Ophthalmic implants containing tyrosine kinase inhibitors

Abstract

The present invention relates to a sustained release biodegradable ophthalmic implant containing a tyrosine kinase inhibitor dispersed in a hydrogel for the treatment of retinal disease over a longer period of time.

Description

[0001] This application is a divisional application of Chinese Patent Application for Invention (filing date: March 24, 2021; application number: 202180030126.1 (International Application Number: PCT / US2021 / 023806); invention title: Ophthalmic Implants Containing Tyrosine Kinase Inhibitors).

[0002] Cross - reference to Related Applications

[0003] This invention claims priority to U.S. Provisional Application No. 62 / 994,391, filed on March 25, 2020, International Application PCT / US2020 / 029827, filed on April 24, 2020, U.S. Provisional Application No. 63 / 106,276, filed on October 27, 2020, and U.S. Provisional Application No. 63 / 148,463, filed on February 11, 2021, the entire disclosures of which are incorporated herein by reference. Field of the Invention

[0004] This invention relates to the treatment of eye diseases, such as neovascular age - related macular degeneration (AMD), also known as "wet AMD". According to the present invention, eye diseases are treated by (e.g., intravitreal) injection of an implant that is biodegradable and continuously releases a tyrosine kinase inhibitor such as axitinib. Background of the Invention

[0006] Macular diseases, including age-related macular degeneration (AMD), are one of the leading causes of visual impairment and irreversible blindness in people over 50 years old worldwide. Specifically, AMD was one of the most common retinal diseases in the United States (US) in 2019, affecting approximately 16.9 million people, and is expected to increase to 18.8 million in 2024 (Market Scope. Ophthalmic Comprehensive Reports. 2019 Retinal Pharmaceuticals Market Report: A Global Analysis for 2018 to 2019, September 2019). AMD can be further divided into different disease stages. Early AMD is characterized by the presence of a few (<20) medium-sized drusen or retinal pigment abnormalities. Intermediate AMD is characterized by at least one large druse, many medium-sized drusen, or geographic atrophy that does not extend to the center of the macula. Late or advanced AMD can be either non-neovascular (dry, atrophic, or non-exudative) or neovascular (wet or exudative). Late non-neovascular AMD is characterized by drusen and geographic atrophy that extends to the center of the macula. Late neovascular AMD is characterized by choroidal neovascularization and its sequelae (Jager et al., Age-related macular degeneration. N Engl J Med. 2008;358(24):2606-17).

[0007] The more advanced forms of wet AMD are characterized by an increase in vascular endothelial growth factor (VEGF), which promotes the growth of new blood vessels (angiogenesis) that grow under the retina and cause blood and body fluid leakage into and under the macula and subretinal space. With the development of vascular endothelial growth factor subtype inhibitors (i.e., VEGF inhibitors) initially used to treat various cancers, this pathway has been successfully disrupted. Photodynamic therapy in combination with anti-VEGF and steroid administration is currently still a second-line therapy for patients who are unresponsive to anti-VEGF agent monotherapy (Al-Zamil et al., Recent developments in age-related macular degeneration: a review. Clin Interv Aging. 2017;12:1313-30).

[0008] Other common retinal diseases are diabetic macular edema (DME) and retinal vein occlusion (RVO). DME was one of the most common retinal diseases in the United States in 2019, affecting approximately 8 million people and expected to increase to 8.8 million by 2024 (Market Scope 2019, ibid.). The disease is classified according to reduced retinal tension and increased vascular pressure caused by VEGF upregulation, retinal vascular autoregulation (Browning et al., Diabetic macular edema: evidence-based management. 2018 Indian journal of ophthalmology, 66(1), p. 1736), and inflammatory cytokines and chemokines (Miller et al., Diabetic macular edema: current understanding, pharmacologic treatment options, and developing therapies. 2018, Asia-Pacific Journal of Ophthalmology, 7(1):28-35). Changes in these inflammatory and angiogenic mediators disrupt the blood-retinal barrier (BRB) in the vascular endothelium (Miller et al., ibid.). Hard exudates enter the extracellular space, causing central vision blurring and distortion, resulting in a decrease in patient visual acuity (Schmidt-Erfurth et al., guidelines for the Management of Diabetic Macular Edema by the European Society of Retina Specialists (EURETINA). 2017, Ophthalmologica. 237(4):185-222). On average, a patient's visual acuity decreases by 8% three years after the onset of the disease.

[0009] The basis of all available treatments for DME attempts to control the metabolic function of hyperglycemia and blood pressure (Browning et al., ibid.). Anti-VEGF therapy is currently regarded as the first-line therapy in the standard of care for DME because it has been proven to be less destructive and damaging compared to other treatment methods (Schmidt-Erfurth et al., ibid.). The pharmacological approach is beneficial because drugs are manufactured to specifically target the VEGF pathway and inhibit the upregulation that accompanies DME (Miller et al., ibid.). Other treatment options include intravitreal corticosteroid injections, focal laser photocoagulation, and vitrectomy (Browning et al., ibid.).

[0010] RVO affected approximately 1.3 million people in the United States in 2019 and is expected to affect 1.4 million people in the United States in 2024 (Market Scope 2019, ibid.). RVO is a chronic disorder in which the retinal circulation contains obstructions that cause leakage, retinal thickening, and visual impairment (Ip and Hendrick, Retinal Vein Occlusion Review. 2018, Asia-Pacific Journal of Ophthalmology, 7(1):40-45; Pierru et al., Occlusions veineuses rétiniennes retinal vein occlusions. 2017, Journal d'Ophtalmologie, 40(8):696-705). The disorder typically occurs in patients 55 years of age and older with pre-existing disorders such as hypertension, diabetes, and glaucoma. There is no predictable course for RVO because it can cause rapid visual deterioration in patients or remain asymptomatic. The prognosis and associated treatment options for RVO depend on the classification of the disease because, although the manifestations are similar, different variants have different risk factors. The disease is classified according to the location of the retinal circulation disorder: branch retinal vein occlusion (BRVO), hemiretinal vein occlusion (HRVO), and central retinal vein occlusion (CRVO). BRVO is more common, affecting 0.4% of the world's population, while CRVO affects 0.08% of the world's population. Studies have shown that BRVO is more prevalent in Asian and Hispanic ethnic groups than in Caucasians (Ip and Hendrick, ibid.).

[0011] The current treatment for RVO includes symptom maintenance of the disorder to avoid other complications, macular edema, and neovascular glaucoma. Anti-VEGF treatment is currently the standard of care and can temporarily improve vision. Other treatment options include laser, steroids, and surgery (Pierru et al., ibid.).

[0012] Anti-VEGF agents are currently considered the standard of care for wet AMD, DME, and RVO. The first treatment approved by the FDA for wet AMD in 2004 was (pegaptanib sodium injection by Bausch & Lomb). Since then, (ranibizumab injection by Genentech) and (Aflibercept injection of Regeneron Pharmaceuticals) was approved for the treatment of wet AMD, as well as DME and secondary macular edema due to RVO in 2006 and 2011, respectively. Additionally, in October 2019, (Brolucizumab injection of Novartis Pharmaceuticals) was approved by the FDA for the treatment of wet AMD. Other progress has been reported in the following literature: Amadio et al., Targeting VEGF in eyeneovascularization: What's new?: A comprehensive review on current therapies and oligonucleotide-based interventions under development. 2016, Pharmacological Research, 103: 253 - 69.

[0013] However, despite these advancements, anti-VEGF therapies still have limitations. Due to rapid vitreous clearance, most patients currently essentially require multiple injections (such as monthly) for the rest of their lives. Additionally, not all patients respond to anti-VEGF therapy. Moreover, these treatment options also have potential risks associated with administration, including infection, macular atrophy, visual decline over time, retinal detachment, and increased intraocular pressure (IOP). The patient's suffering includes discomfort, eye pain, vision loss, and increased light sensitivity. In addition to the burden on patients and the risks associated with frequent injections, there are other limitations known to be associated with current anti-VEGF therapies, such as potential immunogenicity risks, complex manufacturing requirements for biologics, macular atrophy, and retinal vasculitis. Importantly, regardless of the number of drugs, patients are currently expected to remain on treatment indefinitely.

[0014] Tyrosine kinase inhibitors have been developed as chemotherapeutic agents that inhibit the signal transduction of receptor tyrosine kinases (RTKs), a family of tyrosine protein kinases. RTKs span the cell membrane and have an intracellular (internal) and an extracellular (external) portion. After a ligand binds to the extracellular portion, the receptor tyrosine kinases dimerize and initiate an intracellular signal transduction cascade driven by autophosphorylation using the coenzyme messenger adenosine triphosphate (ATP). Many RTK ligands are growth factors, such as VEGF. VEGF is a protein family that binds to numerous types of VEGF receptors (VEGFRs), namely VEGFR1-3 (all RTKs), thereby inducing angiogenesis. VEGF-A, which binds to VEGFR2, is the target of the anti-VEGF drugs described above. In addition to VEGFR1-3, several other RTKs are known to induce angiogenesis, such as the platelet-derived growth factor receptor (PDGFR) activated by PDGF or the stem cell growth factor receptor / type III receptor tyrosine kinase (c-Kit) activated by stem cell factor.

[0015] Some TKIs have been evaluated for the treatment of AMD by different routes of administration, including pazopanib (GlaxoSmithKline: NCT00463320), regorafenib (Bayer: NCT02348359), and PAN90806 (PanOptica: NCT02022540) (all administered in the form of eye drops), as well as the oral TKI X-82 (Tyrogenex; NCT01674569, NCT02348359). However, due to the low solution concentration of TKIs, which tend to have low water solubility, and the short residence time of TKIs on the eye surface, locally applied eye drops result in poor penetration into the vitreous and limited distribution to the retina. In addition, due to rinsing or user error, it is difficult to control the drug concentration after local administration. Moreover, systemic administration of TKIs is not feasible because high doses are required to achieve effective concentrations of the drug in the eye, particularly in the target tissue. This results in unacceptable side effects due to high systemic exposure. Additionally, it is difficult to control the drug concentration. Alternatively, intravitreal injection of TKI suspensions has been performed. However, this mode of administration results in rapid clearance of the drug, and therefore the injection must be repeated frequently, such as once a day or at least once a month. In addition, several TKIs have poor solubility, resulting in the formation of aggregates after intravitreal injection, which may migrate or settle onto the retina and cause local contact toxicity and holes, such as macular or retinal holes.

[0016] Thus, there is an urgent need for an improved treatment of ocular diseases such as AMD, DME, and RVO with a TKI, which is effective over a longer period of time, thereby avoiding the need for frequent (monthly or even daily) injections required by currently commonly used anti-VEGF therapies, especially for individuals who are unresponsive to anti-VEGF therapies (e.g., up to 33% of DME subjects).

[0017] All references disclosed herein are hereby incorporated by reference in their entirety for all purposes. SUMMARY OF THE INVENTION

[0018] Certain embodiments of the present invention are directed to providing an ocular implant comprising a tyrosine kinase inhibitor (TKI) such as axitinib, which is effective in treating ocular diseases such as neovascular age-related macular degeneration (AMD), DME, and RVO in a patient over a longer period of time.

[0019] Another object of certain embodiments of the present invention is to provide an ocular implant comprising a tyrosine kinase inhibitor (TKI) such as axitinib, which continuously releases the TKI into the eye.

[0020] Another object of certain embodiments of the present invention is to provide an ocular implant comprising a TKI such as axitinib, which is pre-loaded into a syringe, thereby avoiding contamination of the implant prior to injection as no other preparation steps are required.

[0021] Another object of certain embodiments of the present invention is to provide an ocular implant comprising a TKI such as axitinib, which is sufficiently biodegradable, i.e., cleared from the eye within a time consistent with TKI release, thereby avoiding the formation of floaters (empty implant vehicle residues) in the patient's eye and / or avoiding the need to remove the empty implant from the eye after the treatment period.

[0022] Another object of certain embodiments of the present invention is to provide an ocular implant comprising a TKI such as axitinib, which is biodegradable, wherein the implant is prevented from decomposing into smaller particles that may, for example, affect vision during implant degradation.

[0023] Another object of certain embodiments of the present invention is to provide an ocular implant comprising a TKI such as axitinib, wherein the stability of the ocular implant is less affected by the changing environment in the eye, such as vitreous humor viscosity, vitreous humor pH, vitreous humor composition, and / or intraocular pressure (IOP), compared to a hydrogel formed in situ after injection.

[0024] Another objective of certain embodiments of the present invention is to provide an ophthalmic implant comprising a TKI such as axitinib, which is biocompatible and non-immunogenic because it contains no or substantially no components of animal or human origin.

[0025] Another objective of certain embodiments of the present invention is to provide an ophthalmic implant comprising a TKI such as axitinib, which contains no preservatives (such as antimicrobial preservatives).

[0026] Another objective of certain embodiments of the present invention is to provide an ophthalmic implant comprising a TKI such as axitinib, which is easy to inject, specifically, intravitreally.

[0027] Another objective of certain embodiments of the present invention is to provide an ophthalmic implant comprising a TKI such as axitinib, which contains a therapeutically effective amount of the TKI but has a relatively small length and / or diameter.

[0028] Another objective of certain embodiments of the present invention is to provide an ophthalmic implant comprising a TKI such as axitinib, which is dimensionally stable in the dry state but changes its dimensions upon hydration, for example, after administration to the eye.

[0029] Another objective of certain embodiments of the present invention is to provide an ophthalmic implant comprising a TKI such as axitinib, which has a small diameter in the dry state to fit into the lumen of a fine-diameter needle (such as a 22- to 30-gauge needle), and upon hydration, for example, after administration to the eye, the diameter increases but the length decreases; thus, providing a minimally invasive administration method.

[0030] Another objective of certain embodiments of the present invention is to provide an ophthalmic implant comprising a TKI such as axitinib, which is injected in a dry form and hydrates in situ (i.e., in the eye) upon injection.

[0031] Another objective of certain embodiments of the present invention is to provide an ophthalmic implant comprising a TKI such as axitinib, which has a low TKI concentration on the surface of the implant when placed in the eye, thereby avoiding TKI toxicity when the implant comes into contact with eye cells or tissues (such as the retina).

[0032] Another objective of certain embodiments of the present invention is to provide an ophthalmic implant comprising a TKI such as axitinib, which is stable and has a defined shape and surface area in both the dry state before injection and the hydrated state after injection (i.e., inside the eye).

[0033] Another objective of certain embodiments of the present invention is to provide an ophthalmic implant comprising a TKI such as axitinib, which is easy to manipulate, specifically, not prone to spillage or breakage.

[0034] Another objective of certain embodiments of the present invention is to provide an ophthalmic implant comprising a TKI such as axitinib, which enables the administration of a precise dose (within a wide dose range), thereby avoiding the risks of overdose and underdose.

[0035] Another objective of certain embodiments of the present invention is to provide an ophthalmic implant comprising a TKI such as axitinib, which generally remains in the eye region where it is administered.

[0036] Another objective of certain embodiments of the present invention is to provide an ophthalmic implant comprising a TKI such as axitinib, wherein the implant causes minimal visual impairment or no visual impairment after administration.

[0037] Another objective of certain embodiments of the present invention is to provide an ophthalmic implant comprising a TKI such as axitinib, which is safe and well-tolerated.

[0038] Another objective of certain embodiments of the present invention is to provide an ophthalmic implant comprising a TKI such as axitinib, which does not induce severe adverse events, such as severe ocular adverse events.

[0039] Another objective of certain embodiments of the present invention is to provide an ophthalmic implant comprising a TKI such as axitinib, which continuously releases a therapeutically effective amount of a TKI such as axitinib over a prolonged period, such as up to 3 months or more, such as at least 6 months, at least 9 months, at least 11 months, or at least 13 months.

[0040] Another objective of certain embodiments of the present invention is to provide an ophthalmic implant comprising a TKI such as axitinib, which continuously releases a TKI such as axitinib over a prolonged period, such as up to 3 months or more, such as at least 6 months, at least 9 months, at least 11 months, or at least 13 months, thereby avoiding the need for frequent implant administrations.

[0041] Another objective of certain embodiments of the present invention is to provide an ophthalmic implant comprising a TKI such as axitinib, which continuously releases a TKI such as axitinib over a prolonged period, such as up to 3 months or more, such as at least 6 months, at least 9 months, at least 11 months, or at least 13 months, thereby inhibiting angiogenesis during this period.

[0042] Another objective of certain embodiments of the present invention is to provide an ophthalmic implant comprising a TKI such as axitinib, which continuously releases the TKI over a long period of time, such as up to 3 months or longer, such as at least 6 months, at least 9 months, at least 11 months or at least 13 months, wherein during this period, the level of the TKI in eye tissues such as the retina, choroid and vitreous humor is always maintained at a therapeutically effective level, specifically, a level sufficient to inhibit angiogenesis.

[0043] Another objective of certain embodiments of the present invention is to provide an ophthalmic implant comprising a TKI such as axitinib, which continuously releases the TKI such as axitinib over a long period of time, such as up to 3 months or longer, such as at least 6 months, at least 9 months, at least 11 months or at least 13 months, wherein during this period, no toxic concentration of the TKI is observed in eye tissues such as the retina, choroid and vitreous humor.

[0044] Another objective of certain embodiments of the present invention is to provide an ophthalmic implant comprising a TKI such as axitinib, which continuously releases the TKI such as axitinib over a long period of time, such as up to 3 months or longer, such as at least 6 months, at least 9 months, at least 11 months or at least 13 months, wherein the TKI does not accumulate in the anterior chamber of the eye.

[0045] Another objective of certain embodiments of the present invention is to provide an ophthalmic implant comprising a TKI such as axitinib, which continuously releases the TKI over a long period of time, such as up to 3 months or longer, such as at least 6 months, at least 9 months, at least 11 months or at least 13 months, wherein the TKI is not or substantially not systemically reabsorbed, thereby substantially avoiding systemic toxicity.

[0046] Another objective of certain embodiments of the present invention is to provide a method for treating ocular diseases such as AMD, DME and RVO in patients in need thereof, with a treatment period of up to 3 months or longer, such as at least 6 months, at least 9 months, at least 11 months or at least 13 months.

[0047] Another objective of certain embodiments of the present invention is to provide a method for treating ocular diseases such as AMD, DME and RVO in patients in need thereof, with a treatment period of up to 3 months or longer, such as at least 6 months, at least 9 months, at least 11 months or at least 13 months, during which no rescue medication needs to be administered, or wherein only occasional administration of rescue medication, such as 1, 2 or 3 times, is required during the treatment period.

[0048] Another objective of certain embodiments of the present invention is to provide a method for treating ocular diseases such as AMD, DME, and RVO in patients in need, such as patients who have been previously treated with anti-VEGF or patients who have not undergone anti-VEGF treatment.

[0049] Another objective of certain embodiments of the present invention is to provide a method for treating ocular diseases such as AMD, DME, and RVO in patients in need, such as patients who have been previously treated with anti-VEGF and who did not respond to the previous anti-VEGF treatment.

[0050] Another objective of certain embodiments of the present invention is to provide a method for treating ocular diseases such as AMD, DME, and RVO in patients in need, such as patients diagnosed with primary subfoveal neovascularization (SFNV) secondary to AMD.

[0051] Another objective of certain embodiments of the present invention is to provide a method for treating ocular diseases such as AMD, DME, and RVO in patients in need, such as patients previously treated with anti-VEGF, diagnosed with previously treated subfoveal neovascularization (SFNV) secondary to neovascular AMD with leakage involving the ocular fossa.

[0052] Another objective of certain embodiments of the present invention is to provide a method for manufacturing an ocular implant comprising a TKI such as axitinib.

[0053] Another objective of certain embodiments of the present invention is to provide a method for preventing premature hydration of an ocular implant during storage and handling, wherein the ocular implant is sensitive to moisture such that it changes its dimensions, for example, upon hydration.

[0054] Another objective of certain embodiments of the present invention is to provide a method for reducing potential tissue damage during injection of an ocular implant.

[0055] Another objective of certain embodiments of the present invention is to provide a kit comprising one or more ocular implants comprising a TKI such as axitinib and optionally comprising means for injecting the ocular implant.

[0056] Another objective of certain embodiments of the present invention is to provide a method for reducing the central subfield thickness (as measured by optical coherence tomography) in patients in whom the central subfield thickness is elevated due to an ocular disease involving angiogenesis, for example, by reducing retinal fluid.

[0057] Another objective of certain embodiments of the present invention is to provide a method for substantially maintaining the central subfield thickness or preventing a clinically significant increase in the central subfield thickness (as measured by optical coherence tomography) in patients in whom the central subfield thickness is elevated due to an ocular disease involving angiogenesis, without increasing retinal fluid.

[0058] Another objective of certain embodiments of the present invention is to provide a method for reducing, substantially maintaining the central subfield thickness or preventing a clinically significant increase in the central subfield thickness (as measured by optical coherence tomography) in patients in whom the central subfield thickness is elevated due to an ocular disease involving angiogenesis, while improving or at least not weakening the visual acuity of said patients (as measured, for example, by best corrected visual acuity).

[0059] Another objective of certain embodiments of the present invention is to provide a method for improving the vision of patients whose vision is impaired due to an ocular disease involving angiogenesis.

[0060] Another objective of certain embodiments of the present invention is to provide a method for improving the vision (as demonstrated, for example, by a reduction in the central subfield thickness measured by optical coherence tomography) of patients whose vision is impaired due to the presence of retinal fluid (e.g., caused by an ocular disease involving angiogenesis) by reducing the retinal fluid in said patients.

[0061] One or more of these and other objectives of the present invention are solved by one or more embodiments as disclosed and claimed herein.

[0062] Individual aspects of the present invention are disclosed in this specification and claimed in the independent claims, while the dependent claims claim specific embodiments and variations of these aspects of the present invention. Details of the various aspects of the present invention are provided in the following detailed description.

[0063] Throughout this application, various references are cited. The disclosures of these references are incorporated herein by reference. In case of conflict, the disclosure in this application shall prevail.

[0064] 1. A sustained-release biodegradable ocular implant comprising a hydrogel and at least about 150 μg of a tyrosine kinase inhibitor (TKI), wherein the TKI particles are dispersed within the hydrogel, and wherein the implant has a length in its dry state of less than about 17 mm.

[0065] 2. The sustained-release biodegradable ocular implant according to item 1, wherein the implant is cylindrical and has a diameter in its dry state of about 0.1 mm to about 0.5 mm.

[0066] 3. The sustained release biodegradable ophthalmic implant according to item 1, wherein the implant is non-cylindrical.

[0067] 4. The sustained release biodegradable ophthalmic implant according to any one of items 1 to 3, wherein the TKI is axitinib.

[0068] 5. The sustained release biodegradable ophthalmic implant according to item 4, wherein the implant comprises axitinib in an amount of about 150 μg to about 1800 μg, preferably in an amount of about 150 μg to about 1200 μg, more preferably in an amount of about 480 μg to about 750 μg or about 160 μg to about 250 μg.

[0069] 6. The sustained release biodegradable ophthalmic implant according to any one of the foregoing items, wherein the total weight of the implant in its dry state is about 0.2 mg to about 1.5 mg, preferably a total weight of about 0.75 mg to 1.25 mg.

[0070] 7. The sustained release biodegradable ophthalmic implant according to any one of the foregoing items, wherein the implant is for administration to the posterior part of the eye.

[0071] 8. The sustained release biodegradable ophthalmic implant according to any one of the foregoing items, wherein the implant is a vitreous implant.

[0072] 9. The sustained release biodegradable ophthalmic implant according to any one of the foregoing items, wherein the implant is cylindrical and has a length of about 6 mm to about 10 mm in its dry state.

[0073] 10. The sustained release biodegradable ophthalmic implant according to any one of the foregoing items, wherein the implant is cylindrical and has a diameter of about 0.2 mm to about 0.4 mm in its dry state.

[0074] 11. The sustained release biodegradable ophthalmic implant according to any one of the foregoing items, wherein the implant is cylindrical and has a length equal to or less than about 10 mm and a diameter equal to or less than about 0.8 mm in its hydrated state (after 24 hours at pH 7.2, 37 °C in phosphate buffered saline).

[0075] 12. The sustained release biodegradable ophthalmic implant according to any one of the foregoing items, wherein the ratio of the diameter of the implant in its hydrated state to the diameter in its dry state is less than about 5, preferably less than about 2.25.

[0076] 13. The sustained release biodegradable ophthalmic implant according to any one of the preceding items, wherein the implant is cylindrical and the ratio of the length in the dry state to the length in the hydrated state is greater than about 0.7, preferably greater than about 0.8.

[0077] 14. The sustained release biodegradable ophthalmic implant according to any one of the preceding items, wherein the TKI is axitinib and the implant releases axitinib at an average rate of about 0.25 μg to about 2.5 μg per day, preferably about 0.25 μg to about 1.5 μg per day, more preferably about 0.3 μg to about 0.5 μg per day, in phosphate buffered saline at pH 7.2 and 37 °C under non-sink simulated physiological conditions, for a period of 30 days.

[0078] 15. The sustained release biodegradable ophthalmic implant according to any one of the preceding items, wherein the implant releases the TKI for a period of at least 3 months after administration, or at least 6 months after administration, or at least 9 months after administration, or at least 12 months after administration, or for a period of about 6 months to about 9 months after administration.

[0079] 16. The sustained release biodegradable ophthalmic implant according to any one of the preceding items, wherein the implant biodegrades within about 2 to about 15 months after administration of vitreous humor, preferably within about 4 to about 13 months, or within about 9 to about 12 months.

[0080] 17. The sustained release biodegradable ophthalmic implant according to any one of the preceding items, wherein the hydrogel comprises a polymer network, and the polymer network comprises units of one or more polyalkylene glycols, polyethylene glycol, poly(ethylene oxide), poly(propylene oxide), poly(vinyl alcohol), poly(vinylpyrrolidone), polylactic acid, poly(lactic-co-glycolic acid), random or block copolymers or combinations or mixtures of any of these, or units of one or more polyamino acids, glycosaminoglycans, polysaccharides or proteins.

[0081] 18. The sustained release biodegradable ophthalmic implant according to item 17, wherein the hydrogel comprises polyethylene glycol (PEG) units.

[0082] 19. The sustained release biodegradable ophthalmic implant according to item 18, wherein the hydrogel comprises multi-arm PEG units, the multi-arm PEG units being the same or different and having a number average molecular weight of about 10,000 to about 60,000 daltons, preferably about 20,000 daltons.

[0083] 20. The sustained release biodegradable ophthalmic implant according to item 18 or 19, wherein the hydrogel comprises crosslinked PEG units, and the crosslinking between the PEG units comprises a group represented by the following formula

[0084]

[0085] Where m is an integer from 0 to 10, and m is preferably 6.

[0086] 21. The sustained release biodegradable ophthalmic implant according to any one of items 18 to 20, wherein the PEG units comprise 4-arm and / or 8-arm PEG units, preferably 4a20k and 8a20k PEG units.

[0087] 22. The sustained release biodegradable ophthalmic implant according to any one of the preceding items, wherein the implant contains no more than about 40% by weight of the TKI in the wet composition in its wet state.

[0088] 23. The sustained release biodegradable ophthalmic implant according to any one of the preceding items, wherein the implant contains about 25% to about 75% by weight of the TKI and about 20% to about 60% by weight of the PEG units (dry composition) in its dry state.

[0089] 24. The sustained release biodegradable ophthalmic implant according to item 23, wherein the implant contains about 60% to about 75% by weight of the TKI and about 21% to about 31% by weight of the PEG units, or contains about 45% to about 55% by weight of the TKI and about 37% to about 47% by weight of the PEG units (dry composition) in its dry state.

[0090] 25. The sustained release biodegradable ophthalmic implant according to any one of the preceding items, wherein the implant contains per mm 3 about 200 μg to about 1000 μg of TKI, and preferably contains per mm 3 about 500 μg to about 800 μg of axitinib.

[0091] 26. The sustained release biodegradable ophthalmic implant according to item 1, wherein the implant is a vitreous implant and contains about 480 μg to about 750 μg of axitinib, preferably about 540 μg to about 660 μg of axitinib, more preferably about 600 μg of axitinib, is cylindrical, and has a length less than or equal to 10 mm and a diameter of about 0.3 mm to about 0.4 mm in its dry state, and has a length of about 6 mm to about 10.5 mm and a diameter of about 0.6 mm to about 0.8 mm in its hydrated state (after 24 hours at pH 7.2, 37 °C in phosphate buffered saline), and wherein the hydrogel comprises crosslinked 4a20k and 8a20k PEG units, and the crosslinking between the PEG units comprises a group represented by the following formula,

[0092]

[0093] where m is 6.

[0094] 27. The sustained release biodegradable ocular implant according to item 1, wherein the implant is a vitreous implant and contains from about 160 μg to about 250 μg axitinib, preferably from about 180 μg to about 220 μg axitinib, more preferably about 200 μg axitinib, is cylindrical, and has a length of less than about 17 mm and a diameter of about 0.2 mm to about 0.3 mm in its dry state, and has a length of about 6.5 mm to about 8 mm and a diameter of about 0.7 mm to about 0.8 mm in its hydrated state (after 24 hours at pH 7.2, 37 °C in phosphate buffered saline), and wherein the hydrogel contains crosslinked 4a20k and 8a20k PEG units, and the crosslinking between the PEG units includes a group represented by the following formula,

[0095]

[0096] where m is 6.

[0097] 28. The sustained release biodegradable ocular implant according to any one of the preceding items, wherein the d90 particle size of the TKI particles is less than about 30 μm as determined by laser diffraction.

[0098] 29. The sustained release biodegradable ocular implant according to any one of the preceding items, wherein the implant does not contain or substantially does not contain antimicrobial preservatives.

[0099] 30. A method of treating an ocular disease in a patient in need thereof, the method comprising administering to the patient a sustained release biodegradable ocular implant comprising a hydrogel and at least about 150 μg of a tyrosine kinase inhibitor (TKI), wherein the TKI particles are dispersed within the hydrogel.

[0100] 31. The method according to item 30, wherein the sustained release biodegradable ocular implant is according to any one of items 1 to 29.

[0101] 32. The method according to item 30 or 31, wherein the implant is administered by injection into the vitreous humor.

[0102] 33. The method according to any one of items 30 to 32, wherein the implant is administered once during a treatment period of at least 3 months, or at least 6 months, or at least 9 months or at least 12 months.

[0103] 34. The method according to item 33, wherein the treatment period is from about 6 to about 9 months.

[0104] 35. The method according to item 33 or 34, wherein the TKI is axitinib, and the dose of axitinib administered once per eye during the treatment period is from about 150 μg to about 1800 μg, preferably from about 150 μg to 1200 μg, and wherein the dose is contained in one implant or in two, three or more implants administered simultaneously.

[0105] 36. The method according to item 35, wherein the axitinib dose is from about 160 μg to about 250 μg, preferably about 200 μg.

[0106] 37. The method according to item 35, wherein the axitinib dose is from about 480 μg to about 750 μg, preferably about 600 μg.

[0107] 38. The method according to any one of items 30 to 37, wherein the ocular disease is a retinal disease.

[0108] 39. The method according to item 38, wherein the disease is retinal vein occlusion (RVO), diabetic macular edema (DME) or neovascular age-related macular degeneration (AMD).

