Ophthalmic implant comprising axitinib polymorph IV

Abstract

The present invention relates to a sustained release biodegradable ocular implant containing axitinib dispersed in a hydrogel for use in the treatment of retinal diseases for an extended period of time.

Description

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

[0002] The present invention relates to sustained release biodegradable ocular implants containing a tyrosine kinase inhibitor (TKI, e.g., axitinib) for the treatment of ocular diseases, including neovascular (wet) age-related macular degeneration (AMD). According to the present invention, ocular diseases are treated by injecting an implant containing a TKI into the eye, wherein the implant releases the TKI over an extended period of time. BACKGROUND

[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 is one of the most common retinal diseases in the United States (US) in 2019, affecting approximately 16.9 million people, and is projected to grow to 18.8 million people in 2024 (Market Scope. Ophthalmic Comprehensive Reports. 2019 Retinal Pharmaceuticals Market Report: A Global Analysis for 2018 to 2019, September 2019). AMD can be subdivided into different disease states. Early AMD is characterized by the presence of a few (<20) medium-sized drusen or retinal pigment abnormalities. Intermediate AMD is characterized by at least one large drusen, many medium-sized drusen, or a geographic atrophy not extending to the center of the macula. Advanced (or late) AMD can be non-neovascular (dry, atrophic, or non-exudative) or neovascular (wet or exudative). Advanced non-neovascular AMD is characterized by drusen and geographic atrophy extending to the center of the macula. Advanced 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] The later forms of wet AMD are characterized by an increase in vascular endothelial growth factor (VEGF), which promotes the growth of new blood vessels (angiogenesis) that grow under the retina and leak blood and fluid into and under the macula and subretinal space. This pathway has been successfully interfered with by the development of inhibitors of the vascular endothelial growth factor isoform originally used to treat various cancers (i.e. VEGF inhibitors). The combination administration of photodynamic therapy with anti-VEGF and steroids is currently reserved as a second line therapy for patients who do not respond to monotherapy with anti-VEGF agents (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 are diabetic eye diseases, such as diabetic retinopathy (DR). DR is one of the most common retinal diseases in the US in 2019, affecting approximately 8 million people, and this is expected to grow to 8.8 million in 2024 (Market Scope 2019, see above). The condition is characterized by vascular leakage, blockage, or neovascular proliferation, which can progress to visual impairment and ultimately to vision loss. The disease can be classified into non-proliferative diabetic retinopathy (NPDR) and proliferative diabetic retinopathy (PDR). With progression of the severity of NPDR, the risk of developing the more severe proliferative stage until vision loss increases. Diabetic macular edema (DME) can occur at any stage of DR and is characterized by a decrease in retinal tension and an increase in vascular pressure caused by upregulation of VEGF, retinal autoregulation (Browning et al. Diabetic macular edema: evidence-based management. 2018 Indian journal of ophthalmology, 66(1), p. 1736) as well as 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 from these inflammatory and vascular-derived mediators lead to disruption of the blood-retinal barrier (BRB) in the vascular endothelium (Miller et al., see above). Hard exudates enter the extracellular space, causing blurring and distortion of central vision, leading to a reduction in visual acuity of the patient (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, the visual acuity of the patient will decrease by 8% after 3 years from the onset of the condition.

[0006] The basis of all available treatments for DR is the attempt to control the metabolic functions of hyperglycemia and blood pressure (Browning et al., supra). Anti-VEGF therapy is currently considered a first-line therapy for the standard-of-care treatment of DME, as it has been proven to be less destructive and damaging than other treatment methods (Schmidt-Erfurth et al., supra). 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, a shift has emerged to treat moderate to severe NDPR with anti-VEGF therapy. Studies have shown that early intervention will reduce the progression of 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 affect 1.4 million by 2024 (Market Scope 2019, see above). RVO is a chronic condition in which retinal circulation contains blockages that lead to leakage, retinal thickening, and visual impairment (Ip and Hendrick, Retinal Vein Occlusion Review. 2018, Asia-Pacific Journal of Ophthalmology, 7(1):40-45; Pierru et al., Occlusions veineuses rétiniennes retinal veinocclusions. 2017, Journal Français d'Ophtalmologie, 40(8):696-705). This condition is commonly seen in patients aged 55 and older with pre-existing conditions such as hypertension, diabetes, and glaucoma. RVO does not have a planned course because it can cause rapid deterioration of vision or remain asymptomatic. The prognosis and associated treatment options for RVO depend on the disease classification because different variants, despite their similar presentations, have different risk factors. The disease is classified according to the location of the affected retinal circulation: branch retinal vein occlusion (BRVO), hemiretinal vein occlusion (HRVO), and central retinal vein occlusion (CRVO). BRVO is more common, affecting 0.4% worldwide, while CRVO affects 0.08% worldwide. Studies have shown that BRVO is more prevalent in Asian and Hispanic populations compared to Caucasians (Ip and Hendrick, see above).

[0008] Treatment for RVO currently includes symptomatic maintenance to avoid other complications, macular edema, and neovascular glaucoma. Anti-VEGF therapy is currently the standard of care and can temporarily improve vision. Other treatment options include laser therapy, steroids, and surgery (Pierru et al., see above).

[0009] Anti-VEGF agents are currently considered the standard of care for wet AMD, DME, DR, and RVO. The first-line treatment for wet AMD approved by the FDA in 2004 was MACUGEN. ® (Bausch & Lomb's pegaptanibsodium injection). Subsequently, LUCENTIS ®(VEGF Trap®-ranibizumab injection by Genentech, Inc.) and EYLEA ® (aflibercept intravitreal injection by Regeneron Pharmaceuticals, Inc.) were approved in 2006 and 2011, respectively, for the treatment of wet AMD, as well as DME and macular edema following RVO. The recommended dosage of EYLEA® is 2 mg (0.05 mL) administered by intravitreal injection every 4 weeks (1 month) for the first 3 months, followed by intravitreal injection of 2 mg (0.05 mL) every 8 weeks (2 months) (EYLEA® Prescribing Information, November 2011). Additionally, in October 2019, FDA approved BEOVU ® (brolucizumab injection by Novartis Pharmaceuticals Corp) for the treatment of wet 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 agents to inhibit the signaling of receptor tyrosine kinases (RTKs), a family of tyrosine protein kinases. RTKs span the cell membrane with intracellular (internal) and extracellular (external) portions. Upon binding of a ligand 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 refers to a family of proteins that bind to VEGF receptors (VEGFRs), types VEGFR1-3 (all RTKs), thereby inducing angiogenesis. VEGF-A binding to VEGFR2 is the target of the anti-VEGF drugs described above. In addition to VEGFR1-3, several other RTKs are known to induce angiogenesis, such as platelet-derived growth factor receptors (PDGFRs) activated by PDGF or stem cell growth factor receptors / type III receptor tyrosine kinases (c-Kit) activated by stem cell factor.

[0011] Recently, ocular implants have been provided that include TKI particles dispersed in a hydrogel, the implants being administered by injection (e.g., into the vitreous humor of a patient with wet AMD), wherein the TKI is released from the implant in a controlled manner over an extended period of time (e.g., several months or longer) such that a therapeutically effective amount of TKI is available over the period of time. These implants are able to reduce or at least maintain (e.g., prevent an increase in) the central subfield thickness (CSFT) of a patient and / or reduce or maintain (again, prevent an increase in) subretinal or intraretinal fluid. See, e.g., WO 2021 / 195163.

[0012] Interim results of an ongoing Phase 1 clinical trial (and other studies) indicate that implants containing TKI axitinib dispersed in a hydrogel composed of a polymer network of cross-linked polyethylene glycol (PEG) units have extended durability in wet AMD patients and, up to 10 months into the study, subjects treated with a single such implant have vision (measured by best-corrected visual acuity (BCVA)) and CSFT levels comparable to subjects treated with the anti-VEGF agent aflibercept (repeated injections every 2 months). The study is still ongoing. To date in this study, 80% of subjects were rescue-free for up to 6 months and 73% of subjects were rescue-free for up to 10 months following a single injection of such an implant. Thus, a clinically meaningful reduction in treatment burden was observed for up to 10 months following treatment with a single implant compared to injections of aflibercept every 2 months. See, e.g., A.A. Moshfeghi, “Update on a Hydrogel-Based Intravitreal Axitinib Implant (OTX-TKI) for the Treatment of Neovascular Age-related Macular Degeneration”, presented at Angiogenesis, Exudation, and Degeneration Meeting (Virtual), February 11, 2023; or D.S. Dhoot, “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”, presented at AAO 2022 Retina Subspecialty Day, Chicago, IL, September 30, 2022, both presentations available via https: / / ocutx.gcs-web.com / scientific-medical- presentations were obtained.

[0013] While known implants comprising TKIs have shown to be safe and effective in wet AMD patients in clinical studies to date, it is still desirable to provide further implants having a release profile that is different from the known implants. For example, it is desirable to provide implants comprising TKIs, e.g. axitinib, which have an increased TKI release rate, e.g. an increased amount of TKI released over a certain time period, or a faster release rate, especially early in the release after injection of the implant. In addition, it is desirable in one aspect to provide ocular implants comprising TKIs for the treatment of ocular diseases, e.g. wet AMD, wherein the largest portion of the TKI content of the implant is released before the hydrogel of the implant biodegrades, so that the remaining amount of TKI that is eventually released at the time of biodegradation is relatively small. However, it is also desirable in another aspect that the release of TKI from the implant is not too fast to avoid or substantially avoid a remaining drug-depleted implant that has to be cleared from the eye first before a new implantable can be injected, i.e. it is also desirable that enough TKI remains in the implant to be eventually released at the time of biodegradation of the implant to maintain a therapeutic effect until the remaining implant has been completely cleared from the eye and a new implant can be placed, thereby providing continuous treatment by repeated dosing of the implant.

[0014] Thus, there is a need in the art for ocular implants comprising TKIs for the treatment of ocular diseases, e.g. AMD, DME, DR and RVO, which are effective over an extended period of time, e.g. several months, and which provide an accelerated release of TKI especially early in the release, compared to previously disclosed ocular implants, and which are suitable for repeated dosing. The present invention addresses this need.

[0015] Objectives of the Invention

[0016] It is an objective of certain embodiments of the present invention to provide new ocular implants comprising TKIs, e.g. axitinib, which provide a sustained release of TKI, e.g. axitinib, over an extended period of time, e.g. a period of at least 3 months or at least 6 months, e.g. about 6 months to about 12 months.

[0017] It is an objective of certain embodiments of the present invention to provide ocular implants comprising TKIs, e.g. axitinib, which provide a sustained release of TKI, e.g. axitinib, of about 1 pg / day or more in vivo (in the vitreous) over at least 3 months.

[0018] It is an objective of certain embodiments of the present invention to provide ocular implants comprising TKIs, e.g. axitinib, which provide a sustained release of TKI, e.g. axitinib, wherein the release of TKI from said implant in vitro or in vivo is accelerated compared to known implants.

[0019] It is an object of certain embodiments of the present application to provide an ocular implant comprising a TKI (e.g., axitinib) that provides sustained release of the TKI (e.g., axitinib), wherein the TKI is released from the implant faster in vitro or in vivo than a comparable known implant containing the same dose of the TKI (e.g., axitinib).

[0020] It is an object of certain embodiments of the present application to provide an ocular implant comprising a TKI (e.g., axitinib) that provides sustained release of the TKI (e.g., axitinib), wherein the TKI is released from the implant faster in vitro or in vivo than a comparable known implant containing the same dose of the TKI (e.g., axitinib).

[0021] It is an object of certain embodiments of the present application to provide an ocular implant comprising a TKI (e.g., axitinib) that provides sustained release of the TKI, wherein a therapeutically effective level of the TKI is reached in the retina, choroid, and / or retinal pigment epithelium (RPE) faster than a comparable known implant containing the same dose of the TKI.

[0022] It is an object of certain embodiments of the present application to provide an ocular implant comprising a TKI (e.g., axitinib) that provides sustained release of the TKI, wherein the in vitro release rate per day over one or more days, and / or the average release rate per day over a period of time, and / or the amount of TKI released over one or more days, and / or the cumulative amount of TKI released over a period of time, and / or the percentage of TKI (based on the total amount of TKI contained in the implant, or based on the total amount of TKI released in in vitro testing) is higher than a comparable known implant containing the same dose of the TKI.

[0023] It is an object of certain embodiments of the present application to provide an ocular implant that meets one or more of the above objects for use in the treatment of ocular diseases, including (wet) AMD, DR, DME, and RVO.

[0024] It is an object of certain embodiments of the present application to provide an ocular implant that meets one or more of the above objects for use in the treatment of ocular diseases, including (wet) AMD, DR, DME, and RVO, wherein the treatment period using 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 months to about 9 months, or about 6 months to about 12 months.

[0025] It is a further object of certain embodiments of the present application to provide a method of increasing the release rate of a TKI (e.g., axitinib) from an ocular implant.

[0026] It is a further object of certain embodiments of the present application to provide a method of increasing the release rate of a TKI (e.g., axitinib) from an ocular implant.

[0027] It is a further object of certain embodiments of the present application to provide forms of axitinib for use in ocular implants, wherein the forms of axitinib have a solubility of greater than 0.3 pg / mL, as measured after incubation in phosphate buffered saline (PBS) at pH 7.2 to 7.4 and 37°C for 5 days, and ocular implants comprising such forms of axitinib.

[0028] It is a further object of certain embodiments of the present application to provide ocular implants having an increased hydrated surface area of at least 25 mm 2 as measured after incubation in phosphate buffered saline (PBS) at pH 7.2 to 7.4 and 37°C for 24 hours.

[0029] It is a further object of certain embodiments of the present application to provide methods of manufacturing ocular implants that meet one or more of the above-mentioned objectives.

[0030] It is a further object of certain embodiments of the present application to provide methods of treating ocular diseases, the methods comprising administering an ocular implant that meets one or more of the above-mentioned objectives.

[0031] It is a further object of certain embodiments of the present application to provide methods of treating (wet) AMD, DR, DME, or RVO, the methods comprising administering an ocular implant that meets one or more of the above-mentioned objectives.

[0032] It is a further object of certain embodiments of the present application to provide methods of treating (wet) AMD, DR, DME, or RVO, the methods comprising administering an ocular implant that meets one or more of the above-mentioned objectives to a patient, wherein the treatment period using 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 months to about 9 months, or about 6 months to about 12 months, wherein only a few administrations of rescue medication, e.g., 1, 2, or 3, are needed during the treatment period.

[0033] Another objective of certain embodiments of the present invention is to provide a method for treating ocular diseases (e.g., (wet) AMD, DR, DME, or RVO, especially (wet) AMD), and an ocular implant for use in such a method, wherein the method provides continuous treatment through repeated administration of the ocular implant.

[0034] Another objective of certain embodiments of the present invention is to provide a method for treating ocular diseases (e.g., (wet) AMD, DR, DME, or RVO, especially (wet) AMD), and an ocular implant for use in such a method, wherein an ocular implant containing a TKI (e.g., axitinib) allows for repeated administration of the implant, for example every 6 to 12 months, such as every 8 to 11 months, or every 6 months, or every 9 months.

[0035] Another objective of certain embodiments of the present invention is to provide a method for treating ocular diseases (e.g., (wet) AMD, DR, DME, or RVO, especially (wet) AMD), and an ocular implant for use in this method, wherein an ocular implant containing a TKI (e.g., axitinib) allows for repeated administration of the implant, for example every 6 to 12 months, such as every 8 to 11 months, or every 6 months, so as to achieve a continuous therapeutic effect without having to administer the drug again at the point when the implant is still present after the residual drug has been depleted.

[0036] Another objective of certain embodiments of the present invention is to provide a method for treating ocular diseases (e.g., (wet) AMD, DR, DME, or RVO, especially (wet) AMD), and an ocular implant for use in this method, wherein the ocular implant contains a TKI (e.g., axitinib) dispersed in a hydrogel, wherein the implant provides a release rate of the TKI (e.g., axitinib) to the vitreous body (and thus delivers the TKI (e.g., axitinib) to ocular tissues, such as the retina or choroid), such that the cumulative amount of TKI (e.g., axitinib) released before the hydrogel degrades (i.e., while the implant / hydrogel is still intact) is higher than the amount of TKI (e.g., axitinib) released upon hydrogel degradation.

[0037] Another objective of certain embodiments of the present invention is to provide a method for treating ocular diseases (e.g., (wet) AMD, DR, DME, or RVO, especially (wet) AMD), and an ocular implant for use in this method, wherein the ocular implant contains a TKI (e.g., axitinib) dispersed in a hydrogel, wherein the implant provides a release rate of the TKI (e.g., axitinib) into the vitreous body (and thus delivers the TKI (e.g., axitinib) to ocular tissues, such as the retina or choroid), such that the TKI (e.g., axitinib) in said tissues reaches a certain concentration (C). max It appears before the implant biodegrades.

[0038] Another objective of certain embodiments of the present invention is to provide a method for treating ocular diseases (e.g., (wet) AMD, DR, DME, or RVO, especially (wet) AMD), and an ocular implant for use in this method, wherein the ocular implant contains a TKI (e.g., axitinib) dispersed in a hydrogel, wherein the implant provides a release rate of the TKI (e.g., axitinib) into the vitreous fluid (and thus delivers the TKI (e.g., axitinib) to ocular tissues, such as the t-cell concentration of the TKI (e.g., axitinib) in said tissues. max The t-term appears before and / or is shorter than that of a TKI provided by a known implant (e.g., axitinib) before the implant biodegrades. max .

[0039] Another objective of certain embodiments of the present invention is to provide a method for treating (wet) AMD, DR, DME, or RVO, the method comprising administering an ocular implant that satisfies one or more of the above objectives to a patient with a history of anti-VEGF treatment or a patient who has not received anti-VEGF treatment.

[0040] Another objective of certain embodiments of the present invention is to provide a method for treating ocular diseases (including (wet) AMD, DR, DME, or RVO) comprising administering an ocular implant that satisfies one or more of the above objectives in combination with an anti-VEGF agent.

[0041] Another objective of certain embodiments of the present invention is to provide a medicament kit that includes one or more ocular implants that satisfy one or more of the above objectives and optionally includes components for injecting the ocular implants.

[0042] One or more of these objectives of the present invention, as well as others, are achieved by one or more embodiments as disclosed and claimed herein. Summary of the Invention

[0043] In one general aspect, the present invention relates to a sustained-release biodegradable ocular implant comprising a hydrogel and a tyrosine kinase inhibitor (TKI), wherein the tyrosine kinase inhibitor particles are dispersed within the hydrogel, the implant being characterized in that the solubility of the tyrosine kinase inhibitor is greater than 0.3 µg / mL, as measured after incubation for 5 days in phosphate-buffered saline (PBS) at pH 7.2 to 7.4 and 37°C.

[0044] For example, in some embodiments, the present invention relates to a sustained-release biodegradable ocular implant comprising a hydrogel and an amount of about 400 µg to about 500 µg of axitinib polymorph IV, wherein axitinib particles are dispersed within the hydrogel.

[0045] In another general aspect, the present invention relates to a sustained-release biodegradable ocular implant comprising a hydrogel and a tyrosine kinase inhibitor, wherein the tyrosine kinase inhibitor particles are dispersed within the hydrogel, the implant being characterized in that the hydrated surface area of ​​the implant is at least 25 mm². 2 As measured after incubation for 24 hours in phosphate-buffered saline (PBS) at pH 7.2 to 7.4 and 37°C.

[0046] In another general aspect, the present invention relates to a sustained-release biodegradable ocular implant comprising a hydrogel and a tyrosine kinase inhibitor, wherein the tyrosine kinase inhibitor particles are dispersed within the hydrogel, wherein the cumulative amount of tyrosine kinase inhibitor released from the implant is higher than the cumulative amount of tyrosine kinase inhibitor released from a comparative implant during a time period defined from any initial day up to the day on which 80% of the tyrosine kinase inhibitor contained in the implant is released, wherein the comparative implant differs from the sustained-release biodegradable ocular implant only in that the solubility of the tyrosine kinase inhibitor in the comparative implant is lower, as measured after incubation in PBS at pH 7.2 to 7.4 and 37°C for 5 days, and wherein the release of the tyrosine kinase inhibitor from both implants is measured under the same conditions.

