Ocular implants containing tyrosine kinase inhibitors

Abstract

The present invention relates to a sustained release biodegradable ocular implant containing a tyrosine kinase inhibitor dispersed in a hydrogel for treating retinal diseases over an extended period of time.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] The present 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, all of which are incorporated herein by reference. Field of the Invention

[0003] The present invention relates to the treatment of ocular diseases, such as neovascular age-related macular degeneration (AMD), also known as "wet AMD". According to the present invention, ocular diseases are treated by administering (e.g., intravitreal) injections of an implant that is biodegradable and that continuously releases a tyrosine kinase inhibitor, such as axitinib. Background of the Invention

[0005] Macular diseases, including AMD, are one of the leading causes of visual impairment and irreversible blindness in people over 50 years of age worldwide. Specifically, AMD is one of the most common retinal diseases in the United States (US) in 2019, affecting approximately 16.9 million people, and is expected to grow to 18.8 million people 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 drusen, many medium-sized drusen, or regional atrophy that does not extend to the center of the macula. Late or late AMD can be non-neovascular (dry, atrophic, or non-exudative) or neovascular (wet or exudative). Late non-neovascular AMD is characterized by drusen and regional 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).

[0006] 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 leak blood and fluid into the macula and subretinal space and below. With the development of vascular endothelial growth factor subtype inhibitors (i.e., VEGF inhibitors) originally used to treat various cancers, this pathway has been successfully interfered with. Photodynamic therapy combined with anti-VEGF and steroid administration is currently still the second-line therapy for patients who do not respond 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).

[0007] Other common retinal diseases are diabetic macular edema (DME) and retinal vein occlusion (RVO). DME is one of the most common retinal diseases in the United States in 2019, affecting about 8 million people, and is expected to grow to 8.8 million people in 2024 (Market Scope 2019, supra). According to the reduction of retinal tension and increased vascular pressure caused by upregulation of VEGF, retinal vascular autoregulation (Browning et al., Diabetic macular edema: evidence-based management. 2018 Indian journal of ophthalmology, 66 (1), page 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), the disease is classified. The changes in these inflammatory and angiogenic mediators destroy the blood retinal barrier (BRB) in the vascular endothelium (Miller et al., supra). Hard exudates enter the extracellular space, causing blurring and distortion of central vision, resulting in decreased visual acuity in patients (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, patients' visual acuity decreases by 8% after 3 years from the onset of the disease.

[0008] The basis of all available treatments for DME is to try to control the metabolic function and blood pressure of hyperglycemia (Browning et al., supra). Anti-VEGF therapy is currently regarded as the first-line therapy in the standard of care treatment for DME because it has been shown to be less destructive and damaging than other treatments (Schmidt-Erfurth et al., supra). Pharmacological approaches are beneficial because drugs are made to specifically target the VEGF pathway and inhibit the upregulation that accompanies DME (Miller et al., supra). Other treatment options include intravitreal corticosteroid injections, focused laser photocoagulation, and vitrectomy (Browning et al., supra).

[0009] 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, supra). RVO is a chronic condition in which the retinal circulation contains blockages that lead to 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 condition usually presents in patients 55 years and older with pre-existing conditions such as hypertension, diabetes, and glaucoma. RVO has no predictable course as it may rapidly worsen the patient's vision or remain asymptomatic. The prognosis and associated treatment options for RVO depend on the classification of the disease as different variants present different risk factors despite similar presentations. The disease is classified based on the location of the retinal circulation disorder: branch retinal vein occlusion (BRVO), hemi-retinal 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, supra).

[0010] Treatment of RVO currently includes symptomatic maintenance of the condition to avoid other complications, macular edema, and neovascular glaucoma. Anti-VEGF therapy is currently the standard of care treatment and can temporarily improve vision. Other treatment options include laser, steroids, and surgery (Pierru et al., supra).

[0011] 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 (Bausch & Lomb's pegaptanib sodium injection). Since then, (Genentech's ranibizumab injection) and (Aflibercept injection from Regeneron Pharmaceuticals) was approved in 2006 and 2011 for the treatment of wet AMD, as well as macular edema secondary to DME and RVO. In addition, in October 2019, (Novartis Pharmaceuticals' brolucizumab injection) is approved by the FDA for the treatment of wet AMD. Other progress is reported in the following literature: Amadio et al., Targeting VEGF in eye neovascularization: What's new?: A comprehensive review on current therapies and oligonucleotide-based interventions under development. 2016, Pharmacological Research, 103: 253-69.

[0012] However, despite these advances, anti-VEGF treatments still have limitations. Due to rapid vitreous clearance, most patients currently require multiple injections (such as once a month) for essentially the rest of their lives. In addition, not all patients respond to anti-VEGF treatments. In addition, these treatment options also have potential risks associated with administration, including infection, macular atrophy, decreased vision over time, retinal detachment, and increased intraocular pressure (IOP). Patient suffering includes discomfort, eye pain, decreased vision, 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 treatments, such as potential immunogenicity risks, complex manufacturing requirements for biologics, macular atrophy, and retinal vasculitis. Importantly, regardless of the number of drugs, it is currently expected that patients can remain on treatment indefinitely.

[0013] Tyrosine kinase inhibitors have been developed as chemotherapeutic agents for signal transduction of receptor tyrosine kinases (RTKs) of the tyrosine protein kinase family. RTKs span the cell membrane and have intracellular (inside) and extracellular (outside) parts. After the ligand binds to the extracellular part, the receptor tyrosine kinase dimerizes and initiates 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 about binding to many VEGF receptor (VEGFR) types, i.e., VEGFR1-3 (all RTKs), thereby inducing angiogenesis. VEGF-A, which is bound to VEGFR2, is the target of the anti-VEGF drugs described above. Except for VEGFR1-3, several other RTKs are known to induce angiogenesis, such as platelet-derived growth factor receptor (PDGFR) activated by PDGF or stem cell growth factor receptor / type III receptor tyrosine kinase (c-Kit) activated by stem cell factor.

[0014] Several 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, and oral TKIX-82 (Tyrogenex; NCT01674569, NCT02348359). However, due to the low solution concentration of TKIs that tend to have low water solubility and the short residence time of TKIs on the ocular surface, topically applied eye drops result in poor penetration into the vitreous and limited distribution to the retina. In addition, drug concentrations after topical administration are difficult to control due to washout or user error. In addition, systemic administration of TKIs is not feasible because high doses are required to achieve effective concentrations of the drug in the eye, especially in the desired tissues. This results in unacceptable side effects due to high systemic exposure. In addition, drug concentrations are difficult to control. Alternatively, intravitreal injections of TKI suspensions have been performed. However, this mode of administration results in rapid clearance of the drug, and therefore injections 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 on the retina and cause local contact toxicity and holes, such as macula or retinal holes.

[0015] Thus, there is a pressing need for improved treatments for ocular diseases such as AMD, DME, and RVO with TKIs that are effective over longer periods of time, thereby avoiding the need for frequent (monthly to daily) injections required for currently commonly used anti-VEGF therapies, especially in individuals who are unresponsive to anti-VEGF therapies (e.g., up to 33% of DME subjects).

[0016] All references disclosed herein are incorporated by reference in their entirety for all purposes. Summary of the invention

[0017] It is an object of certain embodiments of the present invention to provide an ocular implant comprising a tyrosine kinase inhibitor (TKI), such as axitinib, that is effective for treating ocular diseases such as neovascular age-related macular degeneration (AMD), DME, and RVO in patients over an extended period of time.

[0018] It is another object of certain embodiments of the present invention to provide an ocular implant comprising a tyrosine kinase inhibitor (TKI), such as axitinib, which provides sustained release of the TKI into the eye.

[0019] It is another object of certain embodiments of the present invention 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 additional preparation steps are required.

[0020] Another object of certain embodiments of the present invention is to provide an ocular implant comprising a TKI such as axitinib that is sufficiently biodegradable, i.e., cleared from the eye in a time consistent with the release of the TKI, thereby avoiding the generation 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 a treatment period.

[0021] It is another object of certain embodiments of the present invention to provide an ocular implant comprising a TKI such as axitinib which is biodegradable, wherein during implant degradation the implant is prevented from breaking down into smaller particles which could, for example, affect vision.

[0022] It is another object of certain embodiments of the present invention 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.

[0023] It is another object of certain embodiments of the present invention to provide an ocular implant comprising a TKI such as axitinib that is biocompatible and non-immunogenic by being free or substantially free of components of animal or human origin.

[0024] It is another object of certain embodiments of the present invention to provide an ocular implant comprising a TKI, such as axitinib, that is free of preservatives, such as antimicrobial preservatives.

[0025] It is another object of certain embodiments of the present invention to provide an ocular implant comprising a TKI such as axitinib that is easy to inject, in particular, intravitreally.

[0026] It is another object of certain embodiments of the present invention to provide an ocular implant comprising a TKI, such as axitinib, which contains a therapeutically effective amount of the TKI but is relatively small in length and / or diameter.

[0027] It is another object of certain embodiments of the present invention to provide an ocular implant comprising a TKI, such as axitinib, that is dimensionally stable in the dry state but changes its dimensions upon hydration, such as after administration to the eye.

[0028] Another object of certain embodiments of the present invention is to provide an ocular implant comprising a TKI such as axitinib that has a small diameter in a dry state to fit into the lumen of a fine diameter needle (e.g., a 22 to 30 gauge needle), and that increases in diameter but decreases in length when hydrated, e.g., after administration into the eye; thus, providing a minimally invasive method of administration.

[0029] It is another object of certain embodiments of the present invention to provide an ocular implant comprising a TKI such as axitinib that is injected in dry form and hydrates in situ (ie, in the eye) upon injection.

[0030] Another object of certain embodiments of the present invention is to provide an ocular implant comprising a TKI such as axitinib that has a low TKI concentration at the implant surface when placed in the eye, thereby avoiding TKI toxicity when the implant is in contact with ocular cells or tissues such as the retina.

[0031] Another object of certain embodiments of the present invention is to provide an ocular implant comprising a TKI such as axitinib that is stable both in the dry state before injection and in the hydrated state after injection (ie, inside the eye) and has a defined shape and surface area.

[0032] It is another object of certain embodiments of the present invention to provide an ocular implant comprising a TKI such as axitinib that is easy to handle, in particular, is not prone to spillage or breakage.

[0033] It is another object of certain embodiments of the present invention to provide an ocular implant comprising a TKI such as axitinib that enables administration of a precise dose (within a wide dose range), thereby avoiding the risks of over- and under-dosage.

[0034] It is another object of certain embodiments of the present invention to provide an ocular implant comprising a TKI such as axitinib that generally resides in the area of ​​the eye to which it is administered.

[0035] It is another object of certain embodiments of the present invention to provide an ocular implant comprising a TKI such as axitinib, wherein the implant causes minimal or no visual disturbance following administration.

[0036] It is another object of certain embodiments of the present invention to provide an ocular implant comprising a TKI, such as axitinib, that is safe and well tolerated.

[0037] It is another object of certain embodiments of the present invention to provide an ocular implant comprising a TKI, such as axitinib, that does not induce severe adverse events, such as severe ocular adverse events.

[0038] It is another object of certain embodiments of the present invention to provide an ocular implant comprising a TKI such as axitinib that continuously releases a therapeutically effective amount of a TKI such as axitinib over a prolonged period of time, such as over a 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.

[0039] It is another object of certain embodiments of the present invention to provide an ocular implant comprising a TKI such as axitinib that continuously releases the TKI such as axitinib over a longer period of time, such as over a 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, thereby avoiding the need for frequent implant administration.

[0040] It is another object of certain embodiments of the present invention to provide an ocular implant comprising a TKI such as axitinib that continuously releases a TKI such as axitinib over a prolonged period of time, such as over a 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, thereby inhibiting angiogenesis over this period of time.

[0041] It is another object of certain embodiments of the present invention to provide an ocular implant comprising a TKI such as axitinib that continuously releases the TKI over an extended period of time, such as over a 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, wherein during this period, the level of the TKI in the ocular tissues such as the retina and choroid and the vitreous humor is always maintained at a therapeutically effective level, in particular, a level sufficient to inhibit angiogenesis.

[0042] It is another object of certain embodiments of the present invention to provide an ocular implant comprising a TKI such as axitinib that continuously releases the TKI such as axitinib over an extended period of time, such as over a 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, wherein during this period, no toxic concentrations of the TKI are observed in ocular tissues such as the retina and choroid and vitreous humor.

[0043] It is another object of certain embodiments of the present invention to provide an ocular implant comprising a TKI such as axitinib that continuously releases the TKI such as axitinib over an extended period of time, such as over a 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, wherein the TKI does not accumulate in the anterior chamber of the eye.

[0044] It is another object of certain embodiments of the present invention to provide an ocular implant comprising a TKI, such as axitinib, which continuously releases the TKI over a longer period of time, such as over a 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, wherein the TKI is not or substantially not systemically reabsorbed, thereby substantially avoiding systemic toxicity.

[0045] Another object of certain embodiments of the present invention is to provide a method of treating ocular diseases such as AMD, DME and RVO in a patient in need thereof for 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.

[0046] It is another object of certain embodiments of the present invention to provide a method of treating an ocular disease such as AMD, DME, and RVO in a patient in need thereof, for a treatment period of 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, without requiring administration of rescue medication 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.

[0047] It is another object of certain embodiments of the present invention to provide a method of treating ocular diseases such as AMD, DME and RVO in a patient in need thereof, such as a patient previously treated with an anti-VEGF or a patient naive to anti-VEGF treatment.

[0048] It is another object of certain embodiments of the present invention to provide a method of treating ocular diseases such as AMD, DME, and RVO in a patient in need thereof, such as a patient who has been previously treated with an anti-VEGF and has not responded to the previous anti-VEGF treatment.

[0049] It is another object of certain embodiments of the present invention to provide a method of treating ocular diseases such as AMD, DME, and RVO in a patient in need thereof, such as a patient diagnosed with primary subfoveal neovascularization (SFNV) secondary to AMD.

[0050] It is another object of certain embodiments of the invention to provide a method of treating ocular diseases such as AMD, DME, and RVO in a patient in need thereof, such as a patient diagnosed with previously treated suborbital neovascularization (SFNV) secondary to neovascular AMD with leakage involving the orbit who has been previously treated with anti-VEGF.

[0051] It is another object of certain embodiments of the present invention to provide a method of manufacturing an ocular implant comprising a TKI such as axitinib.

[0052] It is another object of certain embodiments of the present invention to provide a method of 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.

[0053] It is another object of certain embodiments of the present invention to provide a method of reducing potential tissue damage during injection of an ocular implant.

[0054] It is another object of certain embodiments of the present invention to provide a kit comprising one or more ocular implants comprising a TKI such as axitinib and optionally comprising means for injecting the ocular implants.

[0055] It is another object of certain embodiments of the present invention to provide a method for reducing central subfield thickness (as measured by optical coherence tomography) in a patient whose central subfield thickness is elevated due to an ocular disease involving angiogenesis by, for example, reducing retinal fluid.

[0056] It is another object of certain embodiments of the present invention to provide a method for substantially maintaining central subfield thickness or preventing a clinically significant increase in central subfield thickness (as measured by optical coherence tomography) in a patient whose central subfield thickness is elevated due to an ocular disease involving angiogenesis without increasing retinal fluid.

[0057] Another object of certain embodiments of the present invention is to provide a method for reducing, substantially maintaining central subfield thickness, or preventing a clinically significant increase in central subfield thickness (as measured by optical coherence tomography) in a patient whose central subfield thickness is elevated due to an ocular disease involving angiogenesis, while improving or at least not impairing the patient's visual acuity (as measured, for example, by best corrected visual acuity).

[0058] It is another object of certain embodiments of the present invention to provide a method of improving vision in a patient whose vision is impaired due to an ocular disease involving angiogenesis.

[0059] It is another object of certain embodiments of the present invention to provide a method for improving vision in a patient whose vision is impaired due to the presence of retinal fluid (e.g., caused by an eye disease involving angiogenesis) by reducing the patient's retinal fluid (as evidenced, for example, by a reduction in central subfield thickness measured by optical coherence tomography).

[0060] One or more of these and other objects of the present invention are addressed by one or more embodiments as disclosed and claimed herein.

[0061] Individual aspects of the 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 invention.Details of various aspects of the invention are provided in the following detailed description.

[0062] Throughout this application, various references are cited. The disclosures of these references are incorporated into the present invention by reference. In the event of a conflict, the disclosure in this application shall prevail. BRIEF DESCRIPTION OF THE DRAWINGS

[0063] Figure 1 Schematic representation of one 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. An all-in-one device is also possible where the needle is already connected to the injection device.

[0064] Figure 2 Schematic representation of one 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.

[0065] Figure 3 Schematic illustration of the biodegradation of a hydrogel over time. During drug release, a clearance zone (black) is formed as low-solubility drug particles (white) gradually dissolve and the drug diffuses from the hydrogel into the surrounding aqueous humor (e.g., vitreous humor). Over time, the gel degrades and is reabsorbed while the drug diffuses out. During the degradation process, the gel gradually swells until degradation proceeds to the shrinkage deformation point.

[0066] Figure 4 One embodiment of daily in vitro axitinib release from 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 556 μg implant.

[0067] FIG5 is an embodiment of a low-dose study in rabbits. (A) Infrared reflectance (IR) of 1, 2, and 3 implants in rabbits one month after injection. The overall shape of the implants remained intact, regardless of the number of implants administered. (B) After 1 month, vascular leakage was effectively inhibited at all three doses (15, 30, and 45 μg), while vascular leakage was higher in control animals without implants. Error bars represent standard deviation (SD; only the upper error bar is presented).

[0068] Figure 6 One embodiment of infrared reflectance (IR) and optical coherence tomography (OCT) imaging of rabbit eyes. IR / OCT images of retinal morphology 1, 3 and 6 months after implant injection. The retinal morphology is normal.

[0069] FIG7 shows an embodiment of implant biodegradation and inflammation. (A) Significant biodegradation of the hydrogel component of the implant was observed in rabbit eyes over time. At 4 and 8 weeks after injection, the implant was still intact, while at 12 weeks, early stages of hydrogel degradation were visible. At 16 weeks, the implant narrowed further due to loss of hydrogel structure. Finally, 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 undissolved axitinib area after 26 weeks. Images are presented at 20x magnification (scale: 1000 μm) and 200x magnification (scale: 100 μm).

[0070] Figure 8An embodiment of inhibition of vascular leakage in rabbits challenged with VEGF after administration of an axitinib implant at a dose of 227 μg. Vascular leakage scores (0 (normal) to 4 (severe leakage)) are presented over time (months) after VEGF challenge for animals with and without implants. Effective inhibition of vascular leakage was observed over a duration of 6 months for animals with implants. Error bars represent standard deviation (SD; only the upper error bar is presented).

[0071] Fig. 9 One embodiment of infrared reflectance (IR) imaging of two implants in a rabbit eye. The implants show degradation over time. From day 27 to day 117, the implants were intact, while implant narrowing was observed due to hydrogel degradation observed at day 141 and day 195. The remaining axitinib particles merged into a single monolithic structure at day 141 and day 195. After hydrogel degradation, free axitinib particles (white samples) were noted near the previous implant site.

[0072] Fig.10 One embodiment of infrared reflectance (IR) imaging of two implants in a rabbit eye. The implants were intact from 0.5 to 3 months after injection. After 6 months, the implants narrowed due to hydrogel degradation and the remaining axitinib particles merged into a single monolithic structure. Free axitinib particles (white samples) were noted near the previous implant site after hydrogel degradation at 24 months up to 38 months.

[0073] Fig.11 In the absence (Group 1) and presence (Group 2) of co-administration Figure 1 shows an embodiment of inhibition of vascular leakage in rabbits challenged with VEGF after administration of two axitinib implants at a total dose of 290 μg in the absence of VEGF. Animals in Groups 1 and 2 and animals without implants present 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 deviations.

[0074] Fig.12 One embodiment of fluorescein angiography (FA) images shows significant leakage, with active leakage of fluorescein from the vasculature visible immediately after injection of fluorescein 48 hours after VEGF challenge in control animals (upper image) and complete inhibition of vascular leakage from a rabbit eye containing the implant (lower image). Images were collected 1 month after implant injection, after VEGF challenge.

[0075] Fig.13 For rabbits not treated with implant or anti-VEGF therapeutic (white squares and dashed line), Rabbits treated with PD-1 (black triangles, curve fit until 3 months), rabbits with implants (black squares, solid line, until 12 months), and rabbits with implants and Figure 1 shows an embodiment of the mean vascular leakage scores for rabbits with VEGF (striped squares and dashed lines, up to 12 months). For all animals that received implants, vascular leakage was effectively inhibited for 12 months. Animals treated with anti-VEGF therapeutics alone showed a rapid onset of leakage inhibition within the first 2 to 4 weeks, but leakage recurred after 3 months. Values ​​represent means and standard errors of the mean (SEM).

[0076] Figure 14 An embodiment of in vitro axitinib release from a 200 μg implant. (A) Axitinib was completely released from a 200 μg implant after 225 days as observed by in vitro immediate analysis. (B) Axitinib was completely released from a 200 μg implant after 12 days as observed by in vitro accelerated analysis. The in vitro data are not applicable to the observed in vivo release.

[0077] Fig.15 One embodiment of an IR image of subject #1 from Group 2 (2 implants, 400 μg total axitinib per eye). On the day of injection, the implant was clearly visible and in good shape. After 9 months, the implant was completely degraded, with undissolved axitinib remaining at the previous implant location. Undissolved axitinib continued to release drug, with almost no undissolved axitinib remaining after 11 months.

[0078] Fig.16 An 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 total axitinib per eye). For a subject who had not undergone this treatment, a significant reduction in central subfield thickness (CSFT) was observed, while best corrected visual acuity (BCVA) was not impaired over 10.5 months.

[0079] Fig.17An embodiment of central subfield thickness (CSFT) in study eyes of patients with neovascular age-related macular degeneration (wet AMD) treated with axitinib implant (one implant, total dose of 200 μg: Group 1; two implants, total dose of 400 μg: Group 2; three implants, total dose of 600 μg: Group 3a; two implants, total dose of 400 μg, and concurrent initial anti-VEGF: Group 3b). The mean change in CSFT from baseline values ​​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 Month 6 and Month 7.5. Two patients in Group 3b were followed up until month 3, and one until month 4.5. Follow-up is ongoing.

[0080] Fig.18 An embodiment of best-corrected visual acuity (BCVA) in study eyes of patients with neovascular age-related macular degeneration (wet AMD) treated with axitinib implants (one implant, total dose of 200 μg: Group 1; two implants, total dose of 400 μg: Group 2; three implants, total dose of 600 μg: Group 3a; two implants, total dose of 400 μg, and concurrent initial anti-VEGF: Group 3b). The mean change in BCVA from baseline Early Treatment Diabetic Retinopathy Study (ETDRS) letter score (the representative value of a letter that can be accurately read at a distance) is presented in this graph with the standard error of the mean (SEM). For this graph (as for the above Fig.17 ): Six patients in Group 1 were followed up to 9 months. Seven patients in Group 2 were followed up to 12 months, five to 14 months, and two to 16 months. Six patients in Group 3a were followed up to Day 14, five to 2 months, two to 4.5 months, and one to 6 and 7.5 months. Two patients in Group 3b were followed up to 3 months, and one to 4.5 months. Follow-up is ongoing.

[0081] Fig.19 A and Fig.19B An embodiment of a spectral domain optical coherence tomography (SD-OCT) image of the study eye of subject No. 1 from Cohort 2 (2 implants, 400 μg total axitinib per eye) with a 16-month history of aflibercept treatment prior to implant injection in the right eye (OD). Subretinal fluid was clearly visible at baseline (before treatment). Importantly, subretinal fluid disappeared after 2 to 3 months post-implant injection and this phase was essentially maintained for more than 15.5 months ( Fig.19 B shows 15.5 months, Fig.19 Earlier visit in A). Best corrected visual acuity (BCVA) was not impaired.

[0082] Fig. 20 An embodiment of spectral domain optical coherence tomography (SD-OCT) images from Subject 7 in Group 2 (2 implants, 400 μg total axitinib per eye). Subject 7, who had received aflibercept for 6 years prior to study entry, showed a significant decrease in CSFT without loss of BCVA within 9 months after implant injection.

[0083] Fig.21 An embodiment of spectral domain optical coherence tomography (SD-OCT) images of Subject No. 1 from Group 3a (3 implants, 600 μg total axitinib per eye). In Subject No. 1 from Group 3a, who had not undergone AMD treatment, a significant reduction in CSFT was observed at 2 months and maintained for 7.5 months. BCVA was not impaired.

[0084] Fig. 22 One embodiment of spectral domain optical coherence tomography (SD-OCT) images from anti-VEGF naive subject No. 1 in Group 3b (2 implants, 400 μg total axitinib per eye, including co-administered anti-VEGF agent). CSFT decreased rapidly within 7 days and further decreased and remained low until month 3.

[0085] Fig.23 One embodiment of spectral domain optical coherence tomography (SD-OCT) images of Subject No. 2 from Cohort 3b (2 implants, 400 μg total axitinib per eye, including initial co-administered anti-VEGF agent) who had received 7 months of anti-VEGF therapy prior to implant injection. CSFT decreased rapidly within 7 days. Low CSFT values ​​were maintained until Month 2.