[0109] 40. The method according to item 39, wherein the disease is AMD.

[0110] 41. The method according to any one of items 30 to 40, wherein the treatment is effective in reducing, substantially maintaining or preventing a clinically significant increase in the central subfield thickness in patients with an elevated central subfield thickness, as measured by optical coherence tomography.

[0111] 42. The method according to any one of items 30 to 41, wherein an anti-VEGF agent is administered to the patient while treating with the sustained-release ocular implant.

[0112] 43. The method according to any one of items 30 to 41, wherein the anti-VEGF agent is administered in combination with the implant and is administered within about 1, about 2 or about 3 months after administering the implant.

[0113] 44. The method according to item 42 or 43, wherein the anti-VEGF agent is selected from the group consisting of aflibercept, bevacizumab, pegaptanib, ranibizumab and brolucizumab, and is administered by intravitreal injection.

[0114] 45. A sustained-release biodegradable ophthalmic implant comprising a hydrogel and at least about 150 μg of a tyrosine kinase inhibitor (TKI), wherein the TKI particles are dispersed within the hydrogel, or a sustained-release biodegradable ophthalmic implant as described in any one of items 1 to 29, which is used in a method as described in any one of items 30 to 44.

[0115] 46. Use of a sustained-release biodegradable ophthalmic implant comprising a hydrogel and at least about 150 μg of a tyrosine kinase inhibitor (TKI), wherein the TKI particles are dispersed within the hydrogel, or a sustained-release biodegradable ophthalmic implant as described in any one of items 1 to 29 for the preparation of a medicament for use in a method as described in any one of items 30 to 44.

[0116] 47. A method of manufacturing a sustained-release biodegradable ophthalmic implant as described in any one of items 1 to 29, the method comprising the steps of: forming a hydrogel comprising a polymer network and TKI particles dispersed within the hydrogel; shaping the hydrogel; and drying the hydrogel.

[0117] 48. The method as described in item 47, wherein the polymer network is formed by mixing and reacting a multi-arm PEG precursor containing an electrophilic group with a multi-arm PEG precursor containing a nucleophilic group or another crosslinking agent containing a nucleophilic group in a buffer solution in the presence of TKI particles and allowing the mixture to gel to form a hydrogel.

[0118] 49. The method as described in item 47 or 48, which comprises shaping the hydrogel by pouring the mixture into a tube to form a hydrogel strand before the hydrogel is completely gelled.

[0119] 50. The method as described in item 49, which further comprises stretching the hydrogel strand (wet stretching or dry stretching) in the longitudinal direction with a stretch factor of about 1 to about 4.5 before or after drying the hydrogel.

[0120] 51. The method as described in item 50, wherein the stretch factor is about 1.3 to about 3.5, preferably about 2 to about 2.5.

[0121] 52. A kit comprising one or more sustained-release biodegradable ophthalmic implants as described in any one of items 1 to 29 and one or more injection needles, wherein each implant is loaded into a needle.

[0122] 53. The kit as described in item 52, wherein the one or more needles are sized 22 to 30.

[0123] 54. The cartridge according to item 52 or 53, wherein the lumen of each needle is blocked by a material that is solid at room temperature and soft or liquid at body temperature.

[0124] 55. The cartridge according to any one of items 52 to 54, further comprising an injection device, wherein each needle is pre-connected or not pre-connected to the injection device. Description of the Drawings

[0125] Figure 1 Schematic illustration of an embodiment of an implant package. In this embodiment, the implant is pre-loaded into a thin-walled needle that is packaged separately from the injection device. It is also possible to have a multi-in-one device where the needle is already connected to the injection device.

[0126] Figure 2 Schematic illustration of an embodiment of implant positioning. After injection, the implant hydrates in situ while maintaining a cylindrical shape. The implant is positioned at the back of the eye.

[0127] Figure 3 Schematic illustration of the biodegradation of the hydrogel over time. During drug release, as the low-solubility drug particles (white) gradually dissolve and the drug diffuses from the hydrogel into the surrounding aqueous fluid (such as vitreous humor), a clearance zone (black) is formed. Over time, the gel degrades and is reabsorbed while the drug diffuses out. During the degradation process, the gel gradually swells until the degradation progresses to the point of shrinkage and deformation.

[0128] Figure 4 An embodiment of the in vitro axitinib release per day for different implants. (A) In vitro axitinib release from different implants containing 625, 716, 245, and 490 (2x245) μg axitinib doses under non-sink dissolution conditions. (B) In vitro accelerated axitinib release from a 556 μg implant.

[0129] Figure 5 An embodiment of a low-dose study conducted in rabbits. (A) Infrared reflectance (IR) of 1, 2, and 3 implants in rabbits one month after injection. The overall shape of the implants remains intact, regardless of the number of implants administered. (B) One month later, vascular leakage was effectively inhibited for all three doses (15, 30, and 45 μg), while vascular leakage was higher in control animals without implants. Error bars represent the standard deviation (SD; only the upper error bar is presented).

[0130] Figure 6 An embodiment of infrared reflectance (IR) and optical coherence tomography (OCT) imaging of the rabbit eye. IR / OCT images of the retinal morphology at 1, 3, and 6 months after implant injection, respectively. The retinal morphology is normal.

[0131] Figure 7. One embodiment of implant biodegradation and inflammation. (A) Significant biodegradation of the hydrogel component of the implant was observed over time in rabbit eyes. At 4 and 8 weeks after injection, the implant remained intact, while at 12 weeks, early stages of hydrogel degradation were visible. At 16 weeks, the implant further narrowed due to loss of the hydrogel structure. Eventually, no hydrogel was present after 20 and 26 weeks, and free (undissolved) axitinib particles (white samples) were visible near the previous implant site. (B) Histopathological analysis showed no inflammation in the area of undissolved axitinib after 26 weeks. Images are presented at 20x magnification (scale: 1000 μm) and 200x magnification (scale: 100 μm).

[0132] Figure 8 One embodiment of inhibition of vascular leakage in rabbits challenged with VEGF after administration of axitinib implants at a dose of 227 μg. For animals with and without implants, vascular leakage scores (0 (normal) to 4 (severe leakage)) were presented over time (months) after VEGF challenge. For animals with implants, effective inhibition of vascular leakage was observed over a 6-month duration. Error bars represent standard deviation (SD; only upper error bars are presented).

[0133] Figure 9 One embodiment of infrared reflectance (IR) imaging of two implants in rabbit eyes. The implants showed degradation over time. From day 27 to day 117, the implants were intact, while narrowing of the implants was observed due to hydrogel degradation observed at days 141 and 195. The remaining axitinib particles merged into a single overall structure at days 141 and 195. Free axitinib particles (white samples) were noted near the previous implant site after hydrogel degradation.

[0134] Figure 10 One embodiment of infrared reflectance (IR) imaging of two implants in rabbit eyes. During the period from 0.5 to 3 months after injection, the implants were intact. After 6 months, the implants narrowed due to hydrogel degradation, and the remaining axitinib particles merged into a single overall structure. From 24 months up to 38 months, free axitinib particles (white samples) were noted near the previous implant site after hydrogel degradation.

[0135] Figure 11 In the absence (Group 1) and presence (Group 2) of co-administration One embodiment of the inhibition of vascular leakage in rabbits challenged with VEGF after administration of two axitinib implants at a total dose of 290 μg. Animals in groups 1 and 2 and animals without implants showed vascular leakage scores (0 (normal) to 4 (severe leakage)) over time (months) after VEGF challenge. Significant inhibition of vascular leakage was observed for all groups of animals with implants. Error bars represent standard deviation.

[0136] Figure 12 One embodiment of fluorescein angiography (FA) images shows significant leakage, with immediate visible leakage of fluorescein actively from the vascular system (upper panel) and complete inhibition of vascular leakage from the rabbit eye including the implant (lower panel) 48 hours after injection of fluorescein in control animals after VEGF challenge. Images were collected 1 month after implant injection, after VEGF challenge.

[0137] Figure 13 For rabbits not treated with implants or anti-VEGF therapeutic agents (white squares and dashed line), rabbits treated only with (black triangles, curve fit up to 3 months), rabbits with implants (black squares, solid line, up to 12 months), and rabbits with implants and (striped squares and dashed line, up to 12 months) of mean vascular leakage scores. For all animals receiving implants, vascular leakage was effectively inhibited for 12 months. Animals treated only with anti-VEGF therapeutic agents showed rapid onset of leakage inhibition within the first 2 to 4 weeks, but leakage recurred after 3 months. Values represent mean and standard error of the mean (SEM).

[0138] Figure 14 One embodiment of in vitro axitinib release from 200 μg implants. (A) As observed by in vitro immediate analysis, after 225 days, axitinib was completely released from the 200 μg implant. (B) As observed by in vitro accelerated analysis, after 12 days, axitinib was completely released from the 200 μg implant. In vitro data do not apply to the in vivo release observed.

[0139] Figure 15 One embodiment of IR images from subject No. 1 in group 2 (2 implants, 400 μg axitinib total per eye). On the injection day, the implants were clearly visible and in good shape. After 9 months, the implants were completely degraded, while undissolved axitinib remained at the previous implant location. The undissolved axitinib continued to release the drug, and little undissolved axitinib remained after 11 months.

[0140] Figure 16An embodiment of a spectral domain optical coherence tomography (SD-OCT) image of the study eye of Subject No. 1 from Group 1 (1 implant, 200 μg axitinib in total per eye). For subjects who had not received this treatment before, a significant reduction in central subfield thickness (CSFT) was observed, while the best corrected visual acuity (BCVA) was not impaired within 10.5 months.

[0141] Figure 17 An embodiment of the central subfield thickness (CSFT) in the study eyes of patients with neovascular age-related macular degeneration (wet AMD) treated with axitinib implants (1 implant, total dose 200 μg: Group 1; 2 implants, total dose 400 μg: Group 2; 3 implants, total dose 600 μg: Group 3a; 2 implants, total dose 400 μg, and concurrent initial anti-VEGF: Group 3b). The average change in CSFT compared to the baseline value and the standard error of the mean (SEM) are presented in this graph. For this graph: Six patients in Group 1 were followed up until month 9. Seven patients in Group 2 were followed up until month 12, five until month 14, and two until month 16. Six patients in Group 3a were followed up until day 14, five until month 2, two until month 4.5, and one until months 6 and 7.5. Two patients in Group 3b were followed up until month 3, and one until month 4.5. Follow-up is ongoing.

[0142] Figure 18 An embodiment of the best corrected visual acuity (BCVA) in the study eyes of patients with neovascular age-related macular degeneration (wet AMD) treated with axitinib implants (1 implant, total dose 200 μg: Group 1; 2 implants, total dose 400 μg: Group 2; 3 implants, total dose 600 μg: Group 3a; 2 implants, total dose 400 μg, and concurrent initial anti-VEGF: Group 3b). The average change in BCVA compared to the baseline value of the Early Treatment Diabetic Retinopathy Study (ETDRS) letter score (representative value of letters that can be accurately read at a certain distance) and the standard error of the mean (SEM) are presented in this graph. For this graph (as for the above Figure 17 ): Six patients in Group 1 were followed up until month 9. Seven patients in Group 2 were followed up until month 12, five until month 14, and two until month 16. Six patients in Group 3a were followed up until day 14, five until month 2, two until month 4.5, and one until months 6 and 7.5. Two patients in Group 3b were followed up until month 3, and one until month 4.5. Follow-up is ongoing.

[0143] Figure 19A and Figure 19B An embodiment of a spectral domain optical coherence tomography (SD-OCT) image of the study eye of Subject No. 1, who had a history of 16 months of aflibercept treatment in the right eye (OD) before injection of the implant in Group 2 (2 implants, 400 μg of axitinib in total per eye). Subretinal fluid was clearly visible at baseline (before treatment). Importantly, after 2 to 3 months following implant injection, the subretinal fluid disappeared and this stage was maintained for more than 15.5 months ( Figure 19B 15.5 months is shown in Figure 19A and earlier visits in ). The best corrected visual acuity (BCVA) was not impaired.

[0144] Figure 20 An embodiment of a spectral domain optical coherence tomography (SD-OCT) image of Subject No. 7 from Group 2 (2 implants, 400 μg of axitinib in total per eye). Subject No. 7, who had received aflibercept for 6 years before the start of the study, showed a significant decrease in CSFT within 9 months after implant injection while the BCVA was not impaired.

[0145] Figure 21 An embodiment of a spectral domain optical coherence tomography (SD-OCT) image of Subject No. 1 from Group 3a (3 implants, 600 μg of axitinib in total per eye). In Subject No. 1 from Group 3a who had not received AMD treatment, a significant decrease in CSFT was observed at 2 months and was maintained for 7.5 months. The BCVA was not impaired.

[0146] Figure 22 An embodiment of a spectral domain optical coherence tomography (SD-OCT) image of Subject No. 1 who had not received anti-VEGF treatment from Group 3b (2 implants, 400 μg of axitinib in total per eye, including co-administered anti-VEGF agent). The CSFT decreased rapidly within 7 days and further decreased and was maintained at a low value until the 3rd month.

[0147] Figure 23 An embodiment of a spectral domain optical coherence tomography (SD-OCT) image of Subject No. 2 who had received 7 months of anti-VEGF treatment before implant injection from Group 3b (2 implants, 400 μg of axitinib in total per eye, including initially co-administered anti-VEGF agent). The CSFT decreased rapidly within 7 days. The low CSFT value was maintained until the 2nd month.

[0148] Figure 24 An embodiment of the aggregation tendency of axitinib when preparing and casting a hydrogel implant according to an embodiment of the present invention using micronized versus non-micronized axitinib under otherwise identical conditions.

[0149] Figure 25A and Figure 25B One embodiment of an injector according to the present invention for injecting an implant into the vitreous humor of a patient. This depicted embodiment of the injector includes a Hamilton syringe body and a Nitinol pusher wire for deploying the implant. Figure 25A The Hamilton syringe body shown inside the injection molded housing. Figure 25B Schematic view showing the components of this embodiment of the injector.

[0150] Figure 26A Exploded view of one embodiment of an injector according to the present invention made of an injection molded body. Figure 26B Photograph showing the fully assembled injector. Figure 26C Exploded view showing the first component of the injector according to the present invention. Figure 26D Exploded view showing the second component of the injector according to the present invention. Figure 26E Showing that the first component and the second component can be aligned. Figure 26F Showing the outer cover of the second component fixed to the body of the first component. Figure 26G Showing the needle guard removed from the outer cover of the second component and the plunger clip removed from the body and plunger of the first component. Figure 26H Showing activation of the plunger of the first component to deploy the implant from the lumen of the needle of the second component.

[0151] Figure 27 Phase 1 study design using an implant containing 200 μg axitinib according to one embodiment of the present invention.

[0152] Figure 28 Proposed Phase 2 study design using an implant containing 600 μg axitinib according to one embodiment of the present invention.

[0153] Define

[0154] As used herein, the term "implant" (sometimes also referred to as "depot") refers to an object that contains an active agent, specifically, tyrosine kinase inhibitors (TKIs) such as axitinib and other compounds as disclosed herein, and is administered into a human or animal body, for example, into the vitreous humor of the eye (also referred to as the "vitreous cavity" or "vitreous"), where it remains for a period of time while releasing the active agent into the surrounding environment. The implant can have any predetermined shape (such as those disclosed herein) before injection, and the shape is maintained to some extent when the implant is placed in the desired location, but after administration, the dimensions of the implant (e.g., length and / or diameter) can change due to hydration as further disclosed herein. In other words, what is injected into the eye is not a solution or suspension, but a shaped coherent mass. Thus, before administration, the implant is fully formed as disclosed herein, and in embodiments of the invention, the implant is not generated in situ at the desired location in the eye (although this may be possible with a suitable formulation in general). Once administered, over time, the implant will biodegrade in the physiological environment (as described below), which can change its shape while reducing its size until it is completely dissolved / absorbed. Herein, the term "implant" is used to refer to the implant in the hydrated (also referred to as "wetted") state when it contains water, for example, after the implant has been administered to the eye or otherwise immersed in an aqueous environment (e.g., in vitro) and hydrated or rehydrated, and to the implant in its / dry (dry / dehydrated) state, i.e., after the implant has been produced and dried and is about to be loaded into a needle, or after being loaded into a needle as disclosed herein, or where the implant has been produced in a dry state without the need for dehydration. Thus, in certain embodiments, the implant in the dry / dry state in the context of the present invention can contain no more than about 1 wt% water. The water content of the implant in the dry / dry state can be measured, for example, by Karl Fischer coulometry. Whenever the dimensions (i.e., length, diameter, or volume) of the hydrated implant are reported herein, these dimensions should be measured after immersing the implant in phosphate buffered saline at 37 °C for 24 hours. Whenever the dimensions of the dry implant are reported herein, these dimensions should be measured after the implant is completely dry (and thus, in certain embodiments, contains no more than about 1 wt% water) and the implant is in the state of being loaded into a needle for subsequent administration. In certain embodiments, the implant is kept in an inert atmosphere glove box containing less than 20 ppm of oxygen and moisture for at least about 7 days. Details of the embodiments for dimension measurement are reported in Example 6.1.

[0155] As used herein, the term "eye" generally refers to the eye, or any part of the eye (e.g., any part of the eye to which an "ophthalmic implant" according to the present invention can in principle be administered) or any eye disease (e.g., in one aspect, the present invention generally refers to the treatment of any eye disease ("ocular disorder") of various origins and natures. In certain embodiments, the present invention relates to the intravitreal injection of an ophthalmic implant (in which case, the "ophthalmic implant" is thus an "intravitreal implant"), and to the treatment of ocular disorders affecting the posterior segment of the eye, as further disclosed below.

[0156] The term "patient" as used herein includes human and animal patients. Thus, the implants according to the present invention are suitable for human or veterinary medical applications. The patients enrolled and treated in the clinical study reported in Example 6 are referred to as "subjects". Generally, a "subject" is an (human or animal) individual to whom an implant according to the present invention has been administered (such as during a clinical study). A "patient" is a subject in need of treatment due to a specific physiological or pathological condition.

[0157] The term "biodegradable" refers to a material or object (such as an ophthalmic implant according to the present invention) that degrades in vivo (i.e., when placed in the human or animal body). In the context of the present invention, as detailed below, an implant comprising a hydrogel in which TKI particles, such as axitinib particles, are dispersed slowly biodegrades over time once deposited in the eye, e.g., in the vitreous humor. In certain embodiments, biodegradation occurs at least in part via ester hydrolysis in the aqueous environment of the vitreous. The implant slowly dissolves until it is completely absorbed and is no longer visible in the vitreous.

[0158] A "hydrogel" is a three-dimensional network of hydrophilic natural or synthetic polymers (as disclosed herein) that can swell in water and retain a certain amount of water while maintaining or substantially maintaining its structure due to, for example, chemical or physical cross-linking of individual polymer chains. Due to its high water content, a hydrogel is soft and elastic, making it very similar to natural tissue. In the present invention, the term "hydrogel" is used to refer to a hydrogel in its hydrated state when it contains water (e.g., after formation of the hydrogel in an aqueous solution, or after the hydrogel has rehydrated once implanted in the eye or other part of the body or otherwise immersed in an aqueous environment), and to a hydrogel in its dry (dried / dehydrated) state when it is dried to a low water content of, for example, not more than 1 wt%. In the present invention, a hydrogel in which an active ingredient is contained (e.g., dispersed) may also be referred to as a "matrix".

[0159] The term "polymer network" describes a structure formed by polymer chains that are crosslinked to each other (having the same or different molecular structures and having the same or different molecular weights). The types of polymers applicable to the purposes of the present invention are disclosed herein. Also as disclosed herein, polymer networks can also be formed by crosslinking agents.

[0160] The term "amorphous" refers to a polymer or polymer network or other chemical substance or entity that does not exhibit a crystalline structure in X-ray or electron scattering experiments.

[0161] The term "semicrystalline" refers to a polymer or polymer network or other chemical substance or entity that has certain crystalline characteristics, i.e., exhibits certain crystalline properties in X-ray or electron scattering experiments.

[0162] The term "crystalline" refers to a polymer or polymer network or other chemical substance or entity that has crystalline characteristics as demonstrated by X-ray or electron scattering experiments.

[0163] The term "precursor" as used herein refers to those molecules or compounds that react with each other and are thus linked via crosslinking to form a polymer network and thus form a hydrogel matrix. Although other substances may be present in the hydrogel, such as active agents or buffers, they are not referred to as "precursors".

[0164] The portion of the precursor molecules that remain in the final polymer network is also referred to herein as "units". Thus, "units" are the building blocks or components of the polymer network that forms the hydrogel. For example, the polymer networks applicable to the present invention may contain the same or different polyethylene glycol units, as further disclosed herein.

[0165] The molecular weight of the polymer precursors as used for the purposes of the present invention and as disclosed herein can be determined by analytical methods known in the art. The molecular weight of polyethylene glycol can be determined, for example, by any method known in the art, including gel electrophoresis, such as SDS-PAGE (sodium dodecyl sulfate-polyacrylamide gel electrophoresis), gel permeation chromatography (GPC), including GPC with dynamic light scattering (DLS), liquid chromatography (LC), and mass spectrometry, such as matrix-assisted laser desorption / ionization-time of flight (MALDI-TOF) mass spectrometry or electrospray ionization (ESI) mass spectrometry. The molecular weight of the polymers, including polyethylene glycol precursors as disclosed herein, is the average molecular weight (based on the molecular weight distribution of the polymer) and can thus be indicated by means of various averages, including weight-average molecular weight (Mw) and number-average molecular weight (Mn). In the case of polyethylene glycol precursors as used in the present invention, the molecular weight indicated herein is the number-average molecular weight (Mn).

[0166] In certain embodiments of the present invention, the term "fiber" (which may be used interchangeably with the term "rod" herein) characterizes an object that generally has an elongated shape (i.e., in this case, the implant according to the present invention). Specific dimensions of the implant of the present invention are disclosed herein. The implant may have a cylindrical or substantially cylindrical shape, or may have a non-cylindrical shape. The cross-section of the fiber or implant may be circular or substantially circular, but in certain embodiments may also be oval or rectangular, or in other embodiments may have different geometries, such as cross-shaped, star-shaped or other shapes as disclosed herein.

[0167] As used herein, the term "release" (and the corresponding terms "released", "releasing", etc.) refers to the provision of an agent such as an API from the implant of the present invention to the surrounding environment. The surrounding environment may be an in vitro or in vivo environment as described herein. In certain specific embodiments, the surrounding environment is the vitreous humor and / or eye tissues, such as the retina and choroid. Thus, whenever it is stated herein that the implant "releases" or "provides a sustained release" of a TKI (such as axitinib), this not only refers to the direct provision of the TKI (such as axitinib) from the implant while the hydrogel has not (fully) biodegraded, but also refers to the continued provision of the TKI (such as axitinib) to the surrounding environment and the continued exertion of its therapeutic effect over a longer period of time when there is still residual TKI (e.g., in an aggregated form as further disclosed herein) present in the surrounding environment after the hydrogel has completely degraded. Thus, even after the implant / hydrogel has completely biodegraded as further disclosed herein, the "treatment period" (i.e., the period to achieve a certain therapeutic effect as described herein) can still be extended for a period of time.

[0168] For the purposes of the present invention, the term "sustained release" is defined as referring to a product (in the case of the present invention, the product is an implant) that is formulated to make a drug available over a longer period of time, thereby reducing the dosing frequency compared to an immediate release dosage form (such as a solution of an active ingredient injected into the eye). Other terms that may be used interchangeably with "sustained release" herein are "extended release" or "controlled release". Thus, "sustained release" characterizes the release of the API, specifically a TKI such as axitinib, contained in the implant according to the present invention. The term "sustained release" itself is not related to or limited to a specific rate of release (in vitro or in vivo), but in certain embodiments of the present invention, the implant may be characterized by a certain average release rate (in vitro or in vivo) or a certain release profile as disclosed herein. Since the implant of the present invention (whether explicitly referred to herein as a "sustained release" implant or simply as an "implant") provides a sustained release of the API, the implant of the present invention may also be referred to as a "depot".

[0169] Whenever it is stated herein that an administration or injection is carried out "concurrently" or "simultaneously" or "at the same time" with the administration or injection of an implant according to the invention, this means that the separate injections of two or more implants or the injection of one or more implants and the injection of a suspension or solution of, for example, an anti-VEGF agent as disclosed herein are carried out, usually one immediately after the other, i.e., without any significant delay. For example, if a total dose of about 400 μg axitinib is administered to an eye and this total dose is contained in two implants according to the invention, each implant containing about 200 μg axitinib, then usually within the same treatment course these two implants are injected into the vitreous cavity one immediately after the other, of course observing all precautions to ensure safe and accurate injection at the desired site without any unnecessary delay. The same applies to the administration of one or more implants according to the invention concurrently / simultaneously / at the same time with the administration of another anti-VEGF agent as described herein. If another anti-VEGF drug is administered by intravitreal injection of a suspension or solution containing the anti-VEGF drug, it is also usually intended to carry out this injection immediately before or after the intravitreal injection of one or more implants according to the invention, i.e., ideally during one treatment course (as described above).

[0170] However, in certain cases, for example if complications are encountered during the administration of the first implant and / or the physician performing the injection concludes that it is advisable not to perform a second injection on the same day or within a few days thereafter within the same treatment course, then the second implant can also be administered, for example, one or two weeks after the first implant. Since, as will be disclosed in more detail herein, the implant can persist in the vitreous of the human eye for a relatively long period, such as about 9 to about 12 months, in the context of the present invention, the administration of two implants, for example, one or two weeks apart, is still considered "simultaneous". Similar considerations also apply to the "concurrent" administration of an implant according to the invention and an anti-VEGF agent. Thus, an anti-VEGF agent can be administered concurrently with the intravitreal administration of an implant of the invention, i.e., at the same time or approximately at the same time as described herein.

[0171] However, in certain other embodiments, the anti-VEGF agent can also be administered in combination with the intravitreal implant of the invention such that the anti-VEGF agent is administered subsequently, such as 1 month or 2 months or 3 months after the intravitreal injection of an implant according to the invention.

[0172] The term "rescue medication" generally refers to a medication that can be administered to a patient under predefined conditions (e.g., during a study, if the patient does not respond adequately to the study treatment), or a medication for managing an emergency. The conditions for administering the rescue medication in the clinical study disclosed in Example 6 of the present application are indicated under the subheading "Rescue Medication" in the description of Example 6 (for the percentage of rescue medication administration, see specifically Table 27). In certain embodiments of the present invention, the "rescue medication" refers to a dose of an anti-VEGF agent as disclosed herein, administered in the form of a solution or suspension of an intravitreal injection of an anti-VEGF agent. In certain specific embodiments, the rescue medication is a dose (2 mg) of aflibercept administered by intravitreal injection.

[0173] As used herein, the term "about" in relation to a measured quantity refers to the normal variation of the measured quantity, as would be expected by a person of ordinary skill in the art when making the measurement and performing a level of care commensurate with the precision of the measurement objective and the measuring device.

[0174] The term "at least about" in relation to a measured quantity refers to the normal variation of the measured quantity, as would be expected by a person of ordinary skill in the art when making the measurement and performing a level of care commensurate with the precision of the measurement objective and the measuring device, and any quantity above the said quantity.

[0175] As used herein, the term "average" refers to the 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 its number (i.e., the average of a set of data).

[0176] Unless the context clearly indicates otherwise, as used herein, the singular forms "a", "an", and "the" include plural references.

[0177] As used herein, the term "and / or" in phrases such as "A and / or B" is intended to include both "A and B" and "A or B".

[0178] As used herein, open terms such as "include", "including", "contain", "containing" and the like are intended to refer to an open list or enumeration of elements, method steps or the like, and thus are not intended to be limited to the recited elements, method steps or the like, and also include other unrecited elements, method steps or the like.

[0179] The term "at most" when used herein with a certain value or number means including the respective value or number.

[0180] The terms "from A to B", "from A to B's", and "A to B's" are used interchangeably herein and all refer to the range from A to B, including the upper and lower limits A and B.

[0181] The terms "API", "active (pharmaceutical) ingredient", "active (pharmaceutical) agent", "active (pharmaceutical) ingredient", "(active) therapeutic agent", "active agent", and "drug" are used interchangeably herein and refer to substances for use in a final pharmaceutical product (FPP) and substances for the preparation of said final pharmaceutical product that are intended to provide pharmacological activity or have a direct effect on the diagnosis, cure, mitigation, treatment, or prevention of disease, or have a direct effect on the restoration, correction, or modification of a patient's physiological functions.

[0182] In certain embodiments, the TKI used according to the present invention is axitinib. Axitinib is the (Pfizer, NY) active ingredient in. It is a small molecule (386.47 Dalton) synthetic tyrosine kinase inhibitor. The main mechanism of action is to inhibit angiogenesis (the formation of new blood vessels) by inhibiting receptor tyrosine kinases, which are mainly: VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-β, and c-Kit (Keating. Axitinib: a review in advanced renal cell carcinoma. 2015, Drugs, 75(16):1903-13; Kernt et al., Inhibitory activity of ranibizumab, sorafenib, and pazopanib on light-induced overexpression of platelet-derived growth factor and vascular endothelial growth factor A and the vascular endothelial growth factor receptors 1 and 2 and neuropilin 1 and 2. 2012, Retina, 32(8):1652-63), which are involved in pathological angiogenesis, tumor growth, and cancer progression. Thus, axitinib is a multi-target inhibitor that inhibits the VEGF and PDGF pathways.

[0183] The molecular formula of axitinib is C 22 H 18N4OS, and its IUPAC name is N-methyl-2-[3-((E)-2-pyridin-2-yl-vinyl)-1H-indazole-6-ylthio]-benzamide. It has the following chemical structure:

[0184]

[0185] Axitinib has been determined to have low solubility in a biologically relevant medium (PBS, pH 7.2 at 37 °C), approximately 0.4 to 0.5 μg / mL. Its partition coefficient (n-octanol / water) is 4.2 (logP; see DrugBank entry "Axitinib").

[0186] For the purposes of the present invention, all possible forms of the active agent (including axitinib) can be used, including any polymorphs of the active agent or any pharmaceutically acceptable salts, anhydrates, hydrates, other solvates or derivatives of the active agent. Whenever the name of the active agent is, for example, "axitinib" in this specification or in the claims, it also refers to any of the said polymorphs, pharmaceutically acceptable salts, anhydrates, solvates (including hydrates) or derivatives of the active agent, even if not explicitly stated.

[0187] As used herein, the term "polymorph" refers to any crystalline form of an active agent such as axitinib. Generally, an active agent that is a solid at room temperature exists in a number of different crystalline forms, i.e., polymorphs, with one polymorph being thermodynamically most stable at a given temperature and pressure.

