Method of treating an articular condition or a condition of a bony canal

Abstract

The present invention relates to the treatment of an articular condition or a condition of a bony canal in a patient in need thereof. In particular, the invention relates to an injection of a sustained release biodegradable depot comprising a hydrogel and a tyrosine kinase inhibitor.

Description

METHOD OF TREATING AN ARTICULAR CONDITION OR A CONDITION OF A BONY CANAL CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] The present invention claims priority to U.S. Provisional Application Serial No. 63 / 472,162 filed June 9, 2023, which is hereby incorporated by reference herein. TECHNICAL FIELD

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

[0003] Joint conditions, such as joint pain, as well as bony canal conditions, are common problems, causing limited mobility and thus preventing subjects from engaging in life. Arthritis, which is one of the most common causes of joint pain, generally describes more than 100 conditions affecting the joints and connective tissues. It entails an inflammation of the joints and can affect one or multiple joint(s). Besides pain, the main symptoms of arthritis include redness, warmth, swelling, stiffness and decreased range of motion of the affected joint(s). The symptoms of arthritis usually develop over time, but they may also appear suddenly. They may vary from week to week, and even from day to day. Many types of arthritis are long-term conditions. The causes for arthritis are not fully known. Most types of arthritis, such as for example rheumatoid arthritis, are thought to be caused by a fault in the immune system directing the body to attack its own tissues. Other types of arthritis derive from a metabolic condition, such as gout. Further, environmental factors, such as for example obesity, age, repetitive activities or injuries, may contribute to the development of particular types of arthritis, including osteoarthritis.

[0004] Osteoarthritis (OA), also referred to as “wear and tear” arthritis, is the most common type of arthritis, affecting about 250 million of people all over the world (Hunter et al., Osteoarthritis. Lancet 2019, 393, 1745–1759). Preceding hip OA and hand OA, approximately 85% of the burden of osteoarthritis is connected with knee OA, wherein the prevalence of knee OA among adults 60 years of age or older 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 a slow-progressive degeneration of the articular cartilage, dysregulation of subchondral bone remodeling and synovial inflammation which ultimately lead to loss of joint function and chronic pain. While the articular cartilage becomes fissured and gradually wears away, the joint tries to heal itself by forming bony out- growths on the sides of the joints (osteophytes). OA is commonly described as a non-inflammatory disease in order to distinguish it from ‘inflammatory arthritis’, such as rheumatoid arthritis (RA). Despite this, 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). Further, angiogenesis, which is the generation of new blood vessels from pre-existing vessels, within an affected joint has also been attributed to OA progression.

[0005] Angiogenesis and inflammation are closely integrated processes: Inflammation can facilitate angiogenesis directly through the release of growth factors from cells such as macrophages, and also by stimulation orsensitization of other cells, such as chondrocytes, nerves and osteoblasts that in turn release additional angiogenic factors. Angiogenesis at the osteochondral junction leads to endochondral ossification and the formation of osteophytes, further exacerbating inflammation. Angiogenesis can also lead to innervation of the articular cartilage, providing a source of pain in OA. Thus, angiogenesis and inflammation are important processes in the pathophysiology of OA (Bonnet et al., Osteoarthritis, angiogenesis and inflammation. Rheumatology 2005, 44(1):7- 16). In regard to this pathophysiology, accumulating evidence suggests the pathological involvement of vascular endothelial growth factor (VEGF) and its signaling pathways through its cognate receptors, VEGFR-1 and VEGFR-2, in OA progression 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-type tyrosine kinase supergene family and consist of a ligand-binding region with seven immunoglobulin-like domains, a trans-membrane domain, and a tyrosine kinase domain with 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 with their ligands, VEGFs, to promote angiogenesis during development, wound healing and endochondral ossification. There are three subtypes of VEGF receptors, VEGFR-1, VEGFR-2 and VEGFR-3, which can be activated by various structurally related VEGFs. The VEGF family of glycoproteins is composed of VEGF-A, VEGF-B, VEGF-C, VEGF-D, and placental growth factor (PlGF), wherein VEGF-A, which provided the VEGF family with its name, is classically – and herein in the following – referred to as VEGF. Even if VEGF is the most widely studied and targeted in the context of OA pathogenesis, 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 beta 1-integrins. Histochem Cell Biol 2003, 120:235-41). During later stages of OA in affected patients, VEGF expression has been found to be increased in the articular cartilage, synovium, synovial fluid, subchondral bone, and serum. Assessment of VEGF as a biomarker in patients with OA demonstrated that increased synovial fluid VEGF is not only correlated with the grade of OA severity 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). In line with this, bevacizumab, a monoclonal anti-VEGF antibody, reduced OA pain in an OA rabbit model and further showed reduction of 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] As OA is a highly debilitating disease, it is associated with a high personal and socioeconomic burden. So far, there is no therapy available that effectively arrests structural deterioration of cartilage and bone or is able to successfully reverse any of the existing structural defects and provide long-lasting symptomatic relief. Thus, about 30-50% of patients will ultimately end up requiring joint prosthesis to address advanced OA, which is currently the most effective measure to improve pain sensation and quality of life. Therapeutic, non-surgical approaches predominantly intend to alleviate symptoms and try to modify / improve structural features of affected joint tissues. For example, several oral medications are prescribed for treatment of OA, mostly addressing the issue of pain, while other, in particular intra-articular, treatments target inflammatory processes or articular cartilage degeneration.

[0008] A typical approach to OA therapy is initiated by symptomatic drugs including acetaminophen and non- steroidal anti-inflammatory drugs (NSAIDs) as first line OA treatment, providing 50-60% adoption. Acetaminophen has been commonly used for the treatment of knee OA, but is inferior when compared to NSAIDs (Towheed et al., Acetaminophen for osteoarthritis. Cochrane Database Syst Rev 2006; 1:CD004257). NSAIDs should only berecognized as a short-term treatment to manage symptomatic knee OA, in view of their side effect profile. Other symptomatic drugs for first line OA treatment may include COX-2 inhibitors, such as celecoxib, duloxetine and opioid analgesics. A 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 cases of OA and provides 15-20% adoption. Intra-articular corticosteroid injections are implemented periodically in moderate to severe disease for reducing acute inflammation and relieving pain in the short-term, but are not a good treatment option for long-term management of knee OA due to 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 third line treatment for large joint OA, such as knee OA and are most effective for early disease with 8-10% adoption. The favorable safety profile of Hyaluronic acid injection makes it a more appealing treatment for long-term use compared to NSAIDs, and the absence of known medication interactions making it a good option for patients on 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 OA treatment before surgery comprises platelet-rich plasma (PRP) therapy. PRP is derived from centrifuging whole blood in order to obtain a platelet concentration above baseline, and growth factors including platelet-derived growth factor, insulin growth factor, transforming growth factor beta-1 and VEGF are believed to be key components of PRP for structural repair. However, PRP therapy is only used in severe disease that is refractory to other therapies, providing 1-2% adoption.

[0009] In addition, since a few years, a novel concept emerged that considers OA as a multifaceted disease involving the whole joint and not only cartilage or synovium. This offers new options to identify and develop novel therapeutics and to re-profile candidate drugs (Grässel et al., Recent advances in the treatment of osteoarthritis. F1000Res.2020, 9:F1000 Faculty Rev-325). For example, SPRIFERMIN®, which is a truncated version 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®which is an ultra-pure, synthetic form of trans-capsaicin targeting transient receptor potential vanilloid 1 (TRPV1) reduced pain in patients with moderate-to-severe knee OA after being injected directly into the site of pain (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). Further, the efficacy limitations and the corticosteroid-related systemic adverse effects of conventional intra-articular corticosteroid formulations have been addressed by triamcinolone acetonide being formulated in extended-release poly (lactic-co- glycolic acid) microspheres, which are available as ZILRETTA®(Paik et al., Triamcinolone Acetonide Extended- Release: A Review in Osteoarthritis Pain of the Knee. Drugs 201979(4):455-462).

[0010] However, despite these advancements, there are limitations to OA treatment. Most injection treatments are only directed to knee OA or OA in larger joints, leaving behind smaller joints such as finger joints. Further, patients usually require multiple injections (such as monthly) essentially for the rest of their lives due to rapid efflux from the joints. Additionally, KENALOG®corticosteroid injection is still the current standard of care for OA joint pain, but has been reported to cause cartilage destruction over long exposure times and repeated doses (Testa et al., Intra-Articular Injections in Knee Osteoarthritis: A Review of Literature. Journal of Functional Morphology and Kinesiology 20216 (1), 15). Thus, corticosteroid injections are generally restricted to at least three months between repeat injections,whereas the time of effective pain relief, however, is only 2-6 weeks, leaving the patient without pain control for the remainder of the 3 months period.

[0011] Therefore, there is an urgent need for an improved treatment of OA throughout the body joints. In particular, in view of drawbacks and challenges experienced with current available treatments, novel treatment methods which effectively alleviate pain and provide durability of pain relief lasting 3-6 months, would provide benefits for patients. Moreover, recognizing the complex pathophysiology of OA progression, novel treatment methods targeting signaling pathways that are not only involved in pain associated with OA but also in inflammation and angiogenesis, such as VEGF signaling pathways, would be highly desirable. OBJECTS AND SUMMARY OF THE INVENTION

[0012] It is an object of certain embodiments of the present invention to provide a method of treating an articular condition such as (osteo-)arthritis, or a condition of a bony canal such as carpal tunnel syndrome or spinal stenosis.

[0013] Another object of certain embodiments of the present invention is to provide a method of treating an articular condition such as (osteo-)arthritis, or a condition of a bony canal such as carpal tunnel syndrome or spinal stenosis, that is suitable for long-term treatment.

[0014] Another object of certain embodiments of the present invention is to provide a method of treating an articular condition such as (osteo-)arthritis, or a condition of a bony canal such as carpal tunnel syndrome or spinal stenosis, that reduces pain, e.g. joint pain.

[0015] Another object of certain embodiments of the present invention is to provide a method of treating an articular condition such as (osteo-)arthritis, , or a condition of a bony canal such as carpal tunnel syndrome or spinal stenosis, providing for an early onset of pain relief, in particular within 48 hours.

[0016] Another object of certain embodiments of the present invention is to provide a method of treating an articular condition such as (osteo-)arthritis, or a condition of a bony canal such as carpal tunnel syndrome or spinal stenosis, providing for an extended durability of pain relief, in particular of at least 3 months.

[0017] Another object of certain embodiments of the present invention is to provide a method of treating an articular condition such as (osteo-)arthritis, or a condition of a bony canal such as carpal tunnel syndrome or spinal stenosis, that reduces inflammation.

[0018] Another object of certain embodiments of the present invention is to provide a method of treating an articular condition such as (osteo-)arthritis, or a condition of a bony canal such as carpal tunnel syndrome or spinal stenosis, that reduces an expression of at least one inflammatory marker such as cytokines.

[0019] Another object of certain embodiments of the present invention is to provide a method of treating an articular condition such as (osteo-)arthritis that reduces hypervascularity.

[0020] Another object of certain embodiments of the present invention is to provide a method of treating an articular condition such as (osteo-)arthritis that allows for slowing down, arresting or reversing progressive structural tissue damage.

[0021] Another object of certain embodiments of the present invention is to provide a method of treating an articular condition such as (osteo-)arthritis that allows for slowing down, arresting or reversing loss of joint function.

[0022] Another object of certain embodiments of the present invention is to provide a method of treating an articular condition such as (osteo-)arthritis that improves joint function.

[0023] Another object of certain embodiments of the present invention is to provide a method of treating an articular condition such as (osteo-)arthritis, which is not restricted to large joints of the body.

[0024] Another object of certain embodiments of the present invention is to provide a method of treating an articular condition such as (osteo-)arthritis that is applicable to knee OA, hip OA and / or finger joint OA.

[0025] Another object of certain embodiments of the present invention is to provide a method of treating a condition of a bony canal such as carpal tunnel syndrome or spinal stenosis that allows for slowing down, arresting or reversing narrowing of the bony canal.

[0026] Another object of certain embodiments of the present invention is to provide a method of treating a condition of a bony canal such as carpal tunnel syndrome or spinal stenosis that allows for slowing down, arresting or reversing tingling, weakness or numbness of extremities.

[0027] Another object of certain embodiments of the present invention is to provide a method of treating a condition of a bony canal such as carpal tunnel syndrome or spinal stenosis that reduces compression of nervous tissue.

[0028] Another object of certain embodiments of the present invention is to provide a method of treating an articular condition such as (osteo-)arthritis, or a condition of a bony canal such as carpal tunnel syndrome or spinal stenosis, providing safety and good tolerability.

[0029] Another object of certain embodiments of the present invention is to provide a method of treating an articular condition such as (osteo-)arthritis, or a condition of a bony canal such as carpal tunnel syndrome or spinal stenosis, that is suitable for repeat dosing without the need of administration pauses.

[0030] Another object of certain embodiments of the present invention is to provide a method of treating an articular condition such as (osteo-)arthritis, or a condition of a bony canal such as carpal tunnel syndrome or spinal stenosis, targeting VEGF signaling pathways.

[0031] Another object of certain embodiments of the present invention is to provide a method of treating an articular condition such as (osteo-)arthritis, or a condition of a bony canal such as carpal tunnel syndrome or spinal stenosis, that comprises administration, e.g. articular administration, of a biodegradable depot providing sustained release of an active agent for targeting VEGF signaling pathways.

[0032] Another object of certain embodiments of the present invention is to provide a method of treating an articular condition such as (osteo-)arthritis, or a condition of a bony canal such as carpal tunnel syndrome or spinal stenosis, that comprises administration, e.g. articular administration, of a biodegradable depot providing sustained release for a period of one or more months.

[0033] Another object of certain embodiments of the present invention is to provide a method of treating an articular condition such as (osteo-)arthritis, or a condition of a bony canal such as carpal tunnel syndrome or spinal stenosis, that comprises administration, e.g. articular administration, of a sustained release biodegradable depot that resists the mechanical load in the joint or the bony canal.

[0034] Another object of certain embodiments of the present invention is to provide a method of treating an articular condition such as (osteo-)arthritis, or a condition of a bony canal such as carpal tunnel syndrome or spinal stenosis, that comprises administration, e.g. articular administration, of a sustained release biodegradable depot that resists efflux from the joint or the bony canal.

[0035] Another object of certain embodiments of the present invention is to provide a method of treating an articular condition such as (osteo-)arthritis, or a condition of a bony canal such as carpal tunnel syndrome or spinalstenosis, that comprises administration, e.g. articular administration, of a sustained release biodegradable depot that enables increased joint residence or bony canal residence.

[0036] Another object of certain embodiments of the present invention is to provide a method of treating an articular condition such as (osteo-)arthritis, or a condition of a bony canal such as carpal tunnel syndrome or spinal stenosis, that comprises administration, e.g. articular administration, of a sustained release biodegradable depot that is safe and well-tolerated.

[0037] Another object of certain embodiments of the present invention is to provide a method of treating an articular condition such as (osteo-)arthritis, or a condition of a bony canal such as carpal tunnel syndrome or spinal stenosis, that comprises administration, e.g. articular administration, of a sustained release biodegradable depot that is biocompatible and low or non-immunogenic due to certain embodiments of the depot being free of animal- or human-derived components.

[0038] Another object of certain embodiments of the present invention is to provide a method of treating an articular condition such as (osteo-)arthritis, or a condition of a bony canal such as carpal tunnel syndrome or spinal stenosis, that comprises administration, e.g. articular administration, of a sustained release biodegradable depot that does not induce severe adverse effects.

[0039] Another object of certain embodiments of the present invention is to provide a method of treating an articular condition such as (osteo-)arthritis, or a condition of a bony canal such as carpal tunnel syndrome or spinal stenosis, that comprises administration, e.g. articular administration, of a sustained release biodegradable depot that does not induce chondrotoxicity.

[0040] Another object of certain embodiments of the present invention is to provide a method of treating an articular condition such as (osteo-)arthritis, or a condition of a bony canal such as carpal tunnel syndrome or spinal stenosis, that comprises administration, e.g. articular administration, of a sustained release biodegradable depot that is non-destructive to joint or cartilage or bony canal or nerves.

[0041] Another object of certain embodiments of the present invention is to provide a pharmaceutical composition that comprises a biodegradable depot providing sustained release of an active agent for targeting VEGF signaling pathways.

[0042] Another object of certain embodiments of the present invention is to provide a pharmaceutical composition, enabling injection, e.g. articular injection.

[0043] Another object of certain embodiments of the present invention is to provide a pharmaceutical composition comprising an active agent for targeting VEGF signaling pathways, enabling safe injection through a small gauge needle.

[0044] Another object of certain embodiments of the present invention is to provide a method of manufacturing a pharmaceutical preparation that comprises a biodegradable depot providing sustained release of an active agent for targeting VEGF signaling pathways.

[0045] Another object of certain embodiments of the present invention is to provide a kit comprising one or more pharmaceutical preparation(s) for injection, e.g. articular injection.

[0046] One or more of these objects of the present invention and others are solved by one or more embodiments as disclosed and claimed herein.

[0047] In certain embodiments, the present invention enables an effective long-term treatment of signs and symptoms of an articular condition such as (osteo-)arthritis, or a condition of a bony canal such as carpal tunnel syndrome or spinal stenosis, by injection of a tyrosine kinase inhibitor (such as axitinib) by means of a sustainedrelease biodegradable depot. In some embodiments, one dose of the tyrosine kinase inhibitor (such as axitinib) is contained in one or more sustained release biodegradable fiber(s). In other embodiments, one dose of the tyrosine kinase inhibitor (such as axitinib) is contained in a plurality of sustained release biodegradable beads.

[0048] Without wishing to be bound by theory, the tyrosine kinase inhibitors (such as axitinib) as used herein may provide OA associated pain relief and reduce inflammation and hypervascularity in OA by inhibition of VEGFR-1 and VEGFR-2 activity, respectively. Likewise, the tyrosine kinase inhibitor (such as axitinib) as used herein may provide relief of pain associated to carpal tunnel syndrome or spinal stenosis and reduce compression and inflammation within the carpal tunnel or spinal canal.

[0049] The individual aspects of the present invention are disclosed in the specification and claimed in the independent claims, while the dependent claims claim particular embodiments and variations of these aspects of the invention. Details of the various aspects of the present invention are provided in the detailed description below. BRIEF DESCRIPTION OF THE DRAWINGS

[0050] Figure 1 In vitro axitinib release from 4a20kPEG-SG fibers according to embodiments of the invention comprising 7.7 µg, 15.4 µg and 30.8 µg axitinib over time (in PBS at a pH of 7.4 at 37 °C).

[0051] Figure 2 In vitro axitinib release from 4a20kPEG-SG and -SAZ fibers according to embodiments of the invention comprising 32.94 µg or 56.30 µg axitinib, respectively, over time (in PBS at a pH of 7.4 at 37 °C).

[0052] Figure 3 In vitro axitinib release from 4a20kPEG-SAZ fibers according to embodiments of the invention comprising 421.6 µg and 103.6 µg axitinib over time (in PBS at a pH of 7.4 at 37 °C).

[0053] Figure 4 In vitro axitinib release from 4a20kPEG-SAZ beads according to embodiments of the invention over time (in PBS at a pH of 7.4 at 37 °C).

[0054] Figure 5 Relative in vivo axitinib release from 4a20kPEG-SG and -SAZ fibers according to embodiments of the invention comprising 32.94 µg or 56.30 µg axitinib, respectively.

[0055] Figure 6 Relative in vivo axitinib release from 4a20kPEG-SAZ fibers according to embodiments of the invention comprising 421.6 µg and 103.6 µg axitinib.

[0056] Figure 7 Effects of 4a20kPEG-SG fibers according to embodiments of the invention comprising 7.7 µg, 15.4 µg and 30.8 µg axitinib on MIA-induced hyperalgesia in rats.

[0057] Figure 8 Effects of 4a20kPEG-SG and -SAZ fibers according to embodiments of the invention comprising 32.94 µg or 56.30 µg axitinib, respectively, on MIA-induced hyperalgesia in rats.

[0058] Figure 9 Effects of 4a20kPEG-SG fibers according to embodiments of the invention comprising 7.7 µg, 15.4 µg and 30.8 µg axitinib on inflammation in rat knees with MIA-induced osteoarthritis.

[0059] Figure 10 Effects of 4a20kPEG-SG fibers according to embodiments of the invention comprising 7.7 µg, 15.4 µg and 30.8 µg axitinib on pannus in rat knees with MIA-induced osteoarthritis.

[0060] Figure 11 Effects of 4a20kPEG-SG fibers according to embodiments of the invention comprising 7.7 µg, 15.4 µg and 30.8 µg axitinib on cartilage degeneration in rat knees with MIA-induced osteoarthritis.

[0061] Figure 12 Effects of 4a20kPEG-SG fibers according to embodiments of the invention comprising 7.7 µg, 15.4 µg and 30.8 µg axitinib on bone resorption in rat knees with MIA-induced osteoarthritis.

[0062] Figure 13 Effects of 4a20kPEG-SG fibers according to embodiments of the invention comprising 7.7 µg, 15.4 µg and 30.8 µg axitinib on IFN-γ expression 14 days (left) or 42 days (right) after administration.

[0063] Figure 14 Effects of 4a20kPEG-SG fibers according to embodiments of the invention comprising 7.7 µg, 15.4 µg and 30.8 µg axitinib on IL-10 expression 14 days (left) or 42 days (right) after administration.

[0064] Figure 15 Effects of 4a20kPEG-SG fibers according to embodiments of the invention comprising 7.7 µg, 15.4 µg and 30.8 µg axitinib on IL-1β expression 14 days (left) or 42 days (right) after administration.

[0065] Figure 16 Effects of 4a20kPEG-SG fibers according to embodiments of the invention comprising 7.7 µg, 15.4 µg and 30.8 µg axitinib on IL-4 expression 14 days (left) or 42 days (right) after administration.

[0066] Figure 17 Effects of 4a20kPEG-SG fibers according to embodiments of the invention comprising 7.7 µg, 15.4 µg and 30.8 µg axitinib on IL-5 expression 42 days after administration.

[0067] Figure 18 Effects of 4a20kPEG-SG fibers according to embodiments of the invention comprising 7.7 µg, 15.4 µg and 30.8 µg axitinib on KC / GRO expression 14 days (left) or 42 days (right) after administration. DEFINITIONS

[0068] The term “articular condition”, similarly referred to as “joint condition”, as used herein broadly refers to any disease, disorder or discomfort affecting joints or involving a joint or joints. In this context, the term “joint” is understood to mean a junction between two or more bones, including the soft tissues around them, such as cartilage, tendons, muscles and ligaments. The articular condition may be inflammatory, i.e. involve inflammation of the bones or related tissues. In certain embodiments, the inflammation is associated with arthritis. In other embodiments, the inflammation is not associated with arthritis.

[0069] The term “condition of a bony canal” as used herein broadly refers to any disease, disorder or discomfort related to a bony canal or bony canals. In this context, the term “bony canal” is understood to mean a body cavity formed at least with the participation of a bone or bones and related soft tissues. This includes, for example, the carpal tunnel, a fibro-osseous canal situated in the volar wrist that acts as a passageway for structures between the anterior forearm and the hand, transmitting inter alia the median nerve. In some circumstances, narrowing of the carpal tunnel can cause an entrapment / pinching of the median nerve which can result in numbness, tingling and weakness in the thumb and fingers, a common condition known as the carpal tunnel syndrome. Another exemplary condition of a bony canal is spinal stenosis, i.e. the narrowing of the spinal and nerve root canal which is an elongated body cavity enclosed within the dorsal bony arches of the vertebral column, containing inter alia the spinal cord and spinal roots. Spinal stenosis This can put pressure on the spinal cord and any of the nerves roots running from the neck to the lower back. and commonly occurs in the cervical (the neck) and lumbar (lower back) regions of the spine. Although some people may have spinal stenosis without experiencing any symptoms, many people experience pain, numbness, tingling, and muscle weakness, all of which can worsen over time if left untreated. The “condition of a bony canal” may be associated with or cause by arthritis.

[0070] The term “angiogenesis” as used herein refers to the growth of new capillary blood vessels from pre-existing vasculature, occurring during essential normal physiological processes, which however also contribute to a variety of pathological conditions, such as the unwanted vessel growth in chronic inflammatory diseases. Angiogenesis is a complex multistep process controlled by a wide range of positive and negative regulatory factors, including VEGF. Conversely, hypervascularity, i.e. an increased number or concentration of blood vessels, can result from misregulation of these factors.

[0071] The term “arthropathy” as used herein refers to a disease of a joint or joints, i.e. a particular abnormal condition that negatively affects the structure or function of all or part of the joint(s), and that is not immediately dueto any external injury. “Arthritis” is a form of arthropathy that involves inflammation of one or more joints. The arthritis may be infectious, i.e. caused by bacterial, viral or fungal infection that spreads from another part of the body, or non-infectious, i.e. caused by other factors.

[0072] As used herein, the phrase “mediated by” shall be understood to include “stimulated and / or inhibited by” as well as “related to”, e.g. the articular condition may be a joint disease related to at least one receptor tyrosine kinase (RTK).

[0073] The term “joint pain”, also referred to as arthralgia, as used herein refers to discomfort, aches or soreness in any of the body’s joints. The pain may be constant or come and go. It may be a result of illness or injury. However, it can also be due to other conditions or factors. In this context, joints are understood to be pivotal structures of the articular system that can be considered as discontinuities in the skeleton permitting controlled mobility, and can have different structures depending on their functional requirements. Further, a “synovial joint”, also known as diarthrosis, is understood to mean an enclosed space with a negative pressure, in which the bone ends that move against each other (the articular surfaces) are covered with articular cartilage. This is made up of proteoglycans and collagen, combined in such a way as to allow it to absorb huge forces of pressure like a shock absorber, while providing a shiny surface for smooth, low-friction movement. A healthy synovial joint is lubricated by a small amount of synovial fluid (0-4 mL), which is an ultrafiltrate of plasma with additional components secreted by the synovium. Cartilage and synovial fluid together maintain coefficients of friction of < 0.02. The fibrous joint capsule surrounds the diarthrosis and unites the articulating bones. It consists of two layers, the outer fibrous membrane that may contain ligaments and the inner synovial membrane that secretes the lubricating, shock absorbing, and joint-nourishing synovial fluid. In certain embodiments, the joint pain is associated with arthritis. In other embodiments, the joint pain is not associated with arthritis.

[0074] The term “chondrotoxicity” as used herein refers to cytotoxicity regarding chondrocytes, i.e. toxicity to cartilaginous tissue.

[0075] Whenever it is stated herein that a certain administration or injection is performed “concurrently with”, also referred to as “simultaneously to” or “at the same time as” an administration or injection of a depot according to the present invention, this means that the respective injection of either two or more depots or the injection of one or more depot(s) of the present invention together with the administration or injection of at least one other drug as disclosed herein is normally performed in close temporal proximity, such as administered in combination at the same time, immediately one after the other, i.e., without any significant delay. In case the at least one other drug is administered by articular injection also, this injection is also normally intended to take place immediately (as disclosed above) before or after the articular injection of the one or more depot(s) according to the present invention, such as during one treatment session. Alternatively, the at least one drug may be administered by articular injection together with the one or more depot(s), i.e. by the same hypodermic needle. Even if the at least one other drug is administered simultaneously with one or more depots of the present invention (as disclosed herein), the other drug does not have to have the same re-dosing frequency as the depot(s) of the present invention. Furthermore, the treatment of an articular condition in accordance with embodiments of the present invention as disclosed may be combined with one or more other treatment(s) of the same or another articular condition. The treatment period and / or dosing intervals of such other treatment(s) may correlate with, may overlap with, or may differ from the treatment period and / or dosing intervals of the depot(s) of the present invention. The other treatment(s) may be administered by any suitable route, including but not limited to orally, topically, by injection such as intravenous, intramuscular, intra-articular or any other type of injection.

[0076] As used herein, the terms “administration” or “administering” or “administered” etc. in the context of the depots of the present invention refer to the process of insertion of the depot(s) into a joint, in particular affected by the articular condition. Thus, “administering a depot” or similar terms refer to the insertion of the depot into the joint cavity or the surrounding tissues. The terms “insertion” or “inserting” or “inserted” etc. in the context of the depots of the present invention equally refer to the process of insertion of the depots into the joint by means of a hypodermic (from hypo- = under and derma = skin) needle, and are thus herein used interchangeably with the terms “administration” or “administering” or “administered”. In contrast, the terms “administration” or “administering” or “administered” etc. in the context of other drugs (which are not the subject of the present invention) may also refer to oral or topical application of these drugs.

[0077] The term “articular injection” as used herein refers to an administration / insertion into a joint including joint cavity and surrounding tissues by injection. In this context, the term “articular” generally refers to a joint or joints. The terms “intra-articular” and “periarticular” are understood to mean in the context of the present invention within the cavity of a joint or around a joint, i.e. into the surrounding tissues. Regardless of whether the injection was intra- articular or periarticular, the depot may change the location by itself to be located intra-articularly or periarticularly.

[0078] The term “injection into or near to the bony canal” as used herein refers to an administration / insertion into a bony canal, such as a carpal tunnel or a spinal canal, including (soft) tissues within or around the bony canal. In this context, an injection into the spinal canal is also referred to as “epidural injection”.

[0079] The term “treatment period” as used herein means that the therapeutic effect of a depot of the present invention once administered is maintained or essentially maintained over that period of time.

[0080] The term “depot” as used herein refers to an object that contains an active agent, specifically a tyrosine kinase inhibitor (TKI) such as axitinib, as well as other compounds as disclosed herein, and that is administered into the human or animal body, e.g., to the joint capsule of a synovial joint where it remains for a certain period of time while it releases the active agent into the surrounding environment. A depot can have any predetermined shape before being inserted, which general shape may be maintained to a certain degree upon placing the depot into the desired location, although 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 invention may be present as one unit or may consist of two or more units. The unit(s) may in certain embodiments be in the form of fiber(s) or beads. One dose of the TKI may be contained in one unit (for example in one fiber as disclosed herein), or in two or more units (for example in a plurality of beads as disclosed herein) that are administered simultaneously e.g. by means of one single injection. Whenever it is referred to the amount of active agent contained in the depot, this should be understood to refer to the total amount of active agent contained in the entirety of units comprised in the depot. The units may be the same or different. In certain embodiments, what is administered into the joint is an already shaped, coherent object. The depot has thus been completely formed (preformed, such as a fiber), e.g., according to the methods disclosed herein prior to being administered. In alternative embodiments, the depot may arise in situ, i.e. a solution or suspension is administered into the joint and the depot forms after injection in the aqueous environment at the desired site. Over the course of time the inserted depot in certain embodiments is biodegraded (as disclosed herein), and may thereby change its shape (e.g. may expand in diameter and optionally decrease in length) until it has been completely dissolved / resorbed. Herein, the term “depot” is used to refer both to a depot in a hydrated (also referred to herein as “wet”) state when it contains water, e.g. after the depot has been hydrated or re-hydrated once administered to the joint or otherwise immersed into an aqueous environment (such as in vitro), as well as to a depot in its / a dry (also referred to herein as “dried” or “dehydrated”) state (i.e., after the depot has been producedand dried, or after the depot has been manufactured in a dry state without the need for dehydration, and just prior to being administered as disclosed herein). In the art, in the dried state a “hydrogel” (such as the hydrogel contained in the depot of the invention) is sometimes also referred to as a “xerogel”. Thus, in certain embodiments, a depot in its dry / dried state in the context of the present invention may contain from about 0.01% by weight to about 10% by weight water, or from about 0.1% by weight to about 7% by weight water, or from about 0.25% by weight to about 5% by weight water, or no more than about 1% by weight water. The water content of a depot in its dry / dried state may be measured e.g. by means of a Karl Fischer coulometric method. Whenever dimensions of a depot (i.e., length, diameter, or volume) are reported herein in the hydrated state, these dimensions are measured after the depot has been immersed in phosphate-buffered saline at a pH value of 7.2 at 37 °C for 24 hours. Whenever dimensions of a depot are reported herein in the dry state, these dimensions are measured after the depot has been fully dried (and thus, in certain embodiments, contains no more than about 1 % by weight water). In certain embodiments, the depot is kept in an inert atmosphere glove box containing below 20 ppm of both oxygen and moisture for at least about 7 days.