[0086] Fig.24 One embodiment of the aggregation propensity of axitinib when a hydrogel implant according to an embodiment of the present invention is prepared and cast under otherwise identical conditions using micronized versus non-micronized axitinib.

[0087] Fig.25 A and Fig.25 B 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 push wire to deploy the implant. Fig.25 A shows the Hamilton syringe body inside the injection molded housing. Fig.25 B shows a schematic view of the components of this embodiment of the injector.

[0088] Fig.26 A Exploded view of one embodiment of an injector according to the invention made from an injection molded body. Fig.26 B shows a photograph of the fully assembled injector. Fig.26 C shows an exploded view of a first component of an injector according to the present invention. Fig.26 D shows an exploded view of a second component of the injector according to the present invention. Fig.26 E shows that the first component and the second component can be aligned. Fig.26 F shows the outer cover of the second component fixed to the body of the first component. Figure 26G The needle guard is shown removed from the housing of the second assembly and the plunger clip is shown removed from the body and plunger of the first assembly. Fig.26H Actuation of the plunger of the first assembly is shown to deploy the implant from the lumen of the needle of the second assembly.

[0089] Fig. 27 A Phase 1 study design utilizing an implant containing 200 μg of axitinib according to one embodiment of the present invention.

[0090] Fig.28 Proposed Phase 2 study design utilizing an implant containing 600 μg of axitinib according to one embodiment of the present invention.

[0091] definition

[0092] As used herein, the term "implant" (sometimes also referred to as a "reservoir") refers to an object that contains an active agent, in particular, a tyrosine kinase inhibitor (TKI) such as axitinib and other compounds as disclosed herein, and is administered into the vitreous humor (also referred to as the "vitreous cavity" or "vitreous") of a human or animal body, for example, where it remains for a period of time as it releases the active agent into the surrounding environment. The implant may have any predetermined shape prior to injection (such as disclosed herein), which is maintained to some extent when the implant is placed in the desired location, but after administration, the size of the implant (e.g., length and / or diameter) may change due to hydration as further disclosed herein. In other words, what is injected into the eye is not a solution or suspension, but rather a shaped, cohesive object. Thus, prior to administration, the implant is already fully formed as disclosed herein, and in embodiments of the present invention, the implant is not generated in situ at the desired location in the eye (as is generally possible if there is an appropriate formulation). Once applied, the implant will biodegrade (as described below) in a physiological environment over time, thereby changing its shape while reducing its size until it is completely dissolved / absorbed. In this article, the term "implant" is used to refer to an implant in a hydrated (also referred to herein as "wet") state when containing water, such as after the implant is hydrated or rehydrated once applied to the eye or otherwise immersed in an aqueous environment (e.g., in vitro), and to an implant in its / dry (dry / dehydrated) state, i.e., after the implant has been produced and dried and is about to be loaded in a needle, or after being loaded in a needle as disclosed herein, or wherein the implant has been prepared in a dry state without dehydration. Therefore, in certain embodiments, an implant in a dry / dry state in the context of the present invention may contain no more than about 1% by weight of water. The water content of an implant in a dry / dry state can be measured, for example, by Karl Fischer coulometry. Whenever the dimensions of the implant in the hydrated state (i.e., length, diameter, or volume) are reported herein, these dimensions should be measured after the implant has been immersed in phosphate buffered saline at 37° C. for 24 hours. Whenever the dimensions of the implant in the dry state are reported herein, these dimensions should be measured after the implant has been completely dried (and therefore, in certain embodiments, contains no more than about 1% by weight of water) and the implant is in a 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 an embodiment of the dimensional measurements are reported in Example 6.1.

[0093] The term "eye" as used in the present invention generally refers to the eye, or any part of the eye (as the "ocular implant" according to the present invention can in principle be applied to any part of the eye) or any eye disease (as in one aspect, the present invention generally refers to the treatment of any eye disease of various origin and nature ("ocular disease"). In certain embodiments, the present invention relates to intravitreal injection of ocular implants (in this case, the "ocular implant" is therefore an "intravitreal implant"), and to the treatment of ocular diseases affecting the posterior segment of the eye, as further disclosed below.

[0094] The term "patient" herein includes both human and animal patients. Thus, the implants according to the present invention are suitable for use in human or veterinary medicine. The patients recruited and treated in the clinical studies reported in Example 6 are referred to as "subjects". In general, a "subject" is a (human or animal) individual to whom an implant according to the present invention is administered (such as during a clinical study). A "patient" is a subject who needs treatment due to a specific physiological or pathological condition.

[0095] The term "biodegradable" refers to a material or object (such as an ocular 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 disclosed in detail below, an implant comprising a hydrogel in which TKI particles, such as axitinib particles, are dispersed, once deposited in the eye, e.g., in the vitreous humor, slowly biodegrades over time. 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.

[0096] A "hydrogel" is a three-dimensional network of a hydrophilic natural or synthetic polymer (as disclosed herein) that can swell in water and hold a certain amount of water while maintaining or substantially maintaining its structure due to, for example, chemical or physical crosslinking of individual polymer chains. Due to its high water content, hydrogels are soft and elastic, thereby making them very similar to natural tissue. In the present invention, the term "hydrogel" is used to refer to a hydrogel in a hydrated state when it contains water (e.g., after the hydrogel is formed in an aqueous solution, or after the hydrogel is (re)hydrated once implanted in the eye or other part of the body or otherwise immersed in an aqueous environment), and to a hydrogel in a dry (dry / dehydrated) state when it is dried to a low water content, e.g., not more than 1% by weight. In the present invention, where an active ingredient is contained (e.g., dispersed) in a hydrogel, the hydrogel may also be referred to as a "matrix."

[0097] The term "polymer network" describes a structure formed by polymer chains (of the same or different molecular structures and of the same or different molecular weights) that are cross-linked to each other. Types of polymers suitable for the purposes of the present invention are disclosed herein. As also disclosed herein, a polymer network can also be formed by a cross-linking agent.

[0098] 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.

[0099] The term "semicrystalline" refers to a polymer or polymer network or other chemical substance or entity that has some crystalline characteristics, ie, exhibits some crystalline properties in X-ray or electron scattering experiments.

[0100] The term "crystalline" refers to a polymer or polymer network or other chemical substance or entity having crystalline characteristics as demonstrated by X-ray or electron scattering experiments.

[0101] The term "precursor" herein refers to those molecules or compounds that react with each other and thus connect via cross-linking to form a polymer network and thus 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".

[0102] The parts of the precursor molecules that are still present in the final polymer network are also referred to herein as "units". Thus, a "unit" is a building block or component of a polymer network that forms a hydrogel. For example, a polymer network suitable for use in the present invention may contain the same or different polyethylene glycol units, as further disclosed herein.

[0103] The molecular weight of the polymer precursor 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 the 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 polymer including the polyethylene glycol precursor as disclosed herein is the average molecular weight (based on the molecular weight distribution of the polymer), and can therefore be indicated by means of various average values, including weight average molecular weight (Mw) and number average molecular weight (Mn). In the case of the polyethylene glycol precursor as used in the present invention, the molecular weight indicated herein is the number average molecular weight (Mn).

[0104] In certain embodiments of the invention, the term "fiber" (used interchangeably with the term "rod" herein) refers to a feature of an object (i.e., in this case, an implant according to the invention) that generally has an elongated shape. Specific dimensions of the implant of the 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 may also be elliptical or rectangular in certain embodiments, or may have different geometric shapes in other embodiments, such as a cross, a star, or other shapes as disclosed herein.

[0105] 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 an 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 vitreous humor and / or ocular tissue, such as the retina and choroid. Therefore, whenever it is stated herein that an implant "releases" or "provides (sustained) release" of a TKI (such as axitinib), this situation refers not only to the provision of the TKI (such as axitinib) directly from the implant when the hydrogel has not yet (completely) biodegraded, but also to the continued provision of the TKI (such as axitinib) to the surrounding environment for a longer period of time and the continued exertion of its therapeutic effect when there is still residual TKI (e.g., in aggregated form as further disclosed herein) in the surrounding environment after the hydrogel is completely degraded. Therefore, even after the implant / hydrogel has been completely biodegraded as further disclosed herein, the "therapeutic period" referred to herein (i.e., the period of time to achieve a certain therapeutic effect as described herein) can also be extended for a period of time.

[0106] For the purposes of the present invention, the term "sustained release" is defined to refer to a product (in the case of the present invention, the product is an implant) that is formulated so that the drug is available over a longer period of time, thereby allowing for a reduced frequency of dosing compared to an immediate release dosage form (such as a solution of the 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" refers to the characteristics of the release of the API, in particular TKI, such as axitinib, contained in the implant according to the present invention. The term "sustained release" itself is not associated with 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".

[0107] Whenever it is stated herein that a certain administration or injection is performed "concurrently" or "simultaneously" or "at the same time" as the administration or injection of an implant according to the invention, this means that the respective injections of two or more implants or the injection of one or more implants and the injection of a suspension or solution of an anti-VEGF agent, e.g. as disclosed herein, are generally performed one after the other, i.e. without any significant delay. For example, if a total dose of about 400 μg of axitinib is administered to one eye and said total dose is contained in two implants according to the invention, each containing about 200 μg of axitinib, these two implants are generally injected into the vitreous cavity one after the other within the same course of treatment, of course, all precautions should be observed to ensure safe and accurate injection at the desired site without any unnecessary delays. The same applies to administration of one or more implants according to the invention being performed concurrently / concurrently / at the same time as the administration of another anti-VEGF agent as described herein. If the further anti-VEGF drug is administered by intravitreal injection of a suspension or solution containing said anti-VEGF drug, said injection is generally also intended to be carried out 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).

[0108] However, in certain circumstances, for example, if complications are encountered during the administration of the first implant and / or the physician performing the injection concludes that a second injection is not recommended on the same day or within a few days of the same course of treatment, the second implant may also be administered, for example, one or two weeks after the first implant. Since, as will be disclosed in more detail herein, the implant may persist in the vitreous of the human eye for a longer period of time, such as from 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 "concurrently". Similar considerations also apply to the "concurrent" administration of an implant according to the present invention and an anti-VEGF agent. Thus, the anti-VEGF agent may be administered concurrently with the intravitreal administration of the implant of the present invention, i.e., at or about the same time as described herein.

[0109] However, in certain other embodiments, the anti-VEGF agent may also be administered in combination with the intravitreal implant of the present invention, such that the anti-VEGF agent is administered subsequently, such as 1 month or 2 months or 3 months after intravitreal injection of the implant according to the present invention.

[0110] The term "rescue medication" generally refers to a medication that can be administered to a patient under predetermined conditions (e.g., during a study if the patient does not respond adequately to the study treatment), or refers to a medication that manages an emergency condition. The conditions used to administer rescue medication in the clinical studies disclosed in Example 6 herein are indicated under the subheading "Rescue Medication" in the description of Example 6 (see Table 27 for specific percentages of rescue medication administration). In certain embodiments of the present invention, "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 anti-VEGF agent for intravitreal injection. In certain specific embodiments, the rescue medication is a dose (2 mg) of aflibercept administered by intravitreal injection.

[0111] 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 one of ordinary skill in the art in making the measurements and exercising a level of care commensurate with the precision of the measurement objective and the measuring device.

[0112] The term "at least about" in relation to a measured quantity refers to the normal variation in the measured quantity as would be expected by one of ordinary skill in the art in making the measurements and exercising a level of care commensurate with the precision of the measurement objective and the measuring equipment, and any amount above the stated quantity.

[0113] As used herein, the term "mean" refers to a central value or typical value in a set of data (points), which is calculated by dividing the sum of the data (points) in the set by their number (ie, the mean of a set of data).

[0114] As used herein, the singular form "a," "an," and "the" include plural references unless the context clearly dictates otherwise.

[0115] The term "and / or" as used herein in phrases such as "A and / or B" is intended to include "A and B" and "A or B."

[0116] 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 listed elements, method steps, or the like, and also include other uncited elements, method steps, or the like.

[0117] The term "up to" when used herein with a certain value or number is meant to include the respective value or number.

[0118] The terms "from A to B", "from A to B" and "A to B" are used interchangeably herein and all refer to a range from A to B, including upper and lower limits A and B.

[0119] 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 used in and for the preparation of a final pharmaceutical product (FPP) and intended to provide pharmacological activity or to have a direct effect on the diagnosis, cure, mitigation, treatment or prevention of disease, or to have a direct effect on restoring, correcting or altering the physiological function of a patient.

[0120] In certain embodiments, the TKI used according to the present invention is axitinib. Axitinib is used to treat advanced renal cell carcinoma. The active ingredient in ANTIBIOL® (Pfizer, NY) is a small molecule (386.47 Daltons) synthetic tyrosine kinase inhibitor. The main mechanism of action is to inhibit angiogenesis (formation of new blood vessels) by inhibiting receptor tyrosine kinases, 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. Therefore, axitinib is a multi-target inhibitor that inhibits the VEGF and PDGF pathways.

[0121] 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-indazol-6-ylsulfanyl]-benzamide. It has the following chemical structure:

[0122]

[0123] The solubility of axitinib in biologically relevant media (PBS, pH 7.2 at 37°C) has been determined to be low, approximately 0.4 to 0.5 μg / mL. Its partition coefficient (n-octanol / water) is 4.2 (logP; see DrugBank entry "axitinib").

[0124] For the purpose of the present invention, all possible forms of active agents (including axitinib) can be used, including any active agent polymorph or any pharmaceutically acceptable salt, anhydrate, hydrate, other solvate or derivative of the active agent. Whenever in this specification or in the scope of the patent application, the name of the active agent is, for example, "axitinib", even if it is not explicitly stated, it also refers to any of the polymorphs, pharmaceutically acceptable salts, anhydrates, solvates (including hydrates) or derivatives of the active agent.

[0125] As used herein, the term "polymorph" refers to any crystalline form of an active agent such as axitinib. Typically, an active agent that is solid at room temperature exists in a number of different crystalline forms, i.e., polymorphs, where one polymorph is the most thermodynamically stable at a given temperature and pressure.

[0126] Regarding axitinib, suitable solid forms and polymorphs of axitinib, including anhydrous forms and solvates, are described, for example, in AM Capeta et al., Journal of Pharmaceutical Sciences, Vol. 99, No. 9, September 2010, 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 most thermodynamically stable polymorph of axitinib, for example, referred to as XLI in US Pat. No. 8,791,140 B2. XLI is an anhydrous crystalline form of axitinib. In certain embodiments of the present invention, the axitinib used to prepare the implant according to the present invention is an 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 form, there are many solvates of axitinib with various solvents, as also described in the cited field, which can also all be used to prepare implants according to the present invention. All of the above forms are well characterized and described in the art, such as in the papers or patent documents cited above by Campeta et al. (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, in particular (but not limited to) the references cited herein, can be used in the present invention.

[0127] In certain specific embodiments, the axitinib used to prepare the implant according to the present invention and / or present in the implant according to the present invention is characterized by an XRD pattern comprising at least five characteristic 2θ peaks selected from the group consisting of 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°. In particular, the axitinib used to prepare the implant according to the present invention and / or present in the implant according to the present invention is characterized by an XRD pattern comprising at least five characteristic 2θ peaks selected from the group consisting of 8.3, 9.3, 15.6, 16.5, 17.6, 21.0, 24.1 and 26.0 (each value ±0.2 2θ°), and / or a DMSO solvent comprising a chemical shift of 26.1, 114.7, 154.8 and 167.8 (each shift ±0.2 ppm). 13 C NMR, and / or chemical shifts including 171.1, 153.2, 142.6, 139.5, 131.2, 128.1 and 126.3 (each shift ± 0.2 ppm) 13C solid state NMR, and / or a DSC isotherm comprising two endothermic peaks ranging between 213°C and 217°C (peak 1) and 219°C and 224°C (peak 2). In a specific embodiment, the non-solvated crystalline form SAB-I of axitinib disclosed in WO2016 / 178150 can be used to prepare an implant according to the present invention.

[0128] Axitinib inhibits VEGF signaling and also inhibits PDGF signaling. In addition to inhibiting VEGF / PDGF, it also inhibits c-kit, a survival factor for vascular development, with an elimination half-life (t 1 / 2 ) for 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 of ranibizumab and aflibercept in the human eye is 1 / 2 The longer t 1 / 2 This enables it to maintain effective tissue concentrations for weeks, while small molecules are cleared more quickly. However, due to the low solubility of axitinib and its inclusion in the hydrogel implant of the present invention, which remains in the vitreous humor (VH) for a longer period of time (such as months), a therapeutically effective amount of axitinib is delivered during the period of time that the implant remains in the VH. Therefore, sustained intravitreal delivery of axitinib provides a multi-target inhibitor that can inhibit VEGF and PDGF pathways without the need for combination therapy and frequent intravitreal injections in principle.

[0129] As used herein, the term "therapeutically effective" refers to the amount of a drug or active agent required to produce a desired therapeutic outcome after administration. For example, in the context of the present invention, one desired therapeutic outcome would be a reduction in central subfield thickness (CSFT) by optical coherence tomography in patients with neovascular AMD, since CSFT is elevated in patients with neovascular AMD. In the context of the present invention, a "therapeutically effective" amount of an active agent may also be the amount of IC provided by the active agent for a particular substrate. 50 Multiples of, such as IC 50 For example, Table 12 lists the IC values ​​of TKI axitinib for angiogenesis-related RTKs. 50 value.

[0130] As used herein, the abbreviation "PBS" means phosphate buffered saline.

[0131] The abbreviation "PEG" as used herein means polyethylene glycol. DETAILED DESCRIPTION

[0132] I. Implants

[0133] Active ingredients:

[0134] One aspect of the invention is a sustained release biodegradable ocular implant comprising a hydrogel and at least about 150 μg of a tyrosine kinase inhibitor (TKI), wherein TKI particles are dispersed within the hydrogel. In one embodiment, the invention provides a sustained release biodegradable ocular implant comprising a hydrogel and at least about 150 μg of a tyrosine kinase inhibitor (TKI), wherein TKI particles are dispersed within the hydrogel, and wherein the implant has a length of less than about 17 mm in its dry state.

[0135] 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 about axitinib, its chemical structure, polymorphs, solvates, salts, etc. and its properties (such as solubility) are provided in the above definition section.

[0136] All features disclosed herein with respect to the implant according to the present invention, either individually or in 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 TKI particles are dispersed within the hydrogel, and wherein the implant has a length of less than about 17 mm in its dry state.

[0137] In a specific embodiment, the implant of the invention is an intravitreal implant, ie, administered into the vitreous humor (also referred to herein as "intravitreously administered").

[0138] TKI (such as axitinib) is included in the implant of the present invention in a dosage range of at least 150 μg as disclosed herein, such as about 150 μg to about 1800 μg, about 150 μg to about 1200 μg, or about 200 μg to about 800 μg. Any TKI (such as axitinib) in an amount within these ranges may 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 dose of TKI (such as axitinib) contained in the implant of the present invention may also be up to 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 dose of TKI (such as axitinib) contained in the implant of the present invention may 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 mentioned values ​​also include a variance of +25% and -20%, or a variance of + / -10%.

[0139] In certain specific embodiments, the dosage of axitinib contained in the implant of the present invention is:

[0140] - A range of about 160 μg to about 250 μg, or about 180 μg to about 220 μg, or about 200 μg (ie, including a variance of +25% and -20%, or a variance of + / -10% of 200 μg)

[0141] - A range of about 320 μg to about 500 μg, or about 360 μg to about 440 μg, or about 400 μg (ie, including a variance of +25% and -20%, or a variance of + / -10% of 400 μg)

[0142] - A range of about 375 μg to about 600 μg, or about 450 μg to about 550 μg, or about 500 μg (ie, including a variance of +25% and -20%, or a variance of + / -10% of 500 μg)

[0143] - A range of about 480 μg to about 750 μg, or about 540 μg to about 660 μg, or about 600 μg (ie, including a variance of +25% and -20%, or a variance of + / -10% of 600 μg)

[0144] - A range of about 640 μg to about 1000 μg, or about 720 μg to about 880 μg, or about 800 μg (ie, including a variance of +25% and -20%, or a variance of + / -10% of 800 μg)

[0145] - A range of about 800 μg to about 1250 μg, or about 900 μg to about 1100 μg, or about 1000 μg (ie, including a variance of +25% and -20%, or a variance of + / -10% of 1000 μg)

[0146] - A range of about 960 μg to about 1500 μg, or about 1080 μg to about 1320 μg, or about 1200 μg (ie, including a variance of +25% and -20%, or a variance of + / -10% of 1200 μg)

[0147] - A range of about 1440 μg to about 2250 μg, or about 1620 μg to about 1980 μg, or about 1800 μg (ie, including a variance of +25% and -20%, or a variance of + / -10% of 1800 μg).

[0148] In a preferred embodiment, an implant of the present invention contains axitinib at a dose of about 480 μg to about 750 μg, or about 540 μg to about 660 μg, or in a specific embodiment about 600 μg.

[0149] The disclosed amounts of TKIs such as axitinib, including the mentioned variations, refer both to the final content of the active ingredient in the implant and to the amount of the active ingredient used as the starting component of each implant when manufacturing the implant.

[0150] As will be disclosed in more detail below and will be apparent from the Examples section, in certain embodiments of the invention, the total dose of a TKI (such as axitinib) administered to a patient may 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 in one implant containing about 400 μg of axitinib, or in two implants containing, for example, about 200 μg of axitinib each, etc. Of course, not only two or more identical implants (or implants containing the same dose) can 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 specific 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 of the implants is administered to a patient in need of the treatment according to the invention. In another embodiment, a total dose of more than 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 about 960 μg to about 1500 μg, or about 1080 μg to about 1320 μg, or about 1200 μg, or 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 of the implants is administered to a patient in need of the treatment according to the invention. In other embodiments, the total dose administered to a patient according to the invention may be contained in two or more implants (containing the same or different amounts of API) administered simultaneously.

[0151] 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, which holds them in the desired location in the eye while slowly releasing the drug.

[0152] In certain embodiments of the invention, TKI particles (such as axitinib particles) may be microencapsulated. The term "microcapsule" (also referred to as "microparticle") is sometimes defined as a generally spherical particle that varies in size, 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 referred to as a shell). For purposes of the present invention, a suitable agent for microencapsulating TKIs (such as axitinib) (without limiting the disclosure thereto) is poly(lactic-co-glycolic acid).

[0153] In other embodiments, the TKI particles (such as axitinib particles) are not microencapsulated and are therefore dispersed in the hydrogel and therefore in the implant of the present invention as is, i.e., not mixed with or adjacent to or microencapsulated by another material such as (but not limited to) poly(lactic-co-glycolic acid).

[0154] 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 refers to the process of reducing the average diameter of particles of a solid material. Particles with reduced diameters may have, among other things, higher dissolution and erosion rates, which increases the bioavailability of the active pharmaceutical ingredient and, in certain embodiments, may have a positive impact on release kinetics. In addition, micronized particles may have a reduced tendency to aggregate during manufacturing operations (see also Fig.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. Therefore, compared with larger TKI particles of similar mass fraction, a hydrogel matrix filled with micronized TKI particles may have improved mechanical properties (e.g., brittleness, failure strain, etc.). The properties are important in the manufacture of implants, during implantation, and during degradation. Micronization can also promote a more homogeneous distribution of active ingredients in a selected dosage form or matrix. The 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 the preparation of the implant of the present invention may 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 specific embodiments, the d90 of a TKI (such as axitinib) may be less than about 30 μm, less than about 20 μm, as determined by laser diffraction. In very specific embodiments, the d90 of a TKI (such as axitinib) is less than about 10 μm, as determined by laser diffraction. In these or other embodiments, the d50 of the TKI (such as axitinib) particles used in preparing the implants of the present invention may be less than about 5 μm, as determined by laser diffraction. In these or other embodiments, the d10 of the TKI (such as axitinib) particles used in preparing the implants of the present invention may be less than about 3 μm, as determined by laser diffraction. In certain embodiments, the d100 of the TKI (such as axitinib) particles used in preparing the implants of the present invention may be less than about 20 μm, as determined by laser diffraction. The "d90" (also referred to herein as "D90") value means that 90% by volume of all particles within a measured bulk material (having a certain particle size distribution) have a particle size below the indicated value. For example, a d90 particle size of less than about 10 μm means that 90% of the particles by volume in the bulk material measured have a particle size below about 10 μm. Corresponding definitions apply to other "d" values, such as "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 having diameters exceeding this specification may also be used.

[0155] Micronized TKI (such as axitinib) particles can be purchased from suppliers according to specifications, or can be prepared, for example, according to the following exemplary procedure (disclosed in WO 2016 / 183296 A1, Example 13): 1800 mL of sterile water for injection (WFI) is measured into a 2L beaker and placed on a stir plate with a stir bar, stirring at 600 RPM, creating a large WFI vortex in the center of the beaker. A 60 mL BD syringe containing axitinib in ethanol is placed on a syringe pump, which is clamped above the WFI beaker. A hypodermic needle (21G, BD) is connected to the syringe and directly aimed at the center of the vortex to disperse the axitinib solution. The syringe pump is then operated at 7.5 mL / min to add the axitinib solution dropwise to the WFI to precipitate the 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 by using a spatula, and vacuum dried for a longer period of time, such as about 12 or about 24 hours, to remove excess solvent. Another exemplary 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 active agents (such as axitinib) may be equally used. The disclosed micronization method (or other method) may also be used for other active agents other than axitinib.

