 months, or at least 12 months.

[0366] 22. The method according to item 20 or 21, wherein the treatment period is at least 3 months, at least 6 months, or at least 9 months.

[0367] 23. The method according to any one of items 1 to 22, wherein the dose per joint or bone canal administered once during the treatment period is contained in one depot, and the one depot contains one or more units.

[0368] 24. The method according to any one of items 1 to 23, wherein the dose administered once per joint or bone canal during the treatment period is approximately 0.5 mg to approximately 120 mg of the tyrosine kinase inhibitor.

[0369] 25. The method according to item 24, wherein the dose administered once during the treatment period per joint or bone is approximately 1 mg to approximately 50 mg of the tyrosine kinase inhibitor.

[0370] 26. The method according to any one of items 1 to 25, wherein the dose per joint or bone canal administered once during a treatment period of at least three months is about 1 mg to about 50 mg, about 5 mg to about 40 mg, or about 10 mg to about 30 mg of the tyrosine kinase inhibitor.

[0371] 27. The method according to any one of items 1 to 26, wherein the dose administered once per knee during the treatment period is approximately 1 mg to approximately 70 mg of the tyrosine kinase inhibitor.

[0372] 28. The method according to item 27, wherein the dose administered once per knee during the treatment period is approximately 2.5 mg to approximately 60 mg of the tyrosine kinase inhibitor.

[0373] 29. The method according to item 27 or 28, wherein the dose administered once per knee during the treatment period is approximately 3 mg to approximately 45 mg of the tyrosine kinase inhibitor.

[0374] 30. The method according to any one of items 1 to 29, wherein the dose per knee administered once during a treatment period of at least three months is approximately 3 mg to approximately 45 mg, approximately 5 mg to approximately 30 mg, or approximately 10 mg to approximately 25 mg of the tyrosine kinase inhibitor.

[0375] 31. The method according to item 30, wherein the dose administered once per knee during a treatment period of at least three months is about 15 mg or about 20 mg of the tyrosine kinase inhibitor.

[0376] 32. The method according to any one of items 1 to 31, wherein the tyrosine kinase inhibitor is axitinib.

[0377] 33. The method according to any one of items 1 to 32, wherein the depot, after administration to the joint or bone canal, releases a therapeutically effective amount of axitinib over a period of at least about 1 month, at least about 2 months, at least about 3 months, at least about 6 months, at least about 9 months, or at least about 12 months after administration.

[0378] 34. The method according to item 33, wherein the depot, after administration to the joint or bone canal, releases a therapeutically effective amount of axitinib over a period of at least three months.

[0379] 35. The method according to item 33 or 34, wherein the depot, after administration to the joint or bone canal, releases a therapeutically effective amount of axitinib over a period of at least six months.

[0380] 36. The method according to any one of items 1 to 35, wherein axitinib is released from the depot at an average rate of approximately 1 μg / day to approximately 600 μg / day after administration.

[0381] 37. The method according to item 36, wherein axitinib is released from the depot at an average rate of approximately 30 μg / day to approximately 500 μg / day after administration.

[0382] 38. The method according to item 36 or 37, wherein axitinib is released from the depot at an average rate of approximately 100 μg / day to approximately 270 μg / day after administration.

[0383] 39. The method according to any one of items 36-38, wherein axitinib is released from the depot at an average rate of approximately 165 μg / day or approximately 220 μg / day after administration.

[0384] 40. The method according to any one of items 1 to 39, wherein the depot yields an in vitro mean release rate of approximately 100 μg to approximately 500 μg per day in phosphate-buffered saline, or approximately 160 μg to approximately 400 μg per day, and / or approximately 150 μg to approximately 600 μg, or approximately 200 μg to approximately 450 μg of axitinib per day in phosphate-buffered saline, for 90 days at 37°C.

[0385] 41. The method according to any one of items 1 to 40, wherein the depot yields an in vitro cumulative dose of axitinib, with the release of approximately 3 mg to approximately 20 mg or approximately 4.5 mg to approximately 18 mg in phosphate-buffered saline over 30 days at 37°C, and / or approximately 7 mg to approximately 36 mg or approximately 9 mg to approximately 33 mg in phosphate-buffered saline over 60 days at 37°C, and / or approximately 12 mg to approximately 50 mg or approximately 15 mg to approximately 42 mg in phosphate-buffered saline over 90 days at 37°C.

[0386] 42. The method according to any one of items 1 to 41, wherein the depot releases approximately 9% to 26% of axitinib in vitro in phosphate-buffered saline at pH 7.2 at 37°C within 1 month, approximately 21% to 48% of axitinib within 2 months, approximately 34% to 77% of axitinib within 3 months, and approximately 70% to 100% of axitinib within 6 months, along with the octanol top layer.

[0387] 43. The method according to item 42, wherein the depot releases approximately 9% to 16% of axitinib in vitro in phosphate-buffered saline at pH 7.2 at 37°C within 1 month, approximately 21% to 28% of axitinib within 2 months, approximately 34% to 41% of axitinib within 3 months, approximately 70% to 77% of axitinib within 6 months, and approximately 93% to 100% of axitinib within 9 months, along with the octanol top layer.

[0388] 44. The method according to any one of items 1 to 43, wherein the depot releases approximately 1% to approximately 5% of axitinib in vitro in phosphate-buffered saline at pH 7.2 at 37°C within 7 days, approximately 3% to approximately 7% of axitinib within 14 days, approximately 8% to approximately 12% of axitinib within 28 days, and / or approximately 15% to approximately 19% of axitinib within 42 days, along with the octanol top layer.

[0389] 45. The method according to any one of items 1 to 44, wherein the depot provides an average axitinib concentration in the synovial fluid of approximately 150 ng / mL to approximately 600 ng / mL three days after administration, and / or approximately 350 ng / mL to approximately 750 ng / mL seven days after administration, and / or approximately 35 ng / mL to approximately 200 ng / mL fourteen days after administration.

[0390] 46. ​​The method according to item 45, wherein the depot provides an average axitinib concentration of approximately 35 ng / mL to approximately 200 ng / mL in the synovial fluid over a period of 14 days, 1 month, 2 months, or 3 months.

[0391] 47. The method according to any one of items 1 to 46, wherein the depot is in vitro in phosphate-buffered saline at 37°C, pH 7.2, releasing approximately 1% to approximately 15% of the tyrosine kinase inhibitor within 14 days, approximately 5% to approximately 30% of the tyrosine kinase inhibitor within 1 month, approximately 15% to approximately 50% of the tyrosine kinase inhibitor within 2 months, approximately 30% to approximately 80% of the tyrosine kinase inhibitor within 3 months, and approximately 70% to approximately 100% of the tyrosine kinase inhibitor within 6 months, together with the top layer of octanol.

[0392] 48. The method according to any one of items 1 to 47, wherein the unit(s) of the depot are in a dry state before administration and become hydrated when administered into the joint.

[0393] 49. The method of item 48, wherein the diameter of the unit of the depot increases when hydrated in vivo in the joint or in vitro.

[0394] 50. Hydration is measured in vitro in phosphate-buffered saline at pH 7.2, 37°C, after 24 hours, according to the method described in item 49.

[0395] 51. The method according to any one of items 1 to 50, wherein the depot is biodegraded within the joint within approximately 2 to 15 months after administration.

[0396] 52. The method according to item 51, wherein the depot is biodegraded within the joint within approximately 4 to 13 months after administration.

[0397] 53. The method according to item 51 or 52, wherein the depot is biodegraded within the joint within approximately 9 to 12 months after administration.

[0398] 54. The method according to any one of items 1 to 53, wherein the dry depot contains about 0.1% to about 7% by weight of water.

[0399] 55. The method according to any one of items 1 to 54, wherein the dry depot contains about 10% to about 75% by weight of the tyrosine kinase inhibitor and about 25% to about 80% by weight of polymer units, or about 25% to about 60% by weight of the tyrosine kinase inhibitor and about 35% to about 65% by weight of polymer units, or about 45% to about 55% by weight of the tyrosine kinase inhibitor and about 40% to about 60% by weight of polymer units.

[0400] 56. The method according to any one of items 1 to 55, wherein the depot comprises one or more phosphates, borates, or carbonates.

[0401] 57. The method according to any one of items 1 to 56, wherein the depot contains a phosphate derived from the phosphate buffer used during the preparation of the hydrogel.

[0402] 58. The method according to any one of items 1 to 57, wherein the wet hydrogel contains approximately 3% to approximately 20% polyethylene glycol, expressed as polyethylene glycol weight ÷ fluid weight × 100, or approximately 7.5% to approximately 15% polyethylene glycol, expressed as polyethylene glycol weight ÷ fluid weight × 100.

[0403] 59. The method according to any one of items 1 to 58, wherein the hydrogel comprises a polymer network, the polymer network being semi-crystalline in a dry state at or below room temperature and amorphous in a wet state.

[0404] 60. The method according to any one of items 1 to 59, wherein the hydrogel comprises one or more units from polyalkylene glycol, polyethylene glycol, polyethylene oxide, polypropylene oxide, polyvinyl alcohol, poly(vinylpyrrolidone), polylactic acid, polylactic acid-coglycolic acid, random or block copolymers, or combinations or mixtures thereof, or a polymer network comprising one or more units from polyamino acids, glycosaminoglycans, polysaccharides, or proteins.

[0405] 61. The method according to any one of items 1 to 60, wherein the hydrogel comprises a polymer network comprising identical or different crosslinked polymer units.