[0081] In certain embodiments of the present invention, the term “fiber” (used interchangeably herein with the term “rod”) characterizes an object (i.e., in the present case a depot according to certain embodiments of the present invention) that in general has an elongated shape. Specific dimensions of depots of the present invention are disclosed herein. The depot or the unit(s) of the depot may have a cylindrical or essentially cylindrical shape, or may have a non-cylindrical shape. The cross-sectional area of the fiber or the depot may be either round or essentially round, but may in certain embodiments also be oval or oblong, or may in other embodiments have different geometries, such as cross-shaped, star-shaped or other as disclosed herein.

[0082] In other certain embodiments of the present invention, the term “beads” as used characterizes an object (i.e., in the present case a depot according to certain embodiments of the present invention) that in general has a spherical shape. The depot or the unit(s) of the depot may have a spherical or essentially spherical shape, or may have a non-spherical shape. The cross-sectional area of the beads or the depot may be either round or essentially round, but may in certain embodiments also be oval or oblong. The beads may be uniform, i.e. have a regular surface, or may be irregular. The particle size of the beads may be chosen with regard to the needle gauge that is intended to be used for administration, the carrier used (aqueous vs non-aqueous), and release kinetics control as a function of hydrated bead diameter. In certain embodiments, they may have a narrow particle size distribution, i.e. all beads constituting the depot may have an almost similar size. E.g., the beads in a dried 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-% of all particles within the measured bulk material (which has a certain particle size distribution) has a particle size below the indicated value. For example, a D90 particle size of less than about 220 μm means that at least 90 volume-% of the particles in the measured bulk material have a particle size below about 220 μm. Corresponding definitions apply to other “D” values, such as the “D50” or the “D100” value. The particle size distribution in any case 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 than axitinib is used in the present invention similar particle sizes may apply as disclosed for axitinib.

[0083] The term “sustained release” is generally defined for the purposes of the present invention to refer to pharmaceutical dosage forms or products (in the case of the present invention these products are depots which are formulated to make an active, such as a tyrosine kinase inhibitor according to the present invention, specifically including but not limited to axitinib), available over an extended period of time after administration, such as one ormore months, thereby allowing a reduction in dosing frequency compared to an immediate release dosage form, e.g. a solution of a tyrosine kinase inhibitor that is topically applied into the joint. Other terms that may be used herein interchangeably with “sustained release” are “extended release” or “controlled release”. “Sustained release” thus generally characterizes the release of an API, specifically, the tyrosine kinase inhibitor, such as axitinib, that is contained in a depot according to the present invention. The term “sustained release” per se is not associated with or limited to a particular rate of (in vitro or in vivo) release, although in certain embodiments of the invention a depot may be characterized by a certain average rate of (in vitro or in vivo) release or a certain release profile as disclosed herein. Within the specific meaning of the present invention, the term “sustained release” also comprises a period of constant or substantially constant (i.e., above a certain level) tyrosine kinase release per day when this period of constant or substantially constant release is followed by a period of tapered tyrosine kinase release. In such specific case, an overall sustained release provided by a 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 as just described (i.e., with an initial period of constant or essentially constant, i.e., sustained release, followed by a period of tapered release). Within the meaning of the invention, the term “tapered” or “tapering” refers to a decreasing release of tyrosine kinase inhibitor such as axitinib over time until the tyrosine kinase inhibitor is completely released. In some specific cases, the release profile may also show an initial drug burst and / or a terminal drug burst, indicated by a short-term increase of the respective release rate (in vitro or in vivo).

[0084] The term “biodegradable” as used herein refers to a material or object (such as the depot according to the present invention) which becomes degraded in vivo, i.e., when placed in the human or animal body. In the context of the present invention, as disclosed in detail herein, the depot comprising the hydrogel within which particles of a tyrosine kinase inhibitor, such as particles of axitinib, are dispersed, slowly biodegrades over time once deposited within the joint, e.g., within the joint capsule. In certain embodiments, biodegradation takes place at least in part via ester hydrolysis in the aqueous environment provided by the synovial fluid. In certain embodiments, the depots of the present invention slowly soften and liquefy, and are eventually cleared (disposed / washed out) from the joint.

[0085] A “hydrogel” is a three-dimensional network of one or more hydrophilic natural or synthetic polymers (as disclosed herein), optionally also containing hydrophobic domains, that can swell in water and hold an amount of water while maintaining or substantially maintaining its structure, e.g., due to chemical or physical cross-linking of individual polymer chains. Due to their high water content, hydrogels are soft and flexible, which makes them very similar to natural tissue. In the present invention the term “hydrogel” is used to refer both to a hydrogel in the hydrated state / “wet state” when it contains water (e.g. after the hydrogel has been formed in an aqueous solution, or after the hydrogel has been hydrated or re-hydrated once inserted into the joint or otherwise immersed into an aqueous environment) and to a hydrogel in its / a dry (dried / dehydrated) state when it has been dried to a low water content of e.g. not more than 1% by weight as disclosed herein. A dried form of a hydrogel is sometimes also referred to in the art as “xerogel”, which is a potential hydrogel or a dried hydrogel that can convert to a hydrogel upon exposure to and imbibition of water. The process of drying to form the xerogel can be accomplished is multiple ways and can result in various degrees of shrinkage and various degrees of 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 small size is advantageous, e.g. to fit into a small needle internal diameter. In some cases fast rehydration rate is advantageous, which is speeded by higher porosity. In the present invention, wherein an active principle is contained (e.g. dispersed) in a hydrogel, the hydrogel may also be referred to as a “matrix”.

[0086] The term “polymer network” as used herein describes a structure formed of polymer chains (of the same or different molecular structure and of the same or different average molecular weight) that are cross-linked with each other. Types of polymers suitable for the purposes of the present invention are disclosed herein. The polymer network may be formed with the aid of a crosslinking agent as also disclosed herein.

[0087] The term “amorphous” refers to a polymer or polymer network or other chemical substance or entity which does not exhibit crystalline structures in X-ray or electron scattering experiments.

[0088] The term “semi-crystalline” refers to a polymer or polymer network or other chemical substance or entity which possesses some crystalline character, i.e., exhibits some crystalline properties in X-ray or electron scattering experiments.

[0089] The term “crystalline” refers to a polymer or polymer network or other chemical substance or entity which has crystalline character as evidenced by X-ray or electron scattering experiments.

[0090] The term “precursor“ or “polymer precursor” or specifically “PEG precursor” herein refers to those molecules or compounds that are reacted with each other and that are thus connected via crosslinks to form a polymer network and thus the hydrogel matrix. While other materials might be present in the hydrogel, such as active agents, visualization agents or buffers, they are not referred to as “precursors”. The molecular weight of a polymer precursor as used for the purposes of the present invention and as disclosed herein may be determined by analytical methods known in the art. The molecular weight of polyethylene glycol can for example be determined by any method known in the art, including gel electrophoresis such as SDS-PAGE (sodium dodecyl sulphate–polyacrylamide gel electrophoresis), gel permeation chromatography (GPC), including GPC with dynamic light scattering (DLS), liquid chromatography (LC), as well as mass spectrometry such as matrix-assisted laser desorption / ionization-time of flight (MALDI-TOF) spectrometry or electrospray ionization (ESI) mass spectrometry. The molecular weight of a polymer, including a polyethylene glycol precursor as disclosed herein, is an average molecular weight (based on the polymer’s molecular weight distribution), and may therefore be indicated by means of various average values, including the weight average molecular weight (Mw) and the number average molecular weight (Mn). Any of such average values may generally be used in the context of the present invention. In the context of the present invention, the average molecular weight of the polyethylene glycol units or other precursors or units as disclosed herein is the number average molecular weight (Mn) and is indicated in the unit “Daltons”. The parts of the precursor molecules that are still present in a final polymer network are also called “units” herein. The “units” are thus the building blocks or constituents of a polymer network forming the 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.

[0091] As used herein, the term “crosslinking agent” or “crosslinker” refers to any molecule that is suitable for connecting precursors via crosslinks to form the polymer network and thus the hydrogel matrix. In certain embodiments, crosslinking agents may be low-molecular weight compounds or may be polymeric compounds as disclosed herein.

[0092] The term “visualization agent” as used herein refers to a molecule or composition that may be contained within a depot of the present invention and that provides the possibility of easily visualizing the depot in a non- invasive manner when it is located in the joint. The visualization agent may be a fluorophore such as fluorescein, rhodamine, coumarin, and cyanine, or other suitable agents as disclosed herein. In certain embodiments the visualization agent is fluorescein or includes a fluorescein moiety.

[0093] The terms “API”, “active (pharmaceutical) ingredient”, “active (pharmaceutical) agent”, “active (pharmaceutical) principle”, “(active) therapeutic agent”, “active”, and “drug” are used interchangeably herein andrefer to the substance used in a finished pharmaceutical product (FPP) as well as the substance used in the preparation of such a finished pharmaceutical product, intended to furnish pharmacological activity or to otherwise have direct effect in the diagnosis, cure, mitigation, treatment or prevention of a disease, or to have direct effect in restoring, correcting or modifying physiological functions in a patient. The API used according to the present invention is a tyrosine kinase inhibitor such as axitinib.

[0094] Tyrosine kinase inhibitors were developed as chemotherapeutics that inhibit signaling of receptor tyrosine kinases (RTKs), which are a family of tyrosine protein kinases. RTKs span the cell membrane with an intracellular (internal) and extracellular (external) portion. Upon ligand binding to the extracellular portion, receptor tyrosine kinases dimerize and initiate an intracellular signaling cascade driven by autophosphorylation using the coenzyme messenger adenosine triphosphate (ATP). Many of the RTK ligands are growth factors such as VEGF. In certain embodiments, the TKI used according to the present invention is axitinib. Axitinib is the active ingredient in INLYTA® (Pfizer, NY), 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 inhibition of angiogenesis (the formation of new blood vessels) by inhibition of receptor tyrosine kinases, primarily: VEGFR-1, VEGFR-2, VEGFR-3, PDGFR- ^ and c-Kit (, Retina, 32(8):1652-63), which are involved in pathologic angiogenesis, tumor growth, and cancer progression. Axitinib is therefore a multi-target inhibitor that inhibits both VEGF and PDGF pathways. The molecular formula of axitinib is C22H18N4OS, and its IUPAC name is N-methyl-2-[3-((E)-2-pyridin-2-yl-vinyl)-1H-indazol-6- ylsulfanyl]-benzamide. It has the following chemical structure: The solubility of axitinib in biorelevant media (PBS, pH 7.2 at 37 ^C) has been determined to be low, such as 0.2 to 0.5 ^g / mL. Its partition coefficient (n-octanol / water) is 4.2 (logP; cf. DrugBank entry “axitinib”). In certain embodiments, for any tyrosine kinase inhibitor used in the present invention, including axitinib, particle sizes (e.g. as expressed by the D90 value) of about 100 μm or below, or of about 75 μm or below, or of about 50 μm or below may be used. In particular embodiments of the present invention, axitinib may be used in the form of micronized particles and may have a D90 particle size of equal to or less than about 100 μm, or of equal to or less than about 75 μm, or of equal to or less than about 50 μm, or of equal to or less than about 20 μm, or of equal to or less than about 10 μm, or of equal to or less than about 5 µm. In these and other embodiments, the D100 particle size of the micronized axitinib may be equal to or less than about 100 μm, or equal to or less than about 75 μm, or equal to or less than about 50 μm, or equal to or less than about 20 μm, or equal to or less than about 10 μm, or equal to or less than about 5 µm. In particular embodiments of the present invention, the micronized axitinib has a D90 particle size of equal to or less than about 10 µm and a d100 particle size of less than about 20 µm. The particle size distribution of the 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 than axitinib is used in the present invention similar particle sizes may apply as disclosed for axitinib.

[0095] For the purposes of the present invention, active agents (including axitinib) in all their possible forms, including any active agent polymorphs or any pharmaceutically acceptable salts, anhydrates, hydrates, othersolvates, prodrugs, or derivatives of active agents, such as axitinib, can be used. Whenever in this description or in the claims an active agent is referred to by name, e.g., “axitinib”, even if not explicitly stated, it also refers to any such polymorphs, pharmaceutically acceptable salts, anhydrates, solvates (including hydrates) or derivatives of the active agent. Particularly, the term “axitinib” refers to axitinib and pharmaceutically acceptable salts thereof, which may all be used for the purposes of the present invention. The term “polymorph” as used herein refers to any crystalline form of an active agent such as axitinib. Frequently, active agents that are solid at room temperature exist in a variety of different crystalline forms, i.e., polymorphs, with one polymorph being the thermodynamically most stable at a given temperature and pressure. With respect to axitinib, solid forms and polymorphs of axitinib including anhydrous forms and solvates are disclosed in the scientific literature, e.g. A.M.Campeta et al., Journal of Pharmaceutical Sciences, Vol.99, No.9, September 2010, 3874-3886; B.P. Chekal et al., Organic Process Research & Development 2009, 13, 1327-1337; and in the patent literature, including, but not limited to US 8,791,140 B2, US 2006 / 0094763 A1, and WO 2016 / 178150 A1. The most thermodynamically stable polymorph of axitinib is referred to as form XLI in e.g. US 8,791,140 B2. XLI is an anhydrous crystalline form of axitinib. In addition to the anhydrous forms, there exist numerous solvates of axitinib with various solvents, as also described in the cited art, which can all be used for preparing depots according to the present invention. Any of the axitinib polymorphic forms known and disclosed in the art, specifically (but not limited to) the references cited herein, may generally be used in the present invention (unless the specific aspect of the invention requires a particular solubility, as explained above, in which case only those axitinib polymorphs that meet this requirement may be used). In certain embodiments of the invention, the axitinib used for preparing the depots according to the present invention is the anhydrous crystalline form XLI. In other embodiments, the axitinib used for preparing the depots according to the present invention is the anhydrous crystalline form IV. In certain other embodiments, crystalline anhydrous forms of axitinib that are suitable for use in the depots of the present invention include (but are not limited to) polymorphs I, VI, and XXV. These forms are disclosed in the Campeta et al. reference cited above.

[0096] In particular aspects and embodiments of the invention, the non-solvated crystalline form SAB-I of axitinib disclosed in WO 2016 / 178150 may be used for preparing the depots according to the present invention. It is characterized by an XRD pattern comprising at least three, or at least four, or at least five characteristic 2 ^° peaks selected from 8.3, 15.6, 16.5, 18.6, 21.0, 23.1, 24.1 and 26.02 ^° (all values ± 0.3), and / or13C NMR in DMSO solvent comprising chemical shifts at 26.1, 114.7, 154.8 and 167.8, each shift ± 0.2 ppm, and / or13C solid state NMR comprising chemical shifts at 171.1, 153.2, 142.6, 139.5, 131.2, 128.1 and 126.3, each shift ± 0.2 ppm, and / or characterized by a DSC isotherm comprising two endothermic peaks ranging between 213 °C to 217 °C (Peak 1) and 219 °C to 224 °C (Peak 2).

[0097] In certain embodiments of the present invention, a tyrosine kinase inhibitor, such as axitinib, may be used for preparing the depots according to the present invention that has a solubility of greater than 0.3 µg / mL as measured in phosphate-buffered saline (PBS) at a pH of 7.2 to 7.4 and 37 °C after five days of incubation. Axitinib polymorph form IV is a particularly suitable polymorph of axitinib. Polymorph IV is disclosed for example in US 2006 / 0094763 A1. Axitinib polymorph IV is thus a particular form of axitinib that may be used in embodiments of all aspects of the present invention. The solubility of axitinib polymorph IV is about twice the solubility of e.g. axitinib polymorph SAB-I, and at 37°C in PBS with a pH of 7.2 to 7.4 (or at a pH of 7.2) after 5 days of incubation has been determined to be above 0.3 µg / mL, and at least 0.4 µg / mL under these conditions.

[0098] In certain specific embodiments, the axitinib contained in or used for preparing the depots according to the present invention alternatively is characterized by a powder X-ray diffraction pattern comprising at least two, such as at least three, or at least four, or at least five of the following peaks at diffraction angles (2 ^) of 8.90, 9.40, 9.50, 12.0, 14.60, 15.25, 15.75, 17.80, 19.30, 20.65, 24.95, 26.10 (all values ± 0.2). Particularly, the axitinib used for preparing the depots according to this aspect of the present invention may be characterized by a powder X-ray diffraction pattern comprising the following peaks at diffraction angles (2 ^) of: 8.90, 12.0, 14.60, 15.75, and 19.30 (all ± 0.2), and / or characterized by a DSC peak at about 221 °C at a scan rate of 5°C / min (over a range of 25 to 300 °C).

[0099] Besides axitinib polymorph IV, any other suitable form of axitinib that has a solubility of greater than 0.3 µg / mL as measured in phosphate-buffered saline (PBS) at a pH of 7.2 to 7.4 and 37 °C after five days of incubation may be used in all aspects of the present invention for preparing the depots of the present invention. Such forms include for example (but are not limited to) co-crystals of axitinib and prodrugs or derivatives of axitinib.

[0100] Axitinib co-crystals with carboxylic acids, including but not limited to one or more of citric acid, fumaric acid, (+)-L- or (-)-D tartaric acid, glutaric acid, (trans- or cis) cinnamic acid, suberic acid, succinic acid, adipic acid, pimelic acid, salicylic acid, as co-formers are particularly suitable to be used in the present invention. Co-crystals of axitinib are disclosed for example in B-Y Ren et al., Cryst Eng Comm.2021, 23, 5504-5515. Suitable axitinib co-crystals for use in the depots according to the present invention as well as their synthesis and properties are also for example disclosed in co-pending US provisional application 63 / 458,558 filed April 11, 2023. All of the axitinib co-crystals disclosed in any of these references, but not limited to these, are generally suitable for use in the present invention.

[0101] In certain embodiments, axitinib co-crystals have a solubility of greater than 0.3 µg / mL as measured in phosphate-buffered saline (PBS) at a pH of 7.2 to 7.4 and 37 °C after five days of incubation.

[0102] In certain embodiments, an axitinib co-crystal may have a solubility that is at least 2 times, at least 5 times, at least 10 times, at least 25 times, at least 50 times, at least 75 times, or at least 100 times the solubility of axitinib free base.

[0103] In certain embodiments, an axitinib co-crystal has a solubility in PBS at pH 7.4 after 24 hours at 37 °C of at least 10 µg / mL, such as at least 12 µg / mL, at least 15 µg / mL, or at least 18 µg / mL. An axitinib co-crystal with citric acid has a mean solubility in PBS at pH 7.4 after 24 hours at 37 °C of about 19 µg / mL; an axitinib co-crystal with fumaric acid has a mean solubility in PBS at pH 7.4 after 24 hours at 37 °C of about 12 µg / mL; and an axitinib co- crystal with (+)-L-tartaric acid has a mean solubility in PBS at pH 7.4 after 24 hours at 37 °C of between about 19 and 20 µg / mL.

[0104] Suitable axitinib prodrugs for use in the depots according to the present invention as well as their synthesis and properties are disclosed in co-pending US provisional application US 63 / 416,292 and in co-pending international application PCT / US2022 / 046750. Further suitable axitinib prodrugs for use in the depots according to the present invention are disclosed in US 2021 / 0078970. All of the axitinib prodrugs disclosed in any of these references, but not limited to these, are generally suitable for use in the present invention.

[0105] In the present invention, examples for particularly suitable axitinib prodrugs are those wherein the axitinib molecule is functionalized at one or more of the nitrogen atoms of the axitinib free base. For example, in an axitinib prodrug for use according to the present invention one or more of the nitrogen atoms in the axitinib free base may 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 ^-aminoalkanoyl, an acyl group derived from a natural or an unnatural amino acid with or without substitution, 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 substituents.

[0106] In certain embodiments, an axitinib prodrug for use in the present invention is a compound of general formula (I) depicted below, or a salt or solvate thereof: (I) wherein: X1is selected from N or N+Y1; X2is selected from NH or NY2; X3is selected from NH or NY3; Y1is selected from –CH2OCO(OCH2CH2)n1OM1; or –CH2OCO(CH2CH2O)n1aZ1; or –CH2OCO(CH2)n1bCOOH; Y2is selected from –CH2OCO(OCH2CH2)n2OM2; or –CH2OCO(CH2CH2O)n2aZ2; or –CH2OCO(CH2)n2bCOOH; Y3is selected from –CH2OCO(OCH2CH2)n3OM3; or –CH2OCO(CH2CH2O)n3aZ3; or –CH2OCO(CH2)n3bCOOH; n1, n1a, n1b, n2n2a, n2b, n3, n3aand n3bare independently 0 or an integer from 1 to 8; M1, M2, M3, Z1, Z2and Z3are independently selected from H, optionally substituted C1-6 alkyl and optionally substituted aryl; wherein at least one of X1, X2and X3is not N or NH; wherein at least one of Y1, Y2or Y3is / are the respective –CH2OCO(CH2CH2O)nZ.

[0107] In certain other embodiments, in the above general formula (I) Y1, Y2and Y3are independently selected from the respective –(CH2)p1OCO(O(CH2)p2)n1OM; or –(CH2)p1aOCO((CH2)p2O)n1(CH2)Z; or –(CH2)p1OCO(CH2)q1COOH; wherein p1, p1aand p2are independently selected from an integer from 1 to 4, and q1is independently selected from an integer from 0 to 4, with the other meanings as defined above for formula (I).

[0108] In certain embodiments, the following prodrugs are suitable in the present invention, wherein in the above formula (I): X1is N+Y1; X2is NH; X3is NH; and Y1is –CH2OCO(CH2CH2O)n1aZ1or –CH2OCO(CH2)n1bCOOH, or: X1is N; X2is NY2; X3is NH; and Y2is –CH2OCO(CH2CH2O)n2aZ2or –CH2OCO(CH2)n2bCOOH, or: X1is N; X2is NH; X3is NY3; and Y3is –CH2OCO(CH2CH2O)n3aZ3or –CH2OCO(CH2)n3bCOOH.

[0109] In certain embodiments, in the above formula (I): n10, 1, 2, 3, 4, 5, 6, 7 or 8; or 1-3 or 4-6 or 7-8; n2is 0, 1, 2, 3, 4, 5, 6, 7 or 8; or 1-3 or 4-6 or 7-8; n3is 0, 1, 2, 3, 4, 5, 6, 7 or 8; or 1-3 or 4-6 or 7-8; n1ais 0, 1, 2, 3, 4, 5, 6, 7 or 8; or 1-3 or 4-6 or 7-8; n2ais 0, 1, 2, 3, 4, 5, 6, 7 or 8; or 1-3 or 4-6 or 7-8; n3ais 0, 1, 2, 3, 4, 5, 6, 7 or 8; or 1-3 or 4-6 or 7-8; n1bis 0, 1, 2, 3, 4, 5, 6, 7 or 8; or 1-3 or 4-6 or 7-8; n2bis 0, 1, 2, 3, 4, 5, 6, 7 or 8; or 1-3 or 4-6 or 7-8;n3bis 0, 1, 2, 3, 4, 5, 6, 7 or 8; or 1-3 or 4-6 or 7-8.

[0110] In certain embodiments, in the above formula (I): M1is methyl, ethyl, propyl or phenyl; M2is methyl, ethyl, propyl or phenyl; M3is methyl, ethyl, propyl or phenyl; Z1is methyl, ethyl, propyl or phenyl; Z2is methyl, ethyl, propyl or phenyl; Z3is methyl, ethyl, propyl or phenyl.

[0111] In certain further embodiments, n1, n2or n3is 2, 3 or 4, and / or n1a, n2aor n3ais 2, 3 or 4 and / or n1b, n2bor n3bis 2, 3 or 4.

[0112] In certain specific embodiments, an axitinib prodrug to be used in the implants according to the present invention is selected from: axitinib-N-succinoyloxymethyl prodrug, axitinib-N-mPEG-oxymethyl prodrug, including but not limited to axitinib-N-m(PEG)1-oxymethyl, axitinib-N-m(PEG)2-oxymethyl, axitinib-N-m(PEG)3-oxymethyl, axitinib-N- m(PEG)4-oxymethyl, or a salt or solvate thereof, as shown below.

[0113] Axitinib prodrugs, especially prodrugs with a hydrophilic substituent as disclosed herein, may exhibit a higher solubility than axitinib free base. Such prodrugs may have a solubility that is 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 the solubility of axitinib free base.

[0114] Axitinib prodrugs for use in implants of the present invention may have a solubility in PBS at pH 7.4 after 24 hours at 22 °C of at least 50 µg / mL, or at least 90 µg / mL, or at least 150 µg / mL, or at least 200 µg / mL.

[0115] The following are exemplary axitinib prodrugs to be used in implants of the present invention: axitinib-N-succinoyloxymethyl prodrug (total Mw: 516.57) solubility in PBS at pH 7.2 to 7.4 after 24 hours incubation at 22 °C: 217.4 µg / mL axitinib-N-m(PEG)4-oxymethyl prodrug (total Mw: 634.74)solubility in PBS at pH 7.2 to 7.4 after 24 hours incubation at 22 °C: 99.37 µg / mL O O O NNS N NH O Axitinib-N-m(PEG)1-oxymethyl prodrug. IUPAC Name: 3-Methoxy-propionic acid 6-(2-methylcarbamoyl- phenylsulfanyl)-3-((E)-2- -pyridin-2-yl-vinyl)-indazol-1-ylmethyl ester (total Mw: 502.28) O O O O NNS N NH O Axitinib-N-m(PEG)2-oxymethyl prodrug. IUPAC Name: 3-(2-Methoxy-ethoxy)-propionic acid 6-(2- methylcarbamoyl-phenylsulfanyl)-3-((E)-2-pyridin-2-yl-vinyl)-indazol-1-ylmethylester (total Mw: 546.63) O O O O O NNS N NH O Axitinib-N-m(PEG)3-oxymethyl prodrug. IUPAC Name: 3-[2-(2-Methoxy-ethoxy)-ethoxy]- propionic acid 6-(2-methylcarbamoyl-phenylsulfanyl)-3-((E)-2-pyridin-2-yl-vinyl)-indazol-1-ylmethyl ester (total Mw: 590.68)

[0116] As used herein, the term “therapeutically effective” refers to the amount of drug or active agent needed to produce a desired therapeutic result after administration. For example, in the context of the present invention, onedesired therapeutic result would be the reduction of pain in a patient suffering from pain. A “therapeutically effective” amount of an active agent in the context of the present invention may also be a multiple of the IC50this active agent provides against a particular substrate, such as 50 or more times the IC50.

[0117] The term “patient” herein includes both human and animal patients. The depots according to the present invention are generally suitable for human or veterinary medicinal applications. The patients may also be referred to as “subjects”. Generally, a “subject” is a (human or animal) individual to which a depot according to the present invention is administered, such as during a clinical study. A “patient” is a subject in need of treatment due to a particular physiological or pathological condition.

[0118] As used herein, the term “room temperature” refers to the unmodified temperature found indoors in the laboratory where the experiments are conducted and usually lies within 15 to 35 °C, preferably about 18 to 25 °C.

[0119] As used herein, the term “body temperature” usually refers to human body temperature which is in a range of 36.5 to 37.5 °C, preferably about 37 °C.

[0120] The term “carrier” as used herein refers to an accompanying medium which may be administered along with the depot (and in which the depot, such as the beads in certain embodiments, is suspended). The carrier may be non-aqueous, thus having the characteristics of a liquid other than water. The (non-aqueous) carrier may be (but is not limited to) an oil-based carrier, i.e. may be based on a pharmaceutically acceptable (vegetable) oil, in particular in diluted form. In this context, a “pharmaceutically acceptable” material is understood to be biologically or pharmacologically compatible for in vivo use in human or animal species.

[0121] The term “average” as used herein refers to a central or typical value in a set of data(points), which is calculated by dividing the sum of the data(points) in the set by their number (i.e., the mean value of a set of data).

[0122] As used herein, the term “about” in connection with a measured quantity refers to the normal variations in that measured quantity, as expected by one of ordinary skill in the art in making the measurement and exercising a level of care commensurate with the objective of measurement and the precision of the measuring equipment.

[0123] As used herein, the term “at least about” in connection with a measured quantity refers to the normal variations in the measured quantity, as expected by one of ordinary skill in the art in making the measurement and exercising a level of care commensurate with the objective of measurement and precisions of the measuring equipment and any quantities higher than that.

[0124] As used herein, the singular forms "a," "an", and "the" include plural references unless the context clearly indicates otherwise.

[0125] The term "and / or" as used in a phrase such as "A and / or B" herein is intended to include both "A and B" and "A or B”.

[0126] Open terms such as "include," "including," "contain," "containing" and the like as used herein mean "comprising" and are intended to refer to open-ended lists or enumerations of elements, method steps, or the like and are thus not intended to be limited to the recited elements, method steps or the like but are intended to also include additional, unrecited elements, method steps or the like.

[0127] The term “up to” when used herein together with a certain value or number is meant to include the respective value or number. For example, the term “up to 14 days” means “up to and including 14 days”.

[0128] The abbreviation “PBS” when used herein means phosphate-buffered saline.

[0129] The abbreviation “PEG” when used herein means polyethylene glycol.

[0130] All references disclosed herein are hereby incorporated by reference in their entireties for all purposes (with the instant specification prevailing in case of conflict).DETAILED DESCRIPTION I. Therapy

[0131] The present invention generally relates to a method of treating a condition and in particular to a method of treating an articular condition or to a method of treating a condition of a bony canal in a patient in need thereof, using a sustained release biodegradable depot comprising a hydrogel and a tyrosine kinase inhibitor. One particular tyrosine kinase inhibitor for use in all aspects of the present invention is axitinib. Details on axitinib, its chemical structure and its properties such as solubility are disclosed herein in the definitions section.

[0132] In one embodiment, the invention also relates to a sustained release biodegradable depot comprising a hydrogel and a tyrosine kinase inhibitor for use in treating a condition and in particular for use in treating an articular condition or for use in treating a condition of a bony canal in a patient in need thereof.