[0156] Another aspect of the invention is a sustained release biodegradable ocular implant comprising a hydrogel and at least about 150 μg of a tyrosine kinase inhibitor (TKI), wherein TKI particles are dispersed within the hydrogel, and wherein the total weight of the implant in its dry state is about 0.2 mg to about 1.5 mg. In certain embodiments, the TKI is axitinib or another TKI as disclosed herein.

[0157] In certain embodiments, the total weight of the implant according to the present invention in its dry state (also referred to herein as "total mass") may 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 may be from about 0.3 mg to about 0.6 mg, such as from about 0.4 mg to about 0.5 mg, or may be from about 0.8 mg to about 1.1 mg, such as from about 0.9 mg to about 1.0 mg.

[0158] All features disclosed herein with respect to the implant according to the present invention, either individually or in 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 TKI particles are dispersed within the hydrogel, and wherein the total weight of the implant in its dry state is about 0.2 mg to about 1.5 mg.

[0159] Polymer Network:

[0160] 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 (i.e., covalent bonds) and / or physical (such as ionic bonds, hydrophobic associations, hydrogen bridges, etc.) in nature.

[0161] The polymer network can be prepared from precursors, from one type of precursor or from two or more types of precursors that allow reactions. The precursor is selected considering the properties required for the resulting hydrogel. There are various suitable precursors for preparing hydrogels. In general, any pharmaceutically acceptable and cross-linkable polymer that forms a hydrogel can be used for the purpose of the present invention. The hydrogel and the components thus incorporated therein, including the polymer for preparing the polymer network, should be physiologically safe so that it does not cause, for example, an immune response or other adverse reactions. The hydrogel can be formed by natural, synthetic or biosynthetic polymers.

[0162] Natural polymers may include glycosaminoglycans, polysaccharides (eg, dextran), polyamino acids, and proteins, or mixtures or combinations thereof.

[0163] Synthetic polymers can generally be any polymer prepared synthetically 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. Polymerization can be initiated by certain initiators, light and / or heat, and can be mediated by catalase.

[0164] In general, for the purposes of the present invention, one or more synthetic polymers from the group comprising one or more of the following units may be used: 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, polylactic-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.

[0165] To form a covalently crosslinked polymer network, the precursors can be covalently crosslinked with each other. In certain embodiments, precursors having at least two reactive centers (eg, in free radical polymerization) can be used as crosslinkers because each reactive group can participate in the formation of a different growing polymer chain.

[0166] Precursors may have biologically inert and hydrophilic portions, such as a core. In the case of a branched polymer, a core refers to a continuous portion of a molecule connected to an arm extending from the core, wherein the arm carries a functional group, typically at the end of the arm or branch. Multi-arm PEG precursors are examples of such precursors and are further disclosed below.

[0167] Therefore, the hydrogel used in the present invention can be prepared, for example, by a multi-arm precursor having a first (group) of functional groups and another multi-arm precursor having a second (group) of functional groups. For example, the multi-arm precursor can have hydrophilic arms terminated by a primary amine (nucleophile), such as polyethylene glycol units, or can have activated ester end groups (electrophiles). The polymer network according to the present invention can contain identical or different polymer units that are cross-linked to each other.

[0168] Certain functional groups can be made more reactive by using activating groups. Such activating groups include, but are not limited to, carbonyldiimidazole, sulfonyl chloride, aryl halide, sulfosuccinimidyl ester, N-hydroxysuccinimidyl ester, succinimidyl ester, epoxide, aldehyde, maleimide, imide ester, acrylate, and the like. N-hydroxysuccinimidyl ester (NHS) is a useful group for crosslinking nucleophilic polymers, such as primary amine-terminated or thiol-terminated polyethylene glycol. 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).

[0169] In certain embodiments, each precursor may contain only nucleophilic or electrophilic functional groups, as long as both nucleophilic and electrophilic precursors are used in the crosslinking reaction. Thus, for example, if the crosslinking agent has only nucleophilic functional groups, such as amines, the precursor polymer may have electrophilic functional groups, such as N-hydroxysuccinimide. On the other hand, if the crosslinking agent has electrophilic functional groups, such as sulfosuccinimide, the functional polymer may have nucleophilic functional groups, such as amines or thiols. Thus, functional polymers, such as proteins, poly(allylamine)s or amine-terminated di- or multifunctional poly(ethylene glycol)s may also be used to prepare the polymer networks of the present invention.

[0170] 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 are allowed to react with the first reactive precursor to form a 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, so for example, reactive precursors with 4, 8, and 16 reactive groups are particularly suitable for the present invention. Any number of functional groups, such as including any of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 groups, is possible for the precursors used according to the present invention while ensuring that the functionality is sufficient to form a fully cross-linked network structure.

[0171] PEG hydrogel:

[0172] In certain embodiments of the invention, the polymer network forming the hydrogel contains polyethylene glycol (PEG) units. It is known in the art that PEG forms hydrogels when cross-linked, and these PEG hydrogels are suitable for pharmaceutical applications, for example as a matrix for drugs intended to be administered to all parts of the human or animal body.

[0173] The polymer network of the hydrogel implant of the present invention can 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 can have different or the same number of arms. In certain embodiments, the PEG units used in the hydrogel 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.

[0174] The number of arms of the PEG used helps control the flexibility or softness of the resulting hydrogel. For example, a hydrogel formed by crosslinking a 4-arm PEG is generally softer and more flexible than a hydrogel formed by an 8-arm PEG of the same molecular weight. Specifically, if it is desired to stretch the hydrogel before or after drying as disclosed below in the section related to the manufacture of the implant, a more flexible hydrogel, such as a 4-arm PEG, can be used, optionally in combination with another multi-arm PEG, such as the 8-arm PEG disclosed above.

[0175] In certain embodiments of the present invention, the mean molecular weight of the polyethylene glycol unit used as a precursor 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 mean molecular weight of the polyethylene glycol unit is in the range of about 10,000 to about 40,000 daltons, or is about 20,000 daltons. PEG precursors with the same mean molecular weight can be used, or PEG precursors with different mean molecular weights can be combined with each other. The mean molecular weight of the PEG precursor used in the present invention is given as a number-average molecular weight (Mn), which can be determined by MALDI in certain embodiments.

[0176] In 4-arm PEG, the average arm length (or molecular weight) of each arm can be the total molecular weight of PEG divided by 4. Therefore, 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. Therefore, 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. Compared with shorter arms, longer arms can provide increased flexibility. Compared with PEG with shorter arms, PEG with longer arms may swell more. Compared with PEG with a higher number of arms, PEG with a lower number of arms may also swell more and be more flexible. In certain specific embodiments, a combination 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. In addition, longer PEG arms have a higher melting temperature when dried, which can provide greater dimensional stability during storage. For example, an 8-arm PEG of molecular weight 15,000 Daltons cross-linked to trilysine may not be able to maintain a stretched configuration at room temperature, whereas a 4-arm 20,000 Dalton PEG cross-linked to an 8-arm 20,000 Dalton PEG may be dimensionally stable in a stretched configuration at room temperature.

[0177] 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., an Mn of 15,000 or 20,000, respectively) refers to the PEG portion of the precursor prior to the addition of the end groups (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 substitution with end groups as disclosed herein can be determined after end group functionalization by means of 1 Confirmed by H-NMR.

[0178] In certain embodiments, the electrophilic end groups used in the PEG precursors used to prepare the hydrogels of the present invention are N-hydroxysuccinimidyl (NHS) esters, including but not limited to: "SAZ", which refers to succinimidyl azelate end group; "SAP", which refers to succinimidyl adipate end group; "SG", which refers to succinimidyl glutarate end group; and "SS", which refers to succinimidyl succinate end group.

[0179] In certain embodiments, the nucleophilic end groups used in the PEG precursors used to prepare 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.

[0180] In certain preferred embodiments, a 4-arm PEG having an average molecular weight of about 20,000 Daltons and having electrophilic end groups as disclosed above and an 8-arm PEG also having an average molecular weight of about 20,000 Daltons and having nucleophilic end groups as disclosed above are cross-linked to form a polymer network, and thus form a hydrogel according to the present invention.

[0181] The reaction of a PEG unit containing a nucleophilic group and a PEG unit containing an electrophilic group (such as a PEG unit containing an amine terminal group and a PEG unit containing an activated ester group) produces a plurality of PEG units cross-linked by a hydrolyzable linker having the formula: wherein m is an integer from 0 to 10, and specifically 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10. In a particular embodiment, m is 6, for example in the case of using PEG containing 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 may be the same, or may be different.

[0182] 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 including hydrogels comprising PEG-SAZ units only biodegrade in the eye, such as in the vitreous humor of the human eye, after a longer period of time (e.g., 9 to 12 months as further disclosed below), and in some cases can last even longer. SAZ groups are more hydrophobic than, for example, SAP, SG or SS end groups because the number of carbon atoms in the chain is larger (m is 6, and the total number of carbon atoms between the amide group and the ester group is 7).

[0183] 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 with a SAZ group (as defined above) and an 8-arm 20,000 Dalton PEG precursor with 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:

[0184]

[0185] Where R represents the neopentylthritol core structure. The chemical structure of 8a20kPEG-NH2 (with a hexaglycerol core) is:

[0186]

[0187] In the above formula, n is determined by the molecular weight of the respective PEG arm.

[0188] In certain embodiments, the molar ratio of the nucleophilic end groups and the electrophilic end groups that react with each other is about 1: 1, that is, each SAZ group provides an amine 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 8-arm PEG is twice that of 4-arm PEG. However, an excess of electrophilic (e.g., NHS end groups, such as SAZ) end groups or nucleophilic (e.g., amine) end groups can be used. Specifically, an excess of nucleophiles, such as precursors containing amine end groups, i.e., the weight ratio of 4a20kPEG-SAZ and 8a20kPEG-NH2 can also be less than 2: 1.

[0189] Each and any combination of the PEG precursor containing electrophilic groups and nucleophilic groups disclosed herein can be used for preparing implants according to the present invention. For example, any 4-arm or 8-arm PEG-NHS precursor (e.g., with 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 with nucleophilic groups). In addition, the PEG unit containing the precursor of electrophilic groups and nucleophilic groups can have the same or different average molecular weights.

[0190] Another cross-linking agent containing a nucleophilic group may be used in place of the PEG-based cross-linking agent. For example, a low molecular weight amine linker such as trilysine (or a trilysine salt or derivative, such as trilysine acetate) or other low molecular weight multi-arm amines may be used.

[0191] In certain embodiments, a cross-linking agent containing a nucleophilic group can be combined or combined with an imaging agent. An imaging agent is a reagent containing a fluorophore or other group that realizes imaging. Fluorophores such as fluorescein, rhodamine, coumarin and cyanine can be used as imaging agents, for example. The imaging agent can be combined with the cross-linking agent, for example, via some nucleophilic groups of the cross-linking agent. Because cross-linking requires a sufficient amount of nucleophilic groups, "conjugated / conjugation" generally includes partial combination, meaning that only a portion of the nucleophilic groups are used to combine with the imaging agent, such as about 1% to about 20% of the cross-linking agent, or about 5% to about 10%, or about 8% of the nucleophilic groups can be combined with the imaging agent. In other embodiments, the imaging agent can also be combined with the polymer precursor, for example, via certain reactive (such as electrophilic) groups of the polymer precursor.

[0192] Additional Ingredients:

[0193] In addition to the polymer units and active ingredients forming the polymer network as disclosed above, the implant of the present invention may also contain other additional ingredients. The additional ingredients are, for example, salts derived from the buffer used in the hydrogel preparation process, such as phosphates, borates, bicarbonates or other buffers, such as triethanolamine. In certain embodiments of the present invention, sodium phosphate buffer (specifically, sodium dihydrogen phosphate and disodium hydrogen phosphate) is used.

[0194] Optionally, preservatives may be used in the implants of the invention. However, in certain embodiments, the implants of the invention, including implants containing axitinib as an active agent, are free of preservatives, such as antimicrobial preservatives (including but not limited to benzalkonium chloride (BAK), chlorobutanol, sodium perborate, and stable oxychloride complex (SOC)), or are substantially free of such preservatives.

[0195] In one embodiment of the present invention, if in situ gelation is preferred, possible additional ingredients may be other agents used in the hydrogel manufacturing process, such as (but not limited to) viscosity influencing agents (such as hyaluronic acid, etc.), surfactants, etc.

[0196] In certain embodiments, the insert of the present invention may contain an imaging agent. Imaging agents that can be used in the context of the present invention are all agents that can be bound to a component of the hydrogel or can be embedded in the hydrogel and are visible or can be visible when exposed to, for example, a certain wavelength of light or are contrast agents. Suitable imaging agents for use in the present invention are, but are not limited to, for example, fluorescein, rhodamine, coumarin, anthocyanin, europium chelates, boron dipyromethene, benzofuran, dansyl, bimane, acridine, triazacyclopentadiene, pyrene and derivatives thereof. The imaging agent can be bound to a precursor containing a nucleophilic or electrophilic group that forms a polymer network as disclosed above, or the imaging agent can be a separate (unbound) agent that is added during the manufacture of the implant and is present in the hydrogel.

[0197] formula:

[0198] In certain embodiments, the implant according to the present invention comprises a TKI, a polymer network made from one or more polymer precursors as disclosed herein above and in the form of a hydrogel, and optional additional components such as salts left in the implant during the production process (such as phosphates used as buffers, etc.). In certain preferred embodiments, the TKI is axitinib.

[0199] In certain embodiments, the implant according to the present invention may contain, in its dry state, about 15% to about 80% by weight, such as about 25% to about 75% TKI and about 15% to about 80% by weight, such as about 20% to about 60% polymer units, or in a specific embodiment, about 35% to about 65% by weight TKI and about 25% to about 50% by weight polymer units (dry composition). In a specific embodiment, the implant according to the present invention may contain about 45% to about 55% by weight TKI and about 37% to about 47% by weight polymer units (dry composition), wherein the TKI and polymer units are selected from those disclosed herein above. In other specific embodiments, the implant according to the present invention may contain, in its dry state, about 55% to about 75% TKI and about 20% to about 40% polymer units (dry composition), wherein the TKI and polymer units are selected from those disclosed herein above. In other specific embodiments, the implant according to the present invention may contain, in its dry state, about 30% to about 45% by weight of a TKI and about 47% to about 70% by weight of polymer units (dry composition), wherein the TKI and the polymer units are selected from those disclosed herein above.

[0200] In a particular embodiment, the implant according to the present invention may contain, in its dry state, about 25% to about 75% by weight of axitinib and about 20% to about 60% by weight of PEG units, or about 35% to about 65% by weight of axitinib and about 25% to about 50% by weight of PEG units, or about 45% to about 55% by weight of axitinib and about 37% to about 47% by weight of PEG units, or about 48% to about 52% by weight of axitinib and 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, about 55% to about 75% by weight of axitinib and about 20% to about 40% by weight of PEG units, or about 60% to about 75% by weight of axitinib and about 21% to about 31% by weight of PEG units (dry composition).

[0201] In another specific embodiment, 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 remainder being phosphate, based on dry weight. Alternatively, the ratio of axitinib to PEG in the implant according to the present invention may be about 1:1 to about 3:1, based on dry weight.

[0202] In certain embodiments, the remainder of the implant in its dry state (i.e., the remainder of the formulation when the TKI (such as axitinib) and the polymer hydrogel (such as PEG hydrogel) have been taken into account) may be a salt remaining from a buffer solution as disclosed above. In certain embodiments, such a salt is a phosphate, borate, or (bi)carbonate. In one embodiment, the buffer salt is sodium phosphate (monobasic sodium phosphate or disodium hydrogen phosphate).

[0203] The amounts of TKI and one or more polymers may vary, and other amounts of TKI and polymer hydrogel may be used to prepare implants according to the present invention.

[0204] In certain embodiments, the maximum amount of drug in the formulation is about twice the amount of polymer (e.g., PEG) units, but may be higher in some cases, but it is expected that the mixture comprising, for example, precursor, buffer and drug (in a state before the hydrogel is fully gelled) can be uniformly cast into a mold or tube.

[0205] In one embodiment of the invention, after formation and before drying, i.e., in a wet state, the hydrogel may comprise about 3% to about 20% polyethylene glycol, expressed as the weight of polyethylene glycol divided by the weight of the fluid x 100. In one embodiment, the hydrogel in a wet state comprises about 5% to about 15%, such as about 7.5% to about 15% or about 5% to about 10%, expressed as the weight of polyethylene glycol divided by the weight of the fluid x 100.

[0206] In one embodiment of the invention, the wet hydrogel composition (i.e., after the hydrogel composition has been formed, i.e., all components that form the hydrogel have been mixed) comprises from about 5% to about 50% by weight of an active ingredient (such as axitinib) and from about 5% to about 50% or from about 5% to about 30% by weight of PEG units.

[0207] In certain embodiments, when forming a hydrogel for an implant according to the present invention, a solid content of about 10% to about 50% or about 25% to about 50% (w / v) may be utilized in the wet composition (where "solids" 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 a hydrogel may 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) may 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, therefore, the pourability of the wet hydrogel composition.

[0208] In certain embodiments, the water content of the hydrogel implant in its dry (dehydrated / dried) state, e.g., before or when loaded into the needle, may be extremely low, such as no more than 1% water by weight. In certain embodiments, the water content may also be lower than the values, and may be 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 an implant in a hydrated state when it contains water (e.g., after it has been (re)hydrated or immersed in an aqueous environment after the implant is applied to the eye), as well as an implant in its dry (dehydrated / dehydrated) state, e.g., when it has been dried to a low water content of, e.g., no more than about 1% by weight or when such a low water content implant is prepared so that no drying step is required. In certain embodiments, an implant in its dry state is an implant that has been kept 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 the needle. The water content of the implant can be measured, for example, using the Karl Fischer coulometric method.

[0209] In certain embodiments, the total weight of the implant according to the present invention (also referred to herein as the "total mass") in its dry state may 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 may 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 axitinib in an amount of 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 may 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 axitinib in an amount of about 480 μg to about 750 μg.

[0210] In certain embodiments, an implant according to the present invention has a diameter of 1 mm in its dry state. 3 (i.e., every 1 mm 3 The dry implant may contain about 200 μg to about 1000 μg of a TKI, such as axitinib. In certain specific embodiments, the implant according to the present invention may contain about 200 μg to about 1000 μg of a TKI, such as axitinib, per mm in its dry state. 3 The implant may contain about 200 μg to about 300 μg of axitinib, for example, in the case where the implant contains about 160 μg to about 250 μg of axitinib. In certain other specific embodiments, the implant according to the present invention has about 100 μg of axitinib per mm in its dry state. 3 From about 500 μg to about 800 μg of axitinib may be contained, for example where the implant contains axitinib in an amount of from about 480 μg to about 750 μg.

[0211] Implants 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 ingredients in the wet composition when the hydrogel is formed and certain conditions in the process of manufacturing the implant. For example, in certain embodiments, the density of the final implant can be increased by sonication or degassing at certain points in the manufacturing process, such as using a vacuum.

[0212] In certain embodiments, implants according to the invention contain a therapeutically effective amount of a TKI, such as axitinib, to be released over a longer period of time, but are relatively small in length and / or diameter. This is advantageous in terms of ease of administration (injection) and in terms of reducing potential damage to ocular tissue and reducing the potential impact of the implant on the patient's vision when in place. The implants of the invention combine the benefits of a suitably high dose of a TKI (i.e., a therapeutically effective dose adjusted to the needs of a particular patient) with a relatively small implant size.

[0213] Exemplary implants according to the present invention are disclosed in Table 1, Table 6, Table 21.1, Table 21.2 and Table 29 of the Examples section (including the prophetic examples of implants according to the present invention containing a large amount of TKI disclosed in Table 29).

[0214] Implant dimensions and dimensional changes due to stretching after hydration:

[0215] The dry implant may 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), wherein a fiber is an object generally having an elongated shape. The implant (or fiber) may have different geometries, with specific dimensions as disclosed herein.

[0216] 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.

[0217] 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, wherein the width is substantially perpendicular to the maximum cross-sectional dimension of the length. In certain embodiments, the width may be from about 0.1 mm to about 0.5 mm. The different geometries of the external implant shape or its cross section may be used for the present invention. For example, instead of a circular diameter fiber (i.e., a cylindrical implant), a cruciform fiber (i.e., wherein the cross-sectional geometry is a cruciform) may be used. Other cross-sectional geometries may generally be used, such as an ellipse or rectangle, rectangle, triangle, star, etc. In certain embodiments, the fiber may also be twisted. In embodiments where the implant is applied to the eye by a needle, the size of the implant (i.e., its length and diameter) and its cross-sectional geometry must enable the implant to be loaded into the needle, especially a thin diameter needle, such as the 25th or 27th needle further disclosed herein.

[0218] The polymer network (such as PEG mesh structure) of the hydrogel implant according to certain embodiments of the present invention can be semi-crystalline at room temperature or below in the dry state, and can be amorphous in the wet state. Even in the stretched form, the dry implant is dimensionally stable at room temperature or below, which may facilitate loading the implant into the needle and quality control.

[0219] After hydration of the implant in the eye (which can be simulated by immersing the implant in pH 7.2 PBS at 37° C.), the size of the implant according to the present invention may change: in general, the diameter of the implant may increase, while its length may decrease or at least may remain substantially the same. The advantage of this size change is that although the implant is thin enough in its dry state to be loaded into a thin 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 be shortened to better fit within the limited small volume of the eye. The needle used to inject the implant of the present invention as disclosed herein, such as a 25 or 27 gauge needle in certain embodiments, is smaller in diameter (and, for example, may have an inner diameter of about 0.4 mm). Since the implant may also become softer after hydration, damage to any eye tissue may be prevented or reduced even if 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 manufacture (also disclosed in the "Methods of Manufacturing" section below). In certain embodiments, the stretching can be performed in a dry or wet state, i.e., after drying the hydrogel implant or before drying. It should be noted that if no stretching is performed, and the hydrogel implant is simply dried and cut into the desired length, both the diameter and length of the implant increase after hydration. If this is not necessary, the hydrogel fibers can be dry stretched or wet stretched.

[0220] In preformed dry hydrogels, molecular orientation can be imparted by dry stretching the material and then solidifying it to lock the molecular orientation. In certain embodiments, this can be achieved by drawing the material (optionally when the material is heated to a temperature above the melting point of the material crystallizable region), followed by crystallization of the crystallizable region. Alternatively, in certain embodiments, the glass transition temperature of the dry hydrogel can be used to lock the molecular orientation of a polymer (such as PVA) with a suitable glass transition temperature. Another alternative is to stretch the gel (also referred to as "wet stretching") before complete drying, and then dry the material when under tension. Molecular orientation provides a mechanism for anisotropic swelling after being introduced into a hydration medium such as a vitreous body. After hydration, the implant of certain embodiments will only swell in the radial dimension, while the length will decrease or remain essentially unchanged. The term "anisotropic swelling" means preferential swelling in one direction relative to another direction, such as in a cylinder that expands mainly in the radial direction but does not significantly increase (or even opposite) in the longitudinal dimension.

[0221] The degree of dimensional change after hydration may depend, among other things, on the stretch factor. For example, stretching (e.g., by wet stretching) at a stretch factor of about 1.3 may have a less noticeable effect, or may not substantially change the length during hydration. In contrast, stretching (e.g., by wet stretching) at a stretch factor of, for example, about 1.8 may result in a significant reduction in length during hydration. Stretching (e.g., by dry stretching) at, for example, a stretch factor of 4 may result in a much shorter length after hydration (e.g., a reduction in length from about 15 mm to about 8 mm). One skilled in the art will appreciate that other factors besides stretching may also affect swelling properties.

[0222] Other factors that affect the possibility of stretching the hydrogel and inducing implant size changes after hydration are the composition of the polymer network. In the case of using PEG precursors, those with lower arm numbers (such as 4-arm PEG precursors) help to provide higher flexibility in the hydrogel compared to those with higher arm numbers (such as 8-arm PEG precursors). If the hydrogel contains more low-flexibility components (e.g., a larger amount of PEG precursors containing a larger number of arms, such as 8-arm PEG units), the hydrogel may be harder and less likely to stretch without breaking. On the other hand, a hydrogel containing a larger flexible component (such as a PEG precursor containing a smaller number of arms, such as a 4-arm PEG unit) may be easier to stretch and soften, and swell to a greater extent after hydration. Thus, the characteristics and properties of the implant after it is placed in the eye (i.e., after the hydrogel is (re)hydrated) can be adjusted by changing the structural features and by modifying its processing after the implant has been initially formed.

[0223] Exemplary dimensions of the implants used in the following examples herein are provided in particular in Table 6, Table 21.1 and Table 21.2 of the Examples section. Specific implants containing about 200 μg and about 600 μg of axitinib are disclosed in Table 21.1 and Table 21.2. However, implants containing about 200 μg or about 600 μg of axitinib may also have dimensions (i.e., length and / or diameter) that differ from those disclosed in these tables. Dry implant dimensions depend, among other things, on the amount of TKI incorporated and the ratio of TKI to polymer units, and may 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, among other things, by stretching (wet or dry) the hydrogel strand after formation. The dried strand (after stretching) is cut into segments of the desired length to form the implant; thus the length may be selected as desired.