[0406] 62. The method according to item 61, wherein the crosslinked polymer unit is one or more crosslinked polyethylene glycol units.

[0407] 63. The method according to any one of items 1 to 62, wherein the polymer network comprises polyethylene glycol units having an average molecular weight in the range of about 2,000 to about 100,000 daltons, or about 10,000 to about 60,000 daltons, or about 20,000 to about 40,000 daltons, or about 15,000 to about 30,000 daltons.

[0408] 64. The method according to item 63, wherein the polyethylene glycol units have an average molecular weight of about 15,000 or 20,000 daltons.

[0409] 65. The method according to any one of items 1 to 64, wherein the polymer network comprises one or more crosslinked multi-arm polymer units.

[0410] 66. The method according to item 65, wherein the multi-arm polymer unit comprises one or more 2- to 10-arm polyethylene glycol units, or one or more 4- to 8-arm polyethylene glycol units.

[0411] 67. The method according to item 65 or 66, wherein the multi-arm polymer unit comprises one or more four-arm polyethylene glycol units.

[0412] 68. The method according to item 67, wherein the 4-arm polyethylene glycol units are 4a20kPEG units or 4a40kPEG units.

[0413] 69. The method according to any one of items 65 to 68, wherein the multi-arm polymer unit comprises one or more 8-arm polyethylene glycol units.

[0414] 70. The method according to item 69, wherein the 8-arm polyethylene glycol units are 8a20kPEG units or 8a15kPEG units.

[0415] 71. The method according to any one of items 1 to 70, wherein the polymer network comprises polyethylene glycol units of both four-arm and eight-arm configurations.

[0416] 72. The method according to item 71, wherein the 4-arm polyethylene glycol unit is a 4a20kPEG unit and the 8-arm polyethylene glycol unit is an 8a20kPEG unit.

[0417] 73. The method according to any one of items 1 to 72, wherein the polymer network is formed by reacting an electrophilic group-containing multi-arm polymer precursor with a nucleophilic group-containing multi-arm polymer precursor.

[0418] 74. The method according to item 73, wherein the nucleophilic group is an amine group.

[0419] 75. The method according to item 73 or 74, wherein the electrophilic group is an activated ester group.

[0420] 76. The method according to item 75, wherein the electrophilic group is an N-hydroxysuccinimidyl (NHS) group.

[0421] 77. The method according to item 76, wherein the electrophilic group is succinimidyl glutarate (SG) or succinimidyl azelaic acid (SAZ) group.

[0422] 78. The method according to any one of items 1 to 77, wherein the polymer network is obtained by reacting 4a20kPEG-SG or 4a20kPEG-SAZ with 8a20kPEG-NH2 in a weight ratio of about 2:1 or less.

[0423] 79. The method according to any one of items 1 to 78, wherein the tyrosine kinase inhibitor is dispersed in the hydrogel as tyrosine kinase inhibitor particles.

[0424] 80. The method according to item 79, wherein the tyrosine kinase inhibitor particles are micronized particles.

[0425] 81. The method according to item 80, wherein the micronized particles are micronized axitinib particles.

[0426] 82. The method according to item 80 or 81, wherein the pulverized particles have a D90 of less than approximately 10 μm and a D100 of less than approximately 20 μm.

[0427] 83. The method according to any one of items 79 to 82, wherein the depot is biodegraded in the joint or the bone canal before or approximately simultaneously with the complete solubilization of the tyrosine kinase inhibitor particles contained in the depot.

[0428] 84. The method according to any one of items 1 to 83, wherein the entire amount of the tyrosine kinase inhibitor contained in the depot is released before the complete degradation of the depot in the joint or bone canal.

[0429] 85. The method according to any one of items 1 to 84, wherein the depot is in the form of at least one sustained-release biodegradable fiber.

[0430] 86. The method according to item 85, wherein the at least one fiber has an essentially cylindrical shape.

[0431] 87. The method according to item 85 or 86, wherein the at least one fiber in a dry state has an average length of about 5 mm to about 15 mm and an average diameter of about 0.10 mm to about 0.50 mm, or an average length of about 6.5 mm to about 14 mm and an average diameter of about 0.15 mm to about 0.45 mm, or an average length of about 11 mm to about 13.5 mm and an average diameter of about 0.30 mm to about 0.40 mm.

[0432] 88. The method according to items 85 to 87, wherein the at least one hydrated fiber has an average length of about 7 mm to about 25 mm and an average diameter of about 0.30 mm to about 0.80 mm, or an average length of about 9.5 mm to about 18 mm and an average diameter of about 0.35 mm to about 0.75 mm, or an average length of about 10 mm to about 15.5 mm and an average diameter of about 0.40 mm to about 0.70 mm.

[0433] 89. The method according to any one of items 85 to 88, wherein the at least one fiber is obtained by preparing a mixture comprising a hydrogel precursor and a tyrosine kinase inhibitor, filling the mixture into a tube or mold, gelling the mixture in the tube or mold, thereby providing the hydrogel in the form of a fiber, or by preparing a mixture comprising a hydrogel precursor and a tyrosine kinase inhibitor, heating and melting the mixture and extruding it into a strand, and cutting the strand.

[0434] 90. The method according to any one of items 85 to 89, wherein one fiber contains the tyrosine kinase inhibitor in an amount of at least about 10 μg, or at least 100 μg, or at least 250 μg, or at least 500 μg, or about 10 μg to about 1200 μg.

[0435] 91. The method according to item 90, wherein one fiber contains an amount of axitinib ranging from approximately 100 μg to approximately 800 μg.

[0436] 92. The method according to item 90 or 91, wherein one fiber contains axitinib in an amount of approximately 250 μg to approximately 600 μg, approximately 300 μg to approximately 500 μg, or approximately 380 μg to approximately 460 μg.

[0437] 93. The method according to any one of items 1 to 84, wherein the depot is in the form of a plurality of sustained-release biodegradable beads.

[0438] 94. The method according to item 93, wherein the beads are spherical or non-spherical particles.

[0439] 95. The method according to item 93 or 94, wherein the beads have a narrow particle size distribution.

[0440] 96. The method according to any one of items 93 to 95, wherein the beads have a D50 of less than about 220 μm or a D90 of less than about 300 μm.

[0441] 97. The method according to any one of items 93 to 96, wherein the beads in a dry state have an average volume particle size of about 50 μm to about 500 μm, about 100 μm to about 300 μm, or about 200 μm, as determined by scanning electron microscope (SEM).

[0442] 98. The method according to any one of items 93 to 97, wherein the hydrated beads have an average volume particle size of about 100 μm to about 1000 μm, about 200 μm to about 600 μm, or about 400 μm, as determined by a light microscope.

[0443] 99. The method according to any one of items 93 to 98, wherein the beads are prepared by preparing a mixture comprising a hydrogel precursor and a tyrosine kinase inhibitor, and the mixture is extruded from a static mixer into a tube having a tangential oil flow to provide a hydrogel in the form of beads containing tyrosine kinase inhibitor particles.

[0444] 100. The method according to any one of items 93 to 98, wherein the beads are prepared by preparing a mixture comprising a hydrogel precursor and a tyrosine kinase inhibitor, filling the mixture into a syringe or mold, allowing the mixture to gel, and extruding it through at least one mesh screen to provide a hydrogel in the form of beads.

[0445] 101. The method according to any one of items 93 to 98, wherein the beads are prepared by preparing a mixture comprising a hydrogel precursor and a tyrosine kinase inhibitor, filling the mixture into a mold having a microcavity, and allowing the mixture to gel in the microcavity to provide a hydrogel in the form of beads.

[0446] 102. The method according to any one of items 93 to 98, wherein the beads are made by preparing a mixture comprising a hydrogel precursor and a tyrosine kinase inhibitor, heating and melting the mixture and extruding it into a strand, cutting or pelletizing the strand to provide a hydrogel in the form of beads.

[0447] 103. The method according to any one of items 93 to 102, wherein the beads are prepared by preparing a mixture comprising a hydrogel precursor and a tyrosine kinase inhibitor, heating the mixture, and extruding the mixture into an oil bath to provide a hydrogel in the form of beads.

[0448] 104. The method according to any one of items 99 to 103, wherein the beads are dried and / or freeze-dried.

[0449] 105. The method according to any one of items 93 to 104, wherein the beads contain the tyrosine kinase inhibitor in an amount of about 0.01 μg to about 50 μg per bead.

[0450] 106. The method according to item 105, wherein the beads contain the tyrosine kinase inhibitor in an amount of about 0.5 μg to about 12 μg per bead.

[0451] 107. The method according to item 105 or 106, wherein the beads contain axitinib in an amount of approximately 1 μg to approximately 8 μg per bead, approximately 1.5 μg to approximately 5 μg per bead, or approximately 2 μg to approximately 4 μg per bead.

[0452] 108. The method according to any one of items 93 to 107, wherein the beads do not aggregate during administration.

[0453] 109. The method according to any one of items 93 to 108, wherein the beads are suspended in a carrier.

[0454] 110. The method according to item 109, wherein the beads are suspended in a carrier at a concentration of about 10% to about 50% by weight, about 15% to about 40% by weight, or about 20% to about 30% by weight, the remainder of which is the carrier.

[0455] 111. The method according to item 109 or 110, wherein the carrier is a non-aqueous carrier such as an oily carrier.

[0456] 112. The method according to item 111, wherein the oily carrier is a natural or synthetic oil.