[0188] Regarding axitinib, suitable solid forms and polymorphs of axitinib, including anhydrous forms and solvates, are described, for example, in A.M. Campeta et al., Journal of Pharmaceutical Sciences, Vol. 99, No. 9, September 2010, pp. 3874 - 3886. All axitinib polymorphs (anhydrous forms or solvates) can be used to prepare implants according to certain embodiments of the present invention, including the thermodynamically most stable polymorph of axitinib, such as that designated XLI in US 8,791,140 B2. XLI is the anhydrous crystalline form of axitinib. In certain embodiments of the present invention, the axitinib used to prepare the implants according to the present invention is the anhydrous crystalline form XLI. In certain other embodiments, the crystalline anhydrous forms of axitinib suitable for the present invention include (but are not limited to) polymorphs I, IV, VI, and XXV. In addition to the anhydrous forms, there are also many solvates of axitinib with various solvents, as also described in the cited art, which can all be used to prepare the implants according to the present invention. All of the above forms are well characterized and are described in the art, such as in the paper by Campeta et al. cited above or in patent literature (including but not limited to US 8,791,140 B2, US 2006 / 0094763, and WO2016 / 178150 A1). Any polymorphic form of axitinib known and disclosed in the art, specifically (but not limited to) in the references cited herein, can be used in the present invention.

[0189] In certain specific embodiments, axitinib used to prepare the implants according to the present invention and / or present in the implants according to the present invention is characterized by an XRD pattern comprising at least five characteristic 2θ peaks selected from the following: 8.3, 9.3, 13.7, 15.6, 16.1, 16.5, 17.6, 18.6, 21.0, 22.6, 23.1, 23.4, 24.1, and 26.0, each value ±0.2 2θ°. Specifically, axitinib used to prepare the implants according to the present invention and / or present in the implants according to the present invention is characterized by an XRD pattern comprising at least five characteristic 2θ peaks selected from 8.3, 9.3, 15.6, 16.5, 17.6, 21.0, 24.1, and 26.0 (each value ±0.2 2θ°), and / or by a 13C NMR in DMSO solvent having chemical shifts of 26.1, 114.7, 154.8, and 167.8 (each displacement ±0.2 ppm), and / or by a 13C NMR having chemical shifts of 171.1, 153.2, 142.6, 139.5, 131.2, 128.1, and 126.3 (each displacement ±0.2 ppm) 13 13C NMR, and / or by a 13C NMR having chemical shifts of 171.1, 153.2, 142.6, 139.5, 131.2, 128.1, and 126.3 (each displacement ±0.2 ppm) 13Characterized by solid-state NMR of C and / or by a DSC isotherm comprising two endothermic peaks ranging between 213 °C and 217 °C (peak 1) and between 219 °C and 224 °C (peak 2). In a particular embodiment, the non-solvated crystalline form SAB-I of axitinib disclosed in WO2016 / 178150 can be used to prepare the implant according to the present invention.

[0190] Axitinib inhibits VEGF signaling and also inhibits PDGF signaling. In addition to inhibiting VEGF / PDGF, it also inhibits c-kit, a survival factor for blood vessel development, and the elimination half-life (t 1 / 2 ) is several hours (Rugo et al., Phase I trial of the oral antiangiogenesis agent AG-013736 in patients with advanced solid tumors. 2005, J Clin Oncol., 23(24):5474-83), while the t 1 / 2 of ranibizumab and aflibercept in the human eye is several days each. The longer t 1 / 2 of these macromolecular antibodies enables them to maintain effective tissue concentrations for several weeks, while small molecules are cleared more rapidly. However, due to the low solubility of axitinib and its inclusion in the hydrogel implant of the present invention that remains in the vitreous humor (VH) for a long period of time, such as several months, a therapeutically effective amount of axitinib is delivered during the period that the implant persists in the VH. Thus, intravitreal sustained delivery of axitinib provides a multi-target inhibitor that, in principle, does not require combination therapy and also does not require frequent intravitreal injections to inhibit the VEGF and PDGF pathways.

[0191] As used herein, the term "therapeutically effective" refers to the amount of a drug or active agent required to produce a desired therapeutic result after administration. For example, in the context of the present invention, a desired therapeutic result would be to reduce the central subfield thickness (CSFT) by optical coherence tomography in patients with neovascular AMD, as the CSFT of patients with neovascular AMD is elevated. In the context of the present invention, a "therapeutically effective" amount of an active agent can also be a multiple of the IC 50 provided by the active agent for a specific substrate, such as 50-fold or more of the IC 50 . For example, the IC 50 values of the TKI axitinib for angiogenesis-related RTKs are listed in Table 12.

[0192] When used herein, the abbreviation "PBS" means phosphate buffered saline.

[0193] As used herein, the abbreviation "PEG" means polyethylene glycol. Detailed Description

[0194] I. Implant

[0195] Active ingredient:

[0196] One aspect of the invention is a sustained-release biodegradable ophthalmic implant comprising a hydrogel and at least about 150 μg of a tyrosine kinase inhibitor (TKI), wherein the TKI particles are dispersed within the hydrogel. In one embodiment, the invention provides a sustained-release biodegradable ophthalmic implant comprising a hydrogel and at least about 150 μg of a tyrosine kinase inhibitor (TKI), wherein the TKI particles are dispersed within the hydrogel, and wherein the implant has a length in its dry state of less than about 17 mm.

[0197] The active ingredient contained in the implant of this aspect of the invention is a TKI. Examples of suitable TKIs are axitinib, sorafenib, sunitinib, nintedanib, pazopanib, regorafenib, cabozantinib, and vandetanib. In a particular embodiment, the TKI used in this and other aspects of the invention is axitinib. Details regarding axitinib, its chemical structure, polymorphs, solvates, salts, etc., and its properties such as solubility are provided in the definition section above.

[0198] All features disclosed herein (individually or any combination of features) regarding the implant according to the invention can be used to describe the features of the sustained-release biodegradable ophthalmic implant comprising a hydrogel and at least about 150 μg of a tyrosine kinase inhibitor (TKI), wherein the TKI particles are dispersed within the hydrogel, and wherein the implant has a length in its dry state of less than about 17 mm.

[0199] In a particular embodiment, the implant of the invention is a intravitreal implant, i.e., administered to the vitreous humor (also referred to herein as "intravitreal administration").

[0200] TKIs (such as axitinib) are included in the implants of the present invention in a dosage range of at least 150 μg as disclosed herein, such as from about 150 μg to about 1800 μg, from about 150 μg to about 1200 μg, or from about 200 μg to about 800 μg. Any TKI (such as axitinib) in amounts within these ranges can be used, such as about 150 μg, about 200 μg, about 300 μg, about 400 μg, about 500 μg, about 600 μg, about 700 μg, about 800 μg, about 900 μg, about 1000 μg, about 1100 μg, or about 1200 μg. In alternative embodiments, the dosage of the TKI (such as axitinib) contained in the implants of the present invention can also be as high as about 1800 μg, such as about 1300 μg, about 1400 μg, about 1500 μg, about 1600 μg, about 1700 μg, or about 1800 μg. In other alternative embodiments, the dosage of the TKI (such as axitinib) contained in the implants of the present invention can even be higher than about 1800 μg or higher than about 2000 μg, such as up to about 3000 μg, up to about 6000 μg or up to about 10000 μg. All values mentioned also include a variance of +25% and -20%, or a variance of + / -10%.

[0201] In certain specific embodiments, the dosage of axitinib contained in the implants of the present invention is:

[0202] - in the range of about 160 μg to about 250 μg, or about 180 μg to about 220 μg, or about 200 μg (i.e., including a variance of +25% and -20% of 200 μg, or a variance of + / -10%)

[0203] - in the range of about 320 μg to about 500 μg, or about 360 μg to about 440 μg, or about 400 μg (i.e., including a variance of +25% and -20% of 400 μg, or a variance of + / -10%)

[0204] - in the range of about 375 μg to about 600 μg, or about 450 μg to about 550 μg, or about 500 μg (i.e., including a variance of +25% and -20% of 500 μg, or a variance of + / -10%)

[0205] - in the range of about 480 μg to about 750 μg, or about 540 μg to about 660 μg, or about 600 μg (i.e., including a variance of +25% and -20% of 600 μg, or a variance of + / -10%)

[0206] - in the range of about 640 μg to about 1000 μg, or about 720 μg to about 880 μg, or about 800 μg (i.e., including the variance of +25% and -20% of 800 μg, or a variance of + / -10%)

[0207] - in the range of about 800 μg to about 1250 μg, or about 900 μg to about 1100 μg, or about 1000 μg (i.e., including the variance of +25% and -20% of 1000 μg, or a variance of + / -10%)

[0208] - in the range of about 960 μg to about 1500 μg, or about 1080 μg to about 1320 μg, or about 1200 μg (i.e., including the variance of +25% and -20% of 1200 μg, or a variance of + / -10%)

[0209] - in the range of about 1440 μg to about 2250 μg, or about 1620 μg to about 1980 μg, or about 1800 μg (i.e., including the variance of +25% and -20% of 1800 μg, or a variance of + / -10%).

[0210] In a preferred embodiment, the dose of axitinib contained in an implant of the present invention is about 480 μg to about 750 μg, or about 540 μg to about 660 μg, or in a particular embodiment, about 600 μg.

[0211] The disclosed amount of the TKI (such as axitinib), including the mentioned variance, refers to both the final content of the active ingredient in the implant and the amount of the active ingredient used as the starting component for each implant during the manufacture of the implant.

[0212] As will be disclosed in more detail hereinafter and will be apparent from the Examples section, in certain embodiments of the present invention, the total dose of a TKI (such as axitinib) administered to a patient can be contained in two, three or more implants administered simultaneously. For example, a dose of about 400 μg of a TKI (such as axitinib) can be administered with one implant containing about 400 μg of axitinib, or with two implants each containing, for example, about 200 μg of axitinib, and so on. Of course, not only can two or more identical implants (or implants containing the same dose) be combined, but also two or more different implants (or implants containing different doses) can be combined to achieve the desired total dose. In a particular embodiment, a total axitinib dose of about 480 μg to about 750 μg, or about 540 μg to about 660 μg, or about 600 μg is contained in one implant, and only one such implant is administered to a patient in need of the treatment according to the present invention. In another embodiment, a total dose above about 600 μg, such as about 800 μg to about 1250 μg, or about 900 μg to about 1100 μg, or about 1000 μg, or a total dose of about 960 μg to about 1500 μg, or about 1080 μg to about 1320 μg, or about 1200 μg, or a total dose of about 1440 μg to about 2250 μg, or about 1620 μg to about 1980 μg, or about 1800 μg is contained in one implant, and only one such implant is administered to a patient in need of the treatment according to the present invention. In other embodiments, the total dose administered to a patient according to the present invention can be contained in two or more implants administered simultaneously (containing the same or different amounts of API).

[0213] The TKI (such as axitinib) is contained in the implant of the present invention and is dispersed or distributed in a hydrogel composed of a polymer network. In certain embodiments, the particles are homogeneously or substantially homogeneously dispersed in the hydrogel. The hydrogel can prevent particle aggregation and can provide a matrix for the particles that holds them in the desired position in the eye while slowly releasing the drug.

[0214] In certain embodiments of the present invention, the TKI particles (such as axitinib particles) can be microencapsulated. The term "microcapsule" (also referred to as "microparticle") is sometimes defined as a generally spherical particle having a size that varies, for example, between about 50 nm and about 2 mm. A microcapsule has at least one discrete domain (or core) of an active agent encapsulated in a surrounding material (sometimes also referred to as a shell). For the purposes of the present invention, a suitable agent for microencapsulating a TKI (such as axitinib) (without limiting the present disclosure thereto) is poly(lactic-co-glycolic acid).

[0215] In other embodiments, the TKI particles (such as axitinib particles) are not microencapsulated and are thus dispersed as such in the hydrogel and thus in the implant of the present invention, i.e., they are not mixed with or adjacent to or microencapsulated by another material such as (but not limited to) poly(lactic-co-glycolic acid).

[0216] In one embodiment, the TKI particles (such as axitinib particles) may be micronized particles. In another embodiment, the TKI particles (such as axitinib particles) may not be micronized. Micronization is a process of reducing the average diameter of particles of a solid material. Particles with reduced diameter may in particular have a higher dissolution and erosion rate, which increases the bioavailability of the active pharmaceutical ingredient and may have a positive impact on the release kinetics in certain embodiments. In addition, micronized particles may have a reduced tendency to aggregate during manufacturing operations (see also Figure 24)。In the field of composite materials, it is known that particle size affects mechanical properties when combined with a matrix, and for a given mass fraction, smaller particles can provide excellent reinforcement. Thus, a hydrogel matrix filled with micronized TKI particles can have improved mechanical properties (e.g., brittleness, breaking strain, etc.) compared to larger TKI particles of a similar mass fraction. Such properties are important during the manufacture, implantation, and degradation of implants. Micronization can also promote a more homogeneous distribution of the active ingredient in the selected dosage form or matrix. Particle size distribution can be measured by methods known in the art, including sieving, laser diffraction, or dynamic light scattering. In certain embodiments of the present invention, as determined by laser diffraction, the TKI (such as axitinib) particles used in preparing the implants of the present invention can have a d90 of less than about 100 μm and / or a d50 of less than about 50 μm, or a d90 of less than about 75 μm and / or a d50 of less than about 20 μm. In a specific embodiment, as determined by laser diffraction, the d90 of the TKI (such as axitinib) can be less than about 30 μm, less than about 20 μm. In highly specific embodiments, as determined by laser diffraction, the d90 of the TKI (such as axitinib) is less than about 10 μm. In these or other embodiments, as determined by laser diffraction, the d50 of the TKI (such as axitinib) particles used in preparing the implants of the present invention can be less than about 5 μm. In these or other embodiments, as determined by laser diffraction, the d10 of the TKI (such as axitinib) particles used in the present invention can be less than about 3 μm. In certain embodiments, as determined by laser diffraction, the d100 of the TKI (such as axitinib) particles used in preparing the implants of the present invention can be less than about 20 μm. The "d90" (also referred to herein as "D90") value means that the particle size of 90 volume% of all particles within the measured bulk material (having a certain particle size distribution) is below the indicated value. For example, a d90 particle size of less than about 10 μm means that the particle size of 90 volume% of the particles in the measured bulk material is below about 10 μm. Corresponding definitions apply to other "d" values, such as the "d10", "d50", or "d100" values (also referred to herein as "D10", "D50", and "D100" values, respectively). In certain other embodiments, TKI (such as axitinib) particles with diameters exceeding this specification can also be used.

[0217] Micronized TKI (such as axitinib) particles can be purchased from a supplier according to specifications or can be prepared, for example, according to the following illustrative procedure (disclosed in WO 2016 / 183296 A1, Example 13): Measure 1800 mL of sterile water for injection (WFI) into a 2 L beaker and place it on a magnetic stirrer plate with a stir bar stirring at 600 RPM to create a large WFI vortex in the center of the beaker. Place a 60 mL BD syringe containing axitinib in ethanol on an infusion pump, which is clamped above the WFI beaker. A subcutaneous needle (21G, BD) is attached to the syringe and directed directly at the center of the vortex to disperse the axitinib solution. The infusion pump is then operated at 7.5 mL / min to add the axitinib solution dropwise to the WFI to precipitate micronized axitinib. After micronization, the axitinib is filtered, for example, through a 0.2 μm vacuum filter and rinsed with WFI. After filtration, the axitinib powder is collected from the filter, for example, using a spatula, and vacuum dried for an extended period, such as about 12 or about 24 hours, to remove excess solvent. Another illustrative method of micronizing axitinib is disclosed in Example 9 of WO 2017 / 091749. The described micronization method is not limiting, and other methods of micronizing an active agent (such as axitinib) can be used equally. The disclosed micronization method (or other methods) can also be used for other active agents other than axitinib.

[0218] Another aspect of the present invention is a sustained release biodegradable ocular implant comprising a hydrogel and at least about 150 μg of a tyrosine kinase inhibitor (TKI), wherein the TKI particles are dispersed within the hydrogel and wherein the total weight of the implant in its dry state is from about 0.2 mg to about 1.5 mg. In certain embodiments, the TKI is axitinib or another TKI as disclosed herein.

[0219] In certain embodiments, the total weight (also referred to herein as the "total mass") of the implant according to the present invention in its dry state can be from about 400 μg to about 1.2 mg. In certain specific embodiments, the total weight of the implant according to the present invention in its dry state can be from about 0.3 mg to about 0.6 mg, such as from about 0.4 mg to about 0.5 mg, or can be from about 0.8 mg to about 1.1 mg, such as from about 0.9 mg to about 1.0 mg.

[0220] All features disclosed herein regarding the implant according to the present invention (individually or any combination of features) can be used to describe the features of the sustained release biodegradable ocular implant comprising a hydrogel and at least about 150 μg of a tyrosine kinase inhibitor (TKI), wherein the TKI particles are dispersed within the hydrogel and wherein the total weight of the implant in its dry state is from about 0.2 mg to about 1.5 mg.

[0221] Polymer network:

[0222] In certain embodiments, the hydrogel can be formed from precursors having functional groups that form crosslinks to produce a polymer network. These crosslinks between polymer strands or arms can be chemical in nature (i.e., can be covalent bonds) and / or physical (such as ionic bonds, hydrophobic associations, hydrogen bridges, etc.).

[0223] The polymer network can be prepared from precursors, from one type of precursor or from two or more types of precursors that allow for reaction. The precursors are selected considering the desired properties of the resulting hydrogel. There are various suitable precursors for preparing hydrogels. Generally, any pharmaceutically acceptable and crosslinkable polymer that forms a hydrogel can be used for the purposes of the present invention. The hydrogel and thus the components incorporated therein, including the polymer used to prepare the polymer network, should be physiologically safe so that they do not cause, for example, an immune response or other adverse reactions. The hydrogel can be formed from natural, synthetic, or biosynthetic polymers.

[0224] Natural polymers can include glycosaminoglycans, polysaccharides (e.g., dextran), polyamino acids, and proteins or mixtures or combinations thereof.

[0225] Synthetic polymers generally can be any polymers synthesized from a variety of starting materials 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 can be initiated by certain initiators, light, and / or heat and can be catalyzed by enzymes.

[0226] Generally, for the purposes of the present invention, one or more synthetic polymers can be used that contain one or more units from the group consisting of polyalkylene glycols such as polyethylene glycol (PEG), polypropylene glycol, poly(ethylene glycol)-block-poly(propylene glycol) copolymers, or polyethylene oxide, polypropylene oxide, polyvinyl alcohol, poly(vinyl pyrrolidone), polylactic acid, poly(lactic acid-co-glycolic acid), random or block copolymers or combinations or mixtures of any of the foregoing, but this list is not intended to be limiting.

[0227] To form a covalently crosslinked polymer network, the precursors can be covalently crosslinked to each other. In certain embodiments, precursors having at least two reactive centers (e.g., in free radical polymerization) can be used as crosslinking agents since each reactive group can participate in forming different growing polymer chains.

[0228] The precursors can have a bioinert and hydrophilic moiety, such as a core. In the case of a branched polymer, the core refers to the continuous portion of the molecule to which the arms extending from the core are attached, where the arms carry functional groups, which are typically at the ends of the arms or branches. Multi-arm PEG precursors are examples of such precursors and are further disclosed below.

[0229] Thus, the hydrogels for use in the present invention can be prepared, for example, from one multi-arm precursor having a first (set of) functional groups and another multi-arm precursor having a second (set of) functional groups. For example, the multi-arm precursor can have hydrophilic arms capped with primary amines (nucleophiles), such as polyethylene glycol units, or can have activated ester end groups (electrophiles). The polymer network according to the present invention can contain the same or different polymer units crosslinked to each other.

[0230] Certain functional groups can be made more reactive by using activating groups. The activating groups include (but are not limited to) carbonyldiimidazole, sulfonyl chloride, aryl halides, sulfosuccinimidyl esters, N-hydroxysuccinimidyl esters, succinimidyl esters, epoxides, aldehydes, maleimides, imidoesters, acrylates, etc. N-hydroxysuccinimide esters (NHS) are useful groups for crosslinking nucleophilic polymers, such as primary amine-capped or thiol-capped polyethylene glycols. The NHS-amine crosslinking reaction can be carried out in aqueous solution and in the presence of a buffer, such as phosphate buffer (pH 5.0 - 7.5), triethanolamine buffer (pH 7.5 - 9.0), borate buffer (pH 9.0 - 12), or sodium bicarbonate buffer (pH 9.0 - 10.0).

[0231] In certain embodiments, each precursor can contain only nucleophilic or electrophilic functional groups, provided that both nucleophilic and electrophilic precursors are used in the crosslinking reaction. Thus, for example, if the crosslinker has only nucleophilic functional groups, such as amines, the precursor polymer can have electrophilic functional groups, such as N-hydroxysuccinimide. On the other hand, if the crosslinker has electrophilic functional groups, such as sulfosuccinimide, the functional polymer can have nucleophilic functional groups, such as amines or thiols. Thus, functional polymers, such as proteins, poly(allylamine), or amine-capped di- or poly-functional poly(ethylene glycol), can also be used to prepare the polymer network of the present invention.

[0232] In one embodiment, each of the first reactive precursors has from about 2 to about 16 nucleophilic functional groups (referred to as functionality), and each of the second reactive precursors that is allowed to react with the first reactive precursors to form the polymer network has from about 2 to about 16 electrophilic functional groups. The number of reactive (nucleophilic or electrophilic) groups is a multiple of 4, and thus reactive precursors having, for example, 4, 8, and 16 reactive groups are particularly suitable for the present invention. Any number of functional groups, such as any one of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 groups, is possible for the precursors used according to the present invention, while ensuring that the functionality is sufficient to form a sufficiently crosslinked network structure.

[0233] PEG hydrogels:

[0234] In certain embodiments of the present invention, the polymer network forming the hydrogel contains polyethylene glycol (PEG) units. It is known in the art that PEG forms hydrogels upon crosslinking, and these PEG hydrogels are suitable for drug applications, such as as a matrix for drugs intended to be administered to all parts of the human or animal body.

[0235] The polymer network of the hydrogel implant of the present invention may comprise one or more multi-arm PEG units having 2 to 10 arms, or 4 to 8 arms, or 4, 5, 6, 7 or 8 arms. The PEG units may have different or the same number of arms. In certain embodiments, the PEG units used in the hydrogels of the present invention have 4 and / or 8 arms. In certain specific embodiments, a combination of 4-arm and 8-arm PEG units is used.

[0236] The number of arms of the PEG used helps to control the flexibility or softness of the resulting hydrogel. For example, a hydrogel formed by crosslinking 4-arm PEG is generally softer and more flexible than a hydrogel formed from 8-arm PEG of the same molecular weight. Specifically, if stretching of the hydrogel before or after drying, as disclosed below in the section related to the manufacture of the implant, is desired, a more flexible hydrogel, such as 4-arm PEG, optionally in combination with another multi-arm PEG, such as the 8-arm PEG disclosed above, can be used.

[0237] In certain embodiments of the present invention, the average molecular weight of the polyethylene glycol units used as precursors is in the range of about 2,000 to about 100,000 daltons, or in the range of about 10,000 to about 60,000 daltons, or in the range of about 15,000 to about 50,000 daltons. In certain specific embodiments, the average molecular weight of the polyethylene glycol units is in the range of about 10,000 to about 40,000 daltons, or is about 20,000 daltons. PEG precursors having the same average molecular weight can be used, or PEG precursors having different average molecular weights can be combined with each other. The average molecular weight of the PEG precursors used in the present invention is given as the number average molecular weight (Mn), which can be determined by MALDI in certain embodiments.

[0238] In a 4-arm PEG, the average arm length (or molecular weight) of each arm can be the total molecular weight of the PEG divided by 4. Thus, the 4a20kPEG precursor, which is a precursor that can be used in the present invention, has 4 arms, and the average molecular weight of each arm is about 5,000 Daltons. Thus, in addition to the 4a20kPEG precursor in the present invention, the 8a20k PEG precursor that can also be used has 8 arms, and the average molecular weight of each arm is 2,500 Daltons. Longer arms can provide increased flexibility compared to shorter arms. PEGs with longer arms may swell more compared to PEGs with shorter arms. PEGs with lower arm numbers may also swell more and be more flexible compared to PEGs with higher arm numbers. In certain specific embodiments, combinations of PEG precursors with different arm numbers can be used in the present invention, such as a combination of a 4-arm PEG precursor and an 8-arm precursor. Additionally, longer PEG arms have a higher melting temperature when dry, which can provide greater dimensional stability during storage. For example, an 8-arm PEG with a molecular weight of 15,000 Daltons crosslinked with tri-lysine may not be able to maintain a stretched configuration at room temperature, while a 4-arm 20,000 Dalton PEG crosslinked with an 8-arm 20,000 Dalton PEG may be dimensionally stable in a stretched configuration at room temperature.

[0239] When referring to a PEG precursor having a certain average molecular weight (such as a 15kPEG precursor or a 20kPEG precursor), the indicated average molecular weight (i.e., Mn of 15,000 or 20,000 respectively) refers to the PEG portion of the precursor before the addition of the end group (here, "20k" 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 portion of the precursor is determined by MALDI. The degree of end-group substitution as disclosed herein can be determined by 1 1H-NMR after end-group functionalization.

[0240] In certain embodiments, the electrophilic end groups used for the PEG precursors for preparing the hydrogels of the present invention are N-hydroxysuccinimide (NHS) esters, including but not limited to: "SAZ", which refers to the azelaic acid succinimide ester end group; "SAP", which refers to the adipic acid succinimide ester end group; "SG", which refers to the glutaric acid succinimide ester end group; and "SS", which refers to the succinic acid succinimide ester end group.

[0241] In certain embodiments, the nucleophilic end groups used for the 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.

[0242] In certain preferred embodiments, a 4-arm PEG having an average molecular weight of about 20,000 Daltons and having an electrophilic end group as disclosed above and an 8-arm PEG having an average molecular weight of also about 20,000 Daltons and having a nucleophilic end group as disclosed above are crosslinked to form a polymer network, and thus a hydrogel according to the present invention is formed.

[0243] The reaction of PEG units containing nucleophilic groups and PEG units containing electrophilic groups (such as PEG units with amine end groups and PEG units with activated ester groups) results in multiple PEG units crosslinked by hydrolyzable linkers having the following formula: where m is an integer from 0 to 10, and specifically 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In one particular embodiment, m is 6, such as in the case of using PEG with SAZ end groups. For SAP end groups, m will be 3, for SG end groups, m will be 2, and for SS end groups, m will be 1. All crosslinks within the polymer network can be the same or can be different.

[0244] In certain preferred embodiments, SAZ end groups are used in the present invention. This end group can increase the duration in the eye, and implants of certain embodiments of the present invention comprising hydrogels containing PEG-SAZ units biodegrade in the eye, such as in the vitreous humor of the human eye, only after a longer period of time (e.g., 9 to 12 months as further disclosed below), and in some cases can persist even longer. The SAZ group is more hydrophobic than, for example, SAP, SG, or SS end groups because of the greater number of carbon atoms in the chain (m is 6, and the total number of carbon atoms between the amide group and the ester group is 7).

[0245] In certain preferred embodiments, a 4-arm 20,000 Dalton PEG precursor is combined with an 8-arm 20,000 Dalton PEG precursor, such as a 4-arm 20,000 Dalton PEG precursor having a SAZ group (as defined above) combined with an 8-arm 20,000 Dalton PEG precursor having an amine group (as defined above). These precursors are also abbreviated herein as 4a20kPEG-SAZ and 8a20kPEG-NH2, respectively. The chemical structure of 4a20kPEG-SAZ is:

[0246]

[0247] where R represents a neopentyl glycol core structure. The chemical structure of 8a20kPEG-NH2 (having a hexaglycerol core) is:

[0248]

[0249] In the above formula, n is determined by the molecular weight of each individual PEG arm.

[0250] In certain embodiments, the molar ratio of the nucleophilic end group and the electrophilic end group reacting with each other is about 1:1, that is, each SAZ group provides one amino group. In the case of 4a20kPEG-SAZ and 8a20kPEG-NH2, this results in a weight ratio of about 2:1 because the amount of end groups contained in the 8-arm PEG is twice that of the 4-arm PEG. However, an excess of the electrophilic (e.g., NHS end group, such as SAZ) end group or the nucleophilic (e.g., amine) end group can be used. Specifically, an excess of the nucleophile, such as a precursor containing an amine end group, can be used, that is, the weight ratio of 4a20kPEG-SAZ and 8a20kPEG-NH2 can also be less than 2:1.

[0251] Each and any combination of the PEG precursors containing electrophilic groups and nucleophilic groups disclosed herein can be used to prepare the implants according to the present invention. For example, any 4-arm or 8-arm PEG-NHS precursor (e.g., having SAZ, SAP, SG or SS end groups) can be combined with any 4-arm or 8-arm PEG-NH2 precursor (or any other PEG precursor having a nucleophilic group). In addition, the PEG units of the precursors containing electrophilic groups and nucleophilic groups can have the same or can have different average molecular weights.

[0252] A crosslinking agent based on PEG can be replaced with another crosslinking agent containing a nucleophilic group. For example, a low molecular weight amine linker, such as trilysine (or trilysine salt or derivative, such as trilysine acetate) or other low molecular weight multi-arm amines, can be used.

[0253] In certain embodiments, the crosslinking agent containing a nucleophilic group can be conjugated or combined with an imaging agent. The imaging agent is a reagent containing a fluorophore or other group for realizing imaging. Fluorophores such as fluorescein, rhodamine, coumarin and cyanine can be used as the imaging agent, for example. The imaging agent can be combined with the crosslinking agent via some nucleophilic groups of the crosslinking agent, for example. Since crosslinking requires a sufficient amount of nucleophilic groups, "conjugated / conjugation" generally includes partial conjugation, meaning that only a part of the nucleophilic groups are used for conjugating with the imaging agent. For example, about 1% to about 20%, or about 5% to about 10%, or about 8% of the nucleophilic groups of the crosslinking agent can be conjugated with the imaging agent. In other embodiments, the imaging agent can also be combined with the polymer precursor via certain reactive (such as electrophilic) groups of the polymer precursor, for example.

[0254] Additional components:

[0255] In addition to the polymer units and active ingredients that form the polymer network as disclosed above, the implant of the present invention may also contain other additional components. The additional components are, for example, salts derived from the buffers used in the hydrogel preparation process, such as phosphates, borates, bicarbonates, or other buffering agents, such as triethanolamine. In certain embodiments of the present invention, sodium phosphate buffer (specifically, sodium dihydrogen phosphate and disodium hydrogen phosphate) is used.

[0256] Optionally, preservatives can be used in the implant of the present invention. However, in certain embodiments, the implant of the present invention, including the implant containing axitinib as the active agent, does not contain preservatives, such as antimicrobial preservatives (including but not limited to benzalkonium chloride (BAK), chlorobutanol, sodium perborate, and stabilized chlorine dioxide complex (SOC)), or is substantially free of such preservatives.

[0257] In one embodiment of the present invention, if in-situ gelling is preferred, possible additional components may be other agents used in the hydrogel manufacturing process, such as (but not limited to) viscosity modifiers (such as hyaluronic acid, etc.), surfactants, etc.

[0258] In certain embodiments, the insert of the present invention may contain imaging agents. Imaging agents that can be used in the context of the present invention are all agents that can bind to the components of the hydrogel or can be embedded in the hydrogel and are visible or can be made visible when exposed to light of a certain wavelength, or are contrast agents. Suitable imaging agents for the present invention are (but not limited to) for example fluorescein, rhodamine, coumarin, anthocyanin, europium chelates, boron dipyromethene, benzofuran, dansyl, bimane, acridine, triazabicyclopentadiene, pyrene, and their derivatives. The imaging agent can be combined with the precursor containing nucleophilic or electrophilic groups that form the polymer network as disclosed above, or the imaging agent can be a separate (unbound) agent added during the implant manufacturing process and present in the hydrogel.