[0224] Hereinafter, embodiments of implants with specific sizes are disclosed. As long as the size ranges or values ​​disclosed herein are about 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 cylindrical implants can be used for the length and width of non-cylindrical implants, as also disclosed herein, respectively.

[0225] 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 about 12 to about 17 mm, or the length in its dry state may be about 6 mm to about 10 mm, or specifically, about 6 mm to about 9 mm.

[0226] 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 certain 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 its 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.

[0227] In certain embodiments, the implant may have a length of about 6 mm to about 10 mm and a diameter of about 0.2 mm to about 0.4 mm in its dry state.

[0228] In certain embodiments, the length of the implant of the present invention in its wet / hydrated state may be about 6 mm to about 12 mm. In certain 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 about 6 mm to about 10 mm. In a specific embodiment, the length of the implant of the present invention in its wet / hydrated state may be about 6 mm to about 8 mm.

[0229] 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 about 0.5 mm to about 0.8 mm, or about 0.65 mm to about 0.8 mm. In a specific embodiment, the diameter of the implant of the present invention in its wet / hydrated state may be about 0.7 mm to about 0.8 mm.

[0230] In certain embodiments, the implant in its wet / hydrated state may have a length equal to or less than about 10 mm and a diameter equal to or less than about 0.8 mm.

[0231] In embodiments of the present invention, the diameter of the implant in its dry state must be such that the implant can be loaded into a thin diameter needle as disclosed herein, such as a 25-gauge or 27-gauge needle. Specifically, in one embodiment, the diameter of the implant containing about 480 μg to about 750 μg of axitinib can 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 is stably retained in the needle during further processing (including packaging, sterilization, transportation, etc.).

[0232] Whenever the length or diameter (mm) of the implant of the present invention in a wet / hydrated state is disclosed herein, the present invention refers to the implant length or diameter, respectively, measured after 24 hours at 37° C., pH 7.2. It should be understood that, in this context, pH 7.2 includes a pH range of about 7.2 to about 7.4.

[0233] When the implant remains under these conditions, the size of the implant may change further over time (i.e., after 24 hours) (e.g., the length may increase slightly again). However, whenever hydrated dimensions of the implant are reported herein, these dimensions are measured after 24 hours at 37° C., pH 7.2 as disclosed above.

[0234] When the length or diameter of an implant are measured several times or when several data points are collected in the measuring process, mean value (that is, average) as defined herein is reported. Length and diameter of implant according to the present invention can be measured, for example, by microscopy or by (optionally automated) camera system as described in Example 6.1.

[0235] In certain embodiments, the ratio of the diameter of the implant of the present invention in the hydrated state to the diameter in the 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.

[0236] In certain identical or other embodiments, the ratio of the dry length to the hydrated length of the implant of the invention 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 dry length of the implant to the hydrated length of the implant may be greater than about 1.5, or even greater than about 2.0. This ratio of dry length to hydrated length may be applied in addition to or in addition to the ratio of hydrated diameter to dry diameter disclosed above.

[0237] The small diameter in the dry state may be advantageous because the implant can fit into a small diameter needle for injection as disclosed herein, such as a 25-gauge or 27-gauge needle. Only moderate swelling upon hydration may also be advantageous in that the implant does not occupy too much space in the vitreous humor. The relatively short length of the implant may be advantageous in reducing the potential for contact with the retina.

[0238] In one embodiment, the implant of the present invention contains about 160 μg to about 250 μg, or about 180 μg to about 220 μg, or about 200 μg of axitinib, in the form of a fiber (or cylinder) and in the dry state has a length of about 14.5 mm to about 17 mm or about 15 mm to about 16.5 mm and a diameter of about 0.20 mm to about 0.30 mm. Such an implant may decrease in length and increase in diameter after hydration in vivo (such as in the vitreous humor) or in vitro in the eye (where in vitro hydration is measured after 24 hours in phosphate buffered saline at pH 7.2, 37°C), reaching a length of about 6.5 mm to about 8 mm or about 7 mm to about 8.5 mm and a diameter of about 0.65 mm to about 0.8 mm or about 0.70 to about 0.80 mm. In one embodiment, the dimensional change can be achieved by dry stretching as disclosed herein with a stretch factor of about 2 to about 5 or a stretch factor of about 3 to about 4.5.

[0239] In another embodiment, the implant of the present invention in the form of a fiber (cylinder) and in its dry state containing about 480 μg to about 750 μg, or about 540 μg to about 660 μg, or about 600 μg of axitinib may have a length ranging from about 6 mm or about 7 mm to about 12 mm and a diameter of about 0.25 mm to about 0.50 mm, or a length of about 7 mm to about 10 mm or about 8 mm to about 11 mm and a diameter of about 0.3 mm to about 0.4 mm. In a specific embodiment, the implant of the present invention in the form of a fiber (cylinder) and in its dry state containing about 480 μg to about 750 μg, or about 540 μg to about 660 μg, or about 600 μg of axitinib may have a length of about 7 mm to about 10 mm, such as about 7 mm to about 9 mm, and a diameter of about 0.3 mm to about 0.4 mm, such as about 0.35 mm to about 0.39 mm.

[0240] Such an implant may increase in diameter after hydration in the eye, such as in vivo in the vitreous humor or in vitro (wherein in vitro hydration is measured after 24 hours in phosphate buffered saline at pH 7.2, 37°C), while in its hydrated state its length may be substantially maintained or may decrease, or only increase slightly to, for example, a length in the range of 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 a particular embodiment, an implant of the invention containing about 480 μg to about 750 μg, or about 540 μg to about 660 μg, or about 600 μg of axitinib and in the form of a fiber (cylinder) may have a length of about 6 mm to about 10.5 mm, such as about 6.5 mm to about 8.5 mm, in its hydrated state (i.e., after 24 hours at 37° C., pH 7.2 as described above), and a diameter of about 0.7 mm to about 0.8 mm.

[0241] In one embodiment, the length of an implant of the invention containing about 480 μg to about 750 μg, or about 540 μg to about 660 μg, or about 600 μg of axitinib in the dry state does not exceed 10 mm, and 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 in phosphate buffered saline at pH 7.2, 37°C after 24 hours).

[0242] In one or more embodiments, the above-mentioned dimensional changes can be achieved by wet stretching with 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 to about 2.5. In other embodiments, an implant of the present invention containing about 480 μg to about 750 μg, or about 540 μg to about 660 μg, or about 600 μg of axitinib may be longer than about 12 mm in a dry state, but may ultimately be shorter than about 10 mm or about 9 mm in a hydrated state.

[0243] In certain embodiments, stretching thereby produces shape memory, meaning that the implant, when administered into the eye, e.g., the vitreous cavity, will shrink in length and widen in diameter upon hydration until it approaches (more or less) its equilibrium size, which is determined by the initial formed size and compositional variables. Although a narrow dry size is advantageous for administering the product via a small gauge needle, the widening of the diameter and shortening of the length after administration can produce an implant that is shorter relative to the diameter of the eye (such as about 9 to 10 mm long, or at least not exceeding said values) in the posterior chamber of the eye, thereby reducing potential contact with surrounding ocular tissue. Thus, in one aspect, the present 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, e.g., axitinib, dispersed in the hydrogel. In another aspect, the present invention relates to a method of manufacturing an ocular implant comprising a hydrogel, the hydrogel comprising an active agent, such as a TKI, e.g., axitinib, dispersed therein, wherein the implant changes its size after administration into the eye, the method comprising preparing fibers of the hydrogel and stretching the fibers in a longitudinal direction.

[0244] In vitro release:

[0245] The in vitro release of TKI from the implant of the present invention can be determined by various methods disclosed in detail in Example 2:

[0246] Briefly, one method for measuring the release of TKI from an implant in vitro is to Non-sink simulates physiological conditions at 37°C PBS (phosphate buffered saline, pH 7.2), with PBS replaced daily with a volume equivalent to the vitreous volume in a human eye. Results of exemplary implants are shown in Figure 4A As described in Example 2, in the test implants comprising axitinib in a PEG hydrogel matrix, higher dose strengths resulted in higher axitinib concentrations in the release medium.

[0247] Generally speaking, in embodiments of the present invention, implants according to the present invention may release an average of 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 may release about 0.25 μg to about 1.5 μg per day in vitro in PBS at pH 7.2 and 37°C for a period of 30 days.

[0248] In one embodiment, an implant according to the present invention containing about 200 μg of axitinib can release about 0.01 μg to about 0.15 μg of axitinib in phosphate buffered saline at pH 7.2 and 37° C. on average per day in vitro for a period of 30 days.

[0249] 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 phosphate buffered saline at pH 7.2 and 37° C. on average per day in vitro for a period of 30 days.

[0250] In the example also described in detail in Example 2 Accelerated in vitro testing In an accelerated in vitro test, the release of 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 approximately 2 weeks. Fig. 14B showing accelerated in vitro release data for implants according to the present invention containing about 200 μg of axitinib, and Figure 4B Accelerated in vitro release data for an implant according to the present invention containing approximately 556 μg of axitinib were shown.

[0251] In one embodiment, an implant according to the present invention containing about 200 μg of axitinib in a 25:75 ethanol / water mixture (v / v) at 37° C. 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.

[0252] 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.

[0253] Finally, it is also possible to describe in detail in Example 2 Real-time sink simulates physiological conditions TKI release from the implants of the invention was measured at 37°C. For this immediate test, TKI release was measured in PBS (pH 7.2) / 0.01% NaF at 37°C with an octanol top layer on the PBS. This is a method to qualitatively simulate the release of TKI from the implant into the vitreous humor and the reabsorption of TKI therefrom into the ocular tissue. An exemplary immediate release profile of an implant according to the invention containing about 200 μg of axitinib is shown in Fig.14A middle.

[0254] In one embodiment, an implant according to the present invention containing about 200 μg of axitinib in phosphate buffered saline at pH 7.2, 37° C., and with an octanol top layer releases about 25% to about 35% axitinib in vitro within 2 months, about 47% to about 57% axitinib in vitro within 3 months, about 70% to about 80% axitinib in vitro within 5 months, and about 90% to about 100% axitinib in vitro within 7 months.

[0255] In vitro release testing, especially the accelerated in vitro release testing described herein, can be particularly useful for comparing different implants (e.g., different production batches, different compositions and different dosage strengths, etc.) with each other, such as for the purpose of quality control or other qualitative assessment.

[0256] In vivo release and persistence:

[0257] In one embodiment of the invention, when the dry implant of the invention is applied to the eye, such as the vitreous humor, it hydrates and changes its size as disclosed above, then biodegrades over time until it has been completely resorbed. As the implant biodegrades, such as via ester hydrolysis, it may gradually swell and soften, then become smaller, softer, and more liquid until it is completely dissolved and no longer visible. As the inventors have recognized from animal studies provided herein in the Examples section below, implants according to the invention may last from about 2 to about 6 months or from about 5 to about 6 months in rabbit eyes (see Fig. 7A , Fig. 9 and Fig.10 ). After the implant is completely degraded, undissolved axitinib particles may remain at the previous location of the implant and have been observed to aggregate, i.e., be incorporated into the overall structure. These remaining undissolved axitinib particles may continue to slowly dissolve 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 Fig. 9 ).

[0258] In the human eye, such as in the vitreous humor, the implants of the present invention, in certain embodiments, biodegrade 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, and 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 Fig.15 .

[0259] In one embodiment, the implant releases (as defined herein) a TKI, such as a therapeutically effective amount of a TKI, such as axitinib, over 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 a specific embodiment, the implant releases a TKI, such as axitinib, for a period of about 6 to about 9 months.

[0260] In one embodiment of the invention, the implant provides a therapeutic 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 into the vitreous humor of the patient.

[0261] 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 over 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 a specific embodiment, release of the TKI, such as axitinib, is maintained for about 6 to about 9 months after administration of the implant.

[0262] As presented in the Examples section herein, preclinical studies in animals and clinical studies in humans have shown that the implants of the present invention can continuously release therapeutically effective amounts of TKI over an extended period of time until the implant is completely biodegraded. Any remaining undissolved TKI particles (if any) can substantially remain at the site of the previous implant and may aggregate to form a substantially monolithic structure (see Fig. 7A , Fig. 9 and Fig.10 ), thereby continuing to release the TKI into the vitreous at a level sufficient to achieve a therapeutic effect. However, in certain embodiments, the entire amount of TKI contained in the implant is released from the implant before the implant is completely biodegraded. In this case, after the implant is completely biodegraded, undissolved TKI particles will not remain (and / or accumulate) near the site of the previous implant or other locations in the eye.

[0263] 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 implant used in the examples herein, this carbon chain comprises 7 carbon atoms because it is derived from the SAZ functional group of the 4a20k PEG precursor. This can provide a longer 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 the implants illustrated in the examples.

[0264] In certain embodiments, the hydrogel implant softens over time as it degrades, which may depend, among other things, on the structure of the linker cross-linking the PEG units in the hydrogel. Implants formed from 4a20kPEG-SAZ and 8a20kPEG-NH2 as used in the examples of the present application soften quite slowly over time.

[0265] Release mechanism:

[0266] Without wishing to be bound by theory, the mechanism of release of TKI from the implant of the present invention can be understood as follows: In embodiments of the present invention, release of TKI into the eye and vitreous humor is determined by diffusion and drug clearance rate. An exemplary TKI according to the present invention is axitinib. The solubility of axitinib in physiological media has been determined to be very low (about 0.4 to about 0.5 μg / mL in pH 7.2 PBS). According to the present invention, TKIs (such as axitinib) are confined in a biodegradable hydrogel with a specific geometry and surface. The fluid in the posterior chamber of the eye is viscous, with a slow clearance rate and relatively stagnant flow (at least compared to the anterior chamber of the eye).

[0267] In certain embodiments, the implant of the present invention comprises a hydrogel made of a polymer network and a drug dispersed in 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 body (that is, the drug particles located in the outermost region of the hydrogel first dissolve and diffuse out, and those located in the innermost region dissolve and diffuse out last). Therefore, in certain embodiments, the outer region of the hydrogel becomes lacking in drug particles. This region is therefore also referred to as a "clearance zone", which is limited to dissolved drugs, wherein 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 tissue from drug particles when the implant contacts such tissue. In other embodiments, after hydration, the "clearance zone" is an outer region, and its active agent concentration is lower than the active agent in the inner region of the hydrated hydrogel.

[0268] In embodiments with a clearance zone, this area of ​​the hydrogel forms voids and becomes softer and weaker as the drug has dissolved and diffused out of the clearance zone. While the drug diffuses 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 volume of the hydrogel. In the late stages of degradation, the hydrogel begins to deform and erode. As this occurs, the hydrogel becomes softer and more liquid (and thus deforms in shape) until the hydrogel eventually dissolves and is completely resorbed. This process is schematically illustrated in Figure 3 and demonstrated by infrared reflectance (IR) imaging, e.g. Fig.10 As proved in .

[0269] Since axitinib is a relatively low solubility drug, in certain embodiments, after the implant has completely degraded, undissolved axitinib particles may remain at the previous location of the implant. Since these remaining undissolved axitinib particles are no longer fixed and separated by the hydrogel, they may aggregate and form a substantially monolithic structure. This monolithic axitinib structure may still continue to release axitinib at a rate sufficient to achieve a therapeutic effect (particularly, reducing CSFT).

[0270] However, in one embodiment, the entire amount of axitinib is released before the hydrogel is completely degraded. Since the hydrogel can hold the axitinib particles in place and prevent them from aggregating, axitinib can be released relatively quickly from the hydrogel as long as the hydrogel has not been completely degraded. When the hydrogel is completely degraded, the remaining axitinib particles can form an overall structure from which axitinib can slowly dissolve. Therefore, in one embodiment of the present invention, it is desirable to completely release axitinib before the hydrogel is completely degraded.

[0271] In certain embodiments, this entire process makes it possible to advantageously maintain the therapeutic effect of the implant of the present invention over a longer 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 major 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 need to be injected at much greater intervals, which is advantageous to the patient for a number of reasons as already disclosed above in the "Objectives and Overview" section.

[0272] A specific implant containing about 160 μg to about 250 μg, such as about 200 μg, of axitinib:

[0273] In a specific embodiment, the present invention relates to a sustained release biodegradable ocular implant containing axitinib dispersed in a hydrogel in an amount ranging from about 160 μg to about 250 μg or from about 180 μg to about 220 μg, and specifically about 200 μg, wherein the hydrogel comprises a polymer network comprising 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 ranging from 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 about 6.5% to about 7.5% polyethylene glycol when formed and before drying (i.e., wet composition), expressed as the weight of polyethylene glycol divided by the weight of fluid x 100. In addition, in this embodiment, the implant 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), with the remainder being sodium phosphate. In addition, the implant may contain no more than about 1% by weight of water or no more than about 0.25% by weight of water in its dry state.

[0274] In this embodiment, an implant containing an amount of axitinib 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 at 37° C. for a period of 30 days in phosphate buffered saline. In addition, in this embodiment, the implant 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 in a 25:75 ethanol / water (v / v) mixture at 37° C. In this embodiment, the implant can also release about 25% to about 35% axitinib in vitro within 2 months, about 47% to about 57% axitinib in vitro within 3 months, about 70% to about 80% axitinib in vitro within 5 months, and about 90% to about 100% axitinib in vitro within 7 months in phosphate buffered saline at pH 7.2, 37°C, and in the presence of an octanol top layer.

[0275] In this embodiment, the implant containing about 200 μg of axitinib may be in the form of a fiber (or cylinder) and in the dry state may be less than about 20 mm, or less than about 17 mm, or about 15 mm to about 16.5 mm in length and about 0.20 mm to about 0.30 mm in diameter, and may decrease in length and increase in diameter after hydration in the vitreous humor in vivo or in vitro (where in vitro hydration is measured after 24 hours in phosphate buffered saline at pH 7.2, 37° C.), reaching a length of about 6.5 mm to 8 mm and a diameter of about 0.70 mm to 0.80 mm in the hydrated state. This dimensional change after hydration may be imparted to the implant shape memory by dry stretching the implant in the longitudinal direction with a stretch factor of about 2 to about 5 or a stretch factor of about 3 to about 4.5 as explained in more detail elsewhere herein. In other embodiments, the implant may be non-cylindrical.

[0276] In this embodiment, the implant containing about 200 μg of axitinib has a ratio of a hydrated diameter to a dry diameter of less than about 3.25 mm and / or a ratio of a dry length to a hydrated length of greater than about 1.5.

[0277] The total weight of the implant disclosed in such an embodiment in its dry state may be about 0.3 mg to about 0.6 mg, such as about 0.4 mg to about 0.5 mg. Such an implant may contain about 10 μg to about 15 μg of axitinib per 1 mm of final length in the dry state, and about 10 μg to about 15 μg of axitinib per mm of final length. 3 It may contain about 200 μg to about 300 μg of axitinib.

[0278] In this embodiment, an implant containing a dose of about 200 μg of axitinib is loaded into a 25-gauge needle or a 27-gauge needle (or an even smaller gauge needle, such as a 30-gauge needle) for injection into the vitreous humor prior to administration.

[0279] For summary and illustration, individual characteristics of the implants of the invention disclosed with respect to the embodiments described in this section containing a dose of about 200 μg, including the implants used in the clinical studies presented in Example 6, are provided in Table 21.1 in the Examples section, which is also reproduced here:

[0280]

[0281]

[0282] The sustained release biodegradable ocular implant of claim 1, wherein the implant is an intravitreal implant and comprises about 180 μg to about 220 μg of axitinib, is cylindrical in shape, and in its dry state is less than about 17 mm in length and about 0.2 mm to about 0.3 mm in diameter, and in its hydrated state (after 24 hours in phosphate buffered saline at pH 7.2, 37°C) is about 6.5 mm to about 8 mm in length and about 0.7 mm to about 0.8 mm in diameter, and wherein the hydrogel comprises cross-linked 4a20k and 8a20k PEG units, wherein the cross-links between the PEG units comprise groups represented by the formula,

[0283]

[0284] Where m is 6.

[0285] Alternatively, the implant of this particular embodiment may also be non-cylindrical as disclosed herein.

[0286] Particular implants containing about 480 μg to about 750 μg, such as about 600 μg, of axitinib:

[0287] In another specific embodiment, the present invention relates to a sustained release biodegradable ocular implant containing axitinib dispersed in a hydrogel in an amount of about 480 μg to about 750 μg, wherein the hydrogel comprises a polymer network comprising cross-linked polyethylene glycol units. The amount of axitinib in the implant may also be in the range of about 540 μg to about 660 μg, and in particular may be about 600 μg.

[0288] In this implant, the polyethylene glycol units include multi-arm polyethylene glycol units, such as 4-arm and / or 8-arm polyethylene glycol units with an average molecular weight ranging from about 10,000 Daltons to about 60,000 Daltons. In this embodiment, the polymer network of the implant comprises 4a20kPEG and 8a20kPEG units and is formed by reacting 4a20kPEG-SAZ with 8a20kPEG-NH2 in a weight ratio of about 2:1.

[0289] In this embodiment, the implant may contain about 45% to about 55% axitinib by weight and about 37% to about 47% polyethylene glycol units by weight in a dry state, or may contain about 60% to about 75% axitinib by weight and about 21% to about 31% polyethylene glycol units by weight, such as about 63% to about 72% axitinib by weight and about 23% to about 27% polyethylene glycol units (dry composition), with the remainder 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 remainder 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.

[0290] In this embodiment, this implant having an axitinib content ranging from about 480 μg to about 750 μg or from about 540 μg to about 660 μg, or specifically about 600 μg, releases about 0.3 μg to about 0.5 μg of axitinib per day in vitro in phosphate buffered saline at 37° C. for a period of 30 days. In addition, this implant releases about 40% to about 60% of axitinib in vitro in 2 days, about 65% to about 85% of axitinib in vitro in 4 days, and about 75% to about 90% of axitinib in vitro in 6 days in a 25:75 (v / v) ethanol / water mixture at 37° C. In this embodiment, the implant may also release about 45% to about 55% axitinib in vitro within 2 days, about 70% to about 80% axitinib in vitro within 4 days, and about 80% to about 90% axitinib in vitro within 6 days in a 25:75 ethanol / water (v / v) mixture at 37°C.

[0291] In this embodiment, the implant containing about 600 μg of axitinib may be in the form of a fiber (or cylinder) and may have a length in its dry state of 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 a diameter of about 0.25 mm to about 0.50 mm, or a length of about 7 mm or about 8 mm to about 11 mm and a diameter of about 0.3 mm to about 0.4 mm, and may increase in diameter in vivo or after hydration in vitro in the vitreous humor (wherein in vitro hydration is measured after 24 hours in phosphate buffered saline at pH 7.2, 37°C). In certain embodiments, an implant containing about 600 μg of axitinib in its dry state may have a length of less than or equal to about 10 mm, or less than or equal to about 8.5 mm, or from about 7 mm to about 9 mm, or from about 7 mm to about 8.5 mm, and a diameter of about 0.3 mm to about 0.4 mm, such as about 0.35 mm to about 0.39 mm.

[0292] The dimensions of this implant after hydration in vivo or in vitro (wherein in vitro hydration is measured after 24 hours in phosphate buffered saline at pH 7.2, 37° C.) may be a length of less than or equal to about 10 mm, such as 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, or a length of no more than about 10 mm or no more than about 9 mm and a diameter of about 0.65 mm to about 0.75 mm or to about 0.80 mm. In a specific embodiment, an implant containing about 600 μg of axitinib in its hydrated state (wherein in vitro hydration is measured after 24 hours in phosphate buffered saline at pH 7.2, 37° C.) may 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 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.

[0293] This dimensional change after hydration can be achieved by wet stretching in the longitudinal direction before drying 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 to about 2.5 as disclosed in more detail below.

[0294] In this embodiment, the implant containing about 600 μg of axitinib may have a ratio of hydrated diameter to dry diameter of less than about 2.25 mm and / or a ratio of dry length to hydrated length of greater than 0.75.

[0295] An implant containing about 600 μg of axitinib as disclosed herein may have a total weight in a dry state of about 0.8 mg to about 1.1 mg, such as about 0.9 mg to about 1.0 mg. Such an implant may contain about 70 μg to about 85 μg of axitinib per 1 mm of final length in a dry state, and about 100 μg of axitinib per mm 3 It may contain about 500 μg to about 800 μg of axitinib.

[0296] In this embodiment, the preferred shape of the implant is cylindrical or substantially cylindrical (and may also be referred to as a fiber). In other embodiments, the implant may be non-cylindrical. Prior to administration, this implant containing a dose of about 600 μg of axitinib is loaded into a 25-gauge (or smaller, such as a 27-gauge) needle for injection into the eye, for example, into the vitreous humor.

