Ophthalmic implants containing axitinib polymorphic IV

Abstract

The present invention relates to a sustained-release biodegradable ophthalmic implant containing axitinib dispersed in a hydrogel for the long-term treatment of retinal diseases.

Description

[Technical Field]

[0001] This application incorporates, for all purposes, U.S. Provisional Application No. 63 / 458,558 filed on 11 April 2023, U.S. Provisional Application No. 63 / 546,064 filed on 27 October 2023, and U.S. Provisional Application No. 63 / 609,334 filed on 12 December 2023, by reference.

[0002] The present invention relates to a sustained-release biodegradable ophthalmic implant containing a tyrosine kinase inhibitor (TKI), such as axitinib, for the treatment of ophthalmic diseases, including neovascular (exudative) age-related macular degeneration (AMD). According to the present invention, the ophthalmic disease is treated by injecting an implant containing a TKI into the eye, the implant releasing the TKI over a long period of time. [Background technology]

[0003] 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 was one of the most common retinal diseases in the United States in 2019, affecting approximately 16.9 million people, and this is projected to increase to 18.8 million by 2024 (Market Scope. Ophthalmic Comprehensive Reports. 2019 Retinal Pharmaceuticals Market Report: A Global Analysis for 2018 to 2019, September 2019). AMD can be subdivided into various stages. Early AMD is characterized by the presence of a few (<20) medium-sized drusen or retinal pigment abnormalities. Mid-stage AMD is characterized by at least one large drusen, numerous medium-sized drusen, or geographic atrophy that does not extend to the center of the macula. Progressive or late-stage AMD can be non-neovascular (dry, atrophic, or non-exudative) or neovascular (wet or exudative). Progressive non-neovascular AMD is characterized by drusen and geographic atrophy extending to the center of the macula. Progressive 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).

[0004] A more advanced form of exudative AMD is characterized by increased vascular endothelial growth factor (VEGF), which promotes the growth of new blood vessels (angiogenesis). These vessels proliferate directly beneath the retina, leaking blood and fluid into the macula and subretinal space. Interference with this pathway has been successfully achieved through the development of vascular endothelial growth factor subtype inhibitors, i.e., VEGF inhibitors, which were originally used to treat various cancers. Anti-VEGF and steroid administration combined with photodynamic therapy remains a second-line treatment for patients who do not respond to monotherapy with anti-VEGF drugs (Al-Zamil et al., Recent developments in age-related macular degeneration: a review. Clin Interv Aging. 2017;12:1313-30).

[0005] Other common retinal diseases include diabetic eye diseases, such as diabetic retinopathy (DR). DR was one of the most common retinal diseases in the United States in 2019, affecting approximately 8 million people, and this is projected to increase to 8.8 million by 2024 (Market Scope 2019, see above). This condition is characterized by vascular leakage, occlusion, or neovascularization, which can progress to visual impairment and ultimately blindness. The disease can be classified into non-proliferative diabetic retinopathy (NPDR) and proliferative diabetic retinopathy (PDR). As the severity of NPDR progresses, the risk of developing a more severe proliferative phase leading to vision loss increases. Diabetic macular edema (DME) can develop at any stage of DR and is characterized by decreased retinal tension and increased vascular pressure caused by upregulation of VEGF, retinal vascular automodulation (Browning et al., Diabetic macular edema: evidence-based management. 2018 Indian Journal of Ophthalmology, 66(1), p.1736), and inflammatory cytokines and chemokines (Miller et al., Diabetic macular edema: current understanding, pharmacologic treatment options, and developing therapies. 2018 Asia-Pacific Journal of Ophthalmology, 7(1):28-35). Changes resulting from these inflammatory and vasogenic mediators lead to disruption of the blood-retinal barrier (BRB) in the vascular endothelium (Miller et al., see above). When hard exudates enter the extracellular space, the central visual field becomes blurred and distorted, leading to 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 experience an 8% decrease in visual acuity three years after the onset of the condition.

[0006] The basis of all available treatments for DR is attempting to control hyperglycemia, metabolic function, and blood pressure (Browning et al., see above). Anti-VEGF therapy has been proven to be less destructive and damaging than other treatment methods, and is currently the first-line treatment in the standard treatment of DME (Schmidt-Erfurth et al., see above). Anti-VEGF therapy and panretinal photocoagulation are commonly used to treat PDR (Brown et al., Evaluation of intravitreal aflibercept for the treatment of severe nonproliferative diabetic retinopathy: results from the PANORAMA randomized clinical trial; JAMA Ophthalmol 2021 Sep 1;139(9):946-955). In recent years, there has been a shift towards treating moderate to severe NDPR with anti-VEGF. Studies have shown that early intervention reduces the progression to PDR (Arabi et al., Update on management of non-proliferative diabetic retinopathy without diabetic macular edema; is there a paradigm shift? J.Ophthalmic Vis.Res.2022;17(1):108-117).

[0007] Another common eye disease is retinal vein occlusion (RVO). RVO affected approximately 1.3 million people in the United States in 2019 and is projected to reach 1.4 million by 2024 (Market Scope 2019, see above). RVO is a chronic condition in which the retinal circulation is obstructed, leading 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 retiniennes retinal vein occlusions. 2017, Journal Francais d'Ophtalmologie, 40(8):696-705). This condition is typically seen in patients aged 55 years or older with a history of hypertension, diabetes, and glaucoma. Because RVO can cause a rapid decline in a patient's vision or remain asymptomatic, there is no planned treatment unit for RVO. The prognosis and associated treatment options for RVO depend on the classification of the disease, as different variants have different risk factors despite behaving similarly. The classification of the disease is based on the location of the retinal circulatory disorder, namely, branch retinal vein occlusion (BRVO), hemiretinal vein occlusion (HRVO), and central retinal vein occlusion (CRVO). BRVO is more common, affecting 0.4% of the world's population, while CRVO affects 0.08% of the world's population. Studies have shown that BRVO is more common in Asian and Hispanic individuals compared to Caucasians (Ip and Hendrick, above).

[0008] Treatment for RVO currently involves maintaining the condition's symptoms to avoid further complications, macular edema, and neovascular glaucoma. Anti-VEGF therapy is currently the standard treatment and may temporarily improve vision. Other treatment options include laser therapy, steroids, and surgery (Pierru et al., see above).

[0009] Anti-VEGF drugs are currently the standard treatment for exudative AMD, DME, DR, and RVO. The first treatment approved by the FDA for exudative AMD in 2004 was MACUGEN® (pegaptanib sodium injection, manufactured by Bausch & Lomb). Subsequently, LUCENTIS® (ranibizumab injection, manufactured by Genentech, Inc.) and EYLEA® (aflibercept intravitreal injection, manufactured by Regeneron Pharmaceuticals, Inc.) were approved for the treatment of exudative AMD in 2006 and 2011, respectively, and similarly for DME and macular edema, following RVO. The recommended dose of EYLEA® is 2 mg (0.05 mL) intravitreally every 4 weeks (1 month) for the first 3 months, followed by 2 mg (0.05 mL) intravitreally every 8 weeks (2 months) thereafter. (EYLEA® Prescription Information, November 2011). Furthermore, in October 2019, BEOVU® (brolucizumab injection manufactured by Novartis Pharmaceuticals Corp.) was approved by the FDA for the treatment of exudative AMD. Other developments are reported in 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.

[0010] Tyrosine kinase inhibitors (TKIs) were developed as chemotherapeutic drugs that inhibit signaling of receptor tyrosine kinases (RTKs), a family of tyrosine protein kinases. RTKs extend across the cell membrane in both intracellular (internal) and extracellular (external) portions. When a ligand binds to the extracellular portion, the receptor tyrosine kinase dimerizes and initiates an intracellular signaling cascade driven by autophosphorylation using the coenzyme messenger adenosine triphosphate (ATP). Many RTK ligands are growth factors such as VEGF. VEGF is associated with a family of proteins of the VEGF receptor (VEGFR) type, i.e., VEGFR1-3 (all of which are RTKs), thereby inducing angiogenesis. VEGF-A, which binds to VEGFR2, is the target of the anti-VEGF drugs mentioned above. In addition to 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 factors.

[0011] Recently, ophthalmic implants containing TKI particles dispersed in a hydrogel have been provided. These implants are administered, for example, by injection into the vitreous fluid of patients with exudative AMD, and the TKI is released from the implant in a controlled manner over a long period, e.g., several months or more, thus ensuring that a therapeutically effective amount of TKI is available over that long period. These implants can reduce, or at least maintain (prevent increase from) the central retinal thickness (CSFT) of patients, and / or reduce or maintain (again, prevent increase from) subretinal or intraretinal fluid. See, for example, WO2021 / 195163.

[0012] Interim results from an ongoing Phase 1 clinical trial (among others) indicate that implants containing the TKI axitinib dispersed in a hydrogel made of a polymer network of cross-linked polyethylene glycol (PEG) units have long-term durability in patients with exudative AMD, and that visual acuity (measured by best corrected visual acuity, BCVA) and CSFT levels in subjects treated with a single such implant were comparable to those of subjects treated with the anti-VEGF drug aflibercept (repeated injections every two months) up to 10 months of the trial. This trial is still ongoing. To date, 80% of subjects have been rescue-free up to 6 months and 73% up to 10 months after a single injection of such implant. This demonstrates a clinically meaningful reduction in treatment burden up to 10 months after treatment with a single implant compared to aflibercept injections every two months. For example, see AAMoshfeghi, “Update on a Hydrogel-Based Intravitreal Axitinib Implant (OTX-TKI) for the Treatment of Neovascular Age-related Macular Degeneration”, February 11, 2023 at the Angiogenesis, Exudation, and Degeneration Meeting (Virtual), or DSDhoot, “Interim Safety and Efficacy Data from a Phase 1 Clinical Trial of Sustained-release Axitinib Hydrogel Implant (OTX-TKI) in Wet AMD Subjects: 7-month Analysis”, September 30, 2022 at the AAO 2022 Retina Subspecialty Day in Chicago, IL. Both presentations are available, in particular, via https: / / ocutx.gcs-web.com / scientific-medical-presentations.

[0013] While known implants containing TKIs have so far demonstrated safety and efficacy in clinical trials in patients with exudative AMD, there is still a desire to provide further implants with different release profiles than those of known implants. For example, it is desirable to provide implants in which the release rate of the TKI, such as axitinib, increases particularly in the early stages of TKI release after injection, for example, by increasing the amount of TKI released over a certain period or by providing implants with a rapid release rate. Furthermore, on the one hand, it is desirable to provide implants in which the maximum portion of the TKI content in an ophthalmic implant containing a TKI for the treatment of eye diseases such as exudative AMD is released before the biodegradation of the hydrogel of the implant, resulting in a relatively small amount of residual TKI being released at the end of biodegradation. However, on the other hand, it is also desirable that the release of TKI from the implant is not too rapid in order to avoid or substantially avoid the need to remove an implant from the eye first when the residual drug is depleted, before it is possible to inject a new implant. In other words, it is desirable that sufficient TKIs remain in the implant so that they are ultimately released during the biodegradation of the implant, thereby providing continuous therapy through repeated administration of the implant, in order to maintain the therapeutic effect until the remaining portion of the implant is completely removed from the eye and a new implant can be placed.

[0014] Therefore, there is a need for an ophthalmic implant that includes a TKI for the treatment of ophthalmic diseases such as AMD, DME, DR, and RVO, is effective over a long period, for example, several months, and provides accelerated release of the TKI, particularly in the initial stages of release, and is suitable for repeated administration, compared to already disclosed ophthalmic implants. The present invention addresses this need.

[0015] Object of the invention An object of a particular embodiment of the present invention is to provide a novel ophthalmic implant containing a TKI, e.g., axitinib, that provides sustained release of the TKI, e.g., axitinib, over a long period of time, e.g., at least 3 months, or at least 6 months, e.g., over a period of about 6 to about 12 months.

[0016] An object of a particular embodiment of the present invention is to provide an ophthalmic implant containing a TKI, e.g., axitinib, which provides sustained release of the TKI, e.g., axitinib, at a dose of approximately 1 μg / day or more for at least 3 months in vivo (intravitreal).

[0017] An object of certain embodiments of the present invention is to provide an ophthalmic implant that results in accelerated in vitro or in vivo release of a TKI, e.g., axitinib, from a TKI-containing implant, compared to known implants, thereby providing sustained release of the TKI, e.g., axitinib.

[0018] An object of certain embodiments of the present invention is to provide an ophthalmic implant that results in sustained release of a TKI, e.g., axitinib, such that the in vitro or in vivo release of the TKI from the implant is faster than the release from a comparative known implant containing the same dose of a TKI, e.g., axitinib.

[0019] An object of certain embodiments of the present invention is to provide an ophthalmic implant that provides a sustained release of a TKI, e.g., axitinib, such as an ophthalmic implant containing a TKI, where the in vitro release rate of the TKI from the implant, e.g., axitinib, is higher than the rate from a comparative known implant containing the same dose of the TKI, for more than one day per day, or the average release rate per day over a particular period of time.

[0020] An object of certain embodiments of the present invention is to provide an ophthalmic implant containing a TKI, such as axitinib, which results in a sustained release of the TKI, faster than comparative known implants containing the same dose of the TKI, in achieving therapeutic efficacy levels of the TKI in the retina, choroid, and / or retinal pigment epithelium (RPE).

[0021] An object of certain embodiments of the present invention is to provide an ophthalmic implant comprising a TKI, such as axitinib, that provides sustained release of the TKI, wherein the in vitro release rate per day for one or more days, and / or the average release rate per day over a specific period, and / or the amount of the TKI released per day, and / or the cumulative amount of the TKI released over a specific period, and / or the percentage of the TKI (based on the total amount of TKI contained in the implant, or based on the total amount of TKI released in an in vitro study) is higher than that of a comparative known implant comprising the same dose of the TKI.

[0022] An object of certain embodiments of the present invention is to provide an ophthalmic implant that satisfies one or more of the above objects for use in the treatment of eye diseases including (exudative) AMD, DR, DME, and RVO.

[0023] An object of a particular embodiment of the present invention is to provide an implant for use in the treatment of ophthalmic diseases including (exudative) AMD, DR, DME, and RVO, wherein the duration of use of a single ophthalmic implant satisfying one or more of the above objects is at least 3 months, for example, at least 6 months, at least 9 months, at least 10 months, or at least 12 months, for example, about 6 to about 9 months, or about 6 to about 12 months.

[0024] An object of certain embodiments of the present invention is to provide an ophthalmic implant that satisfies one or more of the above objects for use in the treatment of ocular diseases including (exudative) AMD, DR, DME, and RVO, wherein TKI levels in ocular tissue, e.g., retina, choroid, or retinal pigment epithelium, and vitreous fluid are maintained at a therapeutically effective level, in particular, a level sufficient for inhibiting or slowing neovascularization, for a period of at least 3 months, e.g., at least 6 months, at least 9 months, at least 10 months, or at least 12 months, e.g., about 6 to about 9 months, or about 6 to about 12 months.

[0025] A further object of certain embodiments of the present invention is to provide a method for increasing the release rate of a TKI, such as axitinib, from an ophthalmic implant.

[0026] A further object of certain embodiments of the present invention is to provide axitinib in forms for use in ophthalmic implants, having a solubility higher than 0.3 μg / mL as measured after incubation for 5 days at 37°C at pH 7.2-7.4 in phosphate-buffered saline (PBS), and ophthalmic implants containing such forms of axitinib.

[0027] A further objective of a particular embodiment of the present invention is to measure at least 25 mm after incubation for 24 hours at 37°C in phosphate-buffered saline (PBS) at pH 7.2-7.4. 2 The objective is to provide an ophthalmic implant that has an increased hydrated surface area.

[0028] A further object of certain embodiments of the present invention is to provide a method for manufacturing an ophthalmic implant that satisfies one or more of the above-mentioned objectives.

[0029] A further object of certain embodiments of the present invention is to provide a method for treating an eye disease, the method comprising administering an ophthalmic implant that satisfies one or more of the above-mentioned objectives.

[0030] A further object of certain embodiments of the present invention is to provide a method for treating (exudative) AMD, DR, DME, or RVO, the method comprising administering an ophthalmic implant that satisfies one or more of the above-mentioned objectives.

[0031] A further object of certain embodiments of the present invention is to provide a method for treating (exudative) AMD, DR, DME, and RVO, the method comprising administering an ophthalmic implant to a patient that satisfies one or more of the above objects, wherein the treatment period with a single implant is at least 3 months, e.g., at least 6 months, at least 9 months, at least 10 months, or at least 12 months, e.g., about 6 to about 9 months, or about 6 to about 12 months, and during the treatment period, administration of rescue medication is rarely required, e.g., only once, twice, or three times.

[0032] A further object of certain embodiments of the present invention is to provide a method for treating eye diseases, such as (exudative) AMD, DR, DME, or RVO, particularly (exudative) AMD, and an ophthalmic implant for use in such a method, the method providing continuous treatment by repeated administration of the ophthalmic implant.

[0033] A further object of certain embodiments of the present invention is to provide a method for treating eye diseases, such as (exudative) AMD, DR, DME, or RVO, particularly (exudative) AMD, and an ophthalmic implant for use in such a method, wherein the ophthalmic implant comprising a TKI, such as axitinib, allows for repeated administration of the implant, for example, every 6 to 12 months, every 8 to 11 months, or every 6 months or every 9 months.

[0034] A further object of certain embodiments of the present invention is to provide a method for treating ocular diseases, such as (exudative) AMD, DR, DME, or RVO, particularly (exudative) AMD, and an ophthalmic implant for use in such a method, in which the ophthalmic implant comprising a TKI, such as axitinib, allows for repeated administration of the implant, for example, every 6 to 12 months, for example, every 8 to 11 months, or every 6 months, so as to achieve a continuous therapeutic effect without the need to re-administer the implant when there is still a remaining drug-depleted implant.

[0035] A further object of certain embodiments of the present invention is to provide a method for treating eye diseases, e.g., (exudative) AMD, DR, DME, or RVO, particularly (exudative) AMD, and an ophthalmic implant for use in such a method, comprising a TKI, e.g., axitinib dispersed in a hydrogel, wherein the implant provides a rate of intravitreal release of the TKI, e.g., axitinib (and consequently, delivery of the TKI, e.g., axitinib to ocular tissue, e.g., retina or choroid) such that the cumulative amount of the TKI, e.g., axitinib released before the degradation of the hydrogel (i.e., while the implant / hydrogel is still intact) is greater than the amount of the TKI, e.g., axitinib released upon degradation of the hydrogel.

[0036] A further object of certain specific embodiments of the present invention is to provide a method for treating eye diseases, such as (exudative) AMD, DR, DME, or RVO, particularly (exudative) AMD, and an ophthalmic implant for use in such a method, the ophthalmic implant comprising a TKI, such as axitinib, dispersed in a hydrogel, the implant having a C1c of the TKI, such as axitinib, in ophthalmic tissue, such as the retina or choroid. max However, this results in a rate of release of the TKI, e.g., axitinib, into the vitreous humor (and consequently, delivery of the TKI, e.g., axitinib, to the tissue) that occurs before the biodegradation of the implant.

[0037] A further object of certain particular embodiments of the present invention is to provide a method for treating eye diseases, such as (exudative) AMD, DR, DME, or RVO, particularly (exudative) AMD, and an ophthalmic implant for use in such a method, the ophthalmic implant comprising a TKI, such as axitinib, dispersed in a hydrogel, the implant providing ophthalmic tissue, such as the retina or choroid, to which the TKI, such as axitinib, is t max However, this occurs before the biodegradation of the implant, and / or TKIs, such as axitinib. max However, this results in a shorter rate of release of the TKI, e.g., axitinib, into the vitreous fluid (and consequently, delivery of the TKI, e.g., axitinib, to the tissue) than that achieved by known implants.

[0038] A further object of certain embodiments of the present invention is to provide a method for treating (exudative) AMD, DR, DME, or RVO, the method comprising administering an ophthalmic implant satisfying one or more of the above-mentioned objectives to a patient with a history of anti-VEGF treatment or a patient naive to anti-VEGF treatment.

[0039] A further object of certain embodiments of the present invention is to provide a method for treating an ophthalmic disease including (exudative) AMD, DR, DME, or RVO, the method comprising administering an ophthalmic implant that satisfies one or more of the above objects in combination with an anti-VEGF agent.

[0040] A further object of certain embodiments of the present invention is to provide a kit comprising one or more ophthalmic implants that satisfy one or more of the above-mentioned objectives, and optionally comprising means for injecting the ophthalmic implants.

[0041] One or more of these objectives of the present invention, as well as others, are addressed by one or more embodiments disclosed and claimed herein. [Overview of the Initiative]

[0042] In one general embodiment, the present invention relates to a sustained-release biodegradable ophthalmic implant comprising a hydrogel and a tyrosine kinase inhibitor (TKI), wherein the particles of the tyrosine kinase inhibitor are dispersed within the hydrogel, and the solubility of the tyrosine kinase inhibitor is greater than 0.3 μg / mL, measured after incubation for 5 days at 37°C in phosphate-buffered saline (PBS) at pH 7.2-7.4.

[0043] For example, in a particular embodiment, the present invention relates to a sustained-release biodegradable ophthalmic implant comprising a hydrogel and approximately 400 μg to approximately 500 μg of axitinib polymorph IV, in which case the axitinib particles are dispersed within the hydrogel.

[0044] In another general embodiment, the present invention relates to a sustained-release biodegradable ophthalmic implant comprising a hydrogel and a tyrosine kinase inhibitor, wherein particles of the tyrosine kinase inhibitor are dispersed within the hydrogel, and the hydrated surface area of ​​the implant is measured to be at least 25 mm² after incubation for 24 hours at 37°C in phosphate-buffered saline (PBS) at pH 7.2-7.4. 2 It is characterized by being such.

[0045] In a more general embodiment, the present invention relates to a sustained-release biodegradable ophthalmic implant comprising a hydrogel and a tyrosine kinase inhibitor, wherein particles of the tyrosine kinase inhibitor are dispersed within the hydrogel, and the cumulative amount of tyrosine kinase inhibitor released from the implant over a period defined by any initial number of days until 80% of the tyrosine kinase inhibitor contained in the implant is released is greater than the cumulative amount of tyrosine kinase inhibitor released from a comparative implant over the same period, and the comparative implant differs from the sustained-release biodegradable ophthalmic implant only in that the solubility of the tyrosine kinase inhibitor in the comparative implant is lower, as measured after 5 days of incubation at 37°C in PBS at pH 7.2-7.4, while the release of tyrosine kinase inhibitor from both implants is measured under identical conditions.

[0046] In a more general embodiment, the present invention relates to a sustained-release biodegradable ophthalmic implant comprising a hydrogel and a tyrosine kinase inhibitor, wherein particles of the tyrosine kinase inhibitor are dispersed within the hydrogel, and the average daily release rate of the tyrosine kinase inhibitor from the implant over a period defined by any initial number of days until 80% of the tyrosine kinase inhibitor contained in the implant is released is higher than the average daily release rate of the tyrosine kinase inhibitor from a comparative implant over the same period, and the comparative implant differs from the sustained-release biodegradable ophthalmic implant only in that the solubility of the tyrosine kinase inhibitor in the comparative implant is lower, as measured after 5 days of incubation at 37°C in PBS at pH 7.2-7.4, while the release of the tyrosine kinase inhibitor from both implants is measured under identical conditions.

[0047] In a further embodiment, the present invention relates to a sustained-release biodegradable ophthalmic implant comprising a hydrogel and axitinib, wherein axitinib particles are dispersed within the hydrogel, the implant comprises axitinib polymorph IV, the implant contains an amount of axitinib equivalent to about 250 to about 700 μg of axitinib free base, for example, an amount equivalent to about 400 to about 500 μg of axitinib free base, and the hydrogel comprises cross-linked PEG units.

[0048] In a further embodiment, the present invention relates to a sustained-release biodegradable ophthalmic implant comprising a hydrogel and axitinib, wherein axitinib particles are dispersed within the hydrogel, the implant contains about 360 μg to about 562.5 μg, or about 405 μg to about 495 μg, of axitinib polymorph IV, for example, about 450 μg, the hydrogel comprises crosslinked multi-arm PEG units having a number average molecular weight of about 20,000 daltons, and the crosslinks between the PEG units comprise groups represented by the following formula [ka] In the formula, m is 6, The implant is cylindrical and, in its dry state, has a length of 10 mm or less, for example, 6 to 9 mm, and a diameter of 0.25 to 0.45 mm, and / or, in its hydrated state (in PBS, pH 7.2 to 7.4 at 37°C for 24 hours), has a length of 12 mm or less, for example, 8 to 9 mm, and a diameter of 0.5 to 0.9 mm, and the axitinib particles have a d90 particle diameter of less than 8 μm and a d50 particle diameter of less than 3 μm.

[0049] In a further embodiment, the present invention relates to a sustained-release biodegradable ophthalmic implant comprising a hydrogel and axitinib, wherein axitinib particles are dispersed within the hydrogel, the implant contains about 480 μg to about 750 μg, or about 540 μg to about 660 μg, for example, about 600 μg of axitinib polymorph IV, the hydrogel comprises crosslinked multi-arm PEG units having a number average molecular weight of about 20,000 daltons, and the crosslinks between the PEG units comprise groups represented by the following formula [ka] In the formula, m is 6, The implant is cylindrical and, in its dry state, has a length of 10 mm or less, for example, 6 to 9 mm, and a diameter of 0.25 to 0.45 mm, and / or, in its hydrated state (in PBS, pH 7.2 to 7.4 at 37°C for 24 hours), has a length of 10 mm or less, for example, 8 to 9 mm, and a diameter of 0.5 to 0.9 mm, and the axitinib particles have a d90 particle diameter of less than 8 μm and a d50 particle diameter of less than 3 μm.

[0050] In a further embodiment, the present invention relates to a sustained-release biodegradable ophthalmic implant comprising a hydrogel and axitinib, wherein axitinib particles are dispersed within the hydrogel, the implant comprises axitinib polymorph IV, and the implant contains an amount of axitinib equivalent to about 360 μg to about 562.5 μg, or about 405 μg to about 495 μg, for example, about 450 μg of free base of axitinib, in a 25% / 75% (v / v) ethanol / water mixture at 37°C. In an in vitro study conducted under 2x sink conditions, at least approximately 60 μg of axitinib is released on day 1, and / or at least approximately 100 μg of axitinib is released over the first two days, and / or at least approximately 130 μg of axitinib is released over the first three days, and / or at least approximately 220 μg of axitinib is released over the first seven days, and / or at least approximately 275 μg of axitinib is released over the first ten days.

[0051] In a further embodiment, the present invention relates to a sustained-release biodegradable ophthalmic implant comprising a hydrogel and axitinib, wherein axitinib particles are dispersed within the hydrogel, the implant comprises axitinib polymorph IV, and the implant contains an amount of axitinib equivalent to about 360 μg to about 562.5 μg, or about 405 μg to about 495 μg, for example, about 450 μg of free base of axitinib, and is stored at 37°C in a 25% / 75% (v / v) ethanol / water mixture. In an in vitro study conducted under 3x sink conditions, at least approximately 35 μg of axitinib is released on day 1, and / or at least approximately 60 μg of axitinib is released over the first two days, and / or at least approximately 100 μg of axitinib is released over the first four days, and / or at least approximately 180 μg of axitinib is released over the first seven days, and / or at least approximately 200 μg of axitinib is released over the first nine days.

[0052] In a further embodiment, the present invention relates to a sustained-release biodegradable ophthalmic implant comprising a hydrogel and axitinib, wherein axitinib particles are dispersed within the hydrogel, the implant comprises axitinib polymorph IV, the implant contains about 480 μg to about 750 μg, or about 540 μg to about 660 μg, for example, an amount of axitinib equivalent to about 600 μg of free base of axitinib, and is dispersed at 37°C in a 25% / 75% (v / v) ethanol / water mixture. In an in vitro study conducted under 2x sink conditions, at least approximately 70 μg of axitinib is released on day 1, and / or at least approximately 130 μg of axitinib is released over the first two days, and / or at least approximately 180 μg of axitinib is released over the first three days, and / or at least approximately 300 μg of axitinib is released over the first seven days, and / or at least approximately 375 μg of axitinib is released over the first ten days.

[0053] In a further embodiment, the present invention relates to a sustained-release biodegradable ophthalmic implant comprising a hydrogel and axitinib, wherein axitinib particles are dispersed within the hydrogel, the implant comprises axitinib polymorph IV, and the implant contains an amount of axitinib equivalent to about 480 μg to about 750 μg, or about 540 μg to about 660 μg, for example, about 600 μg of free base of axitinib, in a 25% / 75% (v / v) ethanol / water mixture at 37°C. In an in vitro study conducted under 3x sink conditions, at least approximately 50 μg of axitinib is released on day 1, and / or at least approximately 100 μg of axitinib is released over the first two days, and / or at least approximately 180 μg of axitinib is released over the first four days, and / or at least approximately 280 μg of axitinib is released over the first seven days, and / or at least approximately 300 μg of axitinib is released over the first nine days.

[0054] In a further embodiment, the present invention relates to a sustained-release biodegradable ophthalmic implant comprising a hydrogel and axitinib, wherein axitinib particles are dispersed within the hydrogel, the implant comprises axitinib polymorph IV, the implant contains about 360 μg to about 562.5 μg, or about 405 μg to about 495 μg of axitinib, for example, an amount equivalent to about 450 μg of free base of axitinib, and in an in vitro test conducted at 37°C in a 25% / 75% (v / v) ethanol / water mixture under 2x sink conditions, the implant releases at least 50% of the total release amount of axitinib over the first 3 days, and / or releases at least 80% of the total release amount of axitinib over the first 7 days, and / or releases at least 92% of the total release amount of axitinib over the first 10 days.

[0055] In a further embodiment, the present invention relates to a sustained-release biodegradable ophthalmic implant comprising a hydrogel and axitinib, wherein axitinib particles are dispersed within the hydrogel, the implant comprises axitinib polymorph IV, the implant contains about 360 μg to about 562.5 μg, or about 405 μg to about 495 μg of axitinib, for example, an amount equivalent to about 450 μg of free base of axitinib, and in an in vitro test conducted at 37°C in a 25% / 75% (v / v) ethanol / water mixture under 2x sink conditions, the implant releases at least 30% of the total release amount of axitinib over the first 3 days, and / or releases at least 60% of the total release amount of axitinib over the first 7 days, and / or releases at least 80% of the total release amount of axitinib over the first 10 days.

[0056] In a further embodiment, the present invention relates to a sustained-release biodegradable ophthalmic implant comprising a hydrogel and axitinib, wherein axitinib particles are dispersed within the hydrogel, the implant comprises axitinib polymorph IV, the implant contains about 360 μg to about 562.5 μg, or about 405 μg to about 495 μg of axitinib, for example, an amount equivalent to about 450 μg of free base of axitinib, and in an in vitro test, releases at least 15% of the total release amount of axitinib over the first two days, and / or releases at least 30% of the total release amount of axitinib over the first four days, and / or releases at least 50% of the total release amount of axitinib over the first seven days, the in vitro test being performed at 37°C in a 25% / 75% (v / v) ethanol / water mixture under 3x sink conditions.

[0057] In a further embodiment, the present invention relates to a sustained-release biodegradable ophthalmic implant comprising a hydrogel and axitinib, wherein axitinib particles are dispersed within the hydrogel, the implant comprises axitinib polymorph IV, the implant contains about 480 μg to about 750 μg, or about 540 μg to about 660 μg, for example, an amount of axitinib equivalent to about 600 μg of free base of axitinib, and in an in vitro test conducted at 37°C in a 25% / 75% (v / v) ethanol / water mixture under 2x sink conditions, the implant releases at least 50% of the total release amount of axitinib over the first 3 days, and / or releases at least 80% of the total release amount of axitinib over the first 7 days, and / or releases at least 92% of the total release amount of axitinib over the first 10 days.

[0058] In a further embodiment, the present invention relates to a sustained-release biodegradable ophthalmic implant comprising a hydrogel and axitinib, wherein axitinib particles are dispersed within the hydrogel, the implant comprises axitinib polymorph IV, the implant contains about 480 μg to about 750 μg, or about 540 μg to about 660 μg of axitinib, for example, an amount equivalent to about 600 μg of free base of axitinib, and in an in vitro test conducted at 37°C in a 25% / 75% (v / v) ethanol / water mixture under 2x sink conditions, the implant releases at least 30% of the total release amount of axitinib over the first 3 days, and / or releases at least 60% of the total release amount of axitinib over the first 7 days, and / or releases at least 80% of the total release amount of axitinib over the first 10 days.

[0059] In a further embodiment, the present invention relates to a sustained-release biodegradable ophthalmic implant comprising a hydrogel and axitinib, wherein axitinib particles are dispersed within the hydrogel, the implant comprises axitinib polymorph IV, the implant contains about 480 μg to about 750 μg, or about 540 μg to about 660 μg of axitinib, for example, an amount equivalent to about 600 μg of free base of axitinib, and in an in vitro test, releases at least 15% or at least 20% of the total release amount of axitinib over the first two days, and / or releases at least 35% of the total release amount of axitinib over the first four days, and / or releases at least 55% of the total release amount of axitinib over the first seven days, the in vitro test being performed at 37°C in a 25% / 75% (v / v) ethanol / water mixture under 3x sink conditions.

[0060] In a further embodiment, the present invention relates to a sustained-release biodegradable ophthalmic implant comprising a hydrogel and approximately 400 μg to approximately 500 μg of axitinib polymorph IV, wherein the axitinib particles are dispersed within the hydrogel, the implant being an intravitreal implant, and having a composition of approximately 30 to approximately 75% axitinib, approximately 20 to approximately 50% PEG units, and approximately 0.5 to approximately 15% sodium phosphate on an anhydrous basis (%w / w), and approximately 5 to approximately 17% axitinib, approximately 4 to approximately 12% PEG units, and approximately 0.2 to approximately 5% sodium phosphate on a wet basis (%w / w), the hydrogel The gel comprises a PEG hydrogel network formed by crosslinking units of 4a20kPEG-SAZ and 8a20kPEG-NH2, wherein the implant has a length greater than its width, and in its dry state, has a length of 11 mm or less, e.g., 5 to 11 mm, and a width of 0.2 to 0.4 mm, e.g., 0.28 to 0.38 mm, and / or in its hydrated state (in PBS, pH 7.4 at 37°C after 24 hours), has a length of 11 mm or less, e.g., 5 to 11 mm, and a width of 0.4 to 2 mm, and the axitinib particles have a d90 particle diameter of less than 8 μm and a d50 particle diameter of less than 3 μm.

[0061] In a further embodiment, the present invention relates to a sustained-release biodegradable ophthalmic implant comprising a hydrogel and approximately 400 μg to approximately 500 μg of axitinib polymorph IV, wherein the axitinib particles are dispersed within the hydrogel, the implant being an intravitreal implant, and comprising approximately 30 to approximately 75% axitinib, approximately 20 to approximately 50% PEG units, and approximately 0.5 to approximately 15% sodium phosphate on an anhydrous basis (%w / w), and approximately 5 to approximately 17% on a wet basis (%w / w). The axitinib has a composition of approximately 4-12% PEG units and approximately 0.2-5% sodium phosphate, and the hydrogel comprises a PEG hydrogel network formed by crosslinking precursors of 4a20kPEG-SAZ and 8a20kPEG-NH2, and the implant has a width of 0.20-0.40 mm in its dry state and a length of 11 mm or less in its hydrated state (in PBS, pH 7.4 at 37°C after 24 hours), and the implant has a length of 10-30 mm.2 It has a hydrated surface area (in PBS, pH 7.2-7.4, after incubation at 37°C for 24 hours).

[0062] In a further embodiment, the present invention relates to a sustained-release biodegradable ophthalmic implant comprising a hydrogel and approximately 400 μg to approximately 500 μg of axitinib polymorph IV, wherein the axitinib particles are dispersed within the hydrogel, the implant is an intravitreal implant, and on an anhydrous basis (%w / w), it comprises approximately 30 to approximately 75% axitinib, approximately 20 to approximately 50% PEG units, and approximately 0.5 to approximately 15% sodium phosphate, and on a wet basis (%w / w), approximately 5 to approximately 17% axitinib The nib has a composition of approximately 4 to 12% PEG units and approximately 0.2 to 5% sodium phosphate, and the hydrogel comprises a PEG hydrogel network formed by crosslinking 4a20kPEG-SAZ and 8a20kPEG-NH2 units, and the implant has a length of 5 to 11 mm and a width of 0.28 to 0.38 mm in its dry state, and / or a length of 5 to 11 mm and a width of 0.4 to 2 mm in its hydrated state (in PBS, pH 7.4 at 37°C after 24 hours).

[0063] In a further embodiment, the present invention relates to a sustained-release biodegradable ophthalmic implant comprising a hydrogel and approximately 400 μg to approximately 500 μg of axitinib polymorph IV, wherein the axitinib particles are dispersed within the hydrogel, the implant being an intravitreous implant, and having a composition on an anhydrous basis (%w / w) of approximately 54 to approximately 69% axitinib, a PEG hydrogel network formed by crosslinking approximately 17 to 26% 4a20kPEG-SAZ and approximately 8 to approximately 13% 8a20kPEG-NH2, approximately 3 to approximately 5% dibasic sodium phosphate, and approximately 1 to approximately 3% monobasic sodium phosphate.