[0133] In one embodiment, the invention also relates to the use of a sustained release biodegradable depot comprising a hydrogel and a tyrosine kinase inhibitor in the preparation of a medicament for treating a condition and in particular in the preparation of a medicament for treating an articular condition or in the preparation of a medicament for treating a condition of a bony canal in a patient in need thereof.

[0134] The present invention in one aspect generally relates to a method of treating an articular condition (such as arthritis) in a patient in need thereof, 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 articular injection.

[0135] The present invention in another aspect generally relates to a method of treating an articular condition (such as arthritis) in a patient in need thereof, the method comprising administering to the patient a plurality of sustained release biodegradable beads, each comprising a hydrogel and a tyrosine kinase inhibitor, wherein the plurality of beads is administered by articular injection.

[0136] The present invention in yet another aspect generally relates to a method of treating an articular condition (such as arthritis) in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of an injectable pharmaceutical preparation comprising a sustained release biodegradable depot and a carrier as disclosed further below or manufactured in accordance with the methods as disclosed further below, wherein by articular injection.

[0137] relates to a method of treating a condition of a bony canal in a patient in need thereof, the method comprising biodegradable fiber comprising a hydrogel and a tyrosine kinase by injection into or near the bony canal.

[0138] The present invention in another aspect generally relates to a method of treating a condition of a bony canal (such as carpal tunnel syndrome or spinal stenosis) in a patient in need thereof, the method comprising administering to the patient a plurality of sustained release biodegradable beads, each comprising a hydrogel and a tyrosine kinase inhibitor, wherein the plurality of beads is administered by injection into or near to the bony canal.

[0139] The present invention in yet another aspect generally relates to a method of treating a condition of a bony canal (such as carpal tunnel syndrome or spinal stenosis) in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of an injectable pharmaceutical preparationcomprising a sustained release biodegradable depot and a carrier as disclosed further below or manufactured in accordance with the methods as disclosed further below, wherein the pharmaceutical preparation is administered by injection into or near to the bony canal.

[0140] In all these aspects, a particular tyrosine kinase inhibitor for use in the present invention is axitinib.

[0141] In all these aspects, the articular condition in certain embodiments of the invention may be (infectious or non-infectious) arthritis.

[0142] In all these aspects, the condition of a bony canal in certain embodiments of the invention may be carpal tunnel syndrome or spinal stenosis.

[0143] The fibers and beads may be used in the method of treatment according to the present invention separately or in combination. They may be present in an injectable pharmaceutical preparation, further comprising a carrier, separately or in combination.

[0144] In one specific aspect, the present invention is generally directed to a method of reducing pain, in particular joint pain in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of an injectable pharmaceutical preparation comprising a sustained release biodegradable depot and a carrier as disclosed further below or manufactured in accordance with the methods as disclosed further below, wherein the pharmaceutical preparation is administered by injection, in particular articular injection.

[0145] In another specific aspect, the present invention is generally directed to a method of reducing inflammation, in particular associated with arthropathy, in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of an injectable pharmaceutical preparation comprising a sustained release biodegradable depot and a carrier as disclosed further below or manufactured in accordance with the methods as disclosed further below, wherein the pharmaceutical preparation is administered by injection, in particular articular injection.

[0146] In another specific aspect, the present invention is generally directed to a method of reducing hypervascularity associated with arthritis in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of an injectable pharmaceutical preparation comprising a sustained release biodegradable depot and a carrier as disclosed further below or manufactured in accordance with the methods as disclosed further below, wherein the pharmaceutical preparation is administered by articular injection.

[0147] In another specific aspect, the present invention is generally directed to a method of slowing down, arresting or reversing progressive structural tissue damage associated with arthritis in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of an injectable pharmaceutical preparation comprising a sustained release biodegradable depot and a carrier as disclosed further below or manufactured in accordance with the methods as disclosed further below, wherein the pharmaceutical preparation is administered by articular injection.

[0148] In another specific aspect, the present invention is generally directed to a method of slowing down, arresting or reversing loss of joint function associated with arthritis in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of an injectable pharmaceutical preparation comprising a sustained release biodegradable depot and a carrier as disclosed further below or manufactured in accordance with the methods as disclosed further below, wherein the pharmaceutical preparation is administered by intra-articular or periarticular injection.

[0149] In another specific aspect, the present invention is generally directed to a method of improving joint function associated with arthritis in a patient in need thereof, the method comprising administering to the patient atherapeutically effective amount of an injectable pharmaceutical preparation comprising a sustained release biodegradable depot and a carrier as disclosed further below or manufactured in accordance with the methods as disclosed further below, wherein the pharmaceutical preparation is administered by intra-articular or periarticular injection.

[0150] In another specific aspect, the present invention is generally directed to a method of slowing down, arresting or reversing tingling, weakness or numbness of extremities, in particular of fingers associated with carpal tunnel syndrome, or of arms or legs associated with spina stenosis, in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of an injectable pharmaceutical preparation comprising a sustained release biodegradable depot and a carrier as disclosed further below or manufactured in accordance with the methods as disclosed further below, wherein the pharmaceutical preparation is administered by injection into or near to the carpal tunnel or by epidural injection.

[0151] In another specific aspect, the present invention is generally directed to a method of reducing compression of nervous tissue, in particular of pressure on the median nerve associated with carpal tunnel syndrome, or of the spinal cord or nerve roots associated with spinal stenosis, in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of an injectable pharmaceutical preparation comprising a sustained release biodegradable depot and a carrier as disclosed further below or manufactured in accordance with the methods as disclosed further below, wherein the pharmaceutical preparation is administered by injection into or near to the carpal tunnel or by epidural injection.

[0152] The patient to be treated in accordance with all aspects of the present invention may be a human or animal subject suffering from an articular condition or a condition of a bony canal. In particular, the patient to be treated may be a human or animal subject in need of an arthritis therapy, such as an osteoarthritis therapy of the hip or knee. Alternatively, the patient to be treated may be a human or animal subject in need of a carpal tunnel syndrome therapy or spinal stenosis therapy. Thus, in some embodiments, the method of treating an articular condition is a method of treating a human patient. Alternatively, the method of treating an articular condition is a method of treating an animal subject, such as a farm animal (such as a horse, including horses for competitions, cow, pig) or a companion animal (such as a dog, cat, or rodent).

[0153] Specific embodiments and features of the method of treating a condition according to the present invention are disclosed below. Method of Treatment Articular Condition:

[0154] The articular condition to be treated may be any articular disease, disorder or discomfort. In certain embodiments, the articular conditions affect at least one joint. In some embodiments, the articular condition affects one single joint. In other embodiments, the articular condition affects two or more joints. The articular condition may further affect the adjacent tissues surrounding the joint or joints.

[0155] In certain embodiments, the articular condition is an inflammatory articular condition. The inflammatory articular condition may be caused by an injury, infection or irritant. An injury to a joint usually causes localized inflammation. In some embodiments, the inflammatory articular condition may include synovitis, bursitis or tendinitis.

[0156] In certain embodiments, the articular condition involves angiogenesis. The angiogenesis may be stimulated by at least one angiogenesis regulator, such as, e.g., angiogenin, angiopeietin-1, angiotensin II, bradykinin, connective tissue growth factor, endoglin, endothelial cell-stimulating 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, pleiothrophin, soluble E-selectin, stem cell-derive factor-1, thrombospondin, vascular cell adhesion molecule-1,or VEGF. In some embodiments, the angiogenesis may be associated with inflammation.

[0157] In certain embodiments, the articular condition is arthropathy. In some embodiments the articular condition is reactive arthropathy, i.e. caused by an infection, enteropathic arthropathy, i.e. caused by colitis and related conditions, or diabetic arthropathy, i.e. caused by diabetes. In other embodiments, the articular condition is neuropathic arthropathy, i.e. associated with a loss of sensation. According to one embodiment, the articular condition may be spondylarthropathy, i.e. any form of arthropathy of the vertebral column.

[0158] In certain particular embodiments, the articular condition is arthritis. The arthritis may be an infectious or non-infectious arthritis. In some embodiments, the articular condition is rheumatoid arthritis (RA), i.e. a long-term autoimmune disorder that primarily affects joints, juvenile arthritis (JA), i.e. an autoimmune, non-infective, inflammatory joint disease that is onset before 16 years of age, or psoriatic arthritis (PsA), a long-term inflammatory arthritis caused by psoriasis. In other embodiments, the articular condition may be gouty or pseudogouty arthritis, i.e. a form of inflammatory arthritis caused by needle-like crystals of uric acid know as monosodium urate crystals or caused by calcium pyrophosphate dehydrate crystals, respectively. In further embodiments, the articular condition may be systemic lupus erythematosus (SLE), i.e. an autoimmune condition that can affect many different organs and the body's tissues, or ankylosing spondylitis (AS), i.e. a long-term inflammatory condition that mainly affects the bones, muscles and ligaments of the spine.

[0159] In one particular embodiment of the present invention, the arthritis is osteoarthritis (OA). The osteoarthritis may be selected from hip osteoarthritis, knee osteoarthritis, feet osteoarthritis, or osteoarthritis of the finger joint.

[0160] The pathological models for OA include intra-articular injection of monosodium iodoacetate (MIA) in the rat fernoro-tibial joint space, which has been has been reported to produce significant pain-related behaviour (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 local inflammation followed by the production of several cytokines (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). The development of the above pathological signs in this animal model are believed to be clinically relevant, reflecting the symptoms displayed by patients presenting 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). For the effects of the method of treatment according to the invention to rats with MIA-induced OA reference is made to Example 4.

[0161] In certain embodiments, the articular condition is a joint disease 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 articular condition is a joint disease mediated by VEGFR-1 and VEGFR-2. VEGFR-1 and / or VEGFR-2 activity may be influenced by at least one tyrosine kinase inhibitor, such as axitinib.

[0162] In certain embodiments, the articular condition is linked to TRPV1 expression, i.e. to the expression of the vanilloid receptor 1, also known as capsaicin receptor.

[0163] In certain embodiments, the articular condition is joint pain. The joint pain may be chronic, and may last for at least 3-6 months. It may be related to problems with the bones of or near the joint, or it may be related to problems with the tendons, ligaments or muscles around the joint. In some embodiments, the joint pain may be nociceptive pain. In other embodiments, the joint pain may be neuropathic pain. In some particular embodiment, the articular condition is joint pain caused by arthritis, such as osteoarthritis.

[0164] The method of treating an articular condition according to the invention in certain embodiments may be provided without or with reduced cartilage destruction, i.e. without being chondrotoxic or with reduced chondrotoxicity. As demonstrated by Example 5, when performing the method of treatment according to the invention by intra-articular administration of an axitinib sustained release biodegradable depot, no histopathologic evidence of chondrotoxicity was detected. In certain embodiments, the method according to the invention does not impair the viability of human chondrocytes. In particular, the chondrotoxicity in human chondrocytes is less than 10%, less than 8% or less than 5% during the period of administration.

[0165] In certain embodiments only mild or moderate adverse events are observed over the treatment period. In certain embodiments no serious articular adverse events are observed over the treatment period, and no treatment- related serious articular adverse events are observed. Condition of a bony canal:

[0166] The condition of a bony canal to be treated may be any disease, disorder or discomfort related to a bony canal. In certain embodiments, the condition of a bony canal affects at least one bony canal. In some embodiments, the condition of a bony canal affects one single bony canal. In other embodiments, the condition of a bony canal affects two or more bony canals. The condition of a bony canal may further affect the adjacent tissues surrounding the bony canal or bony canals.

[0167] In certain embodiments, the condition of a bony canal is an inflammatory condition of a bony canal. The inflammatory condition of a bony cnal may be caused by an injury, infection or irritant. An injury to a bony canal usually causes localized inflammation. In some embodiments, the (inflammatory) condition of a bony canal may be associated with arthritis.

[0168] In certain embodiments, the condition of a bony canal involves angiogenesis. The angiogenesis may be stimulated by at least one angiogenesis regulator, such as, e.g., angiogenin, angiopeietin-1, angiotensin II, bradykinin, connective tissue growth growth factor, epidermal growth factor, fractalkine, hepatocyte growth molecular weight), IL-1, IL-4, IL-8, IL- 18, nitric oxide, platelet-derived E-selectin, stem cell-derive factor- 1, thrombospondin, vascular cell the angiogenesis may be associated with inflammation.

[0169] In certain embodiments, thenarrowing, i.e. stenosis, of the bony canal, such as the carpal tunnel or (cervical or lumbar) spinal canal.

[0170] In certain embodiments, the condition of a bony canal involves compression of nervous tissue, in particular compression of the median nerve as known in connection with carpal tunnel syndrome, or compression of the spinal cord or nerve roots as known in connection with spinal stenosis.

[0171] In certain particular embodiments, the condition of a bony canal is carpal tunnel syndrome. In certain other particular embodiments, the condition of a bony canal is spinal stenosis, in particular cervical spinal stenosis or lumbar spinal stenosis.

[0172] In certain embodiments, the condition of a bony canal is a bony canal disease 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 condition of a bony canal is a bony canal disease mediated by VEGFR-1 and VEGFR-2. VEGFR-1 and / or VEGFR-2 activity may be influenced by at least one tyrosine kinase inhibitor, such as axitinib.

[0173] In certain embodiments, the condition of a bony canal is linked to TRPV1 expression, i.e. to the expression of the vanilloid receptor 1, also known as capsaicin receptor.

[0174] In certain embodiments, the condition of a bony canal is pain in or around the bony canal. The pain may be chronic, and may last for at least 3-6 months. It may be related to problems with the structures of or near the bony canal, or it may be related to problems with the tendons, ligaments or muscles around the bony canal. In some embodiments, the pain may be nociceptive pain. In other embodiments, the pain may be neuropathic pain. In some particular embodiment, the condition of a bony canal is pain caused by carpal tunnel syndrome, or pain caused by spinal stenosis.

[0175] In certain embodiments, the method according to the invention does not impair the viability of human chondrocytes. In particular, the chondrotoxicity in human chondrocytes is less than 10%, less than 8% or less than 5% during the period of administration.

[0176] In certain embodiments only mild or moderate adverse events are observed over the treatment period. In certain embodiments no serious articular adverse events are observed over the treatment period, and no treatment- related serious articular adverse events are observed. Effectiveness:

[0177] The effectiveness of the method of treating a condition according to the present invention in certain embodiments is shown in the examples section (Example 4). Although these embodiments are exemplified with reference to treat osteoarthritis, it should not be inferred that the invention is for these uses only. Rather, it is contemplated that embodiments of the present invention will be useful for treating other forms of articular conditions by articular injection of a sustained release biodegradable depot or a pharmaceutical preparation. Further, it is contemplated that embodiments of the present invention will be useful for treating conditions of a bony canal such as carpal tunnel by injection into or near to the carpal tunnel or such as spinal stenosis by epidural injection of a sustained release biodegradable depot or a pharmaceutical preparation.

[0178] In certain embodiments, the treatment is effective in reducing pain, in particular joint pain. The (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 alleviating (joint) pain. In certain embodiments, the treatment may be effective in removing (joint) pain.

[0179] In certain embodiments, the treatment is effective in reducing inflammation, in particular associated with arthropathy, i.e. in reducing a joint disease inflammation or in reducing a bony canal disease inflammation. In particular, the treatment may be effective in reducing an expression of at least one inflammatory marker. In some embodiments, the treatment is effective in reducing an expression of at least one cytokine. The at least one cytokinemay 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 chemoattractant / human growth-regulated oncogene). In certain embodiments, the expression of the at least one inflammatory marker may be reduced by at least 10%, by at least 20%, or by at least 25% within a period of 14 days, or a period of 1 months, or a period of 2 months after administration.

[0180] In certain embodiments, the treatment is effective in reducing hypervascularity associated with arthritis.

[0181] The method of treating an articular condition according to the invention may be effective if one or more signs or symptoms associated with the articular condition, such as arthritis, in particular osteoarthritis, are alleviated, reduced, inhibited or do not progress to a further, i.e. worse, state. In certain embodiments, the treatment is effective in slowing down, arresting or reversing progressive structural tissue damage associated with arthritis, such as osteoarthritis. In certain embodiments, the treatment is effective in slowing down, arresting or reversing loss of joint function associated with arthritis, such as osteoarthritis. Moreover, the treatment may also be effective in improving joint function associated with arthritis, such as osteoarthritis.

[0182] In certain embodiments, the method of treating an articular condition is effective in reducing at least one sign or symptom associated with arthritis, such as pain, joint stiffness, limited range of motion, swelling around a joint, muscle weakness, or joint instability.

[0183] In certain embodiments, the treatment is effective in reducing compression of nervous tissue associated with narrowing of a bony canal such as carpal tunnel syndrome or spinal stenosis.

[0184] The method of treating a condition of a bony canal according to the invention may be effective if one or more signs or symptoms associated with the condition of a bony canal, such as carpal tunnel syndrome or spinal stenosis, are alleviated, reduced, inhibited or do not progress to a further, i.e. worse, state. In certain embodiments, the treatment is effective in arresting or reversing tingling, weakness or numbness of extremities, such as fingers associated with carpal tunnel syndrome, or such as arms or legs associated with spinal stenosis.

[0185] In certain embodiments, the method of treating condition of a bony canal is 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 around a bony canal, muscle weakness, or pressure on nervous tissue. Administration Injection:

[0186] In certain embodiments of the method of treating an articular condition according to the invention, the depot is administered by articular injection. In some embodiments, the depot is administered by intra-articular injection. In other embodiments, the depot is administered by periarticular injection.

[0187] In certain particular embodiments, the depot is administered into a synovial joint of the patient, such as a hip joint, knee joint, feet joint, or finger joint of a patient. In some embodiments, the depot is administered into a synovial joint cavity of a patient. In other embodiments, the depot may be administered into the tissue surrounding the synovial joint cavity of the patient, such as the synovial membrane.

[0188] The depot may be administered in the area of a knee, an elbow, a finger, a hip, a shoulder, a wrist, an ankle, or in the area of a joint of a foot, hand, shoulder girdle, rotator cuff, pelvis, spine (including all area of the spine, such as the cervical, thoracic, lumbar spine, the sacrum or the coccyx), or jaw of the patient. In oneembodiment, the depot is administered into a knee of a patient, such as into the synovial joint cavity of the knee of the patient.

[0189] In certain embodiments, the joint, patellofemoral joint, humeroulnar joint, humeroradial joint, joint, glenohumeral joint,, acromioclavicular joint, distal radioulnar midcarpal joint, carpometacarpal joint, intermetacarpal joint, talocrural joint, calcaneocuboid joint, metatarsophalangeal joint, joint, sternoclavicular joint, sternocostal joint, atlanto-occipital joint, costotransverse joint, zygapophyseal joint, sacroiliac joint, or embodiments, the depot isadministered into a tibiofemoral joint, i.e. a knee joint, acetabulofemoral joint, i.e. a hip joint, talocrural joint, subtalar joint, i.e. ankle / feet joint, metatarsophalangeal joint, i.e. ankle / feet joint, interphalangeal joint of a foot or hand, atlanto-axial joint, i.e. neck joint, or zygapophyseal joint, i.e. lower back joint of the patient. In one embodiment, the depot is administered into a tibiofemoral joint of the patient.

[0190] In certain according to the invention, the depot is administered some embodiments, the depot is administered by epidural

[0191] In certain a carpal tunnel of the patient. In certain other particular canal of the patient, in particular the depot is or the depot is administeredinto or near to a lumbar some is administered into the bony canal of a patient. In other embodiments, the depot may be administered into the tissue surrounding or lying within the bony canal of a patient.

[0192] In certain embodiments, depot is administered through a hypodermic needle, such as a 18- to 30-gauge needle. The hypodermic needle may be a 20- to 27-gauge needle, or a smaller gauge needle, in particular depending from the site of administration. Without for example be used for hip injections, a 22-gauge needle may for example be needle may for example be used for finger injections.

[0193] In certain embodiments, the needle, such as a 21-gauge, a 22-gauge or a 25-gauge needle, for injection and the joint cavity or the surrounding tissue, through this needle. In one an injection device used for injecting the depot into the joint are providedfurther below. Treatment Period and Dose:

[0194] In certain embodiments of the method of treating an articular condition according to the present invention, the depot is administered once for a certain treatment period. In some embodiments, the treatment period is at least 1 month. In other embodiments, 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. In particular embodiments, the treatment period is at least 3 months, at least 6 months, or at least 9 months. In certain embodiments, the treatment period may also be longer, such as up to about 15 months.

[0195] The dose administered once for a treatment period may be contained in one depot or in multiple depots. In embodiments in which two or more depots are administered, the depots containing the dose are administered concurrently / in combination. The same or different. In cases where an administration during the same complications or patient-related reasons a successive administration alternatively be applied, such as for instance administration of two as a “concurrent” administration in the context of the present

[0196] In some embodiments, the period is contained in one depot containing one unit. Examples foradministered in one unit are depots A-G exemplarily manufactured in the examples section (Examples 1 and 2). In other embodiments, the dose administered once for the treatment periods contained in one depot containing two or more, such as a plurality of, units. In such embodiments, the dose administered once for a treatment period may be contained in two or more fibers or the dose administered once for a treatment period may be contained in two or more, and in particular in a plurality of, beads.

[0197] In accordance with the present invention, the axitinib dose (in case the TKI is axitinib) administered once for a treatment period provides a therapeutic local tissue concentration, but does not exceed safe tissue concentrations, either local to the site of implantation or in remote or systemic tissues. In general, the daily drug elution rate from the depot (R) drug elimination rate constant (ke) yields a steady state tissue exposure will be minimal, but does not exceed tissue for oral axitinib administration (INLYTA®)

[0198] The dose per joint or period may be at least about 0.1 mg, at least about 0.2 mg, or In certain embodiments, thedose per joint or bony canal once a 0.5 mg to about 120 mg of the tyrosine kinase inhibitor, and specifically of axitinib, depending on the site of administration. In some embodiments, the dose per joint or bony canal administered once for a treatment period is from about 1 mg to about 50 mg of the tyrosine kinase inhibitor, and specifically of axitinib. In particular embodiments, the dose per joint or bony canal administered once for a treatment period of at least 3 months is from about 1 mg to about 50 mg, from about 5 mg to about 40 mg, or from about 10 mg to about 30 mg of the tyrosine kinase inhibitor, and specifically of axitinib.

[0199] In certain embodiments, the dose per knee administered once for a treatment period is from about 1 mg to about 70 mg of the tyrosine kinase inhibitor, and specifically of axitinib. In some embodiments, the dose per knee administered once for a treatment period is from about 2.5 mg to about 60 mg of the tyrosine kinase inhibitor, and specifically of axitinib, or the dose per knee administered once for a treatment period is from about 3 mg to about 45 mg of the tyrosine kinase inhibitor, and specifically of axitinib. In particular embodiments, the dose per knee administered once for a treatment period of at least 3 months is from about 3 mg to about 45 mg, from about 5 mg to about 30 mg, or from about 10 mg to about 25 mg of the tyrosine kinase inhibitor, and specifically of axitinib. In one embodiment, the dose per knee administered once for a treatment period of at least 3 months is about 15 mg of the tyrosine kinase inhibitor, and specifically of axitinib. In another embodiment, the dose per knee administered once for a treatment period of at least 3 months is about 20 mg of the tyrosine kinase inhibitor, and specifically of axitinib.

[0200] In certain embodiments, the dose per hip administered once for a treatment period is from about 0.5 mg to about 50 mg of the tyrosine kinase inhibitor, and specifically of axitinib. In some embodiments, the dose per knee administered once for a treatment period is from about 1 mg to about 35 mg of the tyrosine kinase inhibitor, and specifically of axitinib, or the dose per knee administered once for a treatment period is from about 1.5 mg to about 25 mg of the tyrosine kinase inhibitor, and specifically of axitinib. In particular embodiments, the dose per knee administered once for a treatment period of at least 3 months is from about 1.5 mg to about 25 mg, from about 2.5 mg to about 20 mg, or from about 5 mg to about 15 mg of the tyrosine kinase inhibitor, and specifically of axitinib. In one embodiment, the dose per knee administered once for a treatment period of at least 3 months is about 10 mg of the tyrosine kinase inhibitor, and specifically of axitinib. In another embodiment, the dose per knee administered once for a treatment period of at least 3 months is about 12.5 mg of the tyrosine kinase inhibitor, and specifically of axitinib.

[0201] In certain embodiments, the dose per finger administered once for a treatment period is from about 0.1 mg to about 20 mg of the tyrosine kinase inhibitor, and specifically of axitinib. In some embodiments, the dose per knee administered once for a treatment period is from about 0.2 mg to about 15 mg of the tyrosine kinase inhibitor, and specifically of axitinib, or the dose per knee administered once for a treatment period is from about 0.4 mg to about 12 mg of the tyrosine kinase inhibitor, and specifically of axitinib. In particular embodiments, the dose per knee administered once for a treatment period of at least 3 months is from about 0.4 mg to about 12 mg, from about 0.5 mg to about 10 mg, or from about 1 mg to about 8 mg of the tyrosine kinase inhibitor, and specifically of axitinib. In one embodiment, the dose per knee administered once for a treatment period of at least 3 months is about 3 mg of the tyrosine kinase inhibitor, and specifically of axitinib. In another embodiment, the dose per knee administered once for a treatment period of at least 3 months is about 5 mg of the tyrosine kinase inhibitor, and specifically of axitinib.

[0202] In certain very particular embodiments, the dose of the tyrosine kinase inhibitor, and specifically of axitinib, administered once per joint or bony canal for the treatment period is a multiple of about 15 µg, or of about 35 µg, or of about 55 µg, or of about 100 µg, of about 150 µg, of about 200 µg, of about 300 µg, of about 420 µg. In some embodiments, the dose of the tyrosine kinase inhibitor, and specifically of axitinib, administered once per joint such as knee or bony canal, administered once for the treatment period is a multiple of about 420 µg. Where the dose of the tyrosine kinase inhibitor, and especially of axitinib, administered once for the treatment period may be contained in two or more units of the depot, each unit may in certain embodiments comprise axitinib in an amount of about 15 µgm, or of about 35 µg, or of about 55 µg, or of about 100 µg, of about 150 µg, of about 200 µg, of about 300 µg, of about 420 µg, in particular in an amount of about 420 µg. The amount of axitinib comprised in a single unit may be adjusted as appropriate for the administration site and the patient (human or animal). Co-Administration:

[0203] The method of treating a condition by injection of the depots disclosed herein may be combined with the (articular) administration of at least one other drug known for treating the respective condition, or another condition. In certain embodiments, the articular condition may be osteoarthritis and the method of treating osteoarthritis is combined with the (articular) administration of at least one other drug known for osteoarthritis treatment. The other drug known for osteoarthritis may be selected from analgesics, i.e. pain relievers including acetaminophen and opioids, NSAIDs including aspirin, ibuprofen, naproxen and celecoxib, counterirritants containing ingredients likecapsaicin, menthol or lidocaine, corticosteroids such as triamcinolone acetonide (KENALOG®), platelet-rich plasma, or other drugs including hyaluronic acid, the antidepressant duloxetine (CYMBALTA®) or the anti-seizure drug pregabalin (LYRICA®).

[0204] In some embodiments, concurrently with the treatment with the sustained release biodegradable depot containing a TKI, or a treatment with the sustained release biodegradable depot containing axitinib according to the invention, an anti-VEGF agent is administered to the patient. The anti-VEGF agent may be selected from the group consisting of aflibercept, bevacizumab, brolucizumab, faricimab, pegaptanib, and ranibizumab. In certain embodiments the anti-VEGF agent is administered by means of an articular injection concurrently with the administration of the sustained release biodegradable depot.

[0205] In certain embodiments of the method of treating an articular condition according to the present invention, an anti-inflammatory agent is administered concurrently with the depot. In some embodiments, hyaluronic acid is administered concurrently with the depot. In other embodiment, at least one corticosteroid is concurrently administered with the depot. In certain embodiments, the patient has a history of anti-inflammatory treatment, e.g. such as treatment with KENALOG®.

[0206] In some embodiments, the at least one other drug is administered orally or topically. In other embodiments, the at least one other drug is administered articularly. In one embodiment, the at least one other drug may be administered by intra-articular or periarticular injection, or may be administered orally. In such embodiments, the at least one other drug may be contained in the depot according to the present invention, or may be administered in combination with the depot. In some embodiments, the period of treatment with a depot according to the present invention may correspond to the period of treatment with the at least other drug, e.g. may start and / or end at essentially the same time (e.g. by administering the depot of the present invention and the at least other drug concurrently or in close temporal proximity. In other embodiments, the period of treatment with a depot according to the present invention may overlap with (e.g. commence sooner or later than) the period of treatment with the at least other drug. The at least other drug may be a drug that is administered only once. Alternatively, the at least other drug may be a drug that is repeatedly administered. The dosing frequency (and / or the treatment period) of the depot of the present invention and the at least other drug may correspond or essentially correspond to each other, or may differ from each other. In certain embodiments, at or after the end of a treatment period provided for by a depot of the present invention, a new depot according to the present invention may be administered. Such new depot may be identical with or may differ from the previously administered depot. For example, upon re- administration of a depot according to the present invention, the TKI (such as axitinib) dose may be adjusted to a higher or lower dose, according to the individual situation of the patient. A depot according to the present invention may be re-administered multiple times after termination of the treatment period. Additional / Alternative Active Agents

[0207] In certain embodiments, the tyrosine kinase inhibitor is administered with an additional non-tyrosine kinase inhibitor active agent or is present in a pharmaceutical composition with an additional non-tyrosine kinase inhibitor active agent. In other embodiments, the administration and the pharmaceutical compositions include the non- tyrosine kinase inhibitor active agent and do not include a tyrosine kinase inhibitor. Exemplary non-kinase inhibitor active agents include but are not limited the following.

[0208] 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, interferons, infliximab, etanercept, mycophenolate mofetil, 15-deoxyspergualin, thalidomide, glatiramer, leflunomide, vincristine, cytarabine, pharmaceutically acceptable salts thereof and combinations thereof.

[0209] Non-steroidal anti-inflammatory compounds include inhibitors of the cyclooxygenase (COX) enzyme such as cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) isozymes. General classes of non-steroidal anti- inflammatory compounds include salicylates, propionic acid derivatives, acetic acid derivatives, enolic acid derivatives, and anthranilic acid derivatives. Examples of non-steroidal anti-inflammatory compounds include acetylsalicylic acid, diflunisal, salsalate, ibuprofen, dex-ibuprofen, naproxen, fenoprofen, ketoprofen, dex-ketoprofen, flurbiprofen, oxaprozin, loxoprofen, indomethacin, tolmetin, sulindac, etodolac, ketorolac, diclofenac, aceclofenac, nabumetone, piroxicam, tenoxicam, tenoxicam, loroxicam, phenylbutazone, mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid, celecoxib, pharmaceutically acceptable salts thereof and combinations thereof.

[0210] Anti-inflammatory agents that may be utilized 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.