[0297] For summary, individual characteristics of the implant of the present invention containing a dose of about 600 μg of axitinib disclosed with respect to the embodiments described in this section are provided in Table 21.2 in the Examples section, which is also reproduced here:

[0298]

[0299]

[0300] In a specific embodiment, the sustained-release biodegradable ocular implant of the present invention is an intravitreal implant and comprises about 540 μg to about 660 μg of axitinib, is cylindrical, and has a length of 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 in phosphate-buffered saline at pH 7.2, 37° C.), and wherein the hydrogel comprises cross-linked 4a20k and 8a20k PEG units, wherein the cross-links between the PEG units comprise a group represented by the formula,

[0301]

[0302] Where m is 6.

[0303] Alternatively, the implant of this particular embodiment may also be non-cylindrical as disclosed herein.

[0304] II. Fabrication of implants

[0305] Manufacturing process:

[0306] In certain embodiments, the present invention also relates to a method for manufacturing a sustained release biodegradable ocular implant as disclosed herein. In general, the method comprises the following steps: forming a hydrogel comprising a polymer network and TKI particles dispersed in the hydrogel; shaping the hydrogel; and drying the hydrogel. In certain embodiments, the method comprises the following steps: forming a hydrogel comprising a polymer network formed by a precursor containing a reactive group (e.g., comprising a PEG unit) 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 containing an electrophilic group with a multi-arm PEG precursor containing a nucleophilic group or another cross-linking agent containing a nucleophilic group (such as the precursors and cross-linking agents 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 formed into a hydrogel strand as disclosed herein by pouring the mixture into a tube before the hydrogel is completely gelled. In certain embodiments, the hydrogel strand is stretched in the longitudinal direction as further disclosed herein before or after drying.

[0307] 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 an 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. Fig.24 As shown in , the use of micronized TKI (especially micronized axitinib) may have the effect of reducing the tendency of TKI (especially axitinib) particles to aggregate during the casting of hydrogel strands. In another embodiment, TKI (such as axitinib) can be used in a non-micronized form for the preparation of implants.

[0308] The above has been disclosed in detail in the part related to the implant itself for forming the precursor of the hydrogel of certain embodiments. In the case of using PEG precursor to prepare cross-linked PEG mesh structure, in certain embodiments, the method for manufacturing implants may include mixing and reacting in a buffer solution 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 cross-linking agent (such as a multi-arm polyethylene glycol containing a nucleophilic group, such as 8a20kPEG-NH2) in the presence of a tyrosine kinase inhibitor, and allowing the mixture to gel. In certain embodiments, the molar ratio of electrophilic group to nucleophilic group in the PEG precursor is about 1: 1, but nucleophilic groups (such as amine groups) exceeding electrophilic groups 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 or cross-linking agents containing nucleophilic groups.

[0309] In certain embodiments, a mixture of an electrophilic group-containing precursor, a nucleophilic group-containing precursor or other cross-linking agent, a TKI, and an optional buffer (and optional additional ingredients, as disclosed in the "Additional Ingredients" section) is prepared. This can occur in a variety of orders, including but not limited to first preparing a separate mixture of an electrophilic group-containing precursor and a nucleophilic group-containing precursor in a buffer solution, then combining one of the buffer / precursor mixtures, such as a buffer / precursor mixture containing a nucleophilic group, with the TKI, and then combining this TKI-containing buffer / precursor mixture with another buffer / precursor mixture (in this case, a buffer / precursor mixture containing an electrophilic group). After a 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 cast into a suitable mold or tube before the hydrogel is completely gelled to provide the desired final shape of the hydrogel. The mixture is then gelled. The resulting hydrogel is then dried.

[0310] The viscosity of the wet hydrogel composition to be poured into a mold or tube may depend, among other things, 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 may be improved, especially when the composition is poured into a thin diameter tube, by reducing the viscosity of the wet composition, including but not limited to reducing the concentration of ingredients in the solvent and / or reducing the solids content or other measures, such as increasing the temperature, etc. Suitable solids contents are disclosed herein in the "Formulation" section.

[0311] In cases where the implant will have the final shape of the fiber (such as a cylinder), the reaction mixture can be poured into a thin diameter tube (e.g., about 1.0 mm to about 1.5 mm inner diameter), 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 fiber, its initial diameter (which can still be reduced by stretching), and also on the ability of the reaction mixture to uniformly fill the tube.

[0312] Thus, the interior of the tube may have a circular geometry or a non-circular geometry, such as a cruciform (or other) geometry. The surface of the implant may be increased by a cruciform geometry. In addition, in certain embodiments, such a cruciform geometry may be used to increase the amount of TKI incorporated into the implant. In general, in certain embodiments, the release of API from the implant may be increased by using a cruciform geometry. As disclosed herein, other cross-sectional geometries of the implant may be used.

[0313] In certain embodiments, after the hydrogel has been formed and cured to complete gelation, the hydrogel strand may be longitudinally stretched in a wet or dry state as disclosed in detail herein, for example, in the section on dimensional changes of the implant after hydration. In certain embodiments, the stretch factor (also referred to herein as the "stretch factor") may 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 (for example, in but not limited to the "Dimensional changes caused by stretching after hydration of the implant size and hydration" section). The stretch factor indicates the ratio of the length of a certain 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 a wet (undried) state and then left under tension to dry. Optionally, heat can be applied during stretching. More optionally, the hydrogel fibers can be twisted in addition. 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 size even after stretching as long as it is kept at or below room temperature in a dry state.

[0314] After stretching and drying, the hydrogel strand is removed from the tube (if still in the tube) and cut into segments having the desired length of the final implant in its dry state, such as disclosed herein (if cut in 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 the 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.

[0315] In certain embodiments, the final prepared implant is then loaded into a thin diameter needle. In certain embodiments, the gauge size of the needle is 22 to 30, such as 22, 23, 24, 25, 26, 27, 28, 29, or 30. In specific embodiments, the needle is a 25 or 27 gauge needle, or even smaller gauge needles, such as a 30 gauge needle, depending on the diameter of the dry (and optionally stretched) implant.

[0316] In certain embodiments, the needles containing the implants are then packaged separately and sterilized, for example, by gamma irradiation.

[0317] In certain embodiments, an injection device such as a syringe or another injection device may be packaged separately and sterilized, for example by gamma irradiation as disclosed below for the kit (which is another aspect of the invention, see the "Injection Devices and Kits" section).

[0318] A specific embodiment of the manufacturing process according to the present invention is disclosed in detail in Example 1.

[0319] Tip coating of needles (PEG):

[0320] 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, molten PEG can be injected or placed / dripped into the needle tip lumen. This low molecular weight 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, after the needle cools, a hardened droplet or portion of PEG (also referred to herein as the "tip") remains on the needle and the top of the needle, thereby blocking the needle lumen. The location of this tip / plug is shown in Fig.25 In B.

[0321] The low molecular weight PEG used in this embodiment can be a 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 of different average molecular weights as disclosed can also be used. In a specific embodiment, the average molecular weight of the PEG used 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.

[0322] As an alternative to PEG materials, 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 non-irritating) and is solid or hardened at room temperature, but is liquid or substantially liquid or at least soft at body temperature can be used to cover the tip of the injection needle. As an alternative to PEG, the following materials (but not limited to these materials) can also be used: poloxamers 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 acid-glycolic acid) copolymers, ultraviolet curable polymers, chitosan, or a combination of mixtures thereof.

[0323] The plug or tip helps to keep the implant in place in the needle during packaging, storage and transportation, and further prevents the implant from hydrating prematurely during handling due to its blocking of the needle lumen. It also prevents premature rehydration of the implant in the needle due to moisture ingress during the application procedure, i.e., when the physician prepares the needle and injector for application, and when the implant is to be injected and the needle is inserted into the eye (because the positive pressure in the eye may cause the implant to hydrate prematurely to at least a certain degree before it is about to be actually injected). When warmed to body temperature and exposed to moisture, the tip or plug provides smoothness in addition, thereby allowing the implant to be successfully deployed. In addition, by blocking the needle lumen, the needle tip covers the possibility of tissue damage to a minimum, i.e., tissue coring, i.e., the process of removing tissue fragments by the needle as it passes through the tissue.

[0324] In order to apply the PEG (or other material) tip / plug to the needle lumen, in one embodiment, the needle containing the implant can be immersed in a container of molten PEG (or other materials, respectively) manually or by an automated device. The needle can be held and immersed in the molten material for a few seconds so that the molten material flows upward into the needle by capillary action. The residence time, immersion depth and molten material temperature determine the final size or length of the tip / plug. In certain embodiments, the length of the PEG (or other) tip / plug at the top of the needle can be about 1 to about 5 mm, such as about 2 to about 4 mm. In certain embodiments, in the case of using 1kPEG, the weight of the tip / plug can be about 0.1mg to about 0.6mg, such as about 0.15mg to about 0.55mg. It is proved that the implant according to the present invention can be successfully deployed in vivo and in vitro from the injector carrying the needle with 1k PEG tip as disclosed herein.

[0325] Tip covered injection needles as disclosed herein may also be used to inject other implants or other drugs or vaccines that are to be injected through the needle into the human or animal body (including other locations within the eye, or other areas or tissues of the body), where protection of the implant (or drug or vaccine) from moisture and protection of the tissue into which the implant (or drug or vaccine) is injected is desirable and advantageous.

[0326] Stretch:

[0327] The stretched shape memory effect has been disclosed in detail above with respect to the properties of the implant. In certain embodiments, the extent of post-hydration shrinkage depends inter alia on the stretch factor as disclosed above.

[0328] In certain embodiments, the present invention is thus also directed to a method of imparting shape memory to a hydrogel yarn by stretching the hydrogel yarn in a longitudinal direction, the hydrogel yarn comprising an active agent dispersed in the hydrogel.

[0329] Likewise, in certain embodiments, the present invention is thus also directed to a method of making an ocular implant comprising a hydrogel comprising an active agent dispersed therein, wherein the implant changes its size after administration to the eye, the method comprising preparing a hydrogel strand and stretching it in a longitudinal direction.

[0330] The stretch factors for use in these methods of the invention may be utilized as disclosed above. The described manufacturing methods (including the stretching methods) are not limited to implants comprising TKI inhibitors or axitinib, but may also be used for hydrogels comprising other active pharmaceutical agents, or implants comprising hydrogels formed not from PEG units but from other polymer units capable of forming hydrogels as disclosed herein above.

[0331] In embodiments where the implant contains an amount ranging from about 160 μg to about 250 μg of axitinib, or an amount of about 200 μg, stretching (dry stretching) may be performed 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.

[0332] In certain embodiments where the implant contains an amount of axitinib in the range of about 480 μg to about 750 μg, or an amount of about 600 μg, the hydrogel may be stretched in a wet state 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 prior to drying (wet stretching).

[0333] III. Injection Devices and Kits

[0334] In certain embodiments, the present invention also relates to a kit (which may also be referred to as a "system") comprising one or more sustained-release biodegradable ocular 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 ocular implant in a dry state. In certain embodiments, the gauge size of the needle is 22 to 30, such as 22, 23, 24, 25, 26, 27, 28, 29 or 30. In a specific embodiment, the needle may be a 25 or 27 gauge needle, or may be a smaller gauge, such as a 30 gauge needle. The needle diameter is selected based on the final diameter of the implant in a dry (and optionally stretched) state. The active substance contained in the implant is generally a TKI, such as axitinib.

[0335] In one embodiment, the kit comprises one or more, such as two or three, 22 to 30 gauge, such as 25 or 27 gauge needles, each loaded with an implant containing axitinib in an amount ranging from about 180 μg to about 220 μg, or in an amount of about 200 μg.

[0336] In yet another embodiment, the kit comprises a 25 gauge needle loaded with an implant containing an amount ranging from about 540 μg to about 660 μg of axitinib, or an amount of about 600 μg. In another embodiment, the kit comprises a 27 gauge needle loaded with an implant containing an amount ranging from about 540 μg to about 660 μg of axitinib, or an amount of about 600 μg.

[0337] If the kit contains two or more implants, the implants may be the same or different and may contain the same or different doses of the TKI.

[0338] In certain embodiments, the lumen of the needle containing the implant 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 "Manufacturing of the Implant" section and particularly its subsection "(PEG) Tip Covered Needle."

[0339] The kit may further contain an injection device for injecting the implant into the patient's eye, such as into the patient's vitreous humor. In certain 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 before injection.

[0340] In certain embodiments, the number of injection devices provided separately in the kit is equal to the number of needles loaded with implants provided in the kit. In these embodiments, the injection device is only used to inject one implant at a time.

[0341] In other embodiments, the kit contains one or more injection devices for injecting the implant into the patient's eye, such as into the patient's vitreous humor, 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 ocular 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 and injection device containing the implant from the packaging and connect the needle to the injection device so that the implant can be injected into the patient's eye.

[0342] In some embodiments, the injection device contains a push wire to deploy the implant from the needle into the vitreous humor. The push wire can be a Nitinol push wire or can be a stainless steel / Teflon push wire. The push wire allows for easier deployment of the implant from the needle.

[0343] In other embodiments, the injection device and / or injection needle may contain a stop feature to control the injection depth.

[0344] In some embodiments, the injection device is or includes a modified Hamilton glass syringe that can be placed in a plastic syringe housing, such as inside an injection molded housing. A push wire, such as a Nitinol wire, is inserted into the syringe and is advanced with the plunger of the syringe during deployment of the implant. To facilitate entry of the Nitinol push wire into the needle, a hub insert can be added to the needle hub. Fig.25 A and Fig.25B shows 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 push wire to deploy the implant. Fig.25 A shows the Hamilton syringe body inside the injection molded housing. Fig.25 B shows a schematic view of the components of this injector embodiment. In certain embodiments, the injector including the Hamilton syringe body and the plastic housing components is preassembled in a kit according to the present invention, and the injector is ready for use (with or without an installed needle containing an implant). In other embodiments, the injector must be assembled by a physician before installing the needle containing the implant.

[0345] In other embodiments, the injection device is an injection molding injector. A schematic exploded view of an embodiment of such an injection molding injector is shown in Fig.26 In this case, the number of assembly steps to be performed by the physician immediately before the implant is administered to the patient is reduced.

[0346] The kit may also include one or more doses, in particular 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 certain 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 connected to a needle, or may be provided in a sealed vial in the form of a solution or suspension, from which the solution or suspension may be drawn through a needle into a syringe or other injection device before administration.

[0347] The kit may also include an operating manual for a physician injecting the ocular implant. The kit may also include a package insert with product-related information.

[0348] In addition to the kit, in one aspect, the present invention also relates to an injection device itself suitable for injecting the sustained release biodegradable ocular implant according to the present invention into the eye. The injection device may contain a member for connecting the injection device to a needle, wherein the needle is preloaded with an implant. The injection device may further contain a push wire to deploy the implant from the needle into the eye when the injection device is connected to the needle, and the push wire may be made of Nitinol or stainless steel / Teflon or another suitable material. The injection device can be further obtained by fixing the wire to a plunger and encapsulating it between two snap-fit ​​injector body parts and fixing the plunger with a clip. The injection device and the needle preloaded with the implant according to certain embodiments of the present invention are depicted in Figure 1middle.

[0349] like Figure 1 As described in , in some embodiments, an injection device (eg, an implant injector device) can include a first component and a second component that are packaged separately (eg, in separate housings). Fig.26 C is an exploded view of the first component and Fig.26 D is an exploded view of the second component.

[0350] refer to Fig.26 C, a first assembly includes a body forming a first internal volume, a plunger including a first distal end disposed within the first internal volume, a wire including a first distal end fixed to the first distal end of the plunger, and a plunger clip. The plunger clip is configured to interface with the plunger and the body to prevent the plunger from being activated. The body may include a first half body and a second half body configured to be interconnected to each other. The body may include a living hinge connected to the plunger protrusion responsive to plunger activation. The living hinge may allow the plunger to be activated in response to the application of a threshold force.

[0351] refer to Fig.26 D, the second assembly includes an outer cover forming a second internal volume, a needle including a base and an inner cavity, an outer cover cap disposed within the base, and a needle guard configured to be fixed to the outer cover and disposed around a portion of the inner cavity. The implant is configured to be deployed in the needle inner cavity. The outer cover may include a first half outer cover and a second half outer cover configured to be interconnected to each other. The second assembly may also include a polymer tip (e.g., a PEG tip) disposed on a second distal end of the inner cavity. The implant is fixed in the inner cavity between the outer cover cap and the polymer tip. The polymer tip is configured to liquefy (e.g., dissolve) in the user's body to allow the implant to be injected into the user.

[0352] 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 in the 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 in the housing because the implant is not included in the housing with the first component.

[0353] The first component can be Figure 1 The first housing is removed and the second component can be automatically Figure 1 The second housing is removed. Fig.26 E, the first component and the second component can be aligned. One or more external recesses of the first component can be aligned with one or more internal protrusions of the second component. The first component and the second component can include markings (e.g., arrows) to indicate how to align the first component and the second component. Fig.26 F, the outer cover of the second component is fixed to the body of the first component (for example, via the inner protrusion of the outer cover entering the outer recess of the body). Figure 26G , removing the needle guard from the housing of the second assembly, and removing the plunger clip from the body and plunger of the first assembly. Fig.26H , start the plunger of the first component (for example, push into the body of the first component) so as to deploy the implant from the lumen of the needle of the second component. In some embodiments, the body has a living hinge, thereby allowing the plunger to be started in response to the threshold force applied to the plunger. In some embodiments, the needle lumen has a polymer tip (for example, a polymer such as PEG at least deployed at the far end of the lumen) that prevents the implant from being deployed from the lumen. Inserting the lumen with a polymer tip into the user's body can prevent coring of the user's tissue (for example, cutting a piece of tissue from the inner diameter of the lumen to be deployed into the user's body later). The lumen can be inserted into the user's body for a threshold amount of time (for example, 1 to 5 seconds) to liquefy the polymer tip (for example, dissolve). After the polymer tip liquefies, the implant can be deployed from the lumen via starting the plunger.

[0354] IV. Therapy

[0355] In certain embodiments, the present invention is also directed to 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 a tyrosine kinase inhibitor.

[0356] In certain embodiments, the invention relates to 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.

[0357] In this treatment, a dose of at least about 150 μg, such as about 150 μg to about 1800 μg or about 150 μg to about 1200 μg of the tyrosine kinase inhibitor is administered once per eye over a treatment period of at least 3 months. In certain preferred embodiments, the tyrosine kinase inhibitor is axitinib.

[0358] In certain embodiments, the dose of TKI, and in particular axitinib, administered once per eye during the treatment period (ie, 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 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 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 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 about 800 μg. In other embodiments, the dose is in the range of about 800 μg to about 1250 μg or about 900 μg to about 1100 μg or about 1000 μg. In other embodiments, the dose is in the range of about 960 μg to about 1500 μg or about 1080 μg to about 1320 μg or about 1200 μg. In a specific embodiment, the dose administered once per eye during the treatment period is about 600 μg of axitinib. In a specific embodiment, the 600 μg dose is contained in a single implant.

[0359] In certain embodiments, the treatment period for treating an ocular disease as disclosed herein with an 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, from about 6 to about 9 months.

[0360] In certain embodiments, the ocular disease involves angiogenesis.

[0361] In other embodiments, the ocular disease may 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.

[0362] 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 cystic macular edema; wherein the ocular disease is acute multifocal macular pigment epitheliopathy, Behcet's disease, birdshot retinochoroidopathy, infectious diseases (syphilis, Lyme disease, tuberculosis, toxoplasmosis), neuter uveitis (pars planitis), multifocal choroiditis, multiple transient white dot syndrome (MEWDS), ocular sarcoidosis, posterior scleritis, serpiginous choroiditis , subretinal fibrosis, uveitis syndrome or Vogt-Koyanagi-Harada syndrome; wherein the eye disease is a vascular disease or an exudative disease, including Coat's disease, parafoveal telangiectasia, papillary phlebitis, frosted vasculitis, sickle cell retinopathy and other heme diseases, vascular streaks and familial exudative vitreoretinopathy; or wherein the eye disease is caused by trauma or surgery, including sympathetic ophthalmia, uveoretinopathy, retinal detachment, trauma, photodynamic laser therapy, photocoagulation, hypoperfusion during surgery, radiation retinopathy or bone marrow transplant retinopathy.

[0363] In alternative embodiments, the sustained release biodegradable ocular implants comprising a hydrogel and a tyrosine kinase inhibitor of the present invention can be used to treat eye disorders associated with tumors. Such disorders include, for example, retinal diseases associated with tumors, solid tumors, tumor metastases, benign tumors (e.g., hemangiomas), neurofibromas, trachoma and pyogenic granulomas, congenital hypertrophy of the RPE, posterior uveal melanoma, choroidal hemangioma, choroidal osteoma, choroidal metastases, combined retinal and retinal pigment epithelial hamartomas, retinoblastomas, fundus vascular proliferative tumors, retinal astrocytomas, or intraocular lymphoid tumors.

[0364] In general, the ocular implants of the present invention may also be used to treat any ocular disease involving vascular leakage.

[0365] 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 specific embodiments, the ocular disease is neovascular age-related macular degeneration.

[0366] In some embodiments, the treatment is effective in reducing central subfield thickness (CSFT) in patients with elevated central subfield thickness, as measured by optical coherence tomography. Elevated in the context means that the patient's CSFT is higher when compared to other individuals who do not suffer from a specific eye disease. Elevated CSFT may be caused by retinal fluid (such as subretinal or intraretinal fluid). The reduction in the patient's CSFT can be determined relative to the baseline CSFT measured in the patient before the start of treatment, i.e., before the implant of the present invention is administered. The ability of the implant of the present invention to reduce CSFT in a patient group over a longer period of time and maintain or substantially maintain a reduced CSFT is shown in Example 6.3 and Example 6.4. In other embodiments, by treatment according to the present invention, including administering an implant according to the present invention, the CSFT of a patient whose CSFT is elevated due to an eye disease involving angiogenesis is substantially maintained at a specified level, or a clinically significant increase in the patient's CSFT is prevented, while the subretinal or intraretinal fluid is substantially not increased, i.e., also substantially maintained.

[0367] In a specific embodiment, the patient's CSFT 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 administration of the implant of the present invention. In a very specific embodiment, the CSFT is reduced relative to the patient's baseline CSFT before administration of the implant for at least 6 months, at least 9 months, or at least 12 months after administration of the implant. In other specific embodiments, the reduced amount of retinal fluid and / or reduced CSFT is 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 administration of the implant of the present invention, without the need for rescue medication (such as injection of an anti-VEGF agent), or wherein the rescue medication is only occasionally administered, such as 1, 2, or 3 times during the treatment period. Thus, in this embodiment, during a treatment period utilizing an implant according to the present invention, the treated patient may not require any rescue medication, or may only require administration of rescue medication infrequently, such as 1, 2, or 3 times during the treatment period.

[0368] In certain embodiments, the rescue medication is an anti-VEGF agent, such as aflibercept or bevacizumab, administered by intravitreal injection in the form of a suspension or solution. In certain specific embodiments, the rescue medication is a dose (2 mg) of aflibercept administered by intravitreal injection. According to the definition herein, the administration of an anti-VEGF agent simultaneously (i.e., planned) with an implant according to another embodiment of the present invention disclosed herein does not constitute a "rescue medication". In more specific embodiments, the treatment period in which the level of body fluids and / or CSFT (as reduced by the administration of an implant according to the present invention) is maintained or substantially maintained without the administration of a rescue medication (or only minimal administration of a rescue medication) is about 6 to about 9 months after the administration of the implant. In certain embodiments, patients treated with an implant according to the present invention do not require concomitant administration of steroids (e.g., dexamethasone or prednisolone drops) during the treatment period.

[0369] In another embodiment, the CSFT of a patient whose CSFT is elevated due to angiogenesis is reduced, substantially maintained, or a clinically significant increase in CSFT is prevented, without impairing or significantly impairing the patient's vision (e.g., as expressed by best corrected visual acuity, also referred to herein as "BCVA") by treatment according to the invention comprising administering an implant according to the invention. In certain embodiments, the patient's vision as expressed, for example, by BCVA (wherein the patient's vision is impaired due to an eye disease involving angiogenesis) may 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.

[0370] Thus, in certain embodiments, the present invention provides a method of improving the vision of a patient whose vision is impaired, for example, due to retinal fluid caused by an eye disease involving angiogenesis, wherein the method comprises administering to the patient an implant according to the present invention, such as by intravitreal injection. The improvement in the patient's vision can be assessed, for example, by BCVA. The improvement in vision can be reflected by an increase in the patient's BCVA by, for example, at least 10, or at least 15, or at least 20 ETDRS letters.

[0371] 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 axitinib. In other embodiments, the total dose per eye administered once during a treatment period is contained in, for example, two implants, wherein each implant contains, for example, a dose of about 200 μg axitinib (in the 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, wherein each implant contains, for example, a dose of about 200 μg axitinib (in the case, the total dose is about 600 μg). In a specific 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.

[0372] 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 ocular disease such as retinopathy (including AMD), it is generally desirable to use an implant having a therapeutically effective dose of a TKI in a relatively small implant (i.e., an implant that is appropriate in view of the particular patient type and severity of the condition) in order to facilitate administration (injection) and to reduce potential damage to ocular tissue and possible effects on the patient's vision when the implant is in place. The implant of the present invention advantageously combines the benefits of an appropriately high dose of a TKI (i.e., a therapeutically effective dose adjusted to the needs of a particular patient) with a relatively small implant size.