[0064] In a further embodiment, the present invention relates to a sustained-release biodegradable ophthalmic implant containing a hydrogel and axitinib polymorph IV in an amount of about 400 μg to about 500 μg, for example, about 450 μg, wherein the axitinib particles are dispersed within the hydrogel, the hydrogel comprises PEG hydrogel, the implant has a width of 0.30 to 0.36 mm in its dry state, and the implant, in an in vitro test performed in a USP apparatus 4 at 35°C ± 0.5°C in 0.01 N HCl containing 0.25% cetyltrimethylammonium bromide (CTAB), results in an axitinib release characterized by the following: At least about 10% after 0.5 hours, After 2 hours, at least about 30%, After 6 hours, at least about 58%, After 10 hours, at least about 75%, At least approximately 80% after 12 hours, and / or at least about 90% after 16 hours, for example, At least about 10% after 0.5 hours, After one hour, at least about 19%, After 2 hours, at least about 30%, After 4 hours, at least about 45%, After 6 hours, at least about 58%, At least about 70% after 8 hours, After 10 hours, at least about 75%, At least approximately 80% after 12 hours, and / or at least about 90% after 16 hours.

[0065] In a further embodiment, the present invention relates to a sustained-release biodegradable ophthalmic implant comprising a hydrogel and axitinib polymorph IV in an amount of about 400 μg to about 500 μg, for example, about 450 μg, wherein the axitinib particles are dispersed within the hydrogel, the hydrogel comprising a hydrogel network formed by crosslinking units of 4a20kPEG-SAZ and 8a20kPEG-NH2, the implant having a composition of about 60% to about 70% axitinib and about 25% to about 35% PEG units (anhydrous basis, %w / w), and the implant The rant, in its dry state, has a width of 0.30–0.36 mm and a total weight of approximately 0.6 mg–1 mg. In an in vitro test performed in USP apparatus 4 at 35°C ± 0.5°C in 0.01 N HCl containing 0.25% cetyltrimethylammonium bromide (CTAB), the percentage of axitinib released from the implant (based on the maximum amount of axitinib released from the implant, which represents 100%) results in axitinib release characterized by the following: Approximately 10-20% after 0.5 hours, Approximately 30-45% after 2 hours. After 6 hours, approximately 58-81% After 10 hours, approximately 75-98% At least approximately 80% after 12 hours, and / or at least about 90% after 16 hours, for example, Approximately 10-20% after 0.5 hours, Approximately 19-30% after 1 hour. Approximately 30-45% after 2 hours. After 4 hours, approximately 45-65% After 6 hours, approximately 58-81% Approximately 70-90% after 8 hours. After 10 hours, approximately 75-98% At least approximately 80% after 12 hours, and / or at least about 90% after 16 hours.

[0066] In a further embodiment, the present invention relates to a sustained-release biodegradable ophthalmic implant containing a hydrogel and approximately 400 μg to approximately 500 μg of axitinib polymorph IV, wherein the axitinib particles are dispersed within the hydrogel, the hydrogel comprises PEG hydrogel, the implant has a width of 0.30 to 0.36 mm in its dry state, and the implant is characterized in that, in an in vitro test performed in a USP apparatus 4 at 35°C ± 0.5°C in 0.01 N HCl containing 0.25% cetyltrimethylammonium bromide (CTAB), the amount of axitinib released from the implant is as follows: At least approximately 50 μg after 0.5 hours, After 2 hours, at least approximately 140 μg, At least approximately 270 μg after 6 hours, At least approximately 350 μg after 10 hours, At least approximately 400 μg after 12 hours, and / or at least about 410 μg after 16 hours, for example, At least approximately 50 μg after 0.5 hours, After 1 hour, at least about 90 μg, After 2 hours, at least approximately 140 μg, At least approximately 230 μg after 4 hours, At least approximately 270 μg after 6 hours, At least approximately 340 μg after 8 hours, At least approximately 350 μg after 10 hours, At least approximately 400 μg after 12 hours, and / or at least about 410 μg after 16 hours.

[0067] In a further embodiment, the present invention relates to a sustained-release biodegradable ophthalmic implant comprising a hydrogel and approximately 400 μg to approximately 500 μg of axitinib polymorph IV, wherein the axitinib particles are dispersed within the hydrogel, the hydrogel comprising a PEG hydrogel network formed by crosslinking units of 4a20kPEG-SAZ and 8a20kPEG-NH2, the implant comprising approximately 60% to approximately 70% axitinib and approximately 25% to approximately The implant has a composition of 35% PEG units (anhydrous base, %w / w), and in its dry state, it has a width of 0.30 to 0.36 mm and a total weight of approximately 0.6 mg to approximately 1 mg. In an in vitro test performed in a USP apparatus 4 at 35°C ± 0.5°C in 0.01 N HCl containing 0.25% cetyltrimethylammonium bromide (CTAB), the amount of axitinib released from the implant is as follows: Approximately 50-80 μg after 0.5 hours. Approximately 140-210 μg after 2 hours. Approximately 270-380 μg after 6 hours. Approximately 350-470 μg after 10 hours. At least approximately 400 μg after 12 hours, and / or at least about 410 μg after 16 hours, for example, Approximately 50-80 μg after 0.5 hours. Approximately 90-130 μg after 1 hour. Approximately 140-210 μg after 2 hours. Approximately 230-290 μg after 4 hours. Approximately 270-380 μg after 6 hours. Approximately 340 to 440 μg after 8 hours. Approximately 350-470 μg after 10 hours. At least approximately 400 μg after 12 hours, and / or at least about 410 μg after 16 hours.

[0068] In a further embodiment, the present invention relates to a sustained-release biodegradable ophthalmic implant comprising a hydrogel and approximately 400 μg to approximately 500 μg of axitinib polymorph IV, wherein the axitinib particles are dispersed within the hydrogel, the hydrogel contains cross-linked PEG units, and the amount of axitinib released upon final degradation of the hydrogel in the vitreous fluid is less than 200 μg, the implant having a width of approximately 0.3 to approximately 0.4 mm, for example, approximately 0.33 to approximately 0.36 mm, and a length of less than approximately 11 mm in its dry state (before injection), and a length of less than approximately 11 mm, for example, approximately 8 to approximately 10 mm, in its hydrated state (in PBS, pH 7.4, after 24 hours at 37°C).

[0069] In a further embodiment, the present invention relates to a method for treating an eye disease in a patient requiring treatment, the method comprising administering a sustained-release biodegradable ophthalmic implant according to one embodiment of the present invention to the patient's eye, for example, by intravitreal injection.

[0070] In a further embodiment, the present invention relates to a sustained-release biodegradable ophthalmic implant disclosed herein for use in a method of treating a patient requiring treatment for an eye disease, the method comprising administering the sustained-release biodegradable ophthalmic implant according to an embodiment of the present invention to the eye of the patient.

[0071] In a further embodiment, the present invention relates to the use of a sustained-release biodegradable ophthalmic implant disclosed herein for the preparation of a drug for use in a method of treatment of a patient requiring treatment of an eye disease, the method comprising administering a sustained-release biodegradable ophthalmic implant according to an embodiment of the present invention to the eye of the patient.

[0072] In a further embodiment, the present invention relates to a method for producing a sustained-release biodegradable ophthalmic implant according to the present invention, the method comprising the steps of forming a hydrogel containing a polymer network and axitinib particles dispersed within the hydrogel, shaping the hydrogel, and drying the hydrogel.

[0073] In a further embodiment, the present invention relates to another method for producing a sustained-release biodegradable ophthalmic implant according to the present invention, the method comprising melt-extrude or injection-molding a composition comprising a polymer or a polymer (e.g., PEG) precursor and axitinib to form the implant.

[0074] In a further embodiment, the present invention relates to a kit comprising one or more sustained-release biodegradable ophthalmic implants of the present invention and one or more injection needles, wherein each implant is loaded onto a needle, for example, a needle having a gauge size of 25 or less.

[0075] In a further embodiment, the present invention relates to the release rate and / or average release rate and / or release amount of the total TKI contained in an ophthalmic implant, and / or the release ratio of the total TKI contained in the implant, or a method for increasing the total TKI released from the implant over a specific period of time.

[0076] Individual aspects of the present invention are disclosed herein and claimed in independent claims. Dependent claims, on the other hand, claim specific embodiments and variations of these aspects of the present invention. Details of various aspects of the present invention are shown in the following embodiments for carrying out the invention. [Brief explanation of the drawing]

[0077] [Figure 1] TKI release profile from implants manufactured by HME or wet casting (in vitro method B): (A) release mass, (B) release %. [Figure 2] Implant manufactured by HME (3x filaments). [Figure 3] Star-shaped implant and example of dimension calculation. [Figure 4] XPRD results - peaks for citrate, fumarate, and tartaric acid. [Figure 5] Synthesis scheme of the prodrug in Example 5. [Figure 6] 1H-NMR of the prodrug in Example 5.1. [Figure 7] LCMS of the prodrug of Example 5.1. [Figure 8] HPLC of the prodrug from Example 5.1. [Figure 9] 1H-NMR spectrum of axitinib Nm(PEG)4-oxymethyl prodrug in Example 5.2. [Figure 10] LCMS of axitinib Nm(PEG)4-oxymethyl prodrug of Example 5.2. [Figure 11] LCMS of axitinib Nm(PEG)4-oxymethyl prodrug of Example 5.2. [Figure 12] HPLC of axitinib Nm(PEG)4-oxymethyl prodrug of Example 5.2. [Figure 13] 1H-NMR spectrum of axitinib-Nm(PEG)1-oxymethyl prodrug in Example 5.2. [Figure 14] LCMS of axitinib-Nm(PEG)1-oxymethylprodrug of Example 5.2. [Figure 15] LCMS of axitinib-Nm(PEG)1-oxymethylprodrug of Example 5.2. [Figure 16] HPLC of the axitinib-Nm(PEG)1-oxymethyl prodrug of Example 5.2. [Figure 17] Solubility of SAB-I (pulverized, non-pulverized, and ultra-pulverized) and Polymorph IV in PBS at pH 7.2 and 37°C. [Figure 18A] TKI release profiles from implants 7.1A, 7.1B, 7.1C, and 7.1D showing the effect of axitinib solubility (in vitro method A). Release percentage. [Figure 18B] TKI release profiles from implants 7.1A, 7.1B, 7.1C, and 7.1D showing the effect of axitinib solubility (in vitro method A). Release mass. [Figure 18C] TKI release profile from implant 7.1E showing the effect of axitinib solubility (in vitro method A). [Figure 19]TKI release profiles from implants 7.2A, 7.2B, 7.2C, and 7.2D showing the effect of axitinib solubility (in vitro method B). (A) Release %, (B) Release mass. [Figure 20] TKI release profiles from implants 8A, 8B, 8C, and 8D showing the effect of hydration surface area (in vitro method B). [Figure 21] TKI emission profiles of implants 9A, 9B, and 9C showing particle size comparison (in vitro method B). [Figure 22] NHP's quadrant and suture location of the eye [Figure 23A] TKI distribution in the retina / Chr / RPE of NHP patients at 3 months. Retinal and choroidal / RPE tissue quarters (four eyes grouped together). [Figure 23B] TKI distribution in the retina / choroid / RPE of NHP patients at 3 months. The retina and choroid / RPE were grouped into four quarters. [Figure 24] Hydrogel sustained-release score. [Figure 25] Effect of curing time on implant dimensions [Figure 26] Outline of the planned test (Example 16). [Figure 27A] TKI release profiles from implants 7.3A-7.3H over approximately 50 hours in Example 7.3 (release %) over time, in vitro method C. [Figure 27B] TKI release profiles from implants 7.3A–7.3H shown over approximately 11 hours in Example 7.3 (release %) over time, Method C. [Figure 28] TKI release profiles from implants 7.3A-7.3H in Example 7.3 (release mass over time, in vitro method C). [Figure 28A] TKI release profiles from implants 7.3G~7.3K in Example 7.3 (release mass over time, in vitro method C). [Figure 28B] TKI release profiles from implants 7.3G~7.3K in Example 7.3 (release % over time, in vitro method C). [Figure 29] Results of the VEGF administration test (leakage score over time), Example 14. [Figure 30] XRD for photostability testing, Example 15.

[0078] definition As used herein, the term “implant” (sometimes referred to as “depot”) refers to an object containing an active agent, in particular a tyrosine kinase inhibitor (TKI), e.g., axitinib, and / or other compounds disclosed herein, which is administered into the body of a human or animal, e.g., into the vitreous fluid of the eye (also called the “vitreous cavity” or “vitreous body”), where it remains for a specific period of time while simultaneously releasing the active agent into the surrounding environment. The implant may have any predetermined shape (e.g., shapes disclosed herein) before injection, and this shape is maintained to some extent when the implant is placed in the desired position, although the dimensions of the implant (e.g., length and / or diameter) may change after administration due to hydration, as further disclosed herein. In other words, in the case of a pre-formed implant, what is injected into the eye is not a solution or suspension, but a pre-formed, cohesive object. Thus, the implant in this case is fully formed as disclosed herein before administration and is not created in situ at a desired location within the eye. However, in certain alternative embodiments of the present invention, the implant may be created in situ at a desired location by injecting a solution of a precursor compound that will form the implant after injection.

[0079] After administration, the implant of the present invention may be biodegraded over time in the physiological environment (as disclosed herein), thereby changing its shape while decreasing in size until it is completely dissolved / reabsorbed.

[0080] In this specification, the term “implant” refers to both the hydrated state (also referred to herein as “wet”) of the implant when it contains water, for example, after the implant has been administered to the eye and hydrated or rehydrated, or after immersion in an aqueous environment (e.g., in vitro), and the dry state (also referred to herein as “dry” or “anhydrous”) of the implant, i.e., immediately before it is produced, dried, and loaded into a needle, or after it has been loaded into a needle as disclosed herein, or when it is manufactured and is in a dry state without requiring dehydration. In other words, the term “dry” or “anhydrous” in relation to the implant of the present invention refers to the implant before it is injected (in a physiological or other environment). In the art, in a dry state, a “hydrogel” (e.g., a hydrogel contained in the implant of the present invention) may also be called a “xerogel.” Therefore, in certain embodiments, a dry / anhydrous implant in the context of the present invention may contain about 1% by weight or less of water. The water content of a dry / anhydrous implant can be measured, for example, by Karl Fischer coulometry. With regard to the hydrated state, whenever the dimensions of the implant (i.e., length, diameter, surface area, or volume) are reported herein, these dimensions are measured after the implant has been immersed in phosphate-buffered saline (PBS) at 37°C for 24 hours. With regard to the dry state, whenever the dimensions of the implant are reported herein, these dimensions are measured after the implant has been completely dried (and, in certain embodiments, containing about 1% by weight or less of water) and while the implant is being loaded into a needle for subsequent administration. In certain embodiments, the implant is maintained in a glove box in an inert atmosphere containing less than 20 ppm of both oxygen and moisture for at least about 7 days.

[0081] As used in this invention, the term “of the eye” generally refers to the eye, or any part or portion of the eye (for the “ophthalmic implants” according to this invention can, in principle, be administered to any part or portion of the eye), or any disease of the eye of various origins and natures (for in one embodiment, this invention generally refers to the treatment of any disease of the eye (“ophthalmic disease”)). In certain embodiments, this invention focuses on the intravitreal injection of ophthalmic implants (therefore, in this case, “ophthalmic implant” is “intravitreal implant”), and, as further disclosed below, the treatment of ophthalmic diseases affecting the posterior segment of the eye.

[0082] The term “patient” as used herein includes both human and animal patients. Therefore, the implants according to the present invention are suitable for medicinal use in humans or animals. Patients enrolled in and treated in clinical trials may also be referred to as “subjects.” Generally, a “subject” is, for example, an individual (human or animal) to whom the implant according to the present invention is administered during a clinical trial. The test animals in a trial may be, for example, non-human primates, such as monkeys, such as cynomolgus macaques, or rodents, such as rabbits, such as Dutch-belted rabbits. “Patient” is an object requiring treatment due to a particular physiological or pathological condition. In embodiments of the present invention, the patient is human.

[0083] The term “biodegradable” refers to a substance or object that decomposes in vivo, i.e., when placed in the body of a human or animal (e.g., an ophthalmic implant according to the present invention). In the context of the present invention, an implant comprising a hydrogel in which particles of a TKI, e.g., axitinib particles, are dispersed, as disclosed in detail below herein, is slowly biodegraded over time after being placed in the eye, e.g., in the vitreous fluid. This means that the hydrogel dissolves and is reabsorbed by the body after a certain period of time (as shown herein). In certain embodiments, biodegradation occurs, at least in part, via ester hydrolysis of the polymer network forming the hydrogel, which takes place in a physiological environment. The implant slowly decomposes (i.e., the hydrogel dissolves / decomposes), is completely reabsorbed, and becomes invisible in the vitreous. Hereinafter, the terms “biodegradable” or “decomposed” in relation to an implant are used synonymously with the terms “dissolve,” “dissociate,” “reabsorb,” or “bioresorb” of the implant.

[0084] The time it takes for the hydrogel to completely dissolve, i.e., the time it takes for the implant to completely decompose (in vivo or in vitro), is also referred to herein as the "persistence" of the implant.

[0085] A "hydrogel" can be defined as "a polymer material that swells in water and exhibits the ability to hold a significant proportion of water (e.g., more than 20%) within its structure, but is insoluble in water." This definition includes a wide variety of natural materials of both plant and animal origin, materials prepared by modifying naturally occurring structures, and synthetic polymer materials. (BDRatner, ASHoffmann, in: Hydrogels for Medical and Related Applications (Andrade, JD, Ed.); ACS Symposium Series; American Chemical Society, Washington, DC, 1976; Vol. 31; Chapter 1, 1-36).

[0086] Therefore, a "hydrogel" is a three-dimensional network of hydrophilic natural or synthetic polymers (as disclosed herein), optionally including hydrophobic domains, and can maintain or substantially maintain its structure by, for example, chemical or physical crosslinking of individual polymer chains, while swelling in water to retain a certain amount of water. Hydrogels are soft and flexible due to their high water content and are therefore very similar to natural tissues. In the present invention, the term "hydrogel" is used to refer to both a hydrogel in a hydrated / "wet" state when it contains water (e.g., after a hydrogel is formed in an aqueous solution, or after a hydrogel is (re)hydrated after being implanted in the eye or other part of the body, or after being immersed in an aqueous environment), and a hydrogel in a dry (dried / anhydrous) state when it has been dried to a low water content, e.g., 1% by weight or less. The dry state of a hydrogel is sometimes called a "xerogel" in the art, which is a dry hydrogel that can be converted into a hydrogel upon exposure to and absorption of water. The drying process for forming xerogels can be achieved in multiple ways, resulting in varying degrees of shrinkage and porosity.

[0087] In the present invention, if the active ingredient is contained within (for example, dispersed within) the hydrogel, the hydrogel may also be called the "matrix".

[0088] The term "polymer network" refers to a structure formed from polymer chains (with the same or different molecular structures and the same or different molecular weights) that are crosslinked with each other. Types of polymers suitable for the purposes of the present invention are disclosed herein. The polymer network may also be formed using crosslinking agents similarly disclosed herein.

[0089] 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.

[0090] The term "semi-crystalline" refers to a polymer or polymer network, or other chemical substance or entity, that possesses some crystalline properties, i.e., exhibits some crystalline properties in X-ray or electron scattering experiments.

[0091] The term "crystalline" refers to a polymer or polymer network, or other chemical substance or entity, that possesses crystalline properties as demonstrated by X-ray or electron scattering experiments.

[0092] In this specification, the term “precursor” refers to molecules or compounds that react with each other, thereby becoming connected via crosslinking, to form a polymer network, and ultimately a hydrogel matrix. Other materials, such as active agents or buffers, may be present within the hydrogel, but these are not referred to as “precursors.”

[0093] The precursor molecule portions that still exist in the final polymer network are also referred to herein as “units.” Thus, “units” are components or constituents of the polymer network that forms the hydrogel. For example, a polymer network suitable for use in the present invention may comprise identical or different polyethylene glycol units, as further disclosed herein.

[0094] The molecular weights of the polymer precursors used for the purposes of the present invention and disclosed herein can be determined by analytical methods known in the art. The molecular weight of polyethylene glycol can be determined, for example, by gel electrophoresis, such as SDS-PAGE (sodium dodecyl sulfate-polyacrylamide gel electrophoresis), GPC including gel permeation chromatography (GPC) using 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, by any method known in the art. The molecular weight of the polymers including the polyethylene glycol precursors disclosed herein is the average molecular weight (based on the molecular weight distribution of the polymer) and can thus generally be expressed by various average values including the weight average molecular weight (Mw) and the number average molecular weight (Mn). In the case of the polyethylene glycol precursors used in the present invention, the molecular weight indicated herein is the number average molecular weight (Mn).

[0095] As used herein, when referring to the particle size of an active agent, the "d90" value (also referred to herein as "D90") means that 90 volume % of all the particles within the measured bulk material (having a particular particle size distribution) have a particle size that is less than the indicated value. For example, a d90 particle size of less than about 10 μm means that 90 volume % of the particles within the measured bulk material have a particle size of less than about 10 μm. Similar definitions apply to other "d" values, such as the "d10", "d50", or "d100" values (also referred to herein as "D10", "D50", and "D100" values, respectively). Thus, whenever any particle size values (d10, d50 or d90) are reported herein, they always refer to volume %. The particle size can be measured by laser diffraction. Unless otherwise disclosed herein with respect to a particular particle size, the d10, d50, and d90 particle sizes are measured by laser diffraction.

[0096] In certain embodiments of the present invention, the term "fiber" (used interchangeably herein with the term "rod") generally characterizes an object having an elongated shape (i.e., in this case, an implant according to the present invention). Specific dimensions of the implant of the present invention are disclosed herein. The implant may have a cylindrical shape or an essentially cylindrical shape, or, as further disclosed herein, a non-cylindrical shape. The cross-section of the fiber or the implant may be circular or essentially circular, but in certain embodiments may be oval or rectangular, and in other embodiments may have different shapes, such as cross, star, or other shapes further disclosed herein.

[0097] In certain embodiments of the present invention, the term "filament" is also used, particularly when the implant comprises several fibers or filaments to form a "multifilament" implant, to refer to the fibers. In these cases, the composite diameter of the multifilament implant is essentially in the same range as the diameter of a single-fiber implant. In other words, in such a multifilament implant, the individual filaments generally have the shape of fibers but may be relatively thin so that the composite diameter of the multifilament implant does not become unduly large. Embodiments of the multifilament implant are disclosed herein.

[0098] The "hydrated surface area" of an implant is calculated based on its hydrated dimensions. For example, the hydrated surface area of a cylindrical or essentially cylindrical implant (a "fiber" according to the present invention) is given by the formula for the surface area of a cylinder, A = 2πrh + 2πr 2(h is the height in the hydrated state, i.e., the length of the cylinder, and r is the radius, i.e., half of the diameter / width of the cylinder in the hydrated state), and is calculated from the hydrated length and diameter. Whenever the dimensions of the implant (i.e., length, diameter) and values obtained therefrom (e.g., surface area or volume) are reported herein with respect to the hydrated state, these dimensions are measured after the implant has been immersed in phosphate buffered saline (PBS, pH 7.2 - 7.4) at 37 °C for 24 hours.

[0099] As used herein, the term "releasing" (and the terms "released", "releasing", etc. accordingly) refers to the provision of a drug such as an API from the implant of the present invention to the surrounding environment. The surrounding environment can be the in vitro environment or the in vivo environment described herein. In certain embodiments, the surrounding environment is the vitreous humor and / or ocular tissue, e.g., the retina or choroid. Thus, whenever it is stated herein that the implant "releases" or "provides a (sustained) release" of a TKI, e.g., axitinib, it not only refers to the direct provision of the TKI, e.g., axitinib, from the implant where the hydrogel has not yet been (completely) biodegradated, but also refers to the continuous provision of the TKI, e.g., axitinib, to the surrounding environment after complete degradation of the hydrogel, in which case the remaining undissolved TKI remains in this surrounding environment for some time (e.g., individually or as aggregated particles), and the TKI continues to exert its therapeutic effect. In this specification, "vitreous humor" (VH) may also be simply referred to as "vitreous".

[0100] In the context of in vivo studies, e.g., in vivo studies in animals, the terms "C" max " and "t" max " have the following meanings: The term "C" max " indicates the maximum concentration of the active drug measured in a specific (ocular) tissue, e.g., the retina or choroid (as shown, for example, in Examples 10 and 13 of this specification regarding the in vivo study). Generally, C maxはThis refers to the maximum average concentration of the corresponding all samples measured in a particular test (again, as shown in Examples 10 and 13). The C of tissue max Unless otherwise specified, the unit is ng / g. max When measured in plasma, the unit is ng / mL. (Term: T) max (or "t max ", this is referred to as "T" in this specification. max (used synonymously with ")" refers to the maximum plasma concentration (C max This indicates the time it takes to reach ). max This can be expressed over several days, weeks, or months, depending on the circumstances. The "AUC" (Area Under Curve) value corresponds to the area under the drug concentration-time curve in tissue (or possibly plasma). The AUC is expressed over a specific period of time. In this invention, for example, AUC 0-9ヶ月 This refers to the area under the drug concentration-time curve from the injection of the implant of the present invention up to 9 months later.

[0101] As used herein, “treatment period” refers to the period over which a particular therapeutic effect (as described herein) is achieved. As further disclosed herein, the treatment period may be extended for a certain period even after the implant / hydrogel has completely biodegraded / dissolved.

[0102] The term “sustained-release” is defined for the purposes of the present invention to characterize a product (in the present invention, the product is an implant) that is formulated to produce a drug that is available over a long period of time, thereby enabling a reduction in the frequency of administration compared to an immediate-release dosage form (e.g., a solution of the active ingredient injected intraocularly). Other terms that may be used interchangeably with “sustained-release” herein are “continuous release” or “controlled release.” Thus, “sustained-release” characterizes the release of APIs, in particular TKIs, such as axitinib, contained in implants according to the present invention. The term “sustained-release” is not in itself associated with or limited to a particular (in vitro or in vivo) release rate, but in certain embodiments of the present invention, the implant may feature a particular average (in vitro or in vivo) release rate or a particular release profile disclosed herein. Within the specific meaning of the present invention, the term “sustained-release” also includes a constant or substantially constant release period, where a period of constant or substantially constant (i.e., above a certain level) release of the tyrosine kinase inhibitor is followed by a period of tapering release of the tyrosine kinase inhibitor. In such specific cases, the overall sustained release provided by the implant of the present invention may mean that the release rate is not necessarily constant or essentially constant throughout the entire period of TKI release, but may change over time as described above (for example, an initial constant or essentially constant sustained release period followed by a tapering release period). Within the scope of the present invention, the terms “tasting” or “tasting” refer to the decrease over time in the release of a tyrosine kinase inhibitor, e.g., axitinib, until it is completely released. In some specific cases, the release profile may also exhibit an initial drug burst and / or a late drug burst, indicated by a short-term increase in the respective release rates (in vitro or in vivo). Because the implant of the present invention (whether expressly referred to herein as a “sustained-release” implant or simply as “implant”) provides sustained release of the API, the implant of the present invention may therefore also be referred to as a “depot.”

[0103] In certain embodiments of the present invention, the implant is characterized by a release profile of the TKI, for example, axitinib, as measured in a particular in vitro study. In such an in vitro study, as further disclosed herein, the amount of TKI released over a particular period, for example, over a period of one day or more, may be specified in units (e.g., in μg) of the absolute amount released per day on any given day in the course of the in vitro study (the amount released per day also defines the "daily release rate" or "rate of release per day"), or in units (e.g., in μg or mg) of the cumulative absolute amount released over that period, for example, the cumulative amount released over 10 days. In the in vitro study, the release percentage may also be specified as the percentage released per day (or over several days), or as the cumulative percentage released over a particular period, for example, over 10 days. The percentage may be defined as the percentage (ratio / share) of the total amount (drug load) contained in a particular implant, or as the percentage (ratio / share) of the total amount released from a particular implant in each in vitro study (which, in certain cases, may be lower than the actual total amount of activity contained in the implant, for example, if the release identified in the in vitro study approaches an equilibrium release of a drug lower than the actual drug load of the implant for various reasons, or if the in vitro study terminates before all of the contained drug load has been released).

[0104] In relation to in vitro release studies, “quantity” as used herein refers to weight, e.g., μg or mg, and “percentage” (or “share” or “ratio”) refers to a percentage (%).

[0105] The "average release rate" (e.g., μg / day) is the average amount (e.g., μg) released per day over a specific number of days. This is calculated by dividing the absolute (cumulative) amount of the active agent released over that number of days by the number of days. For example, if one implant according to the present invention releases a total (cumulative) amount of 100 μg of axitinib over 5 days, the average release rate over these 5 days is 20 μg / day. The actual release rate on any given day within these 5 days will naturally differ from the average release rate over the entire period.

[0106] In relation to in vitro studies and the identification of the release (rate) of the active agent from the implant of the present invention, whenever the “first” days or “first” period, for example, “the first five days,” is referred to herein, it means the period from the beginning of each in vitro study to the respective number of days (for example, the first five days of the in vitro study).

[0107] In vitro tests can be performed in various solvents and under various conditions as disclosed in detail herein whenever any particular release characteristics are referred to (e.g., “Method A”, “Method B”, or “Method C” (see subsection “In Vitro Release”, Section “I. Implants”)). Generally, in Methods A and B, one implant (or several implants simultaneously, if specifically mentioned) is placed in a certain amount of solvent or solvent mixture disclosed herein at a specific temperature (which is maintained throughout the in vitro test), and the release amount or percentage is specified on a given day. The volume of solvent (mixture) in which the implant is placed for such an in vitro test is specified by the “sink volume” multiplied by the “sink coefficient”. The “sink volume” is calculated by dividing the amount of active agent (e.g., μg) contained in the implant being tested by the solubility of that active agent in the solvent (mixture) in which the test is performed (e.g., μg / mL). For example, an in vitro test of an implant according to the present invention containing axitinib as a TKI may be performed in 25% ethanol / 75% water ( When performed in a v / v) solvent mixture, the sink volume is determined by dividing the amount of axitinib contained in the implant being tested by the solubility of the axitinib in this solvent mixture. The solubility of the active agent may vary depending on the form of the active agent used, as further disclosed herein. For example, active agents in different polymorphic phases may have different solubility in the same solvent (mixture). Similarly, different salts, cocrystals, or derivatives of the active agent may have different solubility in the same solvent (mixture). Depending on the purpose of the test and the specific details of the test method applied, either of these solubility values ​​specific to different forms of the active agent may be used to calculate the “sink volume,” or, in certain simplified or comparative tests, the average solubility of a given active agent may also be used to calculate the “sink volume,” as disclosed herein. The in vitro tests reported herein may be performed under various sink conditions, e.g., 2x sink conditions, 3x sink conditions, or higher sink coefficients, e.g., 4x or higher sink conditions, as disclosed herein."2x sink condition" means that the volume of solvent (mixture) into which the implant according to the present invention (or several implants as indicated) is immersed in a particular test is twice the "sink volume" (as defined above). In this case, the "sink coefficient" is 2, and "3x sink condition" means that the volume of solvent (mixture) into which the implant according to the present invention (or several implants as indicated) is immersed in a particular test is three times the "sink volume" (as defined above). In this case, the "sink coefficient" is 3, and so on for other sink coefficients. Further details regarding in vitro tests performed using implants according to the present invention, in which the TKI is axitinib (in particular with respect to sink coefficients and sink volume) are given in this description in the subsection "In Vitro Release" within the section "Implants". A further method for measuring the in vitro release of axitinib from implants of the present invention is "Method C", which is similarly disclosed herein (see, for example, the subsection "In Vitro Release" in section "I. Implants" and Example 7.3).

[0108] Wherever it is stated herein that a particular administration or injection is performed "concurrently with," "simultaneously to," or "at the same time as" the administration or injection of an implant according to the present invention, this means that the administration of another drug, such as the injection of a suspension or solution of an anti-VEGF drug disclosed herein, together with each of the injections of two or more implants or one or more implants, is usually performed successively and immediately, i.e., without significant delay. For example, if a total dose of approximately 400 μg of axitinib is administered to one eye, and the total dose is contained in two implants according to the present invention, each containing approximately 200 μg of axitinib, these two implants are, of course, injected into the vitreous cavity successively and immediately (and thus "simultaneously") within the same treatment period, without unnecessary delay, while adhering to all precautions for safe and accurate injection at the desired site. The same applies to the administration of further anti-VEGF agents described herein, which are administered concurrently with or simultaneously with the administration of one or more implants according to this specification. If the further anti-VEGF agent is administered by intravitreal injection of a suspension or solution containing the anti-VEGF agent, this injection is also intended to be performed immediately before or after (as disclosed above) the intravitreal injection of one or more implants according to the present invention, i.e., ideally within a single treatment period, when combination therapy / concurrent treatment is intended.

[0109] However, under certain circumstances, for example, if complications are experienced during the administration of the first implant, and / or if the physician administering the injection concludes that a second injection scheduled within the same period, on the same day (e.g., if the scheduled administration involves two or more implants), or within a few days, may be undesirable, the second implant may, in exceptional cases, be administered, for example, within 1-2 weeks after the first implant. As disclosed in more detail herein, the implant can persist in the vitreous humor of the human eye for a long period, for example, about 6-12 months, or about 6-9 months; therefore, administration of two implants, for example, at intervals of 1-2 weeks, may also be considered "simultaneous" in relation to the present invention. Similar considerations apply to the "simultaneous" administration of the implant and the anti-VEGF agent (or other agent) according to the present invention. Thus, the anti-VEGF agent may be administered simultaneously with the intravitreal administration of the implant of the present invention, i.e., simultaneously or nearly simultaneously as described herein.

[0110] However, in certain other embodiments, the anti-VEGF agent may also be administered in combination with the intravitreous implant of the present invention, but the administration of the implant and the anti-VEGF agent is not concurrent or simultaneous as defined above. In these cases, the anti-VEGF agent is administered either after or before the intravitreous injection of the implant according to the present invention, for example, within one month, two months, or three months thereafter or before. Such combination administration of an anti-VEGF agent, such as aflibercept or bevacizumab, with the implant according to the present invention is sometimes referred to as “combination therapy.”

[0111] The term “rescue drug” generally refers to a drug that may be administered to a patient in a given condition (e.g., a subject in a study who does not respond well to the treatment under investigation, or a patient in a given condition or a specific condition as determined by the physician treating the patient), or a drug that may be administered to address an emergency. In certain embodiments of the present invention, “rescue drug” refers to one dose of an anti-VEGF drug disclosed herein, administered as an intravitreal infusion of a solution or suspension of said anti-VEGF drug. In certain embodiments, the rescue drug is one dose (2 mg) of aflibercept administered by intravitreal infusion.

[0112] As used herein, the term “approximately” in relation to a measured quantity (such as duration, weight, or volume) refers to the normal variation in each measured quantity that a person skilled in the art would expect when performing a measurement and exercising a level of care appropriate to the purpose of the measurement and the precision of the measuring instrument. Unless otherwise noted, all values ​​of measured or measurable quantities disclosed herein (again, such as duration, weight, or volume) are intended to include such normal variation in each measured quantity, even if “approximately” does not precede these values.

[0113] The term "at least about" in relation to a measured quantity refers to the normal variation in the measured quantity, and any amount higher than that, that a person skilled in the art would expect when performing a measurement and exercising a level of care appropriate to the purpose of the measurement and the precision of the measuring instrument.

[0114] As used herein, the term “mean” refers to the central or representative value within a set of data (points), calculated by dividing the sum of the data (points) in the set by that number (i.e., the mean of the dataset).

[0115] As used herein, unless otherwise explicitly indicated by the context, the singular forms "a," "an," and "the" refer to multiple objects.

[0116] As used herein, the term "and / or" in expressions such as "A and / or B" is intended to include both "A and B" and "A or B".

[0117] Open terms such as "include", "including", "contain", "containing", etc. used herein mean "comprising" and are intended to refer to an unrestricted list or enumeration of elements, method steps, etc., and thus are not intended to be limited to the recited elements, method steps, etc., but are intended to include additional unrecited elements, method steps, etc.

[0118] When used in connection with a specific value or numerical value herein, the term "up to" means including that respective value or numerical value.

[0119] The terms "A to B", "of from A to B", and "of A to B" are used interchangeably herein and all refer to the range from A to B, including the upper and lower limits A and B.

[0120] For the purposes of the present disclosure, any range defined by upper and lower limits is also intended to include all individual values or ranges between those upper and lower limits.

[0121] In particular, this also applies to the pH value ranges given herein. For example, if a pH range of 7.2 to 7.4 is indicated, this means in particular pH 7.2, or pH 7.4, or an intermediate pH, for example 7.3.

[0122] The terms “API,” “(pharmaceutical) active ingredient,” “active (pharmaceutical) drug,” “active (pharmaceutical) ingredient,” “(active) therapeutic agent,” “active substance,” and “drug” are used interchangeably herein and refer to substances used in the final product (FPP) of a pharmaceutical product that impart pharmacological activity or directly affect the diagnosis, cure, mitigation, treatment or prevention of a disease or directly affect the restoration, correction or modification of a patient’s physiological function, and substances used in the preparation of such final product of a pharmaceutical product.