[0047] In another general aspect, the present invention relates to a sustained-release biodegradable ocular implant comprising a hydrogel and a tyrosine kinase inhibitor, wherein the tyrosine kinase inhibitor particles are dispersed within the hydrogel, wherein, over a period defined from any initial day up to the day on which 80% of the tyrosine kinase inhibitor contained in the implant is released, the average daily release rate of the tyrosine kinase inhibitor from the implant 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 ocular implant only in that the solubility of the tyrosine kinase inhibitor in the comparative implant is lower, as measured after incubation for 5 days in PBS at pH 7.2 to 7.4 and 37°C, and wherein the release of the tyrosine kinase inhibitor from both implants is measured under the same conditions.

[0048] In another aspect, the present invention relates to a sustained-release biodegradable ocular implant comprising a hydrogel and axitinib, wherein axitinib particles are dispersed within the hydrogel, wherein the implant comprises axitinib polymorph IV and the amount of axitinib contained in the implant corresponds to about 250 µg to about 700 µg of axitinib free base, for example about 400 µg to about 500 µg of axitinib free base, wherein the hydrogel comprises cross-linked PEG units.

[0049] In another aspect, the present invention relates to a sustained-release biodegradable ocular implant comprising a hydrogel and axitinib, wherein axitinib particles are dispersed within the hydrogel, wherein the implant comprises an amount of axitinib polymorph IV of about 360 µg to about 562.5 µg, or about 405 µg to about 495 µg, for example about 450 µg, wherein the hydrogel comprises cross-linked multi-arm PEG units with a number average molecular weight of about 20,000 Daltons, wherein the cross-linking between the PEG units comprises groups represented by the following formula.

[0050]

[0051] Where m is 6.

[0052] The implant is cylindrical and has a length of 10 mm or less, for example 6 mm to 9 mm and a diameter of 0.25 mm to 0.45 mm in its dry state, and / or has a length of 12 mm or less, for example 10 mm or less, for example 8 mm to 9 mm and a diameter of 0.5 mm to 0.9 mm in its hydrated state (after 24 hours in PBS at pH 7.2 to 7.4 at 37°C), and wherein the axitinib particles have a d90 particle size of less than 8 µm and a d50 particle size of less than 3 µm.

[0053] In another aspect, the present invention relates to a sustained-release biodegradable ocular implant comprising a hydrogel and axitinib, wherein axitinib particles are dispersed within the hydrogel, wherein the implant comprises an amount of axitinib polymorph IV of about 480 µg to about 750 µg, or about 540 µg to about 660 µg, for example about 600 µg, wherein the hydrogel comprises cross-linked multi-arm PEG units with a number average molecular weight of about 20,000 Daltons, wherein the cross-linking between the PEG units comprises groups represented by the following formula.

[0054]

[0055] Where m is 6.

[0056] The implant is cylindrical and has a length of 10 mm or less, for example 6 mm to 9 mm and a diameter of 0.25 mm to 0.45 mm in its dry state, and / or has a length of 10 mm or less, for example 8 mm to 9 mm and a diameter of 0.5 mm to 0.9 mm in its hydrated state (after 24 hours in PBS at pH 7.2 to 7.4 at 37°C), and the axitinib particles have a d90 particle size of less than 8 µm and a d50 particle size of less than 3 µm.

[0057] In another aspect, the present invention relates to a sustained-release biodegradable ocular implant comprising a hydrogel and axitinib, wherein axitinib particles are dispersed within the hydrogel, wherein the implant comprises axitinib polymorph IV and the amount of axitinib contained in the implant corresponds to about 360 µg to about 562.5 µg, or about 405 µg to about 495 µg, for example about 450 µg of free axitinib, and in an in vitro test performed at 37°C in a 25% / 75% (v / v) ethanol / water mixture under 2× leak conditions, at least about 60 µg of axitinib is released in the first day, and / or at least about 100 µg of axitinib is released in the first two days, and / or at least about 130 µg of axitinib is released in the first three days, and / or at least about 220 µg of axitinib is released in the first seven days, and / or at least about 275 µg of axitinib is released in the first ten days.

[0058] In another aspect, the present invention relates to a sustained-release biodegradable ocular implant comprising a hydrogel and axitinib, wherein axitinib particles are dispersed within the hydrogel, wherein the implant comprises axitinib polymorph IV and the amount of axitinib contained in the implant corresponds to about 360 µg to about 562.5 µg, or about 405 µg to about 495 µg, for example about 450 µg of free axitinib, and in an in vitro test performed at 37°C in a 25% / 75% (v / v) ethanol / water mixture under 3× leak conditions, at least about 35 µg of axitinib is released within the first day, and / or at least about 60 µg of axitinib is released within the first two days, and / or at least about 100 µg of axitinib is released within the first four days, and / or at least about 180 µg of axitinib is released within the first seven days, and / or at least about 200 µg of axitinib is released within the first nine days.

[0059] In another aspect, the present invention relates to a sustained-release biodegradable ocular implant comprising a hydrogel and axitinib, wherein axitinib particles are dispersed within the hydrogel, wherein the implant comprises axitinib polymorph IV and the amount of axitinib contained in the implant corresponds to about 480 µg to about 750 µg, or about 540 µg to about 660 µg, for example about 600 µg of free axitinib, and in an in vitro test performed at 37°C in a 25% / 75% (v / v) ethanol / water mixture under 2× leak conditions, at least about 70 µg of axitinib is released in the first day, and / or at least about 130 µg of axitinib is released in the first two days, and / or at least about 180 µg of axitinib is released in the first three days, and / or at least about 300 µg of axitinib is released in the first seven days, and / or at least about 375 µg of axitinib is released in the first ten days.

[0060] In another aspect, the present invention relates to a sustained-release biodegradable ocular implant comprising a hydrogel and axitinib, wherein axitinib particles are dispersed within the hydrogel, wherein the implant comprises axitinib polymorph IV and the amount of axitinib contained in the implant corresponds to about 480 µg to about 750 µg, or about 540 µg to about 660 µg, for example about 600 µg of free axitinib, and in an in vitro test performed at 37°C in a 25% / 75% (v / v) ethanol / water mixture under 3× leak conditions, at least about 50 µg of axitinib is released within the first day, and / or at least about 100 µg of axitinib is released within the first two days, and / or at least about 180 µg of axitinib is released within the first four days, and / or at least about 280 µg of axitinib is released within the first seven days, and / or at least about 300 µg of axitinib is released within the first nine days.

[0061] In another aspect, the present invention relates to a sustained-release biodegradable ocular implant comprising a hydrogel and axitinib, wherein axitinib particles are dispersed within the hydrogel, wherein the implant comprises axitinib polymorph IV and the amount of axitinib contained in the implant corresponds to about 360 µg to about 562.5 µg, or about 405 µg to about 495 µg, for example about 450 µg of axitinib free base, and releases at least 50% of the total axitinib release within the first 3 days in an in vitro test, and / or releases at least 80% of the total axitinib release within the first 7 days in an in vitro test, and / or releases at least 92% of the total axitinib release within the first 10 days in an in vitro test, said in vitro test being performed at 37°C in a 25% / 75% (v / v) ethanol / water mixture under 2× leak conditions.

[0062] In another aspect, the present invention relates to a sustained-release biodegradable ocular implant comprising a hydrogel and axitinib, wherein axitinib particles are dispersed within the hydrogel, wherein the implant comprises axitinib polymorph IV and the amount of axitinib contained in the implant corresponds to about 360 µg to about 562.5 µg, or about 405 µg to about 495 µg, for example about 450 µg of axitinib free base, and releases at least 30% of the total axitinib release within the first 3 days of in vitro testing, and / or releases at least 60% of the total axitinib release within the first 7 days of in vitro testing, and / or releases at least 80% of the total axitinib release within the first 10 days of in vitro testing, said in vitro testing being performed at 37°C in a 25% / 75% (v / v) ethanol / water mixture under 2× sink conditions.

[0063] In another aspect, the present invention relates to a sustained-release biodegradable ocular implant comprising a hydrogel and axitinib, wherein axitinib particles are dispersed within the hydrogel, wherein the implant comprises axitinib polymorph IV and the amount of axitinib contained in the implant corresponds to about 360 µg to about 562.5 µg, or about 405 µg to about 495 µg, for example about 450 µg of axitinib free base, and releases at least 15% of the total axitinib release within the first 2 days of in vitro testing, and / or releases at least 30% of the total axitinib release within the first 4 days of in vitro testing, and / or releases at least 50% of the total axitinib release within the first 7 days of in vitro testing, wherein the in vitro testing is performed at 37°C in a 25% / 75% (v / v) ethanol / water mixture under 3× sink conditions.

[0064] In another aspect, the present invention relates to a sustained-release biodegradable ocular implant comprising a hydrogel and axitinib, wherein axitinib particles are dispersed within the hydrogel, wherein the implant comprises axitinib polymorph IV and the amount of axitinib contained in the implant corresponds to about 480 µg to about 750 µg, or about 540 µg to about 660 µg, for example about 600 µg of free axitinib, and releases at least 50% of the total axitinib release within the first 3 days of an in vitro test, and / or releases at least 80% of the total axitinib release within the first 7 days of an in vitro test, and / or releases at least 92% of the total axitinib release within the first 10 days of an in vitro test, said in vitro test being performed at 37°C in a 25% / 75% (v / v) ethanol / water mixture under 2× sink conditions.

[0065] In another aspect, the present invention relates to a sustained-release biodegradable ocular implant comprising a hydrogel and axitinib, wherein axitinib particles are dispersed within the hydrogel, wherein the implant comprises axitinib polymorph IV and the amount of axitinib contained in the implant corresponds to about 480 µg to about 750 µg, or about 540 µg to about 660 µg, for example about 600 µg of free axitinib, and releases at least 30% of the total axitinib release within the first 3 days of an in vitro test, and / or releases at least 60% of the total axitinib release within the first 7 days of an in vitro test, and / or releases at least 80% of the total axitinib release within the first 10 days of an in vitro test, said in vitro test being performed at 37°C in a 25% / 75% (v / v) ethanol / water mixture under 2× sink conditions.

[0066] In another aspect, the present invention relates to a sustained-release biodegradable ocular implant comprising a hydrogel and axitinib, wherein axitinib particles are dispersed within the hydrogel, wherein the implant comprises axitinib polymorph IV and the amount of axitinib contained in the implant corresponds to about 480 µg to about 750 µg, or about 540 µg to about 660 µg, for example about 600 µg of free axitinib, and releases at least 15% or at least 20% of the total axitinib release within the first 2 days of in vitro testing, and / or releases at least 35% of the total axitinib release within the first 4 days of in vitro testing, and / or releases at least 55% of the total axitinib release within the first 7 days of in vitro testing, wherein the in vitro testing is performed at 37°C in a 25% / 75% (v / v) ethanol / water mixture under 3× sink conditions.

[0067] On the other hand, the present invention relates to a sustained-release biodegradable ocular implant comprising a hydrogel and an amount of about 400 µg to about 500 µg of axitinib polymorph IV, wherein axitinib particles are dispersed within the hydrogel, wherein the implant is an intravitreal implant and has the following composition: about 30% to about 75% axitinib, about 20% to about 50% PEG units and about 0.5% to about 15% sodium phosphate on a dry basis (in % w / w), and about 5% to about 17% axitinib, about 4% to about 12% PEG units and about 0.2% to about 5% sodium phosphate on a wet basis (in % w / w), wherein the hydrogel comprises a PEG hydrogel network formed by crosslinking 4a20kPEG-SAZ and 8a20kPEG-NH2 units, wherein the length of the implant is greater than its width, and in its dry state has a length of 11 mm or less, for example 5 mm to 11 mm and a length of 0.2 mm to 0.4 mm, for example 0.28 mm. The particles have a width of 0.38 mm and / or, in their hydrated state (after 24 hours in PBS at pH 7.4 at 37°C), a length of 11 mm or less, for example, 5 mm to 11 mm and a width of 0.4 mm to 2 mm, wherein the axitinib particles have a d90 particle size of less than 8 µm and a d50 particle size of less than 3 µm.

[0068] On another aspect, the present invention relates to a sustained-release biodegradable ocular implant comprising a hydrogel and an amount of about 400 µg to about 500 µg of axitinib polymorph IV, wherein axitinib particles are dispersed within the hydrogel, wherein the implant is an intravitreal implant and has the following composition: about 30% to about 75% axitinib, about 20% to about 50% PEG units and about 0.5% to about 15% sodium phosphate on a dry basis (in % w / w), and about 5% to about 17% axitinib, about 4% to about 12% PEG units and about 0.2% to about 5% sodium phosphate on a wet basis (in % w / w), wherein the hydrogel comprises a PEG hydrogel network formed by crosslinking 4a20kPEG-SAZ and 8a20kPEG-NH2 precursors, wherein the implant has a width of 0.20 mm to 0.40 mm in its dry state and in its hydrated state (at 37°C at pH) 7.4% PBS (after 24 hours) has a length of 11 mm or less, and the implant has a length of 10 to 30 mm. 2 The hydrated surface area (after incubation at 37°C in PBS at pH 7.2 to 7.4 for 24 hours).

[0069] On the other hand, the present invention relates to a sustained-release biodegradable ocular implant comprising a hydrogel and an amount of about 400 µg to about 500 µg of axitinib polymorph IV, wherein axitinib particles are dispersed within the hydrogel, wherein the implant is an intravitreal implant and has the following composition: about 30% to about 75% axitinib, about 20% to about 50% PEG units and about 0.5% to about 15% sodium phosphate on a dry basis (in % w / w), and about 5% to about 17% axitinib, about 4% to about 12% PEG units and about 0.2% to about 5% sodium phosphate on a wet basis (in % w / w), wherein the hydrogel comprises a PEG hydrogel network formed by crosslinking 4a20kPEG-SAZ and 8a20kPEG-NH2 units, wherein the implant has a length of 5 mm to 11 mm and a width of 0.28 mm to 0.38 mm in its dry state, and / or in its hydrated state (at 37°C at pH 10 ... (After 24 hours in PBS at 7.4°C) it has a length of 5 mm to 11 mm and a width of 0.4 mm to 2 mm.

[0070] In another aspect, the present invention relates to a sustained-release biodegradable ocular implant comprising a hydrogel and an amount of about 400 µg to about 500 µg of axitinib polymorph IV, wherein axitinib particles are dispersed within the hydrogel, wherein the implant is an intravitreal implant and has the following composition on a dry basis (in % w / w): about 54% to about 69% axitinib, a PEG hydrogel network formed by crosslinking about 17% to 26% of 4a20kPEG-SAZ and about 8% to about 13% of 8a20kPEG-NH2, about 3% to about 5% disodium hydrogen phosphate and about 1% to about 3% sodium dihydrogen phosphate.

[0071] On the other hand, the present invention relates to a sustained-release biodegradable ocular implant comprising a hydrogel and an amount of about 400 µg to about 500 µg, for example about 450 µg, of axitinib polymorph IV, wherein axitinib particles are dispersed within the hydrogel, wherein the hydrogel comprises a PEG hydrogel, wherein the implant has a width of 0.30 mm to 0.36 mm in its dry state, and wherein the implant provides release of axitinib in an in vitro test performed in a USP device 4 at 35 °C ± 0.5 °C in 0.01 N HCl containing 0.25% cetyltrimethylammonium bromide (CTAB), characterized in that the percentage of axitinib released from the implant (wherein the percentage of axitinib released is based on the maximum amount of axitinib representing 100% released from the implant):

[0072] After 0.5 hours, it is at least about 10%.

[0073] After 2 hours, it is at least about 30%.

[0074] After 6 hours, it is at least about 58%.

[0075] After 10 hours, it is at least about 75%.

[0076] After 12 hours, it is at least about 80%.

[0077] And / or at least approximately 90% after 16 hours;

[0078] For example:

[0079] After 0.5 hours, it is at least about 10%.

[0080] After one hour, it is at least about 19%.

[0081] After 2 hours, it is at least about 30%.

[0082] After 4 hours, it is at least about 45%.

[0083] After 6 hours, it is at least about 58%.

[0084] After 8 hours, it is at least about 70%.

[0085] After 10 hours, it is at least about 75%.

[0086] After 12 hours, it is at least about 80%.

[0087] And / or at least about 90% after 16 hours.

[0088] On the other hand, the present invention relates to a sustained-release biodegradable ocular implant comprising a hydrogel and an amount of about 400 µg to about 500 µg, for example about 450 µg, of axitinib polymorph IV, wherein axitinib particles are dispersed within the hydrogel, wherein the hydrogel comprises a hydrogel network formed by crosslinking 4a20kPEG-SAZ and 8a20kPEG-NH2 units, wherein the implant has the following composition (dry basis; % w / w): about 60% to about 70% axitinib and about 25% to about 35% PEG units, wherein the implant has a width of 0.30 mm to 0.36 mm and a total weight of about 0.6 mg to about 1 mg in its dry state, and wherein the implant is subjected to a 0.01N solution containing 0.25% cetyltrimethylammonium bromide (CTAB) in a USP device 4 at 35°C ± 0.5°C. The release of axitinib in an in vitro test performed in HCl is characterized by the percentage of axitinib released from the implant (wherein the percentage of axitinib released is based on a maximum amount representing 100% of the axitinib released from the implant):

[0089] After 0.5 hours, it is approximately 10% to approximately 20%.

[0090] After 2 hours, it is approximately 30% to approximately 45%.

[0091] After 6 hours, it was approximately 58% to approximately 81%.

[0092] After 10 hours, it is approximately 75% to approximately 98%.

[0093] After 12 hours, it is at least about 80%.

[0094] And / or at least approximately 90% after 16 hours.

[0095] For example:

[0096] After 0.5 hours, it is approximately 10% to approximately 20%.

[0097] After one hour, it was approximately 19% to approximately 30%.

[0098] After 2 hours, it is approximately 30% to approximately 45%.

[0099] After 4 hours, it is approximately 45% to approximately 65%.

[0100] After 6 hours, it was approximately 58% to approximately 81%.

[0101] After 8 hours, it is approximately 70% to approximately 90%.

[0102] After 10 hours, it is approximately 75% to approximately 98%.

[0103] After 12 hours, it is at least about 80%.

[0104] And / or at least about 90% after 16 hours.

[0105] On the other hand, the present invention relates to a sustained-release biodegradable ocular implant comprising a hydrogel and an amount of axitinib polymorph IV of about 400 µg to about 500 µg, wherein axitinib particles are dispersed within the hydrogel, wherein the hydrogel comprises a PEG hydrogel, wherein the implant has a width of 0.30 mm to 0.36 mm in its dry state, and wherein the implant is characterized in that, in an in vitro test performed in a USP device 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:

[0106] After 0.5 hours, it is at least about 50 µg.

[0107] After 2 hours, it is at least approximately 140 µg.

[0108] After 6 hours, it was at least approximately 270 µg.

[0109] After 10 hours, it is at least approximately 350 µg.

[0110] After 12 hours, it is at least approximately 400 µg.

[0111] And / or at least approximately 410 µg after 16 hours,

[0112] For example:

[0113] After 0.5 hours, it is at least about 50 µg.

[0114] After 1 hour, it is at least about 90 µg.

[0115] After 2 hours, it is at least approximately 140 µg.

[0116] After 4 hours, it was at least approximately 230 µg.

[0117] After 6 hours, it was at least approximately 270 µg.

[0118] After 8 hours, it was at least approximately 340 µg.

[0119] After 10 hours, it is at least approximately 350 µg.

[0120] After 12 hours, it is at least approximately 400 µg.

[0121] And / or at least about 410 µg after 16 hours.

[0122] On the other hand, the present invention relates to a sustained-release biodegradable ocular implant comprising a hydrogel and an amount of axitinib polymorph IV of about 400 µg to about 500 µg, wherein axitinib particles are dispersed within the hydrogel, wherein the hydrogel comprises a PEG hydrogel network formed by crosslinking 4a20kPEG-SAZ and 8a20kPEG-NH2 units, wherein the implant has the following composition (dry basis; % w / w): about 60% to about 70% axitinib and about 25% to about 35% PEG units, wherein the implant has a width of 0.30 mm to 0.36 mm and a total weight of about 0.6 mg to about 1 mg in its dry state, and wherein the implant is characterized in that, in an in vitro test conducted in a USP device 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:

[0123] After 0.5 hours, it is approximately 50 µg to approximately 80 µg.