[0457] 113. The method according to any one of items 109 to 112, wherein the carrier is at least one pharmaceutically acceptable oil, including almond oil, castor oil, coconut oil, corn oil, cottonseed oil, linseed oil, linseed oil, corn oil, mineral oil, olive oil, palm oil, peanut oil, nata oil, safflower oil, sesame oil, silicone oil, soybean oil, and sunflower oil; at least one pharmaceutically acceptable wax, including beeswax, candelilla wax, carnauba wax, and animal oil; or at least one pharmaceutically acceptable lipid, including fatty acids and esters such as lauric acid, oleic acid, ethyl oleate, triethyl citrate, or acetyl triethyl citrate (ATEC).

[0458] 114. The method according to item 113, wherein the carrier is sesame oil or ethyl oleate.

[0459] 115. The method according to any one of items 1 to 114, wherein the pathology of the joint or the pathology of the bone canal is an inflammatory pathology.

[0460] 116. The method according to any one of items 1 to 115, wherein the pathology of the joint or the pathology of the bone canal is angiogenesis.

[0461] 117. The method according to any one of items 1-10 and 15-116, wherein the pathological condition of the joint is arthropathy.

[0462] 118. The method according to item 117, wherein the arthropathy is reactive arthropathy, enteroarthropathy, diabetic arthropathy, neuropathic arthropathy, or spondyloarthropathy.

[0463] 119. The method according to any one of items 1-10 and 15-118, wherein the pathological condition of the joint is arthritis.

[0464] 120. The method according to item 119, wherein the arthritis is infectious or non-infectious arthritis.

[0465] 121. The method according to item 119 or 120, wherein the arthritis is osteoarthritis (OA), rheumatoid arthritis (RA), juvenile arthritis (JA), psoriatic arthritis (PsA), gouty or pseudogouty arthritis, systemic lupus erythematosus (SLE), or ankylosing spondylitis (AS).

[0466] 122. The method according to any one of items 119 to 121, wherein the arthritis is osteoarthritis (OA).

[0467] 123. The method according to any one of items 11 to 116, wherein the pathological condition of the bone canal is related to stenosis of the bone canal.

[0468] 124. The method according to any one of items 11-116 and 123, wherein the pathological condition of the bone canal is accompanied by compression of nerve tissue.

[0469] 125. The method according to any one of items 11-116, 123, and 124, wherein the pathological condition of the bone canal is carpal tunnel syndrome.

[0470] 126. The method according to any one of items 11-116, 123, and 124, wherein the pathological condition of the bone canal is spinal stenosis.

[0471] 127. The method according to any one of items 1 to 126, wherein the pathology of the joint or the pathology of the bone canal is a disease mediated by at least one receptor tyrosine kinase (RTK).

[0472] 128. The method according to item 127, wherein the at least one receptor tyrosine kinase (RTK) is VEGFR-1 and / or VEGFR-2.

[0473] 129. The method described in any one of items 1 to 128, wherein the aforementioned pathological condition is associated with TRPV1 expression.

[0474] 130. The method described in any one of items 1 to 129, wherein the aforementioned pathological condition is pain.

[0475] 131. The method described in any one of items 1 to 130, wherein the treatment is effective in reducing pain.

[0476] 132. The method described in any one of items 1 to 131, wherein the treatment is effective in reducing inflammation.

[0477] 133. The method according to item 132, wherein the treatment is effective in reducing the expression of at least one inflammatory marker.

[0478] 134. The method according to item 132 or 133, wherein the treatment is effective in reducing the expression of at least one cytokine.

[0479] 135. The method according to item 133 or 134, wherein the at least one cytokine is at least one interferon (IFN), interleukin (IL), and / or chemokine of the CXC family.

[0480] 136. The method according to item 135, wherein the at least one cytokine is IFN-γ, IL-1β, IL-4, IL-5, IL-10, or CXCL1.

[0481] 137. The method according to any one of items 133-136, wherein the expression of the at least one inflammatory marker is reduced by at least 10%, at least 20%, or at least 25% within a period of 14 days, or 1 month, or 2 months after administration.

[0482] 138. The method according to any one of items 1-10, 15-122, and 127-137, wherein the treatment is effective in reducing hypervascularity associated with arthritis.

[0483] 139. The method according to any one of items 1-10, 15-122, and 127-138, wherein the treatment is effective in delaying, halting, or improving progressive structural tissue damage associated with arthritis.

[0484] 140. The method according to any one of items 1-10, 15-122, and 127-139, wherein the treatment is effective in delaying, halting, or improving joint function loss associated with arthritis.

[0485] 141. The method according to any one of items 1-10, 15-122, and 127-140, wherein the treatment is effective in improving joint function associated with arthritis.

[0486] 142. The method described in any one of items 11-116, 123-125, and 127-137, which is effective in delaying, stopping, or improving tingling, weakness, or numbness of the fingers associated with carpal tunnel syndrome.

[0487] 143. The method described in any one of items 11-116, 123-125, and 127-137 and 142, wherein the treatment is effective in reducing compression of the median nerve associated with carpal tunnel syndrome.

[0488] 144. The method described in any one of items 11-116, 123, 124, and 126-137, which is effective in delaying, stopping, or improving stabbing pain, weakness, or numbness in the arm or leg associated with spinal stenosis.

[0489] 145. The method described in any one of items 11-116, 123, 124, 126-137, and 144, which is effective in reducing compression of the spinal cord or nerve roots associated with spinal stenosis.

[0490] 146. The method according to any one of items 1 to 145, wherein the sustained-release biodegradable depot has low cartilage toxicity during administration.

[0491] 147. The method described in item 146, wherein the chondrogenicity in human chondrocytes is less than 10%, less than 8%, or less than 5%.

[0492] 148. The method according to any one of items 1 to 147, wherein the patient has a history of anti-inflammatory treatment.

[0493] 149. The method according to any one of items 1 to 148, wherein an anti-inflammatory agent is administered simultaneously with the depot.

[0494] 150. The method according to item 149, wherein the anti-inflammatory agent may be selected from the group consisting of hyaluronic acid and corticosteroids, such as triamcinolone acetonide.

[0495] 151. The method according to item 149 or 150, wherein the anti-inflammatory agent is administered by intra-articular or peri-articular injection, or by injection into or near the bone canal, or by oral administration.

[0496] 152. The method according to item 1, wherein the depot is administered intraarticularly to the synovial joint of the patient, and the dose per joint administered once during a treatment period of at least three months is about 0.5 mg to about 120 mg of the tyrosine kinase inhibitor, the hydrogel comprises a polymer network containing one or more crosslinked 4- to 8-arm polyethylene glycol units, the tyrosine kinase inhibitor is axitinib, and the depot is in the form of one or more sustained-release biodegradable fibers, each of which contains at least 10 μg or at least 50 μg of axitinib, for example, in an amount of about 100 μg to about 800 μg.

[0497] 153. The method according to item 1, wherein the depot is administered intraarticularly to the synovial joint of the patient, and the dose per joint administered once during a treatment period of at least three months is about 0.5 mg to about 120 mg of the tyrosine kinase inhibitor, the hydrogel comprises a polymer network containing one or more crosslinked 4-8 arm polyethylene glycol units, the tyrosine kinase inhibitor is axitinib, and the depot is in the form of a plurality of sustained-release biodegradable beads, the beads containing at least 0.1 μg or at least 0.5 μg of axitinib, for example, in an amount of about 1 μg to about 8 μg per bead.

[0498] 154. The method according to item 1, wherein the depot is administered to the knee of the patient, and the dose per knee, administered once during a treatment period of at least three months, is about 10 mg to about 25 mg of the tyrosine kinase inhibitor, the hydrogel comprises a polymer network containing one or more crosslinked 4- to 8-arm polyethylene glycol units, the tyrosine kinase inhibitor is axitinib, and the depot is in the form of one or more sustained-release biodegradable fibers, each of which fiber(s) contains at least 10 μg or at least 50 μg, for example, about 100 μg to about 800 μg of axitinib.

[0499] 155. The method according to item 1, wherein the depot is administered to the knee of the patient, and the dose per knee, administered once during a treatment period of at least three months, is about 10 mg to about 25 mg of the tyrosine kinase inhibitor, the hydrogel comprises a polymer network containing one or more crosslinked 4-8 arm polyethylene glycol units, the tyrosine kinase inhibitor is axitinib, and the depot is in the form of a plurality of sustained-release biodegradable beads, the beads containing at least 0.1 μg or at least 0.5 μg of axitinib, for example, in an amount of about 1 μg to about 8 μg per bead.

[0500] 156. A method of treating a human patient, as described in any one of items 1 through 155.

[0501] 157. A pharmaceutical preparation for injection, (i) A sustained-release biodegradable depot containing a hydrogel and a tyrosine kinase inhibitor, (ii) The pharmaceutical preparation comprising a carrier.

[0502] 158. The injectable pharmaceutical composition according to item 157, wherein the depot is in the form of a plurality of sustained-release biodegradable beads.

[0503] 159. The pharmaceutical composition for injection according to item 157 or 158, wherein the beads are spherical or non-spherical particles.

[0504] 160. The injectable pharmaceutical composition according to any one of items 157 to 159, wherein the beads have a narrow particle size distribution.

[0505] 161. The pharmaceutical composition for injection according to any one of items 157 to 160, wherein the beads have a D50 of less than about 220 μm or a D90 of less than about 300 μm.