[0123] As used herein, the term “polymorph” refers to any crystalline form of an active drug, such as axitinib. Active drugs, which are often solid at room temperature, exist in various different crystalline forms, i.e., polymorphs, one of which is thermodynamically most stable at a given temperature and pressure. Axitinib polymorphs for use in the present invention are further disclosed herein.

[0124] As used herein, the term “derivative” of an active agent generally refers to a compound derived from an active agent by a chemical reaction, specifically a compound synthesized from the active agent by substitution / functionalization / exchange of one or more sites, structural parts, or atoms within the structure of the active agent. For example, if the structure of the active agent has an -NH group in the molecule, the hydrogen atoms in such -NH group may be replaced by substituents of various properties disclosed herein. In some cases, a derivative may also be a compound synthesized from the active agent by the removal of a particular substituent, group, or part.

[0125] As used herein, the term “prodrug” refers to a bioreversible derivative of a drug molecule that can undergo enzymatic and / or chemical transformation in vivo into an active (parent) drug, after which it can exert its desired pharmacological effect. Prodrugs can alter the physicochemical, biopharmaceutical, or pharmacokinetic properties of a drug to change, in certain cases improve, one or more aspects of the therapeutic applicability, availability, and utility of the respective drug. For example, a prodrug may be more soluble than the parent drug, and the use of such a prodrug may increase the bioavailability of the parent drug. In certain embodiments, a “prodrug” may be a derivative of the drug as defined above. For example, a prodrug may be a derivative of the drug in which a group is attached to one or more sites of the drug molecule, and the group is also cleaved after immersion in a physiological environment. In other embodiments, a “prodrug” may also be a precursor of the active (parent) drug, which contains a portion of the active drug molecule, and the precursor reacts with other components present in the physiological environment, or is intentionally administered for that purpose, to construct the structure of the active (parent) drug.

[0126] For the purposes of this disclosure, the term "alkyl," used alone or as part of another group, refers to a linear or branched aliphatic hydrocarbon (i.e., C) containing 1 to 12 carbon atoms. 1-12 This refers to a linear or branched aliphatic hydrocarbon (i.e., C1 alkyl, e.g., methyl; C2 alkyl, e.g., ethyl; C3 alkyl, e.g., propyl or isopropyl, etc.) containing any other specified number of carbon atoms. In one embodiment, the alkyl group is a linear C 1-10 Selected from alkyl groups. In another embodiment, the alkyl group is a branched chain C 1-10 Selected from alkyl groups. In another embodiment, the alkyl group is a linear C 1-6 Selected from alkyl groups. In another embodiment, the alkyl group is a branched chain C 1-6 Selected from alkyl groups. In another embodiment, the alkyl group is a linear C 1-4Selected from alkyl groups. In another embodiment, the alkyl group is a branched chain C 1-4 Selected from alkyl groups. In another embodiment, the alkyl group is a linear or branched C 2-4 Selected from alkyl groups. Exemplary C (not limited to) 1-10 Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, iso-butyl, 3-pentyl, hexyl, heptyl, octyl, nonyl, and decyl. (Examples are not limited to C.) 1-4 Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, and iso-butyl.

[0127] For the purposes of this disclosure, the term "optionally substituted alkyl," used alone or as part of another group, means that the alkyl defined above is either unsubstituted or substituted with one, two, or three substituents independently selected from nitro, haloalkoxy, aryloxy, aralkyloxy, alkylthio, sulfonamide, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, cycloalkyl, etc. In one embodiment, the optionally substituted alkyl is substituted with two substituents. In another embodiment, the optionally substituted alkyl is substituted with one substituent. Exemplary optionally substituted alkyls, not limited to these, include -CH2CH2NO2, -CH2CH2CO2H, -CH2CH2SO2CH3, -CH2CH2COPh, and -CH2C6H. 11 These are some examples.

[0128] For the purposes of this disclosure, the term "aryl," used alone or as part of another group, refers to a monocyclic or bicyclic aromatic ring system having 6 to 14 carbon atoms (i.e., C 6-14The term refers to an aryl group. Exemplary aryl groups, not limited to those listed, include phenyl (abbreviated as "Ph"), naphthyl, phenanthryl, anthrasyl, indenyl, azlenyl, biphenyl, biphenylenyl, and fluorenyl groups. In one embodiment, the aryl group is selected from phenyl or naphthyl. The term "aryl" also includes "heteroaryl," which means an "aryl" group in which one or more carbon atoms are exchanged with one or more other atoms, which may be the same or different, including oxygen, nitrogen, and / or sulfur. The "aryl" group may contain one aromatic ring or multiple aromatic rings.

[0129] For the purposes of this disclosure, as used herein, either alone or as part of another group, the term “optionally substituted aryl” means that the aryl as defined above is either unsubstituted or substituted with one or more substituents independently selected from halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy, alkylthio, carboxyamide, sulfonamide, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclo, alkoxyalkyl, (amino)alkyl, hydroxyalkylamino, (alkylamino)alkyl, (dialkylamino)alkyl, (cyano)alkyl, (carboxyamide)alkyl, mercaptoalkyl, (heterocyclo)alkyl, or (heteroaryl)alkyl. In one embodiment, the optionally substituted aryl is an optionally substituted phenyl. In one embodiment, the optionally substituted phenyl has four substituents. In another embodiment, the optionally substituted phenyl has three substituents. In another embodiment, the optionally substituted phenyl has two substituents. In another embodiment, the optionally substituted phenyl has one substituent. Examples of substituted aryl groups, not limited to these examples, include 2-methylphenyl, 2-methoxyphenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 3-methylphenyl, 3-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 4-methylphenyl, 4-ethylphenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 2,6-di-fluorophenyl, 2,6-di-chlorophenyl, 2-methyl,3-methoxyphenyl, 2-ethyl,3-methoxyphenyl, 3,4-di-methoxyphenyl, 3,5-di-fluorophenyl, 3,5-di-methylphenyl, 3,5-dimethoxy,4-methylphenyl, 2-fluoro-3-chlorophenyl, and 3-chloro-4-fluorophenyl.The term "arbitrarily substituted" is intended to include groups having condensed arbitrarily substituted cycloalkyl groups and condensed arbitrarily substituted heterocyclo rings. Examples include (but are not limited to): [ka]

[0130] As used herein, the term “salt” may include, but is not limited to, inorganic salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, etc.; organic salts such as formate, acetate, trifluoroacetate, maleate, tartrate, glutarate, etc.; sulfonates such as methanesulfonate, benzenesulfonate, p-toluenesulfonate, etc.; metal salts such as sodium salt, potassium salt, cesium salt, etc.; alkaline earth metals such as calcium salt, magnesium salt, etc.; and organic amine salts such as triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, etc. Any TKI used herein, such as a salt of axitinib, is intended to be a pharmaceutically acceptable salt.

[0131] As used herein, the term “cocrystal” refers to a combination of a pharmaceutical active ingredient (API) and one or more coformers, e.g., acids (e.g., carboxylic acids), via non-covalent interactions within the same lattice, such as hydrogen bonding, electrostatic interactions, π-π stacking, van der Waals interactions, etc. A cocrystal is therefore a multicomponent solid. The difference between a cocrystal and a salt is that the former consists only of neutral components, while the latter contains ionic components. Coformers suitable for cocrystals of axitinib are further disclosed herein. Cocrystallization may alter the physicochemical properties of the API, for example, with respect to stability, solubility, dissolution rate, mechanical properties, etc., or, in certain cases and for certain applications, may optimize them.

[0132] As used herein, the term “therapeutically effective” refers to the amount of drug or active agent required to produce a particular desired therapeutic outcome after administration. For example, in connection with the present invention, one desired therapeutic outcome is a reduction in central retinal thickness (CSFT), as measured by optical coherence tomography in patients with neovascular AMD, since patients with neovascular AMD have thickening of the CSFT. In connection with the present invention, the “therapeutically effective” amount of an active agent also refers to the IC250 amount that this active agent brings to a particular substrate. 50 Multiples of, for example, IC 50 It could be more than 50 times that amount.

[0133] As used herein, the abbreviation "PBS" means "phosphate-buffered saline."

[0134] As used herein, the abbreviation "TBS" means "Tris-buffered saline."

[0135] As used herein, the abbreviation "PEG" means "polyethylene glycol."

[0136] As used herein, the abbreviation "HME" means "Heat-Metal Extrusion."

[0137] As used herein, the abbreviation "HST" means "heat-drawn yarn".

[0138] As used herein, the abbreviation "NHP" means "non-human primates."

[0139] As used herein, the abbreviation "TLA" means "trillidine acetate".

[0140] All references disclosed herein are incorporated herein by reference in their entirety for any purpose. In the event of any conflict between the incorporated references and this disclosure, this disclosure shall prevail. [Modes for carrying out the invention]

[0141] I. Implants Active ingredients: One aspect of the present invention is a sustained-release biodegradable ophthalmic implant comprising a hydrogel and a tyrosine kinase inhibitor (TKI), wherein the TKI particles are dispersed within the hydrogel, as disclosed herein. The active ingredient contained in the implant of this aspect of the present invention is therefore a TKI. Examples of suitable TKIs are axitinib, sorafenib, sunitinib, nintedanib, pazopanib, regorafenib, cabozantinib, and vandetanib. In certain embodiments, the TKI used in this aspect and other aspects of the present invention is axitinib.

[0142] In embodiments of the present invention, the implant comprises axitinib as the tyrosine kinase inhibitor. The free base of axitinib is the active ingredient of INLYTA® (Pfizer, NY), which is indicated for the treatment of advanced renal cell carcinoma. It is a low molecular weight (386.47 daltons) synthetic tyrosine kinase inhibitor. The primary mechanism of action is the inhibition of angiogenesis (formation of new blood vessels) mainly by inhibiting the following receptor tyrosine kinases: 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). These are involved in pathological angiogenesis, tumor growth, and cancer progression. Therefore, axitinib is a multi-target inhibitor that inhibits both the VEGF pathway and the PDGF pathway.

[0143] Axitinib inhibits both VEGF and PDGF signaling. In addition to inhibiting VEGF / PDGF, axitinib inhibits c-kit, a survival factor for angiogenesis, and has a reduced clearance half-life (t) in the human eye. 1 / 2The incubation period for ranibizumab and aflibercept is several hours (Rugo et al., Phase I trial of the oral antiangiogenesis agent AG-013736 in patients with advanced solid tumors. 2005, J Clin Oncol., 23(24):5474-83), but the incubation period for ranibizumab and aflibercept is several days, respectively. 1 / 2 These large molecule antibodies have t 1 / 2 The longer release time allows for the maintenance of effective tissue concentrations for several weeks, while smaller molecules are removed more rapidly. However, due to the low solubility of axitinib and its inclusion in the hydrogel implant of the present invention, which remains in the vitreous fluid (VH) for a long period, for example, several months, a therapeutically effective amount of axitinib is delivered over the duration that the implant persists in the VH. Thus, sustained intravitreal release of axitinib provides a multi-target inhibitor that can inhibit both the VEGF and PDGF pathways in principle, without the need for combination therapy and frequent intravitreal injections.

[0144] The molecular formula for the free base of axitinib is C 22 H 18 N4OS has the IUPAC name N-methyl-2-[3-((E)-2-pyridine-2-yl-vinyl)-1H-indazole-6-ylsulfanil]-benzamide. It has the following chemical structure: [ka]

[0145] For the purposes of the present invention, in all embodiments thereof, axitinib may be used in all possible forms, including any axitinib polymorph, salt, anhydride, hydrate, other solvates, derivatives, or prodrugs of axitinib. Whenever “axitinib” is referred to in this description or in the claims, unless otherwise specified, it refers to any axitinib polymorph, salt, anhydride, solvate (including hydrate), cocrystal, derivative, or prodrug of axitinib. For the purposes of the present invention, all forms of axitinib used in implants are intended to be pharmaceutically acceptable.

[0146] In certain embodiments of the present invention, a specific form of axitinib is used.

[0147] The solubility of axitinib free base in bio-related media (e.g., PBS, pH 7.2-7.4, e.g., 37°C) has been confirmed to be low. Different forms of axitinib free base, including different axitinib polymorphs, have different solubility. Solubility measurements are reported in Example 6.

[0148] In one embodiment, the present invention relates to a sustained-release biodegradable ophthalmic implant comprising a hydrogel and a tyrosine kinase inhibitor (TKI), such as axitinib, wherein particles of the tyrosine kinase inhibitor are dispersed within the hydrogel, and the solubility of the tyrosine kinase inhibitor is greater than 0.3 μg / mL, measured after incubation for 5 days at 37°C at pH 7.2-7.4 in phosphate-buffered saline (PBS). In a particular embodiment, the TKI is axitinib. According to this embodiment of the present invention, any form of axitinib, such as but not limited to axitinib polymorphs, cocrystals, derivatives, and prodrugs, which are further disclosed herein, may be used, and which have a solubility greater than 0.3 μg / mL, measured after incubation for 5 days at 37°C at pH 7.2-7.4 in phosphate-buffered saline (PBS).

[0149] Another aspect of the present invention relates to a sustained-release biodegradable ophthalmic implant comprising a hydrogel and a tyrosine kinase inhibitor, such as axitinib, wherein particles of the tyrosine kinase inhibitor are dispersed within the hydrogel, and the hydrated surface area of ​​the implant is measured to be at least 25 mm² after incubation for 24 hours at 37°C in phosphate-buffered saline (PBS) at pH 7.2-7.4. 2 This is a characteristic feature. According to this aspect of the present invention, generally, all forms of axitinib, including but not limited to axitinib polymorphs, cocrystals, derivatives, and prodrugs further disclosed herein, regardless of their solubility, have a hydrated surface area of ​​at least 25 mm² as measured after incubation for 24 hours at 37°C in phosphate-buffered saline (PBS) at pH 7.2-7.4. 2 As long as it is so, it can be used.

[0150] The two embodiments of the present invention may be combined, namely, the present invention also relates to a sustained-release biodegradable ophthalmic implant comprising a hydrogel and a tyrosine kinase inhibitor, such as axitinib, wherein particles of the tyrosine kinase inhibitor are dispersed within the hydrogel, the solubility of the tyrosine kinase inhibitor is greater than 0.3 μg / mL as measured after incubation for 5 days at 37°C at pH 7.2-7.4 in phosphate-buffered saline (PBS), and the hydrated surface area of ​​the implant is at least 25 mm² as measured after incubation for 24 hours at 37°C at pH 7.2-7.4 in phosphate-buffered saline (PBS). 2 It is characterized by being such.

[0151] Axitinib polymorphs for use in the present invention: With respect to axitinib, suitable solid forms and polymorphs of axitinib, including anhydrous and solvates, are disclosed in scientific literature, e.g., AMCampeta et al., Journal of Pharmaceutical Sciences, Vol.99, No.9, September 2010, 3874-3886; BPChekal et al., Organic Process Research & Development 2009, 13, 1327-1337; and patent documents, including but not limited to US8,791,140B2, US2006 / 0094763A1, and WO2016 / 178150A1. The thermodynamically most stable polymorph of axitinib is referred to as type XLI in, for example, US8,791,140B2. XLI is the 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 XLI in the anhydrous crystalline form. In addition to the anhydrous form, numerous solvates of axitinib with various solvents exist, as described in the cited art, all of which can be used to prepare implants according to the present invention. Any axitinib polymorphs known in the art and disclosed in the art, in particular (but not limited to), in the references cited herein, can generally be used in the present invention (unless a particular aspect of the present invention requires a specific solubility, as described above, then only axitinib polymorphs that satisfy this requirement may be used).

[0152] In certain aspects and embodiments of the present invention, the non-solvated crystalline form of axitinib SAB-I disclosed in WO2016 / 178150 may be used to prepare the implant according to the present invention. This is an XRD pattern containing at least three, or at least four, or at least five characteristic 2θ° peaks selected from 2θ° at 8.3, 15.6, 16.5, 18.6, 21.0, 23.1, 24.1, and 26.0 (all values ​​±0.3), and / or chemical shifts in DMSO solvent containing 26.1, 114.7, 154.8, and 167.8, each shift ±0.2 ppm. 1313C NMR and / or chemical shifts of 171.1, 153.2, 142.6, 139.5, 131.2, 128.1, and 126.3, each with a range of ±0.2 ppm. 13 Characterized by 13C solid-state NMR and / or by DSC isotherms containing two endothermic peaks between 213°C–217°C (peak 1) and 219°C–224°C (peak 2).

[0153] The solubility of axitinib polymorph SAB-I, measured after 5 days of incubation at 37°C in PBS at pH 7.2–7.4, has been confirmed to be less than 0.3 μg / mL. See Example 6.

[0154] In embodiments and aspects of the present invention, polymorph IV of axitinib is particularly suitable if the solubility of the tyrosine kinase inhibitor is greater than 0.3 μg / mL, measured after 5 days of incubation at 37°C at pH 7.2–7.4 in phosphate-buffered saline (PBS). Polymorph IV is disclosed, for example, in US2006 / 0094763A1. In certain embodiments, axitinib polymorph IV is used to prepare implants according to this embodiment of the present invention. Furthermore, axitinib polymorph IV is also suitable in embodiments where the solubility of the TKI does not need to be within a specific range, for example, if the hydrated surface area of ​​the implant is at least 25 mm², measured after 24 hours of incubation at 37°C at pH 7.2–7.4 in phosphate-buffered saline (PBS). 2 Therefore, it is also suitable for the preparation of implants according to any other aspect of the present invention, including aspects of the present invention. Accordingly, axitinib polymorph IV is a specific form of axitinib used in all aspects of the present invention.

[0155] The solubility of axitinib polymorph IV is, for example, about twice that of axitinib polymorph SAB-I, and has been confirmed to exceed 0.3 μg / mL after 5 days of incubation at 37°C in PBS at pH 7.2–7.4 (or pH 7.2), and is at least 0.4 μg / mL under these conditions. See Example 6 and Figure 17. In one embodiment, axitinib polymorph IV is used to prepare an implant according to this embodiment of the present invention that requires a solubility of more than 0.3 μg / mL, measured after 5 days of incubation at 37°C in phosphate-buffered saline (PBS) at pH 7.2–7.4, but it may also be used to prepare implants according to any other embodiment of the present invention.

[0156] In certain specific embodiments, axitinib, particularly axitinib polymorph IV, included in or used for the preparation of implants according to the present invention, is alternatively characterized by a powder X-ray diffraction pattern containing at least two, for example, at least three, or at least four, or at least five peaks among diffraction angles (2θ) of 8.90, 9.40, 9.50, 12.0, 14.60, 15.25, 15.75, 17.80, 19.30, 20.65, 24.95, and 26.10 (all values ​​±0.2). In particular, the axitinib polymorph IV used to prepare the implant according to this embodiment of the present invention may be characterized by a powder X-ray diffraction pattern including peaks at diffraction angles (2θ) of 8.90, 12.0, 14.60, 15.75, and 19.30 (all ±0.2), and / or by a DSC peak at approximately 221°C with a scanning speed of 5°C / min (over a range of 25–300°C).

[0157] In certain embodiments, the axitinib used in the preparation of the implant according to the present invention is polymorph IV characterized in US2006 / 0094763A1 disclosing axitinib polymorph IV (see, for example, paragraphs

[0021] ,

[0118] , and

[0119] of US2006 / 0094763A1, as well as claims 3-5 and Figures 4A and 4B of US2006 / 0094763A1). Therefore, axitinib, particularly axitinib polymorph IV, having a solubility greater than 0.3 μg / mL as measured after incubation for 5 days at 37°C at pH 7.2-7.4 in phosphate-buffered saline (PBS), used to prepare implants according to certain embodiments of the present invention, may be characterized by a powder X-ray diffraction pattern including peaks at diffraction angles (2θ) of 8.9, 14.6, 15.7, and 19.2 (all ±0.1), or a powder X-ray diffraction pattern including peaks at diffraction angles (2θ) of 8.9 and 15.7 (all ±0.1).

[0158] In one embodiment, the implant according to the present invention comprises axitinib, wherein at least 90% by weight, or at least 95% by weight, of the total axitinib contained in the implant is polymorph IV.

[0159] Polymorph IV has been demonstrated to be chemically and physically stable for 6 months in the implant according to the present invention (see Example 11).

[0160] In photostability tests using implants containing axitinib polymorph IV, the XRD patterns after sterilization and exposure (visible light with wavelengths of 380–700 nm and UV-A light with wavelengths of 315–400 nm) were demonstrated to be unchanged compared to the respective XRD patterns at the start of these tests and before exposure. These results were consistent with those obtained for implants containing axitinib polymorph SAB-I.

[0161] Further photostability tests comparing axitinib polymorph IV powder, implants containing axitinib polymorph IV according to the present invention, such implants loaded onto injection needles, and needles loaded with such implants sealed in secondary foil packaging were performed using visible and UV light as described above, compared to unexposed (control) samples. The main impurities that may result from exposure of axitinib polymorph IV are the dimerization of the axitinib polymorph IV API (in the case of axitinib polymorph SAB-I API, although to a relatively lower degree than in the case of polymorph IV API, there are two main impurities: dimers and cis isomers). In Example 15, the axitinib polymorph IV API powder showed photo-induced degradation, resulting in more than 30% impurities (dimers) (under both visible and UV light). When axitinib polymorph IV was dispersed in a PEG hydrogel within the implant according to the present invention, the dimerization observed upon exposure (both visible and UV light) was less than that observed in the case of the axitinib polymorph IV API powder itself, namely, about 25% (visible light) and about 14% (UV light). While we do not wish to be bound by theory, these data suggest that the hydrogel, e.g., PEG hydrogel, exerts a protective effect against axitinib polymorph IV when it is present in the implant. Accordingly, the present invention also provides a method for forming the implant according to the present invention by increasing the photostability of an active agent, e.g., a TKI, e.g., axitinib, e.g., axitinib polymorph IV, by incorporating it into a PEG hydrogel. The present invention further provides a form of axitinib polymorph IV that is more photostably stable than axitinib polymorph IV in powder form, for example, at least 10%, e.g., at least 15%, e.g., at least 20% more stable in visible light for the same exposure time and under the same exposure conditions than axitinib polymorph IV in powder form, and / or for example, at least 10%, e.g., at least 20%, e.g., at least 30%, e.g., at least 40% more stable in UV light for the same exposure time and under the same exposure conditions than axitinib polymorph IV in powder form.The term "at least 10%" higher photostability means that in the implant according to the present invention (e.g., dispersed in a PEG hydrogel), at least 10% less total impurities (in this case, also primarily dimers) are detected compared to the amount of impurities (i.e., primarily dimers) detected in the API of axitinib polymorph IV as a powder. The same meaning applies to other percentages shown herein. In certain embodiments, exposure to visible light as referred herein means exposure to light with wavelengths of 380–700 nm for, for example, at least one day, or at least two days, for example, at least 500,000 lux hours / m. 2 For example, at least 1 million lux-hours / m 2 For example, at least 1.2 million lux-hours / m² 2 This means exposure to UV light. In a particular embodiment, exposure to UV light means exposure to UVA light with wavelengths of 315-400 nm for, for example, at least 4 hours, for example, at least 8 hours, for example, at least 10 hours, for example, at least 100 watt-hours / m². 2 , or at least 150 hours / m 2 , or at least 200 hours / m 2 This means exposure to [the substance].

[0162] Axitinib polymorph IV has been demonstrated to withstand significant photodegradation (primarily dimerization) under the conditions required to manufacture implants containing axitinib polymorph IV according to the present invention. In particular, when axitinib polymorph IV is contained in a hydrogel, such as PEG hydrogel, dimerization is significantly reduced. Furthermore, when the implant is loaded into an injection needle and / or sealed in a foil pouch, this further significantly protects the implant and, consequently, the API, safeguarding the API during storage and transport.

[0163] While we do not intend to limit ourselves to this theory, the increased solubility of axitinib polymorph IV disclosed herein may accelerate the release of axitinib from the implant according to the present invention compared to a comparative implant in which the solubility of axitinib present in the implant (e.g., axitinib polymorph SAB-I) is lower.

[0164] In certain specific embodiments, the implant of the present invention contains axitinib polymorph IV in an amount of 300 to 600 μg, for example, about 360 μg to about 562.5 μg, or about 405 μg to about 495 μg, or about 450 μg. In certain other specific embodiments, the implant of the present invention contains axitinib polymorph IV in an amount of about 480 μg to about 750 μg, or about 540 μg to about 660 μg, or about 600 μg.

[0165] In other embodiments, further axitinib polymorphs having a solubility greater than 0.3 μg / mL, measured after incubation for 5 days at 37°C in PBS at pH 7.2–7.4, may be used in this embodiment of the present invention.

[0166] With regard to the manufacture of implants according to the present invention (in any embodiment thereof), the manufacturing process and conditions, as well as the composition / amount of the components of the implant, are generally independent of the axitinib polymorph phase used. Therefore, generally, all amounts and compositions disclosed herein with respect to TKI, or in particular axitinib, as well as all manufacturing steps and conditions, are equally applicable to any of the axitinib polymorphs disclosed herein, particularly axitinib polymorph IV and axitinib polymorph SAB-I or XLI.

[0167] Axitinib cocrystal for use in the present invention: In certain embodiments of the present invention, the implant comprises axitinib in the form of axitinib cocrystals. In particular, in embodiments of the present invention in which the TKI (e.g., axitinib) has a solubility greater than 0.3 μg / mL as measured after incubation for 5 days at 37°C at pH 7.2-7.4 in phosphate-buffered saline (PBS), one or more axitinib cocrystals (such as those further disclosed herein) may be used in the implant according to the present invention, provided that they meet the solubility criteria. Alternatively, even if the axitinib cocrystals do not meet the solubility criteria, they may be used in all other embodiments of the present invention in which it is not necessary to meet the solubility criteria.

[0168] Axitinib cocrystals containing a carboxylic acid as a coformer are particularly suitable for use in the present invention because the carboxylic acid generally increases hydrophilicity, thereby increasing the solubility of axitinib. In connection with the present invention, any carboxylic acid is generally suitable for forming cocrystals with axitinib. Specific carboxylic acids that can be used to form axitinib cocrystals are C1-C12. 12 Carboxylic acids, for example, C2-C 10 Carboxylic acids, specifically C2, C3, C4, C5, C6, C7, C8, C9, or C 10 The carboxylic acid is a carboxylic acid. The carboxylic acid may be saturated or unsaturated. They may contain one or more aryl groups, including a heteroaryl group. The carboxylic acid may contain, but not necessarily, one or more further functional groups, in particular, functional groups that further increase hydrophilicity or at least do not significantly decrease hydrophilicity. A suitable such group is, for example, a hydroxyl group. If the carboxylic acid that forms a cocrystal with axitinib can have one or more enantiomer forms or one or more other configurations (e.g., cis / trans), it may be present in the cocrystal in any enantiomer form and / or any configuration. Cocrystals of axitinib are disclosed, for example, in BY Ren et al., Cryst Eng Comm. 2021, 23, 5504-5515.

[0169] Specific examples of carboxylic acids suitable for forming cocrystals with axitinib include one or more of the following: citric acid, fumaric acid, (+)-L- or (-)-D tartaric acid, glutaric acid, (trans- or cis)cinnamic acid, suberic acid, succinic acid, adipic acid, pimelic acid, and salicylic acid. This list is not intended to be limiting, and further carboxylic acids or other compounds mentioned above may be used herein to form axitinib cocrystals. Within the lattice of the cocrystal, there may be more than one coformer per molecule of axitinib, e.g., carboxylic acid. In such cases, the more than one coformer may be the same coformer, e.g., the same carboxylic acid, or different coformers, e.g., different carboxylic acids.

[0170] Axitinib cocrystals can be prepared, for example, by combining a specific amount of axitinib with a selected coformer in a 1:1 molar ratio from a solution or slurry, adding a solvent (e.g., acetonitrile), and crystallizing the resulting slurry by stirring it for a specific number of days (e.g., 3 days) and optionally at a high temperature (e.g., at least 30°C or at least 40°C). The solid can then be isolated and analyzed, for example, by filtration or centrifugation. Alternatively, the cocrystal can also be prepared by seeding the cocrystal in a small amount of solvent (after the desired cocrystal is available for the seeding procedure), and stirring the seeded mixture for a specific number of days (e.g., at least 1 day) and optionally at a high temperature (again, at least 30°C or at least 40°C). The solid can then be isolated as described above. An example of the preparation of a specific axitinib cocrystal is shown in Example 4, and solubility data is shown in Example 6.

[0171] In certain embodiments, the axitinib cocrystal may have a solubility at least twice, at least five times, at least ten times, at least 25 times, at least 50 times, at least 75 times, or at least 100 times greater than that of the free base of axitinib.

[0172] In certain embodiments, axitinib cocrystals have a solubility of at least 10 μg / mL, for example, at least 12 μg / mL, at least 15 μg / mL, or at least 18 μg / mL, in PBS at pH 7.4 after 24 hours at 37°C. Axitinib cocrystals containing citric acid have an average solubility of about 19 μg / mL in PBS at pH 7.4 after 24 hours at 37°C, axitinib cocrystals containing fumaric acid have an average solubility of about 12 μg / mL in PBS at pH 7.4 after 24 hours at 37°C, and axitinib cocrystals containing (+)-L-tartaric acid have an average solubility of about 19-20 μg / mL in PBS at pH 7.4 after 24 hours at 37°C.

[0173] While we do not intend to limit ourselves to this theory, the increased solubility of the axitinib cocrystal disclosed herein may accelerate the release of axitinib from the implant according to the present invention compared to a comparative implant in which the solubility of axitinib (e.g., free axitinib base) present in the implant is lower.

[0174] Axitinib derivatives and prodrugs for use in the present invention: In all aspects of the present invention, a TKI, such as a derivative or prodrug of axitinib, may be used in the implant. However, in aspects of the present invention, if the solubility of the TKI is greater than 0.3 μg / mL as measured after incubation for 5 days at 37°C in phosphate-buffered saline (PBS) at pH 7.2-7.4, then prodrugs that increase the solubility of the parent TKI compound are particularly suitable. In embodiments of the present invention where the TKI is axitinib, a prodrug of axitinib with higher solubility compared to the free base of axitinib is particularly suitable. The axitinib prodrug is converted to axitinib in vivo.

[0175] A prodrug of axitinib with increased solubility may be a derivative of axitinib in which one or more atoms or parts of axitinib are replaced with one or more substituents that increase the solubility of the resulting derivative (i.e., prodrug), for example by introducing a hydrophilic group as a substituent. After immersion in a physiological environment which can be simulated by in vitro testing, these substituents may be removed enzymatically or chemically, and the parent drug molecule may be released. In the present invention, a particularly suitable example of a prodrug of axitinib is one in which the axitinib molecule is functionalized with one or more nitrogen atoms of the free base of the axitinib. For example, in a prodrug of axitinib for use according to the present invention, one or more nitrogen atoms of the free base of axitinib may be independently substituted with one or more of the following groups: acyl, alkylcarbonyl, arylcarbonyl, alkylthiocarbonyl, arylthiocarbonyl, alkylcarbamoyl, arylcarbamoyl, substituted or unsubstituted acetyl, substituted or unsubstituted aminoalkanoyl, substituted or unsubstituted α-aminoalkanoyl, acyl groups obtained from natural or unnatural amino acids with or without substitution, acyl groups of peptide residues, phosphonyl, phosphinyl, aminophosphinyl, alkylaminophosphinyl, sulfonyl, cycloalkane-carbonyl, heterocycloalkane-carbonyl, alkoxycarbonyl, aryloxycarbonyl, heteroalkoxycarbonyl, heteroaryloxycarbonyl, and substituted or unsubstituted O-substituted hydroxymethyl groups.

[0176] In certain embodiments, the axitinib prodrug for use in the present invention is a compound of the following general formula (I), or a salt or solvate thereof: [ka] During the ceremony, X 1 is N or N + Y 1 Selected from, X 2 is NH or NY 2 Selected from, X 3 is NH or NY 3 selected from Y 1 is -CH2OCO(OCH2CH2)n 1 OM 1 or -CH2OCO(CH2CH2O)n 1a Z 1 or -CH2OCO(CH2)n 1b COOH selected from Y 2 is -CH2OCO(OCH2CH2)n 2 OM 2 or -CH2OCO(CH2CH2O)n 2a Z 2 or -CH2OCO(CH2)n 2b COOH selected from<00​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​3 At least one of them is -CH2OCO(CH2CH2O)nZ.

[0177] In certain other embodiments, in the above general formula (I), Y 1 , Y 2 , and Y 3 These are independently -(CH2)p 1 OCO(O(CH2)p 2 )n 1 OM, or -(CH2)p 1a OCO((CH2)p 2 O)n 1 (CH2)Z, or -(CH2)p 1 OCO(CH2)q 1 Selected from COOH, p 1 , p 1a , and p 2 These are independently selected from integers 1 to 4, and q 1 The integers are independently selected from 0 to 4, and their other meanings are as defined above with respect to equation (I).

[0178] In certain embodiments, the following prodrugs are suitable for the present invention, wherein in formula (I) above, X 1 is, N + Y 1 X 2 NH and X 3 NH and Y 1 is -CH2OCO(CH2CH2O)n 1a Z 1 Alternatively, -CH2OCO(CH2)n 1b Is it COOH, or X 1 is N and X 2 , NY 2 X 3 NH and Y 2 is -CH2OCO(CH2CH2O)n 2a Z 2 Alternatively, -CH2OCO(CH2)n 2b Is it COOH, or X 1is N and X 2 NH and X 3 , NY 3 Y 3 is -CH2OCO(CH2CH2O)n 3a Z 3 Alternatively, -CH2OCO(CH2)n 3b It is COOH.

[0179] In a particular embodiment, in formula (I) above, n 1 is either 0, 1, 2, 3, 4, 5, 6, 7, or 8, or 1-3, 4-6, or 7-8. n 2 is either 0, 1, 2, 3, 4, 5, 6, 7, or 8, or 1-3, 4-6, or 7-8. n 3 is either 0, 1, 2, 3, 4, 5, 6, 7, or 8, or 1-3, 4-6, or 7-8. n 1a is either 0, 1, 2, 3, 4, 5, 6, 7, or 8, or 1-3, 4-6, or 7-8. n 2a is either 0, 1, 2, 3, 4, 5, 6, 7, or 8, or 1-3, 4-6, or 7-8. n 3a is either 0, 1, 2, 3, 4, 5, 6, 7, or 8, or 1-3, 4-6, or 7-8. n 1b is either 0, 1, 2, 3, 4, 5, 6, 7, or 8, or 1-3, 4-6, or 7-8. n 2b is either 0, 1, 2, 3, 4, 5, 6, 7, or 8, or 1-3, 4-6, or 7-8. n 3b It is either 0, 1, 2, 3, 4, 5, 6, 7, or 8, or 1-3, 4-6, or 7-8.

[0180] In a particular embodiment, in formula (I) above, M 1 These are methyl, ethyl, propyl, or phenyl. M 2 These are methyl, ethyl, propyl, or phenyl. M 3 These are methyl, ethyl, propyl, or phenyl. Z 1 These are methyl, ethyl, propyl, or phenyl. Z 2 These are methyl, ethyl, propyl, or phenyl. Z 3 These are methyl, ethyl, propyl, or phenyl.

[0181] In a particular further embodiment, n 1 , n 2 , or n 3 is 2, 3, or 4, and / or n 1a , n 2a , or n 3a is 2, 3, or 4, and / or n 1b , n 2b , or n 3b The answer is 2, 3, or 4.

[0182] In certain specific embodiments, the axitinib prodrug used in the implant according to the present invention is selected from: axitinib-N-succinoyloxymethyl prodrug, axitinib-N-mPEG-oxymethyl prodrugs including, but not limited to, axitinib-Nm(PEG)1-oxymethyl, axitinib-Nm(PEG)2-oxymethyl, axitinib-Nm(PEG)3-oxymethyl, axitinib-Nm(PEG)4-oxymethyl, or salts or solvates thereof as shown below.

[0183] Axitinib prodrugs, particularly those having hydrophilic substituents as disclosed herein, may exhibit higher solubility than axitinib free base. Such prodrugs may have solubility at least 2 times, at least 5 times, at least 10 times, at least 25 times, at least 50 times, at least 75 times, at least 100 times, at least 150 times, at least 200 times, at least 250 times, or at least 500 times, or at least 1000 times, compared to a comparative implant in which the solubility of axitinib (e.g., axitinib free base) present in the implant is lower than that of the axitinib prodrug. While we do not wish to be limited by this theory, the increased solubility of the axitinib prodrugs disclosed herein may accelerate the release of axitinib from the implant according to the present invention compared to a comparative implant in which the solubility of axitinib present in the implant (e.g., axitinib free base) is lower than that of the axitinib prodrug.

[0184] The axitinib prodrug for use in the implant of the present invention may have a solubility of at least 50 μg / mL, or at least 90 μg / mL, or at least 150 μg / mL, or at least 200 μg / mL after 24 hours at 22°C in PBS at pH 7.4.

[0185] The following are exemplary axitinib prodrugs used in the implants of the present invention: [ka] [ka] [ka] [ka] [ka]

[0186] Exemplary synthesis and solubility of axitinib prodrugs are disclosed in Examples 5.1 and 5.2. The solubility of axitinib prodrugs is shown in Example 6.