[0124] After 2 hours, it was approximately 140 µg to approximately 210 µg.

[0125] After 6 hours, it was approximately 270 µg to approximately 380 µg.

[0126] After 10 hours, it was approximately 350 µg to approximately 470 µg.

[0127] After 12 hours, it is at least approximately 400 µg.

[0128] And / or at least approximately 410 µg after 16 hours,

[0129] For example:

[0130] After 0.5 hours, it is approximately 50 µg to approximately 80 µg.

[0131] After 1 hour, it was approximately 90 µg to approximately 130 µg.

[0132] After 2 hours, it was approximately 140 µg to approximately 210 µg.

[0133] After 4 hours, it was approximately 230 µg to approximately 290 µg.

[0134] After 6 hours, it was approximately 270 µg to approximately 380 µg.

[0135] After 8 hours, it was approximately 340 µg to approximately 440 µg.

[0136] After 10 hours, it was approximately 350 µg to approximately 470 µg.

[0137] After 12 hours, it is at least approximately 400 µg.

[0138] And / or at least about 410 µg after 16 hours.

[0139] In another aspect, the present invention relates to a sustained-release biodegradable ocular implant comprising a hydrogel and an amount of axitinib polymorph IV of about 400 µg to about 500 µg, wherein axitinib particles are dispersed within the hydrogel, wherein the hydrogel comprises cross-linked PEG units, wherein the amount of axitinib released upon final degradation of the hydrogel in vitreous fluid is less than 200 µg, wherein the implant has a width of about 0.3 mm to about 0.4 mm, for example about 0.33 mm to about 0.36 mm, and a length of less than about 11 mm in its dry state (before injection), and a length of less than about 11 mm, for example about 8 mm to about 10 mm, in its hydrated state (after 24 hours in PBS at pH 7.4 at 37°C).

[0140] In another aspect, the present invention relates to a method for treating an eye disease in a patient in need, the method comprising administering a continuously releasing biodegradable ocular implant according to one aspect of the invention to the patient's eye, for example by intravitreal injection.

[0141] In another aspect, the present invention relates to a sustained-release biodegradable ocular implant as disclosed herein, and a method for treating an eye disease in a patient in need, the method comprising administering the sustained-release biodegradable ocular implant according to aspects thereof to the patient's eye.

[0142] In another aspect, the present invention relates to the use of a sustained-release biodegradable ocular implant as disclosed herein, which is used to prepare a medicament for a method of treating an eye disease in a patient in need, the method comprising administering the sustained-release biodegradable ocular implant according to aspects thereof to the patient's eye.

[0143] In another aspect, the present invention relates to a method for manufacturing the sustained-release biodegradable ocular implant of the present invention, the method comprising the steps of: forming a hydrogel comprising a polymer network and axitinib particles dispersed within the hydrogel, shaping the hydrogel, and drying the hydrogel.

[0144] In another aspect, the present invention relates to another method for manufacturing the sustained-release biodegradable ocular implant of the present invention, the method comprising melt extrusion or injection molding of a composition comprising a polymer or polymer (e.g., PEG) precursor and axitinib to form an implant.

[0145] On the other hand, the present invention relates to a pillbox comprising one or more sustained-release biodegradable ocular implants of the present invention and one or more injection needles, wherein each implant is loaded in a needle, for example, in a needle of gauge 25 or smaller.

[0146] In another aspect, the present invention relates to a method for increasing the release rate and / or average release rate and / or release amount of total TKI contained in an ocular implant and / or the release share of total TKI contained in the implant or the total TKI released from the implant over a period of time.

[0147] Individual aspects of the invention are disclosed in this specification and claimed in the independent claims, while the appended claims claim particular embodiments and variations of these aspects of the invention. Details of various aspects of the invention are provided in the following detailed description. Attached Figure Description

[0148] Figure 1 TKI release profile of implants manufactured via HME or wet casting (in vitro method B): (A) Mass released; (B) Release.

[0149] Figure 2 Implants manufactured via HME (3×wire).

[0150] Figure 3 : Calculation of star-shaped implants and their dimensions.

[0151] Figure 4 XPRD results - peaks for citric acid, fumaric acid and tartaric acid.

[0152] Figure 5 Synthesis scheme of the prodrug in Example 5

[0153] Figure 6 Example 5.1 prodrug 1 H-NMR

[0154] Figure 7 LCMS of the prodrug in Example 5.1

[0155] Figure 8 HPLC analysis of the prodrug in Example 5.1

[0156] Figure 9 Example 5.2: Axitinib Nm(PEG)4-oxymethyl prodrug 1 H-NMR

[0157] Figure 10 and Figure 11 LCMS of axitinib Nm(PEG)4-oxymethyl prodrug from Example 5.2

[0158] Figure 12 HPLC analysis of axitinib Nm(PEG)4-oxymethyl prodrug from Example 5.2

[0159] Figure 13 Example 5.2: Axitinib-Nm(PEG)1-oxymethyl prodrug 1 H-NMR

[0160] Figure 14 and Figure 15 LCMS of axitinib-Nm(PEG)1-oxymethyl prodrug from Example 5.2

[0161] Figure 16 HPLC analysis of axitinib-Nm(PEG)1-oxymethyl prodrug from Example 5.2

[0162] Figure 17 Solubility of SAB-I (micronized, non-micronized, and ultramicronized) and polymorph IV in PBS (pH 7.2) at 37°C.

[0163] Figure 18: TKI release profiles of implants 7.1A, 7.1B, 7.1C and 7.1D (in vitro method A), showing the effect of axitinib solubility: (A) release %; (B) mass released; (C) TKI release profile of implant 7.1E.

[0164] Figure 19: TKI release profiles of implants 7.2A, 7.2B, 7.2C and 7.2D (in vitro method B), showing the effect of axitinib solubility: (A) release%; (B) mass released.

[0165] Figure 20 TKI release profiles of implants 8A, 8B, 8C, and 8D (in vitro method B), showing the effect of hydrated surface area.

[0166] Figure 21 TKI release profiles of implants 9A, 9B, and 9C (in vitro method B), showing particle size comparison.

[0167] Figure 22 NHP eye quadrants and suture locations

[0168] Figure 23: TKI distribution in NHP retina / Chr / RPE at 3 months: (A) Retina and choroid / RPE - tissue quadrants (grouped by four eyes); (B) Retina and choroid / RPE - grouped by four quadrants

[0169] Figure 24 Hydrogel durability score

[0170] Figure 25 Effect of curing time on implant size

[0171] Figure 26 Overview of the planned research (Example 16)

[0172] Figure 27: TKI release profile of implants 7.3A to 7.3H (relevant percentage of release over time, in vitro method C), showing up to approximately 50 hours (A) and up to approximately 11 hours (B), Example 7.3

[0173] Figure 28 TKI release profile of implants 7.3A to 7.3H (mass released over time, in vitro method C), Example 7.3; TKI release profile of implants 7.3G to 7.3K of Example 7.3 (mass released over time, in vitro method C) Figure 28A ; and the percentage released over time, in vitro method C - Figure 28B )

[0174] Figure 29 Results of VEGF activation study (leakage score over time), Example 14

[0175] Figure 30 XRD related to photostability testing, Example 15

[0176] definition

[0177] As used herein, the term "implant" (sometimes also referred to as "reservoir") refers to an object containing an active agent, specifically a tyrosine kinase inhibitor (TKI, such as axitinib), and / or other compounds as disclosed herein, and administered to the human or animal body, such as to the vitreous fluid of the eye (also referred to as the "vitreous chamber" or "vitreous body"), which remains in the human or animal body for a period of time while releasing the active agent into the surrounding environment. The implant may have any predetermined shape prior to injection (e.g., as disclosed herein), which is maintained to some extent when the implant is placed in the desired location, but the size of the implant (e.g., length and / or diameter) may change due to hydration after administration, as further disclosed herein. In other words, in the case of a pre-formed implant, the object injected into the eye is not a solution or suspension, but a pre-formed coherent object. Therefore, in this case, the implant is fully formed as disclosed herein prior to administration, rather than being generated in situ at the desired location in the eye. However, in some alternative embodiments of the invention, the implant can be generated in situ at the desired location by injecting a solution of the precursor compound, which forms the implant immediately after injection.

[0178] Upon application, over time, the implant of the present invention is biodegraded in the physiological environment (as disclosed herein), thereby altering its shape and reducing its size until it is completely dissolved / reabsorbed.

[0179] In this document, the term "implant" is used to refer to an implant in a hydrated (also referred to herein as "wet") state when in contact with water, such as immediately after hydration or rehydration following application to the eye or other immersion in an aqueous environment (e.g., in vitro), and to an implant in a dry (also referred to herein as "dry" or "dehydrated") state, i.e., after the implant has been manufactured and dried and is about to be loaded into a needle, or after being loaded into a needle as disclosed herein, or wherein the implant is manufactured in a dry state without dehydration. In other words, the term "dry" or "dehydrated" in connection with the implants of the present invention refers to the implant prior to injection (to a physiological or other environment). In this art, in the dry state, a "hydrogel" (e.g., the hydrogel contained in the implants of the present invention) is sometimes also referred to as a "dry gel." Thus, in some embodiments, in the context of the present invention, the implant may contain no more than about 1% by weight of water in its dry / dry state. The water content of the implant in its dry / dried state can be measured, for example, by the Karl Fischer coulometric method. Whenever the dimensions (i.e., length, diameter, surface area, or volume) of the hydrated implant are reported herein, these dimensions are measured after the implant has been immersed in phosphate-buffered saline (PBS) at 37°C for 24 hours. Whenever the dimensions of the implant in its dry state are reported herein, these dimensions are measured after the implant has been completely dried (and therefore, in some embodiments, contains no more than about 1% by weight of water) and is in a state ready for loading into a needle for subsequent application. In some embodiments, the implant is maintained in an inert atmosphere glove box containing less than 20 ppm of oxygen and moisture for at least about 7 days.

[0180] As used herein, the term "eye" refers to the entire eye of various origins and natures, or any part or portion of the eye (since the "eye implant" of this invention can, in principle, be applied to any part or portion of the eye), or any eye disease (since, in one aspect, this invention generally relates to the treatment of any eye disease ("eye disease")). In some embodiments, the invention relates to intravitreal injection of an eye implant (in which case, "eye implant" is therefore "intravitreal implant"), and to the treatment of eye diseases affecting the posterior segment of the eye, as further disclosed below.

[0181] The term "patient" in this document includes both human and animal patients. Therefore, the implants of this invention are suitable for human or veterinary medical applications. Patients enrolled and treated in clinical studies may also be referred to as "subjects." Generally, a "subject" is an individual (human or animal) to whom the implants of this invention are administered, for example, during a clinical study. Animal subjects in studies may be, for example, non-human primates, such as monkeys, such as cynomolgus monkeys, or rodents, such as rabbits, such as Dutch Belted rabbits. A "patient" is a subject who requires treatment due to a specific physiological or pathological condition. In embodiments of this invention, the patient is a human.

[0182] The term "biodegradable" refers to a material or object that degrades in vivo (i.e., when placed in the body of a human or animal) (e.g., the ocular implant of the present invention). In the context of the present invention, as detailed below, implants comprising hydrogels containing dispersed TKI particles (e.g., axitinib particles) undergo slow biodegradation over time immediately after deposition in the eye (e.g., within the vitreous fluid). This means that the hydrogel dissolves and undergoes bioreabsorption after a period of time (as indicated herein). In some embodiments, biodegradation occurs at least partially via ester hydrolysis of the polymer network forming the hydrogel, which takes place in a physiological environment. The implant degrades slowly (i.e., the hydrogel dissolves / degrades) until it is completely reabsorbed and no longer visible in the vitreous. In this document, the term "biodegradable" or "degradation" with respect to implants may be used interchangeably with the terms "dissolution," "dissociation," "reabsorption," or "bioreabsorption" of implants.

[0183] The time until the hydrogel completely dissolves, i.e., the implant is completely degraded (in vivo or outside the body), is also referred to in this article as the "durability" of the implant.

[0184] “Hydrogels” can be defined as “polymeric materials that exhibit the ability to swell in water and retain a large proportion (e.g., > 20%) of water within their structure without dissolving in water. This definition includes a wide variety of natural materials of plant and animal origin, materials prepared by modifying natural structures, and synthetic polymeric materials.” (BD Ratner, ASHoffmann, Hydrogels for Medical and Related Applications (Andrade, JD, ed.); ACSSymposium Series; American Chemical Society, Washington, DC, 1976; Vol. 31; Chapter 1, 1–36).

[0185] Therefore, a "hydrogel" is a three-dimensional network of hydrophilic natural or synthetic polymers (as disclosed herein), optionally also containing hydrophobic domains, which can swell in water and retain a certain amount of water while maintaining or substantially maintaining its structure, for example, due to the chemical or physical crosslinking of individual polymer chains. Due to its high water content, a hydrogel is soft and flexible, making it very similar to natural tissue. In this invention, the term "hydrogel" is used to refer to a hydrogel in a hydrated / "wet" state when it is in contact with water (e.g., after the hydrogel has formed in an aqueous solution, or immediately after the hydrogel has been implanted in an eye or other part of the body or otherwise immersed in an aqueous environment and then (re)hydrated), and to a hydrogel in a dry (drying / dehydrating) state when it has been dried to a low water content, for example, not exceeding 1% by weight. The dried form of a hydrogel is sometimes also referred to in this art as a "dry gel," which is a dried hydrogel that can be converted into a hydrogel upon exposure to water and immersion in water. The process of drying to form a dry gel can be carried out in a variety of ways and can result in varying degrees of shrinkage and porosity.

[0186] In this invention, the active ingredient is contained (e.g., dispersed in) a hydrogel, which may also be referred to as a "matrix".

[0187] The term "polymer network" describes a structure formed by polymer chains (of the same or different molecular structures and of the same or different molecular weights) that are cross-linked with each other. Types of polymers suitable for the purposes of this invention are disclosed herein. Polymer networks can also be formed using cross-linking agents, as also disclosed herein.

[0188] The term "amorphous" refers to polymers or polymer networks or other chemical substances or entities that do not exhibit a crystalline structure in X-ray or electron scattering experiments.

[0189] The term "semi-crystalline" refers to a polymer or polymer network or other chemical substance or entity that exhibits some crystalline characteristics, that is, shows some crystalline properties in X-ray or electron scattering experiments.

[0190] The term “crystallization” refers to polymers or polymer networks or other chemical substances or entities that exhibit crystalline characteristics, as confirmed by X-ray or electron scattering experiments.

[0191] The term "precursor" in this article refers to those molecules or compounds that react with each other and thus link together via crosslinking to form a polymer network and thus a hydrogel matrix. Although other materials, such as surfactants or buffers, may be present in the hydrogel, they are not referred to as "precursors".

[0192] The portion of the precursor molecule that remains in the final polymer network is also referred to herein as a "unit". Therefore, a "unit" is a structural unit or component of the polymer network that forms the hydrogel. For example, the polymer network suitable for use in this invention may contain the same or different polyethylene glycol units, as further disclosed herein.

[0193] The molecular weight of polymer precursors used for the purposes of this invention and as disclosed herein can be determined by analytical methods known in the art. The molecular weight of polyethylene glycol can be determined, for example, by any method known in the art, including gel electrophoresis (e.g., SDS-PAGE (sodium dodecyl sulfate-polyacrylamide gel electrophoresis)), gel permeation chromatography (GPC, including GPC with dynamic light scattering (DLS)), liquid chromatography (LC), and mass spectrometry (e.g., matrix-assisted laser desorption / ionization-time-of-flight (MALDI-TOF) mass spectrometry or electrospray ionization (ESI) mass spectrometry). The molecular weight of a polymer (including polyethylene glycol precursors as disclosed herein) is an average molecular weight (based on the molecular weight distribution of the polymer) and is therefore generally indicated by various average values, including weight average molecular weight (Mw) and number average molecular weight (Mn). In the case of polyethylene glycol precursors used in this invention, the molecular weight indicated herein is the number average molecular weight (Mn).

[0194] When the particle size of an surfactant is referred to herein, a “d90” (also referred to herein as “D90”) value means that 90% by volume of all particles in a measured bulk material (which has a certain particle size distribution) have a particle size lower than the indicated value. For example, a d90 particle size of less than about 10 μm means that 90% by volume of particles in a measured bulk material have a particle size of less than about 10 μm. The corresponding definition applies to other “d” values, such as “d10”, “d50”, or “d100” (also referred to herein as “D10”, “D50”, and “D100”, respectively). Therefore, whenever any particle size value (d10, d50, or d90) is reported herein, it refers to a volume percentage. Particle size can be measured by laser diffraction. Unless otherwise disclosed herein in conjunction with a particular particle size, d10, d50, and d90 particle sizes are measured by laser diffraction.

[0195] In some embodiments of the invention, the term "fiber" (which may be used interchangeably with the term "rod" herein) describes an object that generally has an elongated shape (i.e., in the case of the invention, the implant of the invention). Specific dimensions of the implants of the invention are disclosed herein. The implant may have a cylindrical or substantially cylindrical shape, or may have a non-cylindrical shape, as further disclosed herein. The cross-sectional area of ​​the fiber or implant may be circular or substantially circular, but in some embodiments may also be oval or rectangular, or in other embodiments may have different geometries, such as cross-shaped, star-shaped, or other shapes as further disclosed herein.

[0196] In some embodiments of the invention, the term "filament" is also used to refer to a fiber, particularly where the implant comprises several fibers or filaments to form a "multifilament" implant. In these cases, the combined diameter of the multifilament implant is substantially within the same range as that of a single-fiber implant. In other words, in such multifilament implants, the individual filaments, although typically fibrous in shape, may be relatively thin so that the combined diameter of the multifilament implant is not excessively large. Embodiments of multifilament implants are disclosed herein.

[0197] The "hydrated surface area" of an implant is calculated based on its hydrated dimensions. For example, the hydrated surface area of ​​a cylindrical or substantially cylindrical implant (the "fiber" of this invention) is calculated according to the formula for the surface area of ​​a cylinder: A = 2πrh + 2πr 2 Calculated from hydrated length and diameter (where h is the height, i.e., the length of the cylinder in the hydrated state, and r is the radius, i.e., half the diameter / width of the cylinder in the hydrated state). Whenever the dimensions (i.e., length, diameter) and derived values ​​(e.g., surface area or volume) of the implant in the hydrated state are reported herein, these dimensions were measured after the implant had been immersed in phosphate-buffered saline (PBS, pH 7.2 to 7.4) at 37°C for 24 hours.

[0198] As used herein, the term "release" (and correspondingly "released," "releasing," etc.) refers to the delivery of an agent (e.g., an API) from the implant of the present invention to the surrounding environment. The surrounding environment may be an in vitro or in vivo environment as described herein. In some specific embodiments, the surrounding environment is vitreous fluid and / or ocular tissue, such as the retina or choroid. Therefore, whenever the implant is stated herein to "release a TKI (e.g., axitinib)" or "provide (sustained) release of a TKI (e.g., axitinib)," this refers not only to the direct delivery of a TKI (e.g., axitinib) from the implant before the hydrogel has (fully) biodegraded, but also to the continued delivery of a TKI (e.g., axitinib) to the surrounding environment after the hydrogel has fully degraded, while undissolved TKI remains in this surrounding environment (e.g., in the form of single or aggregated particles) for a period of time while the TKI continues to exert its therapeutic effect. In this document, "vitreous fluid" (VH) is sometimes also simply referred to as "vitreous body."

[0199] In the context of in vivo studies (e.g., in vivo studies of animals), the term "C" max " and "t max "C" has the following meanings: the term "C" max "" indicates the maximum concentration of the active agent measured in a specific (ocular) tissue (e.g., the retina or choroid) (as indicated, for example, in Examples 10 and 13 herein concerning in vivo studies). Typically, C max This refers to the maximum average concentration of all corresponding samples measured in a given study (as also described in Examples 10 and 13). Unless otherwise indicated, C in tissues max The unit is ng / g. If measuring C in plasma... max The unit is ng / mL. The term "T" is used in this context. max (or "t") max In this article, it can be used in conjunction with "T". max "Used interchangeably" indicates the attainment of maximum plasma concentration (C). max (Time) T max It can be indicated by days, weeks, or months, depending on the situation. The "AUC" (area under the curve) value corresponds to the area under the curve of drug concentration in tissue (or plasma, depending on the situation) versus time. AUC indicates a specific time period. In this invention, for example, AUC 0-9个月 This refers to the area under the curve of drug concentration versus time from injection of the implant of the present invention to 9 months.