[0211] Analgesics that may be utilized in the implants and methods of the present invention include acetaminophen, acetaminosalol, aminochlorthenoxazin, acetylsalicylic 2-amino-4-picoline acid, acetylsalicylsalicylic acid, anileridine, benoxaprofen, benzylmorphine, 5-bromosalicylic acetate acid, bucetin, buprenorphine, butorphanol, capsaicin, cinchophen, ciramadol, clometacin, clonixin, codeine, desomorphine, dezocine, dihydrocodeine, dihydromorphine, dimepheptanol, dipyrocetyl, eptazocine, ethoxazene, ethylmorphine, eugenol, floctafenine, fosfosal, glafenine, hydrocodone, hydromorphone, hydroxypethidine, ibufenac, p-lactophenetide, levorphanol, meptazinol, metazocine, metopon, morphine, nalbuphine, nicomorphine, norlevorphanol, normorphine, oxycodone, oxymorphone, pentazocine, phenazocine, phenocoll, phenoperidine, phenylbutazone, phenylsalicylate, phenylramidol, salicin, salicylamide, tiorphan, tramadol, diacerein, actarit, pharmaceutically acceptable salts thereof and combinations thereof.

[0212] Steroidal anti-inflammatory agents that may be utilized in the implants and methods of the present invention include dexamethasone, budensonide, triamcinolone, hydrocortisone, fluocinolone, loteprednol, prednisolone, mometasone, fluticasone, rimexolone, fluorometholone, beclomethasone, flunisolide, pharmaceutically acceptable salts thereof and combinations thereof.

[0213] Anesthetics that may be utilized in the implants and methods of the present invention include benzocaine, procaine, chloroprocaine, cinchocaine, ropivacaine, bupivacaine, lidocaine, mepivacaine, prilocaine, and tetracaine.

[0214] Other agents that may be utilized in the implants and methods of the present invention include glycosaminoglycans such as hyaluronic acid.

[0215] For the purposes of the present invention, an active agent includes all its possible forms, including free acid, free base, polymorphs, pharmaceutically acceptable salts, anhydrates, hydrates, other solvates, stereoisomers, crystalline forms, cocrystals, pro-drugs, conjugates (e.g., pegylated compounds), complexes and mixtures thereof. DepotHydrogel:

[0216] The hydrogel may be formed from precursors having functional groups that form crosslinks to create a polymer network. These crosslinks between polymer strands or arms may be chemical (i.e., may be covalent bonds) and / or physical (such as ionic bonds, hydrophobic association, hydrogen bridges etc.) in nature.

[0217] The polymer network may be prepared from precursors, either from one type of precursor or from two or more types of precursors that are allowed to react. Precursors are chosen in consideration of the properties that are desired for the resultant hydrogel. There are various suitable precursors for use in making the hydrogels. Generally, any pharmaceutically acceptable and crosslinkable polymers forming a hydrogel may be used for the purposes of the present invention. The hydrogel and thus the components incorporated into it, including the polymers used for making the polymer network, should be physiologically safe such that they do not elicit e.g. an immune response or other adverse effects. Hydrogels may be formed from natural, synthetic, or biosynthetic polymers.

[0218] Natural polymers may include glycosaminoglycans, polysaccharides (e.g. dextran), polyaminoacids and proteins or mixtures or combinations thereof, while this list is not intended to be limiting.

[0219] Synthetic polymers may generally be any polymers that are synthetically produced from a variety of feedstocks by different types of polymerization, including free radical polymerization, anionic or cationic polymerization, chain-growth or addition polymerization, condensation polymerization, ring-opening polymerization etc. The polymerization may be initiated by certain initiators, by light and / or heat, and may be mediated by catalysts. Synthetic polymers may in certain embodiments be used to lower the potential of allergies in dosage forms that do not contain any ingredients from human or animal origin.

[0220] Generally, for the purposes of the present invention one or more synthetic polymers of the group comprising one or more units of polyalkylene glycol, particularly including but not limited to polyethylene glycol (PEG), polypropylene glycol, poly(ethylene glycol)-block-poly(propylene glycol) copolymers, polyalkylene oxide such as polyethylene oxide, polypropylene oxide, polyvinyl alcohol, poly (vinyl pyrrolidinone), polylactic acid (PLA), polylactic- co-glycolic acid, p-dioxanone, trimethylene carbonate, caprolactone; random or block copolymers or combinations / mixtures of any of these can be used, while this list is not intended to be limiting.

[0221] To form covalently crosslinked polymer networks, the precursors may be covalently crosslinked with each other. In certain embodiments, precursors with at least two reactive centers (for example, in free radical polymerization) can serve as crosslinkers since each reactive group can participate in the formation of a different growing polymer chain.

[0222] The precursors may have function groups that can react with each other, i.e., a first functional group capable of reacting with a second functional group. The functional groups can react with each other, e.g., in electrophile-nucleophile reactions or are configured to participate in other polymerization reactions. Nucleophiles that can be used for the present invention may comprise an amine such as a primary amine, a hydroxyl, a thiol, a carboxyl, a dibenzocyclooctyne, or a hydrazide. Electrophiles that can be used for the present invention may comprise succinimidyl esters, succinimidyl carbonates, nitrophenyl carbonates, aldehydes, ketones, acrylates, acrylamides, maleimides, vinylsulfones, iodoacetamides, alkenes, alkynes, azides, norbornenes, epoxides, mesylates, tosylates, tresyls, cyanurates, orthopyridyl disulfides, or halides.

[0223] Besides classical electrophile-nucleophile condensation reactions other chemical reaction types based on electrophiles and nucleophiles may also be used in the present invention. For example, precursors may be crosslinked via so-called click-chemistry reactions. Functional groups suitable for click chemistry are such functionalgroups that enable click chemistry reactions such as strain promoted alkyne-azide cycloaddition (SPAAC), also termed as the Cu-free click reaction, or inverse electron demand Diels-Alder ligation (IEDDA) type click chemistry coupling reactions. An overview of such types of reaction is given in H. C. Kolb; M. G. Finn; K. B. Sharpless (2001). "Click Chemistry: Diverse Chemical Function from a Few Good Reactions", Angewandte Chemie International Edition, 40 (11): 2004–2021), incorporated herein by reference. SPAAC and IEDDA coupling reactions are bioorthogonal reactions with selective and quantitative yields under mild conditions that can occur even inside of living systems without interfering with native biochemical processes. These click chemistry reactions utilize a pair of functional groups that exclusively and efficiently react with each other while remain inert to naturally occurring functional groups. Suitable functional groups comprise moieties selected from the group consisting of alkyne, cycloalkyne such as a dibenzocyclooctyne (DBCO), or a bicyclo[6.1.0]-nonyne (BCN), strained or terminal alkene such as norbornene, or a trans-cyclooctene (TCO), azide or tetrazine (Tz).

[0224] The precursors may have biologically inert and hydrophilic portions, e.g., a core. In the case of a branched polymer, a core refers to a contiguous portion of a molecule joined to arms that extend from the core, where the arms carry a functional group, which is often at the terminus of the arm or branch. Multi-armed PEG precursors are examples of such precursors and are used in particular embodiments of the present invention as further disclosed herein.

[0225] A hydrogel for use in the present invention can be made e.g. from one multi-armed precursor with a first (set of) functional group(s) and another (e.g. multi-armed) precursor having a second (set of) functional group(s). By way of example, a multi-armed precursor may have hydrophilic arms, e.g., polyethylene glycol units, terminated with primary amines (nucleophile), or may have activated ester end groups (electrophile). The polymer network according to the present invention may contain identical or different polymer units crosslinked with each other. In particular, the polymer network according to the present invention comprises one or more (identical or different) multi-arm polymer units crosslinked with each other. The precursors may be high-molecular weight components (such as polymers having functional groups as further disclosed herein) or low-molecular weight components (such as low-molecular amines, thiols, esters etc. as also further disclosed herein).

[0226] Certain functional groups can be made more reactive by using an activating group. Such activating groups include (but are not limited to) carbonyldiimidazole, sulfonyl chloride, aryl halides, sulfosuccinimidyl esters, N- hydroxysuccinimidyl (abbreviated as “NHS”) ester, succinimidyl ester, benzotriazolyl ester, thioester, epoxide, aldehyde, maleimides, imidoesters, acrylates and the like. The NHS esters are useful groups for crosslinking with nucleophilic polymers, e.g., primary amine-terminated or thiol-terminated polyethylene glycols or other nucleophilic group-containing agents, such as nucleophilic group-containing crosslinking agents. An NHS-amine crosslinking reaction may be carried out in aqueous solution and in the presence of buffers, e.g., 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, respectively.

[0227] In certain embodiments, each precursor may comprise only nucleophilic or only electrophilic functional groups, so long as both nucleophilic and electrophilic precursors are used in the crosslinking reaction. Thus, for example, if a crosslinker has only nucleophilic functional groups such as amines, the precursor polymer may have electrophilic functional groups such as N-hydroxysuccinimides. On the other hand, if a crosslinker has electrophilic functional groups such as sulfosuccinimides, then the functional polymer may have nucleophilic functional groups such as amines or thiols. Thus, functional polymers such as proteins, poly (allyl amine), or amine-terminated di- or multifunctional poly(ethylene glycol) can be also used to prepare the polymer network of the present invention.

[0228] In one embodiment of the present invention, a precursor for the polymer network forming the hydrogel in which the tyrosine kinase inhibitor is dispersed to form the depot that may be used in a method of treating an articular condition according to the present invention has about 2 to about 16 nucleophilic functional groups each (termed functionality), and in another embodiment a precursor has about 2 to about 16 electrophilic functional groups each (termed functionality). Reactive precursors having a number of reactive (nucleophilic or electrophilic) groups as a multiple of 4, thus for example 4, 8 and 16 reactive groups, are particularly suitable for the present invention. However, any number of functional groups, such as including any of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 groups, is possible for precursors to be used in accordance with the present invention, while ensuring that the functionality is sufficient to form an adequately crosslinked network.

[0229] In certain embodiments of the present invention, the polymer network forming the hydrogel contains polyethylene glycol (“PEG”) units. PEGs are known in the art to form hydrogels when crosslinked, and these PEG hydrogels are suitable for pharmaceutical applications e.g. as matrix for drugs intended to be administered to all parts of the human or animal body.

[0230] The polymer network of the hydrogel depots of the present invention may comprise one or more multi-arm PEG units having from 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 hydrogel of the present invention have 4 arms. In certain embodiments, the PEG units used in the hydrogel 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 hydrogel of the present invention. In certain particular embodiments, one or more 4- armed PEGs is / are utilized. Any combination of multi-armed PEGs may be used. In specific embodiments, only 4-arm PEG units are used (which may be the same or different).

[0231] The number of arms of the PEG(s) used contributes to controlling the flexibility or softness of the resulting hydrogel. For example, hydrogels formed by crosslinking 4-arm PEGs are generally softer and more flexible than those formed from 8-arm PEGs of the same molecular weight. In particular, if stretching the hydrogel prior to (or also after) drying as briefly disclosed herein below in the section relating to the manufacture of the fibers is desired, a more flexible hydrogel may be used, such as a 4-arm PEG, optionally in combination with another multi-arm PEG, such as an 8-arm PEG as disclosed above, or another (different) 4-arm PEG.

[0232] In certain embodiments of the present invention, polyethylene glycol units used as precursors have an average molecular weight (Mn) in the range from about 2,000 to about 100,000 Daltons, or in a range from about 10,000 to about 60,000 Daltons, or in a range from about 15,000 to about 50,000 Daltons. In certain particular embodiments, the polyethylene glycol units have an average molecular weight in a range from about 10,000 to about 40,000 Daltons, or in a range from about 15,000 to about 30,000 Daltons, or in a range from about 15,000 to about 25,000 Daltons. In specific embodiments, the polyethylene glycol units used for making the hydrogels according to the present invention have an average molecular weight (Mn) of about 15,000 Daltons. In further specific embodiments, the polyethylene glycol units used for making the hydrogels according to the present invention have an average molecular weight (Mn) of about 20,000 Daltons. Polyethylene glycol precursors of different molecular weight may be combined with each other. When referring herein to a PEG material having a particular average molecular weight (as defined herein), such as about 20,000 Daltons, a variance of ± 10% is intended to be included, i.e., referring to a material having an average molecular weight of about 20,000 Daltons also refers to such a material having an average molecular weight of about 18,000 to about 22,000 Daltons. As used herein, the abbreviation “k” in the context of the molecular weight refers to 1,000 Daltons, i.e., “20k” means 20,000 Daltons.

[0233] Further, when referring to a PEG precursor having a certain average molecular weight, such as a 15kPEG- or a 20kPEG-precursor, the indicated average molecular weight (i.e., a Mn of 15,000 or 20,000, respectively) refers to the PEG part of the precursor, before end groups are added (“20k” here means 20,000 Daltons, and “15k” means 15,000 Daltons – the same abbreviation is used herein for other average molecular weights of PEG precursors). In certain embodiments, the Mn of the PEG part of the precursor is determined by MALDI. The degree of substitution with end groups as disclosed herein may be determined by means of1H-NMR after end group functionalization.

[0234] In a 4-arm (“4a”) PEG, in certain embodiments each of the arms may have an average arm length (or molecular weight) of the total molecular weight of the PEG divided by 4. A 4a20kPEG precursor, which is a particularly suitably precursor for use in the present invention thus has 4 arms with an average molecular weight of about 5,000 Daltons each and a total molecular weight of 20,000 Daltons. An 8a20k PEG precursor, which could also be used in combination with or alternatively to the 4a20kPEG precursor in the present invention, thus has 8 arms (“8a”) each having an average molecular weight of 2,500 Daltons and a total molecular weight of 20,000 Daltons. Longer arms may provide increased flexibility as compared to shorter arms. PEGs with longer arms may swell more as compared to PEGs with shorter arms. A PEG with a lower number of arms also may swell more and may be more flexible than a PEG with a higher number of arms. In certain particular embodiments, only one or more 4-arm PEG precursor(s) is / are utilized in the present invention. In certain other embodiments, a combination of one or more 4- arm PEG precursor(s) and one or more 8-arm PEG precursor(s) is utilized in the present invention. In addition, longer PEG arms have higher melting temperatures when dry, which may provide more dimensional stability during storage.

[0235] In certain embodiments, electrophilic end groups for use with PEG precursors for preparing the hydrogels of the present invention are N-hydroxysuccinimidyl (NHS) esters, including but not limited to NHS dicarboxylic acid esters such as the succinimidyl malonate group, succinimidyl maleate 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 succinimidyl glutaramide end group, ”SC” referring to succinimidyl carbonate, and “SS” referring to a succinimidyl succinate end group. Examples of other activated esters in addition to the NHS esters that are useful in the present invention are (without being limited to these) thioesters, benzotriazolyl esters, and esters of acrylic acids.

[0236] In certain embodiments, nucleophilic end groups for use with electrophilic group-containing PEG precursors for preparing the hydrogels of the present invention are amine (denoted as “NH2”) end groups. Thiol (-SH) end groups or other nucleophilic end groups are also possible.

[0237] In certain embodiments of the present invention, 4-arm PEGs with an average molecular weight of about 20,000 Daltons and electrophilic end groups as disclosed above (such as the SAZ, SAP, SC, SG and SS end groups, particularly the SG end group) are crosslinked for forming the polymer network and thus the hydrogel according to the present invention. Suitable PEG precursors are available from a number of suppliers, such as Jenkem Technology and others.

[0238] Reactions of e.g. nucleophilic group-containing crosslinkers and electrophilic group-containing PEG units, such as reaction of amine group-containing crosslinkers with activated ester-group containing PEG units, result in a plurality of PEG units being crosslinked by a hydrolyzable linker having the formula: , wherein m is an integer from 0 to 10, and specifically is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. For a SAZ-end group, m would be 6, for a SAP-end group, m would be 3, for a SG-end group, m would be 2 and for an SS-end group, m would be1. In particular embodiments, m is 2. All crosslinks within the polymer network may be the same, or may be different.

[0239] In certain embodiments, the polymer precursors used for forming the hydrogel according to the present invention may be selected from 4a20kPEG-SAZ, 4a20kPEG-SAP, 4a20kPEG-SG, 4a20kPEG-SS, 8a20kPEG-SAZ, 8a20kPEG-SAP, 8a20kPEG-SG, 8a20kPEG-SS, or mixtures thereof, with one or more PEG- or lysine based-amine groups selected from 4a20kPEG-NH2, 8a20kPEG-NH2, and trilysine, or a trilysine salt or derivative, such as trilysine acetate (“TLA”).

[0240] In certain embodiments, the SG end group is utilized in the present invention. This end group may provide for a shorter time until the hydrogel is biodegraded in an aqueous environment such as in the synovial fluid, when compared to the use of other end groups, such as the SAZ end group, which provides for a higher number of carbon atoms in the linker and may thus be more hydrophobic and therefore less prone to ester hydrolysis than the SG end group.

[0241] In particular embodiments, a 4-arm 20,000 Dalton PEG precursor having a SAZ group (as defined above) is crosslinked with an 8-arm 20,000 Dalton PEG precursor having an amine group (as defined above). These PEG precursors are abbreviated herein as 4a20kPEG-SAZ and 8a20kPEG-NH2, respectively. A schematic chemical structure of 4a20kPEG-SAZ is reproduced below (wherein R represents a pentaerythritol core structure): A schematic chemical structure of 8a20kPEG-NH2 is reproduced below (wherein R represents a hexaglycerol core structure: In the above formulae, n is determined by the molecular weight of the respective PEG-arm.

[0242] In other particular embodiments, a 4-arm 20,000 Dalton PEG precursor having a SG end group (as defined above), is crosslinked with a crosslinking agent having one or more reactive amine end groups. This PEG precursor is abbreviated herein as 4a20kPEG-SG. A schematic chemical structure of 4a20kPEG-SG is reproduced below:In this formula, n is determined by the molecular weight of the respective PEG-arm.

[0243] In certain particular embodiments, the crosslinking agent (herein also referred to as “crosslinker”) used is a low-molecular weight component containing nucleophilic end groups, such as amine or thiol end groups. In certain embodiments, the nucleophilic group-containing crosslinking agent is a small molecule amine with a molecular weight below 1,000 Da. In certain embodiments, the nucleophilic-group containing crosslinking agent comprises two, three or more primary aliphatic amine groups. Suitable crosslinking agents for use in the present invention are (without being limited to) spermine, spermidine, lysine, dilysine, trilysine, tetralysine, polylysine, ethylenediamine, polyethylenimine, 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 such as conjugates (as long as sufficient nucleophilic groups for crosslinking remain present), and any mixtures thereof. A particular crosslinking agent for use in the present invention is a lysine-based crosslinking agent, such as trilysine or a trilysine salt or derivative. A particular nucleophilic crosslinking agent for use in the present invention is TLA. Other low-molecular weight multi-arm amines may be used as well. The chemical structure of trilysine is reproduced below:

[0244] In very particular embodiments of the present invention, a 4a20kPEG-SG precursor is reacted with a 4a20kPEG-NH2precursor, to form the polymer network. In other very particular embodiments, a 4a20kPEG-SAZ precursor is reacted with a 4a20kPEG-NH2 precursor, to form the polymer network. In further very particular embodiments, a 4a20kPEG-SG or 4a20kPEG-SAZ precursor is reacted with trilysine acetate, to form the polymer network.

[0245] The polymer precursors, e.g. through certain reactive (such as electrophilic) groups of the polymer precursors, or the nucleophilic group-containing crosslinking agent may be bound to or conjugated with a visualization agent. Fluorophores such as fluorescein, rhodamine, coumarin, and cyanine can be used as visualization agents as disclosed herein. In specific embodiments of the present invention, fluorescein is used as the visualization agent. The visualization agent may be conjugated with the crosslinking agent e.g. through some of the nucleophilic groups of the crosslinking agent. Since a sufficient amount of the nucleophilic groups are necessary for crosslinking, “conjugated” or “conjugation” in general includes partial conjugation, meaning that only a part of the nucleophilic groups may be used for conjugation with the visualization agent, such as 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 a visualization agent. In specific embodiments, the crosslinking agent is trilysine acetate and is conjugated with fluorescein.

[0246] In certain embodiments, the molar ratio of the nucleophilic and the electrophilic end groups reacting with each other is about 1:1, i.e., one amine group is provided per one electrophilic, such as SAZ or SG, group. In the case of 4a20kPEG-SAZ and 8a20kPEG-NH2 this results in a molar ratio of the two components of about 2:1 as the 8-arm PEG contains double the amount of end groups as the 4-arm PEG. In the case of 4a20kPEG-SAZ and trilysine (acetate) this results in a molar ratio of the two components of about 1:1 as the trilysine has four primary amine groups that may react with the electrophilic SAZ ester group. However, an excess of either the electrophilic (e.g. NHS, such as the SG or SAZ) end group precursor or of the nucleophilic (e.g. the amine) end group precursor may be used. In particular, an excess of the nucleophilic, such as the amine end group containing precursor or crosslinking agent may be used. In certain embodiments, the molar ratio of the electrophilic group containing precursor to the nucleophilic group-containing crosslinking agent, such as the molar ratio of 4a20kPEG-SG / 4a20kPEG-SAZ to trilysine acetate, is from about 1:2 to about 2:1.

[0247] The hydrogel may be formed beforehand (pre-formed), or in situ, i.e. within the joint or the bony canal after administration. Pre-formed hydrogels may be molded or extruded shapes, such as a fiber, rod, bead, particle, etc. The pre-formed shape can be dried to form a xerogel and packaged for later implantation. Xerogels can also be formed by drying from swollen hydrogels or organogels, or formed directly by melt processing and crosslinking. If an in situ gelation is desired in an embodiment of the invention, additional ingredient may be used during manufacture of the hydrogel, such as (without being limited to) viscosity-influencing agents, such as hyaluronic acid etc. In situ gelation may be accomplished by managing the gelation time after mixing of precursors in solution, so as to allow sufficient time for the operator to mix and inject the components. Alternatively, in situ gelation can be triggered to occur after implantation, where the trigger could be exposure to physiological conditions such as moisture, pH, temperature, etc. Light activation is also a gelation trigger known to those skilled in the art.

[0248] The depot of the present invention may contain, in addition to the polymer units forming the polymer network as disclosed above and the active principle, other additional ingredients. Such additional ingredients are for example salts originating from buffers used during the preparation of the hydrogel, such as phosphates, borates, bicarbonates, or other buffer agents such as triethanolamine. In certain embodiments of the present invention sodium phosphate buffers (specifically, mono- and dibasic sodium phosphate) are used. Optionally, preservativesmay be used in the depots of the present invention. However, in certain embodiments, the depots of the present invention are free of preservatives, such as anti-microbial preservatives (including, but not limited to benzalkonium chloride (BAK), chlorobutanol, sodium perborate, and stabilized oxychloro complex (SOC)), or are substantially free of such preservatives. The active principle:

[0249] The active principle contained in a depot that may be used in a method of treating a condition according to the present invention is a kinase inhibitor and in particular a tyrosine kinase inhibitor (TKI). Examples for suitable kinase inhibitors include (but shall not be limited to) axitinib, baricitinib, cabozantinib, fostamatinib, nintedanib, pazopanib, regorafenib, sorafenib, sunitinib, tofacitinib, vorolanib and vandetanib. In particular embodiments, the TKI for use in all aspects of the present invention is axitinib.

[0250] In particular embodiments of the present invention, the tyrosine kinase inhibitor contained in a sustained release biodegradable depot is axitinib, and is present in the depot in a range of doses of at least about 0.1 mg, at least about 0.2 mg, at least about 0.4 mg, such as from about 0.5 mg to about 120 mg. Any axitinib amount within these dose ranges may be used, such as 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, about 50 mg, about 100 mg etc., all values also including a variance of +25% and -20%, or a variance of ± 10%. In certain particular embodiments, the doses of axitinib contained in a depot of the invention are: - In a range from about 1 mg to about 50 mg, or in a range from about 5 mg to about 40 mg, or in a range from about 10 mg to about 30 mg for administration into any joint or bony canal, or - in a range from about 3 mg to about 45 mg, or in a range from about 5 mg to about 30 mg, or in a range from about 10 mg to about 25 mg for administration into a knee, or - in a range from about 1.5 mg to about 25 mg, or in a range from about 2.5 mg to about 20 mg, or in a range from about 5 mg to about 15 mg for administration into a hip, or - in a range from about 0.4 mg to about 12 mg, or in a range from about 0.5 mg to about 10 mg, or in a range from about 1 mg to about 8 mg for administration into a finger.

[0251] If a tyrosine kinase inhibitor other than axitinib is used in a sustained release biodegradable depot according to the invention, a dose of that other tyrosine kinase inhibitor is contained in the depot that is equivalent to any of the dose amounts and ranges disclosed above for axitinib. The disclosed amounts of tyrosine kinase inhibitor, such as axitinib, including the mentioned variances, refer to both the final content of the active principle in the depot, as well as to the amount of active principle used as a starting component when manufacturing the depot.

[0252] The tyrosine kinase inhibitor, such as axitinib, is contained in the depot of the invention and particles of the tyrosine kinase inhibitor are dispersed or distributed in the hydrogel comprised 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 may be homogeneously dispersed within the hydrogel. The hydrogel may prevent the particles from agglomerating and may provide a matrix for the particles which releases the drug in a sustained manner upon contact with the synovial fluid.

[0253] In one embodiment, the tyrosine kinase inhibitor particles, such as the axitinib particles, may have a small particle size and may be micronized particles. In another embodiment, the tyrosine kinase inhibitor particles, such as the axitinib particles, may not be micronized. Micronization refers to the process of reducing the average diameter ofparticles of a solid material. Particles with reduced diameters may have inter alia higher dissolution rates, which increases the bioavailability of active pharmaceutical ingredients. In the composite materials field, particle size is known to affect the mechanical properties when combined with a matrix, with smaller particles providing superior reinforcement for a given mass fraction. Thus, a hydrogel matrix within which micronized tyrosine kinase inhibitor particles are dispersed may have improved mechanical properties (e.g. brittleness, strain to failure, etc.) compared to a similar mass fraction of larger tyrosine kinase inhibitor particles. Such properties are important in manufacturing, during administration, and during degradation of the depot. Micronization may also promote a more homogeneous distribution of the active ingredient in the chosen dosage form or matrix. In certain embodiments, for any tyrosine kinase inhibitor used in the present invention, including axitinib, particle sizes (e.g. as expressed by the D90 value as defined herein and that are measured as also disclosed herein) of about 100 μm or below, or of about 75 μm or below, or of about 50 μm or below may be used. In particular embodiments, axitinib may be used in the form of micronized particles and may have a D90 particle size of equal to or less than about 100 μm, or of equal to or less than about 75 μm, or of equal to or less than about 50 μm, or of equal to or less than about 20 μm, or of equal to or less than about 10 μm, or of equal to or less than about 5 µm. In these and other embodiments, the D98 particle size of the micronized axitinib may be equal to or less than about 100 μm, or equal to or less than about 75 μm, or equal to or less than about 50 μm, or equal to or less than about 20 μm, or equal to or less than about 10 μm, or equal to or less than about 5 µm. In particular embodiments of the present invention, the micronized axitinib used in (or used for preparing) a depot of the present invention has a D90 particle size of equal to or less than about 5 µm and a D98 particle size of less than about 10 µm. In particular embodiments, the micronized particles have a D90 of less than about 10 µm, and a D100 of less than about 20 µm. In embodiments in which another tyrosine kinase inhibitor than axitinib is used in the present invention similar particle sizes may apply as disclosed for axitinib. Formulation:

[0254] Depots according to the present invention may comprise a tyrosine kinase inhibitor, such as axitinib, a polymer network made from one or more polymer precursors as disclosed herein above in the form of a hydrogel, and optional additional components such as salts etc. remaining in the depot from the production process (such as phosphate salts used as buffers etc.). In certain preferred embodiments, the tyrosine kinase inhibitor is axitinib. The depots used in the present invention may for example be implants such as those disclosed in WO 2021 / 195163, which is incorporated herein by reference.

[0255] The depots according to the present invention in a dry state may contain from about 5% to about 95% by weight of the tyrosine kinase inhibitor, such as axitinib, and from about 5% to about 95% by weight polymer units, such as those disclosed above. In certain embodiments, the depots according to the present invention in a dry state contain from about 10% to about 75% by weight of the tyrosine kinase inhibitor, such as axitinib, and from about 25% to about 80% by weight polymer units, such as those disclosed above. In further embodiments, the depots according to the present invention in a dry state contain from about 25% to about 60% by weight of the tyrosine kinase inhibitor, such as axitinib, and from about 35% to about 65% by weight polymer units, such as those disclosed above.

[0256] In some embodiments, the depots according to the present invention contain from about 45% to about 55% by weight of the tyrosine kinase inhibitor, such as axitinib, and from about 40% to about 60% by weight polymer units, such as polyethylene glycol units as disclosed above.

[0257] In certain particular embodiments, the depots according to the present invention in a dry state contain from about 12% to about 38% by weight axitinib and from about 50% to about 70% by weight polyethylene glycol units.

[0258] In other particular embodiments, the depots according to the present invention in a dry state contain about 50% by weight axitinib and from about 35% to about 55% by weight polyethylene glycol units. In such embodiments, the axitinib to polyethylene glycol ratio is approximately 50% by weight axitinib to approximately 40- 50% by weight polyethylene glycol, the balance being phosphate salt.

[0259] In certain embodiments, the depots according to the present invention may contain in a dry state about 0.1% to about 1% by weight visualization agent, such as fluorescein or a molecule comprising a fluorescein moiety. Also in certain embodiments, the depots according to the present invention may contain in a dry state about 0.5% to about 5% by weight of one or more buffer salt(s) (separately or taken together). In certain embodiments, the depot in a dry state may contain, e.g., from about 0.01% to about 2% by weight or from about 0.05% to about 0.5% by weight of a surfactant.

[0260] In certain embodiments, the balance of the depot in its dry state (i.e., the remainder of the formulation when TKI (such as axitinib) and polymer hydrogel, such as trilysine-crosslinked PEG hydrogel, have already been taken account of) may be salts remaining from buffer solutions that may be used during manufacture of the depots as disclosed herein, or may be other ingredients used during manufacture of the depots as disclosed herein. In certain embodiments, such salts are phosphate, borate or (bi) carbonate salts. In some embodiments, the depots contain phosphate salt(s) originating from phosphate buffer used during the preparation of the hydrogel. In one embodiment, the buffer salt is sodium phosphate (mono- and / or dibasic).

[0261] The amounts of the tyrosine kinase inhibitor and the polymer(s) may be varied, and other amounts of the tyrosine kinase inhibitor and the polymer hydrogel may also be used to prepare depots that may be used in the method of treating an articular condition according to the present invention.

[0262] In certain embodiments, the maximum amount (in weight%) of drug within the formulation is about two times the weight-%amount of the polymer (e.g., PEG), but may be higher in certain cases, as long as the mixture comprising e.g., the precursors, buffers and drug (in the state before the hydrogel has gelled completely) can be uniformly cast into a desired mold or thin-diameter tubing and / or be successfully processed further.

[0263] In one embodiment of the invention, the hydrogel after being formed and prior to being dried, i.e., in a wet state, contains about 3% to about 20% polyethylene glycol representing the polyethylene glycol weight divided by the fluid weight x 100. In one embodiment, the hydrogel in a wet state contains about 7.5% to about 15% polyethylene glycol representing the polyethylene glycol weight divided by the fluid weight x 100.