[0506] 162. The pharmaceutical composition for injection according to any one of items 157 to 161, wherein the beads in a dry state have an average volume particle size of about 50 μm to about 500 μm, about 100 μm to about 300 μm, or about 200 μm, as determined by scanning electron microscope (SEM).

[0507] 163. The hydrated beads, when determined by light microscopy, have an average volume particle size of about 100 μm to about 1000 μm, about 200 μm to about 600 μm, or about 400 μm, according to any one of items 157 to 162, for injection.

[0508] 164. The injectable pharmaceutical composition according to any one of items 157 to 163, wherein the beads contain the tyrosine kinase inhibitor in an amount of about 0.01 μg to about 50 μg per bead.

[0509] 165. The injectable pharmaceutical composition according to item 164, wherein the beads contain the tyrosine kinase inhibitor in an amount of about 0.5 μg to about 12 μg per bead.

[0510] 166. The injectable pharmaceutical composition according to item 164 or 165, wherein the beads contain the tyrosine kinase inhibitor in an amount of about 1 μg to about 8 μg per bead, about 1.5 μg to about 5 μg per bead, or about 2 μg to about 4 μg per bead.

[0511] 167. The injectable pharmaceutical composition according to any one of items 157 to 166, wherein the beads do not aggregate in the carrier.

[0512] 168. The pharmaceutical composition for injection according to any one of items 157 to 167, wherein the beads are suspended in the carrier.

[0513] 169. The pharmaceutical composition for injection according to item 168, wherein the beads are suspended in a carrier at a concentration of about 10% to about 50% by weight of beads, about 15% to about 40% by weight of beads, or about 20% to about 30% by weight of beads, the remainder being the carrier.

[0514] 170. (i) Approximately 100 to 400,000 beads, approximately 10,000 to 100,000 beads, or approximately 40,000 to 70,000 beads in a carrier, for example, (ii) The pharmaceutical composition for injection according to any one of items 157 to 167, comprising approximately 0.1 mL to approximately 5 mL of the carrier, approximately 0.5 mL to approximately 3 mL, or approximately 1 mL of the carrier suspended in it.

[0515] 171. (i) Beads weighing approximately 0.008g to 2g, beads weighing approximately 0.1g to 1g, or beads weighing approximately 0.2g to 0.5g, (ii) The pharmaceutical composition for injection according to any one of items 157 to 170, comprising approximately 0.1 mL to approximately 5 mL of the carrier, approximately 0.5 mL to approximately 3 mL, or approximately 1 mL of the carrier suspended in it.

[0516] 172. The pharmaceutical composition for injection according to any one of items 157 to 171, wherein the carrier is a non-aqueous carrier such as an oily carrier.

[0517] 173. The injectable pharmaceutical composition according to item 172, wherein the oily carrier is liquid at 15°C or higher, such as at room temperature and human body temperature.

[0518] 174. The injectable pharmaceutical composition according to item 172 or 173, wherein the oily carrier has a boiling point above body temperature.

[0519] 175. The injectable pharmaceutical composition according to item 174, wherein the oily carrier has a boiling point of over 50°C, over 70°C, over 100°C, or over 150°C.

[0520] 176. The injectable pharmaceutical composition according to any one of items 172 to 175, wherein the oily carrier has a viscosity of less than about 120 mPa·s, less than about 100 mPa·s, or less than about 85 mPa·s at 20°C.

[0521] 177. The oily carrier is approximately 1.5 g / cm³ 3 Less than approximately 1.0 g / cm³ 3 Less than approximately 0.95 g / cm³ 3 Less than, or approximately 0.92 g / cm³ 3 A pharmaceutical composition for injection according to any one of items 172 to 176, having a density less than 176.

[0522] 178. The pharmaceutical composition for injection according to any one of items 172 to 177, wherein the oily carrier is a natural or synthetic oil.

[0523] 179. The injectable pharmaceutical composition according to any one of items 172 to 178, wherein the oily carrier is a vegetable oil.

[0524] 180. The injectable pharmaceutical composition according to any one of items 157 to 179, wherein the carrier is at least one pharmaceutically acceptable oil, including almond oil, castor oil, coconut oil, corn oil, cottonseed oil, linseed oil, linseed oil, corn oil, mineral oil, olive oil, palm oil, peanut oil, nata oil, safflower oil, sesame oil, silicone oil, soybean oil, and sunflower oil; at least one pharmaceutically acceptable wax, including beeswax, candelilla wax, carnauba wax, and animal oil; or at least one pharmaceutically acceptable lipid, including fatty acids and esters such as lauric acid, oleic acid, ethyl oleate, triethyl citrate, or acetyl triethyl citrate (ATEC).

[0525] 181. The injectable pharmaceutical composition according to item 180, wherein the carrier is sesame oil or ethyl oleate.

[0526] 182. The pharmaceutical composition for injection according to any one of items 157 to 181, wherein the carrier provides axitinib solubility of less than about 160 μg / mL, less than about 100 μg / mL, less than about 50 μg / mL, or less than about 20 μg / mL.

[0527] 183. A pharmaceutical composition for injection according to any one of items 157 to 182, further comprising at least one pharmaceutically acceptable excipient.

[0528] 184. The injectable pharmaceutical composition according to item 183, wherein the at least one pharmaceutically acceptable excipient is selected from the group consisting of antioxidants, free radical scavengers, pH modifiers, preservatives, reducing agents, solubility enhancers, stabilizers, such as UV stabilizers, and viscosity enhancers.

[0529] 185. The injectable pharmaceutical composition according to item 183 or 184, wherein the at least one pharmaceutically acceptable excipient is selected from the group consisting of alginate, calcium phosphate, calcium silicate, carboxymethylcellulose, cellulose, dextrose, gelatin, gum arabic, lactose, mannitol, methylcellulose, microcrystalline cellulose, polyethylene glycol, polysorbate 20, polysorbate 80, polyvinylpyrrolidone, physiological saline, sorbitol, starch, sucrose, and tragacanth.

[0530] 186. The pharmaceutical composition for injection according to item 157, wherein the depot is in the form of a plurality of sustained-release biodegradable beads, the hydrogel comprises a polymer network containing one or more crosslinked 4- to 8-arm polyethylene glycol units, the tyrosine kinase inhibitor is axitinib, the beads contain axitinib in an amount of at least 0.1 μg or at least 0.5 μg per bead, for example, about 1 μg to about 8 μg, and the carrier is sesame oil or ethyl oleate.

[0531] 187. A method for producing an injectable pharmaceutical preparation comprising a sustained-release biodegradable depot and carrier as described in any one of items 157 to 186, I. The steps of forming a hydrogel containing a polymer network and tyrosine kinase inhibitor particles dispersed in the hydrogel, and shaping the hydrogel into beads, and optionally, II. The method comprising the step of suspending the beads in the carrier.

[0532] 188. The method according to item 187, wherein the tyrosine kinase inhibitor particles are micronized and / or uniformly dispersed within the hydrogel.

[0533] 189. The method according to item 188, wherein the micronized particles are micronized axitinib particles.

[0534] 190. The method according to item 188 or 189, wherein the pulverized particles have a D90 of less than about 10 μm and a D100 of less than about 20 μm.

[0535] 191. The method according to any one of items 187 to 190, wherein the polymer network is formed by crosslinking multi-arm polyethylene glycol units.

[0536] 192. The method according to any one of items 187 to 191, wherein the method comprises the steps of mixing and reacting electrophilic group-containing multi-arm polyethylene glycol with nucleophilic group-containing multi-arm polyethylene glycol in a buffer in the presence of tyrosine kinase inhibitor particles, and gelling the mixture.

[0537] 193. The method of item 192, comprising extruding the mixture from a static mixer into a tube having a tangential oil flow to obtain beads before it has completely gelled, and recovering the obtained beads.

[0538] 194. The method according to item 193, wherein the mixture is extruded using a 27-gauge or 30-gauge needle.

[0539] 195. The method according to item 193 or 194, wherein the mixture is extruded at an extrusion rate of about 0.3 mL / min and an oil flow rate of about 1 mL / min.

[0540] 196. The method of item 192, comprising filling the mixture into a syringe or mold and allowing the mixture to gel before complete gelation.

[0541] 197. The method according to item 196, wherein the mixture is gelled in a syringe and extruded from the syringe through at least one mesh screen to obtain beads.

[0542] 198. The method according to item 197, wherein the gel is extruded through one or more mesh screens having different mesh sizes, and the resulting beads are sieved.

[0543] 199. The method according to item 197, wherein the gel is extruded through a 3D printed mesh screen and cut to obtain beads.

[0544] 200. The method according to item 192, wherein the mixture is gelled in a thin sheet mold to obtain a gel sheet, which is removed from the mold and cut using a mesh screen to obtain beads.

[0545] 201. The method according to item 192, wherein the mixture is gelled in a mold having microcavities to obtain beads.

[0546] 202. The method according to any one of items 187 to 191, wherein the method comprises the steps of mixing electrophilic group-containing multi-arm polyethylene glycol powder with nucleophilic group-containing multi-arm polyethylene glycol powder in the presence of the tyrosine kinase inhibitor, and heating the mixture.

[0547] 203. The method according to item 202, wherein the mixture is melt-extruded to obtain strands, which are then cut or pelletized to obtain beads.

[0548] 204. The method according to item 202, wherein the mixture is mixed and heated in a ceramic syringe under nitrogen and extruded into an oil bath to obtain beads.

[0549] 205. The method according to item 204, wherein the mixture is heated at approximately 70°C to approximately 80°C for approximately 20 to approximately 30 minutes.