[0259] Formulation:

[0260] In certain embodiments, the implant according to the present invention comprises a TKI, a polymer network made of one or more polymer precursors as disclosed hereinabove and in the form of a hydrogel, and optionally additional components, such as salts remaining in the implant during production (such as phosphates used as buffers, etc.). In certain preferred embodiments, the TKI is axitinib.

[0261] In certain embodiments, the implant according to the present invention may contain, in its dry state, from about 15% to about 80% by weight, such as from about 25% to about 75% of a TKI and from about 15% to about 80% by weight, such as from about 20% to about 60% of polymer units, or in certain embodiments, from about 35% to about 65% by weight of a TKI and from about 25% to about 50% by weight of polymer units (dry composition). In certain embodiments, the implant according to the present invention may contain from about 45% to about 55% by weight of a TKI and from about 37% to about 47% by weight of polymer units (dry composition), wherein the TKI and polymer units are selected from those TKI and polymer units disclosed hereinabove. In other certain embodiments, the implant according to the present invention may contain, in its dry state, from about 55% to about 75% by weight of a TKI and from about 20% to about 40% by weight of polymer units (dry composition), wherein the TKI and polymer units are selected from those TKI and polymer units disclosed hereinabove. In other certain embodiments, the implant according to the present invention may contain, in its dry state, from about 30% to about 45% by weight of a TKI and from about 47% to about 70% by weight of polymer units (dry composition), wherein the TKI and polymer units are selected from those TKI and polymer units disclosed hereinabove.

[0262] In one particular embodiment, the implant according to the present invention may contain, in its dry state, from about 25% to about 75% by weight of axitinib and from about 20% to about 60% by weight of PEG units, or from about 35% to about 65% by weight of axitinib and from about 25% to about 50% by weight of PEG units, or from about 45% to about 55% by weight of axitinib and from about 37% to about 47% by weight of PEG units, or from about 48% to about 52% by weight of axitinib and from about 40% to about 44% by weight of PEG units (dry composition). In other particular embodiments, the implant according to the present invention may contain, in its dry state, from about 55% to about 75% by weight of axitinib and from about 20% to about 40% by weight of PEG units, or from about 60% to about 75% by weight of axitinib and from about 21% to about 31% by weight of PEG units (dry composition).

[0263] In another particular embodiment, on a dry weight basis, the ratio of axitinib to PEG in the implant according to the present invention may be about 50% or more axitinib by weight to about 40% or less PEG by weight, the balance being phosphate. Alternatively, on a dry weight basis, the ratio of axitinib to PEG in the implant according to the present invention may be from about 1:1 to about 3:1.

[0264] In certain embodiments, the balance of the implant in its dry state (i.e., the remainder of the formulation when TKI (such as axitinib) and the polymeric hydrogel (such as PEG hydrogel) have been accounted for) can be a salt remaining from the buffer solution as disclosed above. In certain embodiments, such salt is phosphate, borate, or carbonate (hydrogen carbonate). In one embodiment, the buffer salt is sodium phosphate (sodium dihydrogen phosphate or disodium hydrogen phosphate).

[0265] The amounts of TKI and one or more polymers can vary, and other amounts of TKI and polymeric hydrogel can be used to prepare the implant according to the present invention.

[0266] In certain embodiments, the maximum amount of drug within the formulation is about twice the amount of polymer (e.g., PEG) units, but may be higher in some cases, but it is desirable that the mixture containing, for example, precursors, buffer, and drug (in the state before the hydrogel is fully gelated) can be uniformly poured into a mold or tube.

[0267] In one embodiment of the present invention, after formation and before drying, i.e., the hydrogel in the wet state can contain polyethylene glycol accounting for about 3% to about 20% expressed as polyethylene glycol weight divided by fluid weight x 100. In one embodiment, the hydrogel in the wet state contains polyethylene glycol accounting for about 5% to about 15%, such as about 7.5% to about 15% or about 5% to about 10% expressed as polyethylene glycol weight divided by fluid weight x 100.

[0268] In one embodiment of the present invention, the wet hydrogel composition (i.e., after the hydrogel composition has been formed, i.e., after all components for forming the hydrogel have been mixed) contains an active ingredient (such as axitinib) accounting for about 5% to about 50% by weight and PEG units accounting for about 5% to about 50% or about 5% to about 30% by weight.

[0269] In certain embodiments, when forming the hydrogel for the implant according to the present invention, the wet composition can utilize a solid content of about 10% to about 50% or about 25% to about 50% (w / v) (where "solid" means the total weight of the polymer precursor, salt, and drug in the solution / suspension). Thus, in certain embodiments, the total solid content of the wet hydrogel composition to be poured into a mold or tube to form the hydrogel can be no more than about 60%, or no more than about 50%, or no more than about 40%, such as equal to or less than about 35% (w / v). The content of TKI (such as axitinib) can account for no more than about 40% or no more than about 30% of the wet composition, such as equal to or less than about 25% (w / v). The solid content may affect the viscosity and thus may also affect the pourability of the wet hydrogel composition.

[0270] In certain embodiments, the hydrogel implant in its dry (dehydrated / dried) state, e.g., prior to loading into a needle or while loaded in a needle, may have a very low water content, such as no more than 1% water by weight. In certain embodiments, the water content may also be lower than this value, possibly no more than 0.25% by weight or even up to 0.1% by weight. In the present invention, the term "implant" is used to refer to the implant in its hydrated state when it contains water (e.g., after the implant has been (re)hydrated or immersed in an aqueous environment after being administered to the eye), as well as the implant in its dry (dried / dehydrated) state, e.g., when it has been dried to a low water content of no more than about 1% by weight or when prepared to produce such a low water content implant such that no drying step is required. In certain embodiments, the implant in its dry state is an implant that has been maintained in an inert nitrogen atmosphere (containing less than 20 ppm of oxygen and moisture) in a glove box for at least about 7 days after production and then loaded into a needle. The water content of the implant can be measured, for example, using the Karl Fischer coulometric method.

[0271] In certain embodiments, the total weight (also referred to herein as "total mass") of the implant according to the present invention in its dry state can be from about 200 μg (i.e., 0.2 mg) to about 1.5 mg or from about 400 μg to about 1.2 mg. In certain specific embodiments, the total weight of the implant according to the present invention in its dry state can be from about 0.3 mg to about 0.6 mg, such as from about 0.4 mg to about 0.5 mg, for example in the case where the implant contains an amount of axitinib from about 160 μg to about 250 μg. In certain other specific embodiments, the total mass of the implant according to the present invention in its dry state can be from about 0.75 mg to about 1.25 mg, or from about 0.8 mg to about 1.1 mg, or from about 0.9 mg to about 1.0 mg, for example in the case where the implant contains an amount of axitinib from about 480 μg to about 750 μg.

[0272] In certain embodiments, the implant according to the present invention in its dry state per mm 3 (i.e., per 1 mm 3 volume of the dry implant) can contain from about 200 μg to about 1000 μg of a TKI, such as axitinib. In certain specific embodiments, the implant according to the present invention in its dry state per mm 3 can contain from about 200 μg to about 300 μg of axitinib, for example in the case where the implant contains an amount of axitinib from about 160 μg to about 250 μg. In certain other specific embodiments, the implant according to the present invention in its dry state per mm 3 can contain from about 500 μg to about 800 μg of axitinib, for example in the case where the implant contains an amount of axitinib from about 480 μg to about 750 μg.

[0273] The implant of the present invention can thus have different densities. The density of the final implant (i.e., in its dry state) can be controlled and determined by various factors, including but not limited to the concentration of the components in the wet composition when forming the hydrogel and certain conditions during the manufacturing process of the implant. For example, in certain embodiments, the density of the final implant can be increased by sonication or degassing at certain points during the manufacturing process, such as using a vacuum.

[0274] In certain embodiments, the implant according to the present invention contains a therapeutically effective amount of a TKI, such as axitinib, for release over a longer period of time, but with a relatively small length and / or diameter. This is advantageous both in terms of ease of administration (injection) and in terms of reducing the possible damage to the eye tissue and minimizing the possible impact on the patient's vision when the implant is in place. The implant of the present invention combines the benefits of an appropriately high dose of a TKI (i.e., a therapeutically effective dose adjusted according to the specific patient's needs) with a relatively small implant size.

[0275] Exemplary implants according to the present invention are disclosed in Tables 1, 6, 21.1, 21.2, and 29 of the Examples section (including the predictive examples of the implants according to the present invention containing a large amount of TKI disclosed in Table 29).

[0276] Size of the implant and dimensional changes due to stretching after hydration:

[0277] The dry implant can have different geometries depending on the manufacturing method, such as using a mold or tube into which a mixture containing a hydrogel precursor (including a TKI) is poured before complete gelation. The implant according to the present invention is also referred to as a "fiber" (the term is used interchangeably with the term "rod" herein), where a fiber is an object generally having an elongated shape. The implant (or fiber) can have different geometries with specific dimensions as disclosed herein.

[0278] In one embodiment, the implant is cylindrical or has a substantially cylindrical shape. In this case, the implant has a circular or substantially circular cross-section.

[0279] In other embodiments of the present invention, the implant is non-cylindrical, wherein the implant is optionally elongated in its dry state, wherein the length of the implant is greater than the width of the implant, and wherein the width is the maximum cross-sectional dimension substantially perpendicular to the length. In certain embodiments, the width can be from about 0.1 mm to about 0.5 mm. Different geometries of the outer implant shape or its cross-section can be used in the present invention. For example, instead of circular diameter fibers (i.e., cylindrical implants), cross-shaped fibers (i.e., wherein the cross-sectional geometry is cross-shaped) can be used. Other cross-sectional geometries can generally be used, such as oval or rectangular, square, triangular, star-shaped, etc. In certain embodiments, the fibers can also be twisted. In embodiments where the implant is administered to the eye through a needle, the size of the implant (i.e., its length and diameter) and its cross-sectional geometry must be such that the implant can be loaded into the needle, particularly a fine diameter needle, such as a 25-gauge or 27-gauge needle further disclosed herein.

[0280] The polymer network of the hydrogel implant (such as a PEG network) according to certain embodiments of the present invention can be semi-crystalline at room temperature or below in its dry state and amorphous in its wet state. Even in the stretched form, the dry implant is dimensionally stable at room temperature or below, which may be beneficial for loading the implant into the needle and for quality control.

[0281] After the implant is hydrated in the eye (which can be simulated by immersing the implant in PBS at pH 7.2 at 37°C), the dimensions of the implant according to the present invention may change: generally, the diameter of the implant may increase, while its length may decrease or at least remain substantially the same. The advantage of this dimensional change is that although the implant is thin enough in its dry state to be loaded into a fine-diameter needle (such as a 25- or 27-gauge needle, or in some cases even a smaller-diameter needle, such as a 30-gauge needle) for injection into the eye, once it has been placed in the eye, for example, in the vitreous humor, the implant can become shorter to better fit within the limited small volume of the eye. The needles for injecting the implants of the present invention as disclosed herein, such as 25- or 27-gauge needles in certain embodiments, have a relatively small diameter (and for example, the inner diameter can be about 0.4 mm). Since the implant may also become softer after hydration, damage to any eye tissue can be prevented or reduced even when the implant comes into contact with such tissue. In certain embodiments, the dimensional change is achieved at least in part by introducing a "shape memory" effect into the implant by stretching the implant in the longitudinal direction during its manufacturing process (as also disclosed in the "Manufacturing Method" section below). In certain embodiments, the stretching can be carried out in the dry or wet state, i.e., after drying the hydrogel implant or before drying. It should be noted that if the stretching is not carried out and only the hydrogel implant is dried and cut to the desired length, both the diameter and length of the implant increase after hydration. If this is not desired, the hydrogel fibers can be stretched either dry or wet.

[0282] In a preformed dry hydrogel, a degree of molecular orientation can be imparted by dry stretching the material and then curing it to lock in the molecular orientation. In certain embodiments, this can be achieved by drawing the material (optionally at a temperature above the melting point of the crystalline region of the material) and then crystallizing the crystalline region. Alternatively, in certain embodiments, the glass transition temperature of the dry hydrogel can be used to lock in the molecular orientation of a polymer (such as PVA) having a suitable glass transition temperature. Another alternative is to stretch the gel before it is completely dry (also known as "wet stretching") and then dry the material while under tension. Molecular orientation provides a mechanism for anisotropic swelling after introduction into a hydrated medium such as the vitreous. After hydration, the implants of certain embodiments will swell only in the radial dimension, while the length will decrease or remain substantially unchanged. The term "anisotropic swelling" means preferential swelling in one direction relative to another, as in a cylinder that swells primarily in the radial direction but shows no significant increase (or even the opposite) in the longitudinal dimension.

[0283] The degree of dimensional change after hydration can depend particularly on the draw factor. For example, drawing at a draw factor of about 1.3 (e.g., by wet drawing) may have a less pronounced effect, or may not substantially change the length during hydration. In contrast, drawing at a draw factor of, for example, about 1.8 (e.g., by wet drawing) may result in a significant shortening of the length during hydration. Drawing at a draw factor of 4 (e.g., by dry drawing) can result in a much shorter length after hydration (e.g., the length decreasing from about 15 mm to about 8 mm). Those skilled in the art will understand that, in addition to drawing, other factors may also affect the swelling characteristics.

[0284] Other factors that affect the likelihood of drawing the hydrogel and causing dimensional changes in the implant after hydration are the composition of the polymer network. In the case of using PEG precursors, those with a lower arm number (such as 4-arm PEG precursors) contribute to providing higher flexibility in the hydrogel compared to those with a higher arm number (such as 8-arm PEG precursors). If the hydrogel contains more less-flexible components (e.g., a larger amount of PEG precursors with a larger arm number, such as 8-arm PEG units), the hydrogel may be harder and less likely to be drawn without breaking. On the other hand, a hydrogel containing more flexible components (such as PEG precursors with a smaller arm number, such as 4-arm PEG units) may be more easily drawn and softened, and swell to a greater extent after hydration. Thus, the properties and characteristics of the implant after placement in the eye (i.e., after (re)hydration of the hydrogel) can be adjusted by varying the structural features and by modifying its processing after the implant has been initially formed.

[0285] Exemplary dimensions of the implants used in the following examples herein are provided particularly in Tables 6, 21.1, and 21.2 of the Examples section. Specific implants containing about 200 μg and about 600 μg of axitinib are disclosed in Tables 21.1 and 21.2. However, implants containing about 200 μg or about 600 μg of axitinib may also have dimensions (i.e., length and / or diameter) different from those disclosed in these tables. The dry implant dimensions depend particularly on the amount of TKI incorporated and the ratio of TKI to polymer units, and can also be controlled by the diameter and shape of the mold or tube in which the hydrogel is gelled. In addition, the diameter of the implant is further determined particularly by (wet or dry) drawing of the hydrogel strands after formation. The dried strands (after drawing) are cut into segments of the desired length to form the implants; thus the length can be selected as needed.

[0286] In the following text, embodiments of an implant having specific dimensions are disclosed. As long as the dimensional ranges or values disclosed herein are for the length and diameter of the implant, the implant is cylindrical or substantially cylindrical. However, all values and ranges disclosed herein for the length and diameter of the cylindrical implant can equally be used for the length and width of non-cylindrical implants as also disclosed herein.

[0287] In certain embodiments, the length of the implant of the present invention in its dry state may be less than about 17 mm. In specific embodiments, the length of the implant in its dry state may be less than about 15 mm, or less than or equal to about 12 mm, or less than or equal to about 10 mm, or less than or equal to about 8.5 mm. In specific embodiments, the length of the implant of the present invention in its dry state may be from about 12 to about 17 mm, or the length in its dry state may be from about 6 mm to about 10 mm or specifically, from about 6 mm to about 9 mm.

[0288] In certain embodiments, the diameter of the implant of the present invention in its dry state may be from about 0.1 mm to about 0.5 mm. In some other embodiments, the diameter of the implant in its dry state may be from about 0.2 mm to about 0.5 mm. In specific embodiments, the diameter of the implant in its dry state may be from about 0.2 mm to about 0.4 mm or from about 0.3 mm to about 0.4 mm. In specific embodiments, the diameter of the implant of the present invention in the dry state may be from about 0.2 mm to about 0.3 mm or from about 0.3 mm to about 0.4 mm.

[0289] In specific embodiments, the length of the implant in its dry state may be from about 6 mm to about 10 mm and the diameter may be from about 0.2 mm to about 0.4 mm.

[0290] In certain embodiments, the length of the implant of the present invention in its wet / hydrated state may be from about 6 mm to about 12 mm. In some other embodiments, the length of the implant of the present invention in its wet / hydrated state may be equal to or less than about 10 mm, or from about 6 mm to about 10 mm. In specific embodiments, the length of the implant of the present invention in its wet / hydrated state may be from about 6 mm to about 8 mm.

[0291] In certain embodiments, the diameter of the implant of the present invention in its wet / hydrated state may be equal to or less than about 0.8 mm, or from about 0.5 mm to about 0.8 mm, or from about 0.65 mm to about 0.8 mm. In specific embodiments, the diameter of the implant of the present invention in its wet / hydrated state may be from about 0.7 mm to about 0.8 mm.

[0292] In certain embodiments, the length of the implant in its wet / hydrated state may be equal to or less than about 10 mm and the diameter may be equal to or less than about 0.8 mm.

[0293] In an embodiment of the present invention, the diameter of the implant in its dry state must be such that the implant can be loaded into a fine-diameter needle as disclosed herein, such as a 25-gauge or 27-gauge needle. Specifically, in one embodiment, the diameter of an implant containing from about 480 μg to about 750 μg of axitinib may be such that it can be loaded into a 25-gauge needle or such that it can be loaded into a 27-gauge needle without causing any damage to the implant during loading, and such that the implant remains stably retained in the needle during further processing (including packaging, sterilization, transportation, etc.).

[0294] Whenever the length or diameter (mm) of the implant of the present invention in its wet / hydrated state is disclosed herein, the present invention refers respectively to the implant length or diameter measured after 24 hours at 37 °C, pH 7.2. It should be understood that herein, pH 7.2 includes a pH range from about 7.2 to about 7.4.

[0295] When the implant is retained under these conditions, the dimensions of the implant may change further over time (i.e., after 24 hours) (e.g., the length may increase slightly again). However, whenever the hydrated dimensions of the implant are reported herein, these dimensions are measured as disclosed above after 24 hours at 37 °C, pH 7.2.

[0296] In the case of making several measurements of the length or diameter of an implant or collecting several data points during the measurement, the average value (i.e., the mean) as defined herein is reported. The length and diameter of the implant according to the present invention can be measured, for example, by microscopy or by an (optionally automated) camera system as described in Example 6.1.

[0297] In certain embodiments, the ratio of the diameter of the implant of the present invention in its hydrated state to the diameter in its dry state may be less than about 5 mm, or less than about 4 mm, or less than about 3.25 mm, or less than about 2.5 mm, or less than about 2.25 mm, or less than about 2.10 mm.

[0298] In certain same or other embodiments, the ratio of the length of the implant of the present invention in its dry state to the length in its hydrated state is greater than about 0.7, or greater than about 0.8, or greater than about 0.9, or greater than about 1.0. In certain specific embodiments, the ratio of the length of the implant in its dry state to the length of the implant in its hydrated state may be greater than about 1.5, or even greater than about 2.0. This ratio of the length in the dry state to the length in the hydrated state may be applied in addition to or independently of the ratio of the diameter in the hydrated state to the diameter in the dry state disclosed above.

[0299] A small diameter in the dry state may be advantageous as the implant may be fitted into a small diameter injection needle, such as a 25 or 27 gauge needle, as disclosed herein. Only moderate swelling upon hydration is also beneficial as the implant does not occupy too much space in the vitreous humor. The relatively short length of the implant may be beneficial in reducing the potential for contact with the retina.

[0300] In one embodiment, the implant of the present invention contains from about 160 μg to about 250 μg, or from about 180 μg to about 220 μg, or about 200 μg axitinib, in the form of a fiber (or cylinder), and has a length of from about 14.5 mm to about 17 mm or from about 15 mm to about 16.5 mm and a diameter of from about 0.20 mm to about 0.30 mm in the dry state. This implant may decrease in length and increase in diameter upon in vivo (such as in the vitreous humor) or in vitro hydration (where in vitro hydration is measured after 24 hours at pH 7.2, 37 °C in phosphate buffered saline), reaching a length of from about 6.5 mm to about 8 mm or from about 7 mm to about 8.5 mm and a diameter of from about 0.65 mm to about 0.8 mm or from about 0.70 to about 0.80 mm. In one embodiment, the dimensional changes can be achieved by dry stretching at a stretching factor of from about 2 to about 5 or from about 3 to about 4.5 as disclosed herein.

[0301] In another embodiment, the implant of the present invention containing from about 480 μg to about 750 μg, or from about 540 μg to about 660 μg, or about 600 μg axitinib, in the form of a fiber (cylinder) and in its dry state may have a length in the range of from about 6 mm or about 7 mm to about 12 mm and a diameter of from about 0.25 mm to about 0.50 mm, or a length of from about 7 mm to about 10 mm or from about 8 mm to about 11 mm and a diameter of from about 0.3 mm to about 0.4 mm. In a particular embodiment, the implant of the present invention containing from about 480 μg to about 750 μg, or from about 540 μg to about 660 μg, or about 600 μg axitinib, in the form of a fiber (cylinder) and in its dry state may have a length of from about 7 mm to about 10 mm, such as from about 7 mm to about 9 mm, and a diameter of from about 0.3 mm to about 0.4 mm, such as from about 0.35 mm to about 0.39 mm.

[0302] This implant, when in the eye, such as in the vitreous humor, either in vivo or after in vitro hydration (where in vitro hydration is measured after 24 hours at pH 7.2, 37 °C in phosphate buffered saline), can increase in diameter, and in its hydrated state, its length can be substantially maintained or can decrease, or only slightly increase to a length in the range of, for example, about 6 mm or about 9 mm to about 12 mm and a diameter of about 0.5 mm to about 0.8 mm, or a length of about 9.5 mm to about 11.5 mm and a diameter of about 0.65 mm to about 0.75 mm or about 0.8 mm. In certain embodiments, the implant of the invention containing about 480 μg to about 750 μg, or about 540 μg to about 660 μg, or about 600 μg axitinib and in the form of a fiber (cylinder) can have a length of about 6 mm to about 10.5 mm, such as about 6.5 mm to about 8.5 mm, and a diameter of about 0.7 mm to about 0.8 mm in its hydrated state (i.e., after 24 hours at 37 °C, pH 7.2 as described above).

[0303] In one embodiment, the length of the implant of the invention containing about 480 μg to about 750 μg, or about 540 μg to about 660 μg, or about 600 μg axitinib does not exceed 10 mm in the dry state and also does not exceed or substantially does not exceed about 10 mm, or does not exceed about 9 mm, or does not exceed about 8 mm in the hydrated state (as measured after 24 hours at pH 7.2, 37 °C in phosphate buffered saline).

[0304] In one or more embodiments, the above-described dimensional changes can be achieved by wet stretching with a stretching factor of about 0.5 to about 5, or about 1 to about 4, or about 1.3 to about 3.5, or about 1.7 to about 3, or about 2 to about 2.5. In other embodiments, the implant of the invention containing about 480 μg to about 750 μg, or about 540 μg to about 660 μg, or about 600 μg axitinib may be longer than about 12 mm in the dry state but may ultimately be shorter than about 10 mm or about 9 mm in the hydrated state.

[0305] In certain embodiments, stretching thus induces shape memory, meaning that when the implant is administered to the eye, such as into the vitreous cavity, it will contract in length and widen in diameter upon hydration until it approaches (more or less) its equilibrium dimensions, which are determined by the starting forming dimensions and compositional variables. Although the narrow dry dimensions facilitate administration of the product via a small gauge needle, the widening in diameter and shortening in length after administration can result in an implant that is relatively short with respect to the eye diameter in the posterior chamber of the eye (such as about 9 to 10 mm in length, or at least not exceeding said value), thereby reducing potential contact with surrounding eye tissue. Thus, in one aspect, the invention also relates to a method of imparting shape memory to a hydrogel fiber by stretching the hydrogel fiber in a longitudinal direction, the hydrogel fiber comprising an active agent, such as a TKI, for example axitinib, dispersed in the hydrogel. In another aspect, the invention relates to a method of manufacturing an ophthalmic implant comprising a hydrogel, the hydrogel comprising an active agent, such as a TKI, for example axitinib, dispersed therein, wherein the implant changes its dimensions after being administered to the eye, the method comprising preparing fibers of the hydrogel and stretching the fibers in a longitudinal direction.

[0306] In vitro release:

[0307] The in vitro release of the TKI from the implants of the invention can be determined by the various methods disclosed in detail in Example 2:

[0308] Briefly, one method of determining the in vitro release of the TKI from the implant is to Non-sink simulated physiological conditions at PBS (phosphate buffered saline, pH 7.2) at 37 °C and replace the PBS daily in a volume equivalent to the vitreous volume in the human eye. The results for exemplary implants are shown in Figure 4A . As described in Example 2, in the test implants containing axitinib in the PEG hydrogel matrix, higher dose strengths resulted in higher axitinib concentrations in the release medium.

[0309] Generally, in embodiments of the invention, implants according to the invention can release on average from about 0.1 μg to about 3 μg, or about 0.25 μg to about 2.5 μg, or about 0.1 μg to about 2 μg, or can release in vitro about 0.25 μg to about 1.5 μg per day in PBS at pH 7.2 and 37 °C for a period of 30 days.

[0310] In one embodiment, an implant according to the invention containing about 200 μg of axitinib can release on average from about 0.01 μg to about 0.15 μg of axitinib per day in phosphate buffered saline at pH 7.2 and 37 °C for a period of 30 days.

[0311] In one embodiment, an implant according to the present invention containing about 600 μg of axitinib can release about 0.3 μg to about 0.5 μg of axitinib in vitro per day on average in phosphate buffered saline at pH 7.2 and 37 °C for a period of 30 days.

[0312] In that also described in detail in Example 2 Accelerated in vitro testing the release of the TKI from the implant can be determined in a 25:75 ethanol / water mixture (v / v) at 37 °C. This accelerated in vitro test can be completed in about 2 weeks. Figure 14B showing the accelerated in vitro release data of an implant according to the present invention containing about 200 μg of axitinib, and Figure 4B showing the accelerated in vitro release data of an implant according to the present invention containing about 556 μg of axitinib.

[0313] In one embodiment, at 37 °C, in a 25:75 ethanol / water mixture (v / v), an implant according to the present invention containing about 200 μg of axitinib releases about 35% to about 45% of axitinib in vitro within 3 days, about 65% to about 75% of axitinib in vitro within 7 days, and about 90% to about 100% of axitinib in vitro within 12 to 13 days.

[0314] In one embodiment, at 37 °C, in a 25:75 ethanol / water mixture (v / v), an implant according to the present invention containing about 600 μg of axitinib releases about 40% to about 60% of axitinib in vitro within 2 days, about 65% to about 85% of axitinib in vitro within 4 days, and about 75% to about 90% of axitinib in vitro within 6 days. At 37 °C, in a 25:75 ethanol / water mixture (v / v), an implant according to the present invention containing about 600 μg of axitinib releases about 45% to about 55% of axitinib in vitro within 2 days, about 70% to about 80% of axitinib in vitro within 4 days, and about 80% to about 90% of axitinib in vitro within 6 days.

[0315] Finally, the release of the TKI of the implant of the present invention can also be determined as described in detail in Example 2 in Immediate sink simulated physiological conditions For this immediate test, the release of the TKI is determined at 37 °C in PBS (pH 7.2) / 0.01% NaF with an octanol top layer on the PBS. This is a method for qualitatively simulating the release of the TKI from the implant into the vitreous humor and the reabsorption of the TKI from it into the eye tissue. An exemplary immediate release profile of an implant according to the present invention containing about 200 μg of axitinib is shown in Figure 14A in.

[0316] In one embodiment, an implant according to the present invention containing about 200 μg of axitinib releases in vitro about 25% to about 35% of axitinib within 2 months, about 47% to about 57% of axitinib within 3 months, about 70% to about 80% of axitinib within 5 months, and about 90% to about 100% of axitinib within 7 months in phosphate buffered saline, at pH 7.2, 37° C. and in the presence of an octanol top layer.

[0317] In vitro release testing, particularly the accelerated in vitro release testing described herein, can be particularly useful for comparing different implants (e.g., different production batches, different compositions, different dose strengths, etc.) to each other, for example for quality control or other qualitative assessment purposes.

[0318] In vivo release and persistence:

[0319] In one embodiment of the present invention, when the dry implant of the present invention is administered to the eye, such as the vitreous humor, it hydrates and changes its dimensions as disclosed above, and then biodegrades over time until it has been completely resorbed. When the implant biodegrades, such as via ester hydrolysis, it can gradually swell and soften, and then become smaller, softer and more liquid until it completely dissolves and is no longer visible. As recognized by the inventors from the animal studies provided in the Examples section herein, the implants according to the present invention can persist in the rabbit eye for about 2 to about 6 months or about 5 to about 6 months (see Figure 7A , Figure 9 and Figure 10 ). After the implant has completely degraded, undissolved axitinib particles can remain at the previous site of the implant and aggregation has been observed, i.e., incorporation into the overall structure. These remaining undissolved axitinib particles can continue to dissolve slowly at a rate sufficient to provide a therapeutically effective axitinib content. If two or more implants are administered in certain embodiments to achieve the desired total dose, they also biodegrade over time and the remaining axitinib particles are also incorporated into a single overall structure (see Figure 9 ).

[0320] In the human eye, such as in the vitreous humor, the implants of the present invention biodegrade in certain embodiments within about 2 to about 15 months after administration, or within about 4 to about 13 months after administration, or within about 9 to about 12 months after administration, specifically within about 9 to about 10.5 months after administration. This has been demonstrated in clinical trials using one or two implants each containing about 200 μg of axitinib. See the Examples section, specifically Examples 6 and Figure 15 .

[0321] In one embodiment, the implant releases (as defined herein) a TKI, such as a therapeutically effective amount of a TKI, such as axitinib, for a period of at least about 3 months, at least about 6 months, at least about 9 months, at least about 10 months, at least about 11 months, or at least about 12 months, or at least about 13 months or longer after administration of the vitreous humor. In certain embodiments, the implant releases a TKI, such as axitinib, for a period of about 6 to about 9 months.

[0322] In one embodiment of the invention, the implant provides a treatment period of at least about 3 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 12 months or at least about 13 months or longer after the (i.e., single) implant is administered to the vitreous humor of a patient.

[0323] In one embodiment of the invention, a TKI, such as axitinib, is released from the implant at an average rate of about 0.1 μg / day to about 10 μg / day, or about 0.5 μg / day to about 7 μg / day, or about 0.5 μg / day to about 2 μg / day, or about 1 μg / day to about 5 μg / day in the vitreous humor for a period of at least 3 months, or at least 6 months, or at least 9 months, or at least 11 months, or at least 12 months, or at least 13 months. In certain embodiments, TKI (such as axitinib) release is maintained for about 6 to about 9 months after administration of the implant.