[0264] In certain embodiments, solid contents of about 20% to about 50% (w / v) (wherein “solids” means the combined weight of polymer precursor(s), salts and the drug in solution, excluding the water content) are utilized for forming the hydrogel of the depots according to the present invention.

[0265] In certain embodiments, the water content of the hydrogel in a dry (dehydrated / dried) state may be low, such as from about 0.01% by weight to about 10% by weight of water, or from about 0.1% by weight to about 7% by weight of water, or from about 0.25% by weight to about 5% by weight water (determined e.g. as disclosed herein). In particular, the water content of the hydrogel in a dry (dehydrated / dried) state is not more than about 1% by weight. The water content may in certain embodiments also be lower than that, possibly no more than about 0.25% by weight or even no more than about 0.1% by weight.Release of the active and biodegradation of the depot:

[0266] In one embodiments, the method of treating a condition may comprise administering a sustained release biodegradable depot comprising a hydrogel and a tyrosine kinase inhibitor, wherein the depot provides for a release of a therapeutically effective amount of the tyrosine kinase inhibitor for a period of an extended period of time, such as at least about 1 month, at least about 2 months, at least about 3 months, up to about 6 months or longer, such as up to about 9 months after administration (i.e., after having been inserted into the joint or the bony canal). In a particular embodiments, the tyrosine kinase inhibitor is axitinib.

[0267] Without wishing to be bound by theory, release of the axitinib into the synovial fluid or into fluid of the carpal tunnel or spinal canal is determined mainly by the axitinib’s solubility in an aqueous environment. The solubility of axitinib has been determined to be very low in a physiological medium (about 0.2 to about 0.5 μg / mL in PBS at pH 7.2), such as the synovial fluid. When administered to the joint or the bony canal, the axitinib is released from the depot primarily at its surface proximal to the fluid.

[0268] In certain embodiments, the active agent gradually dissolves and diffuses out of the hydrogel into the synovial fluid or into fluid of the carpal tunnel or spinal canal. This happens in a directional manner, starting at the interface of the depot and the fluid at the surface of the depot. The rate of drug elution is dependent on the drug solubility in water and the dimensions of the depot, with higher drug solubility and higher surface area resulting in faster drug release. The “drug front” generally progresses in a receding direction from the depot surfaces, i.e., away from the surface until eventually the entire depot is depleted of active agent.

[0269] Exemplary release profiles of depots according to embodiments of the invention are illustrated in Figures 1-4.

[0270] In certain embodiments, the depot according to the present invention provides for the release of a (therapeutically effective amount of) tyrosine kinase inhibitor, such as axitinib, for a period of about 1 month or longer, such as for a period of about 3 months or longer, such as for a period of at least about 3 months, or for a period of at least about 12 months, after administration into the joint or the bony canal.

[0271] In certain embodiments, the depot after administration into the joint or the bony 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. In particular embodiments, the depot after administration into the joint or bony canal releases (a therapeutically effective amount of) axitinib over a period of at least 3 months. In very particular embodiments, the depot after administration into the joint or bony canal releases a therapeutically effective amount of axitinib over a period of at least 6 months.

[0272] In certain embodiments, after administration, the levels of active agent released from the depot per day remain sustained, constant or essentially constant over a certain period of time (due to the limitation of release based on the active agent’s solubility), such as for about 1 month, or for about 2 months, or for about 3 months in the case of axitinib. Then the amount of active agent released per day may decrease for another period of time (also referred to as “tapering”) until all or substantially all of the active agent has been released and the “empty” hydrogel remains in the joint or the bony canal until it is fully degraded, liquefied, solubilized and cleared (disposed / washed out). In some cases the hydrogel may be designed to degrade prior to full drug release. This may be advantageous in chronic disease where serial injections are needed. Having drug residue remain after clearance of the hydrogel vehicle eliminates accumulation of empty vessel material in the joint or the bony canal. The release of free drugparticles provides a “window” of time for administering a second depot before the drug particles released from the first depot are fully depleted.

[0273] In certain embodiments, a depot of the invention provides for an average release rate of at least about 0.5 mg, at least about 1 mg, such as about 5 mg to about 20 mg, such as about 10 mg to about 15 mg, axitinib per month into synovial fluid during the period in which the release is sustained, constant or essentially constant, for example during a period of up to about 3 months, or up to about 6 months, or up to about 9 months after administration, or longer.

[0274] In certain embodiments, axitinib is released from the depot after administration at an average rate of at last about 0.1 µg / day, or at least about 0.5 µg / day, such as about 1 µg / day to about 600 µg / day, such as at an average rate of about 30 µg / day to about 500 µg / day, such as at an average rate of about 100 µg / day to about 270 µg / day, into the synovial fluid, in particular for a period of at least 3 months. In particular embodiments, axitinib is released from the depot after administration at an average rate of about 165 µg / day, or about 220 µg / day.

[0275] Generally, in embodiments of the invention, a depot according to the invention may release at least 1 µg per day in vitro in phosphate-buffered saline at 37 °C for a period of at least 30 days, such as 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 a period of at least 30 days.

[0276] In certain embodiments, the depot provides a mean release rate in vitro of about 100 μg to about 500 μg, or about 160 µg to about 400 µg of axitinib per day in phosphate-buffered saline at 37 °C for a period of 90 days. Alternatively or additionally, the depot may provide a mean release rate in vitro of about 150 µg to about 600 μg, or of about 200 µg to about 450 µg of axitinib per day in phosphate-buffered saline at 37 °C for a period of 30 days.

[0277] In certain embodiments, the depot provides a cumulated amount of axitinib released in vitro of at least 30 µg, or at least 50 µg or at least 100 µg, or at least 500 µg, or at least 1 mg, such as about 3 mg to about 20 mg, or about 4.5 mg to about 18 mg in phosphate-buffered saline at 37 °C over a period of 30 days. Additionally or alternatively, the depot may provide a cumulated amount of axitinib released in vitro of about 7 mg to about 36 mg, or about 9 mg to about 33 mg in phosphate-buffered saline at 37 °C over a period of 60 days. Further, additionally or alternatively, the depot may provide a cumulated amount of axitinib released in vitro of about 12 mg to about 50 mg, or about 15 mg to about 42 mg to about in phosphate-buffered saline at 37 °C over a period of 90 days.

[0278] In certain embodiments, the depot releases in vitro about 1% to about 15% of the tyrosine kinase inhibitor within 14 days, about 5% to about 30% of the tyrosine kinase inhibitor within 1 month, about 15% to about 50% of the tyrosine kinase inhibitor within 2 months, about 30% to about 80% of the tyrosine kinase inhibitor within 3 months, and about 70% to about 100% of the tyrosine kinase inhibitor within 6 months in phosphate buffered saline at a pH of 7.2, at 37 °C and with an octanol top layer.

[0279] In certain embodiments, the depot releases in vitro about 9% to about 16% of the axitinib within 1 month, about 21% to about 28% of the axitinib within 2 months, about 34% to about 41% of the axitinib within 3 months, about 70% to about 77% of the axitinib within 6 months, and about 93% to 100% within 9 months in phosphate buffered saline at a pH of 7.2, at 37 °C and with an octanol top layer. In some embodiments, the depot releases in vitro about 9% to about 16% of the axitinib within 1 month, about 21% to about 28% of the axitinib within 2 months, about 34% to about 41% of the axitinib within 3 months, about 70% to about 77% of the axitinib within 6 months, and about 93% to 100% within 9 months in phosphate buffered saline at a pH of 7.2, at 37 °C and with an octanol top layer. Further, in certain embodiments, the depot releases in vitro about 1% to about 5% of the axitinib within 7 days, about 3% to about 7% of the axitinib within 14 days, about 8% to about 12% of the axitinibwithin 28 days, and / or about 15% to 19% within 42 days in phosphate buffered saline at a pH of 7.2, at 37 °C and with an octanol top layer.

[0280] Generally, in embodiments of the invention, a depot according to the invention may provide an axitinib concentration in the synovial fluid of at least about 1 ng / mL, at least about 5 ng / mL, at least about 10 ng / mL, such as about 20 ng / mL to about 800 ng / mL, or may provide an axitinib concentration in the synovial fluid of about 30 ng / mL to about 750 ng / mL over a period of at least 14 days.

[0281] In certain embodiments, the depot provides a mean axitinib concentration in the synovial fluid of about 150 ng / mL to about 600 ng / mL after a period of 3 days after administration. Additionally or alternatively, the depot may provide a mean axitinib concentration in the synovial fluid of about 350 ng / mL to about 750 ng / mL after a period of 7 days after administration. Additionally or alternatively, the depot may provide a mean axitinib concentration in the synovial fluid of about 35 ng / mL to about 200 ng / mL after a period of 14 days after administration. In certain particular embodiments, the depot provides a means axitinib concentration in the synovial fluid of about 35 ng / mL to about 200 ng / mL over period of 14 days, over a period of 1 month, over a period of 2 months, or over a period of 3 months.

[0282] When 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 may therefore also be called the “clearance zone”. In certain embodiments, upon hydration the clearance zone is thus a region of the depot that has a concentration of active agent that is less than the active agent in another region of the hydrated hydrogel. As the clearance zone increases, it creates a concentration gradient within the depot that may lead to tapering of the release rate of the drug.

[0283] Concurrently with the drug diffusing out of the hydrogel (and also after the entire amount of drug has diffused out of the hydrogel), the hydrogel may be slowly degraded, e.g. by means of ester hydrolysis in the aqueous environment of the synovial fluid. At advanced stages of degradation, distortion and erosion of the hydrogel begins to occur. As this happens, the hydrogel becomes softer and more liquid (and thus its shape becomes distorted) until the hydrogel finally dissolves and is resorbed completely.

[0284] In one embodiment, the persistence of the hydrogel within an aqueous environment such as in a joint or a bony canal depends inter alia on the structure of the linker that crosslinks the polymer units, such as the PEG units, in the hydrogel. 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 biodegrades in the joint or the bony canal prior to or around the same time as complete solubilisation of the tyrosine kinase inhibitor particles contained in the depot.

[0285] In embodiments of the present invention, the hydrogel and thus the depot remains in the joint or the bony canal for a period of up to about 2 months, or up to about 4 months, or up to about 7 months, or up to 10 months, or up to about 15 months, after administration.

[0286] In certain embodiments of the invention, in the case the tyrosine kinase inhibitor is axitinib, the entire amount of axitinib may be released prior to the complete degradation of the hydrogel, and the depot may persist in the joint or the bony canal thereafter, for a period of altogether up to about 2 months after administration, or up to about 4 months after administration, or up to about 7 months, or up to 10 months, or up to about 15 months, after administration. In certain embodiments, after complete release of the axitinib load, a depot of the present invention may persist for up a further 1 month, or up to a further 2 months, or up to a further 3 months or longer. In certain other embodiments, the hydrogel may be fully biodegraded when the tyrosine kinase inhibitor, such as axitinib, has not yet been completely released from the depot. In other embodiments, the depot may be fully degraded followingat least about 50%, or at least about 90%, or at least about 92%, or at least about 95%, or at least about 97% release of the tyrosine kinase inhibitor. In certain particular embodiments, the time until full degradation of the depot (i.e., dissolution of the hydrogel) essentially corresponds to the time until the full drug (i.e., TKI, such as axitinib) load of the depot has been released. In embodiments, the ratio of the time until full degradation of the depot to complete release of the drug may be less than about 2, or less than about 1.5, such as from about 0.5 to about 1.5, or from about 1.8 to about 1.3.

[0287] The depot(s) administered can be visualized by imaging methods known in the art. In particular, auxiliary agents allowing the depot(s) to be discernible from the soft tissues surrounding the administration site can be added to facilitate visualization. For example, a visualization agent, such as fluorescein, may be conjugated with the polymer precursors or the crosslinking agent used for producing the hydrogel. Alternatively or additionally, X-ray contrast agents and / or MRI contrast agents may be incorporated into the hydrogel. Units

[0288] The depots as used herein in the method of treating a condition according to the present invention, or in the pharmaceutical preparation as described further below, according to certain embodiments of the invention may contain one or more unit(s), which may be in the form of fibers or beads. The dried units of the depot may have different geometries, depending on the method of manufacture, such as the use of molds or tubing into which the mixture comprising the hydrogel precursors including the tyrosine kinase inhibitor may be cast, and optionally depending on how the mixture is further processed, prior to (or after) complete gelling. In one embodiment, the units may have an essentially cylindrical shape, with an essentially round cross-section. Such units, generally having a length that exceeds the diameter, are referred to as “fibers” (which term is interchangeably herein with the term “rod”, and have a cylindrical or essentially cylindrical shape). In another embodiment, the units may have an essentially spherical shape. Such essentially spherical units are referred to as “beads”. Further details on fibers and beads in accordance with the present invention are disclosed herein.

[0289] Various geometries of the outer shape of the units or their cross-section may also be used in the present invention. For example, instead of a round diameter fiber (i.e., in the case of a cylindrical depot), an oval (or elliptical) diameter fiber may be used. Other cross-sectional geometries may also be used, such as triangular, cross- shaped, star-shaped, square etc. Likewise, instead of spherical particles, the beads may also be rotationally elliptical (rotational ellipsoid, also referred to as spheroid) or cuboid, such as cubic.

[0290] The polymer network, such as the PEG network, of the hydrogel depot according to certain embodiments of the present invention may be semi-crystalline in the dry state at or below room temperature, and amorphous in the wet state. The dry units of the depot may be dimensionally stable at or below room temperature, which may be advantageous for loading the depot into the needle and for quality control.

[0291] Upon hydration of the depot in the joint or the bony canal (which can be simulated in vitro e.g. by immersing the depot into PBS, pH 7.2 at 37 °C after 24 hours, which is considered equilibrium) the dimensions of the depot according to the invention or its units may change. Generally, the diameter of the units may increase, while optionally their length may increase, decrease or in certain embodiments may stay the same or essentially the same. An advantage of this dimensional change is that, while the units in their dry state are sufficiently thin to be administered and placed into the joint or the bony canal, they may take a larger volume for active agent release once placed in the joint or the bony canal. It should be appreciated that due to the nature of drug diffusion through thehydrogel matrix and release from the depot surface, the duration and rate of drug release will be affected by the final hydrated shape and dimensions.

[0292] In the hydrogels of the present invention, a degree of molecular orientation may be imparted by stretching the material then allowing it to solidify, locking in the molecular orientation. The molecular orientation provides one mechanism for anisotropic swelling upon contacting the depot with a hydrating medium such as synovial fluid. Upon hydration, the depot of certain embodiments of the present invention will swell in the radial dimension, while the length, if any, will either decrease or be maintained or essentially maintained.

[0293] Among other factors influencing the possibility to stretch the hydrogel and to elicit dimensional change of the units upon hydration is the composition of the polymer network. In the case PEG precursors are used, those with a lower number of arms (such as 4-armed PEG precursors) contribute to providing a higher flexibility in the hydrogel than those with a higher number of arms (such as 8-armed PEG precursors). If a hydrogel contains more of the less flexible components (e.g. a higher amount of PEG precursors containing a larger number of arms, such as the 8- armed PEG units), the hydrogel may be firmer and less easy to stretch without fracturing. On the other hand, a hydrogel containing more flexible components (such as PEG precursors containing a lower number of arms, such as 4-armed PEG units) may be easier to stretch and softer, but also swells more upon hydration. Thus, the behavior and properties of the depot once it has been administered and is rehydrated can be tailored by means of varying structural features as well as by modifying the processing of the depot after it has been initially formed.

[0294] The dried depot dimensions inter alia may depend on the amount of tyrosine kinase inhibitor incorporated as well as the ratio of tyrosine kinase inhibitor to polymer units and can additionally be controlled e.g. by the diameter and shape of the mold or tubing in which the hydrogel is allowed to gel and / or by the method of further processing the hydrogel prior to (or after) complete gelling. The diameter of the dried depot may be further controlled by (wet or dry) stretching of the hydrogel strands once formed as disclosed herein. For example, dried hydrogel strands (after stretching) may be cut into segments of the desired length to form the fiber or beads; the length can thus be chosen as desired. Fibers:

[0295] In certain embodiments, the depot is in the form 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 is constituted of two or more units in the form of fibers.

[0296] In one embodiment, the fiber is cylindrical or has an essentially cylindrical shape. Whenever in the specification or in the claims it is herein referred to “cylindrical” in the context of the shape of the units of the depot, this always includes “essentially cylindrical”. In this case, the fibers have a round or an essentially round cross- section. In another embodiment, the fiber is non-cylindrical. The fiber according to the present invention may optionally be elongated in its dry state, wherein the length of the fiber is greater than the width of the fiber, wherein the width is the largest cross-sectional dimension that is substantially perpendicular to the length. In a cylindrical or essentially cylindrical depot, the width is also referred to as the diameter.

[0297] In general, the length and / or diameter of the at least one fiber of the present invention may be restricted, e.g., by the administration site, such as the size of the respective joint cavity, or the needle gauge to be used for administration. In certain embodiments, the at least one fiber of the present invention may have an average lengthof at least about 1 mm, at least about 5 mm, or at least about 10 mm, 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 the dried state. In these or other embodiments, the at least one fiber of the present invention may have an average length of about 5 cm at most, about 1 cm at most, about 0.5 cm at most, or about 0.1 cm at most, and / or an average diameter of about 1 mm at most, about 0.8 mm at most, about 0.50 mm at most, or about 0.01 mm at most in the dried state. In one embodiment, the at least one fiber of the present invention 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 in the dried state. Such a fiber may decrease in length and increase in diameter upon hydration in vitro or in vivo in the joint or the bony canal, such as a knee joint. In some embodiments, the 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 the dried state. In particular embodiments, the 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 the dried state.

[0298] In some embodiments, the fiber according to the present invention may be linear. In other embodiments, the fiber according to the present invention may be coiled, i.e. the fiber adopts a three-dimensional arrangement that shortens its final length. Such arrangement in the form of a coil allows the fiber to contain an increased drug load compared to a linear fiber having the same final length.

[0299] In certain embodiments, one fiber comprises the tyrosine kinase inhibitor, and especially axitinib, 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 from about 10 µg to about 1200 µg. For example, one fiber comprises axitinib in an amount of (or in an amount which is a multiple of) about 15 µgm, or of about 35 µg, or of about 55 µg, or of about 100 µg, or of about 150 µg, or of about 200 µg, of about 300 µg, or of about 420 µg. In some embodiments, one fiber comprises axitinib in an amount of from about 100 µg to about 800 µg. In particular embodiments, one fiber comprises axitinib in an amount of from about 250 µg to about 600 µg, of from about 300 µg to about 500 g, or from about 380 µg to about 460 µg.

[0300] In one specific embodiment, the fiber contains about 420 µg 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.

[0301] In certain embodiments, the at least one fiber is obtainable by preparing a mixture containing hydrogel precursors and tyrosine kinase inhibitor, such as axitinib, filling the mixture into a tubing or mold, allowing the mixture to gel in the tubing or mold to provide a hydrogel in the form of a fiber. In other embodiments, the at least one fiber is obtainable by preparing a mixture containing hydrogel precursors and tyrosine kinase inhibitor, heating and melt extruding the mixture into a strand, and cutting the strand. Methods aand processes for obtaining fibers by hot melt extrusion are disclosed, e.g., in PCT patent application PCT / US2022 / 051993, incorporated herein by reference.

[0302] Exemplarily manufactured fibers according to the invention are described and characterised in Examples 1 A. and 2.

[0303] In one very particular embodiment of the method of treating an articular condition according to the present invention, the depot is administered into a synovial joint of the patient and the dose per joint administered once for a treatment period of at least 3 months is from about 0.5 mg to about 120 mg of the tyrosine kinase inhibitor, wherein the hydrogel comprises a polymer network that comprises one or more crosslinked 4- to 8-arm polyethylene glycol units and the tyrosine kinase inhibitor is axitinib, and wherein the depot is in the form of one or more sustained release biodegradable fibers and each of the fibers comprises axitinib in an amount of at least 10 µg or at least 50 µg, such as from about 100 µg to about 800 µg.

[0304] In another very particular embodiment of the method of treating an articular condition according to the present invention, the depot is administered into a knee of the patient and the dose per knee administered once for a treatment period of at least 3 months is from about 10 mg to about 25 mg of the tyrosine kinase inhibitor, wherein the hydrogel comprises a polymer network that comprises one or more crosslinked 4- to 8-arm polyethylene glycol units and the tyrosine kinase inhibitor is axitinib, and wherein the depot is in the form of one or more sustained release biodegradable fibers and each of the fiber(s) comprises axitinib in an amount of at least 10 µg or at least 50 µg, such as from about 100 µg to about 800 µg.

[0305] In another very particular embodiment of the method of treating an articular condition according to the present invention, the depot is administered into a hip of the patient and the dose per knee administered once for a treatment period of at least 3 months is from about 5 mg to about 15 mg of the tyrosine kinase inhibitor, wherein the hydrogel comprises a polymer network that comprises one or more crosslinked 4- to 8-arm polyethylene glycol units and the tyrosine kinase inhibitor is axitinib, and wherein the depot is in the form of one or more sustained release biodegradable fibers and each of the fiber(s) comprises axitinib in an amount of at least 10 µg or at least 50 µg, such as from about 100 µg to about 800 µg.

[0306] In another very particular embodiment of the method of treating an articular condition according to the present invention, the depot is administered into a finger of the patient and the dose per knee administered once for a treatment period of at least 3 months is from about 1 mg to about 8 mg of the tyrosine kinase inhibitor, wherein the hydrogel comprises a polymer network that comprises one or more crosslinked 4- to 8-arm polyethylene glycol units and the tyrosine kinase inhibitor is axitinib, and wherein the depot is in the form of one or more sustained release biodegradable fibers and each of the fiber(s) comprises axitinib in an amount of at least 10 µg or at least 50 µg, such as from about 100 µg to about 800 µg. Beads:

[0307] In certain embodiments, the depot is in the form of a plurality of sustained release biodegradable beads, i.e. the depot is constituted of two or more units in the form of beads.

[0308] In one embodiment, the beads are spherical or have the general shape of spherical particles. Whenever in the specification or in the claims it is herein referred to “spherical” in the context of the shape of the units of the depot, this always includes “essentially spherical”. In this case, the beads have a round or an essentially round cross- section. In other embodiments of the invention, the beads are non-spherical. The surface of the beads may be regular or irregular.

[0309] A plurality of beads constituting a depot as used in the method according to the present invention may have a narrow particle size distribution, in order to provide for the tyrosine kinase inhibitor being uniformly released from each of the beads. In certain embodiments, for any kind of (dry) beads used in the method according to the present invention, particle sizes (e.g. as expressed by the D50 value as defined herein and that are measured as also disclosed herein) of about 300 μm or below, or of about 250 μm or below, or of about 220 μm or below may be used. In particular embodiments, the beads in a dried state may have a D50 particle size of equal to or less than about 250 μm, or of equal to or less than about 220 μm, or of equal to or less than about 210 μm. In these and other embodiments, the D90 particle size may be equal to or less than about 300 μm, or equal to or less than about 280 μm, or equal to or less than about 250 µm. In particular embodiments of the present invention, the beads constituting a depot of the present invention in a dried state have a mean volumetric particle size of about 50 µm toabout 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 or other embodiments, the beads constituting a depot according to the present invention in the hydrated state have a mean volumetric 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 a mean volumetric particular size of about 200 µm in a dried state and of about 400 µm in a hydrated state, as determined by scanning electron microscopy (SEM), light microscopy or other suitable method.

[0310] In certain embodiments, the beads are obtainable by preparing a mixture containing hydrogel precursors and tyrosine kinase inhibitor, such as axitinib, and further processing to provide a hydrogel in the form of beads comprising tyrosine kinase inhibitor particles, e.g. by the methods as described further below. In one alternative, the mixture may then be extruded from a static mixer into a tubing with tangential oil flow. In a second alternative, the mixture may then be filled into a syringe or mold, allowing the mixture to gel, followed by pushing the mixture through at least one mesh screen. In a third alternative, the mixture may be filled into a mold having micro-cavities, allowing the mixture to gel in the micro-cavities. In a fourth alternative, the mixture may be heated and melt extruded into a strand, followed by cutting or pelletizing the strand. In a fifth alternative, the mixture may be heated and extruded into an oil bath. In certain embodiments, the beads obtained may be dried. In these or other embodiments, the beads obtained may be lyophilized.

[0311] In certain embodiments of the present invention, the tyrosine kinase inhibitor contained in a sustained release biodegradable depot in the form of a plurality of beads is present in an amount of from about 0.01 µg to about 100 µg or about 50 µg per one bead, or in an amount of from about 0.1 µg to about 20 µg per one bead, such as about 1 µg, about 2 µg, about 5 µg, about 10 mg, about 15 µg etc.. In some embodiments, the beads comprise the tyrosine kinase inhibitor in an amount of from about 0.5 µg to about 12 µg per one bead. In particular embodiments, the beads comprise axitinib in an amount of from about 1 µg to about 8 µg per one bead, from about 1.5 µg to about 5 µg per one bead, or from about 2 µg to about 4 µg per one bead.

[0312] In certain embodiments, the beads do not agglomerate during administration, in order to facilitate their storage, their aspiration and administration through a hypodermic needle.

[0313] In certain embodiment, the plurality of beads may be present in a collection medium in order 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 within a short time after administration. The polymer network may be obtained, e.g., by means of injection molding, hot melt extrusion, or 3D printing.

[0314] In certain embodiments, the beads are suspended in a carrier. The carrier may be a non-aqueous carrier, such as an oil-based carrier. The carrier allows for simplified portioning of the beads to be administered by articular injection. Thereby, in some embodiments, the carrier prevents agglomeration of the beads. Further, in terms of a non-aqueous carrier, such as an oil-based carrier, the beads may be prevented from swelling, which allows the beads in its dried state to be delivered in the oil phase and to be funneled through smaller needle gauges for administration. Once in the joint, the carrier may diffuse away and be replaced by the synovial fluid allowing the beads to uptake the aqueous environment to their equilibrium swelling, reaching their hydrated diameter.

[0315] In certain embodiments, the beads are suspended in the carrier in a volume ratio (beads:carrier) of no more than about 45:55, in particular in a volume ratio 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 in a concentration of nomore than about 50 wt.-% beads, in particular in a concentration of about 10 wt.-% to about 50 wt.-% beads, about 15 wt.-% to about 40 wt.-% beads, or about 20 wt.-% to about 30 wt.-% beads, with the remainder being the carrier. In very particular embodiments, the carrier, such as the oil-based carrier, is sesame oil or ethyl oleate, or other suitable pharmaceutically acceptable carrier, e.g. one of the carriers that are disclosed herein below in the context of the pharmaceutical preparation. Specifically, the characteristics of the carrier, including the oil-based carrier that may be used in any of the methods of treatment of the present invention are the same characteristics as disclosed below for the carrier in the context of the pharmaceutical preparation, or other suitable pharmaceutically acceptable carrier, e.g. one of the carriers that are disclosed herein below in the context of the pharmaceutical preparation. Specifically, the characteristics of the carrier, including the oil-based carrier that may be used in any of the methods of treatment of the present invention are the same characteristics as disclosed below for the carrier in the context of the pharmaceutical preparation. Thus, in certain embodiments, the beads may be suspended in an oil- based carrier which is liquid at 15 °C or above, such as at room temperature and / or at body temperature. Further ccharacteristics of the oil-based carrier may include, cumulatively or alternatively, a boiling point greater than body temperature, such as a boiling point greater than 50 °C, greater than 70 °C, greater than 100 °C, or greater than 150 °C, and / or a viscosity of less than about 120 mPa·s, of less than about 100 mPa·s, or of less than about 85 mPa·s at 20 °C, and / or a density of less than about 1.5 g / cm3, less than about 1.0 g / cm3, of less than about 0.95 g / cm3, or of less than about 0.92 g / cm3.

[0316] Exemplarily manufactured beads according to the invention are described and characterised in Examples 1 B. and 2. In particular embodiments, the beads used as the depot in the method of treatment according to any aspect of the present invention may be administered in the form of a pharmaceutical preparation as further disclosed herein below.

[0317] In one very particular embodiment of the method of treating an articular condition according to the present invention, the depot is administered into a synovial joint of the patient and the dose per joint administered once for a treatment period of at least 3 months is from about 0.5 mg to about 120 mg of the tyrosine kinase inhibitor, wherein the hydrogel comprises a polymer network that comprises one or more crosslinked 4- to 8-arm polyethylene glycol units and the tyrosine kinase inhibitor is axitinib, and wherein the depot is in the form of a plurality of sustained release biodegradable beads and the beads comprise axitinib in an amount of at least 0.1 µg or at least 0.5 µg, such as from 1 µg to about 8 µg per one bead.

[0318] In another very particular embodiment of the method of treating an articular condition according to the present invention, the depot is administered into a knee of the patient and the dose per knee administered once for a treatment period of at least 3 months is from about 10 mg to about 25 mg of the tyrosine kinase inhibitor, wherein the hydrogel comprises a polymer network that comprises one or more crosslinked 4- to 8-arm polyethylene glycol units and the tyrosine kinase inhibitor is axitinib, and wherein the depot is in the form of a plurality of sustained release biodegradable beads and the beads comprise axitinib in an amount of at least 0.1 µg or at least 0.5 µg, such as from 1 µg to about 8 µg per one bead.

[0319] In another very particular embodiment of the method of treating an articular condition according to the present invention, the depot is administered into a hip of the patient and the dose per knee administered once for a treatment period of at least 3 months is from about 5 mg to about 15 mg of the tyrosine kinase inhibitor, wherein the hydrogel comprises a polymer network that comprises one or more crosslinked 4- to 8-arm polyethylene glycol units and the tyrosine kinase inhibitor is axitinib, and wherein the depot is in the form of a plurality of sustainedrelease biodegradable beads and the beads comprise axitinib in an amount of at least 0.1 µg or at least 0.5 µg, such as from 1 µg to about 8 µg per one bead.

[0320] In another very particular embodiment of the method of treating an articular condition according to the present invention, the depot is administered into a finger of the patient and the dose per knee administered once for a treatment period of at least 3 months is from about 1 mg to about 8 mg of the tyrosine kinase inhibitor, wherein the hydrogel comprises a polymer network that comprises one or more crosslinked 4- to 8-arm polyethylene glycol units and the tyrosine kinase inhibitor is axitinib, and wherein the depot is in the form of a plurality of sustained release biodegradable beads and the beads comprise axitinib in an amount of at least 0.1 µg or at least 0.5 µg, such as from 1 µg to about 8 µg per one bead. II. Pharmaceutical Preparation

[0321] In certain embodiments, the present invention also relates to an injectable pharmaceutical preparation comprising (i) a sustained release biodegradable depot comprising a hydrogel and a tyrosine kinase inhibitor, and (ii) 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 its aspects is axitinib. In cases where the biodegradable hydrogels are susceptible to hydrolysis, the carrier may be anhydrous, that is having been treated to reduce water content to levels low enough to provide storage stability to the hydrolysable hydrogel depot.