[0550] 206. The method according to any one of items 187 to 205, wherein the obtained beads are dried and / or freeze-dried.

[0551] 207. The method according to any one of items 187 to 206, wherein the beads are suspended in the carrier at a concentration of about 10% to about 50% by weight of beads, about 15% to about 40% by weight of beads, or about 20% to about 30% by weight of beads, the remainder being the carrier.

[0552] 208.III. The method according to any one of items 187 to 207, further comprising the step of loading the pharmaceutical preparation into a subcutaneous injection needle.

[0553] 209. The method according to item 208, wherein the subcutaneous injection needle is a 20-27 gauge needle.

[0554] 210. The method according to item 208 or 209, wherein the subcutaneous injection needle is a 22-25 gauge needle.

[0555] 211. A kit comprising one or more injectable pharmaceutical preparations, each containing a sustained-release biodegradable depot and carrier according to any one of items 157-186, or manufactured according to the methods of items 187-210, and one or more subcutaneous injection needles.

[0556] 212. The kit according to item 211, wherein the at least one sustained-release biodegradable depot is contained in a separate container or pouch from the carrier.

[0557] 213. The kit according to item 211, wherein at least one sustained-release biodegradable depot is suspended in the carrier.

[0558] 214. The kit described in item 213, wherein each of the one or more subcutaneous injection needles is pre-loaded with one type of injectable pharmaceutical preparation.

[0559] 215. The subcutaneous injection needle is a 20-27 gauge needle, as described in any one of items 211-214.

[0560] 216. The kit described in item 215, wherein the subcutaneous injection needle is a 22 or 25 gauge needle.

[0561] 217. A kit according to any one of items 211 to 216, further comprising an injection device for injecting the aforementioned pharmaceutical preparation for injection.

[0562] 218. The kit according to item 217, wherein the injection device is provided in the kit separately from the one or more subcutaneous injection needles.

[0563] 219. The kit according to item 217, wherein the injection device is pre-connected to a subcutaneous injection needle that is pre-loaded with an injectable pharmaceutical preparation.

[0564] 220. The kit according to any one of items 217 to 219, wherein the injection device includes a push wire or plunger for dispensing the subcutaneous injection pharmaceutical preparation from the subcutaneous injection needle.

[0565] 221. A method for reducing pain in patients who require pain reduction, The method comprising administering to the patient a therapeutically effective amount of an injectable pharmaceutical preparation described in any one of items 157 to 186 by injection.

[0566] 222. A method for reducing inflammation in patients who require reduction of inflammation, The method comprising administering to the patient a therapeutically effective amount of an injectable pharmaceutical preparation described in any one of items 157 to 186 by injection.

[0567] 223. A method for reducing hypervascularity associated with arthritis in patients requiring reduction of such hypervascularity, The method comprising administering to the patient a therapeutically effective amount of an injectable pharmaceutical preparation described in any one of items 157 to 186 by joint injection.

[0568] 224. A method for delaying, halting, or improving progressive structural tissue damage associated with arthritis in patients who require such delay, halting, or improvement, The method comprising administering to the patient a therapeutically effective amount of an injectable pharmaceutical preparation described in any one of items 157 to 186 by joint injection.

[0569] 225. Methods for delaying, halting, or improving joint function loss associated with arthritis in patients who require such delay, halting, or improvement; The method comprising administering to the patient a therapeutically effective amount of an injectable pharmaceutical preparation described in any one of items 157 to 186 by joint injection.

[0570] 226. A method for improving joint function in patients who require improvement of joint function related to arthritis, The method comprising administering to the patient a therapeutically effective amount of an injectable pharmaceutical preparation described in any one of items 157 to 186 by joint injection.

[0571] 227. A method for delaying, cessating, or improving tingling, weakness, or numbness in the fingers associated with carpal tunnel syndrome in patients who require such delay, cessation, or improvement; The method comprising administering to the patient a therapeutically effective amount of an injectable pharmaceutical preparation described in any one of items 157 to 186 by injection into or near the carpal tunnel.

[0572] 228. A method for reducing compression of the median nerve in patients who require reduction of compression related to carpal tunnel syndrome, The method comprising administering to the patient a therapeutically effective amount of an injectable pharmaceutical preparation described in any one of items 157 to 186 by injection into or near the carpal tunnel.

[0573] 229. A method for delaying, cessating, or improving stabbing pain, weakness, or numbness in the arm or leg associated with spinal stenosis in patients who require such delay, cessation, or improvement, The method comprising administering to the patient a therapeutically effective amount of an injectable pharmaceutical preparation described in any one of items 157 to 186 by epidural injection.

[0574] 230. A method for reducing compression on the spinal cord or nerve roots in patients who require reduction of compression on the spinal cord or nerve roots related to spinal stenosis, The method comprising administering to the patient a therapeutically effective amount of an injectable pharmaceutical preparation described in any one of items 157 to 186 by epidural injection.

[0575] 231. A sustained-release biodegradable depot comprising a hydrogel and a tyrosine kinase inhibitor for use in the treatment of joint pathologies according to any one of the methods described in items 1-10, 15-122, 127-141, and 146-156.

[0576] 232. A sustained-release biodegradable depot comprising a hydrogel and a tyrosine kinase inhibitor for use in the treatment of osteochondral pathologies according to any one of the methods described in items 11-16, 123-137, 142-151, and 156.

[0577] 233. Use of a sustained-release biodegradable depot comprising a hydrogel and a tyrosine kinase inhibitor in the preparation of a pharmaceutical product for the treatment of joint conditions by any one of the methods described in items 1-10, 15-122, 127-141, and 146-156.

[0578] 234. Use of a sustained-release biodegradable depot containing a hydrogel and a tyrosine kinase inhibitor in the preparation of a pharmaceutical product for the treatment of joint conditions by any one of the methods described in items 11-16, 123-137, 142-151, and 156.

[0579] 235. The method according to items 1 to 156, wherein the tyrosine kinase inhibitor is a polymorph of axitinib.

[0580] 236. The method according to item 235, wherein the polymorph of axitinib is polymorph IV.

[0581] 237. The axitinib is found in an XRD pattern containing at least three, or at least four, or at least five characteristic 2θ° peaks selected from 2θ° at 8.3, 15.6, 16.5, 18.6, 21.0, 23.1, 24.1, and 26.0 (all values ​​±0.3), and / or in a DMSO solvent containing chemical shifts of 26.1, 114.7, 154.8, and 167.8, each shift ±0.2 ppm. 13 13C NMR and / or chemical shifts of 171.1, 153.2, 142.6, 139.5, 131.2, 128.1, and 126.3, each with a range of ±0.2 ppm. 13 The method according to item 235, characterized by 13C solid-state NMR and / or by DSC isotherms containing two endothermic peaks between 213°C and 217°C (peak 1) and 219°C and 224°C (peak 2).

[0582] 238. The method according to item 235, wherein the axitinib is characterized by a powder X-ray diffraction pattern including at least two, e.g., at least three, or at least four, or at least five peaks at diffraction angles (2θ) of 8.90, 9.40, 9.50, 12.0, 14.60, 15.25, 15.75, 17.80, 19.30, 20.65, 24.95, and 26.10 (all values ​​±0.2). In particular, the axitinib used to prepare a depot according to this embodiment of the present invention may be characterized by a powder X-ray diffraction pattern including peaks at diffraction angles (2θ) of 8.90, 12.0, 14.60, 15.75, and 19.30 (all ±0.2), and / or may be characterized by a DSC peak at about 221°C with a scanning speed of 5°C / min (over the range of 25–300°C).

[0583] 239. The method according to item 235, wherein the axitinib is a cocrystal.

[0584] 240. The method according to item 239, wherein the axitinib is a cocrystal of axitinib and a carboxylic acid.

[0585] 241. The injectable preparation according to any one of items 157 to 186, wherein the tyrosine kinase inhibitor is a polymorph of axitinib.

[0586] 242. The injectable preparation described in item 241, wherein the polymorph of axitinib is polymorph IV.

[0587] 243. The axitinib is found to have an XRD pattern containing at least three, or at least four, or at least five characteristic 2θ° peaks selected from 2θ° at 8.3, 15.6, 16.5, 18.6, 21.0, 23.1, 24.1, and 26.0 (all values ​​±0.3), and / or a chemical shift in DMSO solvent containing 26.1, 114.7, 154.8, and 167.8, each with a shift of ±0.2 ppm. 13 14C NMR and / or chemical shifts of 171.1, 153.2, 142.6, 139.5, 131.2, 128.1, and 126.3, each with a range of ±0.2 ppm. 13 The injectable preparation according to item 241, characterized by 13C solid-state NMR and / or by DSC isotherms containing two endothermic peaks between 213°C and 217°C (peak 1) and 219°C and 224°C (peak 2).

[0588] 244. The injectable preparation according to item 241, wherein the axitinib is characterized by a powder X-ray diffraction pattern having at least two, for example, at least three, or at least four, or at least five peaks at diffraction angles (2θ) of 8.90, 9.40, 9.50, 12.0, 14.60, 15.25, 15.75, 17.80, 19.30, 20.65, 24.95, and 26.10 (all ±0.2). In particular, the axitinib used to prepare the depot according to this embodiment of the present invention may be characterized by a powder X-ray diffraction pattern including peaks at diffraction angles (2θ) of 8.90, 12.0, 14.60, 15.75, and 19.30 (all ±0.2), and / or by a DSC peak at approximately 221°C with a scanning speed of 5°C / min (over a range of 25–300°C).