[0324] As presented in the Examples section herein, preclinical studies in animals and clinical studies in humans have shown that the implant of the invention can continuously release a therapeutically effective amount of a TKI for an extended period of time until the implant is completely biodegradable. Any remaining undissolved TKI particles (if present) can remain substantially at the site of the previously implanted device and may aggregate to form a substantially monolithic structure (see Figure 7A , Figure 9 and Figure 10 ), thereby continuing to release TKI into the vitreous humor to an extent sufficient to achieve a therapeutic effect. However, in certain embodiments, all of the amount of TKI contained in the implant is released from the implant before the implant is completely biodegradable. In this case, after the implant is completely biodegradable, undissolved TKI particles do not remain (and / or aggregate) near the site of the previously implanted device or at other locations in the eye.

[0325] In one embodiment, the persistence of the hydrogel in an aqueous environment and in the human eye depends particularly on the hydrophobicity of the carbon chain near the degradable ester group. In the implants used in the examples herein, this carbon chain contains 7 carbon atoms as it is derived from the SAZ functional group of the 4a20k PEG precursor. This can provide a relatively long persistence of up to about 9 to about 12 months or about 9 to about 10.5 months in the human eye. In other embodiments, precursors different from 4a20kPEG-SAZ and 8a20kPEG-NH2 can be used to prepare hydrogel implants that are biodegradable in the human eye and have a persistence similar to or different from that of the implants exemplified in the examples.

[0326] In certain embodiments, the hydrogel implant softens over time as it degrades, which may depend particularly on the structure of the linker that crosslinks the PEG units in the hydrogel. The implant formed from 4a20kPEG-SAZ and 8a20kPEG-NH2 as used in the examples of this application softens rather slowly over time.

[0327] Release mechanism:

[0328] Without wishing to be bound by theory, the mechanism of release of the TKI from the implant of the present invention can be understood as follows: In the embodiments of the present invention, the release of the TKI into the eye and the vitreous humor is determined by diffusion and the drug clearance rate. An exemplary TKI according to the present invention is axitinib. It has been determined that axitinib has a very low solubility in physiological media (about 0.4 to about 0.5 μg / mL in pH 7.2 PBS). According to the present invention, the TKI (such as axitinib) is confined to a biodegradable hydrogel having a specific geometry and surface. The fluid in the posterior chamber of the eye is viscous, has a slow clearance rate and relatively stagnant flow (at least compared to the anterior chamber of the eye).

[0329] In certain embodiments, the implant of the present invention comprises a hydrogel made of a polymer network and a drug dispersed within the hydrogel. The drug gradually dissolves and diffuses from the hydrogel into the eye. This may first occur in the outer region of the hydrogel in contact with the liquid environment of the vitreous (i.e., the drug particles in the outermost region of the hydrogel dissolve and diffuse out first, and those in the innermost region dissolve and diffuse out last). Thus, in certain embodiments, the outer region of the hydrogel becomes depleted of drug particles. This region is therefore also referred to as the "clearance zone", which is limited to the dissolved drug, where the concentration is equal to or lower than the solubility of the drug. In certain embodiments, this low surface concentration can prevent tissue (retina or other cells) from potential drug toxicity by physically separating the tissue from the drug particles when the implant comes into contact with such tissue. In other embodiments, after hydration, the "clearance zone" is the outer region, where the concentration of the active agent is lower than that in the inner region of the hydrated hydrogel.

[0330] In embodiments having a clearance zone, as the drug has dissolved and diffused out of the clearance zone, this region of the hydrogel forms voids and becomes softer and weaker. Concurrent with the diffusion of the drug out of the hydrogel, the hydrogel may also slowly degrade, for example, by ester hydrolysis in the aqueous environment of the eye. This degradation occurs uniformly throughout the hydrogel volume. In the later stages of degradation, the hydrogel begins to deform and erode. When this occurs, the hydrogel becomes softer and more liquid (and thus its shape deforms) until the hydrogel finally dissolves and is completely resorbed. This process is schematically shown in Figure 3 and is demonstrated by infrared reflectance (IR) imaging, for example Figure 10 as demonstrated in

[0331] Since axitinib is a relatively low solubility drug, in some embodiments, after the implant has completely degraded, undissolved axitinib particles may remain at the previous site of the implant. Since these remaining undissolved axitinib particles are no longer held and separated by the hydrogel, they may aggregate and form a substantially monolithic structure. This monolithic axitinib structure may still release axitinib at a rate sufficient to achieve a therapeutic effect (specifically, reducing CSFT).

[0332] However, in one embodiment, the full amount of axitinib is released before the hydrogel is completely degraded. Since the hydrogel can keep the axitinib particles in place and prevent their aggregation, axitinib can be released from the hydrogel more rapidly as long as the hydrogel has not completely degraded. When the hydrogel is completely degraded, the remaining axitinib particles may form a monolithic structure from which axitinib can slowly dissolve. Thus, in one embodiment of the present invention, it is desirable to completely release axitinib before the hydrogel is completely degraded.

[0333] In certain embodiments, this entire process makes it possible to advantageously maintain the therapeutic effect of the implant of the present invention for an extended period of time, such as at least 3 months, or at least 6 months, or at least 9 months, or at least 11 months, or at least 12 months, or at least 13 months, or at least 14 months, or even longer, such as up to 15 months. The inventors have demonstrated that this is a significant advantage for patients receiving treatment for neovascular age-related macular degeneration, which previously involved very frequent intravitreal injections of anti-VEGF agents. In contrast, the implant according to the present invention may only require injections at much larger time intervals, which is advantageous for the patient for a variety of reasons as disclosed above in the "Objectives and Overview" section.

[0334] Particular implants containing from about 160 μg to about 250 μg, such as about 200 μg of axitinib:

[0335] In a particular embodiment, the present invention relates to a sustained release biodegradable ophthalmic implant containing axitinib dispersed in a hydrogel in an amount in the range of about 160 μg to about 250 μg or about 180 μg to about 220 μg and specifically about 200 μg, wherein the hydrogel comprises a polymer network including polyethylene glycol units, and wherein the implant is in a dry state. In this embodiment, the polymer network contains polyethylene glycol units, including multi-arm polyethylene glycol units, such as 4-arm and / or 8-arm polyethylene glycol units having an average molecular weight in the range of about 10,000 daltons to about 60,000 daltons. In this embodiment, the polymer network of this implant is formed by reacting 4a20kPEG-SAZ with 8a20kPEG-NH2 in a weight ratio of about 2:1. In this embodiment, the hydrogel contains polyethylene glycol in an amount of about 6.5% to about 7.5% expressed as polyethylene glycol weight divided by fluid weight x 100 when formed and before drying (i.e., the wet composition). Further, in this embodiment, the implant in the dry state contains about 45% to about 55% by weight of axitinib and about 37% to about 47% by weight of polyethylene glycol units, or about 47% to about 52% by weight of axitinib and about 40% to about 45% by weight of polyethylene glycol units, such as about 49% to about 50% by weight of axitinib and about 42% by weight of PEG units, or about 47% by weight of axitinib and about 44% by weight of PEG units (dry composition), the balance being sodium phosphate. Further, the implant in its dry state may contain not more than about 1% by weight of water or not more than about 0.25% by weight of water.

[0336] In this embodiment, an implant containing axitinib in an amount in the range of about 160 μg to about 250 μg or about 180 μg to about 220 μg and specifically about 200 μg releases about 0.01 μg to about 0.15 μg of axitinib per day in vitro in phosphate buffered saline at 37 °C for a period of 30 days. Further, in this embodiment, the implant releases about 35% to about 45% of axitinib in vitro in a 25:75 ethanol / water (v / v) mixture at 37 °C in 3 days, about 65% to about 75% of axitinib in 7 days, and about 90% to about 100% of axitinib in 12 to 13 days. In this embodiment, the implant in phosphate buffered saline, at pH 7.2, 37 °C and in the presence of an octanol top layer, also releases about 25% to about 35% of axitinib in vitro in 2 months, about 47% to about 57% of axitinib in 3 months, about 70% to about 80% of axitinib in 5 months, and about 90% to about 100% of axitinib in 7 months.

[0337] In this embodiment, an implant containing approximately 200 μg of axitinib can be in the form of a fiber (or cylinder), and in the dry state, the length can be less than approximately 20 mm, or less than approximately 17 mm, or be from approximately 15 mm to approximately 16.5 mm and the diameter be from approximately 0.20 mm to approximately 0.30 mm, and in vivo in the vitreous humor or after in vitro hydration, the length may decrease while the diameter increases (where in vitro hydration is measured after 24 hours in phosphate buffered saline at pH 7.2, 37 °C), reaching a length of approximately 6.5 mm to 8 mm and a diameter of approximately 0.70 mm to 0.80 mm in the hydrated state. This dimensional change after hydration can be imparted to the implant with shape memory by dry stretching the implant in the longitudinal direction with a stretch factor of from approximately 2 to approximately 5 or a stretch factor of from approximately 3 to approximately 4.5 as more detailedly explained in other parts herein. In other embodiments, the implant can be non-cylindrical.

[0338] In this embodiment, the ratio of the diameter of the implant containing approximately 200 μg of axitinib in the hydrated state to the diameter in the dry state is less than approximately 3.25 mm, and / or the ratio of the length in the dry state to the length in the hydrated state is greater than approximately 1.5.

[0339] The total weight of the implant as disclosed in this embodiment in its dry state can be from approximately 0.3 mg to approximately 0.6 mg, such as from approximately 0.4 mg to approximately 0.5 mg. This implant can contain from approximately 10 μg to approximately 15 μg of axitinib per 1 mm of final length in the dry state, and per mm 3 can contain from approximately 200 μg to approximately 300 μg of axitinib.

[0340] In this embodiment, prior to administration, an implant containing a dose of approximately 200 μg of axitinib is loaded into a 25-gauge needle or a 27-gauge needle (or even a smaller gauge needle, such as a 30-gauge needle) for injection into the vitreous humor.

[0341] For summary and illustration, the individual characteristics of the inventive implant containing a dose of approximately 200 μg as disclosed for the embodiments described in this section (including the implants used in the clinical study presented in Example 6) are provided in Table 21.1 in the Examples section, which table is also reproduced herein:

[0342]

[0343]

[0344] The sustained release biodegradable ocular implant of claim 1, wherein the implant is a vitreous implant and contains from about 180 μg to about 220 μg axitinib, is cylindrical, and has a length of less than about 17 mm and a diameter of about 0.2 mm to about 0.3 mm in its dry state, and a length of about 6.5 mm to about 8 mm and a diameter of about 0.7 mm to about 0.8 mm in its hydrated state (after 24 hours at pH 7.2, 37 °C in phosphate buffered saline), and wherein the hydrogel contains crosslinked 4a20k and 8a20k PEG units, and the crosslinking between the PEG units includes a group represented by the following formula,

[0345]

[0346] where m is 6.

[0347] Optionally, the implant of this particular embodiment may also be non-cylindrical as disclosed herein.

[0348] Particular implants containing from about 480 μg to about 750 μg, such as about 600 μg axitinib:

[0349] In another particular embodiment, the present invention relates to a sustained release biodegradable ocular implant containing axitinib dispersed in a hydrogel in an amount of from about 480 μg to about 750 μg, wherein the hydrogel contains a polymer network comprising crosslinked polyethylene glycol units. The amount of axitinib in the implant may also be in the range of from about 540 μg to about 660 μg, and in particular may be about 600 μg.

[0350] In this implant, the polyethylene glycol units include multi-arm polyethylene glycol units, such as 4-arm and / or 8-arm polyethylene glycol units having an average molecular weight in the range of from about 10,000 daltons to about 60,000 daltons. In this embodiment, the polymer network of the implant contains 4a20kPEG and 8a20kPEG units and is formed by reacting 4a20kPEG-SAZ with 8a20kPEG-NH2 in a weight ratio of about 2:1.

[0351] In this embodiment, the implant in the dry state may contain about 45% to about 55% by weight of axitinib and about 37% to about 47% by weight of polyethylene glycol units, or may contain about 60% to about 75% by weight of axitinib and about 21% to about 31% by weight of polyethylene glycol units, such as about 63% to about 72% by weight of axitinib and about 23% to about 27% by weight of polyethylene glycol units (dry composition), with the balance being sodium phosphate. In certain specific embodiments, the implant may contain about 68% to about 69% axitinib and about 26% polyethylene glycol units (dry composition), with the balance being sodium phosphate. The implant may contain no more than about 1% water by weight or no more than about 0.25% water by weight.

[0352] In this embodiment, this implant with an axitinib content in the range of about 480 μg to about 750 μg or about 540 μg to about 660 μg or specifically about 600 μg releases about 0.3 μg to about 0.5 μg of axitinib in vitro per day at 37 °C in phosphate-buffered saline for a period of 30 days. In addition, this implant releases about 40% to about 60% of axitinib in vitro within 2 days, about 65% to about 85% of axitinib in vitro within 4 days, and about 75% to about 90% of axitinib in vitro within 6 days at 37 °C in a 25:75 (v / v) ethanol / water mixture. In this embodiment, this implant may also release about 45% to about 55% of axitinib in vitro within 2 days, about 70% to about 80% of axitinib in vitro within 4 days, and about 80% to about 90% of axitinib in vitro within 6 days at 37 °C in a 25:75 ethanol / water (v / v) mixture.

[0353] In this embodiment, the implant containing about 600 μg of axitinib may be in the form of a fiber (or cylinder), and in its dry state, the length may be less than about 20 mm, or less than about 17 mm, or less than about 15 mm, or less than or equal to about 12 mm, such as about 7 mm to about 12 mm, and the diameter may be about 0.25 mm to about 0.50 mm, or the length may be about 7 mm or about 8 mm to about 11 mm and the diameter may be about 0.3 mm to about 0.4 mm, and may increase in diameter in vivo in the vitreous humor or after in vitro hydration (where in vitro hydration is measured after 24 hours at pH 7.2, 37 °C in phosphate-buffered saline). In a specific embodiment, the length of the implant containing about 600 μg of axitinib in its dry state may be less than or equal to about 10 mm, or less than or equal to about 8.5 mm, or be about 7 mm to about 9 mm or about 7 mm to about 8.5 mm, and the diameter may be about 0.3 mm to about 0.4 mm, such as about 0.35 mm to about 0.39 mm.

[0354] The size of this implant after hydration, either in vivo or in vitro (where in vitro hydration is measured after 24 hours at pH 7.2, 37 °C in phosphate buffered saline), can be a length less than or equal to about 10 mm, such as about 6 mm or from about 9 mm to about 12 mm, and a diameter of about 0.5 mm to about 0.8 mm, or a length of about 9.5 mm to about 11.5 mm, or a length not exceeding about 10 mm or not exceeding about 9 mm and a diameter of about 0.65 mm to about 0.75 mm or up to about 0.80 mm. In certain embodiments, the length of an implant containing about 600 μg axitinib in its hydrated state (where in vitro hydration is measured after 24 hours at pH 7.2, 37 °C in phosphate buffered saline) can be from about 6 mm to about 10.5 mm, such as from about 6.5 mm to about 8.5 mm, and a diameter of about 0.7 mm to about 0.8 mm. In certain embodiments, given the limited volume of the eye, a length of about 10 mm or less, such as about 9 mm or less, is an acceptable length when hydrated in the vitreous humor of the eye.

[0355] This change in size after hydration can be achieved by wet stretching, as disclosed in more detail below, in the longitudinal direction before drying with a draw factor of about 0.5 to about 5, or a draw factor of about 1 to about 4, or a draw factor of about 1.3 to about 3.5, or a draw factor of about 1.7 to about 3, or a draw factor of about 2 to about 2.5.

[0356] In this embodiment, the ratio of the diameter of an implant containing about 600 μg axitinib in its hydrated state to the diameter in its dry state can be less than about 2.25 mm and / or the ratio of the length in its dry state to the length in its hydrated state can be greater than 0.75.

[0357] The total weight of an implant containing about 600 μg axitinib in its dry state, as disclosed herein, can be from about 0.8 mg to about 1.1 mg, such as from about 0.9 mg to about 1.0 mg. This implant can contain from about 70 μg to about 85 μg axitinib per 1 mm of final length in its dry state, and per mm 3 can contain from about 500 μg to about 800 μg axitinib.

[0358] In this embodiment, the preferred shape of the implant is cylindrical or substantially cylindrical (and can also be referred to as a fiber). In other embodiments, the implant can be non-cylindrical. Prior to administration, this implant containing a dose of about 600 μg axitinib is loaded into a 25-gauge (or smaller gauge, such as 27-gauge) needle for injection into the eye, such as the vitreous humor.

[0359] For summary, the individual features of the inventive implant containing a dose of about 600 μg axitinib as disclosed for the embodiments described in this section are provided in the Examples section in

[0360] In Table 21.2, the table is also reproduced here:

[0361]

[0362]

[0363]

[0364] In a particular embodiment, the sustained release biodegradable ophthalmic implant of the present invention is a vitreous implant and comprises from about 540 μg to about 660 μg of axitinib, is cylindrical, and has a length less than or equal to 10 mm and a diameter of about 0.3 mm to about 0.4 mm in its dry state, and a length of about 6 mm to about 10.5 mm and a diameter of about 0.6 mm to about 0.8 mm in its hydrated state (after 24 hours at pH 7.2, 37 °C in phosphate buffered saline), and wherein the hydrogel comprises crosslinked 4a20k and 8a20k PEG units, wherein the crosslinking between the PEG units comprises a group represented by the following formula,

[0365]

[0366] wherein m is 6.

[0367] Alternatively, the implant of this particular embodiment may also be non-cylindrical as disclosed herein.

[0368] II. Manufacture of the implant

[0369] Manufacturing process:

[0370] In certain embodiments, the present invention also relates to a method of manufacturing a sustained release biodegradable ophthalmic implant as disclosed herein. Generally, the method comprises the steps of: forming a hydrogel comprising a polymer network and TKI particles dispersed within the hydrogel; shaping the hydrogel; and drying the hydrogel. In certain embodiments, the method comprises the steps of: forming a hydrogel comprising a polymer network formed from a precursor having reactive groups (e.g., comprising PEG units) and TKI particles dispersed in the hydrogel; shaping the hydrogel; and drying the hydrogel. More specifically, the polymer network is formed by mixing and reacting a multi-arm PEG precursor having an electrophilic group with a multi-arm PEG precursor having a nucleophilic group or another nucleophilic crosslinker (the precursors and crosslinkers disclosed in the "Polymer Network" and "PEG Hydrogel" sections herein) in a buffer solution in the presence of TKI particles and allowing the mixture to gel to form a hydrogel. In an embodiment of the present invention, the hydrogel is shaped into a hydrogel strand as disclosed herein by pouring the mixture into a tube before the hydrogel is fully gelled. In certain embodiments, the hydrogel strand is stretched in the longitudinal direction as further disclosed herein before or after drying.

[0371] In certain embodiments, the TKI in the manufacturing method according to the present invention is axitinib in all its aspects. In one embodiment, a TKI such as axitinib may be in micronized form for preparing the implant as disclosed herein and may have a particle size as also disclosed in the "Active Ingredient" section herein. In certain specific embodiments, the d90 of axitinib may be less than about 30 μm or less than about 10 μm. As Figure 24 shown, using micronized TKI (especially micronized axitinib) may serve to reduce the tendency of TKI (especially axitinib) particles to aggregate during the process of pouring the hydrogel strand. In another embodiment, a TKI such as axitinib may be in non-micronized form for preparing the implant.

[0372] The precursors for forming the hydrogels for certain embodiments have been disclosed in detail above in the section related to the implant itself. In the case of preparing a crosslinked PEG network using PEG precursors, in certain embodiments, the method of manufacturing an implant may include mixing and reacting a polymer precursor containing an electrophilic group (such as a multi-arm polyethylene glycol containing an electrophilic group, such as 4a20kPEG-SAZ) with a polymer precursor containing a nucleophilic group or other crosslinking agent (such as a multi-arm polyethylene glycol containing a nucleophilic group, such as 8a20kPEG-NH2) in a buffer solution in the presence of a tyrosine kinase inhibitor, and allowing the mixture to gel. In certain embodiments, the molar ratio of the electrophilic group to the nucleophilic group in the PEG precursor is about 1:1, but nucleophilic groups (such as amine groups) in excess of the electrophilic group may also be used. As disclosed in the "Polymer Network" section and the "PEG Hydrogel" section herein, other precursors may be used, including other precursors containing electrophilic groups and other precursors containing nucleophilic groups or crosslinking agents.

[0373] In certain embodiments, a mixture of a precursor containing an electrophilic group, a precursor containing a nucleophilic group or other crosslinking agent, a TKI, and an optional buffer (and optional additional components, as disclosed in the "Additional Components" section) is prepared. This can occur in a variety of sequences, including but not limited to first preparing separate mixtures of the precursor containing an electrophilic group and the precursor containing a nucleophilic group each in a buffer solution, then combining one of the buffer / precursor mixtures, such as the buffer / precursor mixture containing a nucleophilic group, with the TKI, and then combining this TKI-containing buffer / precursor mixture with the other buffer / precursor mixture (in this case the buffer / precursor mixture containing an electrophilic group). After the mixture of all components has been prepared (i.e., after all components have been combined and a wet composition has been formed), the mixture is poured into a suitable mold or tube before the hydrogel has fully gelled to provide the desired final shape of the hydrogel. The mixture is then allowed to gel. The resulting hydrogel is then dried.

[0374] The viscosity of the wet hydrogel composition to be poured into a mold or tube may depend particularly on the concentration and solids content of the hydrogel composition, but may also depend on external conditions such as temperature. The pourability of the wet composition can be improved by reducing the viscosity of the wet composition, including (but not limited to) reducing the concentration of components in the solvent and / or reducing the solids content or other measures such as increasing the temperature, especially in the case of pouring the composition into a tube of small diameter. Suitable solids contents are disclosed in the "Formulation" section herein.

[0375] In the case where the implant will have a final shape with fibers, such as a cylinder, the reaction mixture can be poured into a thin-diameter tube (e.g., with an inner diameter of about 1.0 mm to about 1.5 mm), such as a PU or silicone tube, to provide an elongated cylindrical shape. Tubes of different geometries and diameters can be used, depending on the desired final cross-sectional geometry of the hydrogel fibers, their initial diameter (which can still be reduced by stretching), and also on the ability of the reaction mixture to uniformly fill the tube.

[0376] Thus, the interior of the tube can have a circular geometry or a non-circular geometry, such as a cross-shaped (or other) geometry. The surface of the implant can be increased by the cross-shaped geometry. Additionally, in certain embodiments, such a cross-shaped geometry can be used to increase the amount of TKI incorporated into the implant. Generally, in certain embodiments, the release of API from the implant can be increased by using a cross-shaped geometry. As disclosed herein, other cross-sectional geometries of the implant can be used.

[0377] In certain embodiments, after the hydrogel has been formed and has been cured to full gelation, the hydrogel strands can be longitudinally stretched in the wet or dry state, as has been detailed herein, for example, in the section regarding the dimensional changes of the implant after hydration. In certain embodiments, the stretch factor (also referred to herein as the "stretch factor") can be in the range of about 1 to about 4.5, or about 1.3 to about 3.5, or about 2 to about 2.5, or in other ranges as also disclosed herein (e.g., in the section "Dimensions of the Implant and Dimensional Changes Due to Stretching after Hydration", for example, but not limited to). The stretch factor indicates the ratio of the length of a hydrogel strand after stretching to the length of the hydrogel strand before stretching. For example, for dry stretching, a stretch factor of 2 means that the length of the dry hydrogel strand after (dry) stretching is twice the length of the dry hydrogel strand before stretching. The same applies to wet stretching. In certain embodiments, when dry stretching is performed, the hydrogel is first dried and then stretched. In certain embodiments, when wet stretching is performed, the hydrogel is stretched in the wet (not dried) state and then left to dry under tension. Optionally, heat can be applied during stretching. More optionally, the hydrogel fibers can additionally be twisted. In certain embodiments, stretching and / or drying can be performed while the hydrogel is still in the tube. Alternatively, the hydrogel can be removed from the tube before stretching. In certain embodiments, the implant maintains its dimensions even after stretching, as long as it is kept at room temperature or below in the dry state.

[0378] After stretching and drying, the hydrogel strands are removed from the tube (if still inside) and cut into segments having the length desired for the final implant in its dry state, such as disclosed herein (if cutting inside the tube, the cut segments are removed from the tube after cutting). For the purposes of the present invention, a particularly desired length of the implant in its dry state is, for example, a length equal to or less than about 12 mm, or equal to or less than about 10 mm, as disclosed herein.

[0379] In certain embodiments, the finally prepared implant is then loaded into a fine diameter needle. In certain embodiments, the needle is sized 22 to 30 gauge, such as 22 gauge, 23 gauge, 24 gauge, 25 gauge, 26 gauge, 27 gauge, 28 gauge, 29 gauge, or 30 gauge. In a particular embodiment, the needle is a 25 or 27 gauge needle, or even a smaller gauge needle, such as a 30 gauge needle, depending on the diameter of the dried (and optionally stretched) implant.

[0380] In certain embodiments, the needle containing the implant is then separately packaged and sterilized, for example, by gamma irradiation.

[0381] In certain embodiments, an injection device, such as a syringe, or another injection device can be separately packaged and sterilized, for example, by gamma irradiation as disclosed below for the cartridge (which is another aspect of the present invention, see the "Injection Device and Cartridge" section).

[0382] Specific embodiments of the manufacturing process according to the present invention are disclosed in detail in Example 1.

[0383] Perform (PEG) tip covering on the needle:

[0384] In one embodiment, after the implant has been loaded into the needle, the tip of the needle is dipped into molten low molecular weight PEG. Alternatively, the molten PEG can be injected or placed / dripped into the inner lumen of the needle tip. This low molecular PEG is liquid (molten) at body temperature but solid at room temperature. After the molten PEG is applied to the needle tip by dipping or dripping, upon cooling of the needle, a hardened droplet or portion of the PEG (also referred to herein as the "tip") remains at the needle and the top of the needle, thereby blocking the inner lumen of the needle. The location of this tip / plug is shown in Figure 25B in.

[0385] The low molecular weight PEG used in this embodiment can be linear PEG, and the average molecular weight can be up to about 1500 or up to about 1000, or the average molecular weight can be about 400, about 600, about 800, or about 1000. Mixtures of PEGs with different average molecular weights as disclosed can also be used. In a particular embodiment, the average molecular weight of the PEG for this tip-covered needle purpose is about 1000. The melting point of this 1k (1000) molecular weight PEG is between about 33°C and about 40°C and melts at body temperature when the needle is injected into the eye.

[0386] As an alternative to the PEG material, any other material that is water-soluble and biocompatible (i.e., can be used in contact with the human or animal body without causing local or systemic adverse effects, such as being non-irritating) and is solid or hardened at room temperature but liquid or substantially liquid or at least soft at body temperature can be used to tip-cover the injection needle. As an alternative to PEG, the following materials (but not limited to these materials) can also be used: poloxamer or poloxamer blends that melt / are liquid at body temperature; crystalline sugars or salts (such as trehalose or sodium chloride), agarose, cellulose, polyvinyl alcohol, poly(lactic-co-glycolic) copolymer, ultraviolet curable polymers, chitosan, or combinations of mixtures thereof.

[0387] The plug or tip helps to keep the implant in place within the needle during packaging, storage, and transportation, and also further prevents the implant from premature hydration during handling due to its blocking the needle lumen. It also prevents premature rehydration of the implant within the needle due to moisture entry during the administration procedure, i.e., when the physician prepares the needle and injector for administration and when the implant is about to be injected and the needle is inserted into the eye (since the positive pressure in the eye may cause at least some degree of premature hydration of the implant just before its actual injection). When heated to body temperature and exposed to moisture, the tip or plug additionally provides smoothness, thus allowing successful deployment of the implant. In addition, by blocking the needle lumen, the needle tip coverage minimizes the possibility of tissue damage, i.e., tissue coring, which is the process of removing tissue fragments as the needle passes through the tissue.

[0388] To apply a PEG (or other material) tip / plug to the lumen of a needle, in one embodiment, the needle containing the implant may be manually or by an automated device dipped into a container of molten PEG (or respectively other material). The needle may be held dipped into the molten material for several seconds to allow the molten material to flow upward into the needle by capillary action. The dwell time, dip depth, and temperature of the molten material determine the final size or length of the tip / plug. In certain embodiments, the length of the PEG (or other) tip / plug at the tip of the needle may be from about 1 to about 5 mm, such as from about 2 to about 4 mm. In certain embodiments, when using 1k PEG, the weight of the tip / plug may be from about 0.1 mg to about 0.6 mg, such as from about 0.15 mg to about 0.55 mg. It has been demonstrated that the implant according to the present invention can be successfully deployed in vivo and in vitro from an injector carrying a needle with a 1k PEG tip as disclosed herein.

[0389] Tip covers such as those disclosed herein for injection needles can also be used for injecting other implants or other drugs or vaccines intended to be injected through the needle into a human or animal body (including other locations within the eye, or other regions or tissues of the body), where the protective effect of preventing the implant (or drug or vaccine) from being affected by moisture and the protective effect on the tissue into which the implant (or drug or vaccine) is injected are desirable and advantageous.

[0390] Stretching:

[0391] The shape memory effect of stretching has been detailedly disclosed above with respect to the nature of the implant. In certain embodiments, the degree of shrinkage after hydration depends particularly on the stretching factor as disclosed above.

[0392] In certain embodiments, the present invention thus also relates to a method of imparting shape memory to a hydrogel strand by stretching the hydrogel strand in a longitudinal direction, the hydrogel strand comprising an active agent dispersed in the hydrogel.

[0393] Similarly, in certain embodiments, the present invention thus also relates to a method of manufacturing an ophthalmic implant, the ophthalmic implant comprising a hydrogel, the hydrogel comprising an active agent dispersed therein, wherein the implant changes its size after being administered to the eye, the method comprising preparing a hydrogel strand and stretching it in a longitudinal direction.

[0394] The stretching factor as disclosed above can be utilized for these methods of the present invention. The described manufacturing methods (including the stretching method) are not limited to implants containing a TKI inhibitor or axitinib, but can also be used for hydrogels containing other active pharmaceutical agents, or implants containing hydrogels formed not by PEG units but by other polymer units capable of forming hydrogels as disclosed hereinabove.

[0395] In embodiments where the implant contains axitinib in an amount in the range of about 160 μg to about 250 μg or an amount of about 200 μg, stretching (dry stretching) can be carried out after drying the hydrogel at a stretch factor of about 2 to about 5, or a stretch factor of about 3 to about 4.5.

[0396] In certain embodiments where the implant contains axitinib in an amount in the range of about 480 μg to about 750 μg or an amount of about 600 μg, stretching (wet stretching) can be carried out in the wet state before drying the hydrogel at a stretch factor of about 0.5 to about 5, or a stretch factor of about 1 to about 4, or a stretch factor of about 1.3 to about 3.5, or a stretch factor of about 1.7 to about 3, or a stretch factor of about 2.0 to 2.5.