[0200] The “treatment period” mentioned in this article refers to the time during which a particular therapeutic effect (as described herein) is achieved. This period can extend even after the implant / hydrogel has been completely biodegraded / dissolved, as further disclosed herein.

[0201] The term “sustained release” is defined for the purposes of this invention to describe a product (in the case of this invention, an implant) formulated to make the drug available over an extended period of time, thereby allowing for a lower dosing frequency compared to an immediately released dose form (e.g., a solution of the active ingredient injected into the eye). Other terms that may be used interchangeably with “sustained release” herein are “extended release” or “controlled release.” Thus, “sustained release” describes the release of an API, specifically a TKI (e.g., axitinib), contained in the implant of this invention. The term “sustained release” itself is not related to or limited to a specific (in vitro or in vivo) release rate, but in some embodiments of this invention, the implant may be characterized by an average (in vitro or in vivo) release rate or a release profile as disclosed herein. Within the specific meaning of this invention, the term “sustained release” also includes a constant or substantially constant (i.e., above a certain level) daily release of a tyrosine kinase inhibitor, where this constant or substantially constant release period is followed by a gradually decreasing period of tyrosine kinase inhibitor release. In this specific context, the overall sustained release provided by the implant of the present invention may mean that the release rate is not necessarily constant or substantially constant throughout the TKI release period, but may vary over time as just described (e.g., having a constant or substantially constant initial period of sustained release followed by a gradually decreasing period of release). Within the meaning of this invention, the terms "tapered" or "tapering" refer to the decreasing release of a tyrosine kinase inhibitor (e.g., axitinib) over time until the tyrosine kinase inhibitor is fully released. In some specific cases, the release profile may also show an initial drug burst and / or a final drug burst, indicated by a short-term increase in the corresponding release rate (in vitro or in vivo). Because the implant of the present invention (whether explicitly referred to herein as a "sustained-release" implant or simply as an "implant") provides sustained release of the API, the implant of the present invention may also be referred to as a "reservoir".

[0202] In some embodiments of the invention, the implant is characterized by a TKI (e.g., axitinib) release profile, as measured in certain in vitro tests. In such in vitro tests further disclosed herein, the amount of TKI released over a specific time period, such as a period of one or more days, can be determined based on the absolute amount released each day during any given day of the in vitro test (e.g., in µg) (the amount released each day is also defined as a "daily release rate" or "rate of release per day"), or the cumulative absolute amount released over that time period (again, such as in µg or mg), such as the cumulative amount released over a 10-day period. In in vitro tests, a release percentage can also be determined, i.e., the percentage released each day (or over a period of several days) or the cumulative percentage released over a certain time period, such as, for example, 10 days. A percentage can be defined as a percentage (ratio / share) of the total amount (drug load) contained in an implant, or it can be defined as a percentage (ratio / share) of the total amount released from an implant in a corresponding in vitro test (which may be lower than the actual total amount of active ingredient contained in the implant in some cases, such as when the release determined in an in vitro test is close to the equilibrium amount of drug released, which is lower than the actual drug load of the implant for various reasons, or when the in vitro test is terminated before all the drug load contained has been released).

[0203] In the context of in vitro release testing, “amount” in this article refers to weight, such as µg or mg, while “percentage” (or “share” or “ratio”) refers to a percentage (%).

[0204] The “average release rate” (e.g., in µg / day) is the average amount (e.g., in µg) released each day over a given number of days. It is calculated by dividing the absolute (cumulative) amount of active agent released over a given number of days by the number of days. For example, if an implant of the present invention releases a total (cumulative) amount of axitinib of 100 µg over a 5-day period, the average release rate for this 5-day period would be 20 µg / day. Of course, the actual release rate on any single given day within this 5-day period may differ from the average release rate over the entire period.

[0205] Whenever in the context of in vitro testing and determining the release (rate) of the active agent from the implant of the present invention, the references herein to “initial” days or “initial” periods (e.g., “initial period of 5 days”) mean a period of time covering the corresponding number of days from the start of the corresponding in vitro test (e.g., 5 days prior to the in vitro test).

[0206] In vitro tests can be performed in a variety of solvents and under various conditions (e.g., using “Method A”, “Method B”, or “Method C”, see the subsection “In Vitro Release” in section “I. Implants”)), as detailed herein whenever any particular release characteristic is mentioned. Typically, for Methods A and B, an implant (or several implants simultaneously, if specifically mentioned) is placed in a volume of solvent or solvent mixture at a temperature (maintained during the in vitro test), as disclosed herein, and the release amount or percentage is determined on a predetermined date. The volume of the solvent (mixture) in which the implant used for such an in vitro test is placed is determined by multiplying the “leakage volume” by the “leakage factor”. The “leakage volume” is calculated by dividing the amount of active agent contained in the implant under study (e.g., in µg) by the solubility of that active agent in the solvent (mixture) in which the test is performed (e.g., in µg / mL). For example, if an in vitro test of an implant of the present invention containing axitinib as a TKI is performed in a solvent mixture of 25% ethanol / 75% water (v / v), the drain volume is determined by dividing the amount of axitinib contained in the implant under study by the solubility of axitinib in this solvent mixture. The solubility of the active agent can vary depending on the form of the active agent used, as further disclosed herein. For example, different polymorphic forms of the active agent may have different solubilities in the same solvent (mixture). Similarly, different salts or eutectics or derivatives of the active agent may have different solubilities in the same solvent (mixture). Depending on the purpose of the test and the specific details of the test method applied, these specific solubility values ​​of different forms of the active agent are used to calculate the "drain volume," or for some simplified or comparative tests, the average solubility of a given active agent is also used to calculate the "drain volume," as disclosed herein. The in vitro tests reported in this invention can be performed under various leak conditions as disclosed herein, such as 2× leak conditions, or 3× leak conditions, or using higher leak factors, such as 4× or higher leak conditions. "2× leak conditions" means that the volume of the solvent (mixture) in which the implant (or implants, if so indicated) of the invention is impregnated for a particular test is twice the "leak volume" (as defined above), i.e., in this case, the "leak factor" will be 2; "3× leak conditions" means that the volume of the solvent (mixture) in which the implant (or implants, if so indicated) of the invention is impregnated for a particular test is three times the "leak volume" (as defined above), i.e., in this case, the "leak factor" will be 3; and the same applies to other leak factors. Further details regarding in vitro tests performed using the implant of the invention (where the TKI is axitinib) (specifically, regarding leak factors and leak volumes) are provided in the subsection "In Vitro Release" within the section "Implants" of this specification.Another method for measuring the in vitro release of axitinib from the implant of the present invention is “Method C”, as also disclosed in detail herein (see, for example, the subsection “In Vitro Release” in section “I. Implant” and Example 7.3).

[0207] Whenever this document states that an administration or injection is performed “synchronously” or “at the same time” with the administration or injection of an implant of the present invention, it means that the corresponding injections of two or more implants, or one or more implants, are typically administered one immediately after the other (e.g., an injection of a suspension or solution of an anti-VEGF agent as disclosed herein), without any significant delay. For example, if a total dose of approximately 400 µg of axitinib is administered to one eye and this total dose is contained in two implants of the present invention, each containing approximately 200 µg of axitinib, these two implants are typically injected one immediately after the other (and therefore “simultaneously”) into the vitreous chamber within the same treatment course, while adhering to all precautions for safe and precise injection at the desired site, without any unnecessary delay. The same applies to the administration of one or more implants of the present invention synchronously / simultaneously / at the same time with the administration of another anti-VEGF agent as described herein. In cases where another anti-VEGF agent is administered via intravitreal injection of a suspension or solution containing an anti-VEGF agent, this injection is typically intended to be performed immediately before or after intravitreal injection of one or more implants of the present invention (as disclosed above), i.e., ideally within a single treatment course if concurrent / simultaneous treatment is intended.

[0208] However, in specific circumstances, such as when complications occur during the administration of the first implant and / or when the physician administering the injection deduces that a second planned injection on the same day of the same course of treatment (e.g., where the expected dose is contained in two or more implants) or in subsequent days may not be advisable, a second implant may also be administered, for example, one or two weeks after the first implant. As will be disclosed in more detail herein, since implants can remain in the vitreous humor of the human eye for an extended period of time, such as from about 6 months to about 12 months, or from about 6 months to about 9 months, the administration of two implants (e.g., one or two weeks apart) can still be considered “synchronous” in the context of this invention. Similar considerations apply to the “synchronous” administration of the implants of this invention and the anti-VEGF agent (or another agent). Thus, the anti-VEGF agent may be administered synchronously with the intravitreal administration of the implants of this invention, i.e., at the same time or approximately the same time as described herein.

[0209] However, in some other embodiments, the anti-VEGF agent may also be administered in combination with the intravitreal implant of the present invention, wherein the administration of the implant and the anti-VEGF agent is not simultaneous or concurrent as defined above. In these cases, the anti-VEGF agent is administered after or before the intravitreal injection of the implant of the present invention (e.g., within 1, 2, or 3 months after or before). This combination administration of the anti-VEGF agent (e.g., aflibercept or bevacizumab) with the implant of the present invention may also be referred to as "combination therapy".

[0210] The term "emergency medication" generally refers to a medication that can be administered to a patient under predetermined conditions (e.g., during a study, to a subject in a situation where the subject's response to the study treatment is inadequate; or to a patient under specified conditions predetermined or determined by the physician treating the patient) or to manage an emergency. In some embodiments of the invention, "emergency medication" refers to a dose of an anti-VEGF agent as disclosed herein, administered via intravitreal injection of a solution or suspension of the anti-VEGF agent. In some specific embodiments, the emergency medication is a dose (2 mg) of aflibercept administered via intravitreal injection.

[0211] As used herein in conjunction with the term "about," it refers to the normal variation of the corresponding measured quantity, as would be expected by someone skilled in the art when performing measurements and applying a level of caution commensurate with the accuracy of the measurement target and the measuring equipment. Unless otherwise stated, all values ​​of the measured or measurable quantities disclosed herein (again, including time periods, weights, volumes, etc.) are intended to include the aforementioned normal variation of the corresponding measured quantity, even in the absence of "about" preceding these quantities.

[0212] The term “at least about” in conjunction with the measurement quantity refers to normal variations in the measurement quantity, as would be expected by a person skilled in the art when performing the measurement and applying a level of caution commensurate with the accuracy of the measurement target and the measuring equipment, as well as any quantity above that.

[0213] As used in this article, the term “mean” refers to the central or typical value in a set of data (points), which is calculated by dividing the sum of the data (points) in the set by its number (i.e., the mean of a set of data).

[0214] Unless the context clearly indicates otherwise, the singular forms “a” and “the” as used herein include multiple indicators.

[0215] The term “and / or” as used in phrases such as “A and / or B” is intended to include both “A and B” and “A or B”.

[0216] As used herein, open terms (e.g., “include,” “including,” “contain,” “containing,” and the like) mean “include” and are intended to refer to an open list or enumeration of elements, method steps, or the like, and are therefore not intended to be limited to the listed elements, method steps, or the like, but are also intended to include additional unlisted elements, method steps, or the like.

[0217] The term “high” is intended to include the corresponding value or number when used in conjunction with a value or number in this text.

[0218] The terms “from A to B”, “from A to B”, and “from A to B” are used interchangeably in this document and all refer to the range from A to B, including the upper limit A and the lower limit B.

[0219] For the purposes of this disclosure, any range defined by the upper and lower limits is also intended to include all individual values ​​or ranges between those limits.

[0220] Specifically, this also applies to the pH ranges given in this specification. For example, if a pH range of 7.2 to 7.4 is indicated, this specifically means a pH of 7.2; or a pH of 7.4; or a pH in between, such as 7.3.

[0221] The terms “API,” “active (pharmaceutical) ingredient,” “active (pharmaceutical) agent,” “active (pharmaceutical) principle,” “(active) therapeutic agent,” “active substance,” and “drug” are used interchangeably herein and refer to substances used in final pharmaceutical products (FPPs) and substances used in the preparation of such final pharmaceutical products to provide pharmacological activity, or otherwise to have a direct effect in the diagnosis, cure, relief, treatment, or prevention of a disease, or to have a direct effect in restoring, correcting, or improving the physiological function of a patient.

[0222] As used herein, the term "polymorph" refers to any crystalline form of an active agent (e.g., axitinib). Typically, active agents that are solid at room temperature exist in a variety of different crystalline forms (i.e., polymorphs), one of which is thermodynamically most stable at a given temperature and pressure. Axitinib polymorphs used in this invention are further disclosed herein.

[0223] As used herein, the term "derivative" of an surfactant generally refers to a compound derived from the surfactant through a chemical reaction, specifically a compound synthesized from the surfactant by substitution / functionalization / replacement of one or more sites, structural portions, or atoms within the surfactant's structure. For example, if the surfactant's structure has a -NH group in its molecule, the hydrogen atoms in such -NH groups can be substituted with substituents of various properties as disclosed herein. In some cases, derivatives can also be compounds synthesized from the surfactant by removing certain substituents, groups, or portions.

[0224] As used herein, the term "prodrug" refers to a biologically reversible derivative of a drug molecule that undergoes enzymatic and / or chemical transformation in vivo into an active (parent) drug, which then exerts its desired pharmacological effect. Prodrugs can alter the physicochemical, biopharmaceutical, or pharmacokinetic properties of a drug to modify, and in some cases improve, one or more aspects of the therapeutic suitability, availability, and usefulness of the corresponding drug. For example, a prodrug may be more soluble than the parent drug, and the bioavailability of the parent drug can be increased by using such a prodrug. In some embodiments, a "prodrug" may be a derivative of a drug, as defined above. For example, a prodrug may be a derivative of a drug in which one or more sites of a drug molecule group are attached, and the drug molecule group is cleaved again upon immersion in a physiological environment. In other embodiments, a "prodrug" may also be a precursor to an active (parent) drug comprising a portion of an active drug molecule, wherein the precursor reacts in a physiological environment with other components present in or intentionally administered for that purpose to construct the structure of the active (parent) drug.

[0225] For the purposes of this disclosure, the term "alkyl" as used alone or as part of another group refers to an alkyl group containing 1 to 12 carbon atoms (i.e., C12). 1-12 Alkyl groups or any other specified number of carbon atoms (i.e., C1 alkyl (e.g., methyl), C2 alkyl (e.g., ethyl), C3 alkyl (e.g., propyl or isopropyl), etc.) are straight-chain or branched aliphatic hydrocarbons. In one embodiment, the alkyl group is selected from straight-chain C1 alkyl groups. 1-10 Alkyl group. In another embodiment, the alkyl group is selected from branched C4 groups. 1-10 Alkyl group. In another embodiment, the alkyl group is selected from straight-chain C64. 1-6 Alkyl group. In another embodiment, the alkyl group is selected from branched C4 groups. 1-6 Alkyl group. In another embodiment, the alkyl group is selected from straight-chain C64. 1-4 Alkyl group. In another embodiment, the alkyl group is selected from branched C4 groups. 1-4 Alkyl group. In another embodiment, the alkyl group is selected from straight-chain or branched C4 groups. 2-4 Alkyl group. Non-limiting illustrative C 1-10Alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, isobutyl, 3-pentyl, hexyl, heptyl, octyl, nonyl, decyl, and the like. Non-limiting illustrative C 1-4 Alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, and isobutyl.

[0226] For the purposes of this disclosure, the term "optionally substituted alkyl" as used alone or as part of another group means an alkyl group as defined above that is unsubstituted or substituted with one, two, or three independent substituents selected from: nitro, haloalkoxy, aryloxy, aralkyloxy, alkylthio, sulfonamide, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, urea, guanidinyl, carboxyl, carboxylalkyl, cycloalkyl, and the like. In one embodiment, the optionally substituted alkyl group is substituted with two substituents. In another embodiment, the optionally substituted alkyl group is substituted with one substituent. Non-limiting illustrative optionally substituted alkyl groups include -CH2CH2NO2, -CH2CH2CO2H, -CH2CH2SO2CH3, -CH2CH2COPh, and -CH2C6H. 11 And things like that.

[0227] For the purposes of this disclosure, the term "aryl" as 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., C64-C ... 6-14 Aryl). Non-limiting illustrative aryl groups include phenyl (abbreviated as "Ph"), naphthyl, phenanthryl, anthraceneyl, indene, azulel, biphenyl, biphenylene, and fluorenyl. 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 substituted by one or more other atoms, which may be the same or different, including oxygen, nitrogen, and / or sulfur. An aryl group may contain one aromatic ring or more than one aromatic ring.

[0228] For the purposes of this disclosure, the term "optionally substituted aryl" as used herein, either alone or as part of another group, means an aryl group as defined above that is unsubstituted or substituted by one or more substituents independently selected from: halogen, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkylalkyloxy, alkylthio, formamido, sulfonamide, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureo, guanidinyl, carboxyl, carboxylalkyl, alkyl, cycloalkyl, alkenyl, alkynyl, heteroaryl, heterocyclic, alkoxyalkyl, (amino)alkyl, hydroxyalkylamino, (alkylamino)alkyl, (dialkylamino)alkyl, (cyano)alkyl, (formamido)alkyl, mercaptoalkyl, (heterocyclic)alkyl, or (heteroaryl)alkyl. In one embodiment, the optionally substituted aryl group is an optionally substituted phenyl group. In one embodiment, the optionally substituted phenyl group has four substituents. In another embodiment, the optionally substituted phenyl group has three substituents. In another embodiment, the optionally substituted phenyl group has two substituents. In another embodiment, the optionally substituted phenyl group has one substituent. Non-limiting illustrative substituted aryl groups 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-difluorophenyl, 2,6-dichlorophenyl, 2-methyl,3-methoxyphenyl, 2-ethyl,3-methoxyphenyl, 3,4-dimethoxyphenyl, 3,5-difluorophenyl, 3,5-dimethylphenyl, 3,5-dimethoxy,4-methylphenyl, 2-fluoro-3-chlorophenyl, and 3-chloro-4-fluorophenyl. The term "optionally substituted aryl" is intended to include groups having an optionally substituted fused cycloalkyl group and an optionally substituted fused heterocyclic group. Examples include (but are not limited to):

[0229] .

[0230] As used herein, the term "salt" may include (but is not limited to) inorganic acid salts, such as hydrochlorides, hydrobroms, hydroiodates, sulfates, phosphates, and the like; organic acid salts, such as formates, acetates, trifluoroacetates, maleates, tartrates, glutarates, and the like; sulfonates, such as methanesulfonates, benzenesulfonates, p-toluenesulfonates, and the like; and metal salts, such as sodium salts, potassium salts, cesium salts, and the like; alkaline earth metal salts, such as calcium salts, magnesium salts, and the like; and organic amine salts, such as triethylamine salts, pyridine salts, methylpyridine salts, ethanolamine salts, triethanolamine salts, dicyclohexylamine salts, N,N′-dibenzylethylenediamine salts, and the like. Any TKI (e.g., axitinib) salts used herein are intended to be pharmaceutically acceptable salts.

[0231] As used herein, the term "cocrystal" refers to a combination of an active pharmaceutical ingredient (API) and one or more co-forming agents (e.g., acids, such as carboxylic acids) in the same crystal lattice via non-covalent interactions (e.g., hydrogen bonds, electrostatic interactions, π-π stacking, van der Waals interactions, etc.). Therefore, a cocrystal is a multi-component solid. The difference between a cocrystal and a salt is that the former consists only of a neutral component, while the latter contains an ionic component. Co-forming agents suitable for axitinib cocrystals are further disclosed herein. Cocrystallization can modify and, in some cases, optimize the physicochemical properties of the API, such as stability, solubility, dissolution rate, mechanical properties, etc., for certain applications.

[0232] As used herein, the term "therapeuticly effective" refers to the amount of a drug or active agent required to produce a desired therapeutic outcome after administration. For example, in the context of this invention, a desired therapeutic outcome would be a reduction in the central subfield thickness (CSFT), as measured by optical coherence tomography, in patients with neovascular AMD, because patients with neovascular AMD have elevated CSFT. In the context of this invention, the "therapeuticly effective" amount of an active agent can also be the IC (intensity concentration) provided by such active agent to a particular substrate. 50 Multiples of, for example, IC 50 50 times or more.