[0589] 245. The injectable preparation according to item 241, wherein the axitinib is a cocrystal.

[0590] 246. The injectable preparation according to item 245, wherein the axitinib is a cocrystal of axitinib and a carboxylic acid. [Examples]

[0591] The following examples are included to illustrate specific aspects and embodiments of the invention as described in the claims. However, those skilled in the art should understand that the following description is illustrative and should not be construed as limiting the invention in any way.

[0592] Example 1 Preparation of axitinib depot Axitinib depots of some embodiments of the present invention are in the form of either A: one or more sustained-release biodegradable fibers, or B: multiple sustained-release biodegradable beads, which are uniformly dispersed to provide sustained release of axitinib based on its low water solubility in synovial fluid and contain axitinib captured in a PEG-based hydrogel matrix.

[0593] The fibers and beads used in the following manufacturing process are understood to be exemplary embodiments. The amount of TKI or axitinib, the composition and characteristics of the fibers or beads can be appropriately adapted to the required applications in the therapeutic methods according to the present invention, particularly for the treatment of human patients.

[0594] A. Sustained-release biodegradable fiber Four exemplary axitinib sustained-release biodegradable fibers were manufactured as described below. The respective composition percentages in dry and wet states, as well as the function of each component, are shown in Table 1 for all fiber types. [Table 1]

[0595] For fiber preparation, the polyurethane tube was first cut into pieces of appropriate length. The formulation process involved preparing one syringe containing a suspension of axitinib in a solution of 8a20kPEG-NH2 (8-arm 20,000 PEG amine, optionally conjugated with fluorescein) and dibasic sodium phosphate buffer, and another syringe containing a solution of 4a20kPEG-SG (4-arm 20,000 succinimidyl glutarate) or 4a20kPEG-SAZ (4-arm 20,000 succinimidyl azelaate), each in a monobasic sodium phosphate buffer. The contents of these two syringes were then combined to form a mixture (suspension) of the hydrogel component and axitinib. Therefore, an axitinib / 8a20kPEG-NH2 syringe and a 4a20kPEG-SG or 4a20kPEG-SAZ syringe were connected via Luer connectors, and the contents of the syringes were mixed by moving them back and forth between each syringe to produce a mixture, which was then transferred to a single syringe. The suspension was cast through a prepared polyurethane tube before the hydrogel was (completely) gelled. The gelling time was confirmed by performing a gel tap test. The cast strands were stored horizontally for 1–3 hours to allow the hydrogel to harden. The strands were then stored horizontally in a nitrogen flash atmosphere at room temperature for 36–72 hours to allow the strands to dry completely.

[0596] After drying, the dried strands were removed from the polyurethane tubes and cut into segments of the desired length. The surface of the cut fibers was visually inspected for particulate, cylindrical, and all visible surface defects. Fibers that showed no defects and were approximately the correct length proceeded to the next stage of the process. Fibers that did not meet all requirements were discarded.

[0597] After quality inspection, the fibers were loaded into sterile NIPRO needles, individually packaged, and transferred to glove boxes. They were then kept in an inert nitrogen environment for 16–96 hours to reduce residual moisture (moisture content ≤ 1.0%). The nitrogen-adjusted needles were PEG-treated at the tip with 1k linear PEG to improve injection success and retain the depot within the needle during shipment. The packaged fibers were inspected and stored at 2–8°C until sterilization. For sterilization, the packaged fibers were irradiated with gamma rays (delivering an internal dose of 25.0–35.0 kGy). The packaged fibers were then stored in a light-shielded environment at 2–8°C before administration.

[0598] The release rate of each axitinib from the fiber was determined by the in vitro test in Example 2. The persistence of the fiber in the knee joints of rats and the knee and elbow joints of dogs was evaluated in Example 3, and the ability of the fiber to reduce pain sensation and further effects in the rat model was evaluated in Example 4. Finally, the chondrotoxicity of the fiber and axitinib was evaluated in Example 5.

[0599] B. Sustained-release biodegradable beads Exemplary selected axitinib sustained-release biodegradable beads were manufactured using various mesh screens (mesh screen method) or by extrusion from ceramic syringes (Vulcan method), as further described below. The respective composition percentages in dry and / or wet states, as well as the function of each component, are presented in Table 2 for all types of beads. [Table 2]

[0600] For the preparation of beads by the mesh screen method, one syringe was prepared containing a suspension of micronized axitinib in a solution of 8a20kPEG-NH2 (8-arm 20,000 PEG amine) and dibasic sodium phosphate buffer, and another syringe was prepared containing a solution of 4a20kPEG-SAZ (4-arm 20,000 succinimimidylazelaate) and monobasic sodium phosphate buffer. The contents of these two syringes were then combined to form a mixture (suspension) of the hydrogel component and axitinib. To this end, the axitinib / 8a20kPEG-NH2 syringe and the 4a20kPEG-SAZ syringe were connected via Luer connectors, and the contents of the syringes were mixed by moving them back and forth to produce the mixture, which was then transferred to a single syringe. The suspension was allowed to gel completely within the syringe. The gel was extruded from a syringe through various mesh screens: a 900 μm mesh screen, a 500 μm mesh screen (twice), and a 213 μm mesh screen (three times). The resulting bead size range was corrected to 53–500 μm by wet sieving.

[0601] For the preparation of beads using the Vulcan method, dry powders of micronized axitinib, 4a20kPEG-SAZ (4-arm 20,000 succinimimidylazelaic acid), and trilysine acetate were mixed in a ceramic syringe (Vulcan), while simultaneously maintaining all components under nitrogen to prevent pre-crosslinking. The mixture was heated to 80°C, and then the Vulcan wave was initiated, extruding the mixture into mineral oil in the form of beads. The resulting beads had a particle size of 200–400 μm.

[0602] The beads obtained by the mesh screen method and the Vulcan method were collected, dried, and freeze-dried.

[0603] In Example 2, the release rate of axitinib from beads manufactured by the mesh screen method was determined by in vitro testing.

[0604] Example 2 In vitro release of axitinib The release rates of axitinib from depots manufactured as described above were determined in vitro under physiological conditions with a one-week supplementation to simulate real-time sink in different formulations. From the fiber formulations (Table 1), three fiber variants of fiber type #1, one fiber each of fiber types #2 and #2, and two fiber variants of fiber type #4 were tested. From the bead formulations (Table 2), 0.5 mg, 1 mg, and 2 mg bead type #5 were tested.

[0605] Prior to in vitro testing, the initial axitinib content of each fiber was determined by placing one fiber in 1.5 mL of a 90:10 EtOH:H2O solution, and 0.5 mL of each solution was taken two days after extraction and analyzed by UV-Vis at 332 nm (Table 3). The amount of axitinib was determined relative to a standard curve created from an axitinib reference. [Table 3]

[0606] In the next step, we determined the release of axitinib in vitro, as briefly described below. In vitro assays can be used for quality control, for example, to determine the compatibility between batches of depots.

[0607] For fiber samples, one fiber was placed in 20 mL of buffer (1× phosphate-buffered saline, pH 7.2 PBS), with a 5 mL layer of octanol on top to provide a sink phase that allowed axitinib to migrate into the octanol layer. At the corresponding time points, 1 mL of octanol was withdrawn for UV-Vis analysis at 332 nm. 1 mL of fresh octanol was added as a replenishment. The amount of axitinib released at each time point was determined against a standard curve created from an axitinib reference.

[0608] For exemplary release profiles, see Figure 1 (Formulation #1, Depot AC), Figure 2 (Formulation #2, Depot D and Formulation #3, Depot E), and Figure 3 (Formulation #4, Depots F and G) in vitro.

[0609] For the beads, 0.5 mg (axitinib loading: 0.2 mg), 1 mg (axitinib loading: 0.4 mg), and 2 mg (axitinib loading: 0.8 mg) beads were placed in 7 mL of buffer (1 × phosphate-buffered saline, pH 7.2 PBS), and a 40 mL layer of octanol was placed on top to provide a sink phase that allowed axitinib to migrate into the octanol layer. At the corresponding time points, 1 mL of octanol was withdrawn for UV-Vis analysis at 332 nm. 1 mL of fresh octanol was added as a replenishment. The amount of axitinib released at each time point was determined against a standard curve created from an axitinib reference.

[0610] For an exemplary release profile, see Figure 4 (Formulation #5) in vitro.

[0611] These figures show dose-dependent axitinib release from the fibers for at least 1–3 months, with formulations #3 and #4 (4a20kPEG-SAZ) showing slower axitinib release than formulations #1 and #2 (4a20kPEG-SG). Axitinib release from the beads was faster than release from the fibers in all cases.

[0612] Experimental Example 3 Duration of action of axitinib depot To evaluate the in vivo persistence of the axitinib depot manufactured as exemplified above, preclinical studies were conducted in rat knee joints (Example 3.1) and dog knee and elbow joints (Example 3.2).

[0613] Example 3.1: Duration of action of axitinib depot in rats The persistence of fiber types #2 (4a20kPEG-SG) and #3 (4a20kPEG-SAZ) was evaluated by administering either depot D (group 1) or depot E (group 2) to both knees of healthy Sprague Dawley rats (n=12 in group 1 and n=15 in group 2). For depot D, the knees were administered with a theoretical loading of approximately 35 μg of axitinib in a 13.3 × 0.15 mm dry fiber, or for depot E, approximately 55 μg of axitinib in a 7.8 × 0.17 mm dry fiber. At corresponding time points after depot administration, three animals per group were euthanized, and the knees were dissected to recover the administered fibers.