[0397] III. Injection device and cartridge

[0398] In certain embodiments, the present invention also relates to a cartridge (which may also be referred to as a "system") that includes one or more sustained-release biodegradable ophthalmic implants as disclosed above or manufactured according to the methods disclosed above, and one or more injection needles, wherein each of the one or more needles is pre-loaded with a sustained-release biodegradable ophthalmic implant in a dry state. In certain embodiments, the gauge size of the needle is 22 to 30, such as 22 gauge, 23 gauge, 24 gauge, 25 gauge, 26 gauge, 27 gauge, 28 gauge, 29 gauge, or 30 gauge. In a particular embodiment, the needle can be a 25 or 27 gauge needle, or can be a smaller gauge, such as a 30 gauge needle. The needle diameter is selected based on the final diameter of the implant in the dry (and optionally stretched) state. The active substance contained in the implant is generally a TKI, such as axitinib.

[0399] In one embodiment, the cartridge includes one or more, such as two or three needles of 22 to 30 gauge, such as 25 or 27 gauge, each loaded with an implant containing axitinib in an amount in the range of about 180 μg to about 220 μg or an amount of about 200 μg.

[0400] In yet another embodiment, the cartridge includes a 25 gauge needle loaded with an implant containing axitinib in an amount in the range of about 540 μg to about 660 μg or an amount of about 600 μg. In another embodiment, the cartridge includes a 27 gauge needle loaded with an implant containing axitinib in an amount in the range of about 540 μg to about 660 μg or an amount of about 600 μg.

[0401] If the cartridge contains two or more implants, these implants may be the same or different and may contain the same or different doses of TKI.

[0402] In some embodiments, the lumen of the implant-containing needle can be blocked by a material that is solid at room temperature but soft or liquid at body temperature, such as a 1k PEG material, as disclosed in detail herein in the "Manufacture of Implants" section and in particular in its sub-section "(PEG) Tip-Covered Needles".

[0403] The cartridge can further contain an injection device for injecting the implant into the eye of a patient, such as into the vitreous humor of the patient. In some embodiments, the injection device is provided and / or packaged separately from one or more needles loaded with the implant. In such embodiments, the injection device must be connected to one or more needles loaded with the implant prior to injection.

[0404] In some embodiments, the number of injection devices provided separately in the cartridge is equal to the number of needles loaded with the implant provided in the cartridge. In these embodiments, the injection device is only used to inject one implant at a time.

[0405] In other embodiments, the cartridge contains one or more injection devices for injecting the implant into the eye of a patient, such as into the vitreous humor of the patient, wherein each injection device is pre-connected or not pre-connected to a needle loaded with the implant. Thus, in one aspect, the present invention also relates to a pharmaceutical product comprising a sustained-release biodegradable ophthalmic implant loaded in a needle and an injection device, wherein the needle is pre-connected to the injection device. In the case where the needle is not pre-connected to the injection device, the physician administering the implant needs to remove the needle containing the implant and the injection device from the packaging and connect the needle to the injection device in order to be able to inject the implant into the eye of the patient.

[0406] In some embodiments, the injection device contains a pusher wire for deploying the implant from the needle into the vitreous humor. The pusher wire can be a Nitinol pusher wire or can be a stainless steel / Teflon pusher wire. The pusher wire allows for easier deployment of the implant from the needle.

[0407] In other embodiments, the injection device and / or the injection needle can contain a termination feature for controlling the injection depth.

[0408] In some embodiments, the injection device is or includes a modified Hamilton glass syringe, which can be placed in a plastic syringe housing, such as inside an injection-molded housing. A pusher wire, such as a Nitinol wire, is inserted into the syringe and advanced together with the plunger of the syringe during deployment of the implant. To facilitate insertion of the Nitinol pusher wire into the needle, an interface insert can be added to the needle interface. Figure 25A and Figure 25BShows one embodiment of an injector according to the invention for injecting an implant into the vitreous humor of a patient. This depicted embodiment of the injector includes a Hamilton syringe body and a Nitinol pusher wire for deploying the implant. Figure 25A Shows the Hamilton syringe body inside an injection molded housing. Figure 25B Shows a schematic view of the components of this injector embodiment. In some embodiments, the injector, which includes a Hamilton syringe body and a plastic housing component, is pre-assembled in a cartridge according to the invention, and the injector is ready-to-use (with or without a mounting needle containing the implant). In other embodiments, the injector must be assembled by a physician before mounting the needle containing the implant.

[0409] In other embodiments, the injection device is an injection molded injector. A schematic exploded view of an embodiment of such an injection molded injector is shown in FIG. 26. In this case, the number of assembly steps performed by the physician before the implant is to be administered to the patient is reduced.

[0410] The cartridge may further include one or more doses, particularly one dose of an anti-VEGF agent for injection. The anti-VEGF agent may be selected from the group consisting of aflibercept, bevacizumab, pegaptanib, ranibizumab, and brolucizumab. In some embodiments, the anti-VEGF agent is bevacizumab. In other embodiments, the anti-VEGF agent is aflibercept. The anti-VEGF agent may be provided in a separate injection device attached to the needle, or may be provided in the form of a solution or suspension in a sealed vial, and the solution or suspension may be aspirated through the needle into the syringe or other injection device before administration.

[0411] The cartridge may further include an operating manual for the physician for injecting the ocular implant. The cartridge may further include a package insert with product-related information.

[0412] In addition to the cartridge, in one aspect, the invention also relates to an injection device itself suitable for injecting a sustained release biodegradable ocular implant according to the invention into the eye. The injection device may contain a member for connecting the injection device to a needle, wherein the needle is pre-loaded with the implant. The injection device may further contain a pusher wire for deploying the implant from the needle into the eye when the injection device has been connected to the needle, and the pusher wire may be made of Nitinol or stainless steel / Teflon or another suitable material. The injection device may further be obtained by fixing the wire to a plunger and encapsulating it between two snap-fit injector body parts and clamping the plunger. The injection device and the needle pre-loaded with the implant according to certain embodiments of the invention are depicted in Figure 1 in.

[0413] As Figure 1 described herein, in some embodiments, an injection device (e.g., an implant injector device) may include a first component and a second component that are separately packaged (e.g., in separate housings). Figure 26C is an exploded view of the first component and Figure 26D is an exploded view of the second component.

[0414] Referring Figure 26C to, the first component includes a body that forms a first internal volume, a plunger including a first distal end disposed within the first internal volume, a filament including a first distal end fixed to the first distal end of the plunger, and a plunger clip. The plunger clip is configured to engage with the plunger and the body to prevent actuation of the plunger. The body may include a first half-body and a second half-body that are configured to interconnect with each other. The body may include a movable hinge that engages with a plunger projection responsive to actuation of the plunger. The movable hinge may allow actuation of the plunger in response to application of a threshold force.

[0415] Referring Figure 26D to, the second component includes a housing that forms a second internal volume, a needle including a base and a lumen, a housing cap disposed within the base, and a needle guard configured to be fixed to the housing and disposed around a portion of the lumen. An implant is configured to be disposed within the needle lumen. The housing may include a first half-housing and a second half-housing that are configured to interconnect with each other. The second component may further include a polymer tip (e.g., a PEG tip) disposed on a second distal end of the lumen. The implant is fixed within the lumen between the housing cap and the polymer tip. The polymer tip is configured to liquefy (e.g., dissolve) within a user's body to allow injection of the implant into the user.

[0416] In some embodiments, the second component is made of a material that includes less moisture and / or is conditioned (e.g., nitrogen conditioned) before being sealed within a housing to prevent the implant from absorbing moisture. In some embodiments, the first component is made of a material that includes more moisture and / or is not conditioned before being sealed within a housing because the implant is not included within the housing with the first component.

[0417] The first component may be removed from a first housing of Figure 1 and the second component may be removed from a second housing of Figure 1 . Referring Figure 26E to, the first component and the second component may be aligned. One or more external cavities of the first component may be aligned with one or more internal protrusions of the second component. The first component and the second component may include markings (e.g., arrows) to indicate how to align the first component and the second component. Referring Figure 26F to, the housing of the second component is fixed to the body of the first component (e.g., via internal protrusions of the housing entering external cavities of the body). Referring Figure 26G ​​​, remove the needle guard from the outer casing of the second component and remove the plunger clip from the body and plunger of the first component. Refer to Figure 26H , activate the plunger of the first component (e.g., push into the body of the first component) to deploy the implant from the lumen of the needle of the second component. In some embodiments, the body has a movable hinge that allows activation of the plunger in response to a threshold force applied to the plunger. In some embodiments, the needle lumen has a polymeric tip (e.g., a polymer deployed at least at the distal end of the lumen, such as PEG) that prevents deployment of the implant from the lumen. Inserting the lumen with the polymeric tip into a user's body can prevent coring of the user's tissue (e.g., cutting a piece of tissue by the inner diameter of the lumen for later deployment into the user's body). The lumen can be inserted into the user's body for a threshold amount of time (e.g., 1 to 5 seconds) to liquefy (e.g., dissolve) the polymeric tip. After the polymeric tip has liquefied, the implant can be deployed from the lumen by activating the plunger.

[0418] IV. Therapy

[0419] In certain embodiments, the present invention also relates to a method of treating an eye disease in a patient in need thereof, the method comprising administering to the patient a sustained release biodegradable ophthalmic implant comprising a hydrogel and a tyrosine kinase inhibitor.

[0420] In a particular embodiment, the present invention relates to a method of treating an eye disease in a patient in need thereof, the method comprising administering to the patient a sustained release biodegradable ophthalmic implant comprising a hydrogel and at least about 150 μg of a tyrosine kinase inhibitor (TKI), wherein the TKI particles are dispersed within the hydrogel.

[0421] In this treatment, the dose administered once per eye over a treatment period of at least 3 months is at least about 150 μg of a tyrosine kinase inhibitor, such as from about 150 μg to about 1800 μg or from about 150 μg to about 1200 μg. In certain preferred embodiments, the tyrosine kinase inhibitor is axitinib.

[0422] In certain embodiments, the dose of the TKI, and specifically axitinib, administered once per eye during the treatment period (i.e., during) is in the range of about 200 μg to about 800 μg. In certain embodiments, the dose is in the range of about 160 μg to about 250 μg or about 180 μg to about 220 μg or is about 200 μg. In other specific embodiments, this dose is in the range of about 320 μg to about 500 μg or about 360 μg to about 440 μg or is about 400 μg. In other embodiments, this dose is in the range of about 480 μg to about 750 μg or about 540 μg to about 660 μg or is about 600 μg. In other embodiments, this dose is in the range of about 640 μg to about 1000 μg or about 720 μg to about 880 μg or is about 800 μg. In other embodiments, this dose is in the range of about 800 μg to about 1250 μg or about 900 μg to about 1100 μg or is about 1000 μg. In other embodiments, this dose is in the range of about 960 μg to about 1500 μg or about 1080 μg to about 1320 μg or is about 1200 μg. In a specific embodiment, the dose administered once per eye during the treatment period is about 600 μg axitinib. In a specific embodiment, this 600 μg dose is contained in a single implant.

[0423] In certain embodiments, the treatment period for treating an eye disease as disclosed herein with the implant of the present invention is at least 3 months, at least 4.5 months, at least 6 months, at least 9 months, at least 11 months, at least 12 months, at least 13 months, at least 14 months or even longer, and can be, for example, about 6 to about 9 months.

[0424] In certain embodiments, the eye disease involves angiogenesis.

[0425] In other embodiments, the eye disease can be mediated by one or more receptor tyrosine kinases (RTKs), such as VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-α / β and / or by c-Kit.

[0426] In some embodiments, the ocular disease is a retinal disease, including choroidal neovascularization, diabetic retinopathy, diabetic macular edema, retinal vein occlusion, acute macular neuroretinopathy, central serous chorioretinopathy, and cystoid macular edema; wherein the ocular disease is acute multifocal placoid pigment epitheliopathy, Behcet's disease, birdshot retinochoroidopathy, infectious diseases (syphilis, Lyme disease, tuberculosis, toxoplasmosis), intermediate uveitis (pars planitis), multifocal choroiditis, multiple evanescent white dot syndrome (MEWDS), sarcoidosis of the eye, posterior scleritis, serpiginous choroiditis, subretinal fibrosis, uveitic syndromes, or Vogt-Koyanagi-Harada syndrome; wherein the ocular disease is a vascular disease or an exudative disease, including Coats' disease, juxtafoveal telangiectasis, papillophlebitis, frosting branch angiitis, sickle cell retinopathy, and other hemoglobinopathies, angioid streaks, and familial exudative vitreoretinopathy; or wherein the ocular disease is caused by trauma or surgery, including sympathetic ophthalmia, uveoretinopathy, retinal detachment, trauma, photodynamic laser therapy, photocoagulation, intraoperative perfusion insufficiency, radiation retinopathy, or bone marrow transplantation retinopathy.

[0427] In alternative embodiments, the sustained-release biodegradable ophthalmic implant of the present invention comprising a hydrogel and a tyrosine kinase inhibitor can be used to treat ocular disorders associated with tumors. Such disorders include, for example, retinal diseases associated with tumors, solid tumors, tumor metastasis, benign tumors (such as hemangiomas), neurofibromas, trachoma, and pyogenic granulomas, congenital hypertrophy of the RPE, posterior uveal melanoma, choroidal hemangioma, choroidal osteoma, choroidal metastasis, combined retinal and retinal pigment epithelial hamartoma, retinoblastoma, fundus vascular proliferative tumors, retinal astrocytoma, or intraocular lymphoid tumors.

[0428] Generally, the ophthalmic implant of the present invention can also be applied to treat any ocular disease involving vascular leakage.

[0429] In certain embodiments, the ocular disease is one selected from the list consisting of neovascular age-related macular degeneration (AMD), diabetic macular edema (DME), and retinal vein occlusion (RVO). In a particular embodiment, the ocular disease is neovascular age-related macular degeneration.

[0430] In some embodiments, the treatment is effective in reducing the central subfield thickness (CSFT) in patients with elevated central subfield thickness, as measured by optical coherence tomography. Elevation within this context means that the CSFT of the patient is higher when compared to other individuals without the specific eye disease. The elevated CSFT may be caused by retinal fluid, such as subretinal or intraretinal fluid. The reduction of the patient's CSFT can be determined relative to the baseline CSFT measured in the patient before the start of the treatment, i.e., before the administration of the implant of the present invention. The ability of the implant of the present invention to reduce the CSFT and maintain or substantially maintain the reduced CSFT in a group of patients over a longer period of time is shown in Examples 6.3 and 6.4. In other embodiments, by the treatment according to the present invention, including the administration of an implant according to the present invention, the CSFT of patients with elevated CSFT due to an eye disease involving angiogenesis is substantially maintained at a certain specified level, or prevents a clinically significant increase in the CSFT of the patient, while the subretinal or intraretinal fluid does not substantially increase, i.e., is also substantially maintained.

[0431] In a particular embodiment, the CSFT of the patient is reduced and maintained at a reduced level for a period of at least 3 months, at least 4.5 months, at least 6 months, at least 9 months, at least 11 months, at least 12 months, at least 13 months, at least 14 months or even longer after the administration of the implant of the present invention. In a highly particular embodiment, the CSFT is reduced relative to the baseline CSFT of the patient before the administration of the implant at least 6 months or at least 9 months or at least 12 months after the administration of the implant. In other particular embodiments, the reduced amount of retinal fluid and / or the reduced CSFT are maintained for a treatment period of at least 3 months, at least 4.5 months, at least 6 months, at least 9 months, at least 11 months, at least 12 months, at least 13 months, at least 14 months or even longer after the administration of the implant of the present invention without the administration of rescue medications (such as an injection of an anti-VEGF agent), or in which rescue medications are administered only occasionally, such as 1, 2, or 3 times during the treatment period. Thus, in this embodiment, during the treatment period using the implant according to the present invention, the patients being treated may not require any rescue medications, or only very rarely require the administration of rescue medications, such as 1, 2, or 3 times during the treatment period.

[0432] In certain embodiments, the rescue medicament is an anti-VEGF agent administered by intravitreal injection in the form of a suspension or solution, such as aflibercept or bevacizumab. In certain specific embodiments, the rescue medicament is a single dose (2 mg) of aflibercept administered by intravitreal injection. As defined herein, the administration of an anti-VEGF agent simultaneously (i.e., as planned) with an implant according to another embodiment of the invention disclosed herein does not constitute a "rescue medicament". In a more specific embodiment, the treatment period during which the levels of body fluids and / or CSFT are maintained or substantially maintained (as reduced by the administration of an implant according to the invention) without the administration of a rescue medicament (or with only minimal administration of a rescue medicament) is from about 6 to about 9 months after the administration of the implant. In certain embodiments, patients treated with an implant according to the invention do not require concomitant administration of steroids (such as dexamethasone or prednisolone drops) during the treatment period.

[0433] In another embodiment, a method according to the invention for treating a patient with elevated CSFT due to angiogenesis by a treatment according to the invention comprising the administration of an implant according to the invention reduces or substantially maintains the CSFT, or prevents a clinically significant increase in CSFT, without weakening or not significantly weakening the patient's vision (e.g., as represented by best corrected visual acuity, also referred to herein as "BCVA"). In certain embodiments, by a treatment according to the invention comprising the administration of an implant according to the invention, the patient's vision, as represented e.g. by BCVA, can be improved during a treatment period of at least 3 months, at least 6 months, at least 9 months, at least 11 months, at least 12 months, at least 13 months or at least 14 months (wherein the patient's vision is weakened due to an eye disease involving angiogenesis).

[0434] Thus, in certain embodiments, the invention provides a method of improving the vision of a patient whose vision is weakened, for example, due to retinal fluid caused by an eye disease involving angiogenesis, the method comprising administering to the patient an implant according to the invention, such as by intravitreal injection. The improvement of the patient's vision can be evaluated, for example, by BCVA. The improvement of vision can be manifested by an increase in the patient's BCVA of, for example, at least 10, or at least 15, or at least 20 ETDRS letters.

[0435] In certain embodiments, the total dose per eye of a TKI (such as axitinib) administered once during a treatment period may be contained in one or more implants. In certain embodiments, the dose per eye administered once during a treatment period is contained in one implant, for example, in one implant containing a dose of about 600 μg or about 200 μg of axitinib. In other embodiments, the total dose per eye administered once during a treatment period is contained in, for example, two implants, where each implant contains, for example, a dose of about 200 μg of axitinib (in which case, the total dose is about 400 μg). In other embodiments, the dose per eye administered once during a treatment period is contained in, for example, three implants, where each implant contains, for example, a dose of about 200 μg of axitinib (in which case, the total dose is about 600 μg). In a particular embodiment of the treatment method of the present invention, the dose of axitinib administered to one eye is about 600 μg and is contained in one implant.

[0436] In order to inject an implant according to the present invention into a patient's eye, such as into the vitreous humor, during the treatment of an eye disease such as retinopathy (including AMD), generally an implant having a therapeutically effective dose of a TKI in a relatively small implant (i.e., an implant appropriate given the particular patient type and disease severity) is required to facilitate administration (injection) and to reduce the possible damage to eye tissues and the possible impact on the patient's vision when the implant is in place. The implants of the present invention advantageously combine the benefits of an appropriately high dose of a TKI (i.e., a therapeutically effective dose adjusted according to the particular patient needs) with a relatively small implant size.

[0437] In certain embodiments, the implant may be administered by an injection device according to the present invention that is connected to a needle pre-loaded with an implant as disclosed herein or by another injection device suitable for connection to a needle pre-loaded with an implant as disclosed herein, such as a (modified) Hamilton syringe. In other embodiments, a hollow microneedle may be used for suprachoroidal administration as disclosed in US 8,808,225, which is incorporated herein by reference.

[0438] In embodiments where two or more implants are administered, generally the implants are administered simultaneously as disclosed hereinabove. The implants administered simultaneously may be the same or different. In cases where simultaneous administration is not possible, for example, due to administration complications or patient-related reasons, administration may alternatively be applied sequentially in two or more different periods, for example, two implants are administered 7 days apart. In the context of the present invention, this may still be considered "simultaneous" administration.

[0439] In certain embodiments, the dry implant is loaded into a needle, such as a needle having a gauge size of 22 to 23, such as a 25-gauge or 27-gauge needle, or a smaller gauge needle for injection, and is administered through such a needle to the eye, such as the vitreous humor. In one embodiment, the injector for injecting the implant into the eye is an injection device according to another aspect of the present invention as disclosed above. Exemplary implants containing 200 μg and 600 μg, respectively, suitable for the therapeutic applications of the present application are presented in Tables 21.1 and 21.2.

[0440] The implant can generally be administered by intravitreal, subconjunctival, subtenon, suprachoroidal, or intracameral injection. In certain embodiments, the implant is administered to the vitreous humor, such as by intravitreal administration of the implant to the posterior of the vitreous humor. In other embodiments, the implant is administered through a hollow microneedle, such as that disclosed in US 8,808,225, which enters the sclera of the eye at the insertion site into the suprachoroidal space of the eye, and this US patent is incorporated herein by reference.

[0441] In certain embodiments, the treatment period is at least 3 months, but can be at least 4.5 months, at least 6 months, at least 9 months, at least 11 months, or at least 12 months. In certain embodiments, the treatment period is at least 6 months, at least 9 months, at least 11 months, at least 12 months, at least 13 months, or at least 14 months. In certain embodiments, the treatment period can also be longer, such as up to about 15 months. The "treatment period" according to one embodiment of the present invention means that a certain therapeutic effect of the implant of the present invention after administration is maintained, substantially maintained, or partially maintained within such a period. In other words, in certain embodiments, only one injection (of the implant of the present invention) is required to maintain the therapeutic effect of reducing or substantially maintaining the CSFT or preventing its clinically significant increase for a relatively long period of time referred to herein as the "treatment period". This is a significant advantage over the currently used anti-VEGF therapies for AMD that require more frequent administrations, thus improving the quality of life of patients. Another advantage is the very low necessity and / or frequency of administering rescue medications during the treatment period. In certain embodiments, during the treatment period, such as during the treatment period of about 6 to about 9 months after the administration of the implant, rescue medications are not required. In certain other embodiments, only very few administrations of rescue medications are required, such as 1, 2, or 3 times during the treatment period. The patient's vision can be improved, as demonstrated, for example, by an increase in BCVA (such as at least 10, at least 15, or at least 20 ETDRS letters) after the administration of the implant of the present invention.

[0442] In a particular embodiment, the present invention relates to a method for treating neovascular age-related macular degeneration in a patient in need thereof, the method comprising administering to the patient a sustained-release biodegradable ocular implant comprising a hydrogel, the hydrogel comprising a polymer network and about 200 μg of a tyrosine kinase inhibitor, wherein one implant per eye is administered once for a treatment period of at least 9 months, and wherein the patient has a history of anti-VEGF treatment. In this embodiment, the treatment reduces the central subfield thickness (CSFT) or at least maintains the CSFT as measured by optical coherence tomography during the treatment period. In this embodiment, the TKI may further be axitinib, which is dispersed in the hydrogel, the hydrogel comprising a polymer network formed by reacting 4a20kPEG-SAZ with 8a20kPEG-NH2, and wherein the implant is in a dry state prior to administration. In this embodiment, the hydrogel contains about 7.5% polyethylene glycol as represented by polyethylene glycol weight divided by fluid weight x 100 when formed and prior to drying. Alternatively, the treated patient may also have no history of anti-VEGF treatment (no AMD treatment).

[0443] In another particular embodiment, the present invention relates to a method for treating neovascular age-related macular degeneration in a patient in need thereof, the method comprising administering to the patient a sustained-release biodegradable ocular implant comprising a hydrogel comprising a polymer network and about 200 μg of a tyrosine kinase inhibitor, wherein two implants per eye forming a total dose of about 400 μg are administered once over a treatment period of at least 3 months or at least 9 months, and wherein the patient has a history of anti-VEGF treatment or no history of anti-VEGF treatment (no AMD treatment). In this embodiment, the treatment reduces (or at least maintains) the central subfield thickness (CSFT) as measured by optical coherence tomography during the treatment period. In this embodiment, the TKI may further be axitinib, which is dispersed in the hydrogel, the hydrogel comprising a polymer network formed by reacting 4a20kPEG-SAZ with 8a20kPEG-NH2, and wherein the implant is in a dry state prior to administration. In this embodiment, the hydrogel contains about 7.5% polyethylene glycol as represented by polyethylene glycol weight divided by fluid weight x 100 when formed and prior to drying.

[0444] In another specific embodiment, the present invention relates to a method for treating neovascular age-related macular degeneration in a patient in need thereof, the method comprising administering to the patient a sustained-release biodegradable ocular implant comprising a hydrogel comprising a polymer network and about 200 μg of a tyrosine kinase inhibitor, wherein three implants per eye forming a total dose of about 600 μg are administered once over a treatment period of at least 3 months or at least 9 months, and wherein the patient has a history of anti-VEGF treatment or no history of anti-VEGF treatment (has not been treated for AMD). In this embodiment, the treatment reduces (or at least maintains) the central subfield thickness (CSFT) as measured by optical coherence tomography during the treatment period. In this embodiment, the TKI may further be axitinib, which is dispersed in the hydrogel, the hydrogel comprising a polymer network formed by reacting 4a20kPEG-SAZ with 8a20kPEG-NH2, and wherein the implant is in a dry state before administration. In this embodiment, the hydrogel contains about 7.5% polyethylene glycol expressed as the weight of polyethylene glycol divided by the weight of the fluid x 100 when formed and before drying.

[0445] In other embodiments, the present invention relates to a method for treating neovascular age-related macular degeneration in a patient in need thereof, the method comprising administering to the patient a sustained-release biodegradable ocular implant comprising axitinib dispersed in a hydrogel comprising a polymer network in an amount in the range of about 480 μg to about 750 μg, wherein the implant is administered once over a treatment period of at least 3 months. In some of these embodiments, axitinib is included in the implant in an amount of about 560 μg to about 660 μg or about 600 μg. For specific properties of the implant, reference is made to the above section for implants containing axitinib in an amount in the range of about 480 μg to about 750 μg or in an amount of about 560 μg to about 660 μg or about 600 μg according to the present invention. The implant may be administered into the vitreous humor, for example, through a fine diameter, such as a 25-gauge needle. The treatment period as defined above may be at least 4.5 months, or at least 6 months, or at least 9 months, or at least 11 months, or at least 12 months, or at least 13 months, or at least 14 months or even longer, such as up to about 15 months. In a specific embodiment, the treatment period is at least 6 months, or at least 9 months, or at least 12 months, or from about 6 to about 9 months.

[0446] In some embodiments, an anti-VEGF agent is administered to a patient concurrently with treatment with a sustained release biodegradable ocular implant containing a TKI or with a sustained release biodegradable ocular implant containing axitinib according to the present invention. The anti-VEGF agent is optionally selected from aflibercept, bevacizumab, pegaptanib, ranibizumab, and brolucizumab. In certain embodiments, the anti-VEGF agent is bevacizumab. In a specific embodiment, the anti-VEGF agent is aflibercept. In some embodiments, the anti-VEGF agent is administered by intravitreal injection concurrently (as defined above) with the sustained release biodegradable ocular implant, optionally at the same time, i.e., administered over a period of time as has been detailedly disclosed above. In the event that it is not possible to administer the anti-VEGF agent and the implant of the present invention in the same period, for example due to administration complications or patient-related reasons, alternatively, it may be administered sequentially in two or more different periods, for example, two implants are administered 7 days apart. In the context of the present invention, this may still be regarded as "concurrent" administration.

[0447] In other embodiments, the anti-VEGF agent may be combined with the implant of the present invention but not at the same time (i.e., not concurrently), but at an earlier or later time point during the treatment period of the implant of the present invention. In certain embodiments, the anti-VEGF agent may be administered within about 1, about 2, or about 3 or more months from the administration of the implant, i.e., it may be administered before or after the implant. This combination (and schedule) of co-administration of the anti-VEGF agent is different from a rescue medication as defined herein.

[0448] In certain embodiments of the present invention, the patient is diagnosed with subfoveal neovascularization (SFNV) secondary to AMD, such as active subfoveal or juxtafoveal CNV with leakage involving the fovea.

[0449] In certain embodiments of the present invention, the patient is diagnosed with previously treated subfoveal neovascularization (SFNV) secondary to neovascular AMD with leakage involving the fovea. In such patients, the previous treatment utilized an anti-VEGF agent.

[0450] In some embodiments, the patient is at least 50 years old or at least 60 years old. The patient may be male or female. The patient may have retinal fluid, such as intraretinal fluid or subretinal fluid.

[0451] In some embodiments, the patient receiving the implant has a history of anti-VEGF treatment, for example, such as with and / or Treatment. In certain embodiments, a patient receiving the implant has a history of anti-VEGF treatment but does not respond to such anti-VEGF treatment, i.e., the anti-VEGF treatment does not improve the patient's disease state. In embodiments where the patient has a history of anti-VEGF treatment prior to starting treatment with the implant according to the present invention, administration of the implant of the present invention can extend the effect of the prior anti-VEGF treatment over a longer period of time, such as over the treatment period as defined above. In other embodiments, the patient receiving the implant has no history of anti-VEGF treatment (has not received anti-VEGF, has not received AMD treatment).

[0452] In certain embodiments, the systemic plasma concentration of a TKI (such as axitinib) is less than 1 ng / mL, or less than 0.5 ng / mL, or less than 0.3 ng / mL, or less than 0.1 ng / mL (or less than the limit of quantification). Since the systemic concentration of the TKI is kept to a minimum, the risk of drug-drug interactions or systemic toxicity is also kept to a minimum. Thus, in one embodiment, one or more additional drugs taken by the patient do not pose a significant risk. This is particularly beneficial for elderly patients who are often troubled by eye diseases and are taking other drugs in addition.

[0453] Once injected, the implant (comprising the hydrogel and the drug) of certain embodiments of the present invention degrades over a longer period of time as disclosed above, e.g., about 9 to 12 months. In certain embodiments, it is possible that once the hydrogel has completely degraded, the undissolved axitinib particles remain positioned at the location where the implant was located. When the hydrogel degrades, these undissolved particles can further maintain a rate of TKI delivery sufficient to achieve a therapeutic effect (i.e., inhibit vascular leakage). Figure 15 Illustratively presented is the resorption of the hydrogel and remaining axitinib particles at the previous implant location in one patient up to 11 months after administration. However, in certain embodiments, all of the TKI is dissolved before the hydrogel has completely degraded.

[0454] In certain embodiments, only mild or moderate adverse events, such as ocular adverse events, are observed during the treatment period. In certain embodiments, no severe ocular adverse reactions are observed, and no treatment-related severe ocular adverse events are observed. Tables 23 and 25 show the incidence of adverse events in the subjects of Group 1 and Group 2 and Group 3a and Group 3b of the clinical study, the results of which (available to date) are presented in Example 6.4.