[0187] Axitinib prodrugs suitable for use in implants according to the present invention, as well as their synthesis and properties, are disclosed in concurrently pending international applications PCT / US2023 / 035121 and PCT / US2022 / 046750 (published as WO2023 / 064578A1), which are incorporated by reference. Further axitinib prodrugs suitable for use in implants according to the present invention are disclosed in US2021 / 0078970. All axitinib prodrugs disclosed in any of these references, but not limited to those disclosed therein, are generally suitable for use in the present invention.

[0188] solubility The solubility of the TKI, and in particular the solubility of axitinib in certain embodiments of the present invention, is one of the factors that influence the release profile of axitinib from the implant according to the present invention. The solubility of the free base of axitinib, particularly polymorph SAB-I, is relatively low in physiological environments or similar aqueous solvent systems, such as PBS, which limits the rate of release of the drug from the hydrogel-containing implant, where the release of the drug is caused by solubility and diffusion.

[0189] Accordingly, in certain embodiments, the present invention relates to a sustained-release biodegradable ophthalmic implant containing a TKI, the solubility of which axitinib, including any form of axitinib disclosed herein, is 0.3 μg / mL or greater than 0.3 μg / mL after incubation for 5 days at 37°C at pH 7.2-7.4 in phosphate-buffered saline (PBS), for example, at least 0.4 μg / mL, or at least 0.5 μg / mL, or at least 0.6 μg / mL, at least 0.7 μg / mL, at least 0.8 μg / mL, at least 1 μg / mL, at least 2.5 μg / mL, at least 5 μg / mL, at least 10 μg / mL, at least 20 μg / mL, at least 50 μg / mL, at least 100 μg / mL, at least 150 μg / mL, or at least 200 μg / mL. The pH values ​​of 7.2–7.4 referred to herein include the individual values ​​of 7.2, 7.3, and 7.4. In certain embodiments of the present invention, where the TKI is axitinib, the solubility of axitinib used in the sustained-release biodegradable ophthalmic implant of the present invention is higher than that of axitinib polymorph SAB-I, for example, at least 1.5 times the solubility of axitinib polymorph SAB-I, for example, at least about 2 times the solubility of axitinib polymorph SAB-I, for example, at least 2.3 times the solubility of axitinib polymorph SAB-I.

[0190] In certain embodiments, the solubility of a TKI, such as axitinib, in any embodiment of the present invention is 0.3 μg / mL or greater (e.g., at least 0.4 μg / mL, or at least 0.5 μg / mL, or at least 0.6 μg / mL, at least 0.7 μg / mL, at least 0.8 μg / mL, at least 1 μg / mL, at least 2.5 μg / mL, at least 5 μg / mL, at least 10 μg / mL, at least 20 μg / mL, at least 50 μg / mL, at least 100 μg / mL, at least 150 μg / mL, or at least 200 μg / mL) after incubation for 5 days at 37°C at pH 7.2 in PBS. Therefore, any form of axitinib that satisfies any of these solubility ranges (such as axitinib polymorphs, cocrystals, and prodrugs disclosed herein) has higher solubility under these same conditions as axitinib (free base) polymorph SAB-I, which has solubility of approximately 0.2 μg / mL and less than 0.3 μg / mL, as shown in Example 6. Example 6 also includes details of the solubility measurement conditions, similar to Figure 17. Specifically, axitinib polymorph SAB-I has an equilibrium solubility of approximately 0.191 to approximately 0.252 μg / mL (measured by UPLC) after 5 days at 37°C at pH 7.4 in PBS, or an average solubility of approximately 0.223 μg / mL under these conditions, depending on its particle size, i.e., whether it is in a micronized form or not (or the degree of micronization). For example, the non-micronized, micronized, and ultramicronized axitinib polymorph SAB-I have equilibrium solubility of approximately 0.191, 0.226, and 0.252 μg / mL (measured by UPLC) after 5 days at 37°C at pH 7.4 in PBS, respectively. See Example 6. Polymorph IV is an axitinib polymorph particularly suitable for use in all aspects of the present invention. Its solubility is, for example, about twice that of polymorph SAB-I (again, see Example 6 and Figure 17), as disclosed herein. Specifically, axitinib polymorph IV has an equilibrium solubility of approximately 0.435 μg / mL (measured by UPLC) after 5 days at 37°C at pH 7.4 in PBS, for example, in the micronized form (as defined herein). See Example 6.Therefore, in certain embodiments, the implant of the present invention comprises axitinib polymorph IV. In certain embodiments, at least 90% by weight, or at least 95% by weight, of the axitinib contained in the implant of the present invention is axitinib polymorph IV.

[0191] While we do not intend to limit ourselves to this theory, increased solubility of axitinib (e.g., in specific prodrug, cocrystal, or polymorphic form) disclosed herein may accelerate the release of axitinib from implants according to the present invention compared to comparative implants in which the solubility of axitinib (e.g., free base of axitinib, e.g., polymorph SAB-I) present in the implant is lower. This increase in solubility may manifest in an in vitro release study disclosed herein as a higher release rate (amount of axitinib released per day) in the study for one day or longer, and / or as a higher average release rate per day (as defined herein) over a specific number of days, and / or as an increase in the cumulative amount of axitinib released over a specific period (e.g., one day or longer), and / or as an increase in the share / ratio (%) of the total amount of axitinib contained in the implant released per day or over a specific period (any number of days), and / or as an increase in the share / ratio (%) of the total amount of axitinib released in a particular in vitro study.

[0192] Therefore, providing an implant containing a TKI with increased solubility constitutes a method (in vivo or in vitro) of increasing the daily release rate and / or the average daily release rate over a particular period, and / or the percentage of TKI released on one or more individual days, and / or the cumulative percentage of TKI released over a particular period (based on the total released TKI), and / or the absolute amount of TKI released on one or more individual days or over a particular period. Accordingly, the present invention also relates to a method of increasing the release rate and / or average release rate and / or release amount of the total TKI contained in the implant, and / or the release ratio of the total TKI contained in the implant, or the total TKI released from the implant over a particular period, compared to a known implant containing TKI.

[0193] amount / dose The TKI is incorporated into the implant of the present invention in various doses. The amount of TKI incorporated into the implant is expressed herein in units of "μg" or "mg". When the TKI used in accordance with the present invention is axitinib, the amount / dose of axitinib expressed herein refers to the amount of free base of axitinib (as may be expressed in units of μg or mg), including any (anhydrous) axitinib polymorph, e.g., those further disclosed herein, in particular polymorph IV. When axitinib salts, cocrystals, derivatives, or prodrugs (which have different molecular weights than the free base of axitinib) are used, the amount expressed is the amount of the corresponding free base of axitinib unless otherwise specified.

[0194] The TKI, for example, axitinib, is generally included in the implant of the present invention in a dose range of at least 150 μg, for example, about 150 μg to about 1000 μg, about 150 μg to about 900 μg, or about 200 μg to about 800 μg, or about 250 μg to about 700 μg, or about 300 to about 650 μg. Any amount of any TKI, for example, axitinib, within these ranges may be included in the implant of the present invention. If axitinib is used in a form other than free base, the implant of the present invention may contain a dose equivalent to the free base of the mentioned dose of axitinib. For the purposes of this disclosure, when speaking about the dose of a TKI, for example, axitinib, included in the implant, all mentioned values ​​are intended to include variations of +25% and -20%, or + / -10%.

[0195] In a particular embodiment of the present invention, the dose of axitinib contained in the implant (this dose is intended to refer to the amount of free axitinib base, or the amount of another form of axitinib corresponding to the enumerated amount of free axitinib base, e.g., axitinib cocrystal or prodrug) is: - A range of approximately 120 μg to 187.5 μg, or approximately 135 μg to 165 μg, or approximately 150 μg (i.e., including variations of +25% and -20% or + / -10% from 150 μg) - A range of approximately 240 μg to 375 μg, or approximately 270 μg to 330 μg, or approximately 300 μg (i.e., including variations of +25% and -20% or + / -10% from 300 μg) - A range of approximately 360 μg to 562.5 μg, or approximately 400 μg to 500 μg, or approximately 405 μg to 495 μg, or approximately 450 μg (i.e., including variations of +25% and -20% or + / -10% from 450 μg) - The range is approximately 480 μg to 750 μg, or approximately 540 μg to 660 μg, or approximately 600 μg (i.e., including variations of +25% and -20% or + / -10% from 600 μg).

[0196] In one particular embodiment, the dose of axitinib contained in one implant of the present invention is 100–200 μg, or about 150 μg. In a further particular embodiment, the axitinib in such implant is in the form of a free base of axitinib.

[0197] In one particular embodiment, the dose of axitinib contained in one implant of the present invention is 200–400 μg, for example, 250–350 μg, or about 300 μg. In a further particular embodiment, the axitinib in such implant is in the form of a free base of axitinib.

[0198] In one particular embodiment, the dose of axitinib contained in one implant of the present invention is 300 to 600 μg, for example, about 360 μg to about 562.5 μg, or 400 to 500 μg, or about 450 μg. In a further particular embodiment, the axitinib in such implant is in the form of a free base of axitinib.

[0199] In another specific embodiment, the dose of axitinib contained in one implant of the present invention is about 400 to 800 μg, for example, about 480 μg to about 750 μg, or 500 to 700 μg, or about 600 μg. In a further specific embodiment, the axitinib in such implant is in the form of a free base of axitinib.

[0200] In another specific embodiment, the dose of axitinib contained in one implant of the present invention is about 400–1000 μg, about 480 μg–about 800 μg, about 480 μg–about 750 μg, or 500–700 μg, or about 600 μg. In a further specific embodiment, the axitinib in such implant is in the form of axitinib free base. In a specific embodiment, the target dose of axitinib in the implant of the present invention, for example, axitinib polymorph IV, is 600 μg, which means the actual dose minus 20% and plus 25% thereof, i.e., about 480 μg–about 720 μg.

[0201] In one particular embodiment, the dose of axitinib contained in one implant of the present invention is 200 to 1000 μg.

[0202] In certain embodiments, the dose of axitinib contained in one implant of the present invention is about 250 to about 750 μg, for example, about 300 to about 600 μg, for example, about 350 to about 550 μg, for example, about 380 to about 520 μg, for example, about 420 to about 480 μg, for example, about 400 to about 500 μg, for example, about 420 to about 480 μg, for example, about 450 μg. In certain embodiments, the target (also called "indicated") dose of axitinib in the implant of the present invention, for example, axitinib polymorph IV, is 450 μg, which means the actual dose -20% and +25% thereof, i.e., about 360 μg to about 562.5 μg.

[0203] In the most specific embodiment, the implant according to the present invention contains axitinib in polymorph IV form in doses of approximately 400 μg to approximately 500 μg, for example, approximately 405 μg to approximately 495 μg, for example, approximately 410 μg to approximately 490 μg, or approximately 420 μg to approximately 490 μg, for example, approximately 420 μg to approximately 480 μg, for example, approximately 430 μg to approximately 480 μg, for example, approximately 425 μg to approximately 475 μg, for example, approximately 430 μg to approximately 470 μg, for example, approximately 440 μg to approximately 460 μg, for example, approximately 450 μg. In the implant of the present invention having a set (i.e., theoretical / represented) content of 450 μg or about 450 μg of axitinib (in particular, axitinib polymorph IV), the actual amount of (assay) axitinib contained in the implant may vary within the upper and lower limits of the range disclosed in the preceding sentence.

[0204] If axitinib is not in the form of free bases, but for example in the form of a cocrystal or prodrug, one implant may contain an amount of other axitinib such as the amount of free bases of axitinib mentioned.

[0205] The amounts of TKIs, e.g., axitinib, as disclosed herein, including the variations mentioned, refer to both the final content of the active ingredient in the implant and the amount of the active ingredient used as a starting component per implant during the manufacture of the implant. The total dose of a TKI, e.g., axitinib, administered to a patient may, in certain embodiments, comprise two or more implants administered simultaneously, as further disclosed herein. The dose may also comprise a multifilament implant, i.e., an implant according to the present invention, which is made from several filaments that are combined and optionally stretched and twisted to form a single composite strand, as further disclosed herein.

[0206] TKI particles A TKI, such as axitinib, is included in the implant of the present invention and is dispersed or distributed in a hydrogel comprising a polymer network further disclosed herein. In certain embodiments, the particles are uniformly, or essentially uniformly, dispersed within the hydrogel. The hydrogel can prevent aggregation of the particles and provide a matrix for the particles that holds them in a desired position within the eye while gradually releasing the drug.

[0207] In certain embodiments of the present invention, the TKI particles, for example, axitinib particles, can be microencapsulated. The term “microcapsule” (also called “microparticle”) may be defined as a substantially spherical particle having a size that varies, for example, from about 50 nm to about 2 mm. A microcapsule has a separate domain (or core) of at least one active agent encapsulated in a surrounding material, which may also be called a shell. If a suitable agent for microencapsulating the TKI, for example, axitinib, is desired for the purposes of the present invention (without limiting this disclosure), one such agent is poly(lactic acid-coglycolic acid).

[0208] In other embodiments, the TKI particles may contain further compounds other than the TKI. These may be, for example, processing aids, stabilizers, fillers, etc. Sometimes, the active agent is routinely stabilized by the supplier by adding trace amounts of, for example, antioxidants or other stabilizers. This may also apply to the TKI used herein, for example, axitinib.

[0209] However, in certain embodiments, the TKI particles, for example, axitinib particles, are not microencapsulated and / or contain no further compounds, but are dispersed in the hydrogel and, by extension, the implant of the present invention, as received from the supplier, i.e., without being further mixed with or adjacent to another material, or without being microencapsulated.

[0210] In one embodiment, the TKI particles, for example, the axitinib particles, may be pulverized particles or even nano-sized particles. Pulverization refers to the process of reducing the average diameter of particles in a solid material. In another embodiment, the TKI particles, for example, the axitinib particles, may not be pulverized. In the field of composite materials, particle size is known to affect the mechanical properties when combined with a matrix, with smaller particles providing better reinforcement for a given mass fraction. Therefore, a hydrogel matrix filled with pulverized TKI particles may have improved mechanical properties (e.g., brittleness, fracture strain, etc.) compared with larger TKI particles of a similar mass fraction. Such properties are important in the processes of manufacturing, injecting, and disassembling the implant. Pulverization may also promote a more uniform distribution of the active ingredient in the selected dosage form or matrix. The particle size distribution can generally be measured by methods known in the art, including sieving, laser diffraction, or dynamic light scattering.

[0211] While we do not wish to be bound by theory, the particle size of the TKI particles may affect the release kinetics of the TKI from the implant according to the present invention. Smaller particles may, in some cases, have higher dissolution and erosion rates, which may, in some cases, increase the release rate from the implant and, consequently, increase the bioavailability of the TKI in the desired tissue. Furthermore, smaller particles, such as pulverized particles, may have a lower tendency to aggregate during manufacturing and processing, which may, in some cases, result in a more uniform distribution of the TKI particles within the hydrogel. Moreover, again, while we do not wish to be bound by theory, if the TKI particles are still present in the eye, for example, if the hydrogel has already completely dissolved before all the drug load of TKI has been released from the implant, smaller particles may, in some cases, have a lower tendency to aggregate and may be removed more quickly from the vitreous humor. This may be advantageous for repeated administration, for example, to avoid the accumulation of unremoved TKI particles over time in the vitreous humor.

[0212] In certain embodiments, the TKI, for example, the axitinib particles, as determined by laser diffraction, have a d90 particle diameter of less than 10 μm, or less than 8 μm, or less than 7 μm, or 7.5 μm or less, or 6.5 μm or less, or 5 μm or less, or less than 1 μm, or less than 0.5 μm, or less than 0.4 μm.

[0213] In certain embodiments, the TKI particles, for example, the axitinib particles, have a d50 particle diameter of less than 5 μm, less than 3 μm, less than 2.6 μm, less than 2 μm, less than 1.5 μm, less than 1 μm, less than 0.5 μm, less than 0.25 μm, or less than 0.2 μm, as determined by laser diffraction. In certain embodiments, the d50 particle diameter of the TKI particles, for example, the axitinib particles, included in the implant of the present invention is 0.15 μm or less, as determined by laser diffraction. In the latter case, the particles may be referred to herein as “nanoparticles”.

[0214] In certain embodiments, the TKI, for example, the axitinib particles, as determined by laser diffraction, have a d10 particle diameter of less than 1 μm, less than 0.5 μm, 0.25 μm or less, 0.2 μm or less, or less than 0.1 μm.

[0215] In certain embodiments, the TKI present in the implant of the present invention is the free base of axitinib (any polymorphic phase disclosed herein), and the axitinib particles have a d10 particle diameter of less than 8 μm, a d50 particle diameter of less than 20 μm, and / or a d90 particle diameter of less than 50 μm. These particles may be referred to herein as “non-micronized particles.”

[0216] In other specific embodiments, the TKI present in the implant of the present invention is the free base of axitinib (any polymorph phase disclosed herein, including axitinib polymorph IV), and the axitinib particles have a d10 particle diameter of less than 0.25 μm, a d50 particle diameter of less than 3 μm or less than 2.6 μm, and a d90 particle diameter of less than 8 μm or less than 6.5 μm. These particles may also be referred to herein as “micronized particles.” In specific embodiments, the particle diameters of the axitinib, particularly axitinib polymorph IV, contained in the implant of the present invention are, as determined by laser diffraction, less than 0.25 μm for the d10 particle diameter, less than 2.6 μm for the d50 particle diameter, and less than 8 μm for the d90 particle diameter.

[0217] In other specific embodiments, the TKI present in the implant of the present invention is the free base of axitinib (any polymorphic phase disclosed herein), and the axitinib particles have, as identified by laser diffraction, a d10 particle diameter of less than 0.2 μm, a d50 particle diameter of less than 1.5 μm, and a d90 particle diameter of less than 5 μm. These particles may also be referred to herein as “ultrafine particles”.

[0218] In other specific embodiments, the TKI present in the implant of the present invention is the free base of axitinib (in particular any polymorph phase disclosed herein, including polymorph IV), and the axitinib particles have, as identified by laser diffraction, a d10 particle diameter of less than 0.1 μm, a d50 particle diameter of less than 0.2 μm, and a d90 particle diameter of less than 0.4 μm. These particles may also be referred to herein as “nanoparticles”.

[0219] Generally, micronized TKIs, such as axitinib particles, may be purchased from suppliers according to specifications, or they may be prepared according to the exemplary procedure for axitinib disclosed, for example, in WO2016 / 183296A1, Example 13. That is, 1800 mL of sterile water for injection (WFI) is measured into a 2 L beaker, placed on a stirring plate, and stirred at 600 RPM using a stirring bar to create a large vortex of WFI in the center of the beaker. A 60 mL BD syringe containing ethanol with axitinib is placed on a syringe pump fixed above this WFI beaker. A subcutaneous injection needle (21G, BD) is connected to this syringe and directed directly to the center of the vortex to dispense the axitinib solution. The syringe pump is then operated at 7.5 mL / min to drop the axitinib solution into its WFI to precipitate the micronized axitinib. After micronization, axitinib is filtered, for example, through a 0.2 μm vacuum filter and rinsed with WFI. After filtration, the axitinib powder is collected from the filter, for example, using a spatula, and vacuum-dried for a long period, for example, about 12 to about 24 hours, to remove excess solvent. Another exemplary method for micronizing axitinib is disclosed in Example 9 of WO2017 / 091749. The micronization methods described herein are not limiting, and other micronization methods for the active agent, e.g., axitinib, may be used equally. The micronization methods (or other methods) of this disclosure may also be used for TKIs other than axitinib.

[0220] Polymer network: The sustained-release biodegradable ophthalmic implant of the present invention comprises a hydrogel and TKI particles dispersed within the hydrogel. The hydrogel stably releases the active agent embedded within it over time. In certain embodiments, this is achieved by forming the hydrogel from a single material, for example, a PEG precursor according to the present invention, further disclosed herein. While we do not wish to be bound by theory, this stable release is achieved, among other things, because the rate of release of the active agent from the hydrogel is controlled by dissolution (without erosion or degradation / channel formation as in other matrix materials, e.g., PLGA), and because the release occurs throughout the entire process. Generally, hydrogels are inert, do not interact or react with the physiological environment in which they are placed, and have good biocompatibility, not essentially altering, or at least not significantly altering, the physiological environment, such as the local pH in the eye. Furthermore, the low rigidity and high flexibility of hydrogels result in good compatibility with the physical environment, such as internal tissues when inserted into the body of a human or animal. This is particularly advantageous for the injection / insertion into the vitreous fluid of an implant comprising a hydrogel in which TKI particles are dispersed, such as a PEG hydrogel, according to the present invention. Generally, the flexibility of the hydrogel forming the implant of the present invention greatly reduces the possibility of irritation (including foreign body sensation) or harm to ocular tissue, such as the retina.

[0221] One method for evaluating the rigidity or flexibility of the implant of the present invention is, for example, by measuring its modulus of elasticity.

[0222] In certain embodiments, the hydrogel may be formed from a precursor having functional groups that form crosslinks that create a polymer network. These crosslinks between polymer chains or arms may be essentially chemical (i.e., covalent) and / or physical (e.g., ionic, hydrophobic association, hydrogen bonding).

[0223] The polymer network may be prepared from any precursor capable of forming a polymer network that is a hydrogel, from one type of precursor or from two or more types of reactable precursors. The precursor is selected considering the desired properties of the resulting hydrogel. A variety of precursors are available that are suitable for use in the preparation of hydrogels. In general, any pharmaceutically acceptable and crosslinkable polymer that forms a hydrogel may be used for the purposes of the present invention. The polymer forming the hydrogel may be a homopolymer or a copolymer. The copolymer may be a random copolymer or a block copolymer. The hydrogel, and by extension the components including the polymers used to prepare the polymer network incorporated therein, should be physiologically safe, for example, so that they do not induce immune responses or other side effects. The hydrogel may be formed from natural polymers, synthetic polymers, or biosynthetic polymers.

[0224] Examples of natural polymers include glycosaminoglycans, polysaccharides (e.g., dextran), polyamino acids, proteins, or mixtures or combinations thereof.

[0225] Synthetic polymers may generally be any polymer synthesized from various raw materials by various types of polymerization, including free radical polymerization, anionic polymerization or cationic polymerization, chain growth or addition polymerization, condensation polymerization, ring-opening polymerization, etc. The polymerization may be initiated by light and / or heat with a specific initiator, or mediated by a catalyst. In certain embodiments, synthetic polymers may be used to reduce the possibility of allergies in implants that do not contain any human or animal-derived components.

[0226] In general, for the purposes of the present invention, one or more synthetic polymers from the following list (not intended to be limiting) may be used to form the hydrogel according to the present invention: one or more (identical or different) units of polyalkylene glycol, e.g., polyalkylene glycol, e.g., polyethylene glycol (PEG), polypropylene glycol, poly(ethylene glycol)-block-poly(propylene glycol) copolymer, polyethyleneimine, polyalkyl ether, e.g., polyethylene oxide, polypropylene oxide, polyacrylic Acids, acrylate polymers, polyelectrolyte complexes, starch graft polymers, polymaleic acid, polyvinylamine polyacrylamide, poly(hydroxyethyl-methyl acrylate) (PHEMA), polybutylene terephthalate (PBT), polyvinyl alcohol, poly(vinyl acetate), poly(vinylpyrrolidinone), poly(vinylpyrrolidone) (PVP), polyglycolic acid, polylactic acid (PLA), polylactic acid-coglycolic acid (PLGA), water-swellable N-vinyl lactam, ester-crosslinked polyglucan, polydioxanone, and polytrimethylene carbonate. These may be used individually or in combination to form hydrogels. Any polymer capable of forming hydrogels and being biocompatible may be used in the implants according to the present invention.

[0227] The polymers forming the hydrogel may be in the form of homopolymers or copolymers, such as random or block copolymers. Any combination / mixture of any of the monomers mentioned may be used to form a hydrogel. The above list is not intended to be limiting, and other polymers / polymer combinations capable of forming hydrogels, not specifically mentioned, may be used equally.

[0228] In the present invention, PEG polymers are particularly suitable for forming hydrogels for implants according to the present invention, as further disclosed below. Therefore, in certain embodiments of the present invention, the hydrogel comprises a network formed by crosslinking of PEG units (i.e., it is a PEG hydrogel). Specific PEG units that can be crosslinked to form hydrogels according to the present invention are disclosed herein. However, hydrogels formed from polymer networks other than PEG are also suitable for implants according to the present invention if such other hydrogels provide properties comparable to or similar to those of the PEG hydrogels disclosed herein.

[0229] Precursors can be covalently crosslinked to form a polymer network crosslinked by covalent bonds. In certain embodiments, a precursor having at least two reaction centers (for example, in free radical polymerization) can function as a crosslinking agent because each reactive group can participate in the formation of different grown polymer chains.

[0230] The precursor may have a biologically inert and hydrophilic portion, such as a core. In the case of branched polymers, the core refers to a continuous portion of molecules linked to arms extending from the core, and the arms have functional groups, which are often located at the ends of the arms or branches. Multi-armed PEG precursors are examples of such precursors, which are further disclosed below herein.

[0231] The precursor may have a first functional group capable of reacting with a second functional group, which is a functional group further disclosed herein and which can react with each other. The functional groups are configured to react with each other, for example, in an electrophile-nucleophile reaction, or to participate in other polymerization reactions. Nucleophiles that can be used in the present invention may include amines, e.g., primary amines, hydroxyls, thiols, carboxyls, dibenzocyclooctin, or hydrazides. Electrophiles that can be used in the present invention may include succinimidyl esters, succinimidyl carbonates, nitrophenyl carbonates, aldehydes, ketones, acrylates, acrylamides, maleimides, vinyl sulfones, iodoacetamides, alkenes, alkynes, azides, norbornene, epoxides, mesylates, tosylates, tresyl, cyanurates, orthopyridyl disulfide, or halides. Electrophilic and nucleophilic precursors suitable for forming the polymer network are further disclosed herein.

[0232] In addition to classical electrophilic-nucleophilic condensation reactions, other types of chemical reactions based on electrophiles and nucleophiles can also be used in the present invention. For example, precursors can be crosslinked via so-called click chemistry reactions. Functional groups suitable for click chemistry are those that enable click chemistry reactions, such as strain-promoting alkyne-azide cycloaddition (SPAAC), also known as copper catalyst-free click reactions, or reverse electron-demanding Diels-Alder ligation (IEDDA) type click chemistry coupling reactions. An overview of such reaction types is presented by reference in H.Colb; M.G.Finn; K.B.Sharpless (2001). “Click Chemistry: Diverse Chemical Function from a Few Good Reactions”, Angewandte Chemie International Edition, 40(11):2004-2021). The coupling reactions of SPAAC and IEDDA are bioorthogonal reactions with selective and quantitative yields under mild conditions that can occur even within biological systems without interfering with natural biochemical processes. These click chemistry reactions utilize a pair of functional groups that react mutually and efficiently while remaining inert to naturally occurring functional groups. Suitable functional groups include moieties selected from the group consisting of alkynes, cycloalkynes, e.g., dibenzocyclooctyne (DBCO), or bicyclo[6.1.0]-nonine (BCN), strained or terminal alkenes, e.g., norbornene, or trans-cyclooctene (TCO), azides, or tetrazine (Tz).

[0233] The hydrogels used in the present invention can be prepared, for example, from one multi-arm precursor having a first set of functional groups and another multi-arm precursor having a second set of functional groups. For example, the multi-arm precursor may have hydrophilic arms, such as polyethylene glycol units with primary amines (nucleophiles) at their ends, or activated ester end groups (electrophiles). The polymer network according to the present invention may contain identical or different polymer units that are crosslinked with each other.

[0234] Certain functional groups can be prepared with high reactivity by using activating groups. Examples of such activating groups include (but are not limited to) carbonyl diimidazole, sulfonyl chloride, aryl halides, sulfosuccinimidyl esters, N-hydroxysuccinimidyl esters, succinimidyl esters, epoxides, aldehydes, maleimides, imide esters, and acrylates. N-hydroxysuccinimidyl esters (NHS) are useful groups for crosslinking nucleophilic polymers, such as polyethylene glycol with primary amine or thiol terminology. The NHS-amine crosslinking reaction may be carried out in aqueous solution in the presence of a buffer (e.g., phosphate buffer (pH 5.0-7.5), triethanolamine buffer (pH 7.5-9.0), borate buffer (pH 9.0-12), or sodium bicarbonate buffer (pH 9.0-10.0).

[0235] In certain embodiments, each precursor may contain only nucleophilic functional groups or only electrophilic functional groups, insofar as both the nucleophilic and electrophilic precursors are used in the crosslinking reaction. 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. Therefore, the polymer network of the present invention can also be prepared using functional polymers (e.g., proteins, poly(allylamines), or amine-terminated bifunctional or polyfunctional poly(ethylene glycols)).

[0236] In one embodiment, the first reactive precursor each has about 2 to about 16 nucleophilic functional groups (referred to as functionality), and the second reactive precursor that reacts with the first reactive precursor to form a polymer network each has about 2 to about 16 electrophilic functional groups. Reactive precursors having a number of reactive (nucleophilic or electrophilic) groups that is a multiple of 4, and therefore for example, 4, 8, and 16 reactive groups, are particularly suitable for the present invention. Any number of functional groups, for example, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 groups, are possible for precursors used in the present invention while ensuring sufficient functionality to form a properly crosslinked network. It is particularly suitable when the molar ratio of nucleophiles in one precursor to electrophiles in the second precursor is approximately equal.

[0237] PEG hydrogel: In certain embodiments of the present invention, the polymer network forming the hydrogel comprises polyethylene glycol (PEG) units. PEG is known in the art to form hydrogels when crosslinked, and these PEG hydrogels are generally biocompatible and therefore suitable for pharmaceutical applications, such as matrices for drugs intended to be administered to any part of the human or animal body.

[0238] The PEG hydrogels are particularly suitable for forming implants for insertion into ocular tissue, such as the vitreous fluid. Because they are soft and gentle on ocular tissue, they reduce the likelihood of local irritation, discomfort (e.g., foreign body sensation), or damage to ocular tissue (e.g., the retina). Furthermore, the PEG hydrogels allow for the stable release of TKIs, such as axitinib, into the vitreous fluid and from there to be stable delivery to ocular tissue, such as the retina and choroid / RPE. The release of TKIs, such as axitinib, from the PEG hydrogels is essentially diffusion-limited. After the final biodegradation of the hydrogel (as further described herein), any remaining TKIs, such as axitinib, are released into the vitreous fluid, where they dissolve and are further delivered into the ocular tissue, filling their window until a new implant is administered. Implants according to the present invention, including the PEG hydrogels and axitinib, such as axitinib polymorph IV as further described herein, can be administered repeatedly. In certain embodiments, the readmission period in human patients is approximately 6 to 12 months, for example, about 9 months.

[0239] The polymer network of the hydrogel implant of the present invention may include one or more, i.e., identical or different multi-armed PEG units. They may have 2 to 10 arms, or 4 to 8 arms, or 4, 5, 6, 7, or 8 arms. The PEG units may have different or equal numbers of arms. Any combination of multi-armed PEG precursors is possible. In certain embodiments, the PEG units used in the hydrogel of the present invention have 4 and / or 8 arms. In certain embodiments, a combination of 4-armed and 8-armed PEG units is utilized.

[0240] The number of arms of the PEG used contributes to controlling the flexibility or softness of the resulting hydrogel. For example, a hydrogel formed by crosslinking 4-arm PEGs is generally softer and more flexible than one formed from 8-arm PEGs of the same molecular weight. In particular, if it is desired to stretch the hydrogel before or after drying, as disclosed herein below in the section relating to the manufacture of the implant, a more flexible hydrogel, such as a 4-arm PEG, may optionally be used in combination with another multi-arm PEG, such as an 8-arm PEG as disclosed above.

[0241] In certain embodiments of the present invention, the polyethylene glycol units used as precursors have an average molecular weight in the range of about 2,000 to about 100,000 daltons, or about 5,000 to about 60,000 daltons, or about 10,000 to about 60,000 daltons, or about 10,000 to about 50,000 daltons. In certain specific embodiments, the polyethylene glycol units have an average molecular weight in the range of about 10,000 to about 40,000 daltons, or about 15,000 to about 40,000 daltons, or about 15,000 to about 30,000 daltons, or about 15,000 daltons or about 20,000 daltons. PEG precursors with the same average molecular weight may be used, or PEG precursors with different average molecular weights may be combined. Again, any combination of PEG precursors having any molecular weight disclosed herein is possible. The average molecular weight of the PEG precursor used in the present invention is given as the number-average molecular weight (Mn), which in certain embodiments may be determined by MALDI.

[0242] In a 4-arm PEG, each arm may have an average arm length (or molecular weight) obtained by dividing the total molecular weight of PEG by 4. Thus, a 4a20kPEG precursor, one of the specific precursors that can be used in the present invention, has four arms, each with an average molecular weight of approximately 5,000 daltons. An 8a20kPEG precursor, which can be used in the present invention, for example, alone or in addition to the 4a20kPEG precursor of the present invention, therefore has eight arms, each with an average molecular weight of approximately 2,500 daltons. An 8a15kPEG precursor, which can be used in the present invention, for example, alone or in addition to the 4a20kPEG and / or 8a20kPEG precursors, therefore has eight arms, each with an average molecular weight of approximately 1,875 daltons.

[0243] Longer arms may be more flexible than shorter arms. PEGs with longer arms may swell more than PEGs with shorter arms. Also, PEGs with fewer arms may swell more and be more flexible than PEGs with more arms. In certain embodiments, combinations of PEG precursors with different numbers of arms, for example, a combination of a 4-arm PEG precursor and an 8-arm precursor, may be used in the present invention. Furthermore, longer PEG arms result in a higher melting temperature during drying, which may improve dimensional stability during storage.

[0244] When referring to PEG precursors having a particular average molecular weight, e.g., 15kPEG or 20kPEG precursors, the indicated average molecular weight (i.e., Mn of 15,000 or 20,000, respectively) refers to the PEG portion of the precursor before the addition of the end groups ("20k" here means 20,000 daltons, and "15k" means 15,000 daltons; the same abbreviations are used herein for other average molecular weights of PEG precursors). In certain embodiments, the average molecular weight of the PEG precursor used in the present invention is given as the number-average molecular weight (Mn), which in certain embodiments may be specified by MALDI. The degree of substitution by the end groups disclosed herein is after the functionalization of the end groups.1 It can be identified by 1H-NMR.

[0245] In certain embodiments, the electrophilic end groups for use with the PEG precursor for the preparation of the hydrogel of the present invention are N-hydroxysuccinimidyl (NHS) esters, one or more of the following: succinimidylazelate (SAZ) group, succinimidyladipate (SAP) group, succinimidylglutarate (SG) group, succinimidylglutaramide (SGA) group, succinimidylcarbonate (SC) group, or succinimidylsuccinate (SS) group, particularly succinimidylazelate (SAZ) group. PEG precursors containing different groups from these may be combined, for example, SAZ and SG.

[0246] In certain embodiments, the nucleophilic end group for reaction with the electrophile-containing PEG precursor for preparing the hydrogel of the present invention is an amine (indicated as "NH2")-terminated crosslinking agent. Thiol (-SH)-terminated groups or other nucleophilic end groups are also possible. In certain embodiments, the nucleophile-containing crosslinking agent may be an amine, a multi-armed amine, or a salt of any of these, or an amine-substituted PEG. In certain embodiments, the nucleophile-containing crosslinking agent is trilidine, or a salt or derivative thereof, such as trilidine acetate (TLA). In other specific embodiments, the nucleophile-containing agent is an amine-containing multi-armed PEG precursor, such as 8a20kPEG-NH2 or a similar type of amine-containing precursor with a different number of arms and / or different molecular weights.

[0247] In certain preferred embodiments, 4-armed PEG having an average molecular weight of about 20,000 daltons and having the electrophilic end groups disclosed above, for example, N-hydroxysuccinimidyl (NHS) ester end groups, and similarly 8-armed PEG having an average molecular weight of about 20,000 daltons and having the nucleophilic end groups disclosed above, for example, amine (-NH2) end groups, are crosslinked to form a polymer network and, by extension, a hydrogel according to the present invention.

[0248] Reactions between nucleophilic PEG units and electrophilic PEG units, for example, between amine-terminated PEG units and active ester-containing PEG units, yield multiple PEG units crosslinked by a hydrolyzable linker having the following formula: [ka] In the formula, m is an integer from 0 to 10, in particular 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In one particular embodiment, for example, when a PEG containing a SAZ-terminated group is used, m is 6. For an SAP-terminated group, m is 3; for an SG-terminated group, m is 2; and for an SS-terminated group, m is 1. All crosslinks within the polymer network may be the same or different. Any combination of crosslinks is possible within the polymer network.

[0249] The same hydrolyzable linker having the same meaning for m can also be obtained from the reaction of an active ester group-containing PEG unit with a multiamine, such as trilidine or trilidine acetate, as a nucleophilic crosslinking agent.

[0250] In certain preferred embodiments, the SAZ terminal group of the PEG precursor is used in the present invention. This terminal group can extend the persistence of the hydrogel in the eye. Implants of certain embodiments of the present invention, comprising a hydrogel containing PEG-SAZ units, are biodegradable in the eye, for example, in the vitreous fluid of the human eye, for extended periods, for example, after about 6 to about 12 months, as further disclosed below, and may persist even longer under certain circumstances. The SAZ group is more hydrophobic than, for example, SAP, SG, or SS terminal groups, because it has a higher number of carbon atoms in the chain (m is 6, and the total number of carbon atoms in the amide and ester groups is 7). As a result, this linker group is less prone to ester cleavage in aqueous (e.g., physiological) environments compared to other shorter linker groups.