[0233] The abbreviation "PBS" in this article refers to "phosphate-buffered saline".

[0234] The abbreviation "TBS" in this article means "tris buffered saline".

[0235] The abbreviation "PEG" in this article refers to "polyethylene glycol".

[0236] The abbreviation "HME" in this article refers to "hot melt extrusion".

[0237] The abbreviation "HST" in this article means "heat-stretch-twist".

[0238] The abbreviation "NHP" in this article refers to "non-human primates".

[0239] The abbreviation "TLA" in this article refers to "trilysine acetate".

[0240] All references disclosed herein are incorporated herein by reference in their full text for all purposes. In the event of any conflict between the incorporated references and this disclosure, this disclosure shall prevail. Detailed Implementation

[0241] I. Implants

[0242] Active ingredients:

[0243] One aspect of the present invention is a sustained-release biodegradable ocular implant comprising a hydrogel and a tyrosine kinase inhibitor (TKI), wherein the TKI particles are dispersed within the hydrogel, as disclosed herein. Therefore, the active ingredient contained in the implant of this aspect of the invention is a TKI. Examples of suitable TKIs are axitinib, sorafenib, sunitinib, nintedanib, pazopanib, regorafenib, cabozantinib, and vandetanib. In a particular embodiment, the TKI used in this and other aspects of the invention is axitinib.

[0244] In embodiments of the present invention, the implant contains axitinib as a tyrosine kinase inhibitor. Axitinib free base is the active ingredient of INLYTA® (Pfizer, NY), indicated for the treatment of advanced renal cell carcinoma. It is a small molecule (386.47 Daltons) synthetic tyrosine kinase inhibitor. The main mechanism of action is to inhibit angiogenesis (new blood vessel formation) by primarily 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 kinases are involved in pathological angiogenesis, tumor growth, and cancer progression. Therefore, axitinib is a multi-target inhibitor that inhibits the VEGF and PDGF pathways.

[0245] Axitinib inhibits VEGF signaling and also inhibits PDGF signaling. In addition to inhibiting VEGF / PDGF, it inhibits c-kit, a survival factor for developing blood vessels, and has a scavenging half-life (t). 1 / 2 The duration of action is several hours (Rugo et al., Phase I trial of the oral antiangiogenesis agent AG-013736 in patients with advanced solid tumors. 2005, J Clin Oncol., 23(24):5474-83), while lanibizumab and aflibercept each have a duration of action of several days in the human eye. 1 / 2 The longer t-term duration of these macromolecular antibodies 1 / 2This allows it to maintain effective tissue concentrations for several weeks, while smaller molecules are cleared more quickly. However, due to the low solubility of axitinib and its inclusion in the hydrogel implant of the present invention, which maintains its position in the vitreous fluid (VH) for an extended period (e.g., several months), a therapeutically effective dose of axitinib is delivered during the period the implant remains in the VH. Therefore, sustained intravitreal delivery of axitinib provides a multi-target inhibitor that, in principle, inhibits the VEGF and PDGF pathways without the need for combination therapy and frequent intravitreal injections.

[0246] The molecular formula of the free base of axitinib is C1 22 H 18 N4OS, and its IUPAC name is N-methyl-2-[3-((E)-2-pyridin-2-yl-vinyl)-1H-indazole-6-ylthio]-benzamide. It has the following chemical structure:

[0247]

[0248] For all purposes of this invention, all possible forms of axitinib may be used, including any axitinib polymorph, salt, anhydrous form, hydrate, other solvates, derivatives, or prodrugs. Whenever “axitinib” is mentioned in this specification or claims, unless otherwise expressly stated, it refers to any axitinib polymorph, salt, anhydrous form, solvate (including hydrates), cocrystal, derivative, or prodrug. For the purposes of this invention, all forms of axitinib used in implants are intended to be pharmaceutically acceptable.

[0249] In some embodiments of the invention, a specific form of axitinib is used.

[0250] It has been determined that the free base of axitinib has low solubility in biologically relevant media (e.g., PBS (pH 7.2 to 7.4), e.g., at 37°C). Different forms of axitinib (including different forms of the free base of axitinib, e.g., different axitinib polymorphs) have different solubilities. Solubility measurements are reported in Example 6.

[0251] In one aspect, the present invention relates to a sustained-release biodegradable ocular implant comprising a hydrogel and a tyrosine kinase inhibitor (TKI, such as axitinib), wherein the tyrosine kinase inhibitor particles are dispersed within the hydrogel, the implant being characterized in that the solubility of the tyrosine kinase inhibitor is greater than 0.3 µg / mL, as measured after incubation for 5 days in phosphate-buffered saline (PBS) at pH 7.2 to 7.4 and 37°C. In a specific embodiment, the TKI is axitinib. According to this aspect of the invention, any form of axitinib, such as axitinib polymorphs, cocrystals, derivatives, and prodrugs, including (but not limited to) those further disclosed herein, may be used having a solubility greater than 0.3 µg / mL, as measured after incubation for 5 days in phosphate-buffered saline (PBS) at pH 7.2 to 7.4 and 37°C.

[0252] Another aspect of the invention relates to a sustained-release biodegradable ocular implant comprising a hydrogel and a tyrosine kinase inhibitor (e.g., axitinib), wherein the tyrosine kinase inhibitor particles are dispersed within the hydrogel, the implant being characterized in that its hydrated surface area is at least 25 mm². 2 As measured after incubation for 24 hours in phosphate-buffered saline (PBS) at pH 7.2 to 7.4 and 37°C. According to this aspect of the invention, all forms of axitinib, regardless of their solubility, can generally be used, including (but not limited to) axitinib polymorphs, cocrystals, derivatives, and prodrugs as further disclosed herein, provided that the hydrated surface area of ​​the implant is at least 25 mm². 2 It can be measured after incubation for 24 hours in phosphate-buffered saline (PBS) at pH 7.2 to 7.4 and 37°C.

[0253] The two aspects of the present invention can also be combined, i.e., the present invention also relates to a sustained-release biodegradable ocular implant comprising a hydrogel and a tyrosine kinase inhibitor (e.g., axitinib), wherein the tyrosine kinase inhibitor particles are dispersed within the hydrogel, the implant being characterized in that the solubility of the tyrosine kinase inhibitor is greater than 0.3 µg / mL, as measured after incubation for 5 days in phosphate-buffered saline (PBS) at pH 7.2 to 7.4 and 37°C, and further characterized in that the hydrated surface area of ​​the implant is at least 25 mm². 2 As measured after incubation for 24 hours in phosphate-buffered saline (PBS) at pH 7.2 to 7.4 and 37°C.

[0254] Axitinib polymorphs used in this invention:

[0255] Regarding axitinib, suitable solid forms and polymorphs (including anhydrous forms and solvates) of axitinib are disclosed in the following literature: scientific literature, such as AMCampeta et al., Journal of Pharmaceutical Sciences, Vol. 99, No. 9, September 2010, 3874-3886; BP Chekal et al., Organic Process Research & Development 2009, 13, 1327-1337; and patent literature, including (but not limited to) US 8,791,140 B2, US 2006 / 0094763 A1, and WO 2016 / 178150 A1. The thermodynamically most stable polymorph of axitinib is referred to as form XLI, for example, in US 8,791,140 B2. XLI is the anhydrous crystalline form of axitinib. In some embodiments of the present invention, the axitinib used to prepare the implants of the present invention is the anhydrous crystalline form XLI. In addition to its anhydrous form, axitinib exists in various solvates with various solvents, and these solvates can also be used to prepare the implants of the present invention, as described in the referenced art. In this art, specifically (but not limited to) any of the axitinib polymorphs known and disclosed in the references cited herein, can generally be used in the present invention (unless a specific aspect of the invention requires a particular solubility, as explained above, in which case only those axitinib polymorphs that satisfy this requirement may be used).

[0256] In certain aspects and embodiments of the invention, the solvate-crystalline form SAB-I of axitinib disclosed in WO 2016 / 178150 can be used to prepare the implants of the invention. It is characterized by an XRD pattern comprising at least three, or at least four, or at least five characteristic 2θ° peaks selected from 8.3, 15.6, 16.5, 18.6, 21.0, 23.1, 24.1, and 26.0 (all values ​​± 0.3), and / or containing chemical shifts (each ± ​​0.2 ppm) at 26.1, 114.7, 154.8, and 167.8 in DMSO solvent. 13 C NMR, and / or including chemical shifts at 171.1, 153.2, 142.6, 139.5, 131.2, 128.1, and 126.3 (each shift ± 0.2 ppm). 13 C solid-state NMR, and / or characterized by a DSC isotherm containing two endothermic peaks between 213°C and 217°C (peak 1) and between 219°C and 224°C (peak 2).

[0257] The solubility of axitinib polymorph SAB-I, measured after incubation at 37°C in PBS at pH 7.2 to 7.4 for 5 days, was determined to be less than 0.3 µg / mL (see Example 6).

[0258] In those aspects and embodiments of the invention, where the solubility of the tyrosine kinase inhibitor is greater than 0.3 µg / mL, as measured after 5 days of incubation in phosphate-buffered saline (PBS) at pH 7.2 to 7.4 and 37°C, polymorph form IV is a particularly suitable polymorph of axitinib. Polymorph IV is disclosed, for example, in US 2006 / 0094763 A1. In specific embodiments, axitinib polymorph IV is used to prepare implants of this aspect of the invention. Additionally, axitinib polymorph IV is also suitable for preparing implants of any other aspect of the invention, including aspects where the solubility of the TKI does not need to be within a certain range, for example where the hydrated surface area of ​​the implant, as measured after 24 hours of incubation in phosphate-buffered saline (PBS) at pH 7.2 to 7.4 and 37°C, is at least 25 mm². 2 This relates to aspects of the present invention. Therefore, axitinib polymorph IV is a specific form of axitinib used in all aspects of the present invention.

[0259] The solubility of axitinib polymorph IV is approximately twice that of, for example, axitinib polymorph SAB-I, and has been determined to be above 0.3 µg / mL after incubation at 37°C in PBS at pH 7.2 to 7.4 (or pH 7.2) for 5 days, and 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 implants of this aspect of the invention, said implants requiring a solubility greater than 0.3 µg / mL, as measured after incubation for 5 days in phosphate-buffered saline (PBS) at pH 7.2 to 7.4 and 37°C, but may also be used to prepare implants of any other aspect of the invention.

[0260] In some specific embodiments, alternatively, axitinib contained in or used to prepare the implant of the present invention, specifically axitinib polymorph IV, is characterized by having powder X-ray diffraction patterns comprising at least two, for example at least three, or at least four, or at least five of the following peaks at diffraction angles (2θ): 8.90, 9.40, 9.50, 12.0, 14.60, 15.25, 15.75, 17.80, 19.30, 20.65, 24.95, 26.10 (all values ​​± 0.2). Specifically, axitinib used to prepare implants of this aspect of the invention, particularly axitinib polymorph IV, is characterized by a powder X-ray diffraction pattern containing peaks at the following diffraction angles (2θ): 8.90, 12.0, 14.60, 15.75, and 19.30 (all ± 0.2), and / or is characterized by a DSC peak at approximately 221°C at a scan rate of 5°C / min (in the range of 25°C to 300°C).

[0261] In some embodiments, the axitinib used to prepare the implant of the present invention is polymorph IV as characterized in US 2006 / 0094763 A1, which discloses axitinib polymorph IV (e.g., in paragraphs

[0021] ,

[0118] and

[0119] , and in claims 3 to 5 of US 2006 / 0094763 A1, also with reference to US 2006 / 0094763 A1). Figure 4 A and Figure 4 B). Therefore, axitinib, specifically axitinib polymorph IV, is characterized by a powder X-ray diffraction pattern containing peaks at diffraction angles (2θ) of 8.9, 14.6, 15.7, and 19.2 (all ± 0.1) for the preparation of implants according to certain embodiments of the present invention, having a solubility greater than 0.3 µg / mL (as measured after incubation for 5 days in phosphate-buffered saline (PBS) at pH 7.2 to 7.4 and 37°C). It may also be characterized by a powder X-ray diffraction pattern containing peaks at diffraction angles (2θ) of 8.9 and 15.7 (all ± 0.1).

[0262] In one embodiment, the implant of the present invention comprises axitinib, and at least 90% by weight or at least 95% by weight of the whole axitinib contained in the implant is polymorph IV.

[0263] Polymorph IV has been shown to be chemically and physically stable in the implants of the present invention for a full 6 months (see Example 11).

[0264] Photostable studies using implants containing axitinib polymorph IV have shown that the XRD patterns after sterilization and exposure (visible light at wavelengths of 380–700 nm and UV-A light at wavelengths of 315 nm–400 nm) remained unchanged compared to the corresponding XRD patterns before exposure at the start of these studies. These results are consistent with those obtained using implants containing axitinib polymorph SAB-I.

[0265] Further photostability studies have been conducted using visible and UV light as described above to compare axitinib polymorph IV powder, implants of the present invention containing axitinib polymorph IV, such implants loaded in injection needles, and such implant loading needles sealed in secondary foil packaging, and compared with unexposed (control) samples. The main impurity that can be generated by light exposure of axitinib polymorph IV is the dimerization of axitinib polymorph IV API (while the two main impurities generated using axitinib polymorph SAB-I API are dimers and cis isomers, but to a lesser extent than polymorph IV API). In Example 15, axitinib polymorph IV API powder showed photoinduced degradation, resulting in more than 30% (for visible and UV light) of impurities (dimers). When axitinib polymorph IV is dispersed in a PEG hydrogel within the implant of the present invention, less dimerization was observed upon exposure (visible and UV light) compared to the axitinib polymorph IV API powder itself, specifically only about 25% (visible light) and about 14% (UV light). Without wishing to be limited by theory, these data suggest that the hydrogel (e.g., the PEG hydrogel) provides protection for the axitinib polymorph IV form within the implant.

[0266] Therefore, the present invention also provides a method for increasing the photostability of an active agent (e.g., a TKI, e.g., axitinib, e.g., axitinib polymorph IV), which is carried out by incorporating the active agent into a PEG hydrogel to form the implant of the present invention. The present invention further provides a form of axitinib polymorph IV that is more photostably stable than powdered axitinib polymorph IV in visible light after the same exposure time and under the same exposure conditions, for example at least 10%, for example at least 15%, for example at least 20% more stable than powdered axitinib polymorph IV in UV light after the same exposure time and under the same exposure conditions, and / or that is for example at least 10%, for example at least 20%, for example at least 30%, for example at least 40% more stable than powdered axitinib polymorph IV in UV light after the same exposure time and under the same exposure conditions. The term "at least 10%" higher photostable stability means that the total impurities (i.e., mainly dimers) detected in axitinib polymorph IV in implants of the present invention (e.g., dispersed in a PEG hydrogel) are at least 10% less than the amount of impurities (also mainly dimers) detected in powdered axitinib polymorph IV API. The same meaning applies to other percentages indicated herein. In some embodiments, exposure to visible light, as mentioned herein, means exposure to light with wavelengths from 380 nm to 700 nm for, for example, at least one day, or at least two days, for example, at least 500,000 lux-hours / m². 2 For example, at least 1 million lux / m 2 For example, at least 1.2 million lux hours / m 2 In some embodiments, exposure to UV light means exposure to UV A light with a wavelength of 315 nm to 400 nm for, for example, at least 4 hours, at least 8 hours, at least 10 hours, or at least 100 watt-hours / m². 2 or at least 150 watt-hours / m 2 or at least 200 watt-hours / m 2 .

[0267] It has been demonstrated that, under the conditions required for manufacturing the implant containing axitinib polymorph IV of the present invention, axitinib polymorph IV undergoes significant photodegradation (primarily dimerization). Specifically, dimerization is immediately and significantly reduced once axitinib polymorph IV is incorporated into a hydrogel (e.g., a PEG hydrogel). Furthermore, this immediately and significantly further shields the implant and thus the API once the implant is loaded into an injection needle and / or sealed in a foil pouch to protect the API during storage and transportation.

[0268] Not wishing to be limited by this theory, the increased solubility of axitinib polymorph IV, as disclosed herein, can lead to faster release of axitinib from the implants of the present invention compared to comparative implants in which axitinib (e.g., axitinib polymorph SAB-I) present in the implant has lower solubility.

[0269] In some specific embodiments, the implant of the present invention contains an amount of axitinib polymorph IV of 300 µg 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 some other specific embodiments, the implant of the present invention contains an amount of axitinib polymorph IV of about 480 µg to about 750 µg, or about 540 µg to about 660 µg, or about 600 µg.

[0270] In other embodiments, other polymorphic forms of axitinib, which also exhibit solubility higher than 0.3 µg / mL after incubation for 5 days at 37°C in PBS at pH 7.2 to 7.4, can be used in this aspect of the invention.

[0271] With regard to the manufacture of the implants of the present invention (in any aspect thereof), the processes and conditions, as well as the composition / amount of the implant components, are generally independent of the form of the axitinib polymorph used. Therefore, specifically, all amounts and compositions of the TKI or axitinib disclosed herein, as well as all manufacturing steps and conditions, generally apply equally to any of the axitinib polymorphs disclosed herein, specifically axitinib polymorph IV and axitinib polymorphs SAB-I or XLI.

[0272] Axitinib cocrystal used in this invention:

[0273] In certain embodiments of the invention, the implant contains axitinib in the form of an axitinib cocrystal. Specifically, in aspects of the invention where the TKI (e.g., axitinib) has a solubility greater than 0.3 µg / mL (as measured after incubation for 5 days in phosphate-buffered saline (PBS) at pH 7.2 to 7.4 and 37°C), one or more axitinib cocrystals (including those further disclosed herein) may be used in the implants of the invention, provided that they meet this solubility criterion. Alternatively, if the axitinib cocrystal does not meet this solubility criterion, it may still be used in all other aspects of the invention where this solubility criterion need not be met.

[0274] Axitinib cocrystals containing carboxylic acids as co-forming agents are particularly suitable for this invention because carboxylic acids generally increase hydrophilicity and thus increase the solubility of axitinib. In the context of this 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 to C2. 12 Carboxylic acids, such as C2 to C3 10 Carboxylic acids, and specifically C2, C3, C4, C5, C6, C7, C8, C9 or C 10 Carboxylic acids. Carboxylic acids may be saturated or unsaturated. They may contain one or more aryl groups, including heteroaryl groups. Carboxylic acids may or may not contain one or more additional functional groups, specifically functional groups that further increase hydrophilicity or at least do not significantly decrease hydrophilicity. Suitable such groups are, for example, hydroxyl groups. If the carboxylic acid forming a cocrystal with axitinib may have one or more enantiomers or one or more other configurations (e.g., cis / trans), it may exist in the cocrystal in any enantiomer and / or in any configuration. Cocrystals of axitinib are disclosed, for example, in BY Ren et al., Cryst Eng Comm. 2021, 23, 5504-5515.

[0275] Specific examples of carboxylic acids suitable for forming cocrystals with axitinib include one or more of the following: citric acid, fumaric acid, (+)-L-tartaric acid or (-)-D-tartaric acid, glutaric acid, (trans or cis) cinnamic acid, succinic acid, adipic acid, pimelic acid, and salicylic acid. This list is not intended to be limiting, and other carboxylic acids or other compounds mentioned above may be used in this invention to form axitinib cocrystals. In the cocrystal lattice, each molecule of axitinib may also contain more than one molecule of co-forming agent (e.g., carboxylic acid). In this case, the more than one molecule of co-forming agent may be the same co-forming agent, such as the same carboxylic acid, or may be different co-forming agents, such as different carboxylic acids.

[0276] Axitinib cocrystals can be prepared, for example, by crystallizing the cocrystal from a solution or slurry, such as by combining a certain amount of axitinib and a selected co-forming agent in a 1:1 molar ratio, adding a solvent (e.g., acetonitrile), and optionally stirring the resulting slurry at an elevated temperature (e.g., at least 30°C or at least 40°C) for a number of days (e.g., 3 days). The solids can then be separated and analyzed, for example, by filtration or centrifugation. Alternatively, the cocrystal can also be prepared by inoculating the cocrystal (after the cocrystal is desired to be available for the inoculation procedure) in a small amount of solvent and optionally stirring the inoculated mixture at an elevated temperature (again, e.g., at least 30°C or at least 40°C) for several days (e.g., at least 1 day). The solids can then be separated as described above. Examples of the preparation of certain axitinib cocrystals are provided in Example 4, and solubility data are provided in Example 6.