[0373] In certain embodiments, the implant may be administered by an injection device according to the invention connected to a needle preloaded with an implant as disclosed herein or by another injection device suitable for connection to a needle preloaded with an implant as disclosed herein, such as a (modified) Hamilton syringe. In other embodiments, hollow microneedles may be used for suprachoroidal administration, as disclosed in US 8,808,225, which is incorporated herein by reference.

[0374] In the embodiment where two or more implants are used, implants are generally used simultaneously as disclosed above herein. The implants used simultaneously may be identical or different. In the case where it is not possible to use in the same period, for example due to complications or patient-related reasons, it may be alternatively applied to use successively during two or more different periods, for example, two implants are used at a distance of 7 days. In the context of the present invention, this may still be considered as "simultaneous" use.

[0375] In certain embodiments, the dry implant is loaded into a needle, such as a needle of 22 to 23 gauge, such as a 25 gauge or 27 gauge needle, or a smaller gauge needle for injection, and the eye, such as the vitreous humor, is administered via this needle. 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. Implants containing 200 μg and 600 μg, respectively, suitable for therapeutic applications according to the present application are exemplarily presented in Tables 21.1 and 21.2.

[0376] The implant can generally be administered by intravitreal, subconjunctival, subtenon, suprachoroidal or intracameral injection. In certain embodiments, the implant is administered into the vitreous humor, for example, the implant is administered intravitreally into the posterior vitreous humor. In other embodiments, the implant is administered by a hollow microneedle, such as disclosed in US 8,808,225, into the sclera of the eye at an insertion site into the suprachoroidal space of the eye, which is incorporated herein by reference.

[0377] In certain embodiments, the treatment period is at least 3 months, but may be at least 4.5 months, at least 6 months, at least 9 months, at least 11 months, or at least 12 months. In specific 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 may also be longer, such as up to about 15 months. According to one embodiment of the present invention, the "treatment period" means that a certain therapeutic effect of the implant of the present invention after administration is maintained, substantially maintained, or partially maintained during the period. In other words, in certain embodiments, only one injection (implant of the present invention) is required to maintain the therapeutic effect of reducing or substantially maintaining CSFT or preventing its clinically significant increase during a longer period of time referred to herein as the "treatment period". This is a considerable advantage over the current anti-VEGF treatment for AMD that requires more frequent administration, thereby improving the quality of life of patients. Another advantage is that the necessity and / or frequency of administering rescue drugs during the treatment period is extremely low. In certain embodiments, during the treatment period, such as a treatment period of about 6 to about 9 months after the implant is administered, no rescue drug is required. In certain other embodiments, only very infrequent administration of rescue medication is required, such as 1, 2 or 3 times during the treatment period. The patient's vision may 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 administration of an implant of the invention.

[0378] In a 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 one implant per eye is administered at a time 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 central subfield thickness (CSFT) or at least maintains CSFT as measured by optical coherence tomography during the treatment period. In this embodiment, the TKI may further be axitinib, which is dispersed in a 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 when formed and prior to drying, expressed as the weight of polyethylene glycol divided by the weight of fluid x 100. Alternatively, the patient being treated may also have no history of anti-VEGF treatment (no prior AMD treatment).

[0379] 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 two implants per eye to form a total dose of about 400 μg are administered once within 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 has 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 a 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 when formed and prior to drying, expressed as the weight of polyethylene glycol divided by the weight of fluid x 100.

[0380] 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 to form a total dose of about 600 μg are administered once within 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 has 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 a 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 when formed and prior to drying, expressed as the weight of polyethylene glycol divided by the weight of fluid x 100.

[0381] In other embodiments, the present invention relates to 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 dispersed in an amount ranging from about 480 μg to about 750 μg in a hydrogel comprising a polymer network, wherein the implant is administered once within a treatment period of at least 3 months. In certain of these embodiments, axitinib is contained in the implant in an amount ranging from 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 ranging from about 480 μg to about 750 μg or in an amount ranging from about 560 μg to about 660 μg or about 600 μg according to the present invention. The implant can be administered into the vitreous humor, for example, by a thin 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 certain embodiments, 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.

[0382] In some embodiments, the anti-VEGF agent is administered to the patient simultaneously 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 may be 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 certain embodiments, the anti-VEGF agent is administered by intravitreal injection simultaneously with the sustained-release biodegradable ocular implant (as defined above), optionally at the same time, i.e., within one period as disclosed in detail 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, sequential administration in two or more different periods may be applied instead, for example two implants administered 7 days apart. In the context of the present invention, this may still be regarded as "simultaneous" administration.

[0383] In other embodiments, the anti-VEGF agent may be combined with the implant of the invention but not at the same time (i.e., not simultaneously), but rather at an earlier or later time point during the treatment period of the implant of the invention. In certain embodiments, the anti-VEGF agent may be administered within about 1, about 2, or about 3 or more months of administration of the implant, i.e., may be administered before or after administration compared to the implant. This combination (and planned) co-administration of an anti-VEGF agent is distinct from a rescue medication as defined herein.

[0384] In certain embodiments of the invention, the patient is diagnosed with primary suborbital (such as active suborbital or paraorbital CNV with leakage involving the orbit) neovascularization (SFNV) secondary to AMD.

[0385] In certain embodiments of the invention, the patient is diagnosed with previously treated suborbital neovascularization (SFNV) secondary to neovascular AMD with leakage involving the orbit. In such patients, the previous treatment utilized an anti-VEGF agent.

[0386] In some embodiments, the patient is at least 50 years old or at least 60 years old. The patient can be male or female. The patient can have retinal fluid, such as intraretinal fluid or subretinal fluid.

[0387] In some embodiments, the patient receiving the implant has a history of anti-VEGF therapy, such as, for example, and / or Treatment. In certain embodiments, the patient receiving the implant has a history of anti-VEGF treatment, but is not responsive to this 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 before starting treatment with an implant according to the present invention, administration of the implant of the present invention may prolong the effect of the previous anti-VEGF treatment over a longer period of time, such as over the treatment period defined above. In other embodiments, the patient receiving the implant has no history of anti-VEGF treatment (naive anti-VEGF, no AMD treatment).

[0388] 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 quantitation). 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. Therefore, in one embodiment, the one or more additional drugs taken by the patient do not provide significant risks. This is particularly beneficial for elderly patients who often suffer from eye diseases and take other medications in addition.

[0389] Once injected, the implants of certain embodiments of the present invention (comprising the hydrogel and the drug) biodegrade over a long period of time as disclosed above, for example, within about 9 to 12 months. In certain embodiments, it is possible that once the hydrogel is completely degraded, the undissolved axitinib particles remain positioned at the location of the implant. As the hydrogel degrades, these undissolved particles can further maintain a TKI delivery rate sufficient to achieve a therapeutic effect (i.e., inhibit vascular leakage). Fig.15 Resorption of the hydrogel and remaining axitinib particles at the previous implant site in one patient is exemplarily presented up to 11 months after administration. However, in certain embodiments, the entire amount of TKI is dissolved before the hydrogel is completely degraded.

[0390] In certain embodiments, only mild or moderate adverse events, such as ocular adverse events, were observed during the treatment period. In certain embodiments, no serious ocular adverse reactions were observed, and no treatment-related serious ocular adverse events were observed. Tables 23 and 25 show the incidence of adverse events for subjects in Groups 1 and 2 and Groups 3a and 3b of the clinical study, respectively, the results of which (available to date) are presented in Example 6.4.

[0391] In certain embodiments, the present invention also relates to a method of reducing, substantially maintaining central subfield thickness (as measured by optical coherence tomography) or preventing a clinically significant increase in central subfield thickness in a patient whose central subfield thickness is elevated due to an ocular disease involving angiogenesis, the method comprising administering to the patient a sustained release biodegradable ocular 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, the central subfield thickness is reduced, substantially maintained or a clinically significant increase in central subfield thickness is prevented during 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 or at least 14 months or even longer, such as at least 15 months after administration to a patient whose central subfield thickness is elevated due to an ocular disease involving angiogenesis, such as neovascular age-related macular degeneration. In certain embodiments, the patient's vision, for example as indicated by BCVA, is not substantially impaired during the treatment period. In certain other embodiments, the patient's vision, for example as indicated by BCVA, may even be improved. Thus, in certain embodiments, the present invention also relates to a method of improving vision in a patient whose vision 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.

[0392] Additional public content

[0393] In addition to the above disclosure, the present invention also discloses the following items and item lists:

[0394] First list of projects

[0395] 1. A sustained release biodegradable ocular implant comprising a hydrogel and about 150 μg to about 1200 μg of a tyrosine kinase inhibitor.

[0396] 2. The sustained-release biodegradable ocular implant according to item 1, wherein the tyrosine kinase inhibitor is axitinib.

[0397] 3. The sustained release biodegradable ocular implant according to claim 1 or 2, comprising the tyrosine kinase inhibitor in an amount ranging from about 200 μg to about 800 μg.

[0398] 4. The sustained-release biodegradable ocular implant according to item 1 or 2, comprising the tyrosine kinase inhibitor in an amount ranging from about 160 μg to about 250 μg.

[0399] 5. The sustained release biodegradable ocular implant of claim 4, comprising the tyrosine kinase inhibitor in an amount ranging from about 180 μg to about 220 μg.

[0400] 6. The sustained-release biodegradable ocular implant according to item 5, comprising the tyrosine kinase inhibitor in an amount of about 200 μg.

[0401] 7. The sustained release biodegradable ocular implant of claim 1 or 2, comprising the tyrosine kinase inhibitor in an amount ranging from about 320 μg to about 500 μg.

[0402] 8. The sustained-release biodegradable ocular implant according to item 7, comprising the tyrosine kinase inhibitor in an amount ranging from about 360 μg to about 440 μg.

[0403] 9. The sustained release biodegradable ocular implant of claim 8, comprising the tyrosine kinase inhibitor in an amount of about 400 μg.

[0404] 10. The sustained-release biodegradable ocular implant of item 1 or 2, comprising the tyrosine kinase inhibitor in an amount ranging from about 480 μg to about 750 μg.

[0405] 11. The sustained release biodegradable ocular implant of claim 10, comprising the tyrosine kinase inhibitor in an amount ranging from about 540 μg to about 660 μg.

[0406] 12. The sustained-release biodegradable ocular implant according to item 11, comprising the tyrosine kinase inhibitor in an amount of about 600 μg.

[0407] 13. The sustained-release biodegradable ocular implant of item 1 or 2, comprising the tyrosine kinase inhibitor in an amount ranging from about 640 μg to about 1000 μg.

[0408] 14. The sustained-release biodegradable ocular implant according to item 13, comprising the tyrosine kinase inhibitor in an amount ranging from about 720 μg to about 880 μg.

[0409] 15. The sustained-release biodegradable ocular implant according to item 14, comprising the tyrosine kinase inhibitor in an amount of about 800 μg.

[0410] 16. The sustained release biodegradable ocular implant as claimed in any of the preceding items, wherein the implant is for administration to the posterior part of the eye.

[0411] 17. The sustained-release biodegradable ocular implant according to item 16, wherein the administration is administration to the vitreous humor.

[0412] 18. The sustained release biodegradable ocular implant as in any of the preceding items, wherein said tyrosine kinase inhibitor particles are dispersed within said hydrogel.

[0413] 19. The sustained-release biodegradable ocular implant according to item 18, wherein the tyrosine kinase inhibitor particles are micronized particles.

[0414] 20. The sustained release biodegradable ocular implant of any of the preceding items, wherein the implant is in a dry state prior to administration and hydrates once administered into the eye.

[0415] 21. The sustained release biodegradable ocular implant of any of the preceding items, wherein the hydrogel comprises a polymer network comprising units of one or more polyethylene glycol, polyethylene oxide, polypropylene oxide, polyvinyl alcohol, poly(vinyl pyrrolidone), polylactic acid, lactic acid-co-glycolic acid, random or block copolymers of any of the foregoing, or combinations or mixtures thereof, or units of one or more polyamino acids, glycosaminoglycans, polysaccharides, or proteins.

[0416] 22. The sustained release biodegradable ocular implant according to item 21, wherein the hydrogel comprises a polymer network comprising identical or different cross-linked polymer units.

[0417] 23. The sustained-release biodegradable ocular implant according to item 22, wherein the cross-linked polymer unit is one or more cross-linked polyethylene glycol units.

[0418] 24. The sustained release biodegradable ocular implant of any one of items 21 to 23, wherein the polymer network comprises polyethylene glycol units having an average molecular weight ranging from about 2,000 to about 100,000 Daltons.

[0419] 25. The sustained release biodegradable ocular implant according to item 24, wherein the average molecular weight of the polyethylene glycol unit is in the range of about 10,000 to about 60,000 Daltons.

[0420] 26. The sustained release biodegradable ocular implant according to item 25, wherein the average molecular weight of the polyethylene glycol unit is in the range of about 20,000 to about 40,000 Daltons.

[0421] 27. The sustained release biodegradable ocular implant according to item 26, wherein the average molecular weight of the polyethylene glycol unit is about 20,000 Daltons.

[0422] 28. The sustained release biodegradable ocular implant according to any one of items 21 to 27, wherein the polymer network comprises one or more cross-linked multi-arm polymer units.

[0423] 29. The sustained-release biodegradable ocular implant according to item 28, wherein the multi-arm polymer unit comprises one or more 2 to 10-arm polyethylene glycol units.

[0424] 30. The sustained-release biodegradable ocular implant according to item 29, wherein the multi-arm polymer unit comprises one or more 4 to 8-arm polyethylene glycol units.

[0425] 31. The sustained-release biodegradable ocular implant according to item 30, wherein the multi-arm polymer unit comprises one or more 4-arm polyethylene glycol units.

[0426] 32. The sustained release biodegradable ocular implant of any one of items 21 to 31, wherein the polymer network comprises 4-arm and 8-arm polyethylene glycol units.

[0427] 33. The sustained-release biodegradable ocular implant of 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.

[0428] 34. The sustained release biodegradable ocular implant according to any one of items 21 to 33, wherein the nucleophilic group is an amine group.

[0429] 35. The sustained release biodegradable ocular implant according to any one of items 21 to 34, wherein the electrophilic group is an active ester group.

[0430] 36. The sustained release biodegradable ocular implant according to item 35, wherein the electrophilic group is an N-hydroxysuccinimide (NHS) group.

[0431] 37. The sustained release biodegradable ocular implant according to item 36, wherein the electrophilic group is a succinimidyl azelate (SAZ) group.

[0432] 38. The sustained release biodegradable ocular implant of 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 a 8a20kPEG unit.

[0433] 39. The sustained-release biodegradable ocular implant according to item 38, wherein the polymer network is obtained by reacting 4a20kPEG-SAZ and 8a20kPEG-NH2 at a weight ratio of about 2:1 or less.

[0434] 40. The sustained release biodegradable ocular implant of any one of items 1 to 39, wherein the implant contains 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 in a dry state.

[0435] 41. The sustained release biodegradable ocular implant according to item 40, wherein said implant contains from about 35% to about 65% by weight of said tyrosine kinase inhibitor and from about 25% to about 50% by weight of polymer units in a dry state.

[0436] 42. The sustained release biodegradable ocular implant according to item 41, wherein the implant contains 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 in a dry state.

[0437] 43. The sustained release biodegradable ocular implant of any of the preceding items, wherein the implant contains one or more phosphates, borates or carbonates.

[0438] 44. The sustained release biodegradable ocular implant according to item 43, wherein the implant contains phosphate derived from the phosphate buffer used during the preparation of the hydrogel.

[0439] 45. The sustained release biodegradable ocular implant of any of the preceding items, wherein the hydrogel contains about 3% to about 20% polyethylene glycol in a wet state expressed as the weight of polyethylene glycol divided by the weight of the fluid x 100.

[0440] 46. ​​The sustained release biodegradable ocular implant according to item 45, wherein the hydrogel contains polyethylene glycol in an amount of about 7.5% to about 15% expressed as the weight of polyethylene glycol divided by the weight of the fluid x 100.

[0441] 47. The sustained release biodegradable ocular implant of any of the preceding items, wherein said implant contains no more than about 1% water by weight in a dry state.

[0442] 48. The sustained release biodegradable ocular implant as in any of the preceding items, wherein the implant has a substantially cylindrical shape or another shape such as a cross.

[0443] 49. The sustained release biodegradable ocular implant according to any of the preceding items, wherein the implant is in the form of fibers.

[0444] 50. The sustained release biodegradable ocular implant of any of the preceding items, wherein the implant is administered to the eye by needle.

[0445] 51. The sustained release biodegradable ocular implant according to item 50, wherein the needle is a 25 or 27 gauge needle.

[0446] 52. The sustained release biodegradable ocular implant of any of the preceding items, wherein upon hydration in the eye in vivo or in vitro, the diameter of the implant increases, or the length of the implant decreases while its diameter increases.

[0447] 53. The sustained release biodegradable ocular implant according to item 52, wherein the hydration is measured in vitro after 24 hours in phosphate buffered saline at pH 7.2 at 37°C.

[0448] 54. The sustained release biodegradable ocular implant of any one of items 17 to 53, wherein the implant biodegrades in the vitreous humor within about 2 to about 15 months after administration.

[0449] 55. The sustained-release biodegradable ocular implant according to item 54, wherein the implant biodegrades in the vitreous humor within about 4 to about 13 months after administration.

[0450] 56. The sustained-release biodegradable ocular implant according to item 55, wherein the implant biodegrades in the vitreous humor within about 9 to about 12 months after administration.

[0451] 57. The sustained release biodegradable ocular implant of any one of items 2 to 56, wherein the implant releases a therapeutically effective amount of axitinib after administration of the vitreous humor 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, at least about 12 months, at least about 13 months, or at least about 14 months after administration.

[0452] 58. The sustained release biodegradable ocular implant of item 57, wherein the implant releases a therapeutically effective amount of axitinib over a period of at least about 6 months after administration of vitreous humor.

[0453] 59. The sustained release biodegradable ocular implant of item 57, wherein the implant releases a therapeutically effective amount of axitinib over a period of at least about 9 months after administration of vitreous humor.

[0454] 60. The sustained release biodegradable ocular implant of any one 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.

[0455] 61. The sustained release biodegradable ocular implant of item 60, wherein axitinib is released from the implant at an average rate of about 0.5 μg / day to about 7 μg / day.

[0456] 62. The sustained release biodegradable ocular implant of item 61, wherein axitinib is released from the implant at an average rate of about 1 μg / day to about 5 μg / day.

[0457] 63. The sustained-release biodegradable ocular implant according to any one of items 17 to 62, wherein the implant biodegrades in the vitreous humor before the tyrosine kinase inhibitor particles contained in the implant are completely dissolved.

[0458] 64. The sustained release biodegradable ocular implant according to 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.

[0459] 65. A sustained-release biodegradable ocular implant as described in any of the preceding 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 formed into fibers, and stretching the hydrogel fibers.

[0460] 66. The sustained release biodegradable ocular implant according to item 65, wherein the fibers have been stretched and / or twisted before or after drying.

[0461] 67. The sustained release biodegradable ocular implant according to item 66, wherein the fibers have been stretched in the longitudinal direction by a stretch factor of about 1.0 to about 4.5.

[0462] 68. A sustained release biodegradable ocular 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 dispersed in a hydrogel, wherein the hydrogel comprises a polymer network comprising polyethylene glycol units, and wherein the implant is in a dry state prior to administration.

[0463] 69. The sustained release biodegradable ocular implant according to item 68, wherein the polymer network is formed by reacting 4a20kPEG-SAZ with 8a20kPEG-NH2.

[0464] 70. The sustained release biodegradable ocular implant according to item 69, wherein the hydrogel contains 7.5% polyethylene glycol expressed as the weight of polyethylene glycol divided by the weight of fluid x 100 when formed and before drying.

[0465] 71. The sustained release biodegradable ocular implant of 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 a dry state.

[0466] 72. The sustained release biodegradable ocular implant of any one of items 68 to 71, wherein the implant contains no more than about 1% water by weight in a dry state.

[0467] 73. The sustained release biodegradable ocular implant of any one of items 68 to 72, wherein the polymer network is formed by reacting 4a20kPEG-SAZ and 8a20kPEG-NH2 at a weight ratio of about 2:1 or less.

[0468] 74. The sustained release biodegradable ocular implant of 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.

[0469] 75. The sustained release biodegradable ocular implant of any one of items 68 to 74, wherein the implant releases about 35% to about 45% of the axitinib in vitro within 3 days, about 65% to about 75% of the axitinib in vitro within 7 days, and about 90% to about 100% of the axitinib in vitro within 12 to 13 days in a 25:75 ethanol / water mixture (v / v) at 37°C.

[0470] 76. The sustained release biodegradable ocular implant of any one of items 68 to 75, wherein the implant releases about 25% to about 35% of the axitinib in vitro within 2 months, about 47% to about 57% of the axitinib in vitro within 3 months, about 70% to about 80% of the axitinib in vitro within 5 months, and about 90% to about 100% of the axitinib in vitro within 7 months in phosphate buffered saline at 37°C and pH 7.2 with an octanol upper layer.

[0471] 77. The sustained release biodegradable ocular implant of any one of items 68 to 76, wherein the implant in its dry state 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.

[0472] 78. The sustained release biodegradable ocular implant according to item 77, which decreases in length and increases in diameter upon hydration in the eye in vivo or in vitro, wherein hydration is measured in vitro after 24 hours in phosphate buffered saline at pH 7.2 at 37°C.

[0473] 79. The sustained release biodegradable ocular implant of item 77 or item 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.

[0474] 80. The sustained-release biodegradable ocular 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 formed into fibers, and stretching the hydrogel fibers.

[0475] 81. The sustained release biodegradable ocular implant of item 80, wherein the fiber stretches by a factor of about 2 to about 5 after drying.

[0476] 82. The sustained release biodegradable ocular implant of item 81, wherein the fiber stretches by a factor of about 3 to about 4.5 after drying.

[0477] 83. The sustained release biodegradable ocular 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.

[0478] 84. A sustained release biodegradable ocular implant comprising axitinib in an amount ranging from about 480 μg to about 750 μg dispersed in a hydrogel, wherein the hydrogel comprises a polymer network.

[0479] 85. The sustained release biodegradable ocular implant according to item 84, wherein the polymer network comprises cross-linked polyethylene glycol units.

[0480] 86. The sustained-release biodegradable ocular implant according to item 85, wherein the content of axitinib is in the range of about 540 μg to about 660 μg.

[0481] 87. The sustained-release biodegradable ocular implant according to item 86, wherein the content of axitinib is about 600 μg.

[0482] 88. The sustained release biodegradable ocular implant of 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 ranging from about 10,000 Daltons to about 60,000 Daltons.

[0483] 89. The sustained release biodegradable ocular implant according to item 88, wherein the polyethylene glycol unit comprises a 4a20kPEG unit.

[0484] 90. The sustained release biodegradable ocular implant according to item 89, wherein the polymer network is formed by reacting 4a20kPEG-SAZ with 8a20kPEG-NH2.

[0485] 91. The sustained release biodegradable ocular implant of item 90, wherein the weight ratio of 4a20kPEG-SAZ to 8a20kPEG-NH2 is about 2:1 or less.

[0486] 92. The sustained release biodegradable ocular implant of 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 a dry state.

[0487] 93. The sustained release biodegradable ocular implant of any one of items 84 to 92, wherein the implant contains no more than about 1% water by weight in a dry state.

[0488] 94. The sustained release biodegradable ocular implant of any one of items 84 to 93, wherein the implant is in the form of fibers 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.

[0489] 95. The sustained release biodegradable ocular implant according to item 94, wherein the implant is in the form of fibers 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.

[0490] 96. The sustained release biodegradable ophthalmic implant of any one of items 84 to 95, wherein the implant is used for administration of vitreous humor.

[0491] 97. The sustained release biodegradable ocular implant according to items 94 to 96, which increases in diameter upon hydration in the eye in vivo or in vitro, wherein in vitro hydration is measured after 24 hours in phosphate buffered saline at pH 7.2 at 37°C.

[0492] 98. The sustained release biodegradable ocular implant according to 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.

[0493] 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 of no more than about 10 mm or no more than about 9 mm in its hydrated state.

[0494] 100. The sustained release biodegradable ocular implant of any one of items 84 to 99, wherein the implant contains about 600 μg of axitinib and releases about 0.3 μg to about 0.5 μg of axitinib per day in vitro in phosphate buffered saline at 37°C for a period of 30 days.

[0495] 101. The sustained-release biodegradable ocular implant of any one of items 84 to 100, wherein the implant releases about 40% to about 60% of the axitinib in vitro 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 in a 25:75 ethanol / water mixture (v / v) at 37°C.

[0496] 102. The sustained-release biodegradable ocular implant of item 101, wherein the implant releases about 45% to about 55% of the axitinib in vitro 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 in a 25:75 ethanol / water mixture (v / v) at 37°C.

[0497] 103. The sustained-release biodegradable ocular 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 formed into fibers, and stretching the hydrogel fibers.

[0498] 104. The sustained release biodegradable ocular implant of item 103, wherein the fibers are wet stretched by a factor of about 0.5 to about 5 prior to drying.

[0499] 105. The sustained release biodegradable ocular implant of item 104, wherein the fibers are wet stretched by a factor of about 1 to about 4 prior to drying.