[0251] In certain specific embodiments, a 20,000 Dalton 4-arm PEG precursor is combined with a 20,000 Dalton 8-arm PEG precursor, for example, a 20,000 Dalton 4-arm PEG precursor having a SAZ group (disclosed above) is combined with a 20,000 Dalton 8-arm PEG precursor having an amine group (disclosed above). These precursors are also abbreviated herein as 4a20kPEG-SAZ and 8a20kPEG-NH2, respectively. Thus, in certain specific embodiments, the polymer network according to the present invention is a PEG hydrogel network formed by crosslinking of 4a20kPEG-SAZ and 8a20kPEG-NH2. The chemical structure of 4a20kPEG-SAZ is: [ka] Here, R represents the core structure of pentaerythritol. The chemical structure of 8a20kPEG-NH2 (which has a hexaglycerol core) is: [ka] In the above formula, n is determined by the molecular weight of each PEG arm.

[0252] Another possible PEG precursor containing an electrophile is the 4a20kPEG-SG precursor. The schematic chemical structure of 4a20kPEG-SG is reproduced below: [ka] In the above formula, n is determined by the molecular weight of each PEG arm.

[0253] In certain specific embodiments, the crosslinking agent used (also referred to herein as “crosslinker”) is a low molecular weight component containing a nucleophilic terminal group, such as an amine or thiol terminal group. In certain embodiments, the nucleophilic crosslinking agent is a low molecular weight amine having a molecular weight of less than 1,000 Da. In certain embodiments, the nucleophilic crosslinking agent contains two, three, or more primary aliphatic amine groups. Crosslinking agents suitable for use in the present invention include, but are not limited to, spermine, spermidine, lysine, dyridine, trilysine, tetralysine, polylysine, ethylenediamine, polyethyleneimine, 1,3-diaminopropane, 1,3-diaminopropane, diethylenetriamine, trimethylhexamethylenediamine, 1,1,1-tris(aminoethyl)ethane, their pharmaceutically acceptable salts, hydrates or other solvates, and their derivatives, such as conjugates (as long as sufficient nucleophiles are present for crosslinking), and mixtures thereof. Specific crosslinking agents used in the present invention are lysine-based crosslinking agents, such as trilysine or trilysine salts or derivatives. In certain embodiments of the present invention, the nucleophilic crosslinking agent for use with electrophilic group-containing PEG precursors (may include multiple) is torilidine or torilidine acetate (TLA). Other low molecular weight multi-armed amines may also be used. The chemical structure of torilidine is as follows: [ka]

[0254] In certain embodiments, the molar ratio of nucleophilic to electrophilic end groups that react with each other is approximately 1:1, i.e., one amine group is provided for each SAZ group. In the case of 4a20kPEG-SAZ and 8a20kPEG-NH2, the weight ratio is approximately 2:1, since the 8-armed PEG contains twice the amount of end groups as the 4-armed PEG. However, either electrophilic end groups (e.g., NHS end groups such as SAZ) or nucleophilic end groups (e.g., amines) may be used in excess. In particular, nucleophiles, such as amine-end group-containing precursors, may be used in excess, i.e., the weight ratio of 4a20kPEG-SAZ to 8a20kPEG-NH2 may be less than 2:1.

[0255] Each of the electrophile-containing PEG precursors and nucleophile-containing PEG precursors disclosed herein, and any combination thereof, may be used to prepare implants according to the present invention. For example, any 4-arm or 8-arm PEG-NHS precursor (e.g., having SAZ, SAP, SG, or SS terminal groups) may be combined with any 4-arm or 8-arm PEG-NH2 precursor (or any other PEG precursor having a nucleophile). Furthermore, the PEG units of the electrophile-containing precursor and the nucleophile-containing precursor may have the same average molecular weight or may have different average molecular weights.

[0256] Further ingredients: The implant of the present invention may include, in addition to the polymer units and active ingredients that form the polymer network as disclosed above, other further components. Such further components may include, for example, salts derived from buffers used during the preparation of the hydrogel, e.g., phosphates, borates, bicarbonates, or other buffers, e.g., triethanolamine. In certain embodiments of the present invention, sodium phosphate buffer (specifically monobasic and dibasic sodium phosphate) and / or sodium borate buffer are used. Any other buffer known in the art may be used in addition to or instead of sodium phosphate and / or sodium borate buffers to provide a pH value of about 6.5 to about 8.5, i.e., near neutral. The foregoing applies to the final composite solution of the electrophile-containing precursor and the nucleophile-containing precursor, e.g., a composite solution of buffers containing 4a20kPEG-SAZ and 8a20kPEG-NH2. The individual precursor solutions may have different pH values. For example, an electrophile-containing precursor (e.g., 4a20kPEG-SAZ) may be provided in a buffered solution with a pH of approximately 3.5 to 5.5, while a nucleophile-containing precursor (e.g., 8a20kPEG-NH2) may be provided in a buffered solution with a pH of approximately 6.5 to 8.

[0257] In certain embodiments, the implant of the present invention is free from antimicrobial preservatives or, at least, free from a substantial amount of antimicrobial preservatives (including, but not limited to, benzalkonium chloride (BAK), chlorobutanol, sodium perborate, and stabilized oxychloro complex (SOC)).

[0258] In further specific embodiments, the implant of the present invention contains only synthetic components and no animal or human-derived components.

[0259] In one embodiment of the present invention, if in-situ gelation is desired, possible further components may be other agents used in the process of producing the hydrogel, such as (but not limited to) viscosity-inhibiting agents (e.g., hyaluronic acid), surfactants, etc.

[0260] In certain embodiments, the implant of the present invention may include a visualization agent. In other embodiments, the implant of the present invention does not include a visualization agent. When the implant according to the present invention is located in the eye of a patient, it can be visualized by imaging techniques, such as slit-lamp (bioscopy), which can be performed, for example, by an ophthalmologist. Another technique for visualizing intraocular implants is cSLO (confocal laser scanning ophthalmography, sometimes also called IR or OCT). Neither of these two techniques requires a visualization agent such as a fluorescent agent.

[0261] Nevertheless, when a visualization agent is used in connection with the present invention, any agent that can be conjugated with the components of the hydrogel, or can be confined within the hydrogel, and is visible, or can become visible when exposed to light of a particular wavelength, or is a contrast agent may be used. Suitable visualization agents for use in the present invention include, but are not limited to, fluorophores. Suitable visualization agents for use in the present invention include, but are not limited to, fluorescein, rhodamine, coumarin, cyanine, europium chelate complexes, borondipyrromethene, benzofurazan, dansyl, viman, acridine, triazapentalene, pyrene, and their derivatives. In certain embodiments, the visualization agent is a fluorophore, such as fluorescein, or contains a fluorescein moiety. Visualization of an implant containing fluorescein is possible by illumination with blue light and a yellow filter. Fluorescein emits light when excited with blue light, allowing for confirmation of the presence of the implant.

[0262] In certain embodiments, the nucleophile-containing crosslinking agent may be bonded or conjugated with a visualization agent, for example, via some of the nucleophiles of the crosslinking agent. Since a sufficient amount of nucleophiles is required for crosslinking, "conjugated" generally includes partial conjugation, i.e., only some of the nucleophiles are used for conjugation with the visualization agent, for example, about 1% to about 20%, or about 5% to about 10%, or about 8% of the nucleophiles of the crosslinking agent may be conjugated with the visualization agent. In other embodiments, the visualization agent may also be conjugated with the polymer precursor, for example, via certain reactive (e.g., electrophilic) groups of the polymer precursor.

[0263] formulation: In certain embodiments, the implant according to the present invention comprises a TKI, a polymer network prepared in the form of a hydrogel from one or more polymer precursors disclosed herein, and optionally, further components remaining in the implant from the production process, such as salts (e.g., phosphates used as buffers). In certain embodiments, the TKI is axitinib. In certain specific embodiments, the axitinib is axitinib free base. In even more specific embodiments, the axitinib is axitinib polymorph IV.

[0264] The implant according to the present invention may have the following composition (anhydrous base, %w / w): about 10% to about 80% by weight, or about 20% to about 70% by weight of a TKI, e.g., axitinib, and about 10% to about 80% by weight, or about 20% to about 70% by weight of polymer units, e.g., PEG units.

[0265] In certain embodiments, the implant of the present invention may have the following composition (anhydrous base, %w / w): about 10% to about 40% by weight, or about 15% to about 25% by weight of axitinib, and about 55% to about 75% by weight, or about 60% to about 70% by weight of PEG units. In certain specific embodiments, the implant may have the following composition (wet base, %w / w): about 1% to about 8% by weight, or about 2% to about 7% by weight of axitinib, and about 5% to about 15% by weight, or about 6% to about 10% by weight of PEG units. These compositions are applicable to implants according to the present invention, particularly those containing axitinib in an amount equivalent to 100-200 μg, or about 120 μg-187.5 μg, or about 150 μg of axitinib free base (i.e., axitinib free base in any of its polymorphic phases, e.g., polymorph IV, or e.g., its cocrystal or prodrug form).

[0266] In certain other embodiments, the implant of the present invention may have the following composition (anhydrous base, %w / w): about 30% to about 50% by weight, or about 40% to about 57% by weight of axitinib, and about 25% to about 50% by weight, or about 35% to about 45% by weight of PEG units. In certain specific embodiments, the implant may have the following composition (wet base, %w / w): about 4% to about 14% by weight, or about 7% to about 12% by weight of axitinib, and about 5% to about 15% by weight, or about 6% to about 10% by weight of PEG units. These compositions are applicable to implants according to the present invention, particularly those containing axitinib in an amount equivalent to 200-400 μg, or about 240-375 μg, or about 300 μg of axitinib free base (i.e., axitinib free base in any of its polymorphic phases, e.g., polymorph IV, or e.g., its cocrystal or prodrug form).

[0267] In certain other embodiments, the implant of the present invention may have the following composition (anhydrous base, %w / w): about 30% to about 70% by weight, e.g., about 40% to about 70% by weight, or about 45% to about 65% by weight, or about 50% to about 60% by weight, or about 60% to about 70% by weight of axitinib (e.g., axitinib polymorph IV); and about 20% to about 50% by weight, or about 25% to about 45% by weight, or about 30% to about 43% by weight, or about 33% to about 43% by weight of PEG units; or about 25% to about 35% by weight of PEG units. In certain embodiments, an implant of the present invention containing approximately 400 μg to approximately 500 μg of axitinib in the form of axitinib polymorph IV may have the following composition (anhydrous base, %w / w): approximately 60% to approximately 70% by weight of axitinib and approximately 25% to approximately 35% by weight of PEG units.

[0268] In certain specific embodiments, the implant may have the following composition (wet base, %w / w): about 5% to about 20% by weight, or about 6% to about 12% by weight, or about 6% to about 15% by weight, or about 8% to about 10% by weight, or about 5% to about 17% by weight of axitinib, and about 4% to about 12% by weight, or about 5% to about 10% by weight, or about 6% to about 8% by weight of PEG units. In certain embodiments, the implant of the present invention may have the following composition (anhydrous base, %w / w): about 30% to about 70% of axitinib, and about 20% to about 50% of PEG units. In certain embodiments, the implant of the present invention may have the following composition (anhydrous base, %w / w): about 5% to about 17% of axitinib, and about 4% to about 12% of PEG units. These compositions are applicable to implants according to the present invention, particularly those containing axitinib in amounts corresponding to 200-1000 μg, 300-1000 μg, 300-600 μg, or about 360 μg-562.5 μg, or about 400-500 μg, or about 450 μg of axitinib free base (i.e., axitinib free base in any of its polymorphic phases, e.g., polymorph IV, or e.g., its cocrystal or prodrug form).

[0269] In certain embodiments, the implants of the present invention may have the following composition (anhydrous base, %w / w): about 50% to about 70% by weight of axitinib (particularly axitinib polymorph IV), and about 25% to about 45% by weight of PEG units, particularly PEG units obtained by crosslinking 4a20kPEG-SAZ with 8a20kPEG-NH2. These implants may have the following composition (wet base, %w / w): about 7% to about 17% by weight of axitinib (particularly axitinib polymorph IV), and about 5% to about 10% by weight of PEG units, particularly PEG units obtained by crosslinking 4a20kPEG-SAZ with 8a20kPEG-NH2. These compositional ranges are applicable to implants according to the present invention that contain, in particular, axitinib, especially axitinib polymorph IV, in amounts of about 360 μg to about 562.5 μg, or about 400 μg to about 500 μg, or about 450 μg. Exemplary implants according to these embodiments of the present invention are shown in Table 1C of the Examples section.

[0270] In certain other embodiments, the implant of the present invention may have the following composition (anhydrous base, %w / w): about 30% to about 80% by weight, or about 50% to about 70% by weight, or about 55% to about 70% by weight of axitinib, and about 20% to about 60% by weight, or about 20% to about 50% by weight, or about 25% to about 35% by weight of PEG units. In certain specific embodiments, the implant may have the following composition (wet base, %w / w): about 10% to about 22% by weight, or about 12% to about 18% by weight, or about 14% to about 17% by weight of axitinib, and about 2% to about 12% by weight, or about 4% to about 10% by weight, or about 5% to about 8% by weight of PEG units. These compositions are applicable to implants according to the present invention, particularly those containing axitinib in amounts corresponding to 200-1000 μg, 300-1000 μg, 300-800 μg, or about 480 μg-750 μg, or about 540-660 μg, or about 600 μg of axitinib free base (i.e., axitinib free base in any of its polymorphic phases, e.g., polymorph IV, or e.g., its cocrystal or prodrug form).

[0271] In certain other embodiments of the present invention, in which the implant comprises at least two filaments, for example, 2 to 10 or 3 to 7 filaments, the implant, or any of the filaments comprising it, may have the following composition (anhydrous base, %w / w): about 30% to about 70% by weight, or about 30% to about 60% by weight of axitinib, and about 20% to about 60% by weight, or about 30% to about 60% by weight of PEG units. In certain specific embodiments of the present invention, in which the implant comprises at least two filaments, for example, 2 to 10 or 3 to 7 filaments, the implant may have the following composition (wet base, %w / w): about 5% to about 20% by weight, or about 5% to about 15% by weight of axitinib, and about 3% to about 20% by weight, or about 5% to about 10% by weight of PEG units.

[0272] In certain other embodiments of the present invention, where the implant has a cross-sectional shape that is neither circular nor rectangular, particularly a star-shaped cross-section including but not limited to a cross or a five-armed star, the implant may have the following composition (anhydrous base, %w / w): about 30% to about 70% by weight, or about 40% to about 70% by weight of axitinib, and about 20% to about 60% by weight, or about 20% to about 40% by weight of PEG units. In certain specific embodiments of the present invention, where the implant has a cross-sectional shape that is neither circular nor rectangular, particularly a star-shaped cross-section including but not limited to a cross or a five-armed star, the implant may have the following composition (wet base, %w / w): about 5% to about 20% by weight, or about 8% to about 18% by weight of axitinib, and about 3% to about 20% by weight, or about 5% to about 10% by weight of PEG units.

[0273] In certain embodiments, on an anhydrous weight basis, the ratio of axitinib to PEG in the implant according to the present invention may be about 1:1 to about 3:1. In certain embodiments, the maximum amount of drug in the formulation is about twice the amount of polymer (e.g., PEG) units, but in certain cases, for example, the amount may be greater, provided that the mixture containing the precursor, buffer, and drug (before the hydrogel has completely gelled) can be uniformly poured into a mold or tube (when the implant according to the present invention is manufactured by wet casting as further disclosed herein).

[0274] In certain embodiments, the dry remainder of the implant (i.e., the remainder of the formulation after taking into account the TKI, e.g., axitinib, and polymer units, e.g., PEG units) may be salts remaining from the buffer disclosed above. In certain embodiments, such salts may be phosphates, borates, or (bi)carbonates. In one embodiment, the buffer salt is sodium phosphate (monobasic and / or dibasic).

[0275] In certain embodiments, a solid content of about 10% to about 50%, or about 25% to about 50% (w / v) (where "solids" means the combined weight of the polymer precursor(s), salts, and drug in the solution / suspension) may be used in the wet composition when forming the hydrogel for implants according to the present invention by wet casting as further disclosed herein. Thus, in certain embodiments, the total solid content of the wet hydrogel composition cast into a mold or tube to form the hydrogel may be about 60% or less, or about 50% or less, or about 40% or less, for example, about 35% or less (w / v). The content of the TKI, for example, axitinib, may be about 40% or less, or about 30% or less, for example, about 25% or less (w / v) of the wet composition. The solid content may affect the viscosity and, consequently, the castability of the wet hydrogel composition.

[0276] In certain embodiments, the moisture content of the hydrogel implant in its dry (anhydrous / dried) state, for example, before being loaded into a needle or already loaded into a needle, may be very low, for example, 1% by weight or less. In certain embodiments, the moisture content may also be lower, possibly 0.25% by weight or less, or even 0.1% by weight or less. In the present invention, the term “implant” is used to refer to both the implant in its hydrated state when it contains water (for example, after the implant has been (re)hydrated after being administered to the eye or after being immersed in an aqueous environment), and the implant in its dry (anhydrous / dried) state when, for example, the implant has been dried to a low moisture content, for example, about 1% by weight or less, or when the formulation results in such a low moisture content implant without the need for a drying step. In certain embodiments, the implant in its dry state is an implant that, after manufacture and before being loaded into a needle, has been held in a glove box under an inert nitrogen atmosphere (containing less than 20 ppm of both oxygen and moisture) for at least about 7 days. The moisture content of an implant can be measured, for example, using the Karl Fischer coulometry method.

[0277] In certain embodiments, the total dry weight (also referred to herein as “total mass”) of the implant according to the present invention may be about 200 μg (i.e., 0.2 mg) to about 1.5 mg, or about 400 μg to about 1.2 mg, or about 500 μg to about 1 mg. In certain embodiments, the total dry weight of the implant according to the present invention may be about 0.6 mg to about 1 mg, for example, about 600 μg to about 900 μg, or about 600 μg to about 900 μg, for example, about 700 μg to about 875 μg. If the implant is a composite (multifilament) implant, the total weight of the composite implant may be higher depending on the number and total weight of the individual filaments that make it up. In certain embodiments, if the TKI in the implant is axitinib, e.g., axitinib polymorph IV, present in a dose of about 400 to about 500 μg, e.g., about 405 to about 495 μg, e.g., about 410 to about 490 μg, and the axitinib particles are finely ground particles as defined herein, then the total weight of the implant may be about 0.6 to about 1 mg, or about 0.6 to about 0.9 mg, and the hydrated surface area of ​​such implant (as defined herein) is at least 16 mm². 2 For example, 16.0~23.0mm 2 It is possible.

[0278] In a particular embodiment, the implant according to the present invention has a dry state of 1 mm 3 Hit (i.e., dry implant volume 1 mm) 3 Each portion may contain approximately 200 μg to 1000 μg of a TKI, such as axitinib. In a particular embodiment, the implant according to the present invention may contain, for example, approximately 160 μg to 250 μg of axitinib, and in its dry state, 1 mm 3 Each may contain approximately 200 μg to 300 μg of axitinib. In certain other specific embodiments, the implant according to the present invention may contain, for example, approximately 480 μg to 750 μg of axitinib, in its dry state, 1 mm 3 Each dose may contain approximately 500 μg to 800 μg of axitinib.

[0279] Therefore, the implants of the present invention may have different densities. The final density of the implants (i.e., in their dry state) can be controlled and determined by a variety of factors, including, but not limited to, the concentrations of components in the wet composition (in the case of wet casting) used to mold the hydrogel and certain conditions during the manufacture of the implants. For example, the final density of the implant in a particular embodiment can be increased at a certain point in the manufacturing process, for example, by sonication or degassing using a vacuum. In a particular embodiment, the density of an implant manufactured by thermal fusion extrusion may be higher than that of an equivalent implant manufactured by wet casting (with respect to the TKI and polymer content, respectively).

[0280] In certain embodiments, the implant according to the present invention contains a therapeutically effective dose of a TKI, such as axitinib, for long-term release, yet remains relatively small in length and / or diameter. This is advantageous in terms of ease of administration (injection), as well as in reducing the possibility of damage to ocular tissue while the implant is in place and reducing the possibility of impact on the patient's vision. The implant of the present invention combines the advantages of a appropriately high dose of TKI (i.e., a therapeutically effective dose tailored to the specific needs of the patient) with the advantages of a relatively small implant size. Furthermore, the implant of the present invention achieves a relatively high rate of TKI release, particularly in the initial stages of release, i.e., in the initial period after administration (or, in the case of an in vitro release study, in the initial period after the start of the study).

[0281] Exemplary implants of various aspects of the present invention are disclosed in the Examples section (including a benchtop example of the implant).

[0282] Implant dimensions, and dimensional changes during hydration via stretching. Single implant: The dried implant may have different shapes depending on the manufacturing method, for example, the use of a mold or tube in which a mixture containing the hydrogel precursor containing the TKI is cast before gelation is complete (when the wet casting method disclosed herein is used for the manufacture of the implant), or depending on the shape and dimensions of the die from which the molten mixture of the polymer precursor and TKI, prepared by a hot-melt extrusion process (as also disclosed herein), is extruded.

[0283] The implant according to the present invention is also referred to herein as a “fiber” (this term is used herein interchangeably with the term “rod”), and the fiber is generally an elongated object. The implant (or fiber) may have different shapes of specific dimensions disclosed herein. The implant (or fiber) is generally an elongated object having length and width, where the width is the largest cross-sectional dimension of the elongated object and the length is the longest extension of the object. Generally, in the implant of the present invention, the length is longer than the width.

[0284] In one embodiment, the implant is cylindrical or essentially cylindrical. In this case, the implant has a circular or essentially circular cross-section. It has length and width / diameter. In other embodiments of the present invention, the implant is non-cylindrical, and optionally elongated in its dry state.

[0285] Whether cylindrical or non-cylindrical, the length of the implant is generally longer than its width, and the width (also called the “diameter” in implants with a circular or essentially circular cross-section) is the largest cross-sectional dimension substantially perpendicular to the length. This length is generally the longest extension of the implant. In certain embodiments, the width (or diameter) of the implant of the present invention may be about 0.1 mm to about 0.5 mm in a dry state. Various shapes of the external shape or cross-section of the implant can be used in the present invention. For example, instead of a fiber with a circular diameter (i.e., a cylindrical implant), a cruciate fiber (i.e., a cruciate cross-sectional shape) can also be used. Other cross-sectional shapes, such as oval, rectangular, oval, quadrilateral, square, rhombus, cruciate, triangular, star-shaped (a star with any number of arms), or asterisk-shaped (again, with any number of arms), can be commonly used. The implant may also be thin-film or gear-shaped.

[0286] The cross-sectional shape of the implant also determines its hydrated surface area. For example, an implant with a cruciate or star-shaped cross-section has a larger hydrated surface area compared to an implant of the same length with a circular or oval cross-section. For the purposes of this invention, the hydrated surface area of ​​an implant is calculated from the hydrated dimensions of the implant measured after 24 hours at 37°C in phosphate-buffered saline (PBS) at pH 7.2-7.4.

[0287] In one aspect of the present invention, the implant is at least 25 mm 2 For example, 25mm 2 ~100mm 2 , or 25mm 2 ~60mm 2 It has a hydrated surface area (as defined herein). This embodiment of the present invention (i.e., a hydrated surface area of ​​at least 25 mm 2In this case, the TKI, for example axitinib, may have any solubility, that is, it may have a solubility greater than 0.3 μg / mL, for example greater than 0.4 μg / mL, when measured after incubation for 5 days at 37°C in phosphate-buffered saline (PBS) at pH 7.2 to 7.4, or it may have a solubility of 0.3 μg / mL or less.

[0288] In another aspect of the present invention, the implant may have any hydrated surface area as long as the solubility of the TKI contained therein, for example axitinib, is greater than 0.3 μg / mL, for example 0.4 μg / mL, as measured (as disclosed herein) after incubation for 5 days at 37°C at pH 7.2-7.4 in phosphate-buffered saline (PBS). In embodiments of this embodiment in which the TKI, for example axitinib, has the high solubility mentioned, the hydrated surface area of ​​the implant (as defined herein) is at least 10 mm². 2 For example, at least 15mm 2 For example, at least 16mm 2 For example, at least 19mm 2 , or at least 25mm 2 , advantageously, 15mm 2 ~100mm 2 , or 15mm 2 ~90mm 2 , or 16.0mm 2 ~25.0mm 2 , or 16.0mm 2 ~23.0mm 2 This may be the case. Alternatively, if the solubility of the TKI contained in the implant of the present invention, for example axitinib, is greater than 0.3 μg / mL when measured after incubation for 5 days at 37°C in phosphate-buffered saline (PBS) at pH 7.2-7.4 (as disclosed herein), then the hydrated surface area of ​​the implant is 19 mm² when measured after incubation for 24 hours at 37°C in phosphate-buffered saline (PBS) at pH 7.2-7.4. 2 ~90mm 2, or 25mm 2 ~90mm 2 This may be the case. In certain embodiments, the hydrated surface area of ​​the implant of the present invention in either of the two embodiments mentioned immediately above is 25 mm², measured after 24 hours of incubation at 37°C in phosphate-buffered saline (PBS) at pH 7.2–7.4. 2 ~90mm 2 or 25mm 2 ~40mm 2 It is possible.

[0289] In certain embodiments of the present invention, the solubility of the TKI contained in the implant, for example axitinib, is greater than 0.3 μg / mL when measured after 5 days of incubation at 37°C at pH 7.2–7.4 in phosphate-buffered saline (PBS), and if the implant is a single-strand implant, the hydrated surface area is 10 mm when measured after 24 hours of incubation at 37°C at pH 7.2–7.4 in phosphate-buffered saline (PBS) if the cross-section of the implant is circular or essentially circular (i.e., the implant is cylindrical or essentially circular). 2 ~60mm 2 For example, 15mm 2 ~40mm 2 , or 16.0mm 2 ~25.0mm 2 , or 16.0mm 2 ~23.0mm 2 This may be the case. If the cross-section of the implant has an "arm" shape, for example, a cross shape (4 arms) or a star shape (5, 6, or more arms), the hydrated surface area is measured at 37°C at pH 7.2-7.4 in phosphate-buffered saline (PBS) after 24 hours of incubation and is 30 mm². 2 ~90mm 2 It is possible.

[0290] The hydrated surface area of ​​an implant is calculated from the hydrated dimensions of the implant as defined herein (i.e., measured after 24 hours of incubation at 37°C in phosphate-buffered saline (PBS) at pH 7.2–7.4), using the formula for calculating the surface area of ​​each geometry, for example, a cylinder in the case of a cylindrical implant, where the surface area is A = 2πrh + 2πr 2 (where h is the height, i.e., the length of the cylinder, and r is the radius, i.e., half of the diameter / width of the cylinder). Therefore, the hydration dimensions (length and diameter / width) of the implant determine its hydration surface area, which in turn controls, among other things, the rate of release of the active drug from the implant. Generally speaking, the larger the surface area, the faster the release rate (assuming the drug / drug solubility and the implant composition remain the same).

[0291] In the case of multifilament implants further disclosed herein, the hydrated surface area of ​​the composite implant is the sum of the hydrated surface areas of the filaments, for example, if all the filaments are the same size, it is the hydrated surface area of ​​one filament multiplied by the number of filaments (as the filaments are intended to unfold upon contact with the physiological environment, as further disclosed herein). If the filaments are of different sizes, the hydrated surface area of ​​the composite implant is the sum of the hydrated surface areas of all the filaments.

[0292] For implants of other shapes, such as other cross-sectional shapes, the respective hydration dimensions must be measured to calculate the hydration surface area. For example, for a 5-arm star-shaped implant, the hydration surface area is calculated using the following formula, as shown in Figure 3: "Surface area of ​​end face" = Arm width × Arm length × 5 + Center 2 Hydrated surface area (also called total implant surface area) = Outer circumference × implant length + 2 × "surface area of ​​the end face"

[0293] "Arm width" is the width of each arm, "arm length" is the length of each arm, and "center" is the cross-sectional dimension of the center. Irregular multiple arm shapes may also be used, and their hydrated surface areas can be calculated accordingly.

[0294] In certain embodiments, the ratio of the hydrated surface area to the amount of TKI contained in the implant, as defined herein, multiplied by 100, i.e., (hydrated surface area / amount of TKI) × 100, is at least 2, for example, at least 3, or at least 5, or about 2 to about 10 mm². 2 It can be / μg.

[0295] Generally speaking, a larger hydration surface area increases the release rate of APIs from an implant (within certain limits). Increasing the hydration surface area by using different cross-sectional shapes, or, for example, by combining multiple filaments into a single composite strand, is another way to increase the daily release rate and / or the average daily release rate over a particular period, and / or the percentage of APIs released on one or more individual days, and / or the cumulative percentage of APIs released over a particular period (based on all released APIs or all included APIs), and / or the absolute amount of APIs released on one or more individual days or over a particular period (in vivo or in vitro). Accordingly, the present invention also relates to a method for increasing the release rate and / or average release rate and / or release amount of all TKIs contained in the implant, and / or the release ratio of all TKIs contained in the implant, or the total TKIs released from the implant over a particular period, by increasing the hydration surface area of ​​the implant, compared to known implants containing TKIs.

[0296] In certain embodiments, the fibers may also be twisted or coiled, both in the case of single strands and multifilament fibers, as disclosed herein. In other embodiments, the fibers are linear.

[0297] In embodiments in which the implant is administered to the eye using a needle, the dimensions of the implant (i.e., its length and diameter / width) and its cross-sectional shape must be such that the implant can be loaded into a needle, in particular a fine-gauge needle, for example, a 25-gauge, 26-gauge, 27-gauge, or 30-gauge needle, as further disclosed herein. A particularly suitable implant size is one that fits a 25-gauge needle. The dimensions of the implant in a dry state, in particular its width, are therefore important in selecting a suitable needle for injecting the implant into the eye, for example, into the vitreous fluid. Generally, a smaller needle diameter means a lower possibility of irritation and tissue damage during injection.

[0298] A polymer network of a hydrogel implant according to a particular embodiment of the present invention, such as a PEG network, may be semi-crystalline in a dry state below room temperature and amorphous in a wet state. The fact that the dry implant may be dimensionally stable at or below room temperature, even in a stretched form, may be advantageous for loading the implant into the needle and for quality control.

[0299] During intraocular hydration of the implant (which can be simulated by immersing the implant in PBS at pH 7.2–7.4 at 37°C for 24 hours), the dimensions of the implant according to the present invention may change. For example, the diameter of the implant may increase, while its length may decrease or at least remain essentially the same. The advantage of this dimensional change is that, while the implant is thin enough to be loaded into a fine-gauge needle (e.g., 25 or 27, or possibly a smaller needle, e.g., a 30-gauge needle) for intraocular injection when dry, after it is placed in the intraocular, e.g., vitreous fluid, the implant becomes shorter and can better fit into the limited, small volume of the intraocular. The needle used for injecting the implant of the present invention disclosed herein, for example, in certain embodiments, a 25 or 27-gauge needle, has a small diameter (and may have, for example, an inner diameter of about 0.4 mm). The implant also softens during hydration, so that damage to any ocular tissue can be prevented or minimized if the implant comes into contact with such tissue. In certain embodiments, the dimensional change is at least partially made possible by a “shape memory” effect introduced into the implant by stretching it longitudinally during its manufacturing process (as also disclosed below in the “Manufacturing Method” section). In certain embodiments, the stretching may be performed in a dry or wet state, i.e., after or before drying the hydrogel implant. If no stretching is performed and the hydrogel implant is only dried and cut to the desired length, it is known that both the diameter and length of the implant may increase upon hydration.

[0300] In pre-formed dried hydrogels, some degree of molecular orientation can be imparted by promoting crystallization and fixing the molecular orientation after dry stretching the material and then solidifying it. In certain embodiments, this can be achieved by stretching the material (optionally while heating the material to a temperature above the melting point of the crystallizable region of the material) and then crystallizing the crystallizable region. Alternatively, in certain embodiments, the glass transition temperature of the dried hydrogel can be used to fix the molecular orientation of a polymer such as PVA having a suitable glass transition temperature. Yet another alternative is to stretch the gel before it is completely dry (also referred to as "wet stretching") and then dry the material under tension. This molecular orientation results in a mechanism by which it swells anisotropically when introduced into a hydration medium such as a vitreous body. During hydration, in certain embodiments, the implant swells only in the radial dimension, while its length decreases or is essentially maintained. The term "anisotropic swelling" refers to swelling preferentially in one direction, as opposed to another. In a cylinder, this means primarily swelling radially but not noticeably in the longitudinal direction (or even contracting).

[0301] The "fixation" of molecular orientation is reversible by (re)hydration. The degree of dimensional change during hydration may depend, in particular, on the stretch coefficient. For example, stretching at a low stretch coefficient (e.g., by wet stretching) may have little effect or may not significantly change the length during the hydration process. In contrast, stretching at a higher stretch coefficient of about 1.5 or more, for example, about 2 or more, can result in a significantly shorter length during the hydration process. Stretching at a high stretch coefficient of 4 (e.g., by dry stretching) may result in an even shorter length during hydration (e.g., the length is reduced from 15 to 8 mm). Without stretching, the length of the implant during hydration may, in some cases, be maintained or even increased. Those skilled in the art will understand that other factors besides stretching may also affect the swelling behavior.

[0302] In one or more embodiments, the implant of the present invention is processed by wet stretching with a stretch coefficient of about 0.5 to about 5, or about 1 to about 4, or about 1.3 to about 3.5, or about 1.7 to about 3, or about 2 to about 2.5. In certain embodiments, the wet stretching is performed with a stretch coefficient of about 1.3 to about 1.5.

[0303] Another factor influencing the stretchability of the hydrogel and the potential for dimensional changes in the implant during hydration is the composition of the polymer network. When a PEG precursor is used, a precursor with fewer arms (e.g., a 4-arm PEG precursor) contributes more to the flexibility of the hydrogel than a precursor with more arms (e.g., an 8-arm PEG precursor). If the hydrogel contains a large amount of less flexible components (e.g., a large amount of a PEG precursor with more arms, e.g., 8-arm PEG units), the hydrogel may become stiffer and more difficult to stretch without breaking. On the other hand, a hydrogel containing more flexible components (e.g., a PEG precursor with fewer arms, e.g., 4-arm PEG units) may be easier to stretch and softer, but will also swell more during hydration. Therefore, the behavior and properties of the implant after it has been placed in the eye (i.e., after the hydrogel has been (re)hydrated) can be modified by altering its structural characteristics and by changing its processing after it has been initially molded, e.g., by altering the stretching.

[0304] The exemplary dimensions of the implants used in the following examples of this specification are shown in the Examples section. However, implants may have different dimensions (i.e., length and / or diameter) than those disclosed in the Examples table, even if they contain similar TKI drug loads. The dimensions of a dry implant depend, among other things, on the amount of TKI incorporated and the ratio of TKI to polymer units, and can also be adjusted by the diameter and shape of the mold or tube used to gel the hydrogel. Furthermore, the diameter of the implant is further influenced, among other things, by the (wet or dry) stretching of the hydrogel strand after molding. The length can be selected as needed, since the dry strand (after stretching) is cut into pieces of the desired length to form the implant.

[0305] In certain embodiments, the implant of the present invention has a high aspect ratio, i.e., a large ratio of length to width (where the width is the largest cross-sectional dimension of the implant and the length is the longest extension of the implant). In certain embodiments, the aspect ratio may be at least 5:1, for example, at least 10:1, for example, at least 15:1, for example, at least 20:1.

[0306] In certain embodiments of the present invention where the implant does not have a circular or essentially circular cross-section (for example, when the implant is neither cylindrical nor essentially cylindrical), each cross-sectional dimension is referred to as “width.” All values ​​and ranges disclosed herein for the diameter of the implant apply expressly and equally to the width of the implant when the implant is neither cylindrical nor essentially cylindrical.

[0307] In certain embodiments, the implant of the present invention may have a length of less than about 17 mm in its dry state. In certain embodiments, the length of the implant in its dry state may be less than about 15 mm, or about 12 mm or less, or about 11 mm or less, or about 10 mm or less, or about 9 mm or less, or about 8.5 mm or less. In certain embodiments, the implant of the present invention may have a length of about 6 mm to about 10 mm, or about 6 mm to about 9 mm, in its dry state.

[0308] In certain embodiments, the implant of the present invention may have a diameter / width of less than about 0.7 mm in its dry state, for example, about 0.1 mm to about 0.65 mm, or about 0.20 mm to about 0.55 mm, or about 0.2 mm to about 0.5 mm, or about 0.20 mm to about 0.45 mm, or about 0.30 mm to about 0.45 mm, or about 0.30 to about 0.40 mm, or about 0.31 to about 0.36 mm.

[0309] In certain embodiments, the implant may have a length of about 5 mm to about 12 mm and a diameter of about 0.2 mm to about 0.7 mm in its dry state.