[0277] In some embodiments, the solubility of the axitinib cocrystal may be at least 2 times, at least 5 times, at least 10 times, at least 25 times, at least 50 times, at least 75 times, or at least 100 times the solubility of the free axitinib base.

[0278] In a specific embodiment, the solubility of axitinib cocrystals in PBS at pH 7.4 after 24 hours at 37°C is at least 10 µg / mL, for example at least 12 µg / mL, at least 15 µg / mL, or at least 18 µg / mL. The average solubility of axitinib cocrystals containing citrate in PBS at pH 7.4 after 24 hours at 37°C is about 19 µg / mL; the average solubility of axitinib cocrystals containing fumarate in PBS at pH 7.4 after 24 hours at 37°C is about 12 µg / mL; and the average solubility of axitinib cocrystals containing (+)-L-tartaric acid in PBS at pH 7.4 after 24 hours at 37°C is between about 19 µg / mL and 20 µg / mL.

[0279] Not wishing to be limited by this theory, the increased solubility of the axitinib cocrystal, as disclosed herein, can lead to faster release of axitinib from the implants of the present invention compared to comparative implants in which axitinib (e.g., axitinib free base) present in the implant has lower solubility.

[0280] Axitinib derivatives and prodrugs used in this invention:

[0281] In all aspects of this invention, derivatives or prodrugs of TKIs (e.g., axitinib) can be used in implants. However, in aspects of this invention where the solubility of the TKI is greater than 0.3 µg / mL (as measured after 5 days of incubation in phosphate-buffered saline (PBS) at pH 7.2 to 7.4 and 37°C), a prodrug that increases the solubility of the parent TKI compound is particularly desirable. In embodiments of this invention where the TKI is axitinib, an axitinib prodrug with increased solubility compared to the free base of axitinib is particularly desirable. The axitinib prodrug is converted to axitinib in vivo.

[0282] Increased solubility of axitinib prodrugs can be derivatives of axitinib, wherein one or more atoms or portions of axitinib are replaced by one or more substituents, thereby making the resulting derivative (i.e., the prodrug) more soluble, for example by introducing hydrophilic groups into these substituents. These substituents can be removed enzymatically or chemically by immersion in a physiological environment simulated by in vitro testing, thereby releasing the parent drug molecule. In this invention, particularly suitable examples of axitinib prodrugs are those in which the axitinib molecule is functionalized at one or more nitrogen atoms of the free axitinib base. For example, in the axitinib prodrug used according to the present invention, one or more nitrogen atoms in the axitinib free base may be independently substituted with one or more of the following groups: acyl, alkyl carbonyl, aryl carbonyl, alkyl thiocarbonyl, aryl thiocarbonyl, alkyl carbamoyl, aryl carbamoyl, substituted or unsubstituted acetyl, substituted or unsubstituted aminoalkyl acyl, substituted or unsubstituted α-aminoalkyl acyl, acyl derived from natural or non-natural amino acids with or without substitution, acyl of peptide residues, phosphonyl, oxyphosphonyl, aminooxyphosphonyl, alkylaminooxyphosphonyl, sulfonyl, cycloalkane-carbonyl, heterocycloalkane-carbonyl, alkoxycarbonyl, aryloxycarbonyl, heteroalkoxycarbonyl, heteroaryloxycarbonyl, and O-substituted hydroxymethyl with or without substituents.

[0283] In some embodiments, the axitinib prodrug used in this invention is a compound of general formula (I) illustrated below, or a salt or solvate thereof:

[0284]

[0285] (I)

[0286] in:

[0287] X 1 Selected from N or N + Y 1 ;

[0288] X 2 Selected from NH or NY 2 ;

[0289] X 3 Selected from NH or NY 3 ;

[0290] Y 1 Selected from -CH2OCO(OCH2CH2)n 1 OM 1 ; or -CH2OCO(CH2CH2O)n 1a Z 1 ; or -CH2OCO(CH2)n 1b COOH;

[0291] Y 2 Selected from -CH2OCO(OCH2CH2)n 2 OM 2 ; or -CH2OCO(CH2CH2O)n 2a Z 2 ; or -CH2OCO(CH2)n 2b COOH;

[0292] Y 3 Selected from -CH2OCO(OCH2CH2)n 3 OM 3 ; or -CH2OCO(CH2CH2O)n 3a Z 3 ; or -CH2OCO(CH2)n 3b COOH;

[0293] n 1 n 1a n 1b n 2 n 2a n 2b n 3 n 3a and n 3b Independently, it is either 0 or an integer from 1 to 8;

[0294] M 1 M 2 M 3 Z 1 Z 2 and Z 3 C selected independently from H, optionally substituted 1-6 Alkyl groups and optionally substituted aryl groups;

[0295] Where X 1 X 2 and X 3 At least one of them is not N or NH;

[0296] Where Y 1 Y 2 Or Y 3 At least one of them is the corresponding -CH2OCO(CH2CH2O)nZ.

[0297] In some other embodiments, in the above general formula (I), Y 1 Y 2 and Y 3 Independently selected from the corresponding -(CH2)p 1 OCO(O(CH2)p 2 )n 1 OM; or -(CH2)p1a OCO((CH2)p 2 O)n 1 (CH2)Z; or -(CH2)p 1 OCO(CH2)q 1 COOH; where p 1 p 1a and p 2 Independently selected integers from 1 to 4, and q 1 Integers selected independently from 0 to 4, with other meanings as defined above for equation (I).

[0298] In some embodiments, the following prodrug is applicable to the present invention, wherein in the above formula (I):

[0299] X 1 It is N + Y 1 ;X 2 It is NH; X 3 It is NH; and Y 1 It is -CH2OCO(CH2CH2O)n 1a Z 1 or -CH2OCO(CH2)n 1b COOH, or:

[0300] X 1 It is N; X 2 It's NY 2 ;X 3 It is NH; and Y 2 It is -CH2OCO(CH2CH2O)n 2a Z 2 or -CH2OCO(CH2)n 2b COOH, or:

[0301] X 1 It is N; X 2 It is NH; X 3 It's NY 3 And Y 3 It is -CH2OCO(CH2CH2O)n 3a Z 3 or -CH2OCO(CH2)n 3b COOH.

[0302] In some implementations, in equation (I) above:

[0303] n 1 It is 0, 1, 2, 3, 4, 5, 6, 7 or 8; or 1-3 or 4-6 or 7-8;

[0304] n 2It is 0, 1, 2, 3, 4, 5, 6, 7 or 8; or 1-3 or 4-6 or 7-8;

[0305] n 3 It is 0, 1, 2, 3, 4, 5, 6, 7 or 8; or 1-3 or 4-6 or 7-8;

[0306] n 1a It is 0, 1, 2, 3, 4, 5, 6, 7 or 8; or 1-3 or 4-6 or 7-8;

[0307] n 2a It is 0, 1, 2, 3, 4, 5, 6, 7 or 8; or 1-3 or 4-6 or 7-8;

[0308] n 3a It is 0, 1, 2, 3, 4, 5, 6, 7 or 8; or 1-3 or 4-6 or 7-8;

[0309] n 1b It is 0, 1, 2, 3, 4, 5, 6, 7 or 8; or 1-3 or 4-6 or 7-8;

[0310] n 2b It is 0, 1, 2, 3, 4, 5, 6, 7 or 8; or 1-3 or 4-6 or 7-8;

[0311] n 3b It can be 0, 1, 2, 3, 4, 5, 6, 7 or 8; or 1-3 or 4-6 or 7-8.

[0312] In some implementations, in equation (I) above:

[0313] M 1 It is methyl, ethyl, propyl, or phenyl;

[0314] M 2 It is methyl, ethyl, propyl, or phenyl;

[0315] M 3 It is methyl, ethyl, propyl, or phenyl;

[0316] Z 1 It is methyl, ethyl, propyl, or phenyl;

[0317] Z 2 It is methyl, ethyl, propyl, or phenyl;

[0318] Z 3 It is methyl, ethyl, propyl, or phenyl.

[0319] In some other implementations, n 1 n 2 or n 3 It is 2, 3, or 4, and / or n1a n 2a or n 3a It is 2, 3, or 4, and / or n 1b n 2b or n 3b It is 2, 3, or 4.

[0320] In some specific embodiments, the axitinib prodrug to be used in the implant of the present invention is selected from: axitinib-N-succinyloxymethyl prodrug, axitinib-N-mPEG-oxymethyl prodrug, 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.

[0321] Axitinib prodrugs, particularly those with hydrophilic substituents as disclosed herein, can exhibit higher solubility than the free axitinib base. The solubility of such prodrugs can be at least 2, 5, 10, 25, 50, 75, 100, 150, 200, 250, 500, or 1000 times that of the free axitinib base. Not wishing to be limited by this theory, the increased solubility of the axitinib prodrugs as disclosed herein can lead to faster release of axitinib from the implants of the present invention compared to comparative implants in which the solubility of axitinib (e.g., the free axitinib base) present in the implant is lower than that of the axitinib prodrug.

[0322] The axitinib prodrug used in the implants of the present invention has 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 in PBS at pH 7.4 after 24 hours at 22°C.

[0323] The following are exemplary axitinib prodrugs to be used in the implants of this invention:

[0324]

[0325] Axitinib-N-succinyloxymethyl prodrug (Total Mw: 516.57)

[0326] Solubility after incubation at 22°C in PBS at pH 7.2 to 7.4 for 24 hours: 217.4 µg / mL

[0327]

[0328] Axitinib-Nm(PEG)4-oxymethyl prodrug (Total Mw: 634.74)

[0329] Solubility after incubation at 22°C in PBS at pH 7.2 to 7.4 for 24 hours: 99.37 µg / mL

[0330]

[0331] Axitinib-Nm(PEG)1-oxymethyl prodrug. IUPAC name: 6-(2-methylcarbamoyl-phenylthio)-3-((E)-2-pyridin-2-yl-vinyl)-indazole-1-ylmethyl ester of 3-methoxy-propionic acid (Total Mw: 502.28)

[0332]

[0333] Axitinib-Nm(PEG)2-oxymethyl prodrug. IUPAC name: 6-(2-methylcarbamoyl-phenylthio)-3-((E)-2-pyridin-2-yl-vinyl)-indazole-1-ylmethyl ester of 3-(2-methoxy-ethoxy)-propionic acid (total Mw: 546.63)

[0334]

[0335] Axitinib-Nm(PEG) 3-oxymethyl prodrug. IUPAC name: 6-(2-methylcarbamoyl-phenylthio)-3-((E)-2-pyridin-2-yl-vinyl)-indazole-1-yl methyl 3-[2-(2-methoxy-ethoxy)-ethoxy]-propionic acid (Total Mw: 590.68)

[0336] An exemplary synthesis and solubility of the axitinib prodrug are disclosed in Examples 5.1 and 5.2. The solubility of the axitinib prodrug is presented in Example 6.

[0337] The axitinib prodrug suitable for use in the implants of the present invention, as well as its synthesis and characteristics, are disclosed in co-pending international application PCT / US2023 / 035121 and co-pending international application PCT / US2022 / 046750 (published as WO 2023 / 064578 A1), which are incorporated herein by reference. Other axitinib prodrugs suitable for use in the implants of the present invention are disclosed in US 2021 / 0078970. All axitinib prodrugs (but not limited to these prodrugs) disclosed in any of these references are generally applicable to the present invention.

[0338] solubility

[0339] In some embodiments of the invention, the solubility of the TKI, and specifically the solubility of axitinib, is a factor affecting the release profile of axitinib from the implant of the invention. The solubility of the free base of axitinib, and specifically the polymorph SAB-I, is relatively low in physiological environments or similar aqueous solvent systems (e.g., PBS), which limits the rate of drug release from implants containing hydrogels, where release is driven by solubility and diffusion.

[0340] Therefore, in a particular embodiment, the present invention relates to a sustained-release biodegradable ocular implant comprising a TKI, wherein after incubation for 5 days in phosphate-buffered saline (PBS) at pH 7.2 to 7.4 and 37°C, the solubility of the TKI (e.g., axitinib, including any form of axitinib as disclosed herein) is 0.3 µg / mL or greater than 0.3 µg / mL, 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. As mentioned herein, pH values ​​of 7.2 to 7.4 include individual values ​​of 7.2, 7.3, and 7.4. In a particular embodiment of the invention, wherein the TKI is axitinib, the solubility of axitinib in the sustained-release biodegradable ocular implant of the invention is greater than the solubility 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.

[0341] In a particular embodiment, after incubation for 5 days in PBS at pH 7.2 and 37°C, the solubility of the TKI (e.g., axitinib) in any and all embodiments of the invention to which it is mentioned 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). Therefore, axitinib forms (including axitinib polymorphs, cocrystals, and prodrugs as disclosed herein) that satisfy any of these solubility ranges have higher solubility than the axitinib (free base) polymorph SAB-I, which has solubility of about 0.2 µg / mL and less than 0.3 µg / mL under the same conditions, as in Example 6 (which also contains details of the solubility measurement conditions) and Figure 17 As shown in the figure. Specifically, after 5 days at pH 7.4 and 37°C, the equilibrium solubility of axitinib polymorph SAB-I in PBS was approximately 0.191 to approximately 0.252 µg / mL (measured by UPLC), or an average of approximately 0.223 µg / mL under these conditions, depending on its particle size, i.e., whether it is in a micronized form (or the degree of micronization). For example, after 5 days at pH 7.4 and 37°C, the equilibrium solubility of non-micronized, micronized, and ultramicronized axitinib polymorph SAB-I in PBS were approximately 0.191 µg / mL, approximately 0.226 µg / mL, and approximately 0.252 µg / mL (measured by UPLC), respectively, see Example 6. Polymorph IV is an axitinib polymorph particularly applicable to all aspects of the present invention. Its solubility is approximately twice that of, for example, the polymorph SAB-I, as disclosed herein (see also Example 6 and...). Figure 17 Specifically, after 5 days at pH 7.4 and 37°C, the equilibrium solubility of axitinib polymorph IV in PBS was approximately 0.435 µg / mL (measured by UPLC), for example when in micronized form (as defined herein), see Example 6. Therefore, in some embodiments, the implant of the present invention comprises axitinib polymorph IV. In some embodiments, at least 90% by weight, for example at least 95% by weight, of axitinib in the implant of the present invention is axitinib polymorph IV.

[0342] Not wishing to be limited by this theory, any increase in the solubility of axitinib (e.g., in the form of a specific prodrug, cocrystal, or polymorph as disclosed herein) may result in faster release of axitinib from the implants of the present invention compared to comparative implants in which axitinib (e.g., axitinib free base, e.g., polymorph SAB-I) present in the implant has lower solubility. In in vitro release tests as disclosed herein, this increase in solubility may itself manifest as a higher release rate (daily release of axitinib) over one or more days of an in vitro test, and / or a higher average daily release rate over a number of days (as defined herein), and / or an increase in the cumulative amount of axitinib released over a period of time (e.g., one or more days), and / or an increase in the percentage (in percentage) of the total amount of axitinib contained in the implant released daily or over a period of time (any number of days), and / or an increase in the percentage (in percentage) of the total amount of axitinib released in an in vitro test.

[0343] Therefore, providing an implant containing a TKI with increased solubility constitutes a method (in vivo or in vitro) for increasing the daily release rate and / or the average daily release rate over a period of time, and / or the percentage of TKI released in one or more days, and / or the cumulative percentage of TKI released over a period of time (based on total released TKI), and / or the absolute amount of TKI released in one or more days or over a period of time. Therefore, the present invention also relates to such methods for increasing the release rate and / or average release rate and / or release amount of total TKI contained in an implant, and / or the release share of total TKI contained in the implant, or the total TKI released from the implant over a period of time, compared to known implants containing TKI.

[0344] Dosage

[0345] TKIs are present in the implants of the present invention in a series of doses. The amount of TKI contained in the implant is indicated herein in units of “µg” or “mg”. In the case where the TKI used according to the present invention is axitinib, the amount / dose of axitinib indicated herein refers to the amount of axitinib free base (including any (anhydrous) axitinib polymorphs, such as those further disclosed herein, especially polymorph IV) (expressed in µg or mg, as applicable). In the case of the use of axitinib salts, cocrystals, derivatives, or prodrugs (which have a different molecular weight than the axitinib free base), unless otherwise stated, the indicated amount is the corresponding amount of the axitinib free base.

[0346] TKIs (e.g., axitinib) are typically contained in the implants of the present invention at doses within the following ranges: 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 µg to about 650 µg. Any amount of TKI (e.g., axitinib) within these ranges may be contained in the implants of the present invention. In cases where axitinib is used in a form other than the free base, the implants of the present invention may contain a dose corresponding to the mentioned dose of the free base of axitinib. For the purposes of this disclosure, when referring to the dose of TKI (e.g., axitinib) contained in the implant, all references are intended to include variations of +25% and -20% or + / - 10%.

[0347] In certain specific embodiments, the dose of axitinib contained in the implant of the present invention (the dose is intended to refer to the amount of axitinib free base, or a corresponding amount of another form of axitinib (e.g., axitinib cocrystal or prodrug) corresponding to these listed doses of axitinib free base) is:

[0348] - A range of approximately 120 µg to approximately 187.5 µg, or approximately 135 µg to approximately 165 µg, or approximately 150 µg (i.e., including a variation of +25% and -20% or + / - 10% of 150 µg).

[0349] - A range of approximately 240 µg to approximately 375 µg, or approximately 270 µg to approximately 330 µg, or approximately 300 µg (i.e., including a variation of +25% and -20% or + / - 10% of 300 µg).

[0350] - A range of approximately 360 µg to approximately 562.5 µg, or approximately 400 µg to approximately 500 µg, or approximately 405 µg to approximately 495 µg, or approximately 450 µg (i.e., including a variation of +25% and -20% or + / - 10% of 450 µg).

[0351] - A range of approximately 480 µg to approximately 750 µg, or approximately 540 µg to approximately 660 µg, or approximately 600 µg (i.e., including a variation of +25% and -20% or + / - 10% of 600 µg).

[0352] In one particular embodiment, the dose of axitinib contained in an implant of the present invention is 100 µg to 200 µg, or about 150 µg. In other particular embodiments, the axitinib in such implants is in the form of free axitinib base.

[0353] In one particular embodiment, the dose of axitinib contained in an implant of the present invention is 200 µg to 400 µg, for example 250 µg to 350 µg, or about 300 µg. In other particular embodiments, the axitinib in such implants is in the form of free axitinib base.

[0354] In one particular embodiment, the dose of axitinib contained in an implant of the present invention is 300 µg to 600 µg, for example, about 360 µg to about 562.5 µg, or 400 µg to 500 µg, or about 450 µg. In other particular embodiments, the axitinib in such implants is in the form of free axitinib base.

[0355] In another specific embodiment, the dose of axitinib contained in an implant of the present invention is about 400 µg to 800 µg, about 480 µg to about 750 µg, or 500 µg to 700 µg, or about 600 µg. In other specific embodiments, the axitinib in such implants is in the form of free axitinib base.

[0356] In another specific embodiment, the dose of axitinib contained in an implant of the present invention is about 400 µg to 1000 µg, about 480 µg to about 800 µg, about 480 µg to about 750 µg, or 500 µg to 700 µg, or about 600 µg. In other specific embodiments, the axitinib in such implants is in the form of axitinib free base. In a specific embodiment, the target dose of axitinib (e.g., axitinib polymorph IV) in the implant of the present invention is 600 µg, which means that the actual amount is -20% and +25%, i.e., about 480 µg to about 720 µg.

[0357] In one particular embodiment, the dose of axitinib contained in an implant of the present invention is from 200 µg to 1000 µg.