[0614] Since the administered fibers were subjected to mechanical degradation, they could only be recovered as fragments, and the total length was calculated from the measured fragment lengths. Assuming 100% fiber recovery, the total length of the hydrated fiber is assumed to be 20.7 mm for hydration depot D and 11.6 mm for hydration depot E. The data for each recovered fiber fragment and the total fiber length are summarized in Tables 4 and 5. [Table 4] [Table 5]

[0615] After fiber fragment recovery, the release of axitinib from the depot in vivo was determined based on the axitinib recovery rate.

[0616] First, the recovered axitinib content was determined by placing each fragment of the depot into 0.5 mL or 0.8 mL of 90:10 EtOH:H2O. Two days after extraction, 0.15 mL (days 3 and 8) or 0.5 mL (days 15 and 22) of each solution was taken and analyzed by UV-Vis at 332 nm. The amount of axitinib was determined against a standard curve created from an axitinib reference. In the next step, the theoretical axitinib content was calculated from the initial axitinib loading and 100% fiber length using the length of each recovered depot. The recovered axitinib content was divided by the theoretical axitinib content to determine the axitinib release percentage at each time point.

[0617] See Figure 5 for an example in vivo release profile.

[0618] Example 3.2: Duration of action of axitinib depot in beagle dogs The persistence of fiber type #4 (4a20kPEG-SAZ) was evaluated in larger breeds by administering depot F (knee) or depot G (elbow) to both knees and both elbows of Beagle dogs already scheduled for euthanasia (n=3). For the knees, approximately 420 μg of axitinib (the theoretical loading) was administered to a 12.5 × 0.35 mm dry fiber, and for the elbows, approximately 100 μg of axitinib (the theoretical loading) was administered to a 6.5 × 0.25 mm dry fiber. At corresponding time points after depot administration, one dog each was euthanized, and the knee / elbow was dissected to recover the administered fiber. Synovial fluid was collected for analysis. Blood was collected for serum analysis immediately before euthanasia.

[0619] After fiber (fragment) recovery, in vivo axitinib release from the depot was determined based on the axitinib recovery rate. In the case of the knee, the fibers were found to be located within the joint capsule and degraded into fragments, while fibers administered to the elbow were found in the surrounding tissue without mechanical degradation. The total hydrated length was calculated from the measured fragment lengths as appropriate. If 100% of the fibers were recovered, the total fiber length was assumed to be 18.7 mm for hydrated depot F and 9.4 mm for hydrated depot G. The recovered axitinib content was measured by placing each fragment in 4 mL of 90:10 EtOH:H2O in the depot, and 0.5 mL of each solution was taken for UV-Vis analysis at 332 nm two days after extraction. The amount of axitinib was determined against a standard curve created from an axitinib reference. The theoretical axitinib content was calculated from the initial axitinib loading and 100% fiber length using the length of each recovered depot. The axitinib release percentage at each time point was determined by dividing the recovered axitinib content by the theoretical axitinib content.

[0620] See Figure 6 for an example in vivo release profile.

[0621] Axitinib concentrations in synovial fluid and serum samples were determined using a triple quadrupole mass spectrometer combined with high-performance liquid chromatography (LC-MS / MS).

[0622] For sample preparation, 50 μL of each synovial fluid or serum sample was mixed with 20 μL of an internal standard solution (axitinib-D3) in methanol / water / formic acid (75:25:0.1 v / v / v). The samples were vortexed and used for LC-MS / MS analysis.

[0623] The high-performance liquid chromatography (HPLC) system consisted of an Applied Biosystems pump and a CTC autosampler. The mass spectrometer (MS) was an API 4000 tandem mass spectrometer. The HPLC mobile phase was HPLC-grade water containing acetonitrile and 0.1% formic acid (v / v). The analyte was eluted from the column at 0.5 mL / min using the gradient resulting from the mixing of the mobile phases. Axitinib was ionized by cationic electrospray. The MS system was operated in cationic mode. Axitinib (387.2–356.0 m / z) and an internal standard (axitinib-D3, 390.3–356.1 m / z) were fragmented in MS. The total runtime was 6 minutes. Axitinib concentrations were determined from a calibration curve. The method was validated using bovine control synovial fluid and beagle dog control serum before sample analysis. The method was shown to be reproducible, accurate, linear, precise, and specific. The limit of quantification was determined to be 5.00 ng / mL or 0.0200 ng / mL for synovial fluid samples and 0.0500 ng / mL for serum samples.

[0624] Synovial fluid concentrations are summarized in Table 6. [Table 6]

[0625] These values ​​indicate the sustained release of axitinib in the synovial fluid over several days. The degree of synovial fluid concentration depends on whether the depot was located in the intra-articular cavity (knee) or in the surrounding tissue (elbow).

[0626] Serum concentrations of axitinib were below the limit of quantification at all sample time points (LLOQ < 0.0500 ng / mL).

[0627] Example 4 Efficacy of axitinib depot in rats with MIA-induced osteoarthritis Two studies were conducted to evaluate the ability of axitinib depot, manufactured as exemplarily described above, to reduce pain sensation and other effects in Sprague Dawley rats with monosodium iodoacetate (MIA)-induced osteoarthritis—the first study (Study I) using fiber type #1 (4a20kPEG-SG) and the second study (Study II) using fiber types #2 (4a20kPEG-SG) and #3 (4a20kPEG-SAZ), compared to intra-articular injection of an NSAID.

[0628] In Study I, the efficacy of treatment with Depot A, Depot B, and Depot C was compared with celecoxib treatment (reference) and no treatment (control). In Study II, the efficacy of treatment with Depot D and Depot E was compared with celecoxib treatment (reference) and triamcinolone treatment (KENALOG®, reference), as well as hydrogel treatment (control), axitinib alone treatment (control), no API treatment (control), and no treatment (control). Hydrogel treatment was perf...

Claims

1. A method of treatment for a patient requiring treatment of a pathological condition, wherein the pathological condition is a joint condition or a bone canal condition. The method comprises administering to the patient a sustained-release biodegradable depot containing a hydrogel and a tyrosine kinase inhibitor. The method wherein the depot is administered by injection.

2. The method according to claim 1, wherein the pathological condition is a joint pathological condition, and the depot is administered by joint injection, and in particular by intra-articular or peri-articular injection.

3. The method according to claim 2, wherein the depot is administered into the synovial joint of the patient, and in particular, the depot is administered into the synovial joint cavity of the patient.

4. The depot is administered to the patient in the area of ​​the knee, elbow, fingers, buttocks, shoulder, wrist, ankle, or foot, hand, shoulder girdle, rotator cuff, pelvis, spine, or temporomandibular joint, and in particular to the patient's tibiofemoral joint, patellofemoral joint, humeroulnar joint, humerorar joint, proximal radioulnar joint, pelvic femoral joint, glenohumeral joint, acromioclavicular joint, distal radioulnar joint, radiocarpal joint, and intercarpal joint. The method according to claim 2 or 3, wherein the drug is administered to the metacarpal joint, carpometacarpal joint, intermetacarpal joint, talocrural joint, subtalar joint, tibiofibular joint, talonavicular joint, calcaneocuboid joint, metatarsophalangeal joint, interphalangeal joint of the foot or hand, metacarpophalangeal joint, sternoclavicular joint, costochondral joint, atlantooccipital joint, atlantoaxial joint, costovertebral joint, costotransverse joint, articular joint, sacroiliac joint, or temporomandibular joint.

5. The method according to claim 1, wherein the pathological condition is a pathological condition of the bone canal, and the depot is administered by injection into or near the bone canal of the patient, and in particular, the depot is administered by injection into the carpal canal of the patient or the spinal canal of the patient.

6. The method according to any one of claims 1 to 5, wherein the dose per joint or bone administered once during the treatment period is about 0.5 mg to about 120 mg of the tyrosine kinase inhibitor, or the dose per joint or bone administered once during the treatment period is about 1 mg to about 50 mg of the tyrosine kinase inhibitor.

7. The method according to any one of claims 1 to 6, wherein the tyrosine kinase inhibitor is axitinib.

8. The method according to claim 7, wherein the depot, after administration to the joint or bone canal, releases a therapeutically effective amount of axitinib for at least about one month, at least about two months, at least about three months, at least about six months, at least about nine months, or at least about twelve months after administration.

9. The method according to claim 7 or 8, wherein axitinib is released from the depot after administration at an average rate of about 1 μg / day to about 600 μg / day, or axitinib is released from the depot after administration at an average rate of about 30 μg / day to about 500 μg / day, or axitinib is released from the depot after administration at an average rate of about 100 μg / day to about 270 μg / day, or axitinib is released from the depot after administration at an average rate of about 165 μg / day or about 220 μg / day.

10. The method according to any one of claims 7 to 9, wherein the depot provides an in vitro average release rate of approximately 100 μg to approximately 500 μg per day in phosphate-buffered saline, or approximately 160 μg to approximately 400 μg per day, and / or approximately 150 μg to approximately 600 μg, or approximately 200 μg to approximately 450 μg of axitinib per day in phosphate-buffered saline, for 90 days at 37°C.