[0310] In more specific embodiments, the implant may have a length of approximately 6 mm to approximately 10 mm and a diameter of approximately 0.2 mm to approximately 0.5 mm in its dry state. In very specific embodiments, the implant may have a length of approximately 6 mm to approximately 9 mm and a diameter of approximately 0.25 mm to approximately 0.45 mm in its dry state.

[0311] In more specific embodiments, the implant may have a length of 6.5 mm to 8.5 mm, for example, 6.7 to 7.8 mm, and a diameter of 0.30 to 0.40 mm, for example, 0.31 to 0.36 mm, in its dry state.

[0312] In certain embodiments, the implant of the present invention may have a length of approximately 14 mm or less in its wet / hydrated state (i.e., after 24 hours at 37°C in phosphate-buffered saline at pH 7.2-7.4).

[0313] In certain embodiments, the implant of the present invention may have a length of about 12 mm or less, or about 11 mm or less, or about 10 mm or less in its wet / hydrated state, or a length of about 4 mm to about 12 mm, or about 4 mm to about 11 mm, or about 6 mm to about 11 mm, or about 6 mm to about 10 mm, or about 6 mm to about 9 mm. Particularly suitable implants of the present invention have a hydrated length of less than about 11 mm, for example, about 10 mm or less.

[0314] In certain embodiments, the implant of the present invention may have a diameter of about 1.2 mm or less, or about 1 mm or less, or about 0.8 mm or less, in its wet / hydrated state. In certain embodiments, the implant of the present invention may have a diameter of about 0.5 mm to about 0.9 mm, or about 0.5 mm to about 0.8 mm, or about 0.7 mm to about 0.8 mm, in its wet / hydrated state. In very specific embodiments, the implant may have a length of about 7 mm to about 10 mm and a diameter of about 0.5 to 0.9 mm, in its wet / hydrated state.

[0315] In more specific embodiments, the implant of the present invention may have a length of about 8 mm to about 9 mm and a diameter of about 0.70 mm to about 0.80 mm in its wet / hydrated state.

[0316] Wherever the length or diameter / width of the implant of the present invention in a wet / hydrated state is disclosed (in mm), this disclosure refers to the length or diameter / width of the implant as determined after 24 hours in PBS at 37°C with a pH of 7.2–7.4, respectively. The dimensions of the implant may change further over time (i.e., after 24 hours) if the implant remains under these conditions (e.g., the length may increase slightly again). However, wherever the hydrated dimensions of the implant are reported herein, these are measured after 24 hours in PBS at 37°C with a pH of 7.2–7.4, as disclosed above.

[0317] In embodiments of the present invention, the dry diameter or width of the implant is, ideally, such that the implant can be loaded into a fine-gauge needle disclosed herein, for example, a 25-gauge or 27-gauge needle. Specifically, in one embodiment, an implant containing about 480 μg to about 750 μg of axitinib, or about 360 μg to about 562.5 μg of axitinib, for example, about 450 μg of axitinib, may have a diameter such that it can be loaded into a 25-gauge needle. In another embodiment, such an implant can be loaded into a 27-gauge needle without damaging the implant during loading, and as a result, the implant remains stable in the needle during further handling (including packaging, sterilization, transport, etc.).

[0318] If the length or diameter of a single implant is measured multiple times, or if multiple data points are collected during measurement, an average (i.e., mean) value is reported as defined herein. The length and diameter of implants according to the present invention (whether in a dry or hydrated / wet state) can be measured, for example, with a microscope or a (optionally automated) camera system, as described in Example 6.1 of WO2021 / 195163.

[0319] In certain embodiments, the implant of the present invention has a ratio of the diameter in a hydrated state to the diameter in a dry state of less than 5 mm, or less than 4 mm, or less than 3.25 mm, or less than 2.5 mm, or less than 2.25 mm, or about 2.0 mm, relative to about 2.5 mm.

[0320] In certain same or other embodiments of the present invention, the ratio of the dry length to the hydrated length of the implant may be greater than about 0.6, or greater than about 0.7, or greater than about 0.8, or greater than about 0.9, or greater than about 1.0. This ratio of the dry length to the hydrated length may be applied in addition to, or independently of, the ratio of the hydrated diameter to the dry diameter disclosed above.

[0321] In one embodiment, the implant of the present invention contains approximately 360 μg to approximately 562.5 μg of axitinib, or approximately 405 μg to approximately 495 μg, or approximately 450 μg of free axitinib base in the form of polymorph IV, and is in the form of a fiber (cylindrical), having a length of approximately 6 mm to approximately 9 mm and a diameter of approximately 0.25 mm to approximately 0.45 mm in a dry state. When hydrated in vivo in the eye, for example in vitreous fluid, or in vitro (in vitro hydration is measured after 24 hours in phosphate-buffered saline at pH 7.2 at 37°C), such implant may have a length of approximately 7 mm to approximately 9 mm and a diameter of approximately 0.65 mm to approximately 0.80 mm. In one embodiment, this dimensional change can be achieved by wet stretching as disclosed herein with a stretching coefficient of 1.25 to 3.

[0322] In another embodiment, the implant of the present invention contains approximately 360 μg to approximately 562.5 μg of axitinib, or approximately 400 μg to approximately 500 μg, or approximately 405 μg to approximately 495 μg, or approximately 450 μg of free axitinib base in the form of polymorph IV, and has a dry length of approximately 5 mm to approximately 11 mm and a diameter of approximately 0.28 mm to approximately 0.38 mm. When hydrated in vivo in the eye, for example in vitreous fluid, or in vitro (in vitro hydration is measured after 24 hours in phosphate-buffered saline at pH 7.2 at 37°C), such implant may have a hydrated length of approximately 5 mm to approximately 11 mm and a hydrated diameter / width of approximately 0.4 mm to approximately 2 mm. In certain embodiments, this dimensional change can be achieved with a stretching coefficient of 1.0 to 3.0 by wet stretching as disclosed herein.

[0323] In certain embodiments, the implant of the present invention contains approximately 360 μg to approximately 562.5 μg of axitinib, or approximately 400 μg to approximately 500 μg, or approximately 405 μg to approximately 495 μg, or approximately 450 μg of free axitinib base, in the form of polymorph IV, and is in the form of a fiber (cylindrical), having a dry length of approximately 6 mm to approximately 9 mm and a diameter of approximately 0.30 mm to approximately 0.35 mm. When hydrated in vivo in the eye, for example in vitreous fluid, or in vitro (in vitro hydration is measured after 24 hours in phosphate-buffered saline at pH 7.2 at 37°C), such implant may have a hydrated length of approximately 6 mm to approximately 10 mm and a hydrated diameter of approximately 0.5 mm to approximately 0.90 mm. In one embodiment, this dimensional change can be achieved by wet stretching disclosed herein with a stretching coefficient of 1.2 to 1.5. Such implants are approximately 17.0 to approximately 23.0 mm. 2 It may have a hydrated surface area.

[0324] In another embodiment, the implant of the present invention contains approximately 200–1000 μg, 300–1000 μg, 480 μg–approximately 750 μg, or approximately 540 μg–approximately 660 μg, or approximately 600 μg of free axitinib base in the form of polymorph IV, and is in the form of a fiber (cylindrical) having a length of approximately 7 mm to less than 10 mm and a diameter of approximately 0.25 mm to approximately 0.45 mm in a dry state. When hydrated in vivo in the eye, for example in the vitreous fluid or in vitro (in vitro hydration is measured after 24 hours in phosphate-buffered saline at pH 7.2 at 37°C), such implant may have a length of approximately 8 mm to less than 10 mm and a diameter of approximately 0.65 mm to approximately 0.9 mm. In one embodiment, this dimensional change can be achieved by wet stretching as disclosed herein with a stretching coefficient of 1.25–3.

[0325] In one embodiment, the length of the implant of the present invention containing about 300 to about 700 μg of axitinib, for example, about 300 μg, about 450 μg, or about 600 μg of axitinib in a dry state is 10 mm or less, and in a hydrated state (measured after 24 hours at 37°C in phosphate-buffered saline at pH 7.2), it is also about 11 mm or less, or substantially about 11 mm or less, or about 10 mm or less, or about 9 mm or less.

[0326] In certain embodiments of the present invention, particularly when the implant contains axitinib, for example, axitinib polymorph IV, in an amount of about 400 to about 500 μg (or any partial range or dose within that range as disclosed herein), the implant is at least 15.0 mm 2 For example, at least 16.0 mm 2 For example, approximately 16.0 to 25.0 mm 2 For example, approximately 16.0 to 23.0 mm 2 The hydrated surface area (calculated from the hydrated dimensions, measured in vitro in phosphate-buffered saline at pH 7.2–7.4 at 37°C for 24 hours, as described above) is also present. In certain further embodiments, the hydrated surface area is also approximately 17.0–23.0 mm². 2 Especially approximately 18.0 to 22.5 mm 2 This is possible. In any of these embodiments, the implant may be cylindrical or essentially cylindrical, that is, it may have a circular or essentially circular cross-sectional area.

[0327] In an alternative embodiment, the implant of the present invention is created in situ within the eye, for example, within the vitreous humor. In this case, the mixed solution containing the precursor (e.g., one disclosed herein for manufacturing the implant by wet casting) is mixed and immediately injected into the eye. The mixed solution, optionally already present in a syringe or other injection device after mixing the precursor (TKI and polymer precursor, and optionally buffer), needs to be injected into the eye before the gelation of the hydrogel is complete, i.e., while the contents of the syringe are still sufficiently liquid to be easily and completely injected without blocking the needle. Alternatively, gelation in situ may be induced after injection, for example, by exposure to physiological conditions, e.g., moisture, pH, temperature, light, etc. The gelation / crosslinking of the hydrogel is then completed within the eye, for example, within the vitreous humor, forming an implant that is substantially spherical but has specified dimensions, e.g., specified length and diameter, or specified hydrated surface area.

[0328] Multifilament: In certain embodiments, the implant according to the present invention consists of / includes at least two filaments. In certain embodiments, such implant includes at least three or at least four filaments, and / or up to 20, or up to 15, or up to 12 filaments. In certain embodiments, the implant includes 2 to 8, or 3 to 7 filaments, or 2, 3, 4, 5, 6, 7, or 8 filaments. Individual filaments may have the composition disclosed herein with respect to the (single-strand) implant of the present invention (e.g., amounts / percentages of TKI and PEG units) and may be manufactured in the same manner as the (single-strand) implant disclosed herein (i.e., by either wet casting or hot-melt extrusion). The filaments included in a single composite implant may be identical or different (including, but not limited to, differences in their composition and / or differences in their (wet and / or dry) dimensions and / or their shape). Individual filaments may, for example, contain different forms of the same active substance (including, but not limited to, different polymorphic phases) and / or different active substances.

[0329] In certain embodiments, individual filaments may then be combined into a composite strand by a heat-stretching and twisting procedure, as illustrated in Example 3. In another embodiment, individual filaments are braided to form a braided strand. In further embodiments, individual filaments are joined to one another by other means, for example, by attaching them via another material, such as linear PEG. The adhesive material may or may not dissolve after the implant is injected into a physiological environment (e.g., intraocular, e.g., vitreous fluid). If the adhesive material dissolves, the individual filaments will separate from each other after the implant is placed in the physiological environment. Multifilaments may also be attached to each other or formed in a manner that connects them to each other by other means.

[0330] The filaments can be integrated into a single composite implant by twisting them together to form a single twisted strand. Such a composite (twisted) strand may have a combined diameter in dry state that is within the same range as the diameter of the single-strand implant disclosed herein. In certain embodiments, the combined diameter in dry state of the twisted strand is 0.2–0.8 mm, or 0.2–0.5 mm, or 0.3–0.4 mm, or 0.33–0.38 mm. In certain same or other embodiments, the combined diameter in dry state of the individual filaments is less than 0.3 mm, or less than 0.25 mm, or less than 0.2 mm, or less than 0.15 mm. Similar to single-strand implants, multifilament implants can also be loaded into needles with needle gauges in the range of 20–30, for example, 25–27, or 25, or 27, or 30, for intraocular, e.g., intravitreal injection.

[0331] In certain embodiments, in the twisted composite implant of the present invention comprising at least two filaments, the twisted strand can be fully or partially unfolded during hydration (in vivo or in vitro), so that individual filaments are exposed. This effectively results in a multifilament implant having an increased hydration surface area (corresponding to the sum of the hydration surface areas of the individual filaments), thereby increasing the release rate of the TKI from the implant. In certain embodiments, the hydration surface area of ​​a multifilament implant can be at least twice, for example, at least three times, or at least four times, larger than the hydration surface area of ​​a single-strand implant containing the same drug load of TKI and having essentially similar composite dimensions (composite diameter and length) in a dry state. Thus, the release rate (amount of TKI released per day, and / or average daily release rate over a certain number of days) of a single-strand implant and a multifilament implant containing the same drug load of TKI and having essentially similar composite dimensions (composite diameter and length) in a dry state is higher than that of the corresponding single-strand implant, for example, at least 10%, at least 20%, or at least 30% higher. In other words, multifilament composite implants allow multiple implants to be administered in a single injection, resulting in an increased release rate of the API.

[0332] In a particular embodiment of the twisted multifilament implant according to the present invention, the number of twists per cm (of the final twisted implant) is at least about 1 or at least about 2 or at least about 5 or at least about 8 or at least about 10 and / or up to about 20 or up to about 15.

[0333] The multifilament implant is manufactured from individual filaments (manufactured according to the manufacturing methods disclosed herein) as disclosed in the “Implant Manufacturing” section.

[0334] The multifilament implant is considered to meet the following requirements, for example, the solubility of the TKI is greater than 0.3 μg / mL when measured after incubation at 37°C for 5 days in phosphate-buffered saline (PBS) at pH 7.2-7.4 (in this particular embodiment of the present invention), or the hydrated surface area of ​​the implant is at least 25 mm when measured after incubation at 37°C for 24 hours in phosphate-buffered saline (PBS) at pH 7.2-7.4. 2 Insofar as (in this particular aspect of the present invention) it can be used in any aspect of the present invention. If the TKI incorporated into these multifilament implants is axitinib, then any form of axitinib disclosed herein may be included (again, insofar as each of the features of the particular aspect of the present invention is satisfied).

[0335] In a particular embodiment, the multifilament implant contains linear PEG at a concentration of 5% to 30% (w / w) of the dry implant, for example, 10% to 20% (w / w).

[0336] In vitro release: The in vitro release of a TKI from the implant of the present invention, such as axitinib, can be specified by various in vitro methods (see also the Examples section; see also the Definitions section of this application for further explanation).

[0337] In a particular in vitro test, a test implant(s) is placed in a specific volume of a 25% ethanol / 75% water (v / v) solvent mixture at a specific temperature (37°C, or another temperature if specifically mentioned) as disclosed herein. The release rate or release percentage of a TKI, e.g., axitinib, is specified on several predetermined days. The volume of solvent is calculated using the “sink coefficient” as defined in the “Definitions” section. The in vitro tests reported herein may be carried out under a variety of sink conditions. In a particular embodiment, the in vitro test may be carried out under 2x sink conditions, 3x sink conditions, or a higher sink coefficient, as disclosed herein. “2x sink conditions” means that the volume of solvent(s) into which the implant(s) according to the present invention(s) are immersed in a particular test is twice the “sink volume” (as defined above). In this case, the “sink coefficient” is 2. The same continues for any other sink coefficient. The sink volume is defined in the "Definitions" section as the ratio of the amount of TKI [μg] contained in the implant to the solubility of the TKI in the solvent (mixture) used, i.e., 25% ethanol / 75% water (v / v).

[0338] In certain embodiments, for in vitro studies reported in this application using 2x sink conditions (e.g., “Method A” as referred to in the Examples), the sink volume is calculated by dividing the amount (μg) of axitinib contained in the test implant by the average solubility value of 18.3 μg / mL. Thus, in these embodiments, this average solubility value is used regardless of which axitinib polymorph is used in the test implant, for example, whether polymorph IV or polymorph SAB-I is used.

[0339] In certain embodiments, for in vitro tests reported in this application using 3x sink conditions (e.g., “Method B” as referred to in the Examples), the sink volume is calculated by dividing the amount (μg) of axitinib contained in the test implant by the solubility value of 13.41 μg / mL (when axitinib polymorph SAB-I is used) or 20.09 μg / mL (when axitinib polymorph IV is used).

[0340] Specifically, an in vitro test according to the present invention for an implant containing axitinib is performed as follows ("Method A" or "Method B"): Prepare 1 L of a 25%:75% ethanol / water solvent mixture (referred to herein as "buffer") and equilibrate it. Place the test implant in an amber wide-mouthed bottle. Under 2x sink conditions, the volume of buffer added to the implant is equal to twice the volume corresponding to the ratio of the amount of TKI [μg] to the solubility of axitinib [μg / mL] (which, in certain embodiments, is the mean value of axitinib free base, 18.3 μg / mL, as described above). Under 3x sink conditions, the volume of buffer added to the implant is equal to three times the volume corresponding to the ratio of the amount of TKI [μg] divided by the solubility of axitinib [μg / mL] (which, in certain embodiments, is 13.41 μg / mL if the TKI is axitinib polymorph SAB-I, or 20.09 μg / mL if the TKI is axitinib polymorph IV). For example, if the implant contains 600 μg of axitinib polymorph SAB-I and the in vitro test is performed under 3x sink conditions, 134 mL of a 25% / 75% ethanol / water mixture is used as the volume in which the test implant is immersed (i.e., 600 μg divided by 13.41 μg / mL and multiplied by a factor of 3). While the in vitro test is being performed, the wide-mouthed bottles containing the implants in each volume of buffer are stored in a 37°C incubator on a rocker plate for moderate agitation. One mL of buffer solution is taken and replaced on each sampling day. This buffer solution is analyzed against analytical standards prepared within the past two weeks by either UV-VIS (for tests conducted under 2x sink conditions in certain embodiments) or ULC (for tests conducted under 3x sink conditions in certain embodiments).

[0341] Furthermore, the in vitro release of TKIs, particularly axitinib, from the implants of the present invention can also be specified by another enhanced in vitro method ("Method C") as follows (see also the Examples section):

[0342] The dissolution medium for this accelerated in vitro release test is 0.01N HCl containing 0.25% cetyltrimethylammonium bromide (CTAB). The test is performed at a temperature of 35°C using USP apparatus 4. The appropriate test parameters are specified below: [Table 1]

[0343] The sampling time can be selected as needed, for example, one or more of the following: 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 24, 36, 48, 60, and 83 hours. These samples are analyzed against analytical standards by UPLC. When measuring several samples (e.g., n=6) of a single product (e.g., the same production lot), the mean emission can be determined.

[0344] In vitro release of an axitinib-containing implant in an in vitro test conducted at 37°C in a 25% / 75% (v / v) ethanol / water mixture under the 2x sink conditions disclosed herein: In certain embodiments of the present invention, the implant comprises axitinib in any form disclosed herein as a TKI and exhibits one or more of the following release characteristics in an in vitro release test performed under 2x sink conditions in a 25% / 75% (v / v) ethanol / water mixture at 37°C as disclosed herein (this test is also referred to as “Method A” in the embodiments):

[0345] In a particular embodiment, the implant of the present invention releases axitinib at an average rate of at least about 60 μg / day on the first day, and / or at least about 55 μg / day over the first two days, and / or at least about 45 μg / day over the first five days, and / or at least about 40 μg / day over the first seven days, and / or at least about 40 μg / day over the first ten days.

[0346] In certain identical or other embodiments, the implant releases at least 40% or at least 44% of the total axitinib release over the first three days, and / or at least 70% of the total axitinib release over the first seven days, and / or at least 90% of the total axitinib release over the first ten days.

[0347] In a particular embodiment, the implant contains an amount of axitinib equivalent to about 480 μg to about 750 μg, or about 600 μg, of free base of axitinib, and releases at least 40% of the total amount of axitinib released over the first three days, and / or The implant contains an amount of axitinib equivalent to approximately 360 μg to approximately 562.5 μg, or approximately 450 μg of free base of axitinib, and releases at least 50% of the total amount of axitinib released from the implant over the first three days, and / or The implant contains an amount of axitinib equivalent to approximately 240 μg to approximately 375 μg, or approximately 300 μg of free base of axitinib, and releases at least 60% of the total amount of axitinib released over the first three days, and / or The implant contains an amount of axitinib equivalent to approximately 120 μg to approximately 187.5 μg, or approximately 150 μg, of free axitinib base, and releases at least 90% of the total amount of axitinib released over the first three days.

[0348] In certain same or other specific embodiments, the implant contains an amount of axitinib equivalent to about 480 μg to about 750 μg, or about 600 μg, of free base of axitinib, and releases at least 70% of the total amount of axitinib released from the implant over the first 7 days, and / or The implant contains an amount of axitinib equivalent to approximately 360 μg to approximately 562.5 μg, or approximately 450 μg of free base of axitinib, and releases at least 80% of the total amount of axitinib released over the first 7 days, and / or The implant contains an amount of axitinib equivalent to approximately 240 μg to approximately 375 μg, or approximately 300 μg, of free axitinib base, and releases at least 85% of the total amount of axitinib released over the first 7 days, and / or The implant contains an amount of axitinib equivalent to approximately 120 μg to approximately 187.5 μg, or approximately 150 μg, of free axitinib base, and releases at least 95% of the total amount of axitinib released over the first 7 days.

[0349] In certain same or other specific embodiments, the implant contains an amount of axitinib equivalent to about 480 μg to about 750 μg, or about 600 μg, of free base of axitinib, and releases at least 90% of the total amount of axitinib released over the first 10 days, and / or The implant contains an amount of axitinib equivalent to approximately 360 μg to approximately 562.5 μg, or approximately 450 μg of free base of axitinib, and releases at least 92% of the total amount of axitinib released over the first 10 days, and / or The implant contains an amount of axitinib equivalent to approximately 240 μg to approximately 375 μg, or approximately 300 μg, of free axitinib base, and releases at least 95% of the total amount of axitinib released over the first 10 days, and / or The implant contains an amount of axitinib equivalent to approximately 120 μg to approximately 187.5 μg, or approximately 150 μg, of free axitinib base, and releases at least 98% of the total amount of axitinib released over the first 10 days.

[0350] In a particular embodiment, the implant releases at least about 65 μg of axitinib on the first day and / or at least 120 μg over the first two days.

[0351] In certain specific embodiments, the implant of the present invention contains axitinib in an amount equivalent to about 480 μg to about 750 μg of axitinib, or about 600 μg of axitinib free base, and releases at least about 75 μg, or at least about 90 μg, or at least about 100 μg of axitinib on the first day, and / or Release at least approximately 125 μg, or at least approximately 150 μg, or at least approximately 140 μg of axitinib over the first two days, and / or Release at least approximately 150 μg, or at least approximately 180 μg, or at least approximately 200 μg of axitinib over the first three days, and / or Release at least approximately 275 μg, or at least approximately 300 μg, or at least approximately 375 μg of axitinib over the first 7 days, and / or Axitinib is released in doses of at least approximately 350 μg, or at least approximately 400 μg, or at least approximately 450 μg, over the first 10 days.

[0352] In certain other specific embodiments, the implant of the present invention contains axitinib in an amount equivalent to about 360 μg to about 562.5 μg of axitinib, or about 450 μg of axitinib free base, and releases at least about 60 μg, or at least about 70 μg, or at least about 80 μg of axitinib on the first day, and / or Release at least approximately 100 μg, or at least approximately 120 μg, or at least approximately 130 μg of axitinib over the first two days, and / or Release at least approximately 130 μg, or at least approximately 150 μg, or at least approximately 180 μg of axitinib over the first three days, and / or Release at least approximately 220 μg, or at least approximately 260 μg, or at least approximately 290 μg of axitinib over the first 7 days, and / or Axitinib is released in doses of at least approximately 275 μg, or at least approximately 300 μg, or at least approximately 350 μg, over the first 10 days.

[0353] In certain other specific embodiments, the implant of the present invention contains axitinib in an amount equivalent to about 240 μg to about 375 μg of axitinib, or about 300 μg of axitinib free base, and releases at least about 60 μg, or at least about 65 μg, or at least about 70 μg of axitinib on the first day, and / or Release at least approximately 90 μg, or at least approximately 110 μg, or at least approximately 130 μg of axitinib over the first two days, and / or Release at least approximately 120 μg, or at least approximately 140 μg, or at least approximately 180 μg of axitinib over the first three days, and / or Release at least approximately 200 μg, or at least approximately 240 μg, or at least approximately 270 μg of axitinib over the first 7 days, and / or Axitinib is released in doses of at least approximately 250 μg, at least approximately 275 μg, or at least approximately 300 μg over the first 10 days.

[0354] In certain other specific embodiments, the implant of the present invention contains axitinib in an amount equivalent to about 120 μg to about 187.5 μg of axitinib, or an amount equivalent to about 150 μg of free base of axitinib, and releases at least about 75 μg, or at least about 85 μg, or at least about 90 μg, or at least about 100 μg of axitinib on the first day, and / or releases at least about 90 μg, or at least about 100 μg, or at least about 115 μg of axitinib over the first two days.

[0355] In a particular embodiment, the implant contains approximately 240 μg to approximately 375 μg of axitinib and releases at least approximately 90% of the total amount of axitinib released over the first 7 days or the first 10 days.

[0356] In a particular embodiment, the implant contains approximately 480 μg to approximately 750 μg of axitinib and releases at least approximately 90% of the total amount of axitinib released over the first 10 days or the first 14 days.

[0357] In a particular embodiment, the implant contains approximately 120 μg to approximately 187.5 μg of axitinib and releases at least approximately 90% of the total amount of axitinib released over the first two or three days.

[0358] In a particular embodiment, the implant contains approximately 360 μg to approximately 562.5 μg of axitinib and releases at least approximately 90% of the total amount of axitinib released over the first 8 or 9 days.

[0359] In a particular embodiment, with respect to the release characteristics identified in the in vitro test under the 2x sink conditions reported above in this section, the volume of the 25% / 75% (v / v) ethanol / water solvent mixture is twice the volume calculated by dividing the amount of axitinib [μg] contained in the implant by the average solubility value of axitinib [μg / mL], which is 18.3 μg / mL.

[0360] In vitro release of an axitinib-containing implant in an in vitro test conducted at 37°C in a 25% / 75% (v / v) ethanol / water mixture under the 3x sink conditions disclosed herein: In certain embodiments of the present invention, the implant comprises axitinib in any form disclosed herein as a TKI and exhibits one or more of the following release characteristics in an in vitro release test performed under 3x sink conditions in a 25% / 75% (v / v) ethanol / water mixture at 37°C as disclosed herein (this test is also referred to as “Method B” in the embodiments):

[0361] In a particular embodiment, the implant of the present invention comprises axitinib and releases axitinib at an average rate of at least about 40 μg / day on the first day, and / or at least about 35 μg / day over the first two days, and / or at least about 30 μg / day over the first four days, and / or at least about 25 μg / day over the first seven days.

[0362] In a particular embodiment, the implant of the present invention contains axitinib and releases at least 25%, or at least 30%, or at least 34% of the total amount of axitinib released over the first four days.

[0363] In certain embodiments, the implant of the present invention contains an amount of axitinib equivalent to about 480 μg to about 750 μg, or about 600 μg, of free axitinib, and releases at least 35% of the total amount of axitinib released over the first four days, and / or The implant contains an amount of axitinib equivalent to approximately 360 μg to approximately 562.5 μg, or approximately 450 μg of free base of axitinib, and releases at least 30% of the total amount of axitinib released over the first four days, and / or The implant contains an amount of axitinib equivalent to approximately 240 μg to approximately 375 μg, or approximately 300 μg, of free axitinib base, and releases at least 30% of the total amount of axitinib released over the first four days, and / or The implant contains an amount of axitinib equivalent to approximately 120 μg to approximately 187.5 μg, or approximately 150 μg, of free axitinib base, and releases at least 60% of the total amount of axitinib released over the first four days.

[0364] In a particular embodiment, the implant of the present invention comprises axitinib and releases at least 40% or at least 50% of the total amount of axitinib released over the first 7 days or the first 9 days.

[0365] In a particular embodiment, the implant contains an amount of axitinib equivalent to about 480 μg to about 750 μg, or about 600 μg, of free axitinib base, and releases at least 50% of the total amount of axitinib released over the first 7 or 9 days, and / or The implant contains an amount of axitinib equivalent to approximately 360 μg to approximately 562.5 μg, or approximately 450 μg of free base of axitinib, and releases at least 50% of the total amount of axitinib released over the first 7 or first 9 days, and / or The implant contains an amount of axitinib equivalent to approximately 240 μg to approximately 375 μg, or approximately 300 μg, of free axitinib, and releases at least 50% of the total amount of axitinib released over the first 7 or first 9 days, and / or The implant contains an amount of axitinib equivalent to approximately 120 μg to approximately 187.5 μg, or approximately 150 μg, of free axitinib base, and releases at least 90% of the total amount of axitinib released over the first 7 or 9 days.

[0366] In a particular embodiment, the implant contains an amount of axitinib equivalent to about 480 μg to about 750 μg, or about 600 μg, of free base of axitinib, and releases at least about 40 μg, or at least about 50 μg, or at least about 55 μg of axitinib on the first day, and / or Release at least approximately 80 μg, or at least approximately 100 μg, or at least approximately 120 μg of axitinib over the first two days, and / or Release at least approximately 160 μg, or at least approximately 190 μg, or at least approximately 200 μg of axitinib over the first four days, and / or Release at least approximately 290 μg, or at least approximately 300 μg, or at least approximately 350 μg of axitinib over the first 7 days, and / or Axitinib is released at a dose of at least approximately 300 μg, or at least approximately 330 μg, over the first nine days.

[0367] In a particular embodiment, the implant contains an amount of axitinib equivalent to about 360 μg to about 562.5 μg, or about 450 μg, of free base of axitinib, and releases at least about 35 μg, or at least about 40 μg, or at least about 45 μg of axitinib on the first day, and / or Release at least approximately 60 μg, or at least approximately 70 μg, or at least approximately 80 μg of axitinib over the first two days, and / or Release at least approximately 100 μg, or at least approximately 120 μg, or at least approximately 150 μg of axitinib over the first four days, and / or Release at least approximately 180 μg, or at least approximately 200 μg, or at least approximately 240 μg of axitinib over the first 7 days, and / or Axitinib is released in doses of at least approximately 200 μg, or at least approximately 250 μg, or at least approximately 270 μg, over the first nine days.

[0368] In a particular embodiment, the implant contains an amount of axitinib equivalent to about 240 μg to about 375 μg, or about 300 μg, of free base of axitinib, and releases at least about 30 μg, or at least about 35 μg, or at least about 40 μg of axitinib on the first day, and / or Release at least approximately 50 μg, or at least approximately 60 μg, or at least approximately 70 μg of axitinib over the first two days, and / or Release at least approximately 80 μg, or at least approximately 100 μg, or at least approximately 120 μg of axitinib over the first four days, and / or Release at least approximately 150 μg, or at least approximately 160 μg, or at least approximately 180 μg of axitinib over the first 7 days, and / or Axitinib is released in doses of at least approximately 160 μg, at least approximately 180 μg, or at least approximately 200 μg over the first nine days.

[0369] In a particular embodiment, the implant contains an amount of axitinib equivalent to about 120 μg to about 187.5 μg, or about 150 μg, of free base of axitinib, and releases at least about 60 μg, or at least about 70 μg, or at least about 80 μg of axitinib on the first day, and / or Axitinib is released in doses of at least approximately 90 μg, or at least approximately 100 μg, or at least approximately 120 μg, over the first two days.

[0370] In a particular embodiment, the implant contains approximately 240 μg to approximately 375 μg of axitinib and releases at least approximately 85% or at least approximately 90% of the total amount of axitinib released over the first 14 days.

[0371] In a particular embodiment, the implant contains approximately 480 μg to approximately 750 μg of axitinib and releases at least approximately 90% of the total amount of axitinib released over the first 16 or first 18 days.

[0372] In a particular embodiment, the implant contains approximately 120 μg to approximately 187.5 μg of axitinib and releases at least approximately 90% of the total amount of axitinib released over the first seven days.

[0373] In a particular embodiment, the implant contains approximately 360 μg to approximately 562.5 μg of axitinib and releases at least approximately 90% of the total amount of axitinib released over the first 14 to 16 days.

[0374] In certain embodiments, with respect to the release characteristics identified in in vitro tests under the 3x sink conditions reported above in this section, the volume of the 25% / 75% (v / v) ethanol / water solvent mixture is three times the volume identified by the ratio of the amount of axitinib [μg] contained in the implant divided by the solubility of axitinib polymorph SAB-I in the solvent mixture (13.41 μg / mL, when polymorph SAB-I is used) and the solubility of axitinib polymorph IV (20.09 μg / mL, when polymorph IV is used).

[0375] Any in vitro release test, in particular the accelerated in vitro release test described herein, may also be used to compare different implants (e.g., different production batches, different compositions, and different dosing intensities, etc.) with one another, for purposes such as quality control or other qualitative evaluation.

[0376] In vitro release of an axitinib-containing implant in a accelerated in vitro test performed in USP apparatus 4 at 35°C ± 0.5°C in 0.01N HCl containing 0.25% CTAB ("Method C") disclosed herein: In some embodiments of the present invention, an implant containing axitinib is tested in an in vitro test performed in a USP apparatus 4 at 35°C ± 0.5°C in 0.01N HCl containing 0.25% cetyltrimethylammonium bromide (CTAB), and the percentage of axitinib released from the implant is: Approximately 10-25% after 0.5 hours, Approximately 30-50% after 2 hours. Approximately 60-90% after 6 hours. After 10 hours, approximately 79-100% At least approximately 90% after 12 hours, and / or characterized by being at least about 92% after 16 hours, Alternatively, in an in vitro test performed in USP apparatus 4 at 35°C ± 0.5°C in 0.01N HCl containing 0.25% cetyltrimethylammonium bromide (CTAB), the percentage of axitinib released from the implant is: Approximately 10-25% after 0.5 hours, After 1 hour, approximately 19-35% Approximately 30-50% after 2 hours. Approximately 55-70% after 4 hours. Approximately 60-90% after 6 hours. After 8 hours, approximately 78-95% After 10 hours, approximately 79-100% At least approximately 90% after 12 hours, and / or characterized by being at least about 92% after 16 hours.

[0377] In a particular embodiment of the present invention, an implant containing axitinib is tested in an in vitro test performed in a USP apparatus 4 at 35°C ± 0.5°C in 0.01N HCl containing 0.25% cetyltrimethylammonium bromide (CTAB), and the percentage of axitinib released from the implant is: Approximately 10-18% after 0.5 hours, Approximately 30-45% after 2 hours. Approximately 60-80% after 6 hours. After 10 hours, approximately 79-98% At least approximately 90% after 12 hours, and / or characterized by being at least about 92% after 16 hours, Alternatively, in an in vitro test performed in USP apparatus 4 at 35°C ± 0.5°C in 0.01N HCl containing 0.25% cetyltrimethylammonium bromide (CTAB), the percentage of axitinib released from the implant is: Approximately 10-18% after 0.5 hours, After one hour, approximately 19-27% Approximately 30-45% after 2 hours. After 4 hours, approximately 55-65% Approximately 60-80% after 6 hours. Approximately 78-90% after 8 hours. After 10 hours, approximately 79-98% At least approximately 90% after 12 hours, and / or characterized by being at least about 92% after 16 hours.

[0378] In a particular embodiment of the present invention, an implant containing axitinib is tested in an in vitro test performed in a USP apparatus 4 at 35°C ± 0.5°C in 0.01N HCl containing 0.25% cetyltrimethylammonium bromide (CTAB), and the percentage of axitinib released from the implant is: Approximately 12-17% after 0.5 hours, After 2 hours, approximately 32-42% After 6 hours, approximately 62-78% After 10 hours, approximately 83-97% and / or characterized by being at least about 94% after 16 hours, Alternatively, in an in vitro test performed in USP apparatus 4 at 35°C ± 0.5°C in 0.01N HCl containing 0.25% cetyltrimethylammonium bromide (CTAB), the percentage of axitinib released from the implant is: Approximately 12-17% after 0.5 hours, Approximately 23-25% after 1 hour. Approximately 32-42% after 2 hours. After 4 hours, approximately 57-62% After 6 hours, approximately 62-78% After 8 hours, approximately 80-88% After 10 hours, approximately 83-97% After 12 hours, at least about 94%, and / or characterized by being at least about 94% after 16 hours.

[0379] In a particular embodiment of the present invention, an implant containing axitinib is tested in an in vitro test performed in a USP apparatus 4 at 35°C ± 0.5°C in 0.01N HCl containing 0.25% cetyltrimethylammonium bromide (CTAB), and the percentage of axitinib released from the implant is: Approximately 12-16% after 0.5 hours, After 2 hours, approximately 34-41% After 6 hours, approximately 66-77% Approximately 85-96% after 10 hours. and / or characterized by being at least about 95% after 16 hours, Alternatively, in an in vitro test performed in USP apparatus 4 at 35°C ± 0.5°C in 0.01N HCl containing 0.25% cetyltrimethylammonium bromide (CTAB), the percentage of axitinib released from the implant is: Approximately 12-16% after 0.5 hours, Approximately 23-25% after 1 hour. After 2 hours, approximately 34-41% After 4 hours, approximately 57-62% After 6 hours, approximately 66-77% After 8 hours, approximately 80-88% Approximately 85-96% after 10 hours. After 12 hours, at least about 94%, and / or characterized by being at least about 95% after 16 hours.