[0322] In some embodiments, the depot is in the form of a plurality of 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 an articular condition according to the invention. The beads in a dried state as contained in the pharmaceutical preparation may have a narrow particle size distribution, in particular having a D50 particle size of equal to or less than about 250 μm, or of equal to or less than about 220 μm, or of equal to or less than about 210 μm, or a D90 particle size of equal to or less than about 300 μm, or equal to or less than about 280 μm, or equal to or less than about 250 µm. In particular embodiments of the present invention, the beads in a dried state constituting a depot as contained in a pharmaceutical preparation according to the invention have a mean volumetric 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 or other embodiments, the beads in hydrated state constituting a depot as contained in a pharmaceutical preparation according to the present invention have a mean volumetric 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.

[0323] In certain embodiments, the tyrosine kinase inhibitor such as axitinib contained in a sustained release biodegradable depot in the form of a plurality of beads is present in an amount of from about 0.01 µg to about 100 µg or about 50 µg per one bead, or in an amount of from about 0.1 µg to about 20 µg per one bead, such as in an amount of from 0.5 µg to about 12 µg per one bead. In particular embodiments, the beads comprise axitinib in an amount of from about 1 µg to about 8 µg per one bead, from about 1.5 µg to about 5 µg per one bead, or from about 2 µg to about 4 µg per one bead.

[0324] Suitable precursors for forming the hydrogel of the beads in certain embodiments of the invention are as disclosed above in the section relating to the depot itself. In particular embodiments, the hydrogel may comprise 4a20kPEG units derived from reacting a 4a20kPEG-SG or a 4a20kPEG-SAZ precursor with a 4a20kPEG-NH2precursor or trilysine acetate, to form the polymer network.

[0325] In certain embodiments of the pharmaceutical preparation, the beads are suspended in the carrier in a volume ratio (beads:carrier) of no more than about 45:55, in particular in a volume ratio 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 of the pharmaceutical preparation, the beads may be suspended in the carrier, and may in particular not be agglomerated, in a concentration of no more than about 50 wt.-% beads, such as in a concentration of about 10 wt.-% to about 50 wt.- % beads, with the remainder being the carrier. In some embodiments, the beads are suspended in the carrier in a concentration of about 15 wt.-% to about 40 wt.-% beads, with the remainder being the carrier. In particular embodiments, the beads are suspended in the carrier in a concentration of about 20 wt.-% to about 30 wt.-% beads, with the remainder being the carrier. The beads may be homogeneously suspended in the carrier, in order to ensure uniform concentrations when portioning the pharmaceutical preparation. The concentration of the beads in relation to the carrier determines the dosing of the tyrosine kinase inhibitor, such as axitinib.

[0326] The injectable pharmaceutical preparation according to the present invention may comprise 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 given amount) of the carrier. In certain embodiments, the injectable pharmaceutical composition according to the present invention comprises (i) about 100 to about 400,000 beads, suspended in the carrier, such as in about 0.1 mL to about 0.5 mL of the carrier, or in about 0.5 mL to about 3 mL of the carrier. In some embodiments, the pharmaceutical preparation comprises (i) about 10,000 to about 100,000 beads, suspended in the carrier, such as in about 1 mL of the carrier. In particular embodiments, the pharmaceutical composition comprises (i) about 40,000 to about 70,000 beads, suspended in (ii) about 1 ml of the carrier.

[0327] In these or other embodiments, the injectable pharmaceutical preparation according to the present invention may comprise at least about 0.001 g beads, at least about 0.003 g beads, at least about 0.008 g beads, at least about 0.02 g beads, at least about 0.03 g beads, at least about 0.05 g beads, or at least about 0.08 g beads, suspended (in a given amount) of the carrier. In some embodiments, the injectable pharmaceutical composition according to the present invention comprises (i) about 0.008 g to about 2 g beads, suspended in the carrier, such as in about 0.1 mL to about 0.5 mL of the carrier, or in about 0.5 mL to about 3 mL of the carrier. In some embodiments, the pharmaceutical preparation comprises (i) about 0.1 g to about 1 g beads, suspended in the carrier, such as in about 0.5 mL to about 0.5 mL of the carrier, or in about 0.5 mL to about 3 mL of the carrier. In particular embodiments, the pharmaceutical preparation comprises (i) about 0.1 g to about 1 g, such as about 0.2 g to about 0..5 g, suspended in about 1 mL of the carrier.

[0328] The carrier contained in the pharmaceutical preparation according to the invention may be any carrier medium which may suspend the depot, such as the plurality of beads, without agglomeration and which does not interact with the hydrogel and is furthermore tolerable in the patient’s body after being injected. Particular carrier media according to the present invention shall be easily injectable, i.e. liquid during injection as well as in the patient’s body, having a low- to medium viscosity.

[0329] In certain embodiments, the carrier is a non-aqueous carrier. In particular embodiments, the carrier is an oil-based carrier, in particular a pharmaceutically acceptable oil-based carrier. This may include (but is not limited to) pharmaceutically acceptable oils, low melting waxes, fats, lipids, liposomes and any other pharmaceutically acceptable substance that is lipophilic, substantially insoluble in water. The carrier should be removable by natural processes of the patient’s body. The oil based carrier may be a natural or synthetic oil, and is in particular a natural oil that may include oils of plants such as vegetables or seeds. In particular embodiments, the carrier, such as theoil-based carrier, is at least one pharmaceutically acceptable oil including almond oil, castor oil, coconut oil, corn oil, cotton seed oil, flax oil, linseed oil, maize oil, mineral oil, olive oil, palm oil, peanut oil, rape 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 tallow, 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 very particular embodiments, the oil based carrier is sesame oil. In other very particular embodiments, the oil-based carrier is ethyl oleate. Tolerability of these oil-based carriers has been confirmed in the knees of Sprague Dawley rats by histological assessment and dissection, as well as blood analysis full necropsy (results not shown).

[0330] Characteristics of the oil-based carrier may include, cumulatively or alternatively, - a boiling point greater than body temperature, such as a boiling point greater than 50 °C, greater than 70 °C, greater than 100 °C, or greater than 150 °C, and / or - a viscosity of less than about 120 mPa·s, of less than about 100 mPa·s, or of less than about 85 mPa·s at 20 °C, and / or - a density of less than about 2.0 g / cm3such as less than about 1.5 g / cm3, less than about 1.0 g / cm3, of less than about 0.95 g / cm3, or of less than about 0.92 g / cm3.

[0331] The oil-based carrier, in certain embodiments, may be liquid at 15 °C or above. In particular embodiments, the oil-based carrier is liquid at room temperature and at body temperature.

[0332] In certain embodiments, the carrier, such as the oil-based carrier, provides a very low axitinib solubility, in order that the active agent is not released from the depot into the carrier before being administered into a joint or a bony 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, such as less than about 50 µg / ml. In particular embodiments, the solubility of axitinib in the carrier is less than about 20 µg / ml. In certain very particular embodiments, axitinib is essentially insoluble in the carrier.

[0333] 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 enhancers. Examples of such viscosity enhancing excipient may include, but are not limited to oil-soluble, bioresorbable polymers.

[0334] In one very particular embodiment of the pharmaceutical preparation according to the present invention, the depot is in the form of a plurality of sustained release biodegradable beads, wherein the hydrogel comprises a polymer network that comprises one or more crosslinked 4- to 8-arm polyethylene glycol units and the tyrosine kinase inhibitor is axitinib, wherein the beads comprise axitinib in an amount of at least 0.1 µg or at least 0.5 µg, such as from 1 µg to about 8 µg per one bead, and wherein the carrier is sesame oil or ethyl oleate. III. Production of the Pharmaceutical Preparation

[0335] In certain embodiments, the present invention also relates to a method of producing an injectable pharmaceutical preparation comprising (i) a sustained release biodegradable depot comprising a hydrogel and a tyrosine kinase inhibitor, and (ii) a carrier. In certain embodiments, the method comprises I. steps of forming a hydrogel comprising a polymer network (e.g., comprising PEG units) and tyrosine kinase inhibitor particles dispersed in the hydrogel, and shaping the hydrogel into beads, and optionallyII. a step of suspending the beads in the carrier.

[0336] In certain preferred embodiments, the tyrosine kinase inhibitor in the method of producing an injectable pharmaceutical composition according to the present invention in all its aspects is axitinib. In one embodiment, the tyrosine kinase inhibitor, such as axitinib, may be used in micronized form for preparing the depots. The micronized particles may 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, such as axitinib, may be used in non-micronized from for preparing the depots.

[0337] Suitable precursors for forming the of the invention are as disclosed above in the section relating to the depot itself. In the hydrogel is made of a polymernetwork comprising crosslinked polyethylene as herein. The PEG units in particular embodiments are multi-arm, such as 4-arm, PEG units having an average molecular weight from about 2,000 to about 100,000 Daltons, or from about 10,000 to about 60,000 Daltons, or from about 15,000 to about 50,000 Daltons or 30,000 Daltons, or of about 20,000 Daltons. Suitable PEG precursors having reactive groups such as electrophilic groups as disclosed herein are crosslinked to form the polymer network. Crosslinking may be performed by means of a crosslinking agent that is either a low molecular compound or another polymeric compound, including another PEG precursor, having reactive groups such as nucleophilic groups as also disclosed herein. In certain embodiments, a PEG precursor with electrophilic end groups is reacted with a crosslinking agent (a low-molecular compound, or another PEG precursor) with nucleophilic end groups to form the polymer network.

[0338] In specific embodiments, the method of producing an injectable pharmaceutical preparation comprises mixing and reacting an electrophilic group-containing multi-arm polyethylene glycol, such as 4a20kPEG- SG / 4a20kPEG-SAZ, with a nucleophilic group-containing multi-arm polyethylene glycol, such as 8a20kPEG-NH2, or a nucleophilic group-containing crosslinking agent, such as trilysine acetate, in a buffered solution in the presence of axitinib particles (liquid mixture), and allowing the mixture to gel. In other specific embodiments, the method of producing an injectable pharmaceutical preparation comprises mixing an electrophilic group-containing multi-arm polyethylene glycol powder, such as 4a20kPEG-SG / 4a20kPEG-SAZ powder, with a nucleophilic group-containing multi-arm polyethylene glycol powder, such as 8a20kPEG-NH2 powder, or a nucleophilic group-containing crosslinking agent in powder from, such as trilysine acetate powder in the presence of axitinib particles (powdered mixture), and heating the mixture for reaction. In certain embodiments, the molar ratio of the electrophilic groups in the PEG precursor to the nucleophilic groups in the other PEG precursor or crosslinking agent is about 1:1, but may also be in a range from about 2:1 to about 1:2.

[0339] In certain embodiments, a visualization agent as disclosed herein is included in the mixture forming the hydrogel so that the depot can be visualized once it has been administered into the synovial fluid joint cartilage or the space of the bony canal. For example, the visualization agent may be a fluorophore, such as fluorescein or a molecule comprising a fluorescein or another visualization as disclosed above. In certain embodiments, the visualization agent network so that it remains in the depot at for example be conjugated with either weight) crosslinking agent. In of the present invention a(optionally buffered) such as the axitinib and the 4a20kPEG-SAZ, in water is prepared. This tyrosine kinase inhibitor / PEG precursor mixture is then combined with a (optionally buffered) solution containing the PEG precursor and the visualization agent conjugated thereto,such as the 8a20kPEG-NH2 / fluorescein conjugate. The resulting combined mixture thus contains the tyrosine kinase inhibitor, the polymer precursors, the visualization agent and (optionally) buffer.

[0340] In certain polymer precursor, the nucleophilic group-containing kinase inhibitor, such as axitinib, optionally the visualizationor the crosslinking agent), and optionally buffer has been prepared (i.e., after these components have been combined), the resulting mixture is processed in several manufacturing methods, such as gel extrusion, mesh screening, micro-molding, melt extrusion or Vulcan extrusion, to obtain a hydrogel in the form of beads. The beads obtained may then be dried and / or lyophilized.

[0341] In some embodiments, the method of producing an injectable pharmaceutical preparation comprises extruding the liquid mixture from a static mixer prior to complete gelling into a tubing with tangential oil flow to obtain beads, and collecting the beads obtained (gel extrusion). In such embodiments, a suspension of the tyrosine kinase inhibitor, glycol, such as 4a20kPEG- arm polyethylene glycol, such as acetate, in a buffered solution be extruded using a 27- to 30-gauge is extruded with an extrusion rate of mixture is extruded with a rate of the the beads obtained may be controlled needle gauge.

[0342] In some comprises filling the liquid mixture gel. In such embodiments, a and an electrophilic group-containing solution and a nucleophilic group- containing in a syringe and the mixture is allowed

[0343] In certain embodiments, the mixture is allowed to gel in a syringe, and is pushed from the syringe through at least one mesh screen to obtain beads (mesh screening). In specific embodiments, the gel is pushed through one or more mesh screens having different mesh sizes, and the beads obtained are sieved. For example, the gel may be pushed at least once through a 900 µm mesh screen, followed by a 500 µm mesh screen and a 213 µm mesh screen, and the size range of the beads obtained is corrected by wet sieving between 53-500 µm. In other embodiments, the gel may be pushed through a 3D printed mesh screen and cut to obtain beads (modified mesh screening). This enables the bead size to be constrained in two dimensions.

[0344] In certain embodiments, the mixture is allowed to gel in a thin sheet mold to obtain a gel sheet, which is removed from the mold and cut by means of a mesh screen to obtain beads (gel sheet mesh screening). The thickness of the gel sheet constrains the bead size in one dimension and may be about 0.4 mm or less.

[0345] In certain embodiments, the mixture is allowed to gel in a mold having micro-cavities to obtain beads (micro-molding). This enables the bead size to be constrained in all dimensions.

[0346] In certain embodiments, the method of producing an injectable pharmaceutical preparation comprises melt extruding the powdered mixture to obtain a strand, which is cut or pelletized to obtain beads (melt extrusion). The particle size of the beads obtained may be controlled by the melt extrusion diameter, which is in particular 0.4 mm.

[0347] In certain embodiments, the method of producing an injectable pharmaceutical preparation comprises mixing and heating the powdered mixture in a (Vulcan) ceramic syringe under nitrogen, and extruding it into an oil bath to obtain beads (Vulcan extrusion). Heating may be performed for at least 20 min at about 70°C to about 80°C. By initiating the Vulcan wave sequence, the beads are extruded from the Vulcan ceramic syringe.

[0348] The dried and / or lyophilized beads may be packaged into a packaging that keeps out moisture, such as a sealed foil pouch. In certain carrier in a volume ratio (beads:carrier) of no more than about 45:55, in to 45:55, about 12:88 to about 32:68, or about 16:84 to about 24:76. In these suspended in the carrier in a concentration of no more than about of about 10 wt.-% to about 50 wt.- % beads, about 15 wt.-% to about 40 about 30 wt.-% beads, with the remainder being the carrier. The as an oil-based carrier. The carrier may be at least one pharmaceutically oil, coconut oil, corn oil, cotton seed oil, flax oil, linseed oil, maize oil, mineraloil, safflower oil, sesame oil, silicone oil, soybean oil and sunflower oil, at least one pharmaceutically acceptable wax including beeswax, candelilla wax, carnauba wax and tallow, 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.

[0349] In certain embodiments, the final prepared beads, optionally suspended in a carrier, are then loaded into a fine diameter hypodermic needle, such as a 18- to 30-gauge needle. In certain embodiments, the needle is a 20- to 27-gauge needle, or an even smaller gauge needle, such as a 30-gauge needle, depending on the diameter of the dried beads and / or the volume of the carrier. If the pharmaceutical preparation is provided for hip injections, the hypodermic needle may be a 21- or 22-gauge needle. If the pharmaceutical preparation is provided for knee injections, the hypodermic needle may be a 25-gauge needle. In general, the more spacious the site is into which the depot should be injected, the smaller the needle gauge (i.e., the larger the needle diameter) may be.

[0350] In certain embodiments, the hypodermic needles containing the pharmaceutical preparation are then separately packaged and sterilized e.g. by means of gamma irradiation. IV. Kit

[0351] In certain embodiments, the present invention is further directed to a kit comprising one or more injectable pharmaceutical preparations(s) comprising a sustained release biodegradable depot and a carrier as disclosed above or manufactured in accordance with the methods as disclosed above, and one or more hypodermic needle(s). If two or more injectable pharmaceutical preparation(s) are contained in the kit, these preparations may be identical or different, and may contain identical or different doses of the tyrosine kinase inhibitor, such as axitinib.

[0352] In certain embodiments, the at least one sustained release biodegradable depot (in the form of beads) is present in the kit in a separate container or pouch from the carrier. In such embodiments, the at least one sustained release biodegradable depot must be suspended in or mixed with the carrier prior to injection. For example, in some embodiments the beads may be stored in a separate compartment from the carrier, where the two compartments are separated from each other by means of e.g. a foil or other separator between the separate compartments. Inthis case, to prepare the suspension of the beads in the carrier, the separator has to be removed, punctured or otherwise opened so that the carrier is able to surround and suspend the beads. In other embodiments, the carrier and the beads are provided in individual containers (such as individual vials), and the carrier is contacted with the beads, and the suspension of the beads in the carrier is prepared, by the physician from the separate containers immediately prior to administration of the depot to the patient’s joint or bony canal. In other embodiments, the at least one sustained release biodegradable depot is contained in the kit already pre-suspended in the carrier.

[0353] In certain embodiments, the one or more hypodermic needle(s) is / are each pre-loaded with the sustained release injectable pharmaceutical preparation(s) (being either one or more fiber(s) or a plurality of beads suspended in a carrier as disclosed herein). This / These hypodermic needle(s) is / are ready for injection.

[0354] The hypodermic needle(s) pre-loaded with the pharmaceutical preparations(s) may be a 18- to 30-gauge needle. In certain embodiments, the hypodermic needle is a 20- to 27-gauge needle. The diameter of the needle is chosen based on the size of the sustained release biodegradable depot in a dried state and / or the volume of the injectable pharmaceutical preparation. Further, the diameter of the hypodermic needle may be chosen based on the synovial joint into which the injectable pharmaceutical preparation is to be deployed. In one embodiment, the kit comprises one or more 22-gauge hypodermic needle(s). In such embodiments, each of the one or more pharmaceutical preparation(s) may comprise a dose of the tyrosine kinase inhibitor, such as axitinib, of about 15 mg, or about 20 mg, or another dose as disclosed herein. In yet another embodiment, the kit comprises one or more 25 gauge hypodermic needle(s).

[0355] The kit may further contain an injection device for injecting the injectable pharmaceutical preparation(s), in particular into a synovial joint of a patient, such as into the knee of a patient. In certain embodiments, the injection device is provided and / or packaged separately from the one or more hypodermic needle(s). In such embodiments, the injection device must be connected to the one or more hypodermic needle(s) prior to injection. In other embodiments, the kit contains one or more injection device(s) for injecting the injectable pharmaceutical preparation(s), in particular into a synovial joint of a patient, such as into the knee of the patient, wherein each injection device is pre-connected to a hypodermic needle pre-loaded with injectable pharmaceutical preparation, or with an injectable fiber. The present invention thus in one aspect also relates to a pharmaceutical product comprising an injectable pharmaceutical preparation loaded in a hypodermic needle and an injection device, wherein the hypodermic needle is pre-connected to the injection device.

[0356] In certain embodiments the injection device contains a push wire or plunger to deploy the injectable pharmaceutical preparation from the hypodermic needle, in particular into the synovial joint. The push wire may be a Nitinol push wire / plunger or may be a stainless steel / Teflon push wire / plunger. The push wire or plunger allows deploying the injectable pharmaceutical preparation from the needle more easily.

[0357] In some embodiments the injection device and / or the injection needle may contain a stop feature that controls the injection depth.

[0358] In some embodiments the injection device is a modified Hamilton glass syringe.

[0359] The kit may further comprise one or more doses, in particular one dose, of at least one other drug, such as an anti-inflammatory agent ready for injection. 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 provided in a separate injection device connected to a needle, ormay be provided in a sealed vial, from which it may be aspirated through a needle into a syringe or other injection device prior to administration.

[0360] In some embodiments, the one or more injectable pharmaceutical preparation(s) are individually packaged for a single administration. In some embodiments, the one or more injectable pharmaceutical preparation(s) are individually packaged for a single administration in a hermetically sealed vial, such as an ampoule, from which the preparation may be aspirated through the hypodermic needle into a syringe or other injection device prior to administration.

[0361] The kit may further comprise an operation manual for the physician who is injecting the injectable pharmaceutical preparation(s). The kit may further comprise a package insert with product-related information.