11. The method according to any one of claims 7 to 10, wherein the depot yields a cumulative amount of axitinib released in vitro over 30 days at 37°C to about 30 mg in phosphate-buffered saline, or about 4.5 mg to about 18 mg, and / or over 60 days at 37°C to about 7 mg to about 36 mg in phosphate-buffered saline, or about 9 mg to about 33 mg, and / or over 90 days at 37°C to about 12 mg to about 50 mg in phosphate-buffered saline, or about 15 mg to about 42 mg.

12. The method according to any one of claims 7 to 11, wherein the depot yields an average axitinib concentration in the synovial fluid of about 150 ng / mL to about 600 ng / mL three days after administration, and / or about 350 ng / mL to about 750 ng / mL seven days after administration, and / or about 35 ng / mL to about 200 ng / mL fourteen days after administration, and / or the depot yields an average axitinib concentration in the synovial fluid of about 35 ng / mL to about 200 ng / mL over 14 days, over 1 month, over 2 months, or over 3 months.

13. The method according to any one of claims 1 to 12, wherein the depot, in a dry state, contains about 0.1% to about 7% by weight of water, and / or the depot, in a dry state, contains about 10% to about 75% by weight of the tyrosine kinase inhibitor and about 25% to about 80% by weight of polymer units, or about 25% to about 60% by weight of the tyrosine kinase inhibitor and about 35% to about 65% by weight of polymer units, or about 45% to about 55% by weight of the tyrosine kinase inhibitor and about 40% to about 60% by weight of polymer units.

14. The method according to any one of claims 1 to 13, wherein the hydrogel comprises a polymer network comprising the same or different crosslinked polymer units, in particular the crosslinked polymer units being one or more crosslinked polyethylene glycol units, in particular the polymer network comprising polyethylene glycol units having an average molecular weight in the range of about 2,000 to about 100,000 daltons, or about 10,000 to about 60,000 daltons, or about 20,000 to about 40,000 daltons, or about 15,000 to about 30,000 daltons.

15. The method according to any one of claims 1 to 14, wherein the polymer network comprises one or more crosslinked multi-arm polymer units, the multi-arm polymer unit comprises one or more four-arm polyethylene glycol units, the four-arm polyethylene glycol unit being a 4a20kPEG unit or a 4a40kPEG unit, or the multi-arm polymer unit comprises one or more eight-arm polyethylene glycol units, the eight-arm polyethylene glycol unit being an 8a20kPEG unit or an 8a15kPEG unit, or the polymer network comprises both four-arm and eight-arm polyethylene glycol units, the four-arm polyethylene glycol unit being a 4a20kPEG unit and the eight-arm polyethylene glycol unit being an 8a20kPEG unit.

16. The method according to any one of claims 1 to 15, wherein the polymer network is formed by reacting an electrophilic group-containing multi-arm polymer precursor with a nucleophilic group-containing multi-arm polymer precursor, wherein the nucleophilic group is an amine group and / or the electrophilic group is an activated ester group, and in particular the electrophilic group is an N-hydroxysuccinimidyl (NHS) group, or the electrophilic group is a succinimidyl glutarate (SG) or succinimidyl azelaic acid (SAZ) group.

17. The method according to any one of claims 1 to 16, wherein the depot is in the form of at least one sustained-release biodegradable fiber, in particular the at least one fiber having an essentially cylindrical shape, and in particular the one fiber containing the tyrosine kinase inhibitor in an amount of at least about 10 μg, or at least 100 μg, or at least 250 μg, or at least 500 μg, or about 10 μg to about 1200 μg.

18. The method according to any one of claims 1 to 164, wherein the depot is in the form of a plurality of sustained-release biodegradable beads, in particular the beads are spherical or non-spherical particles, and in particular the beads contain the tyrosine kinase inhibitor in an amount of about 0.01 μg to about 50 μg per bead, or the beads contain the tyrosine kinase inhibitor in an amount of about 0.5 μg to about 12 μg per bead.

19. The method according to any one of claims 1 to 18, wherein the pathology of the joint or the pathology of the bone canal is an inflammatory pathology, and / or the pathology of the joint or the pathology of the bone canal is accompanied by angiogenesis.

20. The method according to any one of claims 2 to 4 and 6 to 19, wherein the pathological condition of the joint is arthropathy, and / or the pathological condition of the joint is arthritis, and in particular the arthritis is osteoarthritis (OA).

21. The method according to any one of claims 5 to 19, wherein the pathology of the bone canal is related to stenosis of the bone canal, and / or the pathology of the bone canal is accompanied by nerve compression, in particular, the pathology of the bone canal is carpal tunnel syndrome, or the pathology of the bone canal is spinal stenosis.

22. The method according to any one of claims 1 to 21, wherein the treatment is effective in reducing pain.

23. The method according to any one of claims 1 to 22, wherein the treatment is effective in reducing the expression of at least one inflammatory marker, and in particular the treatment is effective in reducing the expression of at least one cytokine, and in particular the at least one cytokine is at least one interferon (IFN), interleukin (IL), and / or chemokine of the CXC family.

24. A pharmaceutical preparation for injection, (i) A sustained-release biodegradable depot containing a hydrogel and a tyrosine kinase inhibitor, (ii) The pharmaceutical preparation comprising a carrier.

25. The injectable pharmaceutical composition according to claim 24, wherein the depot is in the form of a plurality of sustained-release biodegradable beads, in particular the beads are spherical or non-spherical particles, in particular the beads contain the tyrosine kinase inhibitor in an amount of about 0.01 μg to about 50 μg per bead, or the beads contain the tyrosine kinase inhibitor in an amount of about 0.5 μg to about 12 μg per bead, or the beads contain the tyrosine kinase inhibitor in an amount of about 1 μg to about 8 μg per bead, or about 1.5 μg to about 5 μg per bead, or about 2 μg to about 4 μg per bead.

26. The pharmaceutical composition for injection according to claim 24 or 25, wherein the beads are suspended in the carrier at a concentration of about 10% to about 50% by weight of beads, about 15% to about 40% by weight of beads, or about 20% to about 30% by weight of beads, and the remainder is the carrier.

27. The carrier is a non-aqueous carrier, for example, an oily carrier, and in particular the carrier is at least one pharmaceutically acceptable oil, including almond oil, castor oil, coconut oil, corn oil, cottonseed oil, linseed oil, linseed oil, corn oil, mineral oil, olive oil, palm oil, peanut oil, nata oil, safflower oil, sesame oil, silicone oil, soybean oil, and sunflower oil; at least one pharmaceutically acceptable wax, including beeswax, candelilla wax, carnauba wax, and animal oil; or at least one pharmaceutically acceptable lipid, including fatty acids and esters such as lauric acid, oleic acid, ethyl oleate, triethyl citrate, or acetyl triethyl citrate (ATEC), and in particular the carrier is sesame oil or ethyl oleate, according to any one of claims 24 to 26.

28. A method for producing an injectable pharmaceutical preparation comprising a sustained-release biodegradable depot and carrier according to any one of claims 24 to 27, I. The steps of forming a hydrogel comprising a polymer network and tyrosine kinase inhibitor particles dispersed in the hydrogel, and forming the hydrogel into beads, and optionally, II. The method comprising the step of suspending the beads in the carrier.

29. III. The method according to claim 28, further comprising the step of loading the pharmaceutical preparation into a subcutaneous injection needle, wherein the subcutaneous injection needle is a 20-27 gauge needle, or a 22 or 25 gauge needle.

30. A kit comprising one or more injectable pharmaceutical preparations manufactured by any one of claims 24 to 27, or by the method of claim 28 or 29, and one or more subcutaneous injection needles.

31. The kit according to claim 30, wherein each of the one or more subcutaneous injection needles is pre-loaded into a single injectable pharmaceutical preparation, and in particular, the subcutaneous injection needle is a 20-27 gauge needle, or the subcutaneous injection needle is a 22 or 25 gauge needle.

32. The kit according to claim 30 or 31, further comprising an injection device for injecting the pharmaceutical preparation for injection, wherein the injection device is provided in the kit separately from the one or more subcutaneous injection needles, or, in particular, the injection device is pre-connected to a subcutaneous injection needle pre-loaded with the pharmaceutical preparation for injection.

33. A method for reducing pain in patients who require pain reduction, The method comprising administering to the patient a therapeutically effective amount of the injectable pharmaceutical preparation described in any one of claims 24 to 17 by injection.

34. A method for reducing inflammation in patients who require reduction of inflammation, The method comprising administering to the patient a therapeutically effective amount of the injectable pharmaceutical preparation described in any one of claims 24 to 27 by injection.

35. A method for delaying, halting, or improving progressive structural tissue damage associated with arthritis, or delaying, halting, or improving loss of joint function associated with arthritis in patients who require such delaying, halting, or improvement, The method comprising administering to the patient a therapeutically effective amount of the injectable pharmaceutical preparation according to any one of claims 24 to 27 by joint injection.

36. A method for delaying, cessating, or improving stinging, weakness, or numbness in the fingers associated with carpal tunnel syndrome, or in the arms or legs associated with spinal stenosis, in patients who require such delaying, cessation, or improvement. The method comprising administering to the patient a therapeutically effective amount of the injectable pharmaceutical preparation according to any one of claims 24 to 27 by injection into or near the carpal tunnel, or by epidural injection.

37. A sustained-release biodegradable depot comprising a hydrogel and a tyrosine kinase inhibitor for use in the treatment of joint pathologies according to any one of claims 1 to 23.

38. Preparation of a pharmaceutical product for the treatment of joint pathologies by the method of any one of claims 1 to 23, using a sustained-release biodegradable depot comprising a hydrogel and a tyrosine kinase inhibitor.

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