[0380] In all of the above embodiments of in vitro release implants, as measured according to Method C and defined by the release percentage of axitinib, the axitinib contained in the implant is the free base of axitinib, which is axitinib polymorph IV, or contains it. In certain embodiments, the axitinib contained in the implant is axitinib polymorph IV. In embodiments in which the implant contains axitinib polymorph IV, at least 90% by weight of the free base of axitinib contained in the implant is polymorph IV. In certain embodiments, the amount of axitinib contained in these implants is about 300 to about 600 μg, for example, about 400 to about 500 μg, for example, about 450 μg. In certain embodiments, the implant is a single-strand implant, for example, a single-strand implant having an essentially cylindrical shape, and at least 16 mm 2 For example, approximately 16.0 to 23.0 mm 2It has a hydrated surface area (measured in PBS at pH 7.2-7.4 after 24 hours of incubation at 37°C).

[0381] In certain embodiments of these models, the implant contains about 400 to about 500 μg of axitinib polymorph IV, for example, about 450 μg, and the percentage of axitinib released is based on the maximum amount of axitinib released from the implant representing 100% (also referred to herein as "normalized release %"), as described in Example 7.3 with respect to the in vitro method C. In other specific embodiments, the implant contains about 400 to about 500 μg of axitinib polymorph IV, for example, about 450 μg, and the percentage of axitinib released is based on the theoretical (represented) amount of 450 μg of axitinib representing 100%. This means that although the theoretical (stated) amount of axitinib in the implant is 450 μg, if the actual axitinib content (assay) is, for example, slightly more than 450 μg, the percentage of axitinib released after a certain period as described above still refers to the theoretical / stated content of 450 μg, as also explained in Example 7.3 for Method C.

[0382] In some embodiments of the present invention, an implant containing axitinib is tested in an in vitro test performed in a USP apparatus 4 at 35°C ± 0.5°C in 0.01N HCl containing 0.25% cetyltrimethylammonium bromide (CTAB), and the amount of axitinib released from the implant is as follows: Approximately 50-80 μg after 0.5 hours. Approximately 140-210 μg after 2 hours. Approximately 270-360 μg after 6 hours. Approximately 350 to 450 μg after 10 hours. and / or characterized by being at least about 410 μg after 16 hours, Alternatively, in an in vitro test performed in USP apparatus 4 at 35°C ± 0.5°C in 0.01N HCl containing 0.25% cetyltrimethylammonium bromide (CTAB), the amount of axitinib released from the implant is: Approximately 50-80 μg after 0.5 hours. Approximately 100-120 μg after 1 hour, Approximately 140-200 μg after 2 hours, Approximately 240-295 μg after 4 hours. Approximately 270-360 μg after 6 hours. Approximately 350-410 μg after 8 hours. Approximately 350 to 450 μg after 10 hours. After 12 hours, at least approximately 400 μg, The present invention is characterized by being at least about 410 μg after 16 hours.

[0383] In a particular embodiment of the present invention, an implant containing axitinib is tested in an in vitro test performed in a USP apparatus 4 at 35°C ± 0.5°C in 0.01N HCl containing 0.25% cetyltrimethylammonium bromide (CTAB), and the amount of axitinib released from the implant is Approximately 55-72 μg after 0.5 hours. Approximately 147-190 μg after 2 hours. Approximately 280-350 μg after 6 hours. Approximately 360 to 440 μg after 10 hours. and / or characterized by being at least about 420 μg after 16 hours, Alternatively, in an in vitro test performed in USP apparatus 4 at 35°C ± 0.5°C in 0.01N HCl containing 0.25% cetyltrimethylammonium bromide (CTAB), the amount of axitinib released from the implant is: Approximately 55-72 μg after 0.5 hours. Approximately 105-112 μg after 1 hour. Approximately 147-190 μg after 2 hours. Approximately 250-280 μg after 4 hours. Approximately 280-350 μg after 6 hours. Approximately 360-400 μg after 8 hours. Approximately 360 to 440 μg after 10 hours. At least approximately 420 μg after 12 hours, The present invention is characterized by being at least about 420 μg after 16 hours and / or after 16 hours.

[0384] In a particular embodiment of the present invention, an implant containing axitinib is tested in an in vitro test performed in a USP apparatus 4 at 35°C ± 0.5°C in 0.01N HCl containing 0.25% cetyltrimethylammonium bromide (CTAB), and the amount of axitinib released from the implant is Approximately 57-70 μg after 0.5 hours. Approximately 150-180 μg after 2 hours. Approximately 290 to 345 μg after 6 hours. Approximately 370 to 430 μg after 10 hours. and / or characterized by being at least about 420 μg after 16 hours, Alternatively, in an in vitro test performed in USP apparatus 4 at 35°C ± 0.5°C in 0.01N HCl containing 0.25% cetyltrimethylammonium bromide (CTAB), the amount of axitinib released from the implant is: Approximately 57-70 μg after 0.5 hours. Approximately 105-112 μg after 1 hour. Approximately 150-180 μg after 2 hours. Approximately 250-280 μg after 4 hours. Approximately 290 to 345 μg after 6 hours. Approximately 360-400 μg after 8 hours. Approximately 370 to 430 μg after 10 hours. At least approximately 420 μg after 12 hours, The present invention is characterized by being at least about 420 μg after 16 hours and / or after 16 hours.

[0385] In all of the above embodiments of in vitro-released implants, as measured according to Method C and defined by the amount of axitinib released (μg), the axitinib contained in the implant is the free base of axitinib, which is axitinib polymorph IV, or contains it. In certain embodiments, the axitinib contained in the implant is axitinib polymorph IV. In embodiments in which the implant contains axitinib polymorph IV, at least 90% by weight of the free base of axitinib contained in the implant is polymorph IV. In certain embodiments, the amount of axitinib contained in these implants is about 300 to about 600 μg, for example, about 400 to about 500 μg, for example, about 450 μg. In certain embodiments of these embodiments, the implant contains an amount of axitinib polymorph IV of about 400 to about 500 μg, for example, about 450 μg. In certain embodiments of these designs, the implant is a single-strand implant, for example, a single-strand implant having an essentially cylindrical shape, and is at least 16 mm long. 2 For example, approximately 16.0 to 23.0 mm 2 It has a hydrated surface area (measured in PBS at pH 7.2-7.4 after 24 hours of incubation at 37°C).

[0386] In a particular embodiment of the present invention, the implant is optionally a single-strand implant containing about 400 μg to about 500 μg of axitinib in polymorph IV form (e.g., micronized axitinib polymorph IV particles as defined herein), wherein the hydrated surface area (measured in PBS, pH 7.2 to 7.4 after 24 hours of incubation at 37°C) is at least 16 mm². 2 For example, approximately 16.0 to 23.0 mm 2 The total weight in dry state is optionally about 0.6 mg to about 1 mg, and the implant is further tested in an in vitro test performed in a USP apparatus 4 at 35°C ± 0.5°C in 0.01 N HCl containing 0.25% cetyltrimethylammonium bromide (CTAB), and the amount of axitinib released from the implant is After 0.5 hours, at least about 50 μg, for example, at least about 51 μg, After 2 hours, at least about 140 μg, for example, at least about 150 μg, After 6 hours, at least about 270 μg, for example, at least about 290 μg, After 10 hours, at least approximately 350 μg, for example, at least approximately 370 μg, After 12 hours, at least about 400 μg, for example, at least about 410 μg, and / or characterized by being at least about 410 μg, for example, at least about 430 μg after 16 hours, Alternatively, the implant may further be used in an in vitro test performed in a USP apparatus 4 at 35°C ± 0.5°C in 0.01N HCl containing 0.25% cetyltrimethylammonium bromide (CTAB), and the amount of axitinib released from the implant is After 0.5 hours, at least about 50 μg, for example, at least about 51 μg, After one hour, at least about 90 μg, for example, at least about 95 μg, After 2 hours, at least about 140 μg, for example, at least about 150 μg, After 4 hours, at least about 230 μg, for example, at least about 240 μg, After 6 hours, at least about 270 μg, for example, at least about 290 μg, After 8 hours, at least approximately 340 μg, for example, at least approximately 350 μg, After 10 hours, at least approximately 350 μg, for example, at least approximately 370 μg, After 12 hours, at least about 400 μg, for example, at least about 410 μg, and / or after 16 hours, the amount is at least about 410 μg, for example, at least about 430 μg.

[0387] The implant is a single-strand implant containing approximately 400 μg to approximately 500 μg, for example 450 μg, of axitinib in polymorph IV form (e.g., micronized axitinib polymorph IV particles as defined herein), and has a hydrated surface area (measured after 24 hours of incubation at 37°C in PBS at pH 7.2–7.4) of at least 16 mm². 2 For example, approximately 16.0 to 23.0 mm 2 The total weight in dry state is approximately 0.6 mg to approximately 1 mg. In these or other specific embodiments, the implant further comprises a percentage of axitinib released from the implant (the percentage of axitinib released is based on the maximum amount of axitinib released from the implant, which represents 100%) in an in vitro test performed in a USP apparatus 4 at 35°C ± 0.5°C in 0.01 N HCl containing 0.25% cetyltrimethylammonium bromide (CTAB). After 0.5 hours, at least about 10%, for example, at least about 12%, After 2 hours, at least about 30%, for example, at least about 32%, After 6 hours, at least about 58%, for example, at least about 60%, After 10 hours, at least about 75%, for example, at least about 80%, After 12 hours, at least about 80%, for example, at least about 85%, and / or characterized by being at least about 90%, for example, at least about 95%, after 16 hours. Alternatively, the implant may further be used in an in vitro test performed in a USP apparatus 4 at 35°C ± 0.5°C in 0.01N HCl containing 0.25% cetyltrimethylammonium bromide (CTAB), where the percentage of axitinib released from the implant (the percentage of axitinib released is based on the maximum amount of axitinib released from the implant, which represents 100%) After 0.5 hours, at least about 10%, for example, at least about 12%, After one hour, at least about 19%, for example, at least about 20%, After 2 hours, at least about 30%, for example, at least about 32%, After 4 hours, at least about 45%, for example, at least about 50%, After 6 hours, at least about 58%, for example, at least about 60%, After 8 hours, at least about 70%, for example, at least about 74%, After 10 hours, at least about 75%, for example, at least about 80%, After 12 hours, at least about 80%, for example, at least about 85%, and / or after 16 hours, it is characterized by being at least about 90%, for example, at least about 95%.

[0388] In a particular, more specific embodiment, the implant is optionally a single-strand implant containing about 400 μg to about 500 μg of axitinib in polymorph IV form (e.g., micronized axitinib polymorph IV particles as defined herein), with a hydrated surface area (measured in PBS, pH 7.2–7.4 after 24 hours of incubation at 37°C) of at least 16 mm². 2 For example, approximately 16.0 to 23.0 mm 2 The total weight in dry state is optionally about 0.6 mg to about 1 mg, and the implant is further tested in an in vitro test performed in a USP apparatus 4 at 35°C ± 0.5°C in 0.01 N HCl containing 0.25% cetyltrimethylammonium bromide (CTAB), and the amount of axitinib released from the implant is Approximately 50-80 μg after 0.5 hours, for example, approximately 55-75 μg, for example, approximately 57-72 μg. After one hour, approximately 90 to 130 μg, for example, approximately 95 to 120 μg, for example, approximately 100 to 120 μg. After 2 hours, approximately 140 to 210 μg, for example, approximately 140 μg to 200 μg, for example, approximately 147 to 195 μg. After 4 hours, approximately 230 to 290 μg, for example, approximately 235 to 290 μg, for example, approximately 240 to 280 μg. After 6 hours, approximately 270 to 380 μg, for example, approximately 295 to 370 μg, for example, approximately 300 to 360 μg. After 8 hours, approximately 340 to 440 μg, for example, approximately 350 to 430 μg, for example, approximately 355 to 420 μg. After 10 hours, approximately 350 to 470 μg, for example, approximately 380 to 460 μg, for example, approximately 390 to 450 μg. After 12 hours, at least about 400 μg, for example, at least about 410 μg, The present invention is characterized by having at least about 410 μg, for example, at least about 430 μg, after and / or 16 hours.

[0389] The implant is a single-strand implant containing approximately 400 μg to approximately 500 μg, for example 450 μg, of axitinib in polymorph IV form (e.g., micronized axitinib polymorph IV particles as defined herein), and has a hydrated surface area (measured after 24 hours of incubation at 37°C in PBS at pH 7.2–7.4) of at least 16 mm². 2 For example, approximately 16.0 to 23.0 mm 2 In these or other more specific embodiments of the present invention, the total weight is approximately 0.6 mg to approximately 1 mg, and the implant is further configured such that, in an in vitro test performed in a USP apparatus 4 at 35°C ± 0.5°C in 0.01 N HCl containing 0.25% cetyltrimethylammonium bromide (CTAB), the percentage of axitinib released from the implant (the percentage of axitinib released is based on the maximum amount of axitinib released from the implant, which represents 100%) is After 0.5 hours, approximately 10-20%, for example, approximately 10-18%, for example, approximately 12-17%. After one hour, approximately 19-30%, for example, approximately 20-27%, for example, approximately 20-26%. After 2 hours, approximately 30-45%, for example, approximately 31-43%, for example, approximately 32-41%. After 4 hours, approximately 45-65%, for example, approximately 48-63%, for example, approximately 49-60%. After 6 hours, approximately 58-81%, for example, approximately 60-80%, for example, approximately 62-78%. After 8 hours, approximately 70-90%, for example, approximately 73-87%, for example, approximately 74-86%. After 10 hours, approximately 75-98%, for example, approximately 78-95%, for example, approximately 80-95%. After 12 hours, at least about 80%, for example, at least about 85%, and / or after 16 hours, it is characterized by being at least about 90%, for example, at least about 95%.

[0390] In vivo release and sustained-release properties of hydrogels: In embodiments of the present invention, when the dried implant of the present invention is administered to the eye, for example, the vitreous fluid, it hydrates and changes its dimensions as disclosed herein, and its hydrogel then biodegrades over time and is completely reabsorbed. When the implant is biodegraded, for example by ester hydrolysis, it may gradually swell and soften, then shrink, become softer, and further liquefy to completely dissolve and become invisible. After the hydrogel has completely decomposed, undissolved TKI particles may remain at the former site of the implant, and in some cases may aggregate, i.e., form a single, integrated structure. These remaining undissolved axitinib particles may continue to dissolve slowly at a rate sufficient to deliver a therapeutically effective level of TKI. In certain embodiments, when two or more implants are administered to achieve a desired total dose, they biodegrade equally over time, and the remaining axitinib particles also aggregate to form a single, integrated structure.

[0391] In certain embodiments, the hydrogel implant softens over time as it degrades. This may depend, among other things, on the structure, i.e., the hydrophilicity or hydrophobicity of the carbon chain near the degradable ester group of the linker that crosslinks the PEG units of the hydrogel. For example, in the implant used in the examples herein, the carbon chain contains seven carbon atoms when it arises from the SAZ functional group of PEG, e.g., a 4a20kPEG precursor. This carbon chain can provide long-lasting persistence of up to about nine months or up to about twelve months in the human eye compared to, for example, shorter carbon chains when using the SG functional group which gives a shorter carbon chain to the linker.

[0392] In the human eye, for example, in the vitreous fluid, the implant of the present invention in certain embodiments will biodegrade (i.e., the hydrogel will dissolve) within about 2 to 15 months after administration, or within about 4 to 13 months after administration, or within about 6 to 12 months after administration, or within about 6 to 18 months after administration, particularly within about 6 to 9 months after administration, for example, within about 8 months after administration, or within about 9 to 12 months after administration. In certain embodiments (for example, embodiments in which the hydrogel includes cross-linked PEG units, for example, cross-linked 4a20kPEG-SAZ and 8a20kPEG-NH2 units), the hydrogel will degrade (be reabsorbed) within about 8 to 9 months after injection into the human vitreous fluid. In other species, the implant of the present invention may or may not biodegrade faster or slower than in the human vitreous fluid. For example, in non-human primates, such as monkeys, particularly cynomolgus macaques, the hydrogel dissolves within about 5-6 months (especially in embodiments where the hydrogel contains cross-linked PEG units, e.g., cross-linked 4a20kPEG-SAZ and 8a20kPEG-NH2 units), and in rabbits, particularly Dutch-belted rabbits, the hydrogel dissolves within about 4-5 months (especially in embodiments where the hydrogel contains cross-linked PEG units, e.g., cross-linked 4a20kPEG-SAZ and 8a20kPEG-NH2 units). While we do not wish to be bound by theory, the degradation of the hydrogel (e.g., by ester hydrolysis) is largely determined by the intravitreous temperature. The intravitreous temperature is approximately 33°C in humans, 35°C in monkeys, and 37°C in rabbits (F. Lorget et al., Molecular pharmaceutics, 13(9), pp.2891-2896, and MBLanders III et al., Retina 32(1), p.172-176(1 / 2012), which leads to certain differences in the persistence of hydrogels among different species, such as rabbits, monkeys, and humans. The solubility of drugs such as TKIs, for example axitinib itself, is not affected to the same extent by these temperature differences.

[0393] In one embodiment, the implant, after administration to the vitreous fluid (as defined herein), releases the TKI, e.g., a therapeutically effective dose of axitinib, for example, 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 (i.e., infusion). In a particular embodiment, the implant releases the TKI, e.g., axitinib, over a period of about 6 to about 9 months after administration.

[0394] In one embodiment of the present invention, the implant provides a treatment 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, or at least about 13 months, or longer, after the implant (i.e., a single) is administered (i.e., injected) into the patient's vitreous fluid. In a particular embodiment, the implant of the present invention provides a treatment period of about 6 to about 12 months, for example, about 8 to about 11 months, or about 6 months. In a particular embodiment, the implant of the present invention provides a treatment period of about 9 months. After one treatment period, a new implant of the present invention can be injected as disclosed herein. This sequence can be repeated as many times as necessary. For example, a second new implant can be injected about 9 months after the injection of the first implant. In particular, in embodiments of the present invention in which the hydrogel comprises an implant obtained by crosslinking crosslinked PEG units, e.g., precursors of 4a20kPEG-SAZ and 8a20kPEG-NH2, and the amount of TKI contained in the implant is about 400 to about 500 μg, the hydrogel is completely biodegraded by about 9 months after the injection of the first implant, and the remaining axitinib is released into the vitreous humor and delivered to the retina and / or choroid / RPE, so that a new implant can be injected about 9 months after the injection of the first implant.

[0395] In one embodiment of the present invention, a TKI, for example, axitinib, is released from the implant into the vitreous humor in vivo at an average rate of typically about 0.1 μg / day to about 10 μg / day, or about 0.5 μg / day to about 5 μg / day, or about 0.5 μg / day to about 2 μg / day. In a particular embodiment of the present invention, a TKI, for example, axitinib, is released from the implant in vivo (into the vitreous fluid, e.g., into human vitreous fluid) at an average rate of at least 0.8 μg / day, e.g., about 0.8 μg / day to about 1.5 μg / day, or about 0.9 μg / day to about 1.3 μg / day, e.g., about 1.2 μg / day, for at least 3 months, e.g., at least 6 months, or at least 9 months, or at least 10 months after injection. In certain embodiments, the release of such TKI, e.g., axitinib, is maintained for at least about 3 months after the injection of the implant, for example, about 6 to 9 months, or about 6 to 12 months. In certain embodiments, the above average release rate applies to the vitreous humor of non-human primates, e.g., monkeys (but not limited to, especially cynomolgus monkeys). In certain embodiments, the above average release rate applies to the vitreous humor of humans. In certain embodiments, an implant of the present invention, for example, comprising a hydrogel and axitinib particles, wherein the hydrogel comprises crosslinked PEG units obtained by crosslinking precursors of 4a20kPEG-SAZ and 8a20kPEG-NH2, and the amount of axitinib (particularly axitinib polymorph IV) contained in the implant is about 400 to about 500 μg, results in the release of axitinib into the human vitreous humor at an average rate of about 0.8 μg / day to about 1.5 μg / day, for example, about 0.9 μg / day to about 1.3 μg / day, or about 1.0 μg / day to about 1.2 μg / day, for example, about 1.0 μg / day. In certain embodiments, the release rate is essentially constant for at least about 3 months, or for the first quarter or first half of the treatment period.

[0396] In vivo release and preclinical studies in non-human primates (NHPs) Preclinical studies in non-human primates (NHPs) have shown that, in particular, approximately 300 μg of axitinib in polymorphic form IV is present, and approximately 20 mm 2The studies were conducted using implants with a hydrated surface area. In short, in these intraocular distribution and pharmacokinetic studies, the in vivo release of such implants after a single intravitreal injection was identified in cynomolgus monkeys and then compared with the results obtained with a reference implant containing axitinib in the form of polymorph SAB-I, using three implants containing the following doses: approximately 600 μg, approximately 300 μg, and approximately 200 μg each of axitinib. The results of these studies are reported and compared in Example 10. Three months after intravitreal injection of a single implant according to the present invention containing approximately 300 μg of axitinib polymorph IV, axitinib levels in the retina, choroid, and retinal pigment epithelium (RPE) were found to be higher compared to the reference implant (containing axitinib polymorph SAB-I). While we do not wish to be bound by this theory, these elevated levels of axitinib in the above ocular tissues are thought to be due to the solubility of axitinib polymorph IV. This solubility is approximately twice that of axitinib polymorph SAB-I, as disclosed herein, which in turn accelerates the release of axitinib from the implant into the vitreous fluid. IC of VEGFR-2 from cell-based assays 50 Based on the value of 0.077 ng / mL, and considering the vitreous half-life of axitinib, which is 2 hours, it was determined that 256 ng / day of axitinib is released from the intravitreous implant to deliver a therapeutically effective concentration of axitinib into the vitreous (US2020 / 0375889A1, paragraphs

[0048] -

[0050] ). To date, in this study in NHP, a release rate of 986 ng / day from an implant containing approximately 300 μg of axitinib (polymorph IV) has been measured, which is nearly four times the required release rate of 256 ng / day mentioned above.

[0397] Example 10 also provides further data on in vivo release of the implant according to the present invention in NHP (particularly cynomolgus monkeys) at more than 3 months, i.e., 6 months and 9 months. In this example, the retinal and choroidal / RPE t of an implant containing axitinib polymorph IV (e.g., implant 10D of Example 10 containing a dose of about 300 μg of axitinib) max However, while this occurred at 3 months during the sustained-release period, implants containing axitinib polymorphic SAB-I (implants 10A, 10B, and 10C) showed retinal and choroidal / RPE t maxThis demonstrates that this occurred within 6 or 9 months. The hydrogel of the implant according to the present invention used in this study biodegrades within approximately 5-6 months in NHP. This means that, in certain embodiments of the present invention relating to implants containing a more soluble form of axitinib, e.g., axitinib polymorph IV, the majority of the drug payload contained in the implant is released before the final release that occurs during the final biodegradation of the hydrogel, compared to release from a comparative implant that contains a less soluble form of axitinib (e.g., axitinib polymorph SAB-I) but is otherwise comparable to the implant of the present invention (e.g., in terms of implant composition and the amount of drug contained in the implant). Therefore, in a particular embodiment of the present invention, where the axitinib contained in the sustained-release biodegradable ophthalmic implant is axitinib (e.g., axitinib polymorph IV) having a solubility of at least 0.3 μg / mL as measured after incubation at 37°C for 5 days at pH 7.2-7.4 in phosphate-buffered saline (PBS), the maximum axitinib concentration in the retina and / or choroid / RPE at the time of final hydrogel degradation provided by the sustained-release biodegradable ophthalmic implant is lower than the maximum axitinib concentration in the retina and / or choroid / RPE at the time of final hydrogel degradation provided by a comparative implant in which axitinib has a solubility lower than 0.3 μg / mL as measured after incubation at 37°C for 5 days at pH 7.2-7.4 in phosphate-buffered saline (PBS), respectively. In certain embodiments of these cases, the total amount of axitinib contained in the comparative implant differs by no more than 10% from the total amount of axitinib contained in the sustained-release biodegradable ophthalmic implant.

[0398] Therefore, in certain embodiments of the present invention, particularly when the implant contains about 400 to about 500 μg of axitinib polymorph IV, the cumulative amount of axitinib released before the biodegradation of the hydrogel is greater than the amount of axitinib ultimately released during biodegradation. In certain embodiments, the final amount of axitinib released during the biodegradation of the hydrogel in the vitreous fluid is not greater than, or substantially less than, the cumulative amount of axitinib released by the implant before biodegradation, provided the implant is still intact. In certain embodiments, the amount of axitinib remaining in the vitreous fluid 6 months after implant injection (including the amount of axitinib present in the implant in the vitreous fluid) is 250 μg or less, for example, 200 μg or less. In certain embodiments, after injection into the vitreous fluid, the concentration of axitinib in the retina or choroid / RPE resulting from the final release during biodegradation of the hydrogel is not higher, or substantially higher, than the maximum concentration of axitinib in the retina or choroid / RPE, respectively, that would be achieved by the implant at any point after injection of the hydrogel but before biodegradation, provided the implant is still intact. For example, it is no higher than about 25% and no higher than about 10%.

[0399] In certain embodiments of the present invention, in the retina and choroid / RPE of NHP, the maximum concentration of a TKI, particularly axitinib, is achieved before the hydrogel biodegrades in implants according to the present invention containing a more soluble TKI (e.g., axitinib polymorph IV, in an amount of, for example, about 400 to about 500 μg), whereas in implants containing a less soluble TKI (e.g., axitinib polymorph SAB-I), the maximum concentration of the TKI in the retina and choroid / RPE of NHP is achieved only during / after the degradation of the hydrogel (which occurs in about 5 to 6 months in NHP, as described herein). For example, implant 10D of Example 10 containing about 0.3 mg of axitinib polymorph IV should be compared with implants 10A to 10C containing various amounts of axitinib polymorph SAB-I. An implant according to the present invention (Sample 10D), containing approximately 0.3 mg of axitinib in the more soluble form of axitinib polymorph IV, reaches a steady state faster than an implant containing the less soluble axitinib polymorph SAB-I and maintains it without increasing release during hydrogel biodegradation. In Example 10, the maximum exposure of axitinib to the retina and choroid / RPE after hydrogel biodegradation was considerably lower in the implant containing the more soluble axitinib polymorph IV (Implant 10D) due to less drug remaining during hydrogel biodegradation. The mean daily release rate (μg / day) over the first three months after implant injection reflects that the release of axitinib from the 0.3 mg dose axitinib polymorph IV implant (10D) used in this study was faster compared to the corresponding implant containing the less soluble axitinib polymorph SAB-I.

[0400] In certain embodiments, the implant of the present invention may release a TKI, e.g., axitinib, into the vitreous humor, but the cumulative amount of TKI (e.g., axitinib) released before the biodegradation of the hydrogel is greater than the amount of TKI (e.g., axitinib) ultimately released at final biodegradation. In these embodiments, the amount of axitinib released at biodegradation may be less than about 200 μg, e.g., less than about 150 μg, less than or equal to about 130 μg, or less than or equal to about 100 μg, or the final amount of axitinib released at final biodegradation of the hydrogel may be about 50 to about 200 μg, e.g., about 100 to about 170 μg, e.g., about 110 to 150 μg. In these or other embodiments, the maximum TKI (e.g., axitinib) concentration (C) reached in ocular tissue, e.g., the retina or choroid, before the biodegradation of the hydrogel is greater than the maximum TKI (e.g., axitinib) concentration (C) reached in ocular tissue, e.g., the retina or choroid. max The concentration of the TKI (e.g., axitinib) delivered to the eye tissue during biodegradation is within + / - 50%, for example, within + / - 30%.

[0401] In some embodiments, the implant according to the present invention delivers a certain concentration of TKI (e.g., axitinib) to ocular tissue (e.g., retina or choroid), but the t max This is achieved with comparative implants. maxFor example, the maximum concentration of the TKI (e.g., axitinib) delivered to the tissue at least about one month or at least about two months earlier, and / or higher, than the maximum concentration of the TKI delivered by the comparative implant, in which case the comparative implant contains the TKI in an amount within + / - 10%, for example, within + / - 5%, of the total amount of the TKI contained in the implant of the present invention, and differs from the implant of the present invention (for example, only in this respect) in that the comparative implant contains the TKI in a form having lower solubility than...

Claims

1. A sustained-release biodegradable ophthalmic implant comprising a hydrogel and approximately 400 μg to approximately 500 μg of axitinib polymorph IV, wherein the axitinib particles are dispersed within the hydrogel.

2. A sustained-release biodegradable ophthalmic implant according to claim 1, comprising approximately 410 μg to approximately 490 μg of axitinib polymorph IV.

3. The hydrated surface area of ​​the implant was measured after 24 hours of incubation at 37°C in phosphate-buffered saline (PBS) at pH 7.2–7.4, and was at least 15 mm². ２ The sustained-release biodegradable ophthalmic implant according to claim 1 or 2.

4. The hydrated surface area of ​​the implant was measured after 24 hours of incubation at 37°C in phosphate-buffered saline (PBS) at pH 7.2–7.4, and was approximately 16.0 mm². ２ ~approximately 23.0 mm ２ A sustained-release biodegradable ophthalmic implant according to any of the prior claims.

5. A sustained-release biodegradable ophthalmic implant according to any of the prior claims, wherein the axitinib particles, as identified by laser diffraction, have a d10 particle diameter of less than 0.25 μm, a d50 particle diameter of less than 2.6 μm, and a d90 particle diameter of less than 8 μm.

6. A sustained-release biodegradable ophthalmic implant according to any of the prior claims, wherein the total weight is approximately 0.6 mg to approximately 1 mg in a dry state.

7. A sustained-release biodegradable ophthalmic implant according to any of the prior claims, comprising an elongated object having a length and a width, wherein the width is the largest cross-sectional dimension of the object and the length is the longest extension of the object.

8. A sustained-release biodegradable ophthalmic implant according to any of the prior claims, which is cylindrical or essentially cylindrical.

9. A sustained-release biodegradable ophthalmic implant according to any of the prior claims, wherein the implant, in a dry state, has a length of 11 mm or less, for example, 6 mm to 10 mm, or 6 mm to 9 mm, and / or a width of less than 0.7 mm, for example, 0.1 mm to 0.65 mm, or 0.20 mm to 0.45 mm.

10. A sustained-release biodegradable ophthalmic implant according to any of the prior claims, having a length of 6.7 to 7.8 mm and / or a width of 0.30 to about 0.40 mm in a dry state.

11. A sustained-release biodegradable ophthalmic implant according to any of the prior claims, having a length of 4 to 12 mm, or 4 to 11 mm, or 6 to 11 mm, or 6 to 10 mm, and / or a width of 0.5 to 0.9 mm, or 0.5 to 0.8 mm, in a hydrated state of the implant (in phosphate-buffered saline, pH 7.2 to 7.4, at 37°C for 24 hours).

12. A sustained-release biodegradable ophthalmic implant according to any of the prior claims, having a length of 7 to 10 mm and a width of 0.5 to 0.9 mm in a hydrated state (in PBS, pH 7.2 to 7.4 at 37°C for 24 hours).

13. The sustained-release biodegradable ophthalmic implant according to any of the prior claims, wherein the hydrogel comprises a synthetic polymer network.

14. The sustained-release biodegradable ophthalmic implant according to claim 13, wherein the polymer network comprises cross-linked polyethylene glycol (PEG) units.

15. A sustained-release biodegradable ophthalmic implant according to any of the prior claims, wherein the hydrogel comprises multi-armed PEG units, for example, 4-armed and / or 8-armed PEG units, having the same or different number-average molecular weights of about 10,000 to about 60,000 daltons, or about 15,000 to about 40,000 daltons, for example, about 20,000 daltons.

16. The sustained-release biodegradable ophthalmic implant according to any one of claims 13 to 15, wherein the polymer network is formed by reacting an electrophile-containing PEG precursor with a nucleophile-containing crosslinking agent, and the crosslinking agent is a nucleophile-containing PEG precursor or another nucleophile-containing crosslinking agent.

17. The sustained-release biodegradable ophthalmic implant according to claim 16, wherein the nucleophile is an amine group, for example, the nucleophile-containing crosslinking agent is trilysine, or a salt or derivative thereof, and the electrophile is an active ester group, for example, an N-hydroxysuccinimidyl (NHS) group.

18. The sustained-release biodegradable ophthalmic implant according to claim 16 or 17, wherein the electrophile is one or more of succinimidyl azelate (SAZ) group, succinimidyl adipate (SAP) group, succinimidyl glutarate (SG) group, succinimidyl glutaramide (SGA) group, succinimidyl carbonate (SC) group, or succinimidyl succinate (SS) group, particularly succinimidyl azelate (SAZ) group.

19. The hydrogel contains crosslinked PEG units, and the crosslinks between the PEG units contain groups represented by the following formula. 【Chemistry 1】 A sustained-release biodegradable ophthalmic implant according to any of the prior claims, wherein m is an integer from 0 to 10, for example, m is 1, 2, 3, or 6, and in particular m is 6.

20. The polymer network consists of 4a20kPEG-SAZ and 8a20kPEG-NH ２ A sustained-release biodegradable ophthalmic implant according to any one of claims 13 to 19, formed by crosslinking.

21. A sustained-release biodegradable ophthalmic implant according to any of the prior claims, comprising approximately 30% to approximately 70% by weight of axitinib, or approximately 40% to approximately 70% by weight, or approximately 45% to approximately 65% ​​by weight of axitinib and approximately 20% to approximately 50% by weight, or approximately 25% to approximately 45% by weight, or approximately 30% to approximately 43% by weight of PEG units (anhydrous base, % w / w), or approximately 60% to approximately 70% by weight of axitinib and approximately 25% to approximately 35% by weight of PEG units (anhydrous base, % w / w).

22. A sustained-release biodegradable ophthalmic implant according to any of the prior claims, having a composition (wet base, % w / w) of approximately 5% to approximately 20% by weight, or approximately 6% to approximately 15% by weight, of axitinib and approximately 4% to approximately 12% by weight, or approximately 5% to approximately 10% by weight, of PEG units.

23. In an in vitro test performed in a USP apparatus 4 at 35°C ± 0.5°C in 0.01N HCl containing 0.25% cetyltrimethylammonium bromide (CTAB), the percentage of axitinib released from the implant (the percentage of axitinib released is based on the maximum amount of axitinib released from the implant, which represents 100%) was: At least about 10% after 0.5 hours, After two hours, at least about 30%, After 6 hours, at least about 58%, After 10 hours, at least about 75%, At least approximately 80% after 12 hours, and / or at least about 90% after 16 hours, for example, At least about 10% after 0.5 hours, After one hour, at least about 19%, After two hours, at least about 30%, After 4 hours, at least about 45%, After 6 hours, at least about 58%, At least about 70% after 8 hours, After 10 hours, at least about 75%, At least approximately 80% after 12 hours, A sustained-release biodegradable ophthalmic implant according to any of the prior claims, characterized in that it is at least about 90% after and / or 16 hours.

24. In an in vitro test performed in a USP apparatus 4 at 35°C ± 0.5°C in 0.01N HCl containing 0.25% cetyltrimethylammonium bromide (CTAB), the percentage of axitinib released from the implant (the percentage of axitinib released is based on the maximum amount of axitinib released from the implant, which represents 100%) was: Approximately 10-20% after 0.5 hours, Approximately 30-45% after 2 hours. After 6 hours, approximately 58-81% Approximately 75-98% after 10 hours. At least approximately 80% after 12 hours, and / or at least about 90% after 16 hours, for example, Approximately 10-20% after 0.5 hours, Approximately 19-30% after one hour, Approximately 30-45% after 2 hours. After 4 hours, approximately 45-65% After 6 hours, approximately 58-81% Approximately 70-90% after 8 hours. After 10 hours, approximately 75-98% At least approximately 80% after 12 hours, A sustained-release biodegradable ophthalmic implant according to any of the prior claims, characterized in that it is at least about 90% after and / or 16 hours.

25. In an in vitro test performed in a USP apparatus 4 at 35°C ± 0.5°C in 0.01N HCl containing 0.25% cetyltrimethylammonium bromide (CTAB), the percentage of axitinib released from the implant (the percentage of axitinib released is based on the maximum amount of axitinib released from the implant, which represents 100%) was: Approximately 10-18% after 0.5 hours, After two hours, approximately 31-43% Approximately 60-80% after 6 hours. Approximately 78-95% after 10 hours. After 12 hours, at least about 85%, and / or at least about 95% after 16 hours, for example, Approximately 12-17% after 0.5 hours, After two hours, approximately 32-41% After 6 hours, approximately 62-78% Approximately 80-95% after 10 hours. After 12 hours, at least about 85%, A sustained-release biodegradable ophthalmic implant according to any of the prior claims, characterized in that it is at least about 95% after and / or 16 hours.

26. In an in vitro test performed in a USP apparatus 4 at 35°C ± 0.5°C in 0.01N HCl containing 0.25% cetyltrimethylammonium bromide (CTAB), the amount of axitinib released from the implant was: At least approximately 50 μg after 0.5 hours, After 2 hours, at least approximately 140 μg, After 6 hours, at least approximately 270 μg, After 10 hours, at least approximately 350 μg, After 12 hours, at least about 400 μg, and / or at least about 410 μg after 16 hours, for example, At least approximately 50 μg after 0.5 hours, After one hour, at least about 90 μg, After 2 hours, at least approximately 140 μg, At least approximately 230 μg after 4 hours, After 6 hours, at least approximately 270 μg, At least approximately 340 μg after 8 hours, After 10 hours, at least approximately 350 μg, After 12 hours, at least about 400 μg, A sustained-release biodegradable ophthalmic implant according to any of the prior claims, characterized in that the amount is at least about 410 μg after and / or 16 hours.