[0362] The invention relates in particular to the following further items: 1. A method of treating an articular condition in a patient in need thereof, the method comprising administering to the patient a sustained release biodegradable depot comprising a hydrogel and a tyrosine kinase inhibitor, wherein the depot is administered by injection. 2. The method according to item 1, wherein the depot is administered by articular injection. 3. The method according to item 1 or 2, wherein the depot is administered by intra-articular or periarticular injection. 4. The method according to any of items 1 to 3, wherein the depot is administered into a synovial joint of the patient. 5. The method according to any of items 1 to 4, wherein the depot is administered into a synovial joint cavity of the patient. 6. The method according to any of items 1 to 5, wherein the depot is administered in the area of a knee, an elbow, a finger, a hip, a shoulder, a wrist, an ankle, or in the area of a joint of a foot, hand, shoulder girdle, rotator cuff, pelvis, spine, or jaw of the patient. 7. The method according to item 6, wherein the depot is administered into a knee of the patient. 8. The method according to any of items 1 to 7, wherein the depot is administered into a tibiofemoral joint, patellofemoral joint, humeroulnar joint, humeroradial joint, proximal radioulnar joint, acetabulofemoral joint, glenohumeral joint,, acromioclavicular joint, distal radioulnar joint, radiocarpal joint, intercarpal joint, midcarpal joint, carpometacarpal joint, intermetacarpal joint, talocrural joint, subtalar joint, tibiofibular joint, talonavicular joint, calcaneocuboid joint, metatarsophalangeal joint, interphalangeal joint of a foot or hand, metacarpophalangeal joint, sternoclavicular joint, sternocostal joint, atlanto-occipital joint, atlanto-axial joint, costovertebral joint, costotransverse joint, zygapophyseal joint, sacroiliac joint, or temporomandibular joint of the patient. 9. The method according to item 8, wherein the depot is administered into a tibiofemoral joint, acetabulofemoral joint, talocrural joint, subtalar joint, metatarsophalangeal joint, interphalangeal joint of a foot or hand, atlanto-axial joint, or zygapophyseal joint of the patient. 10. The method according to item 8 or 9, wherein the depot is administered into a tibiofemoral joint of the patient. 11. A method of treating a condition of a bony canal in a patient in need thereof,the method comprising administering to the patient a sustained release biodegradable depot comprising a hydrogel and a tyrosine kinase inhibitor, wherein the depot is administered by injection. The method according to item 11, wherein the depot is administered by injection into or near to the bony canal of the patient. The method according to item 11 or 12, wherein the depot is administered into or near to a carpal tunnel of the patient or into or near to a spinal canal of the patient. The method according to any of items 11 to 13, wherein the depot is administered by epidural injection. The method according to any of items 1 to 14, wherein the injection is an ultrasound-guided injection. The method according to any of items 1 to 15, wherein the depot is administered through a hypodermic needle. The method according to item 16, wherein the hypodermic needle is a 20- to 27-gauge needle. The method according to item 16 or 17, wherein the hypodermic needle is a 22- or 25-gauge needle. The method according to any of items 1 to 18, wherein depot is loaded into the needle in a dried state. The method according to any of items 1 to 19, wherein the depot is administered once for a treatment period of at least 1 month. 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. 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. The method according to any of items 1 to 22, wherein the dose per joint or bony canal administered once for a treatment period is contained in one depot, which contains one or more units. The method according to any of items 1 to 23, wherein the dose per joint or bony canal administered once for a treatment period is from about 0.5 mg to about 120 mg of the tyrosine kinase inhibitor. The method according to item 24, wherein the dose per joint or bony canal administered once for a treatment period is from about 1 mg to about 50 mg of the tyrosine kinase inhibitor. The method according to any of items 1 to 25, wherein the dose per joint or bony canal administered once for a treatment period of at least 3 months is from about 1 mg to about 50 mg, from about 5 mg to about 40 mg, or from about 10 mg to about 30 mg of the tyrosine kinase inhibitor. The method according to any of items 1 to 26, wherein the dose per knee administered once for a treatment period is from about 1 mg to about 70 mg of the tyrosine kinase inhibitor. The method according to item 27, wherein the dose per knee administered once for a treatment period is from about 2.5 mg to about 60 mg of the tyrosine kinase inhibitor. The method according to item 27 or 28, wherein the dose per knee administered once for a treatment period is from about 3 mg to about 45 mg of the tyrosine kinase inhibitor. The method according to any of items 1 to 29, wherein the dose per knee administered once for a treatment period of at least 3 months is from about 3 mg to about 45 mg, from about 5 mg to about 30 mg, or from about 10 mg to about 25 mg of the tyrosine kinase inhibitor. The method according to item 30, wherein the dose per knee administered once for a treatment period of at least 3 months is about 15 mg, or about 20 mg of the tyrosine kinase inhibitor. The method according to any of items 1 to 31, wherein the tyrosine kinase inhibitor is axitinib.The method according to any of items 1 to 32, wherein the depot after administration into the joint or the bony canal releases a therapeutically effective amount of axitinib over a period of at least about 1 months, 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. The method according to item 33, wherein the depot after administration into the joint or the bony canal releases a therapeutically effective amount of axitinib over a period of at least 3 months. The method according to item 33 or 34, wherein the depot after administration into the joint or the bony canal releases a therapeutically effective amount of axitinib over a period of at least 6 months. The method according to any of items 1 to 35, wherein axitinib is released from the depot after administration at an average rate of about 1 µg / day to about 600 µg / day. The method according to item 36, wherein axitinib is released from the depot after administration at an average rate of about 30 µg / day to about 500 µg / day. The method according to item 36 or 37, wherein axitinib is released from the depot after administration at an average rate of about 100 µg / day to about 270 µg / day. The method according to any of items 36 to 38, wherein axitinib is released from the depot after administration at an average rate of about 165 µg / day, or about 220 µg / day. The method according to any of items 1 to 39, wherein the depot provides a mean release rate in vitro of about 100 μg to about 500 μg per day, or of about 160 µg to about 400 µg of axitinib per day in phosphate- buffered saline at 37 °C for a period of 90 days, and / or about 150 µg to about 600 μg, or of about 200 µg to about 450 µg to about of axitinib per day in phosphate-buffered saline at 37 °C for a period of 30 days. The method according to any of items 1 to 40, wherein the depot provides a cumulated amount of axitinib released in vitro of about 3 mg to about 20 mg, or of about 4.5 mg to about 18 mg in phosphate-buffered saline at 37 °C over a period of 30 days, and / or of about 7 mg to about 36 mg, or of about 9 mg to about 33 mg in phosphate-buffered saline at 37 °C over a period of 60 days, and / or of about 12 mg to about 50 mg, or of about 15 mg to about 42 mg to about in phosphate-buffered saline at 37 °C over a period of 90 days. The method according to any of items 1 to 41, wherein the depot releases in vitro about 9% to about 26% of the axitinib within 1 month, about 21% to about 48% of the axitinib within 2 months, about 34% to about 77% of the axitinib within 3 months, and about 70% to about 100% of the axitinib within 6 months in phosphate buffered saline at a pH of 7.2, at 37 °C and with an octanol top layer. The method according to item 42, wherein the depot releases in vitro about 9% to about 16% of the axitinib within 1 month, about 21% to about 28% of the axitinib within 2 months, about 34% to about 41% of the axitinib within 3 months, about 70% to about 77% of the axitinib within 6 months, and about 93% to 100% within 9 months in phosphate buffered saline at a pH of 7.2, at 37 °C and with an octanol top layer. The method according to any of items 1 to 43, wherein the depot releases in vitro about 1% to about 5% of the axitinib within 7 days, about 3% to about 7% of the axitinib within 14 days, about 8% to about 12% of the axitinib within 28 days, and / or about 15% to 19% within 42 days in phosphate buffered saline at a pH of 7.2, at 37 °C and with an octanol top layer. The method according to any of items 1 to 44, wherein the depot provides a mean axitinib concentration in the synovial fluid of about 150 ng / mL to about 600 ng / mL after a period of 3 days after administration, and / or of about 350 ng / mL to about 750 ng / mL after a period of 7 days after administration, and / or of about 35 ng / mL to about 200 ng / mL after a period of 14 days after administration.The method according to item 45, wherein the depot provides a means axitinib concentration in the synovial fluid of about 35 ng / mL to about 200 ng / mL over period of 14 days, over a period of 1 month, over a period of 2 months, or over a period of 3 months. The method according to any of items 1 to 46, wherein the depot releases in vitro about 1% to about 15% of the tyrosine kinase inhibitor within 14 days, about 5% to about 30% of the tyrosine kinase inhibitor within 1 month, about 15% to about 50% of the tyrosine kinase inhibitor within 2 months, about 30% to about 80% of the tyrosine kinase inhibitor within 3 months, about 70% to about 100% of the tyrosine kinase inhibitor within 6 months in phosphate buffered saline at a pH of 7.2, at 37 °C and with an octanol top layer. The method according to any of items 1 to 47, wherein the unit(s) of the depot is / are in a dried state prior to administration and become(s) hydrated once administered into the joint. The method according to item 48, wherein upon hydration in vivo in the joint or in vitro the diameter of the units of the depot is increased. The method according to item 49, wherein hydration is measured in vitro in phosphate-buffered saline at a pH of 7.2 at 37 °C after 24 hours. The method according to any of items 1 to 50, wherein the depot biodegrades in the joint within about 2 to about 15 months after administration. The method according to item 51, wherein the depot biodegrades in the joint within about 4 to about 13 months after administration. The method according to item 51 or 52, wherein the depot biodegrades in the joint within about 9 to about 12 months after administration. The method according to any of items 1 to 53, wherein the depot in a dried state contains from about 0.1% by weight to about 7% by weight water. The method according to any of items 1 to 54, wherein the depot in a dried state contains from about 10% to about 75% by weight of the tyrosine kinase inhibitor and from about 25% to about 80% by weight polymer units, or from about 25% to about 60% by weight of the tyrosine kinase inhibitor and from about 35% to about 65% by weight polymer units, or from about 45% to about 55% by weight of the tyrosine kinase inhibitor and from about 40% to about 60% by weight polymer units. The method according to any of items 1 to 55, wherein the depot contains one or more phosphate, borate or carbonate salt(s). The method according to any of items 1 to 56, wherein the depot contains phosphate salt originating from phosphate buffer used during the preparation of the hydrogel. The method according to any of items 1 to 57, wherein the hydrogel in a wet state contains about 3% to about 20% polyethylene glycol representing the polyethylene glycol weight divided by the fluid weight x 100, or about 7.5% to about 15% polyethylene glycol representing the polyethylene glycol weight divided by the fluid weight x 100. The method according to any of items 1 to 58, wherein the hydrogel comprises a polymer network, which is semi-crystalline in the dry state at or below room temperature, and amorphous in the wet state. The method according to any of items 1 to 59, wherein the hydrogel comprises a polymer network comprising one or more units of polyalkylene glycol, polyethylene glycol, polyethylene oxide, polypropylene oxide, polyvinyl alcohol, poly (vinyl pyrrolidone), polylactic acid, polylactic-co-glycolic acid, random or blockcopolymers or combinations or mixtures of any of these, or one or more units of polyaminoacids, glycosaminoglycans, polysaccharides, or proteins. The method according to any of items 1 to 60, wherein the hydrogel comprises a polymer network that comprises crosslinked polymer units that are identical or different. The method according to item 61, wherein the crosslinked polymer units are one or more crosslinked polyethylene glycol units. The method according to any of items 1 to 62, wherein the polymer network comprises polyethylene glycol units having an average molecular weight in the range from about 2,000 to about 100,000 Daltons, or in the range from about 10,000 to about 60,000 Daltons, or in the range from about 20,000 to about 40,000 Daltons, or in the range from about 15,000 to about 30,000 Daltons. The method according to item 63, wherein the polyethylene glycol units have an average molecular weight of about 15,000 or 20,000 Daltons. The method according to any of items 1 to 64, wherein the polymer network comprises one or more crosslinked multi-arm polymer units. The method according to item 65, wherein the multi-arm polymer units comprise one or more 2- to 10-arm polyethylene glycol units, or one or more 4- to 8-arm polyethylene glycol units. The method according to item 65 or 66, wherein the multi-arm polymer units comprise one or more 4-arm polyethylene glycol units. The method according to item 67, wherein the 4-arm polyethylene glycol units are 4a20kPEG units or 4a40kPEG units. The method according to any of items 65 to 68, wherein the multi-arm polymer units comprise one or more 8- arm polyethylene glycol units. The method according to item 69, wherein the 8-arm polyethylene glycol units are 8a20kPEG units or 8a15kPEG units. The method according to any of items 1 to 70, wherein the polymer network comprises both 4-arm and 8-arm polyethylene glycol units. The method according to item 71, wherein the 4-arm polyethylene glycol units are 4a20kPEG units and the 8-arm polyethylene glycol units are 8a20kPEG units. The method according to any 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. The method according to item 73, wherein the nucleophilic group is an amine group. The method according to item 73 or 74, wherein the electrophilic group is an activated ester group. The method according to item 75, wherein the electrophilic group is an N-hydroxysuccinimidyl (NHS) group. The method according to item 76, wherein the electrophilic group is a succinimidyl glutarate (SG) or a succinimidyl azelate (SAZ) group. The method according to any of items 1 to 77, wherein the polymer network is obtained by reacting 4a20kPEG-SG or 4a20kPEG-SAZ with 8a20kPEG-NH2in a weight ratio of about 2:1 or less. The method according to any of items 1 to 78, wherein the tyrosine kinase inhibitor is dispersed within the hydrogel as tyrosine kinase inhibitor particles. The method according to item 79, wherein the tyrosine kinase inhibitor particles are micronized particles.The method according to item 80, wherein the micronized particles are micronized axitinib particles. The method according to item 80 or 81, wherein the micronized particles have a D90 of less than about 10 μm, and a D100 of less than about 20 μm. The method according to any of items 79 to 82, wherein the depot biodegrades in the joint or the bony canal prior to or around the same time as complete solubilisation of the tyrosine kinase inhibitor particles contained in the depot. The method according to any of items 1 to 83, wherein the entire amount of the tyrosine kinase inhibitor contained in the depot is released prior to complete degradation of the depot in the joint or the bony canal. The method according to any of items 1 to 84, wherein the depot is in the form of at least one sustained release biodegradable fiber. The method according to item 85, wherein the at least one fiber has an essentially cylindrical shape. The method according to item 85 or 86, wherein the at least one fiber in a dried 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. The method according to any of items 85 to 87, wherein the at least one fiber in a hydrated state 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. The method according to any of items 85 to 88, wherein the at least one fiber is obtainable by preparing a mixture containing hydrogel precursors and tyrosine kinase inhibitor, filling the mixture into a tubing or mold, allowing the mixture to gel in the tubing or mold to provide a hydrogel in the form of a fiber; or by preparing a mixture containing hydrogel precursors and tyrosine kinase inhibitor, heating and melt extruding the mixture into a strand, and cutting the strand. The method according to any of items 85 to 89, wherein one fiber comprises 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 from about 10 µg to about 1200 µg. The method according to item 90, wherein one fiber comprises axitinib in an amount of from about 100 µg to about 800 µg. The method according to item 90 or 91, wherein one fiber comprises axitinib in an amount of from about 250 µg to about 600 µg, of from about 300 µg to about 500 µg, or of from about 380 µg to about 460 µg. The method according to any of items 1 to 84, wherein the depot is in the form of a plurality of sustained release biodegradable beads. The method according to item 93, wherein the beads are spherical or non-spherical particles. The method according to item 93 or 94, wherein the beads have a narrow particle size distribution. The method according to any 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.The method according to any of items 93 to 96, wherein the beads in a dried state have a mean volumetric particle size of about 50 µm to about 500 µm, of about 100 µm to about 300 µm, or of about 200 µm, as determined by scanning electron microscopy (SEM). The method according to any of items 93 to 97, wherein the beads in a hydrated state have a mean volumetric particle size of about 100 µm to about 1000 µm, of about 200 µm to about 600 µm, or of about 400 µm, as determined by light microscopy. The method according to any of items 93 to 98, wherein the beads are obtainable by preparing a mixture containing hydrogel precursors and tyrosine kinase inhibitor, and extruding the mixture from a static mixer into a tubing with tangential oil flow to provide a hydrogel in the form of beads comprising tyrosine kinase inhibitor particles. The method according to any of items 93 to 98, wherein the beads are obtainable by preparing a mixture containing hydrogel precursors and tyrosine kinase inhibitor, filling the mixture into a syringe or mold, allowing the mixture to gel, and pushing the mixture through at least one mesh screen to provide a hydrogel in the form of beads. The method according to any of items 93 to 98, wherein the beads are obtainable by preparing a mixture containing hydrogel precursors and tyrosine kinase inhibitor, filling the mixture into a mold having micro- cavities, allowing the mixture to gel in the micro-cavities to provide a hydrogel in the form of beads. The method according to any of items 93 to 98, wherein the beads are obtainable by preparing a mixture containing hydrogel precursors and tyrosine kinase inhibitor, heating and melt extruding the mixture into a strand, and cutting or pelletizing the strand to provide a hydrogel in the form of beads. The method according to any of items 93 to 102, wherein the beads are obtainable by preparing a mixture containing hydrogel precursors and tyrosine kinase inhibitor, heating the mixture, and extruding the mixture into an oil bath to provide a hydrogel in the form of beads. The method according to any of items 99 to 103, wherein the beads are dried and / or lyophilized. The method according to any of items 93 to 104, wherein the beads comprise the tyrosine kinase inhibitor in an amount of from about 0.01 µg to about 50 µg per one bead. The method according to item 105, wherein the beads comprise the tyrosine kinase inhibitor in an amount of from about 0.5 µg to about 12 µg per one bead. The method according to item 105 or 106, wherein the beads comprise axitinib in an amount of from about 1 µg to about 8 µg per one bead, of from about 1.5 µg to about 5 µg per one bead, or of from about 2 µg to about 4 µg per one bead. The method according to any of items 93 to 107, wherein the beads do not agglomerate during administration. The method according to any of items 93 to 108, wherein the beads are suspended in a carrier. The method according to item 109, wherein the beads are suspended in the carrier in a concentration of about 10 wt.-% to about 50 wt.-% beads, of about 15 wt.-% to about 40 wt.-% beads, or of about 20 wt.-% to about 30 wt.-% beads, with the remainder being the carrier. The method according to item 109 or 110, wherein the carrier is a non-aqueous carrier, such as an oil-based carrier. The method according to item 111, wherein the oil-based carrier is a natural or synthetic oil.The method according to any of items 109 to 112, wherein the carrier is at least one pharmaceutically acceptable oil including almond oil, castor oil, coconut oil, corn oil, cotton seed oil, flax oil, linseed oil, maize oil, mineral oil, olive oil, palm oil, peanut oil, rape 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 tallow, 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). The method according to item 113, wherein the carrier is sesame oil or ethyl oleate. The method according to any of items 1 to 114, wherein the articular condition or the condition of a bony canal is an inflammatory condition. The method according to any of items 1 to 115, wherein the articular condition or the condition of a bony canal involves angiogenesis. The method according to any of items 1 to 10 and 15 to 116, wherein the articular condition is arthropathy. The method according to item 117, wherein the arthropathy is reactive arthropathy, enteropathic arthropathy, diabetic arthropathy, neuropathic arthropathy, or spondylarthropathy. The method according to any of items 1 to 10 and 15 to 118, wherein the articular condition is arthritis. The method according to item 119, wherein the arthritis is infectious or non-infectious arthritis. 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). The method according to any of items 119 to 121, wherein the arthritis is osteoarthritis (OA). The method according to any of items 11 to 116, wherein the condition of a bony canal is related to narrowing of the bony canal. The method according to any of items 11 to 116 and 123, wherein the condition of a bony canal involves compression of nervous tissue. The method according to any of items 11 to 116, 123 and 124, wherein the condition of a bony canal is carpal tunnel syndrome. The method according to any of items 11 to 116, 123 and 124, wherein the condition of a bony canal is spinal stenosis. The method according to any of items 1 to 126, wherein the articular condition or the condition of a bony canal is a disease mediated by at least one receptor tyrosine kinase (RTK). The method according to item 127, wherein the at least one receptor tyrosine kinase (RTK) is VEGFR-1 and / or VEGFR-2. The method according to any of items 1 to 128, wherein the condition is linked to TRPV1 expression. The method according to any of items 1 to 129, wherein the condition is pain. The method according to any of items 1 to 130, wherein the treatment is effective in reducing pain. The method according to any of items 1 to 131, wherein the treatment is effective in reducing inflammation. The method according to item 132, wherein the treatment is effective in reducing an expression of at least one inflammatory marker. The method according to item 132 or 133, wherein the treatment is effective in reducing an expression of at least one cytokine.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. 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. The method according to any of items 133 to 136, wherein the expression of the at least one inflammatory marker is reduced by at least 10%, by at least 20%, or by at least 25% within a period of 14 days, or a period of 1 months, or a period of 2 months after administration. The method according to any items 1 to 10, 15 to 122 and 127 to 137, wherein the treatment is effective in reducing hypervascularity associated with arthritis. The method according to any of items 1 to 10, 15 to 122 and 127 to 138, wherein the treatment is effective in slowing down, arresting or reversing progressive structural tissue damage associated with arthritis. The method according to any of items 1 to 10, 15 to 122 and 127 to 139, wherein the treatment is effective in slowing down, arresting or reversing loss of joint function associated with arthritis. The method according to any of items 1 to 10, 15 to 122 and 127 to 140, wherein the treatment is effective in improving joint function associated with arthritis. The method according to any of items 11 to 116, 123 to 125 and 127 to 137, wherein the treatment is effective in slowing down, arresting or reversing tingling, weakness or numbness of fingers associated with carpal tunnel syndrome. The method according to any of items 11 to 116, 123 to 125, 127 to 137 and 142, wherein the treatment is effective in reducing pressure on the median nerved associated with carpal tunnel syndrome. The method according to any of items 11 to 116, 123, 124 and 126 to 137, wherein the treatment is effective in slowing down, arresting or reversing tingling, weakness or numbness of arms or legs associated with spinal stenosis. The method according to any of items 11 to 116, 123, 124, 126 to 137 and 144, wherein the treatment is effective in reducing pressure on the spinal cord or nerve roots associated with spinal stenosis. The method according to any of items 1 to 145, wherein the chondrotoxicity during the administration of the sustained release biodegradable depot is low. The method according to item 146, wherein the chondrotoxicity in human chondrocytes is less than 10%, less than 8% or less than 5%. The method according to any one of items 1 to 147, wherein the patient has a history of anti-inflammatory treatment. The method according to any one of items 1 to 148, wherein an anti-inflammatory agent is administered concurrently with the depot. The method according to item 149, wherein the anti-inflammatory agent is selected from the group consisting of hyaluronic acid and corticosteroids such as triamcinolone acetonide. The method according to item 149 or 150, wherein the anti-inflammatory agent is administered by means of intra-articular or periarticular injection, or by means of injection into or near to the bony canal, or is administered orally. The method according to item 1, wherein the depot is administered into a synovial joint of the patient and the dose per joint administered once for a treatment period of at least 3 months is from about 0.5 mg to about 120 mg of the tyrosine kinase inhibitor, wherein the hydrogel comprises a polymer network that comprisesone or more crosslinked 4- to 8-arm polyethylene glycol units and the tyrosine kinase inhibitor is axitinib, and wherein the depot is in the form of one or more sustained release biodegradable fiber(s) and each of the fibers comprises axitinib in an amount of at least 10 µg or at least 50 µg, such as from about 100 µg to about 800 µg. The method according to item 1, wherein the depot is administered into a synovial joint of the patient and the dose per joint administered once for a treatment period of at least 3 months is from about 0.5 mg to about 120 mg of the tyrosine kinase inhibitor, wherein the hydrogel comprises a polymer network that comprises one or more crosslinked 4- to 8-arm polyethylene glycol units and the tyrosine kinase inhibitor is axitinib, and wherein the depot is in the form of a plurality of sustained release biodegradable beads and the beads comprise axitinib in an amount of at least 0.1 µg or at least 0.5 µg, such as from 1 µg to about 8 µg per one bead. The method according to item 1, wherein the depot is administered into a knee of the patient and the dose per knee administered once for a treatment period of at least 3 months is from about 10 mg to about 25 mg of the tyrosine kinase inhibitor, wherein the hydrogel comprises a polymer network that comprises one or more crosslinked 4- to 8-arm polyethylene glycol units and the tyrosine kinase inhibitor is axitinib, and wherein the depot is in the form of one or more sustained release biodegradable fibers and each of the fiber(s) comprises axitinib in an amount of at least 10 µg or at least 50 µg, such as from about 100 µg to about 800 µg. The method according to item 1, wherein the depot is administered into a knee of the patient and the dose per knee administered once for a treatment period of at least 3 months is from about 10 mg to about 25 mg of the tyrosine kinase inhibitor, wherein the hydrogel comprises a polymer network that comprises one or more crosslinked 4- to 8-arm polyethylene glycol units and the tyrosine kinase inhibitor is axitinib, and wherein the depot is in the form of a plurality of sustained release biodegradable beads and the beads comprise axitinib in an amount of at least 0.1 µg or at least 0.5 µg, such as from 1 µg to about 8 µg per one bead. The method according to any of items 1 to 155, being a method of treating a human patient. An injectable pharmaceutical preparation comprising (i) a sustained release biodegradable depot comprising a hydrogel and a tyrosine kinase inhibitor, and (ii) a carrier. The injectable pharmaceutical composition according to item 157, wherein the depot is in the form of a plurality of sustained release biodegradable beads. The injectable pharmaceutical composition according to item 157 or 158, wherein the beads are spherical or non-spherical particles. The injectable pharmaceutical composition according to any of items of 157 to 159, wherein the beads have a narrow particle size distribution. The injectable pharmaceutical composition according to any of items of 157 to 160, wherein the beads have a D50 of less than about 220 µm, or a D90 of less than about 300 µm. The injectable pharmaceutical composition according to any of items 157 to 161, wherein the beads in a dried state have a mean volumetric particle size of about 50 µm to about 500 µm, of about 100 µm to about 300 µm, or of about 200 µm, as determined by scanning electron microscopy (SEM).The injectable pharmaceutical composition according to any of items 157 to 162, wherein the beads in a hydrated state have a mean volumetric particle size of about 100 µm to about 1000 µm, of about 200 µm to about 600 µm, or of about 400 µm, as determined by light microscopy. The injectable pharmaceutical composition according to any of items 157 to 163, wherein the beads comprises the tyrosine kinase inhibitor in an amount of from about 0.01 µg to about 50 µg per one bead. The injectable pharmaceutical composition according to item 164, wherein the beads comprise the tyrosine kinase inhibitor in an amount of from about 0.5 µg to about 12 µg per one bead. The injectable pharmaceutical composition according to item 164 or 165, wherein the beads comprise the tyrosine kinase inhibitor in an amount of from about 1 µg to about 8 µg per one bead, of from about 1.5 µg to about 5 µg per one bead, or of from about 2 µg to about 4 µg per one bead. The injectable pharmaceutical composition according to any of items 157 to 166, wherein the beads do not agglomerate in the carrier. The injectable pharmaceutical composition according to any of items 157 to 167, wherein the beads are suspended in the carrier. The injectable pharmaceutical composition according to item 168, wherein the beads are suspended in the carrier in a concentration of about 10 wt.-% to about 50 wt.-% beads, about 15 wt.-% to about 40 wt.-% beads, or about 20 wt.-% to about 30 wt.-% beads, with the remainder being the carrier. The injectable pharmaceutical composition according to any of items 157 to 169, comprising (i) about 100 to about 400,000 beads, about 10,000 to about 100,000 beads, or about 40,000 to about 70,000 beads, suspended in the carrier, such as in (ii) about 0.1 mL to about 5 mL of the carrier, about 0.5 mL to about 3 mL, or about 1 mL of the carrier. The injectable pharmaceutical composition according to any of item 157 to 170, comprising (i) about 0.008 g to about 2 g beads, about 0.1 g to about 1 g beads, or about 0.2 g to about 0.5 g beads, suspended in (ii) about 0.1 mL to about 5 mL of the carrier, about 0.5 mL to about 3 mL, or about 1 mL of the carrier. The injectable pharmaceutical composition according to any of items 157 to 171, wherein the carrier is a non- aqueous carrier, such as an oil-based carrier. The injectable pharmaceutical composition according to item 172, wherein the oil-based carrier is liquid at 15 °C or above, such as at room temperature and at human body temperature. The injectable pharmaceutical composition according to item 172 or 173, wherein the oil-based carrier has a boiling point greater than body temperature. The injectable pharmaceutical composition according to item 174, wherein the oil-based carrier has a boiling point greater than 50 °C, greater than 70 °C, greater than 100 °C, or greater than 150 °C. The injectable pharmaceutical composition according to any of items 172 to 175, wherein the oil-based carrier has a viscosity of less than about 120 mPa·s, of less than about 100 mPa·s, or of less than about 85 mPa·s at 20 °C. The injectable pharmaceutical composition according to any of items 172 to 176, wherein the oil-based carrier has a density of less than about 1.5 g / cm3, less than about 1.0 g / cm3, of less than about 0.95 g / cm3, or of less than about 0.92 g / cm3. The injectable pharmaceutical composition according to any of items 172 to 177, wherein the oil-based carrier is a natural or synthetic oil.The injectable pharmaceutical composition according to any of items 172 to 178, wherein the oil-based carrier is a plant-based oil. The injectable pharmaceutical composition according to any of items 157 to 179, wherein the carrier is at least one pharmaceutically acceptable oil including almond oil, castor oil, coconut oil, corn oil, cotton seed oil, flax oil, linseed oil, maize oil, mineral oil, olive oil, palm oil, peanut oil, rape 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 tallow, 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). The injectable pharmaceutical composition according to item 180, wherein the carrier is sesame oil or ethyl oleate. The injectable pharmaceutical composition according to any of items 157 to 181, wherein the carrier provides for an axitinib solubility of less than about 160 µg / mL, of less than about 100 µg / mL, of less than about 50 µg / mL, or of less than about 20 µg / mL. The injectable pharmaceutical composition according to any of items 157 to 182, further comprising at least one pharmaceutically acceptable excipient. 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. 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 alginates, calcium phosphate, calcium silicate, carboxymethyl cellulose, cellulose, dextrose, gelatin, gum acacia, lactose, mannitol, methyl cellulose, microcrystalline cellulose, polyethylene glycol, polysorbate 20, polysorbate 80, polyvinylpyrrolidone, saline, sorbitol, starches, sucrose and tragacanth. An injectable pharmaceutical preparation according to item 157, wherein the depot is in the form of a plurality of sustained release biodegradable beads, wherein the hydrogel comprises a polymer network that comprises one or more crosslinked 4- to 8-arm polyethylene glycol units and the tyrosine kinase inhibitor is axitinib, wherein the beads comprise axitinib in an amount of at least 0.1 µg or at least 0.5 µg, such as from 1 µg to about 8 µg per one bead, and wherein the carrier is sesame oil or ethyl oleate. A method of producing an injectable pharmaceutical preparation comprising a sustained release biodegradable depot and a carrier according to any of items 157 to 186, the method comprising I. steps of forming a hydrogel comprising a polymer network and tyrosine kinase inhibitor particles dispersed in the hydrogel, and shaping the hydrogel into beads, and optionally II. a step of suspending the beads in the carrier. The method according to item 187, wherein the tyrosine kinase inhibitor particles are micronized and / or homogeneously dispersed within the hydrogel. The method according to item 188, wherein the micronized particles are micronized axitinib particles. The method according to item 188 or 189, wherein the micronized particles have a D90 of less than about 10 μm, and a D100 of less than about 20 μm. The method according to any of items 187 to 190, wherein the polymer network is formed by crosslinking multi-arm polyethylene glycol units.The method according to any of items 187 to 191, wherein the method comprises steps of mixing and reacting an electrophilic group-containing multi-arm polyethylene glycol with a nucleophilic group-containing multi-arm polyethylene glycol in a buffered solution in the presence of the tyrosine kinase inhibitor particles, and allowing the mixture to gel. The method according to item 192, comprising extruding the mixture from a static mixer prior to complete gelling into a tubing with tangential oil flow to obtain beads, and collecting the beads obtained. The method according to item 193, wherein the mixture is extruded using a 27- or 30-gauge needle. The method according to item 193 or 194, wherein the mixture is extruded with an extrusion rate of about 0.3 mL / min and an oil flow rate of about 1 mL / min. The method according to item 192, comprising filling the mixture into a syringe or mold prior to complete gelling, and allowing the mixture to gel. The method according to item 196, wherein the mixture is allowed to gel in a syringe, and is pushed from the syringe through at least one mesh screen to obtain beads. The method according to item 197, wherein the gel is pushed through one or more mesh screens having different mesh sizes, and the beads obtained are sieved. The method according to item 197, wherein the gel is pushed through a 3D printed mesh screen and cut to obtain beads. The method according to item 192, wherein the mixture is allowed to gel in a thin sheet mold to obtain a gel sheet, which is removed from the mold and cut by means of a mesh screen to obtain beads. The method according to item 192, wherein the mixture is allowed to gel in a mold having micro-cavities to obtain beads. The method according to any of items 187 to 191, wherein the method comprises steps of mixing an electrophilic group-containing multi-arm polyethylene glycol powder with a nucleophilic group-containing multi-arm polyethylene glycol powder in the presence of the tyrosine kinase inhibitor, and heating the mixture. The method according to item 202, wherein the mixture is melt extruded to obtain a strand, which is cut or pelletized to obtain beads. The method according to item 202, wherein the mixture is mixed and heated in a ceramic syringe under nitrogen, and is extruded into an oil bath to obtain beads. The method according to item 204, wherein the mixture is heated to about 70°C to about 80 °C for about 20 minutes to about 30 minutes. The method according to any of items 187 to 205, wherein the beads obtained are dried and / or lyophilized. The method according to any of items 187 to 206, wherein the beads are suspended in the carrier in a concentration of about 10 wt.-% to about 50 wt.-% beads, of about 15 wt.-% to about 40 wt.-%, or of about 20 wt.-% to about 30 wt.-%, with the remainder being the carrier. The method according to any of items 187 to 207, further comprising III. a step of loading the pharmaceutical preparation into a hypodermic needle. The method according to item 208, wherein the hypodermic needle is a 20- to 27-gauge needle. The method according to item 208 or 209, wherein the hypodermic needle is a 22- or 25-gauge needle.A kit comprising one or more injectable pharmaceutical preparation(s) comprising a sustained release biodegradable depot and a carrier according to any of items 157 to 186 or manufactured in accordance with the method of any of items 187 to 210 and one or more hypodermic needle(s). 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. The kit according to item 211, wherein the at least one sustained release biodegradable depot is suspended in the carrier. The kit according to item 213, wherein the one or more hypodermic needle(s) is / are each pre-loaded with one injectable pharmaceutical preparation. The kit according to any of items 211 to 214, wherein the hypodermic needle is a 20- to 27-gauge needle. The kit according to item 215, wherein the hypodermic needle is a 22- or 25-gauge needle. The kit according to any of items 211 to 216, further comprising an injection device for injecting the injectable pharmaceutical preparation. The kit according to item 217, wherein the injection device is provided in the kit separately from the one or more hypodermic needle(s). The kit according to item 217, wherein the injection device is pre-connected to a hypodermic needle pre- loaded with injectable pharmaceutical preparation. The kit according to any of items 217 to 219, wherein the injection device contains a push wire or plunger to deploy the injectable pharmaceutical preparation from the hypodermic needle. A method of reducing pain in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of the injectable pharmaceutical preparation according to any of items 157 to 186 by injection. A method of reducing inflammation in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of the injectable pharmaceutical preparation according to any of items 157 to 186 by injection. A method of reducing hypervascularity associated with arthritis in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of the injectable pharmaceutical preparation according to any of items 157 to 186 by articular injection. A method of slowing down, arresting or reversing progressive structural tissue damage associated with arthritis in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of the injectable pharmaceutical preparation according to any of items 157 to 186 by articular injection. A method of slowing down, arresting or reversing loss of joint function associated with arthritis in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of the injectable pharmaceutical preparation according to any of items 157 to 186 by articular injection. A method of improving joint function associated with arthritis in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of the injectable pharmaceutical preparation according to any of items 157 to 186 by articular injection. A method of slowing down, arresting or reversing tingling, weakness or numbness of fingers associated with carpal tunnel syndrome in a patient in need thereof,the method comprising administering to the patient a therapeutically effective amount of the injectable pharmaceutical preparation according to any of items 157 to 186 by injection into or near to the carpal tunnel. A method of reducing pressure on the median nerved associated with carpal tunnel syndrome in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of the injectable pharmaceutical preparation according to any of items 157 to 186 by injection into or near to the carpal tunnel. A method of slowing down, arresting or reversing tingling, weakness or numbness of arms or legs associated with spinal stenosis in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of the injectable pharmaceutical preparation according to any of items 157 to 186 by epidural injection. A method of reducing pressure on the spinal cord or nerve roots associated with spinal stenosis in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of the injectable pharmaceutical preparation according to any of items 157 to 186 by epidural injection. A sustained release biodegradable depot comprising a hydrogel and a tyrosine kinase inhibitor for use in treating an articular condition according to a method according to any of items 1 to 10, 15 to 122, 127 to 141 and 146 to 156. A sustained release biodegradable depot comprising a hydrogel and a tyrosine kinase inhibitor for use in treating a condition of a bony canal according to a method according to any of items 11 to 16, 123 to 137, 142 to 151 and 156. Use of a sustained release biodegradable depot comprising a hydrogel and tyrosine kinase inhibitor in the preparation of a medicament for treating an articular condition according to a method according to any of items 1 to 10, 15 to 122, 127 to 141 and 146 to 156. Use of a sustained release biodegradable depot comprising a hydrogel and tyrosine kinase inhibitor in the preparation of a medicament for treating an articular condition according to a method according to any of items 11 to 16, 123 to 137, 142 to 151 and 156. The method of any of items 1 to 156, wherein the tyrosine kinase inhibitor is a polymorph of axitinib. The method of item 235, wherein the polymorph of axitinib is polymorph IV. The method of item 235, wherein the axitinib is characterized by an XRD pattern comprising at least three, or at least four, or at least five characteristic 2 ^° peaks selected from 8.3, 15.6, 16.5, 18.6, 21.0, 23.1, 24.1 and 26.02 ^° (all values ± 0.3), and / or13C NMR in DMSO solvent comprising chemical shifts at 26.1, 114.7, 154.8 and 167.8, each shift ± 0.2 ppm, and / or13C solid state NMR comprising chemical shifts at 171.1, 153.2, 142.6, 139.5, 131.2, 128.1 and 126.3, each shift ± 0.2 ppm, and / or characterized by a DSC isotherm comprising two endothermic peaks ranging between 213 °C to 217 °C (Peak 1) and 219 °C to 224 °C (Peak 2). The method of item 235, wherein the axitinib is characterized by a powder X-ray diffraction pattern comprising at least two, such as at least three, or at least four, or at least five of the following peaks at diffraction angles (2 ^) of 8.90, 9.40, 9.50, 12.0, 14.60, 15.25, 15.75, 17.80, 19.30, 20.65, 24.95, 26.10 (all values ± 0.2). Particularly, the axitinib used for preparing the depots according to this aspect of the present invention may be characterized by a powder X-ray diffraction pattern comprising the following peaks atdiffraction angles (2 ^) of: 8.90, 12.0, 14.60, 15.75, and 19.30 (all ± 0.2), and / or characterized by a DSC peak at about 221 °C at a scan rate of 5°C / min (over a range of 25 to 300 °C). The method of item 235, wherein the axitinib is a co-crystal. The method of item 239, wherein the axitinib is a co-crystal of axitinib and a carboxylic acid. The injectable preparation of any of items 157 to 186, wherein the tyrosine kinase inhibitor is a polymorph of axitinib. The injectable preparation of item 241, wherein the polymorph of axitinib is polymorph IV. The injectable preparation of item 241, wherein the axitinib is characterized by an XRD pattern comprising at least three, or at least four, or at least five characteristic 2 ^° peaks selected from 8.3, 15.6, 16.5, 18.6, 21.0, 23.1, 24.1 and 26.02 ^° (all values ± 0.3), and / or13C NMR in DMSO solvent comprising chemical shifts at 26.1, 114.7, 154.8 and 167.8, each shift ± 0.2 ppm, and / or13C solid state NMR comprising chemical shifts at 171.1, 153.2, 142.6, 139.5, 131.2, 128.1 and 126.3, each shift ± 0.2 ppm, and / or characterized by a DSC isotherm comprising two endothermic peaks ranging between 213 °C to 217 °C (Peak 1) and 219 °C to 224 °C (Peak 2). The injectable preparation of item 241, wherein the axitinib is characterized by a powder X-ray diffraction pattern comprising at least two, such as at least three, or at least four, or at least five of the following peaks at diffraction angles (2 ^) of 8.90, 9.40, 9.50, 12.0, 14.60, 15.25, 15.75, 17.80, 19.30, 20.65, 24.95, 26.10 (all values ± 0.2). Particularly, the axitinib used for preparing the depots according to this aspect of the present invention may be characterized by a powder X-ray diffraction pattern comprising the following peaks at diffraction angles (2 ^) of: 8.90, 12.0, 14.60, 15.75, and 19.30 (all ± 0.2), and / or characterized by a DSC peak at about 221 °C at a scan rate of 5°C / min (over a range of 25 to 300 °C). The injectable preparation of item 241, wherein the axitinib is a co-crystal. The injectable preparation of item 245, wherein the axitinib is a co-crystal of axitinib and a carboxylic acid.EXAMPLES

[0363] The following Examples are included to demonstrate certain aspects and embodiments of the invention as described in the claims. It should be appreciated by those of skill in the art, however, that the following description is illustrative only and should not be taken in any way as a restriction of the invention. EXAMPLE 1 Preparation of Axitinib Depots

[0364] The axitinib depots of some embodiments of the present invention are in the form of either A: one or more sustained release biodegradable fiber(s) or B: a plurality of sustained release biodegradable beads, with axitinib homogeneously dispersed and entrapped within a PEG-based hydrogel matrix to provide sustained release of axitinib based on its low aqueous solubility in the synovial fluid.