[0500] 106. The sustained release biodegradable ocular implant of item 105, wherein the fibers are wet stretched by a factor of about 1.5 to about 3.5 prior to drying.

[0501] 107. The sustained release biodegradable ocular implant of item 106, wherein the fibers are wet stretched by a factor of about 1.7 to about 3 prior to drying.

[0502] 108. The sustained-release biodegradable ocular implant according to 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.

[0503] 109. The sustained-release biodegradable ocular implant of item 108, wherein the implant is loaded onto a 25-gauge or 27-gauge needle in a dry state.

[0504] 110. The sustained release biodegradable ocular implant of any one of items 1 to 109, wherein the hydrogel comprises a polymer network that is semi-crystalline in a dry state at or below room temperature and amorphous in a wet state.

[0505] 111. The sustained release biodegradable ocular implant of any one of items 1 to 110, wherein the implant has been wet or dry stretched during manufacture, and wherein the implant in stretched form is dimensionally stable in the dry state at or below room temperature.

[0506] 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 ocular implant comprising a hydrogel and a tyrosine kinase inhibitor according to any of the preceding items, wherein the dose administered once per eye over a treatment period of at least 3 months is from about 150 μg to about 1200 μg of the tyrosine kinase inhibitor.

[0507] 113. The method of item 112, wherein the tyrosine kinase inhibitor is axitinib.

[0508] 114. The method of item 112 or item 113, wherein the dose administered once per eye during the treatment period is in the range of about 200 μg to about 800 μg.

[0509] 115. The method of item 112 or item 113, wherein the dose is in the range of about 160 μg to about 250 μg or about 180 μg to about 220 μg.

[0510] 116. The method of item 115, wherein the dose is about 200 μg.

[0511] 117. The method of item 112 or item 113, wherein the dose is in the range of about 320 μg to about 500 μg or about 360 μg to about 440 μg.

[0512] 118. The method of item 117, wherein the dose is about 400 μg.

[0513] 119. The method of item 112 or item 113, wherein the dose is in the range of about 480 μg to about 750 μg or about 540 μg to about 660 μg.

[0514] 120. The method of item 119, wherein the dose is about 600 μg.

[0515] 121. The method of item 112 or item 113, wherein the dose is in the range of about 640 μg to about 1000 μg or about 720 μg to about 880 μg.

[0516] 122. The method of item 121, wherein the dose is about 800 μg.

[0517] 123. The method of any one of items 112 to 122, wherein the eye disease involves angiogenesis.

[0518] 124. A method as described in 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.

[0519] 125. A method as described in any one of items 112 to 124, wherein the eye disease is a retinal disease, including choroidal neovascularization, diabetic retinopathy, diabetic macular edema, retinal vein occlusion, acute macular neuroretinopathy, central serous chorioretinopathy and cystic macular edema; wherein the eye disease is acute multifocal macular pigment epitheliopathy, Behcet's disease, birdshot retinochoroidopathy, infectious (syphilis, Lyme disease, tuberculosis, toxoplasmosis), neutrophil uveitis, multifocal choroiditis, multiple transient white dot syndrome (MEWDS), ocular sarcoidosis, posterior scleritis, herpes simplex virus, leukoplakia, leukoplakia, leukoplakia, leukoplakia, leukoplakia, leukoplakia, leukoplakia, leukoplakia, leukoplakia, leukoplakia, leukoplakia, leukoplakia, leukoplakia, leukoplakia, leukoplakia choroiditis, subretinal fibrosis, uveitis syndrome, or Vogt-Koyanagi-Harada syndrome; wherein the ocular disease is a vascular disease or an exudative disease, including Coat's disease, parafoveal telangiectasia, papillary phlebitis, frosted vasculitis, sickle cell retinopathy and other heme diseases, 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, hypoperfusion during surgery, radiation retinopathy, or bone marrow transplant retinopathy.

[0520] 126. The method of any one of items 112 to 124, wherein the eye disease is neovascular age-related macular degeneration, diabetic macular edema, or retinal vein occlusion.

[0521] 127. The method of item 126, wherein the disease is neovascular age-related macular degeneration.

[0522] 128. A method as described in 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 a patient with elevated central subfield thickness, as measured by optical coherence tomography.

[0523] 129. The method of 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.

[0524] 130. The method of any one of items 112 to 129, wherein the implant is administered by injection into the vitreous humor.

[0525] 131. The method of 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.

[0526] 132. The method of item 131, wherein the treatment period is at least 6 months, at least about 9 months, or at least about 12 months.

[0527] 133. The method of any one of items 112 to 132, wherein the anti-VEGF agent is administered to the patient concurrently with treatment with the sustained release ocular implant, or wherein the anti-VEGF agent is administered within about 1, about 2, or about 3 months after administration of the implant.

[0528] 134. The method of item 133, wherein the anti-VEGF agent is selected from the group consisting of aflibercept, bevacizumab, pegaptanib, ranibizumab, and brolucizumab.

[0529] 135. The method of item 134, wherein the anti-VEGF agent is bevacizumab.

[0530] 136. The method of any one of items 133 to 135, wherein the anti-VEGF agent is administered by intravitreal injection.

[0531] 137. The method of any one of items 112 to 136, wherein the patient receiving the implant has a history of anti-VEGF treatment.

[0532] 138. The method of 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).

[0533] 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 ocular 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.

[0534] 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 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, and wherein the patient has or has no history of anti-VEGF treatment.

[0535] 141. The method of item 139 or item 140, wherein the treatment results in a decrease in central subfield thickness (CSFT) as measured by optical coherence tomography during the treatment period.

[0536] 142. The method of 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 prior to administration.

[0537] 143. The method of item 142, wherein the hydrogel contains about 7.5% polyethylene glycol when formed and before drying, expressed as the weight of polyethylene glycol divided by the weight of the fluid x 100.

[0538] 144. The method of any one of items 140 to 143, wherein the treatment period is at least 9 months.

[0539] 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 ranging from about 480 μg to about 750 μg dispersed in a hydrogel comprising a polymer network, wherein the implant is administered once within a treatment period of at least 3 months.

[0540] 146. The method of item 145, wherein the content of the axitinib in the implant is about 560 μg to about 660 μg.

[0541] 147. The method of item 146, wherein the content of the axitinib in the implant is about 600 μg.

[0542] 148. The method of any one of items 145 to 147, wherein the implant is as defined in items 84 to 111.

[0543] 149. The method of any one of items 145 to 148, wherein the implant is administered into the vitreous humor.

[0544] 150. The method of 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.

[0545] 151. The method of 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.

[0546] 152. The method of any one of items 145 to 151, wherein the patient receiving the implant has a history of anti-VEGF treatment or has no history of anti-VEGF treatment (has not undergone anti-VEGF).

[0547] 153. The method of any one of items 145 to 152, wherein an anti-VEGF agent is administered to the patient simultaneously with the implant.

[0548] 154. The method of item 153, wherein the anti-VEGF agent is selected from the group consisting of aflibercept, bevacizumab, pegaptanib, ranibizumab, and brolucizumab.

[0549] 155. The method of item 154, wherein the anti-VEGF agent is bevacizumab.

[0550] 156. The method of any one of items 153 to 155, wherein the anti-VEGF agent is administered by intravitreal injection.

[0551] 157. The method of any one of items 112 to 156, wherein the number of adverse events is low during administration of the sustained release biodegradable ocular implant.

[0552] 158. The method of item 157, wherein the number of treatment-related ocular adverse events is low during administration of the sustained-release biodegradable ocular implant.

[0553] 159. A method for manufacturing a sustained-release biodegradable ocular implant comprising a hydrogel and about 150 μg to about 1200 μg of a tyrosine kinase inhibitor according to any one of items 1 to 111, 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.

[0554] 160. The method of item 159, wherein the tyrosine kinase inhibitor is axitinib.

[0555] 161. The method of item 159 or item 160, wherein the tyrosine kinase inhibitor particles are micronized and / or homogenously dispersed within the hydrogel.

[0556] 162. The method of any one of items 159 to 161, wherein the polymer network is formed by cross-linking multi-arm polyethylene glycol units in a buffer solution.

[0557] 163. A method as described in 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 with 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.

[0558] 164. The method of item 163, comprising reacting 4a20kPEG-SAZ and 8a20kPEG-NH2 in a weight ratio of about 2:1.

[0559] 165. A method as described in item 163 or item 164, wherein the method includes the following steps: filling the mixture into a mold or tube, followed by complete gelation to provide the desired final shape of the hydrogel; gelling the mixture; and drying the hydrogel.

[0560] 166. The method of item 165, wherein the mixture is filled into a thin diameter tube to prepare the hydrogel fiber.

[0561] 167. The method of item 166, wherein the interior of the tube has a circular geometry.

[0562] 168. The method of item 166, wherein the interior of the tube has a non-circular geometry.

[0563] 169. The method of item 168, wherein the interior of the tube has a cross-shaped geometry.

[0564] 170. The method of any one of items 166 to 169, wherein the method further comprises stretching the fiber and / or twisting the fiber.

[0565] 171. The method of item 170, wherein the stretching is performed before or after drying the hydrogel.

[0566] 172. The method of item 171, wherein the fiber is stretched at a stretch factor of about 1 to about 4.5.

[0567] 173. The method of item 171, wherein the implant contains axitinib in an amount of about 200 μg, and the stretching is performed at a stretch factor of about 2 to about 5 or a stretch factor of about 3 to about 4.5 after drying the hydrogel.

[0568] 174. The method of item 171, wherein the implant contains axitinib in an amount of about 600 μg, and the stretching is performed in a wet state 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 before drying the hydrogel.

[0569] 175. The method of any one of items 159 to 174, wherein the method further comprises loading the implant in a dry state into a needle.

[0570] 176. The method of item 175, wherein the needle is a 25 or 27 gauge needle.

[0571] 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.

[0572] 178. A method of making an ocular implant comprising a hydrogel containing 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.

[0573] 179. The method of item 177 or item 178, wherein the method comprises the step of drying the hydrogel, wherein the fibers are stretched in a longitudinal direction (wet or dry stretching) before or after said drying.

[0574] 180. A method as described in any one of items 177 to 179, wherein the fiber is stretched by a factor of about 0.5 to about 5, or a factor of about 1 to about 4.5, or a factor of about 3 to about 4.5, or a factor of about 1 to about 2.

[0575] 181. The method of any one of items 177 to 180, wherein the active agent is a tyrosine kinase inhibitor, such as axitinib.

[0576] 182. The method of any one of items 177 to 181, wherein the hydrogel comprises a polymer network comprising cross-linked polyethylene glycol units.

[0577] 183. The method of any one of items 177 to 182, wherein the fiber, after hydration, fully or partially recovers to approximately its original length and / or original diameter that it had before stretching.

[0578] 184. The method of any one of items 177 to 183, wherein the size change is an increase in diameter or an increase in diameter combined with a decrease in length.

[0579] 185. A kit comprising one or more sustained-release biodegradable ocular implants manufactured according to any one of items 1 to 111 or according to the method of 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 ocular implant in a dry state.

[0580] 186. The kit of item 185, wherein the one or more needles are 25 or 27 gauge needles.

[0581] 187. The kit of item 185 or item 186, wherein the kit comprises one or more 25 or 27 gauge needles, each of the one or more needles being loaded with an implant containing an amount of axitinib in the range of about 180 μg to about 220 μg.

[0582] 188. The kit of item 187, wherein the implant contains axitinib in an amount of about 200 μg.

[0583] 189. The kit of item 185 or 186, wherein the kit comprises a 25 gauge or 27 gauge needle loaded with an implant containing an amount of axitinib in the range of about 540 μg to about 660 μg.

[0584] 190. The kit of item 189, wherein the implant contains axitinib in an amount of about 600 μg.

[0585] 191. The kit of any one of items 185 to 190, further comprising an injection device for injecting the implant into an eye of a patient.

[0586] 192. The kit of item 191, wherein the injection device is provided in the kit separately from the one or more needles loaded with the implant.

[0587] 193. The kit of item 191, wherein the injection device is pre-connected to a needle loaded with an implant.

[0588] 194. The kit of item 191 or 192, wherein the injection device comprises a push wire to deploy the implant from the needle into the eye.

[0589] 195. The kit of any one of items 185 to 194, further comprising a dose of an anti-VEGF agent for injection.

[0590] 196. An injection device suitable for injecting the sustained-release biodegradable ocular implant according to items 1 to 111 into an eye.

[0591] 197. The injection device of item 196, comprising a component for connecting the injection device to a needle.

[0592] 198. The injection device of item 196 or item 197, wherein the needle is pre-loaded with the implant.

[0593] 199. The injection device of any one of items 196 to 198, comprising a push wire for deploying the implant from the needle into the eye when the injection device is connected to the needle.

[0594] 200. The injection device of item 199, wherein the push wire is made of Nitinol or stainless steel / Teflon.

[0595] 201. The injection device of item 199 or item 200, which is obtained by fixing the wire to the plunger and enclosing it between two snap-fit ​​injector body parts and fixing the plunger with a clip.

[0596] 202. A pharmaceutical product comprising the sustained-release biodegradable ocular implant according to any one of items 1 to 111 loaded in a needle and an injection device according to any one of items 196 to 201, wherein the needle is pre-connected to the injection device.

[0597] 203. A sustained-release biodegradable ocular implant containing a tyrosine kinase inhibitor according to any one of items 1 to 111, for use in treating an ocular disease in a patient in need thereof according to any one of items 112 to 138 or for use in treating neovascular age-related macular degeneration in a patient in need thereof according to any one of items 139 to 158, item 210 or item 211.

[0598] 204. 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 treating an ocular 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, item 210 or item 211.

[0599] 205. A method for reducing, substantially maintaining central subfield thickness, or preventing a clinically significant increase in central subfield thickness (as measured by optical coherence tomography) in a patient having elevated central subfield thickness due to an ocular disease involving angiogenesis, the method comprising administering to the patient a sustained-release biodegradable ocular implant containing a tyrosine kinase inhibitor according to any one of items 1 to 111.

[0600] 206. The method of item 205, wherein the eye disease is neovascular age-related macular degeneration.

[0601] 207. A method as described in item 205 or item 206, wherein the central subfield thickness is reduced, substantially maintained, or a clinically significant increase in central subfield thickness is prevented 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, relative to a baseline central subfield thickness measured in the patient before administration of the implant.

[0602] 208. A sustained-release biodegradable ocular implant containing a tyrosine kinase inhibitor according to any one of items 1 to 111, which reduces, substantially maintains central subfield thickness or prevents a clinically significant increase in central subfield thickness (as measured by optical coherence tomography) in a patient with increased central subfield thickness due to an ocular disease involving angiogenesis according to any one of items 205 to 207, 210 or 211.

[0603] 209. 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 reducing, substantially maintaining central subfield thickness or preventing a clinically significant increase in central subfield thickness (as measured by optical coherence tomography) in a patient whose central subfield thickness is increased due to an ocular disease involving angiogenesis according to any one of items 205 to 207, item 210 or item 211.

[0604] 210. The method of any one of items 128 to 158 or any one of items 205 to 207, wherein the patient's vision as represented by best corrected visual acuity is not impaired or is improved.

[0605] 211. The method of 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 rescue medication only needs to be administered occasionally, such as 1, 2, or 3 times, during the treatment period.

[0606] 212. The method of item 211, wherein the duration of the treatment period is about 6 to about 9 months after administration of the sustained-release biodegradable ocular implant.

[0607] 213. A method of improving vision in a patient whose vision is impaired due to an ocular disease involving angiogenesis, the method comprising administering to the patient a sustained-release biodegradable ocular implant comprising a tyrosine kinase inhibitor as described in any one of items 1 to 111.

[0608] 214. The method of item 213, wherein the eye disease is neovascular age-related macular degeneration, diabetic macular edema, or retinal vein occlusion.

[0609] 215. The method of item 213 or item 214, wherein the patient's vision is impaired due to the presence of retinal fluid.

[0610] 216. The method of any one of items 213 to 215, wherein the improvement in vision is manifested by an increase in best corrected visual acuity.

[0611] 217. The method of item 216, wherein the best corrected visual acuity increases by at least 10, at least 15, or at least 20 ETDRS letters.

[0612] 218. A sustained-release biodegradable ocular implant containing a tyrosine kinase inhibitor according to any one of items 1 to 111, for use in improving the vision of a patient whose vision is impaired due to an ocular disease involving angiogenesis according to the method of any one of items 213 to 217.

[0613] 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 ocular disease involving angiogenesis according to the method of any one of items 213 to 217.

[0614] Second list of items

[0615] 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 prior to TKI release.

[0616] 2. The ocular hydrogel according to item 1, wherein when the TKI is contained inside the hydrogel implant, the TKI does not contact retinal cells.

[0617] 3. The ophthalmic hydrogel according to item 1 or 2, wherein the TKI is present in the hydrogel implant at or close to its saturation level.

[0618] 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.

[0619] 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.

[0620] 6. The ocular hydrogel implant of any one of items 1 to 5, wherein the ocular hydrogel implant completely degrades after about 30 days or after about 3 months after completely releasing the TKI.

[0621] 7. The ocular hydrogel implant of any one of items 1 to 4, wherein degradation of the ocular hydrogel occurs prior to release of the TKI.

[0622] 8. The ocular hydrogel implant of any one of items 1 to 7, wherein the polymer network comprises a plurality of polyethylene glycol (PEG) units.

[0623] 9. The ocular hydrogel implant of any one of items 1 to 8, wherein the polymer network comprises a plurality of multi-arm PEG units.

[0624] 10. The ocular hydrogel implant of any one of items 1 to 9, wherein the polymer network comprises a plurality of 4-arm or 8-arm PEG units.

[0625] 11. The ocular hydrogel implant of any one of items 1 to 9, wherein the polymer network comprises a plurality of PEG units having the formula:

[0626]

[0627] wherein n represents an ethylene oxide repeating unit and the wavy lines represent the dots of the repeating units of the polymer network.

[0628] 12. The ocular hydrogel implant of 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 amine groups or salts thereof selected from 4a20kPEG-NH2, 8a20k PEG-NH2 and trilysine.

[0629] 13. The ocular hydrogel implant of any one of items 1 to 12, wherein the polymer network is formed by reacting 4a20k PEG-SAZ with 8a20k PEG-NH2.

[0630] 14. The ocular hydrogel implant of any one of items 1 to 13, wherein the polymer network is amorphous (under aqueous conditions).

[0631] 15. The ocular hydrogel implant of any one of items 1 to 14, wherein the polymer network is semi-crystalline in the absence of water.

[0632] 16. The ocular hydrogel implant of any one of items 1 to 15, wherein the tyrosine kinase inhibitor is homogeneously dispersed within the polymer network.

[0633] 17. The ocular hydrogel implant of any one of items 1 to 16, wherein the tyrosine kinase inhibitor is released over a period of at least 15 days.

[0634] 18. The ocular hydrogel implant of any one of items 1 to 17, wherein the tyrosine kinase inhibitor is released over a period of at least 30 days.

[0635] 19. The ocular hydrogel implant of any one of items 1 to 18, wherein the tyrosine kinase inhibitor is released over a period of at least 60 days.

[0636] 20. The ocular hydrogel implant of any one of items 1 to 19, wherein the tyrosine kinase inhibitor is released over a period of at least 90 days.

[0637] 21. The ocular hydrogel implant of any one of items 1 to 20, wherein the tyrosine kinase inhibitor is released over a period of at least 180 days.

[0638] 22. The ocular hydrogel implant of any one of items 1 to 21, wherein the tyrosine kinase inhibitor is released over a period of at least 365 days.

[0639] 23. The ocular hydrogel implant of any one of items 1 to 22, wherein the tyrosine kinase inhibitor is in the form of encapsulated microparticles.

[0640] 24. The ocular hydrogel implant of any one of items 1 to 23, wherein the tyrosine kinase inhibitor is in the form of encapsulated microparticles comprising poly(lactic-co-glycolic acid).

[0641] 25. The ocular hydrogel implant of 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, ketoconazole, tadalafil ... 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.

[0642] 26. The ocular hydrogel implant of item 1 or item 25, wherein the tyrosine kinase inhibitor is axitinib.

[0643] 27. The ocular hydrogel implant of any one of items 1 to 26, wherein the ocular 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.

[0644] 28. A method of treating an ocular disorder in a subject in need thereof, comprising injecting or affixing the ocular hydrogel implant of any one of items 1 to 27 into the subject.

[0645] 29. The method of item 28, wherein the ocular disorder is selected from maculopathy, retinal degeneration, uveitis, retinitis, choroiditis, vascular disease, exudative disease, trauma, proliferative disease, infectious disorders, genetic disorders, retinal tears, holes and tumors.

[0646] 30. A method as in item 28 or item 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 macular pigment epitheliopathy, Behcet's disease, birdshot retinochoroidopathy, neuter uveitis, multifocal choroiditis, multiple transient white dot syndrome (MEWDS), ocular sarcoidosis, posterior scleritis, serpiginous choroiditis, subretinal fibrosis and uveitis syndrome, Vogt-Koyanagi-Harada syndrome, Coat's disease, Parafoveal telangiectasia, papillary phlebitis, frosted vasculitis, sickle cell retinopathy, vascular 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 tumors, retinal astrocytoma and intraocular lymphoma.

[0647] 31. The method of item 29 or item 30, wherein the disorder is age-related macular degeneration.

[0648] 32. The method of any one of items 29 to 31, wherein the subject was previously treated with anti-VEGF therapy.

[0649] Example

[0650] 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 will appreciate that the following description is illustrative only and should not be construed as limiting the present invention in any way.

[0651] Example 1: Preparation of axitinib implant

[0652] The axitinib implant of the present application is (substantially) cylindrical (and also referred to herein as "fiber"), in which axitinib is homogeneously dispersed and embedded in a PEG-based hydrogel matrix to continuously release axitinib based on its low aqueous solubility in the vitreous humor of the eye.

[0653] The polymer network of the implant is formed by reacting 2 parts of 4a20K PEG-SAZ (a 20 kDa PEG with 4 arms containing N-hydroxysuccinimide reactive end groups, sometimes also referred to as "NHS" end groups) with 1 part of 8a20K PEG NH2 (a 20 kDa PEG with 8 arms containing amine end groups). Therefore, the polyurethane tube is cut into pieces of appropriate length. Thereafter, a solution of 8a20K PEG NH2 disodium hydrogen phosphate is prepared and sterile filtered through 0.2 μm (pore size of the filter) to remove endotoxin and other particles. The desired volume of the PEG amine solution is then 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. The syringe containing the suspension mixture is then sonicated to break up any powder aggregates. Thereafter, a 4a20K PEG SAZ sodium dihydrogen phosphate solution is prepared and sterile filtered as described for the PEG amine solution. The desired volume of PEG SAZ solution is then weighed into another syringe. In the next step, the contents 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 the material is then cross-linked and cured. The gelation time is confirmed by performing a gel tapping test. The tube containing the gel is then placed in a high humidity curing chamber for 2 hours to prevent the hydrogel from drying prematurely before the hydrogel gels. In the chamber, the hydrogel axitinib suspension in the tube is cross-linked to completion, thereby producing a highly reactive and uniform gel, thereby forming a hydrogel strand.

[0654] After curing, different implant stretching methods are performed as disclosed herein. As outlined below, the implant is subjected to dry stretching or wet stretching. For dry stretching, the strand is cut into shorter sections after curing, and the strand is dried for 48 to 96 hours. After drying, the dried strand section is removed from the tube and placed in the clamps of a custom stretcher. The strand is then slowly dry-stretched at a controlled rate until the desired diameter (stretch factor of about 2 to about 5 or about 3 to about 4.5) suitable for a small-sized needle is reached. The stretching step is performed in an environment without oxygen and moisture to protect the product. For wet stretching, the strand is placed on the clamps of a custom stretcher. The strand is then slowly wet-stretched at a controlled rate until the desired diameter (stretch factor of about 1 to about 3 or about 1.3 to about 2.6) suitable for a small-sized needle is reached. After stretching, the strand is dried under tension under the conditions described for the dry stretching process.

[0655] Stretching produces shape memory, meaning that when applied to the vitreous cavity of the eye, the implant will quickly shorten in length and widen in diameter after hydration until it reaches its original wet cast size. Although the narrow dry size is advantageous for applying the product via a smaller gauge needle, the widening of the diameter and shortening of the length after application can produce an implant that is shorter in length relative to the diameter of the eye in the posterior chamber (in some embodiments, the length does not exceed about 10 mm), thereby reducing potential contact with surrounding eye tissue. In general, the degree of shrinkage after hydration depends, among other things, on the stretch factor. For example, stretching with a stretch factor of about 1.3 (wet stretching) will have a less noticeable effect, or will not substantially change the length during hydration. In contrast, stretching with a stretch factor of, for example, about 1.8 (wet stretching) will result in a significant shortening of the length during hydration. Stretching with a stretch factor of, for example, about 4 (dry stretching) can result in a much shorter length after hydration (e.g., the length is reduced from about 15 mm to about 8 mm).

[0656] Remove the stretched hydrogel strand from the tensioner and then cut to the desired final length. Implant fiber is then placed on the inspection station. If the implant passes quality control, a customized vacuum device is used to load it 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 with an internal diameter of about 0.4 mm), and securely cover it to avoid any needle tip damage.