27. In an in vitro test performed in a USP apparatus 4 at 35°C ± 0.5°C in 0.01N HCl containing 0.25% cetyltrimethylammonium bromide (CTAB), the amount of axitinib released from the implant was: Approximately 50 to 80 μg after 0.5 hours, Approximately 140 to 210 μg after 2 hours. After 6 hours, approximately 270 to 380 μg, Approximately 350 to 470 μg after 10 hours. After 12 hours, at least about 400 μg, and / or at least about 410 μg after 16 hours, for example, Approximately 50 to 80 μg after 0.5 hours, Approximately 90 to 130 μg after one hour. Approximately 140 to 210 μg after 2 hours. Approximately 230 to 290 μg after 4 hours. After 6 hours, approximately 270 to 380 μg, Approximately 340 to 440 μg after 8 hours. Approximately 350 to 470 μg after 10 hours. After 12 hours, at least about 400 μg, A sustained-release biodegradable ophthalmic implant according to any of the prior claims, characterized in that the amount is at least about 410 μg after and / or 16 hours.

28. In an in vitro test performed in a USP apparatus 4 at 35°C ± 0.5°C in 0.01N HCl containing 0.25% cetyltrimethylammonium bromide (CTAB), the amount of axitinib released from the implant was: Approximately 55 to 75 μg after 0.5 hours. Approximately 140 to 200 μg after 2 hours, After 6 hours, approximately 295 to 370 μg Approximately 350 to 460 μg after 10 hours. After 12 hours, at least approximately 410 μg, and / or at least about 430 μg after 16 hours, for example, Approximately 57 to 72 μg after 0.5 hours. After 2 hours, approximately 147 to 195 μg After 6 hours, approximately 300 to 360 μg, Approximately 390 to 450 μg after 10 hours. After 12 hours, at least approximately 410 μg, A sustained-release biodegradable ophthalmic implant according to any of the prior claims, characterized in that the amount is at least about 430 μg after 16 hours.

29. A sustained-release biodegradable ophthalmic implant according to any of the prior claims, wherein the axitinib polymorph IV contained in the implant contains at least about 10% less total impurities, for example, at least about 15% less total impurities, for example, at least about 20% less total impurities, compared to axitinib polymorph IV in powder form after exposure to visible light, after the same exposure time, and under the same exposure conditions.

30. A sustained-release biodegradable ophthalmic implant according to any of the prior claims, wherein the axitinib polymorph IV contained in the implant contains at least about 10% less total impurities, for example, at least about 20% less total impurities, for example, at least about 30% less total impurities, for example, at least about 40% less total impurities, compared to axitinib polymorph IV in powder form after exposure to UV light, after the same exposure time and under the same exposure conditions.

31. A sustained-release biodegradable ophthalmic implant, which is an intravitreous implant, as described in any of the prior claims.

32. The hydrogel comprises crosslinked multi-arm PEG units having a number-average molecular weight of approximately 20,000 Daltons, and the crosslinks between the PEG units comprise groups represented by the following formula. 【Chemistry 2】 In the formula, m is 6, The sustained-release biodegradable ophthalmic implant according to claim 1, which is cylindrical in shape and, in a dry state, has a length of 10 mm or less and a diameter of 0.25 to 0.45 mm, and / or, in a hydrated state (in PBS, pH 7.2 to 7.4 at 37°C for 24 hours), has a length of 10 mm or less and a diameter of 0.5 to 0.9 mm, wherein the axitinib particles have a d90 particle diameter of less than 10 μm, for example, less than 8 μm and / or less than 3 μm.

33. The intravitreous implant has a composition of approximately 30-75% axitinib, 20-50% PEG units, and 0.5-15% sodium phosphate on an anhydrous basis (% w / w), and approximately 5-17% axitinib, 4-12% PEG units, and 0.2-5% sodium phosphate on a wet basis (% w / w). The hydrogel is 4a20kPEG-SAZ and 8a20kPEG-NH ２ It includes a PEG hydrogel network formed by crosslinking units of the same type. The implant has a length greater than its width, and in its dry state, has a length of 11 mm or less, for example, 5 to 11 mm, and a width of 0.2 to 0.4 mm, for example, 0.28 to 0.38 mm, and / or in its hydrated state (in PBS, pH 7.4 at 37°C for 24 hours), has a length of 11 mm or less, for example, 5 to 11 mm, and a width of 0.4 to 2 mm. The sustained-release biodegradable ophthalmic implant according to claim 1, wherein the axitinib particles have a d90 particle diameter of less than 8 μm and a d50 particle diameter of less than 3 μm.

34. The intravitreous implant has a composition of approximately 30-75% axitinib, 20-50% PEG units, and 0.5-15% sodium phosphate on an anhydrous basis (% w / w), and approximately 5-17% axitinib, 4-12% PEG units, and 0.2-5% sodium phosphate on a wet basis (% w / w). The hydrogel is 4a20kPEG-SAZ and 8a20kPEG-NH ２ It contains a PEG hydrogel network formed by crosslinking the precursor, The implant, in its dry state, has a width of 0.20 to 0.40 mm, and in its hydrated state (in PBS at pH 7.4 at 37°C for 24 hours), has a length of 11 mm or less. 10-30 mm ２ A sustained-release biodegradable ophthalmic implant according to claim 1, having a hydrated surface area (measured after incubation at 37°C for 24 hours in phosphate-buffered saline (PBS) at pH 7.2 to 7.4).

35. In its dry state, the implant has a width of 0.30 to 0.36 mm, and in its hydrated state (in PBS at pH 7.4 at 37°C for 24 hours), it has a length of 10.5 mm or less. 16 to 25 mm ２ e.g., 16 to 23 mm ２ The sustained-release biodegradable ophthalmic implant according to claim 34, having a hydrated surface area (measured after incubation at 37° C. for 24 hours at pH 7.2 to 7.4 in phosphate buffered saline (PBS)).

36. The intravitreous implant has a composition of approximately 30-75% axitinib, 20-50% PEG units, and 0.5-15% sodium phosphate on an anhydrous basis (% w / w), and approximately 5-17% axitinib, 4-12% PEG units, and 0.2-5% sodium phosphate on a wet basis (% w / w). The hydrogel is 4a20kPEG-SAZ and 8a20kPEG-NH ２ It includes a PEG hydrogel network formed by crosslinking units of the same type. The sustained-release biodegradable ophthalmic implant according to claim 1, wherein in a dry state the implant has a length of 5 to 11 mm and a width of 0.28 to 0.38 mm, and / or in a hydrated state (in PBS, pH 7.4 at 37°C for 24 hours), it has a length of 5 to 11 mm and a width of 0.4 to 2 mm.

37. This is an intravitreous implant with an anhydrous base (% w / w), containing approximately 54% to 69% axitinib, approximately 17% to 26% 4a20kPEG-SAZ, and approximately 8% to 13% 8a20kPEG-NH ２ A sustained-release biodegradable ophthalmic implant according to claim 1, having a composition of a PEG hydrogel network formed by crosslinking, approximately 3% to approximately 5% dibasic sodium phosphate, and approximately 1% to approximately 3% monobasic sodium phosphate.

38. The sustained-release biodegradable ophthalmic implant according to claim 37, wherein in a dry state the implant has a length of 5 mm to 11 mm and a width of 0.28 mm to 0.38 mm, and / or in a hydrated state (in PBS, pH 7.4 at 37°C for 24 hours), it has a length of 5 to 11 mm and a width of 0.4 to 2 mm.

39. The hydrogel comprises PEG hydrogel, and the implant has a width of approximately 0.30 mm to approximately 0.36 mm in its dry state. In an in vitro test performed in a USP apparatus 4 at 35°C ± 0.5°C in 0.01N HCl containing 0.25% cetyltrimethylammonium bromide (CTAB), the percentage of axitinib released from the implant (the percentage of axitinib released is based on the maximum amount of axitinib released from the implant, which represents 100%) was: At least about 10% after 0.5 hours, After two hours, at least about 30%, After 6 hours, at least about 58%, After 10 hours, at least about 75%, At least approximately 80% after 12 hours, and / or at least about 90% after 16 hours, for example, At least about 10% after 0.5 hours, After one hour, at least about 19%, After two hours, at least about 30%, After 4 hours, at least about 45%, After 6 hours, at least about 58%, At least about 70% after 8 hours, After 10 hours, at least about 75%, At least approximately 80% after 12 hours, A sustained-release biodegradable ophthalmic implant according to claim 1, which results in the release of axitinib, characterized in that at least about 90% is released after 16 hours.

40. The hydrogel is 4a20kPEG-SAZ and 8a20kPEG-NH ２ It includes a hydrogel network formed by crosslinking units, The implant has a composition of approximately 60% to 70% axitinib and approximately 25% to 35% PEG units (anhydrous base, % w / w), In its dry state, the implant has a width of approximately 0.30 mm to approximately 0.36 mm and a total weight of approximately 0.6 mg to approximately 1 mg. In an in vitro test performed in a USP apparatus 4 at 35°C ± 0.5°C in 0.01N HCl containing 0.25% cetyltrimethylammonium bromide (CTAB), the percentage of axitinib released from the implant (the percentage of axitinib released is based on the maximum amount of axitinib released from the implant, which represents 100%) was: Approximately 10-20% after 0.5 hours, Approximately 30-45% after 2 hours. After 6 hours, approximately 58-81% After 10 hours, approximately 75-98% At least approximately 80% after 12 hours, and / or at least about 90% after 16 hours, for example, Approximately 10-20% after 0.5 hours, Approximately 19-30% after one hour, Approximately 30-45% after 2 hours. After 4 hours, approximately 45-65% After 6 hours, approximately 58-81% Approximately 70-90% after 8 hours. After 10 hours, approximately 75-98% At least approximately 80% after 12 hours, A sustained-release biodegradable ophthalmic implant according to claim 1, which results in the release of axitinib, characterized in that at least about 90% is released after 16 hours.

41. The hydrogel comprises PEG hydrogel, and the implant has a width of approximately 0.30 mm to approximately 0.36 mm in its dry state. In an in vitro test performed in a USP apparatus 4 at 35°C ± 0.5°C in 0.01N HCl containing 0.25% cetyltrimethylammonium bromide (CTAB), the amount of axitinib released from the implant was: At least approximately 50 μg after 0.5 hours, After 2 hours, at least approximately 140 μg, After 6 hours, at least approximately 270 μg, After 10 hours, at least approximately 350 μg, After 12 hours, at least about 400 μg, and / or at least about 410 μg after 16 hours, for example, At least approximately 50 μg after 0.5 hours, After one hour, at least about 90 μg, After 2 hours, at least approximately 140 μg, At least approximately 230 μg after 4 hours, After 6 hours, at least approximately 270 μg, At least approximately 340 μg after 8 hours, After 10 hours, at least approximately 350 μg, After 12 hours, at least about 400 μg, The sustained-release biodegradable ophthalmic implant according to claim 1, characterized in that the amount is at least about 410 μg after and / or 16 hours.

42. The hydrogel is 4a20kPEG-SAZ and 8a20kPEG-NH ２ It includes a PEG hydrogel network formed by crosslinking units of the same type. The implant has a composition of approximately 60% to 70% axitinib and approximately 25% to 35% PEG units (anhydrous base, % w / w), In its dry state, the implant has a width of approximately 0.30 mm to approximately 0.36 mm and a total weight of approximately 0.6 mg to approximately 1 mg. In an in vitro test performed in a USP apparatus 4 at 35°C ± 0.5°C in 0.01N HCl containing 0.25% cetyltrimethylammonium bromide (CTAB), the amount of axitinib released from the implant was: Approximately 50 to 80 μg after 0.5 hours, Approximately 140 to 210 μg after 2 hours. After 6 hours, approximately 270 to 380 μg, Approximately 350 to 470 μg after 10 hours. After 12 hours, at least about 400 μg, and / or at least about 410 μg after 16 hours, for example, Approximately 50 to 80 μg after 0.5 hours, Approximately 90 to 130 μg after one hour. Approximately 140 to 210 μg after 2 hours. Approximately 230 to 290 μg after 4 hours. After 6 hours, approximately 270 to 380 μg, Approximately 340 to 440 μg after 8 hours. Approximately 350 to 470 μg after 10 hours. After 12 hours, at least about 400 μg, The sustained-release biodegradable ophthalmic implant according to claim 1, characterized in that the amount is at least about 410 μg after and / or 16 hours.

43. A single-strand implant, at least 16 mm long. ２ For example, 16-23 mm ２ A sustained-release biodegradable ophthalmic implant according to claims 39 to 42, having a hydrated surface area (in PBS, pH 7.2 to 7.4 at 37°C for 24 hours).

44. The sustained-release biodegradable ophthalmic implant according to claim 43, wherein the axitinib particles have a d90 particle diameter of less than 8 μm and a d50 particle diameter of less than 3 μm.

45. The hydrogel contains crosslinked PEG units, The amount of axitinib released during the final decomposition of the hydrogel in the vitreous fluid is less than 200 μg. The sustained-release biodegradable ophthalmic implant according to claim 1, wherein the implant, in its dry state (before injection), has a width of about 0.3 mm to about 0.4 mm and a length of less than about 11 mm, and in its hydrated state (in PBS, pH 7.4 at 37°C for 24 hours), has a length of less than about 11 mm.

46. A sustained-release biodegradable ophthalmic implant comprising a hydrogel and a tyrosine kinase inhibitor (TKI), wherein the particles of the tyrosine kinase inhibitor are dispersed within the hydrogel, and the solubility of the tyrosine kinase inhibitor is 0.3 μg / mL or more, as measured after incubation for 5 days at 37°C in phosphate-buffered saline (PBS) at pH 7.2 to 7.

4.

47. A sustained-release biodegradable ophthalmic implant comprising a hydrogel and a tyrosine kinase inhibitor, wherein the particles of the tyrosine kinase inhibitor are dispersed within the hydrogel, and the hydrated surface area of ​​the implant is measured to be at least 25 mm² after 24 hours of incubation at 37°C in phosphate-buffered saline (PBS) at pH 7.2–7.

4. ２ The implant characterized by being such.

48. A sustained-release biodegradable ophthalmic implant comprising a hydrogel and a tyrosine kinase inhibitor, wherein particles of the tyrosine kinase inhibitor are dispersed within the hydrogel, and the cumulative amount of the tyrosine kinase inhibitor released from the implant over a period defined by an arbitrary initial number of days until 80% of the tyrosine kinase inhibitor contained in the implant is released is greater than the cumulative amount of the tyrosine kinase inhibitor released from a comparative implant over the same period, wherein the comparative implant differs from the sustained-release biodegradable ophthalmic implant only in that the solubility of the tyrosine kinase inhibitor in the comparative implant is lower, as measured in PBS at pH 7.2 to 7.4 at 37°C after 5 days of incubation, and the release of the tyrosine kinase inhibitor from both implants is measured under identical conditions.

49. A sustained-release biodegradable ophthalmic implant comprising a hydrogel and a tyrosine kinase inhibitor, wherein particles of the tyrosine kinase inhibitor are dispersed within the hydrogel, and the average daily release rate of the tyrosine kinase inhibitor from the implant over a period defined by an arbitrary initial number of days until 80% of the tyrosine kinase inhibitor contained in the implant is released is higher than the average daily release rate of the tyrosine kinase inhibitor from a comparative implant over the same period, wherein the comparative implant differs from the sustained-release biodegradable ophthalmic implant only in that the solubility of the tyrosine kinase inhibitor in the comparative implant is lower, as measured in PBS at pH 7.2-7.4 at 37°C after 5 days of incubation, and the release of the tyrosine kinase inhibitor from both implants is measured under identical conditions.

50. A sustained-release biodegradable ophthalmic implant according to any one of claims 46 to 49, wherein the TKI is axitinib, the particles of the axitinib are dispersed in the hydrogel, and the solubility of the axitinib in the sustained-release biodegradable ophthalmic implant is at least 0.4 μg / mL, for example, at least 0.5 μg / mL, or at least 0.6 μg / mL, at least 0.7 μg / mL, at least 0.8 μg / mL, at least 1 μg / mL, at least 2.5 μg / mL, at least 5 μg / mL, at least 10 μg / mL, at least 20 μg / mL, at least 50 μg / mL, at least 100 μg / mL, at least 150 μg / mL, or at least 200 μg / mL.

51. The sustained-release biodegradable ophthalmic implant according to claim 50, wherein the TKI in the sustained-release biodegradable ophthalmic implant is axitinib, and the axitinib is in the form of its free base, solvate, salt, cocrystal, derivative, prodrug, or mixture thereof.

52. A sustained-release biodegradable ophthalmic implant according to any one of claims 46 to 50, comprising a free base of axitinib in the form of one or more axitinib polymorphs.

53. A sustained-release biodegradable ophthalmic implant according to any of the prior claims, characterized in that the axitinib polymorph has a powder X-ray diffraction pattern including at least one, for example, at least two, at least three, or at least four peaks among diffraction angles (2θ) of 8.90, 9.50, 12.0, 14.60, 15.25, 15.75, 17.80, 19.30, 20.65, 24.95, and 26.10 (all ±0.2).

54. A sustained-release biodegradable ophthalmic implant according to any one of claims 1 to 52, characterized in that the axitinib polymorph has a powder X-ray diffraction pattern that includes peaks at diffraction angles (2θ) of 8.90, 12.0, 14.60, 15.75, and 19.30 (all ±0.2).

55. The sustained-release biodegradable ophthalmic implant according to any one of claims 1 to 52, characterized in that the axitinib polymorph has a powder X-ray diffraction pattern that includes peaks at diffraction angles (2θ) of 8.9, 14.6, 15.7, and 19.2 (all ±0.1), or 8.9 and 15.7 (all ±0.1).

56. A kit comprising one or more sustained-release biodegradable ophthalmic implants according to any one of claims 1 to 55, and one or more injection needles, wherein each implant is loaded onto a needle having a gauge size of 25 or less.

57. The kit according to claim 56, further comprising one or more injection devices, each needle being pre-connected to the injection device.

58. The kit according to claim 56, further comprising one or more injection devices, wherein the needle(s) are not pre-connected to the injection devices.

59. A method for treating an eye disease in a patient requiring treatment, comprising administering a sustained-release biodegradable ophthalmic implant according to any one of claims 1 to 55 to the eye of the patient, wherein the implant is administered by intravitreal injection.

60. The aforementioned eye disease is a retinal disease including age-related macular degeneration (AMD), choroidal neovascularization, diabetic retinopathy, diabetic macular edema, retinal vein occlusion, acute macular neuroretinopathy, central serous chorioretinopathy, and cystoid macular edema, or the aforementioned eye disease is acute multifocal macular pigment epitheliopathy, Behçet's disease, birdshot chorioretinopathy, infectious diseases (syphilis, Lyme disease, tuberculosis, toxoplasmosis), intermediate uveitis (tonsillar adenoma), multifocal choroiditis, multiple transient white spot syndrome (MEWDS), ocular sarcoidosis, posterior scleritis, creeping choroiditis, subretinal fibrosis, uvea The method according to claim 59, wherein the eye disease is an inflammatory syndrome or Vogt-Koyanagi-Harada syndrome, or the eye disease is a vascular or exudative disease including Coats' disease, parafoveal telangiectasia, papillary phlebitis, dendritic vasculitis, sickle cell retinopathy and other hemoglobinopathy, vascular streaks and familial exudative vitreoretinopathy, or the eye disease is caused by trauma or surgery including sympathetic ophthalmitis, uveitis retina, retinal detachment, trauma, photodynamic laser therapy, photocoagulation, intraoperative hypoperfusion, radiation retinopathy, or bone marrow transplant retinopathy.

61. The method according to claim 59, wherein the eye disease is neovascular age-related macular degeneration, diabetic macular edema, diabetic retinopathy, or retinal vein occlusion.

62. The method according to claim 59, wherein the disease is neovascular (exudative) age-related macular degeneration (AMD).

63. The method according to any one of claims 59 to 62, wherein the treatment period with a single implant lasts for at least about three months, or at least about six months, or at least about nine months, or at least about twelve months.

64. The method according to any one of claims 59 to 62, wherein the treatment period with the aforementioned single implant lasts for approximately 6 to 12 months after administration, or for approximately 6 to 9 months after administration.

65. The method according to any one of claims 59 to 64, wherein the hydrogel biodegrades within approximately 6 to 9 months, for example, within approximately 8 to 9 months, after being injected into the vitreous fluid of a human patient.

66. The method according to any one of claims 59 to 65, wherein the ratio of the time to complete degradation of the hydrogel to the time to complete release of the axitinib is about 0.5 to about 1.5, or about 0.75 to about 1.

25.

67. The method according to any one of claims 59 to 66, wherein at the completion of or after the completion of one treatment period with one implant, a new implant according to any one of claims 1 to 55 is administered to the patient for the next treatment period.

68. The method according to any one of claims 59 to 67, wherein the new implant is administered after the hydrogel of the preceding implant has been biodegraded.

69. The method according to claim 68, wherein the biodegradation of the hydrogel of the preceding implant is determined by slit-lamp biomicroscopy or cSLO (confocal laser scanning ophthalmoscope).

70. The method according to any one of claims 59 to 69, wherein the new implant according to any one of claims 1 to 55 is administered about six months, or about nine months, or about twelve months after the administration of the preceding implant.

71. The method according to any one of claims 59 to 70, wherein a new implant according to any one of claims 1 to 55 is administered every 6 to 12 months.

72. The method according to any one of claims 59 to 71, wherein the administration of the implant according to claims 1 to 55 is repeated at least two times, or at least three times, or at least four times.

73. The method according to any one of claims 59 to 72, wherein the treatment results in inhibition or substantial inhibition, prevention or substantial prevention, prevention of progression, delay or reduction of VEGF-induced retinal vascular leakage during the treatment period.

74. The method according to any one of claims 59 to 73, wherein the patient has been diagnosed with extrafoveal choroidal neovascularization (CNV) or subfoveal neovascularization (SFNV) secondary to neovascular AMD (nAMD).

75. The method according to any one of claims 59 to 74, wherein the patient is naive to treatment for the nAMD.

76. The method according to any one of claims 59 to 74, wherein the patient has previously been administered an anti-VEGF drug for the treatment of the nAMD.

77. The method according to any one of claims 59 to 76, wherein, by treatment with the sustained-release biodegradable ophthalmic implant, visual acuity (BCVA) is maintained or essentially maintained during the treatment period.

78. The method according to any one of claims 59 to 76, wherein treatment with the sustained-release biodegradable ophthalmic implant prevents or essentially prevents a decrease in visual acuity (BCVA) during the treatment period.

79. The method according to any one of claims 59 to 78, characterized in that, at 9 or 12 months after the injection of the implant, the patient experiences a loss of fewer than 15 ETDRS letters of BCVA compared to baseline.

80. The method according to claim 79, wherein the patient experiences a loss of fewer than 15 ETDRS letters of BCVA at 9 or 12 months, compared to baseline, without or with one or fewer doses of rescue medication after the injection of the implant.

81. The method according to any one of claims 59 to 80, wherein the implant provides an average axitinib release rate in the vitreous fluid of more than about 0.8 μg / day, for example, at least about 1.0 μg / day, for at least three months after injection.

82. The method according to any one of claims 59 to 81, wherein the final amount of axitinib released during the biodegradation of the hydrogel in the vitreous fluid is not greater than, or substantially greater than, the cumulative amount of axitinib released by the implant before biodegradation, provided the implant is still intact.

83. The method according to any one of claims 59 to 82, wherein the amount of axitinib ultimately released during the biodegradation of the hydrogel is less than about 200 μg, for example less than about 150 μg, for example 130 μg or less.

84. The method according to any one of claims 59 to 83, wherein the amount of axitinib remaining in the vitreous fluid six months after the injection of the implant (including the amount of axitinib present in the implant and present in the vitreous fluid) is 250 μg or less, for example, 200 μg or less.

85. The method according to any one of claims 59 to 84, wherein, after injection into the vitreous fluid, the concentration of axitinib in the retina or choroid / RPE resulting from the final release during the biodegradation of the hydrogel is not higher, or substantially higher, than, the maximum concentration of axitinib in the retina or choroid / RPE, respectively, at any point after injection of the hydrogel but before biodegradation, provided the implant is still intact, for example, not higher by about 25% or less, for example, not higher by about 10% or less.

86. The method according to any one of claims 59 to 85, wherein, after injection into the vitreous fluid, the maximum axitinib concentration in the retina and / or choroid / RPE is reached before the final biodegradation of the hydrogel by the sustained-release biodegradable ophthalmic implant.

87. After injection into the vitreous fluid, the t of axitinib in the retina or choroid / RPE ｍａｘ However, if the implant is injected into the eye of a cynomolgus monkey less than 6 months, for example less than 5 months, for example less than 4 months, for example less than 3 months, or less than 3 months, for example less than 2 months, The axitinib in the retina or choroid / RPE ｍａｘ However, if the implant is injected into the eye of a Dutch Belted rabbit less than approximately 6 months, for example less than approximately 5.5 months, or less than approximately 5 months, for example less than approximately 4 months, for example at approximately 3 months, or less than approximately 3 months, for example less than approximately 2 months, for example less than approximately 1 month, The axitinib in the retina or choroid / RPE ｍａｘ The method according to any one of claims 59 to 86, wherein the time after injection into the eye of a human patient is less than approximately 9 months, for example less than approximately 8 months, for example less than approximately 7 months, for example less than approximately 6 months, for example less than approximately 5 months, for example less than approximately 4 months.

88. The final release of axitinib from the sustained-release biodegradable ophthalmic implant during the biodegradation of the hydrogel was less than the final release of axitinib from the comparative implant during its biodegradation. The method according to any one of claims 59 to 87, wherein the comparative implant contains axitinib in an amount within + / - 10% of the total amount of axitinib contained in the sustained-release biodegradable ophthalmic implant, for example, within + / - 5%, and the comparative implant differs from the sustained-release biodegradable ophthalmic implant in that the comparative implant contains axitinib in a form having lower solubility than axitinib polymorph IV, as measured after incubation for 5 days at 37°C at pH 7.2 to 7.4 in PBS, and the comparative implant has a hydrated surface area within + / - 20%, for example, within + / - 10% of the hydrated surface area of ​​the sustained-release biodegradable ophthalmic implant (measured after incubation for 24 hours at 37°C at pH 7.2 to 7.4 in phosphate-buffered saline (PBS)),

89. After injection into the vitreous fluid, the sustained-release biodegradable ophthalmic implant releases axitinib from the comparative implant in the retina or choroid / RPE before the hydrogel biodegrades. ｍａｘ Higher C of the axitinib ｍａｘ Bringing about, The method according to any one of claims 59 to 88, wherein the comparative implant contains axitinib in an amount within + / - 10% of the total amount of axitinib contained in the sustained-release biodegradable ophthalmic implant, for example, within + / - 5%, and the comparative implant differs from the sustained-release biodegradable ophthalmic implant in that the comparative implant contains axitinib in a form having lower solubility than axitinib polymorph IV, as measured after incubation for 5 days at 37°C at pH 7.2 to 7.4 in PBS, and the comparative implant has a hydrated surface area within + / - 20%, for example, within + / - 10% of the hydrated surface area of ​​the sustained-release biodegradable ophthalmic implant (measured after incubation for 24 hours at 37°C at pH 7.2 to 7.4 in phosphate-buffered saline (PBS)),

90. After injection into the vitreous fluid, the sustained-release biodegradable ophthalmic implant delivers axitinib to the retina or choroid / RPE, compared to the axitinib delivered by the comparative implant. ｍａｘ Faster, the axitinib t ｍａｘ Bringing about, The method according to any one of claims 59 to 89, wherein the comparative implant contains axitinib in an amount within + / - 10% of the total amount of axitinib contained in the sustained-release biodegradable ophthalmic implant, for example, within + / - 5%, and the comparative implant differs from the sustained-release biodegradable ophthalmic implant in that the comparative implant contains axitinib in a form having lower solubility than axitinib polymorph IV, as measured after incubation for 5 days at 37°C at pH 7.2 to 7.4 in PBS, and the comparative implant has a hydrated surface area within + / - 20%, for example, within + / - 10% of the hydrated surface area of ​​the sustained-release biodegradable ophthalmic implant (measured after incubation for 24 hours at 37°C at pH 7.2 to 7.4 in phosphate-buffered saline (PBS)),

91. After injection into the vitreous fluid, the geometric mean amount (μg) of axitinib in the vitreous fluid (including the amount of axitinib in the sustained-release biodegradable ophthalmic implant present in the vitreous fluid after injection) is lower than the geometric mean amount (μg) of axitinib in the vitreous fluid at any of the following time points selected from 3 months, 6 months, or 9 months after injection of the sustained-release biodegradable ophthalmic implant compared to the geometric mean amount (μg) of axitinib in the vitreous fluid at each of the following time points selected from 3 months, 6 months, or 9 months after injection of the comparison implant. The method according to any one of claims 59 to 90, wherein the comparative implant differs from the sustained-release biodegradable ophthalmic implant in that the solubility of the axitinib contained in the comparative implant is lower than that of axitinib polymorph IV when measured in PBS at pH 7.2 to 7.4 at 37°C after 5 days of incubation (for example, only in that respect).

92. After injection into the vitreous fluid, the elimination rate (μg / day) of axitinib from the vitreous fluid at a time point selected from 3 months or 6 months after injection of the sustained-release biodegradable ophthalmic implant was higher than the elimination rate (μg / day) of axitinib from the vitreous fluid at a time point selected from 3 months or 6 months after injection of the control implant. The comparative implant differs from the sustained-release biodegradable ophthalmic implant in that the solubility of axitinib in the comparative implant is lower than that of axitinib polymorph IV, as measured in PBS at pH 7.2-7.4 at 37°C after 5 days of incubation (for example, only in this respect). The method according to any one of claims 59 to 91, wherein the elimination rate is calculated by (i) the difference between the total amount of axitinib contained in the implant and the geometric mean amount of axitinib remaining in the vitreous fluid identified at 3 months (which includes the amount of axitinib contained in the implant present in the vitreous fluid), or (ii) the difference between the geometric mean amount of axitinib remaining in the vitreous fluid identified at 3 months and the geometric mean amount of axitinib remaining in the vitreous fluid identified at 6 months, divided by the number of days elapsed in each period, wherein the period is (i) 0 to 3 months or (ii) 3 to 6 months.

93. The method according to any one of claims 59 to 86 or 88 to 92, wherein the subject is a non-human primate, for example, a monkey, for example, a cynomolgus macaque, and the release of axitinib in the vitreous fluid and / or the amount and concentration of axitinib in the retina and / or choroid / RPE are measured in the non-human primate.

94. After injecting the implant into the vitreous fluid, the geometric mean concentration (ng / g) of axitinib in the retina and / or choroid / RPE was higher than the geometric mean concentration (ng / g) of axitinib in the retina and / or choroid / RPE six weeks after injection of the sustained-release biodegradable ophthalmic implant and six weeks after injection of the control implant. The method according to any one of claims 59 to 86, wherein the comparative implant differs from the sustained-release biodegradable ophthalmic implant in that the solubility of axitinib in the comparative implant is lower than that of axitinib polymorph IV, as measured after incubation for 5 days at 37°C at pH 7.2 to 7.4 in PBS (for example, only in this respect).

95. After injecting the implant into the vitreous fluid, the sum of geometric mean concentrations (ng / g) of axitinib identified in the retina and / or choroid / RPE at 6, 13, and 24 weeks after injection of the sustained-release biodegradable ophthalmic implant was higher than the sum of geometric mean concentrations (ng / g) of axitinib identified at 6, 13, and 24 weeks after injection of the comparison implant. The method according to any one of claims 59 to 86 or 94, wherein the comparative implant differs from the sustained-release biodegradable ophthalmic implant in that the solubility of axitinib in the comparative implant is lower than that of axitinib polymorph IV, as measured in PBS at pH 7.2 to 7.4 at 37°C after 5 days of incubation.

96. The method according to claim 94 or 95, wherein the subject is a rabbit, for example, a Dutch Belted rabbit, and the axitinib concentration in the retina and / or choroid / RPE is measured in the rabbit.

97. The sustained-release biodegradable ophthalmic implant contains axitinib polymorphic IV, and the comparative implant is different from the sustained-release biodegradable ophthalmic implant. (a) The solubility of the axitinib contained in the comparative implant was measured in PBS at pH 7.2 to 7.4 at 37°C after 5 days of incubation, and was found to be lower than that of axitinib polymorph IV. (b) The hydrated surface area of ​​the comparative implant (measured after incubation at 37°C for 24 hours in phosphate-buffered saline (PBS) at pH 7.2 to 7.4) differs by 5% or less, and (c) The only difference is that the total amount of axitinib contained in the comparative implant differs by 5% or less, (a) The solubility of the axitinib contained in the comparative implant was measured in PBS at pH 7.2 to 7.4 at 37°C after 5 days of incubation, and was found to be lower than that of axitinib polymorph IV. (b) The total amount of axitinib contained in the comparative implant is at least 1.5 times greater, and (c) The comparative implant differs only in that the hydrated surface area (measured in phosphate-buffered saline (PBS) at pH 7.2 to 7.4 after 24 hours of incubation at 37°C) differs by 10% or less, or (a) The solubility of the axitinib contained in the comparative implant was measured in PBS at pH 7.2 to 7.4 at 37°C after 5 days of incubation, and was found to be lower than that of axitinib polymorph IV. (b) The hydrated surface area of ​​the comparative implant (measured after incubation at 37°C for 24 hours in phosphate-buffered saline (PBS) at pH 7.2 to 7.4) differs by 10% or less, and (c) The method according to any one of claims 88 to 96, differing only in that the total amount of axitinib contained in the comparative implant is at least twice as large.

98. The method according to any one of claims 88 to 97, wherein the comparative implant comprises axitinib polymorph SAB-I.

99. The method according to any one of claims 59 to 98, wherein the treatment is characterized in that, as measured in a VEGF administration study in rabbits (e.g., Dutch Belted rabbits), VEGF-induced retinal vascular leakage is reduced or delayed for at least up to about one month after injection of the sustained-release biodegradable ophthalmic implant, for example, at least up to about two months, for example, at least up to about three months, compared to the VEGF-induced retinal leakage for each of the same periods after administration of bevacizumab (Avastin), wherein the study comprises intravitreal injection of the sustained-release biodegradable ophthalmic implant into the eye of a rabbit, the rabbit then similarly administering 1 μg of VEGF to the eye at least three times over a period of three months, compared to administration of 50 μL of 25 mg / mL of bevacizumab under the same conditions including the VEGF administration.

100. An implant according to any one of claims 1 to 55, for use in the method according to any one of claims 59 to 99.

101. Use of the implant according to any one of claims 1 to 55 for the manufacture of a drug for use in the method according to any one of claims 59 to 99.

102. A method for producing a sustained-release biodegradable ophthalmic implant according to any one of claims 1 to 55, comprising the steps of: forming a hydrogel containing a polymer network and axitinib particles dispersed within the hydrogel; molding the hydrogel; and drying the hydrogel.

103. The method according to claim 102, wherein the polymer network is formed by mixing and reacting an electrophile-containing multi-arm polymer (e.g., PEG) precursor with a nucleophile-containing multi-arm polymer (e.g., PEG) precursor or another nucleophile-containing crosslinking agent in a buffer in the presence of axitinib particles, and gelling the mixture to form the hydrogel.

104. The method according to claim 102 or 103, comprising pouring the mixture into a tube to form a hydrogel strand before the complete gelation of the hydrogel, drying the hydrogel strand, and cutting the strand.

105. The method according to claim 102 or 103, comprising melt-extruding strands of a composition comprising a polymer (e.g., PEG) or a precursor and axitinib to form the implant.

106. The method according to claim 105, wherein the extrusion is performed in the absence of water.

107. The method according to any one of claims 105 to 106, further comprising the steps of cooling the strand, curing the strand, stretching the strand, and / or drying the strand.

108. The method according to claim 103 or any of claims 105 to 107, wherein the nucleophilic crosslinking agent is a nucleophilic group-containing salt, for example, an amine or a multiamine salt, the extrusion is carried out in the absence of water, the curing comprises exposing the extruded composition to moisture and / or high temperature, and the polymer network is formed by crosslinking the polymer precursor during curing in a humid atmosphere.

109. The curing process lasts for at least 0.5 hours, or at least 1 hour, or at least 2 hours. At temperatures higher than the ambient temperature, for example, at temperatures of approximately 25 to 50°C, or approximately 30 to 40°C, The method according to claim 108, carried out in an atmosphere of at least 50% relative humidity (RH), or at least 60% RH, or at least 80% RH, or at least 90% RH, or about 98% RH.

110. The method according to any one of claims 102 to 109, comprising stretching the hydrogel strand longitudinally (wet stretching or dry stretching) before or after drying the hydrogel, wherein the stretching coefficient is in the range of about 1 to about 4.5, or about 1.3 to about 3.5, or about 1.3 to about 1.5.

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