[0358] In a particular embodiment, the dose of axitinib contained in an implant of the present invention is from about 250 µg to about 750 µg, for example from about 300 µg to about 600 µg, for example from about 350 µg to about 550 µg, for example from about 380 µg to about 520 µg, for example from about 420 µg to about 480 µg, for example from about 400 µg to about 500 µg, for example from about 420 µg to about 480 µg, for example from about 450 µg. In a particular embodiment, the target (also referred to as “marked”) dose of axitinib (e.g., axitinib polymorph IV) in the implant of the present invention is 450 µg, which means that its actual amount is -20% and +25%, i.e., from about 360 µg to about 562.5 µg.

[0359] In the most specific embodiment, the implant of the present invention contains the following doses of axitinib in the form of polymorph IV: about 400 µg to about 500 µg, for example about 405 µg to about 495 µg, for example about 410 µg to about 490 µg, or about 420 µg to about 490 µg, for example about 420 µg to about 480 µg, for example about 430 µg to about 480 µg, for example about 425 µg to about 475 µg, for example about 430 µg to about 470 µg, for example about 440 µg to about 460 µg, for example about 450 µg. In the implant of the present invention with a nominal (i.e., theoretical / labeled) content of 450 µg or about 450 µg of axitinib (specifically, axitinib polymorph IV), the actual (analytical) amount of axitinib contained in the implant may vary within the range limits disclosed in the preceding sentence.

[0360] If axitinib is not in the form of a free base but in the form of, for example, a cocrystal or prodrug, an implant may contain a certain amount of such other forms of axitinib, corresponding to the mentioned dose of the axitinib free base.

[0361] The disclosed amounts (including any variations mentioned) of a TKI (e.g., axitinib) refer to the final amount of the active ingredient in the implant and the amount of the active ingredient used as the starting component for each implant during manufacturing. In some embodiments, the total dose of the TKI (e.g., axitinib) to be administered to a patient may be contained in two or more implants administered simultaneously as further disclosed herein. This dose may also be contained in the implants of the present invention, which are multifilament implants, i.e., composed of several filaments, optionally stretched and twisted to form a strand, as further disclosed herein.

[0362] TKI granules

[0363] TKIs (such as axitinib) are contained in the implants of the present invention and dispersed or distributed in a hydrogel comprising a polymer network as further disclosed herein. In some embodiments, the particles are uniformly or substantially uniformly dispersed in the hydrogel. The hydrogel prevents particle aggregation and provides a matrix for holding the particles in the desired location in the eye while gradually releasing the drug.

[0364] In some embodiments of the invention, TKI particles (e.g., axitinib particles) may be microencapsulated. The term "microcapsule" (also referred to as "microparticle") is sometimes defined as a generally spherical particle with a size varying, for example, from about 50 nm to about 2 mm. Microcapsules have at least one discrete domain (or core) of an active agent encapsulated in a surrounding material (sometimes also called a shell). If desired for the purposes of the invention, an agent suitable for microencapsulating TKIs (e.g., axitinib) (not limited thereto) is poly(lactic acid-co-glycolic acid).

[0365] In other embodiments, the TKI particles contain additional compounds besides the TKI. These compounds may be, for example, processing aids, stabilizers, fillers, etc. Sometimes, the active agent is typically stabilized by the supplier by adding small amounts of, for example, antioxidants or other stabilizers, which may also apply to TKI (e.g., axitinib) particles used herein.

[0366] However, in some embodiments, the TKI particles (e.g., axitinib particles) are not microencapsulated and / or do not contain any additional compounds, but are dispersed in the hydrogel as is (i.e., as accepted from the supplier, i.e., not further mixed with or adjacent to another material or not microencapsulated with another material), and thus dispersed in the implant of the present invention.

[0367] In one embodiment, the TKI particles (e.g., axitinib particles) may be micronized or even nano-sized particles. Micronization refers to the process of reducing the average diameter of particles in a solid material. In another embodiment, the TKI particles (e.g., axitinib particles) may not be micronized. In the field of composite materials, it is known that particle size affects mechanical properties when combined with a matrix, and that smaller particles provide superior reinforcement for a given mass fraction. Therefore, a hydrogel matrix filled with micronized TKI particles can have improved mechanical properties (e.g., brittleness, fracture strain, etc.) compared to larger TKI particles of similar mass fraction. Such properties are crucial in manufacturing, during implantation, and during implant degradation. Micronization can also promote a more uniform distribution of the active ingredient in the selected dosage form or matrix. Particle size distribution can typically be measured using methods known in this art, including sieving, laser diffraction, or dynamic light scattering.

[0368] Not wishing to be limited by theory, the particle size of TKI particles may affect the release kinetics of TKI from the implant of the present invention. Smaller diameter particles may, in some cases, exhibit particularly high dissolution and erosion rates, which can increase the rate of release from the implant and thus increase the bioavailability of TKI in the desired tissue. Additionally, smaller particles (e.g., micronized particles) may have a reduced tendency to aggregate during manufacturing and processing operations, which may, in some cases, result in a more uniform distribution of TKI particles within the hydrogel. Furthermore, again not wishing to be limited by theory, smaller particles may, in some cases, have a lower tendency to aggregate and may also be cleared from the vitreous more rapidly when TKI particles are still residing in the eye, for example, when the hydrogel has completely dissolved before the entire TKI drug load has been released from the implant. This can be advantageous for repeated administration, for example, by preventing the accumulation of unremoved TKI particles in the vitreous over time.

[0369] In some embodiments, TKI (e.g., axitinib) particles have a d90 particle size 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, as determined by laser diffraction.

[0370] In some embodiments, the TKI (e.g., axitinib) particles have a d50 particle size 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 a specific embodiment, the d50 particle size of the TKI particles (e.g., axitinib particles) contained 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 “nanoscaled particles”.

[0371] In some embodiments, the TKI (e.g., axitinib) particles have a d10 particle size of less than 1 µm, or less than 0.5 µm, or 0.25 µm or less, or 0.2 µm or less, or less than 0.1 µm, as determined by laser diffraction.

[0372] In a specific embodiment, the TKI present in the implant of the present invention is axitinib free base (as in any polymorphic form disclosed herein), wherein the axitinib particles have a d10 particle size of less than 8 µm, a d50 particle size of less than 20 µm, and / or a d90 particle size of less than 50 µm. These particles may sometimes be referred to herein as “non-micronized particles”.

[0373] In other specific embodiments, the TKI present in the implant of the present invention is axitinib free base (as in any polymorph form disclosed herein, including axitinib polymorph IV), wherein the axitinib particles have a d10 particle size of less than 0.25 µm, a d50 particle size of less than 3 µm or less than 2.6 µm, and a d90 particle size of less than 8 µm or less than 6.5 µm. These particles may also be referred to herein as “micronized particles.” In a particular embodiment, the axitinib contained in the implant of the present invention, specifically axitinib polymorph IV, has the following particle sizes: a d10 particle size of less than 0.25 µm, a d50 particle size of less than 2.6 µm, and a d90 particle size of less than 8 µm, as determined by laser diffraction.

[0374] In other specific embodiments, the TKI present in the implant of the present invention is axitinib free base (as in any polymorphic form disclosed herein), wherein the axitinib particles have a d10 particle size of less than 0.2 µm, a d50 particle size of less than 1.5 µm, and a d90 particle size of less than 5 µm, as determined by laser diffraction. These particles may also be referred to herein as “ultrafine pulverized particles”.

[0375] In other specific embodiments, the TKI present in the implant of the present invention is axitinib free base (as in any polymorph form disclosed herein, particularly including polymorph IV), wherein the axitinib particles have a d10 particle size of less than 0.1 µm, a d50 particle size of less than 0.2 µm, and a d90 particle size of less than 0.4 µm, as determined by laser diffraction. These particles may also be referred to herein as “nanoscaled particles”.

[0376] Typically, micronized TKI (e.g., axitinib) particles can be purchased from the supplier according to the instructions, or can be prepared, for example, according to the exemplary procedure for axitinib disclosed in Example 13 of WO 2016 / 183296 A1: 1800 mL of sterile water for injection (WFI) is measured into a 2 L beaker and placed on a stirring plate with a stir bar at 600 RPM to create a large WFI vortex at the center of the beaker. A 60 mL BD syringe containing axitinib in ethanol is placed on an infusion pump clamped above the WFI beaker. A hypodermic needle (21G, BD) is attached to the syringe and aimed directly at the center of the vortex to dispense the axitinib solution. The infusion pump is then run at 7.5 mL / min to add the axitinib solution dropwise to the WFI to precipitate the micronized axitinib. After micronization, the axitinib is filtered, for example, through a 0.2 µm vacuum filter and rinsed with WFI. After filtration, the axitinib powder is collected from the filter, for example, by using a scraper, and vacuum dried for an extended period, such as about 12 hours or about 24 hours, to remove excess solvent. Another illustrative method for micronizing axitinib is disclosed in Example 9 of WO2017 / 091749. The micronization method is not limiting, and other methods for micronizing active agents (e.g., axitinib) can also be used. The disclosed micronization method (or other methods) can also be used for TKIs other than axitinib.

[0377] Polymer network:

[0378] The sustained-release biodegradable ocular implant of the present invention comprises a hydrogel and TKI particles dispersed within the hydrogel. The hydrogel provides a stable release of the active agent embedded within it over time. In some embodiments, this is achieved by a single material forming the hydrogel (e.g., by forming the hydrogel from a PEG precursor of the present invention as further disclosed herein). Not wishing to be limited by theory, this stable release is achieved particularly by the fact that the release rate of the active agent from the hydrogel is controlled by dissolution (rather than by erosion or degradation / channel formation as in other matrix materials (e.g., PLGA)) and that release occurs in all directions. Typically, the hydrogel is inert because it does not interact or react with its surrounding physiological environment and has good biocompatibility because it substantially does not alter, or at least does not significantly alter, the local pH in the physiological environment (e.g., the eye). Additionally, the hydrogel has low stiffness and high flexibility, which provides high compliance with the physical environment (e.g., body tissues) when inserted into the human or animal body. In the context of this application, this is particularly advantageous when the implant of the present invention is injected / inserted into vitreous fluid, the implant comprising a hydrogel, such as a PEG hydrogel, in which TKI particles are dispersed. Typically, the softness of the hydrogel forming the implant of the present invention greatly reduces the likelihood of irritation (including foreign body sensation) or damage to ocular tissues (e.g., the retina).

[0379] One way to assess the toughness or softness of the implant of the present invention is, for example, by measuring its elastic modulus.

[0380] In some embodiments, the hydrogel may be formed from a precursor having functional groups that form crosslinks to create a polymer network. These crosslinks between polymer chains or arms may be chemical crosslinks (i.e., covalent bonds) and / or physical crosslinks (e.g., ionic bonds, hydrophobic associations, hydrogen bridges, etc.).

[0381] The polymer network can be prepared from any precursor capable of forming a hydrogel polymer network, from one type of precursor, or from two or more types of precursors that allow the reaction. The precursor is selected with consideration of the desired properties of the resulting hydrogel. Various precursors suitable for manufacturing hydrogels exist. Generally, for the purposes of this invention, any pharmaceutically acceptable and crosslinkable polymer that forms the hydrogel can be used. The polymer forming the hydrogel can be a homopolymer or a copolymer. The copolymer can be a random or block copolymer. The hydrogel and therefore the components incorporated therein (including the polymer used to manufacture the polymer network) should be physiologically safe so that they do not induce, for example, immune responses or other side effects. The hydrogel can be formed from natural, synthetic, or biosynthetic polymers.

[0382] Natural polymers may include glycosaminoglycans, polysaccharides (such as polydextrose), polyamino acids and proteins, or mixtures or combinations thereof.

[0383] Synthetic polymers can generally be any polymer synthesized from a variety of raw materials through different types of polymerization, including free radical polymerization, anionic or cationic polymerization, chain growth or addition polymerization, condensation polymerization, ring-opening polymerization, etc. The polymerization may be initiated by certain initiators, by light and / or heat, and may be mediated by catalysts. In some embodiments, synthetic polymers can be used to reduce the likelihood of allergies in implants that do not contain any components of human or animal origin.

[0384] Generally, for the purposes of this invention, one or more synthetic polymers listed below (which are not intended to be limiting) can be used to form the hydrogels of this invention: one or more (identical or different) polyalkylene glycol units (e.g., polyethylene glycol (PEG), polypropylene glycol, poly(ethylene glycol)-block-poly(propylene glycol) copolymers), polyethyleneimine, polyalkyl ethers (e.g., polyethylene oxide, polypropylene oxide), polyacrylic acid, acrylate polymers, poly(electrolyte complexes), starch-grafted polymers, polymaleic acid, polyethyleneamine, polyacrylamide, poly(hydroxyethyl methacrylate) (PHEMA), polybutylene terephthalate (PBT), polyvinyl alcohol, poly(vinyl acetate), poly(vinylpyrrolidone), poly(vinylpyrrolidone) (PVP), polyglycolic acid, polylactic acid (PLA), polylactic-co-glycolic acid (PLGA), water-swellable N-vinyl lactam, ester-crosslinked polyglucan, polydioxanone, and polytrimethylene carbonate. These polymers may be used alone or in combination as appropriate to form hydrogels. Any polymer that can form a hydrogel and is biocompatible can be used in the implants of this invention.

[0385] The polymers that form hydrogels can be in the form of homopolymers or copolymers (e.g., random or block copolymers). Any combination / mixture of any of the monomers mentioned can be used to form hydrogels. Since the above list is not intended to be limiting, other polymers / polymer combinations not specifically listed but capable of forming hydrogels can also be used.

[0386] In this invention, PEG polymers are particularly suitable for forming hydrogels for the implants of this invention, as further disclosed below. Therefore, in some embodiments of this invention, the hydrogel comprises a network formed by crosslinking PEG units (i.e., a PEG hydrogel). Specific PEG units that can be crosslinked to form the hydrogels of this invention are disclosed herein. However, other hydrogels formed from polymer networks other than PEG provide properties equivalent to or similar to those of PEG hydrogels as disclosed herein, and such other hydrogels are also suitable for the implants of this invention.

[0387] To form a covalently cross-linked polymer network, precursors can be covalently cross-linked with each other. In some embodiments, a precursor having at least two reaction centers (e.g., in free radical polymerization) can act as a cross-linking agent because each reactive group can participate in the formation of different growing polymer chains.

[0388] The precursor may have a bioinert and hydrophilic portion, such as a core. In the case of branched polymers, the core refers to a continuous portion of the molecule connected to an arm extending from the core, wherein the arm carries a functional group, which is typically located at the end of the arm or branch. Multi-armed PEG precursors are examples of such precursors and are further disclosed below.

[0389] The precursor may have functional groups as further disclosed herein, which are reactive with each other, i.e., a first functional group is capable of reacting with a second functional group. The functional groups may react with each other, for example, in an electrophile-nucleophile reaction, or be configured to participate in other polymerization reactions. Nucleophiles that can be used in this invention may comprise amines, such as primary amines, hydroxyl groups, thiols, carboxyl groups, dibenzocyclooctylenes, or hydrazides. Electrophiles that can be used in this invention may comprise succinimide esters, succinimide carbonates, nitrophenyl carbonates, aldehydes, ketones, acrylates, acrylamides, maleimides, vinyl sulfones, iodoacetamides, alkenes, alkynes, azides, norbornenes, epoxides, methanesulfonates, toluenesulfonates, trifluoroethanesulfonyl chlorides, cyanurates, o-dithiopyridines, or halides. Precursors containing both electrophilic and nucleophilic groups suitable for forming polymer networks are further disclosed herein.

[0390] Besides classic electrophile-nucleophile condensation reactions, other types of chemical reactions based on electrophiles and nucleophiles can also be used in this invention. For example, precursors can be crosslinked via so-called click chemistry reactions. Functional groups suitable for click chemistry are those that can undergo click chemical reactions (e.g., strain-promoted alkyne-azide cycloaddition (SPAAC), also known as Cu-free click reactions, or inverse electron demand Diels-Alderligation (IEDDA) type click chemical coupling reactions). An overview of such reactions is given in HC Kolb; MG Finn; KB Sharpless (2001). “Click Chemistry: Diverse Chemical Function from a Few Good Reactions”, Angewandte Chemie International Edition, 40 (11): 2004-2021, which is incorporated herein by reference. The SPAAC and IEDDA coupling reactions are bioorthogonal reactions with selectivity and quantitative yields under mild conditions, which can even occur within living systems without interfering with natural biochemical processes. These click chemistry reactions utilize a pair of functional groups that react only and efficiently with each other, while remaining inert to the native functional groups. Suitable functional groups include moieties selected from the group consisting of: alkynes, cycloalkynes (e.g., dibenzocyclooctyne (DBCO) or bicyclic [6.1.0]-nonyne (BCN)), strained or terminal alkenes (e.g., norbornene or trans-cyclooctylene (TCO)), azides, or tetrazines (Tz).

[0391] The hydrogel used in this invention can be manufactured, for example, from a multi-armed precursor having a first set of functional groups and another multi-armed precursor having a second set of functional groups. For example, the multi-armed precursor may have hydrophilic arms capped with a primary amine (nucleophile), such as polyethylene glycol units, or may have activated ester end groups (electrophiles). The polymer network of this invention may contain the same or different polymer units crosslinked together.

[0392] Certain functional groups can be made more reactive by using activating groups. Such activating groups include (but are not limited to) carbonyl diimidazoles, sulfonyl chlorides, aryl halides, sulfosuccinimides, N-hydroxysuccinimides, succinimides, epoxides, aldehydes, maleimides, imide esters, acrylates, and the like. N-hydroxysuccinimides (NHS) are groups that can be used to crosslink nucleophilic polymers (e.g., primary amine-terminated or thiol-terminated polyethylene glycol). NHS-amine crosslinking reactions can be carried out in aqueous solutions and in the presence of buffers (e.g., phosphate buffers (pH 5.0–7.5), triethanolamine buffers (pH 7.5–9.0), borate buffers (pH 9.0–12), or sodium bicarbonate buffers (pH 9.0–10.0)).

[0393] In some embodiments, each precursor may contain only nucleophilic functional groups or only electrophilic functional groups, provided that both nucleophilic and electrophilic precursors are used in the crosslinking reaction. Thus, for example, if the crosslinking agent has only nucleophilic functional groups (e.g., amines), the precursor polymer may have electrophilic functional groups (e.g., N-hydroxysuccinimide). On the other hand, if the crosslinking agent has electrophilic functional groups (e.g., sulfosuccinimide), the functional polymer may have nucleophilic functional groups (e.g., amines or thiols). Therefore, functional polymers (e.g., proteins, poly(allylamine), or amine-terminated difunctional or polyfunctional poly(ethylene glycol)) can also be used to prepare the polymer networks of the present invention.

[0394] In one embodiment, each of the first reactive precursors has about 2 to about 16 nucleophilic functional groups (referred to as functionality), and the second reactive precursor is permitted to react with the first reactive precursor to form a polymer network each having about 2 to about 16 electrophilic functional groups. Reactive precursors having multiple reactive (nucleophilic or electrophilic) groups in multiples of 4, and thus, for example, 4, 8, and 16 reactive groups, are particularly suitable for the present invention. Any number of functional groups (e.g., including any of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 groups) is possible for precursors used according to the present invention, while ensuring sufficient functionality to form a sufficiently cross-linked network. It is particularly suitable if the molar ratio of nucleophiles in one precursor to electrophiles in the second precursor is approximately equal.

[0395] PEG hydrogel:

[0396] In some embodiments of the invention, the polymer network forming the hydrogel contains polyethylene glycol (PEG) units. PEG is known in this art to form hydrogels upon crosslinking, and these PEG hydrogels are generally biocompatible and therefore suitable for pharmaceutical applications, such as as a matrix for drugs intended to be applied to all parts of the human or animal body.

[0397] PEG hydrogels are particularly suitable for forming implants inserted into ocular tissues (e.g., vitreous fluid). They are soft and gentle on ocular tissues and thus reduce the likelihood of local irritation, discomfort (e.g., foreign body sensation), or damage to ocular tissues (e.g., the retina). Additionally, PEG hydrogels provide stable release of TKIs (e.g., axitinib) into and from the vitreous fluid to ocular tissues such as the retina and choroid / RPE. The release of TKIs (e.g., axitinib) from the PEG hydrogel is substantially diffusion-controlled. Upon final biodegradation of the hydrogel (as further described herein), the remaining TKI (e.g., axitinib) is released into the vitreous fluid, dissolves there, and is further delivered to ocular tissues to bridge the window until a new implant is administered. Implants of the present invention comprising the PEG hydrogel as described herein and axitinib (e.g., axitinib polymorph IV, also as further described herein) are re-administerable. In some embodiments, the re-administration period in human patients is from about 6 months to about 12 months, for example, about 9 months.