[0657] The loaded needles are placed in a glove box for 6 to 9 days to remove any moisture (with the intention that the residual water content in the implant does not exceed 1% water). From that time on, all steps are performed in the glove box. The loaded needles are immersed in molten low molecular weight 1kPEG to cover the needles with the tip. After cooling, retaining a small drop of hardened PEG can provide smoothness, keep the implant in the proper position in the needle, allow successful deployment, and prevent the implant in the needle from rehydrating prematurely during administration. In addition, PEG tip coverage reduces tissue damage, i.e., tissue coring, which is the process of removing tissue fragments through the needle when it passes through the tissue. The needles covered with PEG tips are then checked again and needles that do not meet quality requirements are discarded. Qualified needles are covered again to ensure that the needles do not suffer any other damage. The needles are then individually encapsulated and sealed to prevent them from getting wet and keep them sterile. The injection device (e.g., an improved Hamilton glass syringe) has a push wire (e.g., a Nitinol push wire) that allows implants to be deployed more easily from the needle. The injection needle may contain a termination feature that controls the injection depth. The injection devices can be packaged separately in the same manner as described for the needles and sealed in foil pouches under nitrogen ( Figure 1 ), or can be pre-assembled with a needle loaded with an implant or pre-assembled in a pre-loaded injector. The packaged needle and injection device are removed from the glove box and stored refrigerated (2-8°C), followed by sterilization using gamma irradiation. After sterilization, the package is refrigerated (2-8°C) or frozen and stored away from light before use, and equilibrated to room temperature for 30 minutes before injection.

[0658] The implant is administered via intravitreal injection, where the implant is positioned in the posterior segment of the eye ( Figure 2 ). After injection, the implant is hydrated in situ. After hydration upon contact with the vitreous, the implant softens and increases in diameter, and may also shrink in length. By entrapping axitinib in the hydrogel, defined and limited localization of axitinib in the eye can be provided. The hydrogel matrix of the implant is formulated so as to biodegrade via ester hydrolysis in the aqueous environment of the vitreous. Axitinib is released from the hydrogel for a sustained period of time ( ) by diffusion into the vitreous and subsequently to the surrounding ocular tissues due to the low solubility of the drug under physiological conditions. Figure 3 The rate of drug release from an implant is influenced by, among other things, diffusion, drug clearance rate, vitreous viscosity, concentration gradients in and around the implant, implant dose, implant surface area and geometry, and the number of implants and their positioning within the vitreous.

[0659] Example 2: In vitro axitinib release

[0660] In the next step, the axitinib release rate of implants with different formulations was determined by in vitro testing. In vitro analysis can additionally be used for quality control of implants.

[0661] In vitro axitinib release under non-sink mimicking physiological conditions

[0662] In an in vitro assay setup, axitinib release was assessed under non-sink simulated physiological conditions at a daily replacement volume comparable to the volume of vitreous humor in the human eye.

[0663] Three exemplary selected implant formulations were examined (Table 1). Implant variants No. 1 and No. 2 were examined using one implant, and implant variant No. 3 was examined using one and two implants (four conditions total). All conditions were performed in duplicate.

[0664] Table 1. Formulations, configurations and dry sizes of three exemplary selected axitinib implants. Formulation percentages represent weight / weight (w / w).

[0665]

[0666] Prior to in vitro release analysis, the initial drug content of the implants was checked by liquid chromatography coupled with fragmentation-based mass spectrometry (LC-MS / MS) using ethanol as the extraction solvent (Table 2; see Example 3.5 for details on implant dissolution and LC-MS / MS). The measured amount of axitinib matched well with the formulated amount.

[0667] Table 2 Initial axitinib content in implants as determined by LC-MS / MS.

[0668]

[0669]

[0670] The in vitro released and unreleased axitinib in each group was determined without (control group) and with daily release medium sampling.

[0671] For control implant release, 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 cap. The samples were then placed in a 37°C incubator and gently shaken for 20 days (1x implant No. 3) or 30 days (1 and 2 implants, 2x implant No. 3). At the end of the test period, PBS was removed (1 mL of PBS was saved for testing). 1 mL of ethanol was added to the residual sample. The PBS sample and the residual sample were tested for axitinib release.

[0672] For daily implant release, samples were placed in tubes. 5 mL of PBS was added to each tube on day 0 and the tubes were covered with lids. The samples were then placed in a 37°C incubator and gently shaken. After 24 hours, 4 mL of PBS was removed from each sample, 1 mL of which was used for testing and the remaining 3 mL was disposed of. 4 mL of fresh PBS was added back to each tube. This process was repeated for 20 days (1x implant No. 3) or 30 days (implant No. 1 and No. 2, 2x implant No. 3). On the last day of the study, 1 mL of PBS was used to test each sample and the remaining 4 mL was disposed of. 1 mL of ethanol was added to the remaining residual implants and the total remaining axitinib was tested.

[0673] The axitinib concentrations in PBS from control implant release measurements after 20 or 30 days represent the maximum solubility determination of axitinib after prolonged incubation in the release medium (Table 3). The higher the dose strength, the higher the axitinib concentration in the release medium. The apparent maximum axitinib solubility ranged from 0.24 to 0.40 μg / mL, which is consistent with the literature for The results are consistent with those reported in [NDA 202324].

[0674] Table 3 Controlled release data. Axitinib amounts and concentrations are presented as mean values ​​and standard deviations (SD).

[0675]

[0676]

[0677] The test results showed that the two high-dose samples (implant No. 1 and No. 2) released more axitinib per day compared to the lower dose group (Table 4). The amount of axitinib released per day during the study duration is presented in Figure 4A Total axitinib release was higher in the group with daily PBS removal and replacement compared to no PBS exchange (control group). Implants 1 and 2 released more axitinib per day compared to both implants in implant 3. The total axitinib release means were slightly different in the two high-dose groups, but the median daily release was comparable, indicating no significant difference between the two higher dose groups.

[0678] Table 4. Daily sampling data. Axitinib amounts are presented as mean and standard deviation (SD).

[0679]

[0680] The results of the study showed that a single administration of an implant containing approximately 0.6 to 0.7 mg of axitinib released more axitinib per day in a volume of solution representing the volume of vitreous humor of the eye under non-sink conditions under simulated physiological conditions compared to one or two lower dose total strengths. Under these conditions, two implants (each containing approximately 0.2 mg) did not release as much axitinib as a single higher dose implant. These in vitro results indicate that a single implant of a higher dose can release more axitinib per day in the eye under non-sink conditions of the eye compared to two implants of a lower total dose.

[0681] In vitro axitinib release in an instant sink mimicking physiological conditions

[0682] In another in vitro setting, axitinib release was assessed in an immediate sink mimicking physiological conditions.

[0683] Therefore, the implants were placed in 5 mL of physiologically relevant medium, i.e., pH 7.2 PBS containing 0.01% NaF, with a 1-octanol layer on top of the solution to provide a leaky phase, thereby allowing axitinib to transfer into the octanol layer. The implants were incubated in an air chamber at 37°C with gentle agitation. Axitinib was measured in the octanol layer by acquiring UV absorbance at 333 nm at predetermined sampling time points. The amount of axitinib released at each time point was determined relative to a standard curve prepared from an axitinib reference. The accelerated in vitro release profile was determined as the cumulative percentage of axitinib released. The duration of complete drug release was several months.

[0684] For exemplary release profiles under immediate sink conditions, refer to Fig.14A .

[0685] In vitro axitinib release under accelerated conditions

[0686] In another in vitro setting, axitinib release was evaluated under accelerated conditions.

[0687] Therefore, the implants were placed in an ethanol and water mixture (25:75 ratio, v / v) with gentle stirring in an air chamber at 37°C to increase the solubility of axitinib. The solubility of axitinib in pure ethanol is 1.4 mg / mL and in a 25% ethanol / 75% water mixture (v / v; physiologically irrelevant medium) is approximately 19 μg / mL. At predetermined sampling time points, aliquots were removed and analyzed for axitinib by acquiring UV at 332 nm. The amount of axitinib released at each time point was determined relative to a standard curve prepared from an axitinib reference. The accelerated in vitro release profile was determined as the cumulative release percentage of axitinib. The duration of release under accelerated conditions was approximately two weeks.

[0688] For exemplary release profiles under accelerated conditions, refer to Fig. 14B (200 μg implant) and Figure 4B (556 μg implant).

[0689] Example 3: Evaluation of axitinib implants in rabbits

[0690] To evaluate the safety, tolerability, drug release, and efficacy of axitinib implants, several preclinical studies were conducted in Dutch belted rabbits. A range of doses delivered by one or more implants were examined. An overview of the different rabbit studies conducted is presented in Table 5. Further studies were conducted in beagle dogs and African green monkeys.

[0691] Table 5 Overview of preclinical studies conducted with axitinib implants in rabbits.

[0692]

[0693]

[0694] Table 6 provides an exemplary overview of the formulations, configurations and sizes of the implants used in the animal studies (see Examples 3.2 to 6). The dimensions of the hydrated implants were checked after 24 hours in a biologically relevant medium (PBS, pH 7.2, 37° C.). Although the length of implant No. 5 increased slightly, the hydrated length was still less than 10 mm.

[0695] Table 6 Formulations, configurations and sizes of different implants (No. 1 to No. 5) used in animal studies. For example, implant No. 4 was used in African green monkey studies (see Example 5). Formulation percentages represent weight / weight (w / w).

[0696]

[0697]

[0698] Prior to implant administration, animals were anesthetized with an intramuscular injection of ketamine hydrochloride (20 mg / kg) and xylazine (5 mg / kg). The eyes and surrounding area were cleaned with a 5% Betadine solution and rinsed with a balanced salt solution. One to two drops of topical proparacaine hydrochloride anesthetic (0.5%) were applied. The eyes were covered and a sterile wire speculum was placed to retract the eyelids. The injection needle was placed approximately 3 to 5 mm from the limbus and deployed in a single stroke.

[0699] In summary, axitinib implants showed a good safety profile, were well tolerated and highly effective, regardless of dose or mode of delivery (via one or more implants). In addition, the drug was efficiently released in target tissues, while systemic concentrations in the blood remained extremely low or undetectable.

[0700] Example 3.1: Primary Low-Dose Screening of Axitinib Implants

[0701] For the primary safety, tolerability, and efficacy study of implants containing axitinib, a low dose of 15 μg axitinib / implant was administered via intravitreal injection in rabbits (including control animals receiving normal saline) using a 30G 0.5" needle as one (Group 1, n=5), two (Group 2, n=5), or three implants (Group 3, n=5) per eye bilaterally. The implants used in this study were 0.15±0.13 mm in diameter and 6.9±0.1 mm in length in the dry state. After hydration for 24 hours in a biorelevant medium (PBS, pH 7.2, 37°C), the diameter was 0.42±0.02 mm and the length was 10.6±0.4 mm.

[0702] General health, body weight, and intraocular pressure (IOP) were recorded over a period of 1 month. Clinical ophthalmologic examinations were scored at baseline and 1 month according to a modified McDonald-Shadduck scoring system (McDonald, TO and Shadduck, JA "Eye irritation". Advances in Mondern Toxicology, IV: Dermatotoxicology and Pharmacology, 1977). Infrared reflectance (IR) imaging was collected at 1 month to obtain representative images of one, two, and three implants in the vitreous. The ocular distribution of axitinib was examined using LC-MS / MS, essentially as described under Example 3.5. To evaluate the efficacy of the implant, rabbits with and without implants were challenged by repeated intravitreal injections of VEGF to induce retinal vascular leakage, essentially as described under Example 3.2.

[0703] No significant effects on body weight were observed in all groups. In addition, IOP values ​​were normal and comparable between all groups. Ocular health was not affected or only slightly affected, indicating overall safety and tolerability. Clinical ophthalmological examination at one month showed no ocular findings in any animal administered a single implant. Mild corneal opacity was observed in one eye of animals administered two or three implants. Mild and moderate conjunctival discharge was observed in both eyes of animals administered three implants.

[0704] IR imaging showed that regardless of the number of administrations, the overall shape of the implant remained intact ( Figure 5A ).

[0705] The pharmacokinetic results of axitinib concentrations in ocular tissues at 1 month for each group are presented in Table 7. Since one eye in the retinal tissue sample in Group 2 and one eye in the choroid / RPE (retinal pigment epithelium) sample in Group 3 may have included a portion of the implant, erroneously producing high concentrations in those two tissue samples due to preferential dissolution in the extraction organic solvent system employed prior to LC-MS / MS analysis, two eyes were excluded from analysis (see Example 3.5). The solubility of axitinib in pH 7.2 PBS at 37°C was determined to be approximately 0.5 μg / mL, and any tissue value significantly above this value may indicate tissue accumulation or sample contamination. Axitinib concentrations were low or absent in AH compared to other ocular tissues, indicating minimal migration of axitinib from the posterior chamber to the anterior chamber. The ocular distribution results showed that a single implant dose (Group 1) appeared to be almost completely depleted at 1 month, with only 0.3 μg remaining in VH. 25.5 μg was released from a 30 μg priming dose (two implants, Group 2) in the first month, with a daily release rate of approximately 0.8 μg / day. 33.8 μg was released from a 45 μg priming dose (three implants, Group 3) in the first month, with a daily release rate of approximately 1.1 μg / day. The median axitinib levels in the retina were 31 ng / g for Group 1, 65 ng / g for Group 2, and 148 ng / g for Group 3, showing a dose-dependent release into the retinal tissue. Saturation was not achieved in this study.

[0706] Table 7 Ocular tissue distribution of axitinib released from 1, 2 and 3 implants with 15 μg / implant axitinib dose (Group 1, Group 2 and Group 3, respectively). After 1 month, the axitinib concentrations in AH, retina and choroid / RPE and the remaining axitinib in the implant (recovered from VH) are presented as average values ​​(means), including standard deviations of the means, coefficients of variation (CVs) and confidence intervals (CIs). In addition, the minimum, median and maximum values ​​for each data point are presented.

[0707]

[0708] Of note, all three doses showed inhibition of vascular leakage after VEGF challenge at one month compared to control animals without implants (n=3), indicating that even the lowest dose (15 μg) exhibited good efficacy even after a short period of 1 month ( Figure 5B ).

[0709] In conclusion, the safety, tolerability, and axitinib release and efficacy of TKI implants administered as one, two, or three implants per eye were successfully demonstrated in a primary low-dose study.

[0710] Example 3.2: Tolerability, safety and efficacy study using an axitinib implant

[0711] To investigate the tolerability, safety and efficacy of one implant per eye with a higher axitinib dose, rabbits were bilaterally administered one implant per eye with a dose of 227 μg axitinib via intravitreal injection with a 25G ultra-thin wall needle. For implant dimensions, refer to Table 6 (implant type No. 3).

[0712] Tolerability and safety

[0713] For tolerability and safety studies, the general health status (daily), body weight (0, 1, 3, 6 months), IOP and ophthalmological examinations (each 0.5 month interval) of 9 animals were monitored over 6 months. Clinical ophthalmological examinations were scored according to the modified McDonald-Shadduck scoring system. Electroretinography (ERG) and fluorescein angiography (FA) were performed at 1, 3 and 6 months to assess retinal function and evaluate the ocular vascular system. Optical coherence tomography (OCT) was performed monthly to obtain cross-sectional images of the retina. IR imaging was performed monthly to monitor the biodegradation of the implant over the time and the persistence of axitinib in the vitreous.

[0714] After sacrifice (3 animals at 1, 3 and 6 months), the whole eyes were prepared for histopathological analysis. Therefore, a suture was placed at the 12 o'clock position for orientation and collection. Typically, the eyes were trimmed in half along the midline through the lens and optic nerve in the 12 o'clock to 6 o'clock plane. This allows as many optical structures as possible to be captured in one plane. The trimmed eyes were fully examined and abnormalities were noted. Hematoxylin and eosin (H&E) stained slides were prepared, 1 mm apart. Each slide contained 2 serial sections. Histopathological assessments at each time point included vitreous, retina, sclera or episcleral inflammation, retinal destruction and fibrosis around the injection area. Any abnormality was scored on a semiquantitative scale of 0-5, with 0 indicating no change (normal), 1 indicating occasional focal change (minimal), 2 indicating mild diffuse change or more prominent focal change, 3 indicating moderate diffuse change, 4 indicating marked diffuse change, and 5 indicating severe diffuse change.

[0715] No significant effects on daily health or weight were observed. IOP was normal throughout the study duration. No significant effects from the implant were found based on electroretinography (ERG) measurements. Fluorescein angiography (FA) and OCT imaging showed no pathology during the study. For example, normal retinal morphology was maintained for more than 6 months ( Figure 6 ). In addition, ophthalmologic findings were normal or mild. IR imaging at weeks 4 and 8 showed intact implants, while images at week 12 showed early stages of hydrogel degradation ( Fig. 7A ). Images at week 16 showed that the implant had narrowed due to loss of hydrogel structure. Finally, images at weeks 20 and 26 showed that the hydrogel was absent, while undissolved axitinib particles remained near the previous implant site and formed a single integral structure. However, any undissolved axitinib remaining at the implant site continued to release axitinib to an extent sufficient to inhibit vascular leakage (as shown, for example, in VEGF challenge studies up to 21 months, see Example 3.4). In addition, no inflammation was observed in the area of ​​undissolved axitinib particles ( Figure 7B ).

[0716] The amount of axitinib in the histopathology sections decreased over time indicating bioresorption of the injected material. No macroscopic lesions were observed in the sections during the study duration. The mean histopathology results with standard deviations are presented in Table 8. The mean inflammation scores showed that the retinal, scleral or extrascleral, vitreous cavity, and chronic subcorneal (lymphocytes and phagocytes at the corneal edge) inflammation scores were normal to minimal during the study duration. The mean fibrosis scores around the injected test article were normal to minimal during the study duration. The mean retinal destruction scores were minimal during the study duration. The mean retinal cavitation scores were minimal during the study duration. Retinal detachment was not observed clinically but was noted in 1 / 68, 5 / 71, and 1 / 72 histological sections at 1, 3, and 6 months, respectively. The location of the detachment was generally associated with the site of retinal rupture and was consistent with the location of the needle puncture site, indicating that it may be related to the procedure.

[0717] Table 8 Results of histopathological analysis of rabbits with one implant (227 μg axitinib per implant). Results were scored on a scale of 0-5, where 0 represents no change (normal), 1 represents occasional focal changes (minimal), 2 represents mild diffuse changes or more obvious focal changes, 3 represents moderate diffuse changes, 4 represents obvious diffuse changes, and 5 represents severe diffuse changes. Results are presented as mean and standard deviation (SD).

[0718]

[0719]

[0720] Effectiveness

[0721] For efficacy studies, 12 animals (with and without implants) received an intravenous VEGF challenge (1 μg) 48 hours prior to selected time points (1, 2, 3, and 6 months after implant injection; 3 animals were euthanized at each time point) to induce vascular proliferation and leakage. Rabbits were followed up for 6 months from the time of implant administration. After intravenous injection of fluorescein, eyes were imaged using fluorescein angiography (FA) 48 hours after VEGF challenge and graded on a scale of 0 to 4 (Table 9). The left and right sides of each eye were scored to account for the heterogeneity of the inflammatory response. The FA scores for each eye were then averaged.

[0722] Table 9 Description of the scoring method by fluorescein angiography (FA) imaging.

[0723]

[0724] When compared to control animals that received saline instead of implants over a 6-month period, animals with implants had a significant reduction in vascular leakage ( Figure 8 ). The blank control eyes showed high distortion and leakage at all time points.

[0725] Overall, the data showed good tolerability and safety of a higher dose implant, as well as a favorable biodegradation rate and the implant's potential to inhibit neovascularization in vivo.

[0726] Example 3.3: Tolerability and safety study using two axitinib implants

[0727] In the next step, the tolerability and safety of two implants with a higher axitinib dose (128 μg / implant, total dose 256 μg / eye) were investigated. Therefore, rabbits (n=9) received two implants (implant type No. 1 in Table 6) bilaterally via intravitreal injection with a 27G ultra-thin wall needle, with a total axitinib dose of 256 μg (128 μg / implant).

[0728] During the 6.5-month study period, the health status, IOP and body weight of the rabbits were monitored daily. According to the modified McDonald-Shadduck scoring system, clinical ophthalmological examinations (daily) were scored. Optical coherence tomography (OCT) was performed to obtain cross-sectional images of the retina (monthly). Infrared (IR) imaging was performed to monitor the persistence and degradation of the implant and axitinib in the vitreous (monthly). At 1, 3 and 6.5 months, electroretinography (ERG) was performed to assess retinal function, and fluorescein angiography (FA) was performed to assess the ocular vascular system. At 1, 3 and 6.5 months, 3 rabbits were each killed. After killing, the whole eye was prepared for histopathological analysis (see Example 3.2).

[0729] No abnormal general health observations were observed. All rabbits gained or maintained body weight for the duration of the study. Ocular health findings were limited to occasional, generally mild and transient irritation, swelling and / or discharge. Clinical ophthalmologic examinations revealed no ocular abnormalities during the study, except for mild conjunctival discharge in half of the animals on Day 14 (probably procedure related, resolved by Day 27), a single case of mild retinal hemorrhag...

Claims

1. A sustained release biodegradable ocular implant comprising a hydrogel and axitinib particles dispersed in the hydrogel, wherein the hydrogel comprises a network of cross-linked polymer units, wherein the implant contains an amount of axitinib ranging from 200 μg to 800 μg, and wherein the implant contains 25% to 75% by weight of axitinib and 20% to 60% by weight of polymer units in a dry state, wherein the hydrogel comprises cross-linked PEG units, the PEG units are 4-arm and / or 8-arm PEG units, and the number average molecular weight of the 4-arm and / or 8-arm PEG units is 10,000 to 60,000 Daltons, and wherein the implant is injectable in dry form, and wherein the diameter of the implant in its dry state is such that it can be loaded into a needle of 25 gauge or smaller diameter.

2. The sustained release biodegradable ocular implant of claim 1, wherein the implant contains axitinib in an amount ranging from 320 μg to 500 μg.

3. The sustained release biodegradable ocular implant of claim 1, wherein the implant is loaded into a needle of 25 gauge or smaller diameter in its dry state.

4. The sustained-release biodegradable ocular implant of claim 1 or 3, wherein the needle is a 25-gauge or 27-gauge needle.

5. The sustained release biodegradable ocular implant of claim 1, wherein the crosslinks between the PEG units comprise a group represented by the formula Here, m is an integer from 0 to 10.

6. The sustained-release biodegradable ocular implant of claim 5, wherein m is 6.

7. The sustained release biodegradable ocular implant according to claim 1, wherein the cross-linked PEG units are 4a20kPEG units and 8a20kPEG units.

8. The sustained release biodegradable ocular implant according to claim 1, wherein the polymer network is obtained by reacting 4a20kPEG-SAZ and 8a20kPEG-NH2 at a weight ratio of 2:1 or less.

9. The sustained release biodegradable ocular implant of claim 1, wherein the implant contains 35% to 65% by weight of axitinib and 25% to 50% by weight of polymer units in a dry state.

10. The sustained release biodegradable ocular implant of claim 1, wherein the implant has a cylindrical or substantially cylindrical shape.

11. The sustained release biodegradable ocular implant of claim 1, wherein the implant is an intravitreal implant.

12. The sustained release biodegradable ocular implant of claim 11, wherein the implant biodegrades in the vitreous humor within about 4 to about 13 months after administration.

13. The sustained-release biodegradable ocular implant according to claim 11, wherein: The implant releases a therapeutically effective amount of axitinib over a period of at least 3 months after administration to the vitreous humor.

14. The sustained-release biodegradable ocular implant according to any one of claims 11 to 13, wherein The implant releases a therapeutically effective amount of axitinib over a period of at least 6 months following administration to the vitreous humor.

15. Use of the sustained release biodegradable ocular implant according to any one of claims 1 to 14 in the preparation of a medicament for treating neovascular age-related macular degeneration in a patient in need thereof, the treatment comprising administering the sustained release biodegradable ocular implant to the patient, wherein the dose of axitinib administered once per eye during the treatment period is 200 μg to 800 μg and is contained in one implant, and wherein the implant is administered by injection into the vitreous humor.

16. Use of the sustained release biodegradable ocular implant of claim 15, wherein the patient is a human patient.

17. Use of a sustained release biodegradable ocular implant according to claim 15, wherein the implant is administered through a needle of 25 gauge or less.

18. The use of the sustained-release biodegradable ocular implant according to claim 17, wherein the needle is a 25-gauge or 27-gauge needle.

19. A method for producing a sustained-release biodegradable ocular implant according to any one of claims 1 to 14, the method comprising the following steps: forming a hydrogel comprising a polymer network and axitinib particles dispersed in the hydrogel, shaping the hydrogel, and drying the hydrogel.

20. A kit comprising one or more sustained-release biodegradable ocular implants manufactured according to any one of claims 1 to 14 or according to the method of claim 19 and one or more needles, wherein each of the one or more needles is pre-loaded with a sustained-release biodegradable ocular implant in a dry state, wherein the needle is a needle of 25 gauge or less in diameter.

21. The kit of claim 20, further comprising an injection device for injecting the implant into an eye of a patient.

22. A kit according to claim 20 or 21, wherein the injection device is pre-connected to a needle loaded with an implant.

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