[0455] In certain embodiments, the present invention also relates to a method of reducing, substantially maintaining (as measured by optical coherence tomography), or preventing a clinically significant increase in central subfield thickness in a patient in which the central subfield thickness is elevated due to an ocular disease involving angiogenesis, the method comprising administering to the patient a sustained release biodegradable ophthalmic implant comprising a tyrosine kinase inhibitor of the present invention as disclosed herein. In certain embodiments, the ocular disease involving angiogenesis is neovascular age-related macular degeneration. In other embodiments, at least 3 months, at least 4.5 months, at least 6 months, at least 9 months, at least 11 months, at least 12 months, at least 13 months, or at least 14 months or even longer, such as at least 15 months, after administering to a patient in which the central subfield thickness is elevated due to an ocular disease involving angiogenesis, such as neovascular age-related macular degeneration, the central subfield thickness is reduced, substantially maintained, or prevented from increasing clinically significantly. In certain embodiments, the patient's visual acuity, as represented, for example, by BCVA, is not substantially impaired during treatment. In certain other embodiments, the patient's visual acuity, as represented, for example, by BCVA, may even be improved. Accordingly, in certain embodiments, the present invention also relates to a method of improving visual acuity in a patient in which visual acuity is impaired, for example, due to retinal fluid caused by an ocular disease involving angiogenesis, wherein the method comprises administering to the patient an implant according to the present invention, such as by intravitreal injection.

[0456] Additional disclosure

[0457] In addition to the foregoing disclosure, the present invention also discloses the following items and lists of items:

[0458] First list of items

[0459] 1. A sustained release biodegradable ophthalmic implant comprising a hydrogel and from about 150 μg to about 1200 μg of a tyrosine kinase inhibitor.

[0460] 2. The sustained release biodegradable ophthalmic implant of item 1, wherein the tyrosine kinase inhibitor is axitinib.

[0461] 3. The sustained release biodegradable ophthalmic implant of claim 1 or 2, which comprises the tyrosine kinase inhibitor in an amount in the range of from about 200 μg to about 800 μg.

[0462] 4. The sustained release biodegradable ophthalmic implant of item 1 or item 2, which comprises the tyrosine kinase inhibitor in an amount in the range of from about 160 μg to about 250 μg.

[0463] 5. The sustained release biodegradable ophthalmic implant of claim 4, which comprises the tyrosine kinase inhibitor in an amount in the range of from about 180 μg to about 220 μg.

[0464] 6. The sustained release biodegradable ophthalmic implant of item 5, which comprises the tyrosine kinase inhibitor in an amount of about 200 μg.

[0465] 7. The sustained release biodegradable ophthalmic implant of claim 1 or 2, which comprises the tyrosine kinase inhibitor in an amount in the range of from about 320 μg to about 500 μg.

[0466] 8. The sustained release biodegradable ophthalmic implant of item 7, which comprises the tyrosine kinase inhibitor in an amount in the range of from about 360 μg to about 440 μg.

[0467] 9. The sustained release biodegradable ophthalmic implant of claim 8, which comprises the tyrosine kinase inhibitor in an amount of about 400 μg.

[0468] 10. The sustained release biodegradable ophthalmic implant of claim 1 or 2, which comprises the tyrosine kinase inhibitor in an amount in the range of from about 480 μg to about 750 μg.

[0469] 11. The sustained release biodegradable ophthalmic implant of claim 10, which comprises the tyrosine kinase inhibitor in an amount in the range of from about 540 μg to about 660 μg.

[0470] 12. The sustained release biodegradable ophthalmic implant of item 11, which comprises the tyrosine kinase inhibitor in an amount of about 600 μg.

[0471] 13. The sustained release biodegradable ophthalmic implant of claim 1 or 2, which comprises the tyrosine kinase inhibitor in an amount in the range of from about 640 μg to about 1000 μg.

[0472] 14. The sustained release biodegradable ophthalmic implant of item 13, which comprises the tyrosine kinase inhibitor in an amount in the range of from about 720 μg to about 880 μg.

[0473] 15. The sustained release biodegradable ophthalmic implant of item 14, which comprises the tyrosine kinase inhibitor in an amount of about 800 μg.

[0474] 16. The sustained release biodegradable ophthalmic implant of any one of the foregoing items, wherein the implant is for administration to the posterior part of the eye.

[0475] 17. The sustained release biodegradable ophthalmic implant of item 16, wherein the administration is by intravitreal administration.

[0476] 18. A sustained-release biodegradable ophthalmic implant as in any of the preceding items, wherein the tyrosine kinase inhibitor particles are dispersed within the hydrogel.

[0477] 19. The sustained-release biodegradable ophthalmic implant of item 18, wherein the tyrosine kinase inhibitor particles are micronized particles.

[0478] 20. A sustained-release biodegradable ophthalmic implant as in any of the preceding items, wherein the implant is in a dry state before administration and hydrates once administered into the eye.

[0479] 21. A sustained-release biodegradable ophthalmic implant as in any of the preceding items, wherein the hydrogel comprises a polymer network that comprises units of one or more of polyethylene glycol, poly(ethylene oxide), poly(propylene oxide), poly(vinyl alcohol), poly(vinylpyrrolidone), polylactic acid, a copolymer of lactic acid and glycolic acid, a random or block copolymer or combination or mixture of any of the foregoing, or units of one or more polyamino acids, glycosaminoglycans, polysaccharides, or proteins.

[0480] 22. The sustained-release biodegradable ophthalmic implant of item 21, wherein the hydrogel comprises a polymer network that comprises crosslinked polymer units that are the same or different.

[0481] 23. The sustained-release biodegradable ophthalmic implant of item 22, wherein the crosslinked polymer units are one or more crosslinked polyethylene glycol units.

[0482] 24. A sustained-release biodegradable ophthalmic implant as in any of items 21 to 23, wherein the polymer network comprises polyethylene glycol units having an average molecular weight in the range of about 2,000 to about 100,000 daltons.

[0483] 25. The sustained-release biodegradable ophthalmic implant of item 24, wherein the polyethylene glycol units have an average molecular weight in the range of about 10,000 to about 60,000 daltons.

[0484] 26. The sustained-release biodegradable ophthalmic implant of item 25, wherein the polyethylene glycol units have an average molecular weight in the range of about 20,000 to about 40,000 daltons.

[0485] 27. The sustained-release biodegradable ophthalmic implant of item 26, wherein the polyethylene glycol units have an average molecular weight of about 20,000 daltons.

[0486] 28. A sustained-release biodegradable ophthalmic implant according to any one of items 21 to 27, wherein the polymer network comprises one or more crosslinked multi-arm polymer units.

[0487] 29. A sustained-release biodegradable ophthalmic implant according to item 28, wherein the multi-arm polymer unit comprises one or more polyethylene glycol units having 2 to 10 arms.

[0488] 30. A sustained-release biodegradable ophthalmic implant according to item 29, wherein the multi-arm polymer unit comprises one or more polyethylene glycol units having 4 to 8 arms.

[0489] 31. A sustained-release biodegradable ophthalmic implant according to item 30, wherein the multi-arm polymer unit comprises one or more polyethylene glycol units having 4 arms.

[0490] 32. A sustained-release biodegradable ophthalmic implant according to any one of items 21 to 31, wherein the polymer network comprises 4-arm and 8-arm polyethylene glycol units.

[0491] 33. A sustained-release biodegradable ophthalmic implant according to any one of items 21 to 32, wherein the polymer network is formed by reacting a multi-arm polymer precursor containing an electrophilic group with a multi-arm polymer precursor containing a nucleophilic group.

[0492] 34. A sustained-release biodegradable ophthalmic implant according to any one of items 21 to 33, wherein the nucleophilic group is an amino group.

[0493] 35. A sustained-release biodegradable ophthalmic implant according to any one of items 21 to 34, wherein the electrophilic group is an active ester group.

[0494] 36. A sustained-release biodegradable ophthalmic implant according to item 35, wherein the electrophilic group is an N-hydroxysuccinimide (NHS) group.

[0495] 37. A sustained-release biodegradable ophthalmic implant according to item 36, wherein the electrophilic group is a suberic acid succinimide ester (SAZ) group.

[0496] 38. A sustained-release biodegradable ophthalmic implant according to any one of items 32 to 37, wherein the 4-arm polyethylene glycol unit is a 4a20kPEG unit and the 8-arm polyethylene glycol unit is an 8a20kPEG unit.

[0497] 39. A sustained-release biodegradable ophthalmic implant according to item 38, wherein the polymer network is obtained by reacting 4a20kPEG-SAZ with 8a20kPEG-NH2 at a weight ratio of about 2:1 or less.

[0498] 40. A sustained-release biodegradable ophthalmic implant according to any one of items 1 to 39, wherein the implant contains, in the dry state, from about 25% to about 75% by weight of the tyrosine kinase inhibitor and from about 20% to about 60% by weight of polymer units.

[0499] 41. A sustained-release biodegradable ophthalmic implant according to item 40, wherein the implant contains, in the dry state, from about 35% to about 65% by weight of the tyrosine kinase inhibitor and from about 25% to about 50% by weight of polymer units.

[0500] 42. A sustained-release biodegradable ophthalmic implant according to item 41, wherein the implant contains, in the dry state, from about 45% to about 55% by weight of the tyrosine kinase inhibitor and from about 37% to about 47% by weight of polymer units.

[0501] 43. A sustained-release biodegradable ophthalmic implant according to any one of the preceding items, wherein the implant contains one or more phosphates, borates or carbonates.

[0502] 44. A sustained-release biodegradable ophthalmic implant according to item 43, wherein the implant contains phosphates derived from the phosphate buffer used during the preparation of the hydrogel.

[0503] 45. A sustained-release biodegradable ophthalmic implant according to any one of the preceding items, wherein the hydrogel contains, in the wet state, from about 3% to about 20% polyethylene glycol expressed as (weight of polyethylene glycol / weight of fluid) x 100.

[0504] 46. A sustained-release biodegradable ophthalmic implant according to item 45, wherein the hydrogel contains, in the wet state, from about 7.5% to about 15% polyethylene glycol expressed as (weight of polyethylene glycol / weight of fluid) x 100.

[0505] 47. A sustained-release biodegradable ophthalmic implant according to any one of the preceding items, wherein the implant contains, in the dry state, not more than about 1% water by weight.

[0506] 48. A sustained-release biodegradable ophthalmic implant according to any one of the preceding items, wherein the implant has a substantially cylindrical shape or another shape such as a cross.

[0507] 49. A sustained-release biodegradable ophthalmic implant according to any one of the preceding items, wherein the implant is in fibrous form.

[0508] 50. A sustained release biodegradable ophthalmic implant as in any of the foregoing items, wherein the implant is administered to the eye through a needle.

[0509] 51. A sustained release biodegradable ophthalmic implant as in item 50, wherein the needle is a 25- or 27-gauge needle.

[0510] 52. A sustained release biodegradable ophthalmic implant as in any of the foregoing items, wherein, in vivo in the eye or after in vitro hydration, the diameter of the implant increases, or the length of the implant decreases while its diameter increases.

[0511] 53. A sustained release biodegradable ophthalmic implant as in item 52, wherein in vitro hydration is measured after 24 hours at pH 7.2 and 37 °C in phosphate buffered saline.

[0512] 54. A sustained release biodegradable ophthalmic implant as in any of items 17 to 53, wherein the implant biodegrades in the vitreous humor within about 2 to about 15 months after administration.

[0513] 55. A sustained release biodegradable ophthalmic implant as in item 54, wherein the implant biodegrades in the vitreous humor within about 4 to about 13 months after administration.

[0514] 56. A sustained release biodegradable ophthalmic implant as in item 55, wherein the implant biodegrades in the vitreous humor within about 9 to about 12 months after administration.

[0515] 57. A sustained release biodegradable ophthalmic implant as in any of items 2 to 56, wherein the implant releases a therapeutically effective amount of axitinib for at least about 3 months, at least about 6 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least about 13 months, or at least about 14 months after administration of the vitreous humor.

[0516] 58. A sustained release biodegradable ophthalmic implant as in item 57, wherein the implant releases a therapeutically effective amount of axitinib for at least about 6 months after administration of the vitreous humor.

[0517] 59. A sustained release biodegradable ophthalmic implant as in item 57, wherein the implant releases a therapeutically effective amount of axitinib for at least about 9 months after administration of the vitreous humor.

[0518] 60. A sustained release biodegradable ophthalmic implant as in any of items 17 to 59, wherein axitinib is released from the implant at an average rate of about 0.1 μg / day to about 10 μg / day after administration.

[0519] 61. The sustained release biodegradable ophthalmic implant as in item 60, wherein axitinib is released from the implant at an average rate of about 0.5 μg / day to about 7 μg / day.

[0520] 62. The sustained release biodegradable ophthalmic implant as in item 61, wherein axitinib is released from the implant at an average rate of about 1 μg / day to about 5 μg / day.

[0521] 63. The sustained release biodegradable ophthalmic implant as in any one of items 17 to 62, wherein the implant biodegrades in the vitreous humor before all of the tyrosine kinase inhibitor particles contained in the implant are completely dissolved.

[0522] 64. The sustained release biodegradable ophthalmic implant as in any one of items 17 to 63, wherein the entire amount of the tyrosine kinase inhibitor contained in the implant is released before the implant is completely degraded in the vitreous humor.

[0523] 65. The sustained release biodegradable ophthalmic implant as in any one of the foregoing items, wherein the implant is obtained by preparing a mixture containing a hydrogel precursor and a tyrosine kinase inhibitor, filling the mixture into a tube, gelling the hydrogel in the tube to provide a hydrogel shaped into fibers, and stretching the hydrogel fibers.

[0524] 66. The sustained release biodegradable ophthalmic implant as in item 65, wherein the fibers have been stretched and / or twisted before or after drying.

[0525] 67. The sustained release biodegradable ophthalmic implant as in item 66, wherein the fibers have been stretched in the longitudinal direction by a stretch factor of about 1.0 to about 4.5.

[0526] 68. A sustained release biodegradable ophthalmic implant comprising axitinib in an amount of 160 μg to about 250 μg or about 180 μg to about 220 μg, or about 200 μg and dispersed in a hydrogel, wherein the hydrogel comprises a polymer network including polyethylene glycol units, and wherein the implant is in a dry state before administration.

[0527] 69. The sustained release biodegradable ophthalmic implant as in item 68, wherein the polymer network is formed by reacting 4a20kPEG-SAZ with 8a20kPEG-NH2.

[0528] 70. The sustained release biodegradable ophthalmic implant as in item 69, wherein the hydrogel contains polyethylene glycol in an amount of 7.5% expressed as polyethylene glycol weight divided by fluid weight x 100 when formed and before drying.

[0529] 71. A sustained-release biodegradable ophthalmic implant according to any one of items 68 to 70, wherein the implant contains about 45% to about 55% by weight of axitinib and about 37% to about 47% by weight of polyethylene glycol units in the dry state.

[0530] 72. A sustained-release biodegradable ophthalmic implant according to any one of items 68 to 71, wherein the implant contains no more than about 1% by weight of water in the dry state.

[0531] 73. A sustained-release biodegradable ophthalmic implant according to any one of items 68 to 72, wherein the polymer network is formed by reacting 4a20kPEG-SAZ with 8a20kPEG-NH2 at a weight ratio of about 2:1 or less.

[0532] 74. A sustained-release biodegradable ophthalmic implant according to any one of items 68 to 73, wherein the implant releases about 0.01 μg to about 0.15 μg of axitinib per day in vitro in phosphate-buffered saline at 37°C for a period of 30 days.

[0533] 75. A sustained-release biodegradable ophthalmic implant according to any one of items 68 to 74, wherein the implant releases about 35% to about 45% of the axitinib in vitro in a 25:75 ethanol / water mixture (v / v) at 37°C within 3 days, about 65% to about 75% of the axitinib within 7 days, and about 90% to about 100% of the axitinib within 12 to 13 days.

[0534] 76. A sustained-release biodegradable ophthalmic implant according to any one of items 68 to 75, wherein the implant releases about 25% to about 35% of the axitinib in vitro in phosphate-buffered saline at pH 7.2 with an octanol upper layer at 37°C within 2 months, about 47% to about 57% of the axitinib within 3 months, about 70% to about 80% of the axitinib within 5 months, and about 90% to about 100% of the axitinib within 7 months.

[0535] 77. A sustained-release biodegradable ophthalmic implant according to any one of items 68 to 76, wherein the implant is in the form of fibers having an average length of about 15 mm to about 16.5 mm and an average diameter of about 0.20 mm to about 0.30 mm in its dry state.

[0536] 78. The sustained release biodegradable ophthalmic implant of item 77, which decreases in length and increases in diameter in vivo in the eye or after in vitro hydration, wherein the hydration is measured in vitro after 24 hours at pH 7.2 and 37 °C in phosphate buffered saline.

[0537] 79. The sustained release biodegradable ophthalmic implant of item 77 or 78, wherein the implant has an average length of about 6.5 to about 8 mm and an average diameter of about 0.70 to about 0.80 mm in its hydrated state.

[0538] 80. The sustained release biodegradable ophthalmic implant of any one of items 68 to 79, wherein the implant is obtained by preparing a mixture containing a hydrogel precursor and axitinib, filling the mixture into a tube, gelling the hydrogel in the tube to provide a hydrogel shaped as a fiber, and stretching the hydrogel fiber.

[0539] 81. The sustained release biodegradable ophthalmic implant of item 80, wherein the fiber is stretched by a factor of about 2 to about 5 after drying.

[0540] 82. The sustained release biodegradable ophthalmic implant of item 81, wherein the fiber is stretched by a factor of about 3 to about 4.5 after drying.

[0541] 83. The sustained release biodegradable ophthalmic implant of any one of items 68 to 82, wherein the implant is loaded in a needle, such as a 25-gauge needle or a 27-gauge needle, in a dry state for injection into the vitreous humor.

[0542] 84. A sustained release biodegradable ophthalmic implant containing axitinib in an amount in the range of about 480 μg to about 750 μg and dispersed in a hydrogel, wherein the hydrogel comprises a polymer network.

[0543] 85. The sustained release biodegradable ophthalmic implant of item 84, wherein the polymer network comprises crosslinked polyethylene glycol units.

[0544] 86. The sustained release biodegradable ophthalmic implant of item 85, wherein the content of axitinib is in the range of about 540 μg to about 660 μg.

[0545] 87. The sustained release biodegradable ophthalmic implant of item 86, wherein the content of axitinib is about 600 μg.

[0546] 88. A sustained release biodegradable ophthalmic implant according to any one of items 84 to 87, wherein the polyethylene glycol units comprise 4-arm and / or 8-arm polyethylene glycol units having an average molecular weight in the range of about 10,000 daltons to about 60,000 daltons.

[0547] 89. The sustained release biodegradable ophthalmic implant according to item 88, wherein the polyethylene glycol units comprise 4a20kPEG units.

[0548] 90. The sustained release biodegradable ophthalmic implant according to item 89, wherein the polymer network is formed by reacting 4a20kPEG-SAZ with 8a20kPEG-NH2.

[0549] 91. The sustained release biodegradable ophthalmic implant according to item 90, wherein the weight ratio of 4a20kPEG-SAZ to 8a20kPEG-NH2 is about 2:1 or less.

[0550] 92. The sustained release biodegradable ophthalmic implant according to any one of items 84 to 91, wherein the implant contains about 45% to about 55% by weight of axitinib and about 37% to about 47% by weight of polyethylene glycol units in the dry state.

[0551] 93. The sustained release biodegradable ophthalmic implant according to any one of items 84 to 92, wherein the implant contains no more than about 1% by weight of water in the dry state.

[0552] 94. The sustained release biodegradable ophthalmic implant according to any one of items 84 to 93, wherein the implant is in the form of a fiber having an average length of about 7 mm to about 12 mm and an average diameter of about 0.25 mm to about 0.50 mm in its dry state.

[0553] 95. The sustained release biodegradable ophthalmic implant according to item 94, wherein the implant is in the form of a fiber having an average length of about 8 mm to about 11 mm and an average diameter of about 0.3 mm to about 0.4 mm in its dry state.

[0554] 96. The sustained release biodegradable ophthalmic implant according to any one of items 84 to 95, wherein the implant is for administration to the vitreous humor.

[0555] 97. The sustained release biodegradable ophthalmic implant according to items 94 to 96, which increases in diameter in vivo in the eye or after in vitro hydration, wherein in vitro hydration is measured after 24 hours at pH 7.2, 37 °C in phosphate buffered saline.

[0556] 98. The sustained release biodegradable ophthalmic implant of item 97, wherein the implant has an average length of about 9 mm to about 12 mm and an average diameter of about 0.5 mm to about 0.8 mm in its hydrated state.

[0557] 99. The sustained release biodegradable ophthalmic implant of item 98, wherein the implant has an average length of about 9.5 mm to about 11.5 mm and an average diameter of about 0.65 mm to about 0.75 mm in its hydrated state, or an average length not exceeding about 10 mm or not exceeding about 9 mm in its hydrated state.

[0558] 100. The sustained release biodegradable ophthalmic implant of any one of items 84 to 99, wherein the implant contains about 600 μg axitinib and releases about 0.3 μg to about 0.5 μg axitinib per day in vitro in phosphate buffered saline at 37°C for a period of 30 days.

[0559] 101. The sustained release biodegradable ophthalmic implant of any one of items 84 to 100, wherein the implant releases about 40% to about 60% of the axitinib in vitro in a 25:75 ethanol / water mixture (v / v) at 37°C within 2 days, about 65% to about 85% of the axitinib in vitro within 4 days, and about 75% to about 90% of the axitinib in vitro within 6 days.

[0560] 102. The sustained release biodegradable ophthalmic implant of item 101, wherein the implant releases about 45% to about 55% of the axitinib in vitro in a 25:75 ethanol / water mixture (v / v) at 37°C within 2 days, about 70% to about 80% of the axitinib in vitro within 4 days, and about 80% to about 90% of the axitinib in vitro within 6 days.

[0561] 103. The sustained release biodegradable ophthalmic implant of any one of items 84 to 102, wherein the implant is obtained by preparing a mixture containing a hydrogel precursor and axitinib, filling the mixture into a tube, gelling the hydrogel in the tube to provide a hydrogel shaped as a fiber, and stretching the hydrogel fiber.

[0562] 104. The sustained release biodegradable ophthalmic implant of item 103, wherein the fiber is wet stretched by a factor of about 0.5 to about 5 before drying.

[0563] 105. The sustained release biodegradable ophthalmic implant of item 104, wherein the fiber is wet stretched by a factor of about 1 to about 4 before drying.

[0564] 106. The sustained release biodegradable ophthalmic implant of item 105, wherein the fibers are wet stretched by a factor of about 1.5 to about 3.5 before drying.

[0565] 107. The sustained release biodegradable ophthalmic implant of item 106, wherein the fibers are wet stretched by a factor of about 1.7 to about 3 before drying.

[0566] 108. The sustained release biodegradable ophthalmic implant of any one of items 84 to 107, wherein the implant is loaded into a needle in a dry state for injection into the vitreous humor.

[0567] 109. The sustained release biodegradable ophthalmic implant of item 108, wherein the implant is loaded into a 25-gauge or 27-gauge needle in a dry state.

[0568] 110. The sustained release biodegradable ophthalmic implant of any one of items 1 to 109, wherein the hydrogel comprises a polymer network that is semi-crystalline at room temperature or below in the dry state and amorphous in the wet state.

[0569] 111. The sustained release biodegradable ophthalmic implant of any one of items 1 to 110, wherein the implant has been wet or dry stretched during manufacture, and wherein the stretched form of the implant is dimensionally stable at room temperature or below in the dry state.

[0570] 112. A method of treating an eye disease in a patient in need thereof, the method comprising administering to the patient a sustained release biodegradable ophthalmic implant comprising a hydrogel and a tyrosine kinase inhibitor according to any one of the foregoing items, wherein the dose administered once per eye during a treatment period of at least 3 months is about 150 μg to about 1200 μg of the tyrosine kinase inhibitor.

[0571] 113. The method of item 112, wherein the tyrosine kinase inhibitor is axitinib.

[0572] 114. The method of item 112 or 113, wherein the dose administered once per eye during the treatment period is in the range of about 200 μg to about 800 μg.

[0573] 115. The method of item 112 or 113, wherein the dose is in the range of about 160 μg to about 250 μg or about 180 μg to about 220 μg.

[0574] 116. The method of item 115, wherein the dose is about 200 μg.

[0575] 117. The method according to item 112 or 113, wherein the dose is in the range of about 320 μg to about 500 μg or about 360 μg to about 440 μg.

[0576] 118. The method according to item 117, wherein the dose is about 400 μg.

[0577] 119. The method according to item 112 or 113, wherein the dose is in the range of about 480 μg to about 750 μg or about 540 μg to about 660 μg.

[0578] 120. The method according to item 119, wherein the dose is about 600 μg.

[0579] 121. The method according to item 112 or 113, wherein the dose is in the range of about 640 μg to about 1000 μg or about 720 μg to about 880 μg.

[0580] 122. The method according to item 121, wherein the dose is about 800 μg.

[0581] 123. The method according to any one of items 112 to 122, wherein the eye disease involves angiogenesis.

[0582] 124. The method according to any one of items 112 to 123, wherein the eye disease is mediated by one or more receptor tyrosine kinases (RTKs), specifically VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-α / β, and / or c-Kit.

[0583] 125. The method according to any one of items 112 to 124, wherein the ocular disease is a retinal disease, including choroidal neovascularization, diabetic retinopathy, diabetic macular edema, retinal vein occlusion, acute macular neuroretinopathy, central serous chorioretinopathy, and cystoid macular edema; wherein the ocular disease is acute multifocal placoid pigment epitheliopathy, Behcet's disease, birdshot retinochoroidopathy, infectious (syphilis, Lyme disease, tuberculosis, toxoplasmosis), intermediate uveitis, multifocal choroiditis, multiple evanescent white dot syndrome (MEWDS), sarcoidosis, posterior scleritis, serpiginous choroiditis, subretinal fibrosis, uveitis syndrome, or Vogt-Koyanagi-Harada syndrome; wherein the ocular disease is a vascular disease or an exudative disease, including Coats' disease, juxtafoveal telangiectasis, peripapillary vasculitis, frosting branch angiitis, sickle cell retinopathy, and other hemoglobinopathies, angioid streaks, and familial exudative vitreoretinopathy; or wherein the ocular disease is caused by trauma or surgery, including sympathetic ophthalmia, uveoretinitis, retinal detachment, trauma, photodynamic laser therapy, photocoagulation, intraoperative perfusion insufficiency, radiation retinopathy, or bone marrow transplantation retinopathy.

[0584] 126. The method according to any one of items 112 to 124, wherein the ocular disease is neovascular age-related macular degeneration, diabetic macular edema, or retinal vein occlusion.

[0585] 127. The method according to item 126, wherein the disease is neovascular age-related macular degeneration.

[0586] 128. The method according to any one of items 112 to 127, wherein the treatment is effective in reducing, substantially maintaining, or preventing a clinically significant increase in central subfield thickness in patients with elevated central subfield thickness, as measured by optical coherence tomography.

[0587] 129. The method according to any one of items 112 to 128, wherein the dose administered once per eye during the treatment period is contained in one implant or in two, three, or more implants administered simultaneously.

[0588] 130. The method according to any one of items 112 to 129, wherein the implant is administered by injection into the vitreous humor.

[0589] 131. A method according to any one of items 112 to 130, wherein the treatment period is at least about 3 months, at least about 4.5 months, at least about 6 months, at least about 9 months, at least about 11 months, at least about 12 months, at least about 13 months or at least about 14 months.

[0590] 132. A method according to item 131, wherein the treatment period is at least 6 months, at least about 9 months or at least about 12 months.

[0591] 133. A method according to any one of items 112 to 132, wherein an anti-VEGF agent is administered to the patient concurrently with treatment with the sustained-release ophthalmic implant, or wherein the anti-VEGF agent is administered within about 1, about 2 or about 3 months after administration of the implant.

[0592] 134. A method according to item 133, wherein the anti-VEGF agent is selected from the group consisting of aflibercept, bevacizumab, pegaptanib, ranibizumab and brolucizumab.

[0593] 135. A method according to item 134, wherein the anti-VEGF agent is bevacizumab.

[0594] 136. A method according to any one of items 133 to 135, wherein the anti-VEGF agent is administered by intravitreal injection.

[0595] 137. A method according to any one of items 112 to 136, wherein the patient receiving the implant has a history of anti-VEGF treatment.

[0596] 138. A method according to any one of items 112 to 136, wherein the patient receiving the implant has no history of anti-VEGF treatment (has not undergone anti-VEGF).

[0597] 139. A method of treating neovascular age-related macular degeneration in a patient in need thereof, the method comprising administering to the patient a sustained-release biodegradable ophthalmic implant comprising a hydrogel comprising a polymer network and about 200 μg of a tyrosine kinase inhibitor, wherein one implant per eye is administered once over a treatment period of at least 9 months, and wherein the patient has a history of anti-VEGF treatment.

[0598] 140. A method of treating neovascular age-related macular degeneration in a patient in need thereof, the method comprising administering to the patient a sustained-release biodegradable ophthalmic implant comprising a hydrogel comprising a polymer network and about 200 μg of a tyrosine kinase inhibitor, wherein two implants per eye forming a total dose of about 400 μg are administered once over a treatment period of at least 3 months, and wherein the patient has a history or no history of anti-VEGF treatment.

[0599] 141. A method according to item 139 or 140, wherein the treatment results in a reduction in central subfield thickness (CSFT), as measured by optical coherence tomography during the treatment period.

[0600] 142. A method according to any one of items 139 to 141, wherein the tyrosine kinase inhibitor is axitinib and is dispersed in the hydrogel, the hydrogel comprising a polymer network formed by reacting 4a20kPEG-SAZ with 8a20kPEG-NH2, and wherein the implant is in a dry state before administration.

[0601] 143. A method according to item 142, wherein the hydrogel contains polyethylene glycol in an amount of about 7.5% as represented by polyethylene glycol weight divided by fluid weight x 100 when formed and before drying.

[0602] 144. A method according to any one of items 140 to 143, wherein the treatment period is at least 9 months.

[0603] 145. A method of treating neovascular age-related macular degeneration in a patient in need thereof, the method comprising administering to the patient a sustained-release biodegradable ocular implant comprising axitinib in an amount in the range of about 480 μg to about 750 μg and dispersed in a hydrogel comprising a polymer network, wherein the implant is administered once during a treatment period of at least 3 months.

[0604] 146. A method according to item 145, wherein the amount of axitinib in the implant is about 560 μg to about 660 μg.

[0605] 147. A method according to item 146, wherein the amount of axitinib in the implant is about 600 μg.

[0606] 148. A method according to any one of items 145 to 147, wherein the implant is as defined in items 84 to 111.

[0607] 149. A method according to any one of items 145 to 148, wherein the implant is administered into the vitreous humor.

[0608] 150. A method according to any one of items 145 to 149, wherein the treatment period is at least about 3 months, at least about 6 months, at least about 9 months, at least about 11 months, at least about 12 months, at least about 13 months or at least about 14 months.

[0609] 151. The method according to any one of items 145 to 150, wherein the implant is administered by injection into the vitreous humor using a 25- or 27-gauge needle.

[0610] 152. The method according to any one of items 145 to 151, wherein the patient receiving the implant has a history of anti-VEGF treatment or no history of anti-VEGF treatment (has not undergone anti-VEGF).

[0611] 153. The method according to any one of items 145 to 152, wherein an anti-VEGF agent is administered to the patient simultaneously with the implant.

[0612] 154. The method according to item 153, wherein the anti-VEGF agent is selected from the group consisting of aflibercept, bevacizumab, pegaptanib, ranibizumab, and brolucizumab.

[0613] 155. The method according to item 154, wherein the anti-VEGF agent is bevacizumab.