[0365] The fibers and beads as manufactured below shall be understood as exemplary embodiments. The amount of TKI or axitinib, the composition and the characteristics of the fibers or beads may be appropriately adapted to the required use in a method of treatment according to the present invention, in particular for treating a human patient. A. Sustained Release Biodegradable Fiber

[0366] Four types of exemplarily selected axitinib sustained release biodegradable fibers were manufactured as described further below. The respective percent composition in dry and in wet state, as well as the function of each ingredient are presented in Table 1 for all types of fibers. Table 1 Axitinib fiber composition (Fiber type #1, Fiber type #2, Fiber type #3, Fiber type #4). Percentages refer to percent by weight (% w / w). Fiber type Ingredient#1 #2 #3 #4WetDry Wet Dry Wet Dry Wet DryFunction(%) (%) (%) (%) (%) (%) (%) (%) Active Axitinib 1.60 14.88 1.90 17.19 5.30 36.68 4.00 29.09 Pharmaceutical Ingredient 4a20kPEG-SG 5.00 46.51 5.00 45.25 NA NA NA NAHydrogelmatrix4a20kPEG-SAZ NA NA NA NA 5.00 34.60 5.34 38.80Hydrogelmatrix8a20kPEG-NH2 2.50 23.26 2.50 22.62 2.50 17.30 2.67 19.38HydrogelmatrixSodium Phosphate Dibasic1.20 11.16 1.20 10.86 1.20 8.30 1.20 8.73 Buffer saltSodium Phosphate Monobasic Anhydrous0.45 4.19 0.45 4.07 0.45 3.11 0.45 3.27 Buffer saltNHS-Fluorescein NA NA NA NA NA NA 0.10 0.73VisualizationagentWater 89.25 0 88.95 0 85.55 0 86.25 0 Total Fiber 100 100 100 100

[0367] For preparation of the fibers, a polyurethane tubing was cut into appropriate length pieces first. 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 sodium phosphate dibasic buffer and another syringe containing a solution of 4a20kPEG-SG (4-arm 20,000 succinimidyl glutarate ester) or 4a20kPEG-SAZ (4-arm 20,000 succinimidyl azelate ester), respectively, and sodium phosphate monobasic buffer. The contents of these two syringes are then combined to form a mixture (suspension) of hydrogel components and axitinib. For this, the axitinib / 8a20kPEG-NH2syringe and the 4a20kPEG-SG or 4a20kPEG-SAZ syringe were connected luer-to-luer and mixed by passing the contents of the syringes back and forth between each syringe, creating a mixture which was then transferred into a single syringe. The suspension was cast through the prepared polyurethane tubing before (complete) gelling of the hydrogel. Gelling time was confirmed by performing a gel tap test. The casted strands were stored horizontally for 1 to 3 hours to allow the hydrogel to cure. The strands were stored horizontally in nitrogen- flashed atmosphere for 36 to 72 hours at room temperature to allow the strands to dry completely.

[0368] After drying, the dried strands were removed from the polyurethane tubing and cut into segments of the desired length. The surface of the cut fibers was visually inspected for particulate, cylindrical shape and any visible surface defects. Fibers that did not show any defects and had approximately the correct length went to the next stage of the process. Fibers that did not meet all requirements were rejected.

[0369] After quality inspection, the fibers were loaded into sterile NIPRO needles, packaged separately and transferred into a glovebox to be kept there for 16-96 hours in an inert nitrogen environment to reduce residual moisture (moisture content ≤ 1.0%). Nitrogen conditioned needles were PEG tipped in 1k linear PEG to improve injection success and retain the depot in the needle during shipping. The packaged fibers were inspected and stored at 2-8 °C until sterilization. For sterilization, packaged fibers were gamma irradiated (internal dose delivered 25.0- 35.0 kGy). Afterwards, the packaged fibers were stored protected from light at 2-8 °C prior to administration.

[0370] The respective release rate of axitinib from the fibers was determined by in vitro testing in Example 2. The persistence of the fibers in rat stifles as well as in dog stifles and elbows was assessed in Example 3, and the ability of the fibers to reduce pain sensation in a rat model as well as further effects were assessed in Example 4. Finally, the chondrotoxicity of the fibers and axitinib was evaluated in Example 5. B. Sustained Release Biodegradable Beads

[0371] Exemplarily selected axitinib sustained release biodegradable beads were manufactured as described further below, using various mesh screens (mesh screen method) or by extrusion from a ceramic syringe (Vulcan method). The respective percent composition in dry and / or in wet state, as well as the function of each ingredient are presented in Table 2 for all types of beads. Table 2 Axitinib beads composition (Bead type #5, Bead type #6). Percentages refer to percent by weight (% w / w). Beads type #5 #6 Ingredient Function Wet Dry Dry (%) (%) (%) Active Micronized Axitinib 9.75 50 50 Pharmaceutical Ingredient 4a20kPEG-SAZ 5.00 27.69 48.58 Hydrogel matrix 8a20kPEG-NH2 2.50 13.85 Hydrogel matrix Trilysine Acetate NA NA 1.42 Hydrogel matrixSodium Phosphate Dibasic1.20 6.15 NA Buffer saltSodium Phosphate Monobasic Anhydrous0.45 2.31 NA Buffer saltWater 81.10 0 NA Total Bead 100 100

[0372] For preparation of the beads according to the mesh screen method, one syringe containing a suspension of micronized axitinib in a solution of 8a20kPEG-NH2(8-arm 20,000 PEG amine) and sodium phosphate dibasic buffer and another syringe containing a solution of 4a20kPEG-SAZ (4-arm 20,000 succinimidyl azelate ester) and sodium phosphate monobasic buffer were prepared. The contents of these two syringes are then combined to form a mixture (suspension) of hydrogel components and axitinib. For this, the axitinib / 8a20kPEG-NH2 syringe and the 4a20kPEG-SAZ syringe were connected luer-to-luer and mixed by passing the contents of the syringes back and forth between each syringe, creating a mixture which was then transferred into a single syringe. The suspension was allowed to completely gel in the syringe. The gel was pushed from the syringe through various mesh screens using a 900 µm mesh screen, twice a 500 µm mesh screen, and thrice a 213 µM mesh screen. The size range of the beads obtained was corrected by wet sieving between 53-500 µm.

[0373] For preparation of the beads according to the Vulcan method, dry powders of micronized axitinib, 4a20kPEG-SAZ (4-arm 20,000 succinimidyl azelate ester) and trilysine acetate were mixed in a ceramic syringe (Vulcan), while keeping all ingredients under nitrogen to prevent pre-crosslinking. The mixture was heated to 80 °C and then the Vulcan wave sequence was initiated to extrude the mixture into mineral oil in the form of beads. The beads obtained had particles sizes between 200-400 µm.

[0374] The beads obtained by means of the mesh screen method and the Vulcan method were collected as well as dried and lyophilized.

[0375] The release rate of axitinib from the beads as exemplarily manufactured by the mesh screen method was determined by in vitro testing in Example 2. EXAMPLE 2 In vitro Axitinib release

[0376] The release rate of axitinib from depots as exemplarily manufactured above in different formulations was determined by in vitro testing under real-time sink simulated physiological conditions at a weekly replacement. 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 examined. From the beads formulations (Table 2), 0.5 mg, 1 mg and 2 mg of beads type #5 was examined.

[0377] Prior to the performance of the in vitro testing the respective starting axitinib content for the fibers was measured by placing one fiber in 1.5 mL 90:10 EtOH:H2O and removing 0.5 mL of each solution after two days of extraction for UV-Vis analysis at 332 nm (Table 3). The amount of axitinib was determined relative to a standard curve prepared from an axitinib reference. Table 3 Starting axitinib content per depot. The values for depots A and C are theoretical only. Fiber type #1 #2 #3 #4Depot A B C D E F G Axitinib load ½x 15.40 15.40 2x 15.40 32.94 56.30 421.6 103.6 (µg) = 7.7 ± 1.25 =30.8 ± 2.41 ± 6.00 ± 10.00 ± 3.9

[0378] In a next step, the in vitro axitinib release was determined as briefly described in the following. The in vitro assays can be used e.g. for quality control to determine batch-to-batch conformity of the depots.

[0379] In case of the fibers, one fiber was placed in 20 mL of buffer solution (1x phosphate buffer saline, PBS at pH 7.2) with a 5 mL layer of octanol on top to provide a sink phase allowing transference of axitinib into the octanol layer. At corresponding time points, 1 mL of octanol was removed for UV-Vis analysis at 332 nm. 1 mL of fresh octanol was added as replacement. The amount of axitinib released at each time point was determined relative to a standard curve prepared from an axitinib reference.

[0380] For an exemplary release profile in vitro reference is made to Figure 1 (formulation #1, depots A-C), Figure 2 (formulation #2, depot D and formulation #3, depot E) and Figure 3 (formulation #4, depots F and G).

[0381] In case of the beads, 0.5 mg (axitinib load: 0.2 mg), 1 mg (axitinib load: 0.4 mg) and 2 mg (axitinib load: 0.8 mg) of beads were placed in 7 mL of buffer solution (1x phosphate buffer saline, PBS at pH 7.2) with a 40 mL layer of octanol on top to provide a sink phase allowing transference of axitinib into the octanol layer. At corresponding time points, 1 mL of octanol was removed for UV-Vis analysis at 332 nm.1 mL of fresh octanol was added as replacement. The amount of axitinib released at each time point was determined relative to a standard curve prepared from an axitinib reference.

[0382] For an exemplary release profile in vitro reference is made to Figure 4 (formulation #5).

[0383] The figures show dose-dependent axitinib release from the fibers for a period of at least one to three 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 in all cases than release from the fibers. EXAMPLE 3 Persistence of Axitinib Depots

[0384] In order to assess the persistence of axitinib depots as exemplarily manufactured above in vivo, pre-clinical studies were performed in rat stifles (Example 3.1) as well as in dogs stifles and elbows (Example 3.2). Example 3.1: Persistence of Axitinib Depots in Rats

[0385] The respective persistence of fiber types #2 (4a20kPEG-SG) and #3 (4a20kPEG-SAZ) was assessed by administering depot D (group 1) or depot E (group 2), respectively, into both knees of healthy Sprague Dawley rats (n= 12 for group 1, n= 15 for group 2). The knees received a theoretic load of approximately 35 µg axitinib in a 13.3x0.15 mm fiber (dry) in case of depot D or of approximately 55 µg axitinib in a 7.8x0.17 mm fiber (dry) in case of depot E, respectively. At corresponding time points after administration of the depots, three animals per group were euthanized and the knees were dissected to collect the administered fibers.

[0386] As the administered fibers were subjected to mechanical degradation, they only could be collected in fragments and the total length was calculated from the fragments length as measured. If 100% of the fiber were collected, the total hydrated fiber length is assumed to be 20.7 mm for hydrated depot D and 11.6 mm for hydrated depot E. The data of the respective fiber fragments collected and the total fiber length are summarized in Table 4 and Table 5.Table 4 Number and length of fiber fragments collected for group 1. Time Hydrated Length (mm) point Animal Knee Fragments Total (days) 1 2 3 4 5 6 Right 13.2 6.9 20.1 3 10 Left 7.4 12.1 19.5 Right Not measured 1 Left 3.5 3.9 1.6 5.3 14.3 Right 6.4 14.8 21.2 8 2 Left 10 3.9 4 17.9 Right 11.5 11.5 3 Left 3.4 2.2 11.6 2.3 19.5 Right 1.47 17.3 18.77 4 Left 3.99 0.99 2.25 1.37 1.21 1.44 11.25 Right 1.66 4.12 4.41 2.98 13.17 15 5 Left 4.07 2.01 5.79 1.5 13.37 Right 7.04 2.57 9.61 6 Left 6.02 1.16 5.06 12.24 Right 0.65 1.59 2.24 7 Left 0.95 0.17 1.12 Right Not obtainable 22 8 Left Not obtainable Right Not obtainable 9 Left Not obtainable Table 5 Number and length of fiber fragments collected for group 2. Time Length (mm) point Animal Knee Fragments Total (days) 1 2 3 4 5 6 Right 8.3 8.3 13 Left 1.3 2 0.8 6 10.1 Right 6.2 4.2 0.9 6 17.3 8 14 Left 2.5 6.9 1.1 0.9 11.4 Right 11.1 11.1 15 Left 6.8 1 7.8 Right 2.24 1.16 3.4 16 Left 0.79 1.79 3.71 1.33 7.56 15 Right 0.4 1.37 2.2 3.97 17 Left 4.01 0.89 1.23 1.7 0.69 8.52Right 6 3.91 9.91 18 Left 2.53 8.16 10.69 Right 1.59 1.91 1.16 4.66 19 Left 3.95 0.54 4.49 Right 2.15 3.49 0.62 6.26 22 20 Left 2.72 3.01 3.76 9.49 Right 11.55 (lined-up) 11.55 21 Left Not found

[0387] After collection of the fiber fragments, the axitinib release from the depots in vivo was determined on the basis of the axitinib recovery.

[0388] First, the recovered axitinib content was determined placing the respective fragments of the depots in 0.5 mL or 0.8 mL of 90:10 EtOH:H2O and removing 0.15 mL (for days 3 and 8) or 0.5 mL (for days 15 and 22) of each solution after two days of extraction for UV-Vis analysis at 332 nm. The amount of axitinib was determined relative to a standard curve prepared from an axitinib reference. In a next step, the recovered length of each depot was used to calculate the theoretical axitinib content from the initial axitinib load and the 100% fiber length. The recovered axitinib content was divided by the theoretical axitinib content to determine the percent axitinib release at each time point.

[0389] For an exemplarily release profile in vivo reference is made to Figure 5. Example 3.2: Persistence of Axitinib Depots in Beagle Dogs

[0390] The persistence of fiber type #4 (4a20kPEG-SAZ) was assessed in larger species by administering depot F (knees) or depot G (elbows), respectively, into both knees and both elbows of Beagle dogs which were already scheduled for euthanasia (n= 3). The knees received a theoretic load of approximately 420 µg axitinib in a 12.5x0.35 mm fiber (dry) and the elbows received a theoretical load of approximately 100 µg axitinib in a 6.5x0.25 mm fiber (dry). At corresponding time points after administration of the depots, one dog each was euthanized and the knees / elbows were dissected to collect the administered fibers. The synovial fluid was collected for analysis. Just prior to euthanasia, blood was collected for serum analysis.

[0391] After collection of the fiber (fragments), the axitinib release from the depots in vivo was determined on the basis of the axitinib recovery. While, in case of the knees, the fibers were found to have degraded into fragments located in the joint capsule, the fibers administered into the elbows were found in the surrounding tissue without having been subjected to mechanical degradation. The total hydrated length was calculated from the fragments length as measured, where appropriate. If 100% of the fiber were collected, the total fiber length is assumed to be 18.7 mm for hydrated depot F and 9.4 mm for hydrated depot G. The recovered axitinib content was determined placing the respective fragments of the depots in 4 mL of 90:10 EtOH:H2O and removing 0.5 mL of each solution after two days of extraction for UV-Vis analysis at 332 nm. The amount of axitinib was determined relative to a standard curve prepared from an axitinib reference. The recovered length of each depot was used to calculate the theoretical axitinib content from the initial axitinib load and the 100% fiber length. The recovered axitinib content was divided by the theoretical axitinib content to determine the percent axitinib release at each time point.

[0392] For an exemplarily release profile in vivo reference is made to Figure 6.

[0393] Axitinib concentration in synovial fluid and serum samples were determined by high performance liquid chromatography combined with tandem mass spectrometry (LC-MS / MS) using a triple quadrupole mass spectrometer.

[0394] For preparation of the samples, 50 µL of each synovial fluid or serum sample were mixed with 20 µL of internal standard solution (Axitnib-D3) in methanol / water / formic acid (75:25:0.1 v / v / v). The samples were vortexed and used for LC-MS / MS analysis.

[0395] The high performance liquid chromatography (HPLC) system consisted of Applied Biosystems pumps and a CTC autosampler. The mass spectrometer (MS) was an API 4000 tandem mass spectrometer. The HPLC mobile phases were acetonitrile and HPLC-grade water with 0.1% formic acid (v / v). The analytes were eluted from the column at 0.5 mL / min using a gradient resulting from mixture of the mobile phases. Axitinib was ionized by positive ion electrospray. The MS system was operated at positive ion mode. Axitinib (387.2-356.0 m / z) and the internal standard (Axitinib-D3, 390.3-356.1 m / z) were fragmented in the MS. The total run time was 6 min. Axitinib concentration was determined from a calibration curve. Prior to analysis of the samples, the method was validated using bovine control synovial fluid and beagle dog control serum. The method was shown to be reproducible, precise, linear, accurate and specific. The lower limit of quantification was determined to be 5.00 ng / mL or 0.0200 ng / mL for the synovial fluid samples, and 0.0500 ng / mL for the serum samples.

[0396] Synovial fluid concentrations are summarized in Table 6. Table 6 Axitinib concentrations in synovial fluid of beagle dogs. Time Axitinib Lower limit of point Animal Knee Elbow concentration quantitation (LLOQ) (days) (ng / mL) Right 110 0.0200 ng / mL Left 190 5.00 ng / mL 3 1 Right 46.5 5.00 ng / mL Left 0.975 0.0200 ng / mL Right 122 5.00 ng / mL Left 135 5.00 ng / mL 7 2 Right 0.118 0.0200 ng / mL Left 3.34 0.0200 ng / mL Right 14.5 0.0200 ng / mL Left 37.8 0.0200 ng / mL 14 3 Right 0.497 0.0200 ng / mL Left 0.462 0.0200 ng / mL

[0397] The values demonstrate a sustained release of axitinib in the synovial fluid for several days. The extent of the synovial fluid concentration depends on whether the depot was located inside the joint cavity (knees) or in the surround tissue (elbows).

[0398] Serum concentrations of axitinib were below the lower limit of quantification (LLOQ< 0.0500 ng / mL) at all samples time-points.EXAMPLE 4 Effects of Axitinib Depots on Rats with MIA-induced Osteoarthritis

[0399] In order to assess the ability of axitinib depots as exemplarily manufactured above to reduce pain sensation and other effects on Sprague Dawley rats with monosodium iodoacetate (MIA)-induced osteoarthritis, two studies were performed – the first (study I) using fiber type #1 (4a20kPEG-SG), and the second (study II) using fiber types #2 (4a20kPEG-SG) and #3 (4a20kPEG-SAZ) compared to an NSAID injected intra-articularly.

[0400] In study I, the effects of a treatment with depot A, depot B and depot C were compared to a celecoxib treatment (reference), as well as to the absence of any treatment (control). In study II, the effects of a treatment with depot D and depot E were compared to a celecoxib treatment (reference) and triamcinolone treatment (KENALOG®, reference), as well as to a hydrogel treatment (control), a treatment with axitinib only (control), the absence of an API treatment (control) and the absence of any treatment (control). The hydrogel treatment was performed with a depot corresponding to fiber type #3 (without axitinib). An overview over the setup of these two studies is given in Table 7. Table 7 Overview of treatments in studies I and II in rats. The route of administration were intra-articular (i.a.) or oral (p.o.). Study I Study II Monosodium Group Cohort A iodoacetate API Treatment API Treatment n= (82) Treatment n= (59) Depot D Depot A 1 YES 10 (32.9 µg axitinib, 10 (7.7 µg axitinib, i.a.) i.a.) Depot B Depot E 2 YES (15.4 µg axitinib, 11 (56.3 µg axitinib, 10 i.a.) i.a.) Depot C 3 YES (30.8 µg axitinib, 9 - - i.a.) NO NO 10 NO 4 YES - - NO 10 Control Axitinib Group YES - - 10 (55 µg, i.a.) YES - - Hydrogel, i.a. 9 Celecoxib Celecoxib YES 10 10 Reference (50 mg / kg, p.o.) (50 mg / kg, p.o.) Group Triamcinolone YES - - 10 (60 µg, i.a.)

[0401] In both study I and II, osteoarthritis was induced via injection of 25 µl of 80mg / mL monosodiumiodoacetate solution into the knee of the left hind leg of male, naïve Sprague Dawley rats.

[0402] Intra-articular administration of monosodium iodoacetate (MIA) in the ipsilateral knee of Sprague Dawley rats leads to development of a robust and long-lasting hyperalgesia and allodynia associated initially with an inflammatory response. The development of these signs in this animal model are believed to be clinically relevant, reflecting the symptoms displayed by patients presenting with chronic inflammatory pain associated with underlying conditions such as osteoarthritis. The time course of MIA-induced hyperalgesia follows a bi-phasic pattern with an early predominantly inflammatory component which is Cox-2 sensitive and may be markedly reduced by the gold standard celecoxib.

[0403] After three days, the API treatment was started by intra-articularly administering depots A-C (study I) or depots D and E, the hydrogel, axitinib and triamcinolone (study II), respectively. Celecoxib was administered orally once daily for the first four days.

[0404] Upon sacrifice (2-4 animals per group of study I at day 14 and 42), right and left knees were harvested and fixed in formalin for histological assessment Muscle Tissues (B.). Synovial fluid was collected at day 14 and 42 (3-8 ani...

Claims

CLAIMS 1. A method of treating a condition in a patient in need thereof, wherein the condition is an articular condition or a condition of a bony canal, the method comprising administering to the patient a sustained release biodegradable depot comprising a hydrogel and a tyrosine kinase inhibitor, wherein the depot is administered by injection.

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

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

4. The method according to claim 2 or 3, wherein the depot is administered in the area of a knee, an elbow, a finger, a hip, a shoulder, a wrist, an ankle, or in the area of a joint of a foot, hand, shoulder girdle, rotator cuff, pelvis, spine, or jaw of the patient, in particular wherein the depot is administered into a tibiofemoral joint, patellofemoral joint, humeroulnar joint, humeroradial joint, proximal radioulnar joint, acetabulofemoral joint, glenohumeral joint,, acromioclavicular joint, distal radioulnar joint, radiocarpal joint, intercarpal joint, midcarpal joint, carpometacarpal joint, intermetacarpal joint, talocrural joint, subtalar joint, tibiofibular joint, talonavicular joint, calcaneocuboid joint, metatarsophalangeal joint, interphalangeal joint of a foot or hand, metacarpophalangeal joint, sternoclavicular joint, sternocostal joint, atlanto-occipital joint, atlanto-axial joint, costovertebral joint, costotransverse joint, zygapophyseal joint, sacroiliac joint, or temporomandibular joint of the patient.

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

6. The method according to any of claims 1 to 5, wherein the dose per joint or bony canal administered once for a treatment period is from about 0.5 mg to about 120 mg of the tyrosine kinase inhibitor, or wherein the dose per joint or bony canal administered once for a treatment period is from about 1 mg to about 50 mg of the tyrosine kinase inhibitor.

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

8. The method according to claim 7, wherein the depot after administration into the joint or the bony canal releases a therapeutically effective amount of axitinib over a period of at least about 1 months, 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.

899. 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 wherein axitinib is released from the depot after administration at an average rate of about 30 µg / day to about 500 µg / day, or wherein axitinib is released from the depot after administration at an average rate of about 100 µg / day to about 270 µg / day, or wherein 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 of claims 7 to 9, wherein the depot provides a mean release rate in vitro of about 100 μg to about 500 μg per day, or of about 160 µg to about 400 µg of axitinib per day in phosphate- buffered saline at 37 °C for a period of 90 days, and / or about 150 µg to about 600 μg, or of about 200 µg to about 450 µg to about of axitinib per day in phosphate-buffered saline at 37 °C for a period of 30 days.

11. The method according to any of claims 7 to 10, wherein the depot provides a cumulated amount of axitinib released in vitro of about 3 mg to about 20 mg, or of about 4.5 mg to about 18 mg in phosphate-buffered saline at 37 °C over a period of 30 days, and / or of about 7 mg to about 36 mg, or of about 9 mg to about 33 mg in phosphate-buffered saline at 37 °C over a period of 60 days, and / or of about 12 mg to about 50 mg, or of about 15 mg to about 42 mg to about in phosphate-buffered saline at 37 °C over a period of 90 days.

12. The method according to any of claims 7 to 11, wherein the depot provides a mean axitinib concentration in the synovial fluid of about 150 ng / mL to about 600 ng / mL after a period of 3 days after administration, and / or of about 350 ng / mL to about 750 ng / mL after a period of 7 days after administration, and / or of about 35 ng / mL to about 200 ng / mL after a period of 14 days after administration, and / or wherein the depot provides a means axitinib concentration in the synovial fluid of about 35 ng / mL to about 200 ng / mL over period of 14 days, over a period of 1 month, over a period of 2 months, or over a period of 3 months.

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

14. The method according to any of claims 1 to 13, wherein the hydrogel comprises a polymer network that comprises crosslinked polymer units that are identical or different, wherein in particular the crosslinked polymer units are one or more crosslinked polyethylene glycol units, in particular wherein the polymer network comprises polyethylene glycol units having an average molecular weight in the range from about 2,000 to about 100,000 Daltons, or in the range from about 10,000 to about 60,000 Daltons, or in the range from about 20,000 to about 40,000 Daltons, or in the range from about 15,000 to about 30,000 Daltons. 9015. The method according to any of claims 1 to 14, wherein the polymer network comprises one or more crosslinked multi-arm polymer units, wherein the multi-arm polymer units comprise one or more 4-arm polyethylene glycol units, wherein in particular the 4-arm polyethylene glycol units are 4a20kPEG units or 4a40kPEG units, or wherein the multi-arm polymer units comprise one or more 8-arm polyethylene glycol units, wherein in particular the 8-arm polyethylene glycol units are 8a20kPEG units or 8a15kPEG units, or wherein the polymer network comprises both 4-arm and 8-arm polyethylene glycol units, wherein in particular the 4-arm polyethylene glycol units are 4a20kPEG units and the 8-arm polyethylene glycol units are 8a20kPEG units.

16. The method according to any 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 in particular the nucleophilic group is an amine group, and / or wherein the electrophilic group is an activated ester group, in particular wherein the electrophilic group is an N- hydroxysuccinimidyl (NHS) group, or wherein the electrophilic group is a succinimidyl glutarate (SG) or a succinimidyl azelate (SAZ) group.

17. The method according to any of claims 1 to 16, wherein the depot is in the form of at least one sustained release biodegradable fiber, wherein in particular the at least one fiber has an essentially cylindrical shape, in particular wherein one fiber comprises 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 from about 10 µg to about 1200 µg.

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

19. The method according to any of claims 1 to 18, wherein the articular condition or the condition of a bony canal is an inflammatory condition, and / or wherein the articular condition or the condition of a bony canal involves angiogenesis.

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

21. The method according to any of claims 5 to 19, wherein the condition of a bony canal is related to narrowing of the bony canal, and / or wherein the condition of a bony canal involves nerve compression, wherein in particular the condition of a bony canal is carpal tunnel syndrome, or wherein the condition of a bony canal is spinal stenosis.

22. The method according to any of claims 1 to 21, wherein the treatment is effective in reducing pain. 9123. The method according to any of claims 1 to 22, wherein the treatment is effective in reducing an expression of at least one inflammatory marker, in particular wherein the treatment is effective in reducing an expression of at least one cytokine, wherein in particular the at least one cytokine is at least one interferon (IFN), interleukin (IL), and / or chemokine of the CXC family.

24. An injectable pharmaceutical preparation comprising (i) a sustained release biodegradable depot comprising a hydrogel and a tyrosine kinase inhibitor, and (ii) 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, wherein in particular the beads are spherical or non- spherical particles, in particular wherein the beads comprise the tyrosine kinase inhibitor in an amount of from about 0.01 µg to about 50 µg per one bead, or wherein the beads comprise the tyrosine kinase inhibitor in an amount of from about 0.5 µg to about 12 µg per one bead, or wherein the beads comprise the tyrosine kinase inhibitor in an amount of from about 1 µg to about 8 µg per one bead, of from about 1.5 µg to about 5 µg per one bead, or of from about 2 µg to about 4 µg per one bead.

26. The injectable pharmaceutical composition according to claim 24 or 25, wherein the beads are suspended in the carrier in a concentration of about 10 wt.-% to about 50 wt.-% beads, about 15 wt.-% to about 40 wt.-% beads, or about 20 wt.-% to about 30 wt.-% beads, with the remainder being the carrier.

27. The injectable pharmaceutical composition according to any of claims 24 to 26, wherein the carrier is a non- aqueous carrier, such as an oil-based carrier, in particular wherein the carrier is at least one pharmaceutically acceptable oil including almond oil, castor oil, coconut oil, corn oil, cotton seed oil, flax oil, linseed oil, maize oil, mineral oil, olive oil, palm oil, peanut oil, rape 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 tallow, 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, wherein in particular the carrier is sesame oil or ethyl oleate.

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

29. The method according to claim 28, further comprising III. a step of loading the pharmaceutical preparation into a hypodermic needle, wherein in particular the hypodermic needle is a 20- to 27-gauge needle, or wherein the hypodermic needle is a 22- or 25- gauge needle. 9230. A kit comprising one or more injectable pharmaceutical preparation(s) comprising a sustained release biodegradable depot and a carrier according to any of claims 24 to 27 or manufactured in accordance with the method of claim 28 or 29 and one or more hypodermic needle(s).

31. The kit according to claim 30, wherein the one or more hypodermic needle(s) is / are each pre-loaded with one injectable pharmaceutical preparation, wherein in particular the hypodermic needle is a 20- to 27-gauge needle, or wherein the hypodermic 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 injectable pharmaceutical preparation, wherein in particular the injection device is provided in the kit separately from the one or more hypodermic needle(s), or wherein in particular the injection device is pre-connected to a hypodermic needle pre-loaded with injectable pharmaceutical preparation.

33. A method of reducing pain in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of the injectable pharmaceutical preparation according to any of claims 24 to 17 by injection.

34. A method of reducing inflammation in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of the injectable pharmaceutical preparation according to any of claims 24 to 27 by injection.

35. A method of slowing down, arresting or reversing progressive structural tissue damage associated with arthritis or of slowing down, arresting or reversing loss of joint function associated with arthritis in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of the injectable pharmaceutical preparation according to any of claims 24 to 27 by articular injection.

36. A method of slowing down, arresting or reversing tingling, weakness or numbness of fingers associated with carpal tunnel syndrome or of slowing down, arresting or reversing tingling, weakness or numbness of arms or legs associated with spinal stenosis in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of the injectable pharmaceutical preparation according to any of items 24 to 27 by injection into or near to the carpal tunnel or by epidural injection.

37. A sustained release biodegradable depot comprising a hydrogel and a tyrosine kinase inhibitor for use in treating an articular condition according to a method according to any of claims 1 to 23.

38. Use of a sustained release biodegradable depot comprising a hydrogel and tyrosine kinase inhibitor in the preparation of a medicament for treating an articular condition according to a method according to any of claims 1 to 23. 93

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