[0614] 156. The method according to any one of items 153 to 155, wherein the anti-VEGF agent is administered by intravitreal injection.

[0615] 157. The method according to any one of items 112 to 156, wherein the number of adverse events is low during administration of the sustained-release biodegradable ophthalmic implant.

[0616] 158. The method according to item 157, wherein the number of treatment-related ocular adverse events is low during administration of the sustained-release biodegradable ophthalmic implant.

[0617] 159. A method of manufacturing a sustained-release biodegradable ophthalmic implant according to any one of items 1 to 111, comprising a hydrogel and from about 150 μg to about 1200 μg of a tyrosine kinase inhibitor, the method comprising the steps of: forming a hydrogel comprising a polymer network and tyrosine kinase inhibitor particles dispersed in the hydrogel; shaping the hydrogel; and drying the hydrogel.

[0618] 160. The method according to item 159, wherein the tyrosine kinase inhibitor is axitinib.

[0619] 161. The method according to item 159 or 160, wherein the tyrosine kinase inhibitor particles are micronized and / or homogeneously dispersed within the hydrogel.

[0620] 162. The method according to any one of items 159 to 161, wherein the polymer network is formed by crosslinking multi-arm polyethylene glycol units in a buffer solution.

[0621] 163. The method according to any one of items 159 to 162, wherein the hydrogel comprises a polymer network formed by mixing and reacting a multi-arm polyethylene glycol containing an electrophilic group and a multi-arm polyethylene glycol containing a nucleophilic group in a buffer solution in the presence of the tyrosine kinase inhibitor and allowing the mixture to gel.

[0622] 164. The method according to item 163, which comprises reacting 4a20kPEG-SAZ with 8a20kPEG-NH2 at a weight ratio of about 2:1.

[0623] 165. The method according to item 163 or 164, wherein the method comprises the steps of: filling the mixture into a mold or a tube, and then completely gelling to provide the desired final shape of the hydrogel; gelling the mixture; and drying the hydrogel.

[0624] 166. The method according to item 165, wherein the mixture is filled into a thin-diameter tube to prepare a hydrogel fiber.

[0625] 167. The method according to item 166, wherein the interior of the tube has a circular geometry.

[0626] 168. The method according to item 166, wherein the interior of the tube has a non-circular geometry.

[0627] 169. The method according to item 168, wherein the interior of the tube has a cross-shaped geometry.

[0628] 170. The method according to any one of items 166 to 169, wherein the method further comprises stretching the fiber and / or twisting the fiber.

[0629] 171. The method according to item 170, wherein the stretching is performed before or after drying the hydrogel.

[0630] 172. The method according to item 171, wherein the fiber is stretched at a stretching factor of about 1 to about 4.5.

[0631] 173. The method according to item 171, wherein the implant contains an amount of axitinib of about 200 μg, and the stretching is performed at a stretching factor of about 2 to about 5 or about 3 to about 4.5 after drying the hydrogel.

[0632] 174. The method according to item 171, wherein the implant contains an amount of axitinib of about 600 μg, and the stretching is performed at a stretching factor of about 0.5 to about 5 or about 1 to about 4 or about 1.3 to about 3.5 or about 1.7 to about 3 in a wet state before drying the hydrogel.

[0633] 175. The method according to any one of items 159 to 174, wherein the method further comprises loading the implant in a dry state into a needle.

[0634] 176. The method according to item 175, wherein the needle is a 25- or 27-gauge needle.

[0635] 177. A method of imparting shape memory to a hydrogel fiber by stretching the hydrogel fiber in a longitudinal direction, the hydrogel fiber comprising an active agent dispersed in the hydrogel.

[0636] 178. A method of manufacturing an ophthalmic implant comprising a hydrogel, the hydrogel comprising an active agent dispersed therein, wherein the implant changes its size after administration to the eye, the method comprising preparing fibers of the hydrogel and stretching the fibers in a longitudinal direction.

[0637] 179. The method according to item 177 or 178, wherein the method comprises a step of drying the hydrogel, wherein the fibers are stretched in a longitudinal direction (wet or dry stretching) before or after the drying.

[0638] 180. The method according to any one of items 177 to 179, wherein the fibers are stretched by a factor of about 0.5 to about 5, or about 1 to about 4.5, or about 3 to about 4.5, or about 1 to about 2.

[0639] 181. The method according to any one of items 177 to 180, wherein the active agent is a tyrosine kinase inhibitor, such as axitinib.

[0640] 182. The method according to any one of items 177 to 181, wherein the hydrogel comprises a polymer network comprising crosslinked polyethylene glycol units.

[0641] 183. The method according to any one of items 177 to 182, wherein the fibers fully or partially return to approximately their original length and / or original diameter that they had before stretching after hydration.

[0642] 184. The method according to any one of items 177 to 183, wherein the size change is an increase in diameter or an increase in diameter together with a decrease in length.

[0643] 185. A kit comprising one or more sustained-release biodegradable ophthalmic implants manufactured by the method according to any one of items 1 to 111 or according to any one of items 159 to 176 and one or more needles, wherein each of the one or more needles is pre-loaded with a sustained-release biodegradable ophthalmic implant in a dry state.

[0644] 186. The medicine box as in item 185, wherein the one or more needles are 25 - or 27 - gauge needles.

[0645] 187. The medicine box as in item 185 or item 186, wherein the medicine box includes one or more 25 - or 27 - gauge needles, and each of the one or more needles is loaded with an implant containing axitinib in an amount in the range of about 180 μg to about 220 μg.

[0646] 188. The medicine box as in item 187, wherein the implant contains about 200 μg of axitinib.

[0647] 189. The medicine box as in item 185 or item 186, wherein the medicine box contains a 25 - or 27 - gauge needle, and the needle is loaded with an implant containing axitinib in an amount in the range of about 540 μg to about 660 μg.

[0648] 190. The medicine box as in item 189, wherein the implant contains about 600 μg of axitinib.

[0649] 191. The medicine box as in any one of items 185 to 190 further contains an injection device for injecting the implant into a patient's eye.

[0650] 192. The medicine box as in item 191, wherein the injection device is provided separately in the medicine box from the one or more needles loaded with the implant.

[0651] 193. The medicine box as in item 191, wherein the injection device is pre - connected to the needle loaded with the implant.

[0652] 194. The medicine box as in item 191 or item 192, wherein the injection device contains a pusher wire for deploying the implant from the needle into the eye.

[0653] 195. The medicine box as in any one of items 185 to 194 further includes a dose of an anti - VEGF agent for injection.

[0654] 196. An injection device suitable for injecting a sustained - release biodegradable ophthalmic implant according to items 1 to 111 into an eye.

[0655] 197. The injection device as in item 196 contains a member for connecting the injection device to a needle.

[0656] 198. The injection device as in item 196 or item 197, wherein the needle is pre - loaded with the implant.

[0657] 199. An injection device as claimed in any one of items 196 to 198, comprising a pusher wire for deploying the implant from the needle into the eye when the injection device is connected to the needle.

[0658] 200. The injection device as claimed in item 199, wherein the pusher wire is made of Nitinol or stainless steel / Teflon.

[0659] 201. The injection device as claimed in item 199 or 200, which is obtained by fixing the wire to the plunger and encapsulating it between two snap-fit injector body parts and securing the plunger with a clip.

[0660] 202. A pharmaceutical product comprising a sustained release biodegradable ophthalmic implant as claimed in any one of items 1 to 111 loaded in a needle and an injection device as claimed in any one of items 196 to 201, wherein the needle is pre-connected to the injection device.

[0661] 203. A sustained release biodegradable ophthalmic implant containing a tyrosine kinase inhibitor as claimed in any one of items 1 to 111, for treating an eye disease in a patient in need thereof according to any one of items 112 to 138 or for treating neovascular age-related macular degeneration in a patient in need thereof according to any one of items 139 to 158, 210 or 211.

[0662] 204. Use of a sustained release biodegradable ophthalmic implant containing a tyrosine kinase inhibitor as claimed in any one of items 1 to 111 for the preparation of a medicament for treating an eye disease in a patient in need thereof according to any one of items 112 to 138 or for treating neovascular age-related macular degeneration in a patient in need thereof according to any one of items 139 to 158, 210 or 211.

[0663] 205. A method of reducing, substantially maintaining or preventing a clinically significant increase in central subfield thickness (as measured by optical coherence tomography) in a patient in whom the central subfield thickness is elevated due to an eye disease involving angiogenesis, the method comprising administering to the patient a sustained release biodegradable ophthalmic implant containing a tyrosine kinase inhibitor as claimed in any one of items 1 to 111.

[0664] 206. The method as claimed in item 205, wherein the eye disease is neovascular age-related macular degeneration.

[0665] 207. A method according to item 205 or 206, wherein, relative to the baseline central subfield thickness measured in the patient before administration of the implant, the central subfield thickness is decreased, substantially maintained, or clinically significantly increased prevention is achieved in the patient during a period of at least about 3 months, at least about 6 months, at least about 9 months, at least about 11 months, at least about 12 months, at least about 13 months, or at least about 14 months after administration of the implant.

[0666] 208. A sustained release biodegradable ophthalmic implant containing a tyrosine kinase inhibitor according to any one of items 1 to 111, which decreases, substantially maintains, or prevents a clinically significant increase in central subfield thickness (as measured by optical coherence tomography) in a patient in whom the central subfield thickness is elevated due to an ocular disease involving angiogenesis according to any one of items 205 to 207, item 210, or item 211.

[0667] 209. Use of a sustained release biodegradable ophthalmic implant containing a tyrosine kinase inhibitor according to any one of items 1 to 111 for the preparation of a medicament for decreasing, substantially maintaining, or preventing a clinically significant increase in central subfield thickness (as measured by optical coherence tomography) in a patient in whom the central subfield thickness is elevated due to an ocular disease involving angiogenesis according to any one of items 205 to 207, item 210, or item 211.

[0668] 210. A method according to any one of items 128 to 158 or according to any one of items 205 to 207, wherein the visual acuity of the patient, as represented by the best corrected visual acuity, is not impaired or is improved.

[0669] 211. A method according to any one of items 128 to 158, any one of items 205 to 207, or item 210, wherein no rescue medication needs to be administered during the treatment period, or wherein only occasional administration of rescue medication, such as 1, 2, or 3 times, is required during the treatment period.

[0670] 212. A method according to item 211, wherein the duration of the treatment period is about 6 to about 9 months after administration of the sustained release biodegradable ophthalmic implant.

[0671] 213. A method of improving the visual acuity of a patient whose visual acuity is impaired due to an ocular disease involving angiogenesis, the method comprising administering to the patient a sustained release biodegradable ophthalmic implant containing a tyrosine kinase inhibitor according to any one of items 1 to 111.

[0672] 214. The method of item 213, wherein the eye disease is neovascular age-related macular degeneration, diabetic macular edema, or retinal vein occlusion.

[0673] 215. The method of item 213 or 214, wherein the patient's vision is impaired due to the presence of retinal fluid.

[0674] 216. The method of any one of items 213 to 215, wherein the vision improvement is manifested by an increase in best corrected visual acuity.

[0675] 217. The method of item 216, wherein the increase in best corrected visual acuity is at least 10, at least 15, or at least 20 ETDRS letters.

[0676] 218. A sustained release biodegradable ocular implant containing a tyrosine kinase inhibitor according to any one of items 1 to 111, for improving the vision of a patient whose vision is impaired due to an eye disease involving angiogenesis according to the method of any one of items 213 to 217.

[0677] 219. Use of a sustained release biodegradable ocular implant containing a tyrosine kinase inhibitor according to any one of items 1 to 111 for the preparation of a medicament for improving the vision of a patient whose vision is impaired due to an eye disease involving angiogenesis according to the method of any one of items 213 to 217.

[0678] Second list of items

[0679] 1. A sustained release biodegradable ocular hydrogel implant comprising a tyrosine kinase inhibitor, a polymer network, and a clearance zone, wherein the clearance zone is free of TKI before TKI release.

[0680] 2. The ocular hydrogel of item 1, wherein the TKI does not contact retinal cells when the TKI is contained inside the hydrogel implant.

[0681] 3. The ocular hydrogel of item 1 or 2, wherein the TKI is present in the hydrogel implant at or near its saturation level.

[0682] 4. The ocular hydrogel implant of any one of items 1 to 3, wherein the size of the clearance zone increases with the amount of TKI released.

[0683] 5. The ocular hydrogel implant of any one of items 1 to 4, wherein the ocular hydrogel implant completely degrades after releasing the TKI or after releasing at least 90% of the TKI.

[0684] 6. The ocular hydrogel implant according to any one of items 1 to 5, wherein the ocular hydrogel implant is completely degraded about 30 days or about 3 months after the complete release of the TKI.

[0685] 7. The ocular hydrogel implant according to any one of items 1 to 4, wherein the degradation of the ocular hydrogel occurs before the release of the TKI.

[0686] 8. The ocular hydrogel implant according to any one of items 1 to 7, wherein the polymer network comprises a plurality of polyethylene glycol (PEG) units.

[0687] 9. The ocular hydrogel implant according to any one of items 1 to 8, wherein the polymer network comprises a plurality of multi-arm PEG units.

[0688] 10. The ocular hydrogel implant according to any one of items 1 to 9, wherein the polymer network comprises a plurality of 4-arm or 8-arm PEG units.

[0689] 11. The ocular hydrogel implant according to any one of items 1 to 9, wherein the polymer network comprises a plurality of PEG units having the following formula:

[0690]

[0691] wherein n represents the ethylene oxide repeat unit and the wavy line represents the point of the repeat unit of the polymer network.

[0692] 12. The ocular hydrogel implant according to any one of items 1 to 11, wherein the polymer network is formed by reacting a plurality of polyethylene glycol (PEG) units selected from 4a20k PEG-SAZ, 4a20k PEG-SAP, 4a20k PEG-SG, 4a20k PEG-SS, 8a20k PEG-SAZ, 8a20k PEG-SAP, 8a20k PEG-SG, and 8a20k PEG-SS with one or more PEG- or lysine-based amines or salts thereof selected from 4a20k PEG-NH2, 8a20k PEG-NH2, and tri-lysine.

[0693] 13. The ocular hydrogel implant according to any one of items 1 to 12, wherein the polymer network is formed by reacting 4a20k PEG-SAZ with 8a20k PEG-NH2.

[0694] 14. The ocular hydrogel implant according to any one of items 1 to 13, wherein the polymer network is amorphous (under aqueous conditions).

[0695] 15. An ocular hydrogel implant according to any one of items 1 to 14, wherein the polymer network is semi-crystalline in the absence of water.

[0696] 16. An ocular hydrogel implant according to any one of items 1 to 15, wherein the tyrosine kinase inhibitor is homogeneously dispersed within the polymer network.

[0697] 17. An ocular hydrogel implant according to any one of items 1 to 16, wherein the tyrosine kinase inhibitor is released over a period of at least 15 days.

[0698] 18. An ocular hydrogel implant according to any one of items 1 to 17, wherein the tyrosine kinase inhibitor is released over a period of at least 30 days.

[0699] 19. An ocular hydrogel implant according to any one of items 1 to 18, wherein the tyrosine kinase inhibitor is released over a period of at least 60 days.

[0700] 20. An ocular hydrogel implant according to any one of items 1 to 19, wherein the tyrosine kinase inhibitor is released over a period of at least 90 days.

[0701] 21. An ocular hydrogel implant according to any one of items 1 to 20, wherein the tyrosine kinase inhibitor is released over a period of at least 180 days.

[0702] 22. An ocular hydrogel implant according to any one of items 1 to 21, wherein the tyrosine kinase inhibitor is released over a period of at least 365 days.

[0703] 23. An ocular hydrogel implant according to any one of items 1 to 22, wherein the tyrosine kinase inhibitor is in the form of encapsulated microparticles.

[0704] 24. An ocular hydrogel implant according to any one of items 1 to 23, wherein the tyrosine kinase inhibitor is in the form of encapsulated microparticles comprising a poly(lactic-co-glycolic acid) copolymer.

[0705] 25. The ophthalmic hydrogel implant according to any one of items 1 to 24, wherein the tyrosine kinase inhibitor is selected from abemaciclib, acalabrutinib, afatinib, alectinib, axitinib, barictinib, binimetinib, brigatinib, cabozantinib, ceritinib, coblmetinib, crizotinib, dabrafenib, dacomitinib, dasatinib, encorafenib, erlotinib, everolimus, fostamatinib, gefitinib, gilteritinib, ibrutinib, imatinib, larotrectinib, lenvatinib, lorlatinib, axitinib, idelalisib, lenvatinib, midostaurin, neratinib, netarsudil, nilotinib, nintedanib, osimertinib, palbociclib, pazopanib, ponatinib, regorafenib, ribociclib, ruxolitinib, sirolimus, sorafenib, sunitinib, temsirolimus, tofacitinib, trametinib, vandetanib, and vemurafenib.

[0706] 26. The ophthalmic hydrogel implant according to item 1 or 25, wherein the tyrosine kinase inhibitor is axitinib.

[0707] 27. The ophthalmic hydrogel implant according to any one of items 1 to 26, wherein the ophthalmic hydrogel implant is injected into the vitreous humor, injected into the anterior chamber, or fixed to the upper or lower lacrimal punctum of the eye.

[0708] 28. A method of treating an ocular disorder in a subject in need thereof, comprising injecting or fixing an ocular hydrogel implant according to any one of items 1 to 27 to the subject.

[0709] 29. The method according to item 28, wherein the ocular disorder is selected from macular diseases, retinal degeneration, uveitis, retinitis, choroiditis, vascular diseases, exudative diseases, trauma, proliferative diseases, infectious conditions, genetic disorders, retinal tears, holes and tumors.

[0710] 30. The method according to item 28 or 29, wherein the ocular disorder is selected from age-related macular degeneration, choroidal neovascularization, diabetic retinopathy, acute macular neuroretinopathy, central serous chorioretinopathy, cystoid macular edema, diabetic macular edema, acute multifocal placoid pigment epitheliopathy, Behcet's disease, birdshot retinochoroidopathy, intermediate uveitis, multifocal choroiditis, multiple evanescent white dot syndrome (MEWDS), ocular sarcoidosis, posterior scleritis, serpiginous choroiditis, subretinal fibrosis and uveal inflammatory syndrome, Vogt-Koyanagi-Harada syndrome, Coat's disease, juxtafoveal telangiectasis, papillophlebitis, frosting branch angiitis, sickle cell retinopathy, angioid streaks, familial exudative vitreoretinopathy, sympathetic ophthalmia, uveoretinopathy, retinal detachment, proliferative diabetic retinopathy, ocular histoplasmosis, ocular toxocariasis, viral retinitis, acute retinal necrosis, ocular syphilis, ocular tuberculosis, congenital stationary night blindness, cone dystrophy, retinal detachment, macular hole, giant retinal tear, solid tumors, posterior uveal melanoma, choroidal hemangioma, choroidal osteoma, choroidal metastasis, retinoblastoma, fundus vascular proliferative tumor, retinal astrocytoma and intraocular lymphoma.

[0711] 31. The method according to item 29 or 30, wherein the disorder is age-related macular degeneration.

[0712] 32. The method according to any one of items 29 to 31, wherein the subject has been previously treated with anti-VEGF therapy.

[0713] Examples

[0714] The following examples are included to illustrate certain aspects and embodiments of the present invention as described in the claims. However, those skilled in the art should understand that the following description is illustrative only and should in no way be construed as limiting the present invention.

[0715] Example 1: Preparation of axitinib implant

[0716] The axitinib implant of the present application is (substantially) cylindrical (and is also referred to herein as a "fiber"), wherein axitinib is homogeneously dispersed and embedded within a PEG-based hydrogel matrix for sustained release of axitinib based on its low aqueous solubility in the vitreous humor of the eye.

[0717] The polymer network of the implant is formed by reacting 2 parts of 4a20K PEG-SAZ (20 kDa PEG with 4 arms having N-hydroxysuccinimide group-reactive end groups, sometimes also referred to as "NHS" end groups) with 1 part of 8a20KPEG NH2 (20 kDa PEG with 8 amine end groups). Accordingly, polyurethane tubes are cut into appropriate length segments. Thereafter, a disodium hydrogen phosphate solution of 8a20K PEG NH2 is prepared and sterile filtered through a 0.2 μm (pore size of the filter) to remove endotoxins and other particles. Subsequently, the desired volume of the PEG amine solution is weighed into a syringe. Next, the corresponding amount of solid axitinib is weighed into another syringe depending on the desired final axitinib dose in the implant. The powdered axitinib syringe and the PEG amine syringe are carefully mixed to suspend and disperse the particles. Subsequently, the syringe containing the suspension mixture is sonicated to break up any powder aggregates. Thereafter, a sodium dihydrogen phosphate solution of 4a20K PEG SAZ is prepared and sterile filtered as described for the PEG amine solution. Subsequently, the desired volume of the PEG SAZ solution is weighed into another syringe. In the next step, the components of the two syringes (4a20K PEG SAZ sodium dihydrogen phosphate solution and axitinib-8a20K PEG NH2 mixture) are mixed to initiate a reaction, thereby causing gelation. The liquid suspension is poured through the prepared polyurethane tube, and then the material crosslinks and cures. The gelation time is confirmed by performing a gel tapping test. Subsequently, the tube containing the gel is placed in a high humidity curing chamber for 2 hours to prevent the hydrogel from drying prematurely before hydrogel gelation. Inside the chamber, the hydrogel axitinib suspension in the tube is crosslinked completely to produce a highly reactive and uniform gel, thereby forming a hydrogel strand.

[0718] After curing, different implant stretching methods are performed as disclosed herein. As outlined below, the implants are stretched either dry or wet. For dry stretching, after curing the strands are cut into shorter segments and the strands are dried for 48 to 96 hours. After drying, the dried strand segments are removed from the tube and placed in the jaws of a custom stretcher. The strands are then slowly dry stretched at a controlled rate until the desired diameter for a small gauge needle is reached (a stretch factor of about 2 to about 5 or about 3 to about 4.5). The stretching step is performed in an environment free of oxygen and moisture to protect the product. For wet stretching, the strands are placed on the jaws of a custom stretcher. The strands are then slowly wet stretched at a controlled rate until the desired diameter for a small gauge needle is reached (a stretch factor of about 1 to about 3 or about 1.3 to about 2.6). After stretching, the strands are dried under tension under the conditions described for the dry stretching process.

[0719] Stretching creates shape memory, meaning that when implanted in the vitreous cavity of the eye, the implant will rapidly shorten in length and widen in diameter upon hydration until it reaches its original wet cast dimensions. Although the narrow dry dimensions facilitate product delivery via a smaller gauge needle, the widening in diameter and shortening in length after delivery can result in an implant that is shorter relative to the eye diameter in the posterior chamber (in some embodiments, the length is no more than about 10 mm), thereby reducing potential contact with the surrounding eye tissue. Generally, the degree of shrinkage upon hydration depends particularly on the stretch factor. For example, stretching (wet stretching) with a stretch factor of about 1.3 will have a less pronounced effect, or will essentially not change in length during hydration. In contrast, stretching (wet stretching) with a stretch factor of, for example, about 1.8 will result in a significant shortening in length during hydration. Stretching (dry stretching) with a stretch factor of, for example, about 4 can result in a much shorter length after hydration (e.g., the length is reduced from about 15 mm to about 8 mm).

[0720] The stretched hydrogel strands are removed from the stretcher and then cut to the desired final length. The implant fibers are then placed on an inspection station. If the implant passes quality control, it is loaded into a 25 or 27 gauge needle (e.g., an FDA approved 25G UTW 1 / 2” or 25G UTW 1” or 27G TW 1.25” needle) of about 0.4 mm inner diameter using a custom vacuum device and securely capped to avoid any damage to the needle tip.

[0721] Place the loaded needles in a glove box for 6 to 9 days to remove any moisture (the remaining water content in the intended implant should not exceed 1% water). All steps are then carried out in the glove box. Immerse the loaded needles in molten low molecular weight 1k PEG to cover the needle tips. After cooling, retaining a small drop of hardened PEG provides smoothness, keeps the implant in place within the needle, allows for successful deployment, and prevents premature rehydration of the implant within the needle during administration. Additionally, PEG tip coverage reduces tissue damage, i.e., tissue coring, which is the process of removing tissue fragments through the tissue as the needle passes through it. Subsequently, reinspect the needles with PEG tip coverage and discard needles that do not meet the quality requirements. Re-cap the qualified needles to ensure that the needles do not suffer any other damage. Subsequently, individually encapsulate and seal the needles to prevent them from getting wet and to maintain their sterility. The injection device (e.g., a modified Hamilton glass syringe) has a pusher wire (e.g., a Nitinol pusher wire) that allows for easier deployment of the implant from the needle. The injection needle may contain a termination feature to control the injection depth. The injection device can be separately packaged in the same manner as described for the needles and sealed in a foil bag under nitrogen ( Figure 1 ), or can be pre-assembled with the implant-loaded needles or pre-assembled within a pre-loaded injector. Remove the packaged needles and injection device from the glove box and store them refrigerated (2 - 8 °C), and then sterilize them using gamma irradiation. After sterilization, the packaging is refrigerated (2 - 8 °C) or frozen in the dark before use and equilibrated to room temperature for 30 minutes before injection.

[0722] Administer the implant via intravitreal injection, where the implant is positioned in the posterior segment of the eye ( Figure 2 ). After injection, the implant hydrates in situ. After hydrating upon contact with the vitreous, the implant softens and increases in diameter and may also contract in length. By entrapping axitinib within the hydrogel, a defined and limited localization of axitinib in the eye can be provided. The hydrogel matrix of the implant is formulated to biodegrade via ester hydrolysis in the aqueous environment of the vitreous. Axitinib is released from the hydrogel over a prolonged period by diffusing into the vitreous and subsequently into the surrounding eye tissues due to the low solubility of the drug under physiological conditions ( Figure 3 ). The release rate of the drug from the implant is particularly influenced by diffusion, drug clearance rate, vitreous viscosity, concentration gradients within and near the implant, implant dose, implant surface area and geometry, and the number of implants and their localization within the vitreous.

[0723] Example 2: In vitro axitinib release

[0724] In the next step, determine the axitinib release rate of implants with different formulations through in vitro testing. In vitro analysis can additionally be used for quality control of the implants.

[0725] In vitro axitinib release under non-sink simulated physiological conditions

[0726] In an in vitro assay setting, axitinib release was evaluated at a daily replacement volume equivalent to the volume of vitreous humor in the human eye under non-sink simulated physiological conditions.

[0727] Three exemplary selected implant formulations (Table 1) were examined. Implant variants 1 and 2 were examined using one implant, and implant variant 3 was examined using one and two implants (a total of four conditions). All conditions were performed in duplicate.

[0728] Table 1 Formulations, configurations, and dry dimensions of three exemplary selected axitinib implants. Formulation percentages represent weight / weight (w / w).

[0729]

[0730] Prior to performing the in vitro release analysis, the starting drug content of the implants was examined by liquid chromatography combined with fragmentation-based mass spectrometry (LC-MS / MS) using ethanol as the extraction solvent (Table 2; for details on implant dissolution and LC-MS / MS, see Example 3.5). The amount of axitinib measured matched well with the formulated amount.

[0731] Table 2 Starting axitinib content in the implants as determined by LC-MS / MS.

[0732] Conditions Axitinib (μg) Implant No. 1 609±48.1 Implant No. 2 720±35.4 Implant No. 3 x 2 458±38.9 Implant No. 3 x 1 258±33.9

[0733] In vitro release and unreleased axitinib of each group were determined in the absence (control group) and presence of daily release medium sampling.

[0734] For control implant release, the samples were placed in tubes. On day 0, 5 mL of PBS (pH 7.2) was added to each tube, and each tube was covered with a lid. Subsequently, the samples were placed in an incubator at 37 °C and gently shaken for 20 days (1x implant variant 3) or 30 days (implant variants 1 and 2, 2x implant variant 3). At the end of the test period, the PBS was removed (1 mL of PBS was saved for testing). 1 mL of ethanol was added to the remaining samples. The axitinib release amounts of the PBS samples and the remaining samples were tested.

[0735] For daily implant release, place the samples in tubes. Add 5 mL of PBS to each tube on Day 0 and cover the tubes with caps. Then place the samples in an incubator at 37 °C and gently shake. After 24 hours, remove 4 mL of PBS from each sample, use 1 mL of it for testing and dispose of the remaining 3 mL. Add 4 mL of fresh PBS back to each tube. Repeat this process for 20 days (1x implant No. 3) or 30 days (implants No. 1 and No. 2, 2x implant No. 3). On the last day of the study, test each sample with 1 mL of PBS and dispose of the remaining 4 mL. Add 1 mL of ethanol to the remaining residual implants and test for total remaining axitinib.

[0736] The axitinib concentrations in PBS from the control implant release measurements after 20 or 30 days represent the determination of the maximum solubility of axitinib after long-term incubation in the release medium (Table 3). The higher the dose strength, the higher the axitinib concentration in the release medium. The apparent maximum solubility of axitinib ranges from 0.24 to 0.40 μg / mL, which is consistent with the results reported in the literature for [NDA 202324].

[0737] Table 3 Control release data. Axitinib amounts and concentrations are presented as mean and standard deviation (SD).

[0738]

[0739] The test results show that compared with the lower-dose groups, the two high-dose samples (implants No. 1 and No. 2) release more axitinib per day (Table 4). The amount of axitinib released per day during the study duration is presented in Figure 4A . The ...

Claims

1. A sustained-release biodegradable ophthalmic implant comprising a hydrogel and at least about 150 μg of a tyrosine kinase inhibitor (TKI), wherein the TKI particles are dispersed within the hydrogel, and wherein the implant has a length in its dry state of less than about 17 mm.

2. The sustained-release biodegradable ophthalmic implant according to claim 1, wherein the implant is cylindrical and has a diameter in its dry state of from about 0.1 mm to about 0.5 mm.

3. The sustained-release biodegradable ophthalmic implant according to claim 1, wherein the implant is non-cylindrical.

4. The sustained-release biodegradable ophthalmic implant according to any one of claims 1 to 3, wherein the TKI is axitinib.

5. The sustained-release biodegradable ophthalmic implant according to claim 4, wherein the implant comprises axitinib in an amount of from about 150 μg to about 1800 μg, preferably in an amount of from about 150 μg to about 1200 μg, more preferably in an amount of from about 480 μg to about 750 μg or from about 160 μg to about 250 μg.

6. The sustained-release biodegradable ophthalmic implant according to any one of the preceding claims, wherein the implant has a total weight in its dry state of from about 0.2 mg to about 1.5 mg, preferably a total weight of from about 0.75 mg to 1.25 mg.

7. The sustained-release biodegradable ophthalmic implant according to any one of the preceding claims, wherein the implant is for administration to the posterior segment of the eye.

8. The sustained-release biodegradable ophthalmic implant according to any one of the preceding claims, wherein the implant is a vitreous implant.

9. The sustained-release biodegradable ophthalmic implant according to any one of the preceding claims, wherein the implant is cylindrical and has a length in its dry state of from about 6 mm to about 10 mm.

10. The sustained-release biodegradable ophthalmic implant according to any one of the preceding claims, wherein the implant is cylindrical and has a diameter in its dry state of from about 0.2 mm to about 0.4 mm.

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