[0398] The polymer network of the hydrogel implant of the present invention may comprise one or more (i.e., the same or different) multi-arm PEG units. It may have 2 to 10 arms, or 4 to 8 arms, or 4, 5, 6, 7, or 8 arms. PEG units may have different or the same number of arms. Any combination of multi-arm PEG precursors is possible. In some embodiments, the PEG units used in the hydrogel of the present invention have 4 and / or 8 arms. In certain specific embodiments, a combination of 4-arm and 8-arm PEG units is used.

[0399] The number of arms of the PEG used helps control the flexibility or suppleness of the resulting hydrogel. For example, a hydrogel formed by crosslinking a 4-arm PEG is generally softer and more flexible than a hydrogel formed by an 8-arm PEG of the same molecular weight. Specifically, if it is desired to stretch the hydrogel before or after drying, as disclosed below in the section on manufacturing implants, a more flexible hydrogel (e.g., a 4-arm PEG) can be used, optionally in combination with another multi-arm PEG (e.g., an 8-arm PEG as disclosed above).

[0400] In some embodiments of the invention, the average molecular weight of the polyethylene glycol unit used as a precursor is in the range of about 2,000 Daltons to about 100,000 Daltons, or in the range of about 5,000 Daltons to about 60,000 Daltons, or in the range of about 10,000 Daltons to about 60,000 Daltons, or in the range of about 10,000 Daltons to about 50,000 Daltons. In some specific embodiments, the average molecular weight of the polyethylene glycol unit is in the range of about 10,000 Daltons to about 40,000 Daltons, or about 15,000 Daltons to about 40,000 Daltons, or about 15,000 Daltons to about 30,000 Daltons, or about 15,000 Daltons or about 20,000 Daltons. PEG precursors with the same average molecular weight can be used, or PEG precursors with different average molecular weights can be combined with each other. Similarly, any combination of PEG precursors having any molecular weight as disclosed herein is possible. The average molecular weight of the PEG precursors used in this invention is given as number average molecular weight (Mn), which can be determined by MALDI in some embodiments.

[0401] In a 4-arm PEG, each arm may have an average arm length (or molecular weight) of the total molecular weight of PEG divided by 4. Therefore, a 4a20k PEG precursor (which is a specific precursor that can be used in this invention) has four arms, each with an average molecular weight of about 5,000 Daltons. Similarly, an 8a20k PEG precursor (e.g., alone or in combination with the 4a20k PEG precursor of this invention) can also be used in this invention with eight arms, each with an average molecular weight of about 2,500 Daltons. Likewise, an 8a15k PEG precursor (e.g., alone or in combination with 4a20k PEG and / or 8a20k PEG precursors) can also be used in this invention with eight arms, each with an average molecular weight of about 1,875 Daltons.

[0402] Longer arms provide increased flexibility compared to shorter arms. PEG with longer arms may swell more than PEG with shorter arms. PEG with fewer arms may also swell more and be more flexible than PEG with a higher number of arms. In certain specific embodiments, combinations of PEG precursors with different numbers of arms (e.g., a combination of a 4-arm PEG precursor and an 8-arm precursor) can be used in this invention. Additionally, longer PEG arms have a higher melting temperature upon drying, which provides greater dimensional stability during storage.

[0403] When referring to a PEG precursor having a certain average molecular weight (e.g., a 15k PEG precursor or a 20k PEG precursor), the indicated average molecular weight (i.e., Mn of 15,000 or 20,000 respectively) refers to the PEG portion of the precursor before the addition of end groups (“20k” here means 20,000 Daltons, and “15k” means 15,000 Daltons; the same abbreviation is used herein for other average molecular weights of PEG precursors). In some embodiments, the average molecular weight of the PEG precursor used in this invention is given as a number average molecular weight (Mn), which in some embodiments can be determined by MALDI. The degree of substitution with end groups as disclosed herein can be determined after end group functionalization by... 1 Measured by H-NMR.

[0404] In some embodiments, the electrophilic end group used with the PEG precursor to prepare the hydrogel of the present invention is an N-hydroxysuccinimide (NHS) ester, including (but not limited to) one or more of the following: succinimide azelaate (SAZ) group, succinimide adipate (SAP) group, succinimide glutarate (SG) group, succinimide glutaramide (SGA) group, succinimide carbonate (SC) group, or succinimide succinate (SS) group, especially the succinimide azelaate (SAZ) group. For example, PEG precursors having different groups among these groups, such as SAZ and SG, can be combined.

[0405] In some embodiments, the nucleophilic end group used to react with an electrophilic PEG precursor to prepare the hydrogel of the present invention is a crosslinking agent containing an amine (denoted as "NH2") end group. Thiol (-SH) end groups or other nucleophilic end groups are also possible. In some embodiments, the nucleophilic crosslinking agent may be an amine, a multi-arm amine, or a salt of any of these amines, or may be an amine-substituted PEG. In a specific embodiment, the nucleophilic crosslinking agent is trilysine or a salt or derivative thereof, such as trilysine acetate (TLA). In other specific embodiments, the nucleophilic agent is an amino-containing multi-arm PEG precursor, such as 8a20kPEG-NH2, or a similar type of amino-containing precursor with different arm numbers and / or different molecular weights.

[0406] In some preferred embodiments, a 4-arm PEG having an average molecular weight of about 20,000 Daltons and an electrophilic end group (e.g., an N-hydroxysuccinimide (NHS) ester end group) as disclosed above, and an 8-arm PEG having an average molecular weight of about 20,000 Daltons and a nucleophilic end group (e.g., an amine (-NH2) end group) as disclosed above, are crosslinked to form a polymer network, and thus form the hydrogel of the present invention.

[0407] The reaction of PEG units containing nucleophilic groups and PEG units containing electrophilic groups (e.g., PEG units with amine-terminated groups and PEG units with activated ester groups) produces multiple PEG units crosslinked through hydrolyzable linkers having the following formula:

[0408]

[0409] Where m is an integer from 0 to 10, and specifically 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In a particular embodiment, m is 6, for example, in the case of using PEG with SAZ end groups. For SAP end groups, m will be 3, for SG end groups, m will be 2, and for SS end groups, m will be 1. All crosslinks within the polymer network may be the same or different. Any combination of crosslinks in the polymer network is possible.

[0410] The same hydrolyzable linker with the same meaning as m is also produced by the reaction of PEG units containing activated ester groups and polyamines (such as trilysine or trilysine acetate) as nucleophilic crosslinking agents.

[0411] In some preferred embodiments, the SAZ end group of the PEG precursor is used in this invention. This end group provides increased durability of the hydrogel in the eye. Implants of certain embodiments of this invention comprising hydrogels containing PEG-SAZ units biodegrade in the eye (e.g., in the vitreous fluid of the human eye) over extended periods (e.g., from about 6 months to about 12 months, as further disclosed below), and in some cases may persist for even longer. The SAZ group is more hydrophobic than, for example, SAP, SG, or SS end groups because of the higher number of carbon atoms in the chain (m is 6, and the total number of carbon atoms between the amide and ester groups is 7), which makes this linker group less susceptible to ester degradation in aqueous (e.g., physiological) environments compared to other shorter linker groups.

[0412] In certain embodiments, a 4-arm 20,000 Dalton PEG precursor is combined with an 8-arm 20,000 Dalton PEG precursor, for example, a 4-arm 20,000 Dalton PEG precursor having a SAZ group (as disclosed above) is combined with an 8-arm 20,000 Dalton PEG precursor having an amino group (as disclosed above). These precursors are also abbreviated herein as 4a20kPEG-SAZ and 8a20kPEG-NH2, respectively. Therefore, in certain embodiments, the polymer network of the present invention is a PEG hydrogel network formed by crosslinking 4a20kPEG-SAZ and 8a20kPEG-NH2. The chemical structure of 4a20kPEG-SAZ is:

[0413]

[0414] Where R represents the neopentyl tetrol core structure. The chemical structure of 8a20kPEG-NH2 (with a hexaglycerol core) is:

[0415]

[0416] In the above formula, n is determined based on the molecular weight of the corresponding PEG arm.

[0417] Another possible PEG precursor with an electrophilic group is the 4a20kPEG-SG precursor. The schematic chemical structure of 4a20kPEG-SG is reproduced below:

[0418]

[0419] In the above formula, n is determined based on the molecular weight of the corresponding PEG arm.

[0420] In certain embodiments, the crosslinking agent used (also referred to herein as a "crosslinking agent") is a low molecular weight component containing a nucleophilic terminal group (e.g., an amine or thiol terminal group). In some embodiments, the nucleophilic crosslinking agent is a small molecular weight amine with a molecular weight of less than 1,000 Da. In some embodiments, the nucleophilic crosslinking agent comprises two, three, or more aliphatic primary amine groups. Crosslinking agents suitable for use in this invention are (but not limited to) spermine, spermidine, lysine, dilysine, trilysine, tetralysine, polylysine, ethylenediamine, polyethyleneimine, 1,3-diaminopropane, 1,3-diaminopropane, diethylenetriamine, trimethylhexamethylenediamine, 1,1,1-tris(aminoethyl)ethane, pharmaceutically acceptable salts, hydrates, or other solvates thereof, and derivatives thereof (e.g., conjugates, provided that a sufficient nucleophilic group is present for crosslinking) and any mixture thereof. Specific crosslinking agents used in this invention are lysine-based crosslinking agents, such as trilysine or trilysine salts or derivatives. In a specific embodiment of the invention, the nucleophilic crosslinking agent used with the electrophilic PEG precursor is trilysine or trilysine acetate (TLA). Other low molecular weight multiarm amines may also be used. The chemical structure of trilysine is as follows:

[0421]

[0422] In some embodiments, the molar ratio of nucleophilic to electrophilic end groups reacting with each other is approximately 1:1, meaning each SAZ group provides one amino group. In the case of 4a20kPEG-SAZ and 8a20kPEG-NH2, this results in a weight ratio of approximately 2:1, because the 8-arm PEG contains twice the number of end groups as the 4-arm PEG. However, excess electrophilic (e.g., NHS end groups, e.g., SAZ) or nucleophilic (e.g., amine) end groups can be used. Specifically, excess precursors containing nucleophilic (e.g., amine) end groups can be used, meaning the weight ratio of 4a20kPEG-SAZ to 8a20kPEG-NH2 can also be less than 2:1.

[0423] The implants of the present invention can be prepared using each and any combination of the electrophilic and nucleophilic PEG precursors disclosed herein. For example, any 4-arm or 8-arm PEG-NHS precursor (e.g., having SAZ, SAP, SG, or SS end groups) can be combined with any 4-arm or 8-arm PEG-NH2 precursor (or any other PEG precursor having a nucleophilic group). Furthermore, the PEG units of the electrophilic and nucleophilic precursors may have the same average molecular weight or may have different average molecular weights.

[0424] Additional ingredients:

[0425] In addition to the polymer units and active ingredients that form the polymer network as disclosed above, the implants of the present invention may contain other additional components. Such additional components are, for example, salts derived from buffers (e.g., phosphates, borates, bicarbonates, or other buffers such as triethanolamine) used during the preparation of the hydrogel. In some embodiments of the invention, sodium phosphate buffers (specifically, sodium dihydrogen phosphate and disodium hydrogen phosphate) and / or sodium borate buffers are used. Other buffers known in the art, besides or in lieu of sodium phosphate and / or sodium borate buffers, can generally be used to provide a pH of about 6.5 to about 8.5 (i.e., about neutral). The above applies to the final combined solution of precursors containing electrophilic groups and precursors containing nucleophilic groups, such as a combined solution of 4a20kPEG-SAZ and 8a20kPEG-NH2 in a buffer. Individual precursor solutions may have different pH values ​​from each other. For example, precursors containing electrophilic groups (e.g., 4a20kPEG-SAZ) may be provided in solutions buffered to pH from about 3.5 to about 5.5, and precursors containing nucleophilic groups (e.g., 8a20kPEG-NH2) may be provided in solutions buffered to pH from about 6.5 to about 8.

[0426] In specific embodiments, the implants of the present invention are free of antimicrobial preservatives or at least free of substantial amounts of antimicrobial preservatives (including, but not limited to, benzalkonium chloride (BAK), chlorobutanol, sodium perborate, and stable oxychloride complex (SOC)).

[0427] In another specific embodiment, the implant of the present invention contains no animal or human-derived components, but only synthetic components.

[0428] If in-situ gelation is desired in an embodiment of the invention, possible additional components may be other agents used during the manufacture of the hydrogel, such as (but not limited to) viscosity-influencing agents (e.g., hyaluronic acid, etc.), surfactants, etc.

[0429] In some embodiments, the implant of the present invention may contain a visualization agent. In other embodiments, the implant of the present invention does not contain a visualization agent. The implant of the present invention, when residing in a patient's eye, can be visualized by imaging techniques (e.g., slit-lamp (biological microscope)), which may be performed, for example, by an ophthalmologist. Another technique for visualizing implants in the eye is cSLO (confocal scanning laser ophthalmoscopy, sometimes also called IR or OCT). Neither of these techniques requires a visualization agent, such as a fluorescent agent.

[0430] However, in the context of this invention, when using a visualization agent, any agent that can be conjugated to or embedded within a hydrogel component, and any agent that is visible or becomes visible upon exposure to light, for example, a certain wavelength, or any agent that is a contrast agent, can be used. Visualization agents suitable for this invention are (but not limited to) fluorophores. Suitable visualization agents for this invention are (but not limited to) fluorescein, rhodamine, coumarin, anthocyanins, europium chelate complexes, dipyrrole methylene boron, benzofuran, dansyl sulfonyl, bimane, acridine, triazapentaene, pyrene, and their derivatives. In some embodiments, the visualization agent is a fluorophore (e.g., fluorescein) or contains a fluorescein moiety. Visualization of fluorescein-containing implants is made possible by illumination with blue light and yellow filters. Fluorescein emits light when excited with blue light, thereby enabling confirmation of the implant's presence.

[0431] In some embodiments, the crosslinking agent containing a nucleophilic group may be bound to or conjugated with the visualization agent, for example via some nucleophilic groups of the crosslinking agent. Since crosslinking requires a sufficient amount of nucleophilic group, "conjugated" or "conjugated" typically includes partial conjugation, meaning that only a portion of the nucleophilic group is used to conjugate with the visualization agent, for example, about 1% to about 20%, or about 5% to about 10%, or about 8% of the nucleophilic group of the crosslinking agent may be conjugated with the visualization agent. In other embodiments, the visualization agent may also be conjugated with a polymer precursor, for example via some reactive (e.g., electrophilic) groups of the polymer precursor.

[0432] preparation:

[0433] In some embodiments, the implant of the present invention comprises a TKI, a polymer network in the form of a hydrogel made of one or more polymer precursors as disclosed above, and additional components such as salts (e.g., phosphates as buffers) optionally retained in the implant from the manufacturing process. In a particular embodiment, the TKI is axitinib. In a particular specific embodiment, axitinib is axitinib free base. In other particular specific embodiments, axitinib is axitinib polymorph IV.

[0434] The implant of the present invention may have the following composition (dry basis; in % w / w): about 10 wt% to about 80 wt%, or about 20 wt% to about 70 wt% of a TKI (e.g., axitinib), and about 10 wt% to about 80 wt%, or about 20 wt% to about 70 wt% of a polymer unit, such as a PEG unit.

[0435] In some embodiments, the implant of the present invention may have the following composition (dry basis; % w / w): about 10 wt% to about 40 wt%, or about 15 wt% to about 25 wt% of axitinib, and about 55 wt% to about 75 wt%, or about 60 wt% to about 70 wt% of PEG units. In some specific embodiments, the implant may have the following composition (wet basis; % w / w): about 1 wt% to about 8 wt%, or about 2 wt% to about 7 wt% of axitinib, and about 5 wt% to about 15 wt%, or about 6 wt% to about 10 wt% of PEG units. These compositions are particularly suitable for the implant of the present invention, which contains axitinib (i.e., in any polymorph form (e.g., polymorph IV) or in the form of, for example, cocrystals or prodrugs) corresponding to an amount of axitinib free base of 100 µg to 200 µg, or about 120 µg to about 187.5 µg, or about 150 µg of axitinib free base.

[0436] In some other embodiments, the implant of the present invention may have the following composition (dry basis; % w / w): about 30 wt% to about 50 wt%, or about 40 wt% to about 57 wt% of axitinib, and about 25 wt% to about 50 wt%, or about 35 wt% to about 45 wt% of PEG units. In some specific embodiments, the implant may have the following composition (wet basis; % w / w): about 4 wt% to about 14 wt%, or about 7 wt% to about 12 wt% of axitinib, and about 5 wt% to about 15 wt%, or about 6 wt% to about 10 wt% of PEG units. These compositions are particularly suitable for the implant of the present invention, which contains axitinib (i.e., in any polymorph form (e.g., polymorph IV) or in the form of, for example, cocrystals or prodrugs) corresponding to an amount of axitinib free base of 200 µg to 400 µg, or about 240 µg to about 375 µg, or about 300 µg.

[0437] In some other embodiments, the implant of the present invention may have the following composition (dry basis; % w / w): about 30 wt% to about 70 wt%, for example about 40 wt% to about 70 wt%, or about 45 wt% to about 65 wt%, or about 50 wt% to about 60 wt%, or about 60 wt% to 70 wt% of axitinib (e.g., axitinib polymorph IV), and about 20 wt% to about 50 wt%, or about 25 wt% to about 45 wt%, or about 30 wt% to about 43 wt%, or about 33 wt% to about 43 wt% of PEG units, or about 25 wt% to about 35 wt% of PEG units. In a particular embodiment, the implant of the present invention comprising about 400 µg to about 500 µg of axitinib in the form of axitinib polymorph IV may have the following composition (dry basis; % w / w): about 60 wt% to about 70 wt% of axitinib and about 25 wt% to about 35 wt% of PEG units.

[0438] In some specific embodiments, the implant may have the following composition (wet basis; % w / w): about 5 wt% to about 20 wt%, or about 6 wt% to about 12 wt%, or about 6 wt% to about 15 wt%, or about 8 wt% to about 10 wt%, or about 5 wt% to 17 wt% of axitinib, and about 4 wt% to about 12 wt%, or about 5 wt% to about 10 wt%, or about 6 wt% to about 8 wt% of PEG units. In a particular embodiment, the implant of the present invention may have the following composition (dry basis; % w / w): about 30% to about 70% of axitinib and about 20% to about 50% of PEG units. In a particular embodiment, the implant of the present invention may have the following composition (wet basis; % w / w): about 5% to about 17% of axitinib and about 4% to about 12% of PEG units. These compositions are particularly suitable for the implants of the present invention, which contain axitinib (i.e., axitinib free base in any polymorph form (e.g., polymorph IV) or in the form of cocrystals or prodrugs) corresponding to 200 µg to 1000 µg, 300 µg to 1000 µg, 300 µg to 600 µg, or about 360 µg to about 562.5 µg, or about 400 µg to about 500 µg or about 450 µg) of axitinib free base.

[0439] In certain embodiments, the implants of the present invention may have the following composition (dry basis; % w / w): about 50 wt% to about 70 wt% of axitinib (specifically, axitinib polymorph IV), and about 25 wt% to about 45 wt% of PEG units, specifically PEG units obtained from crosslinking 4a20kPEG-SAZ and 8a20kPEG-NH2. These implants may have the following composition (wet basis; % w / w): about 7 wt% to about 17 wt% of axitinib (specifically, axitinib polymorph IV), and about 5 wt% to about 10 wt% of PEG units, specifically PEG units obtained from crosslinking 4a20kPEG-SAZ and 8a20kPEG-NH2. These composition ranges are particularly applicable to the implants of the present invention, which contain amounts of axitinib of about 360 µg to about 562.5 µg, or about 400 µg to about 500 µg, or about 450 µg, specifically axitinib polymorph IV. Exemplary implants of these embodiments of the present invention are presented in Table 1C of the Examples section.

[0440] In some other embodiments, the implant of the present invention may have the following composition (dry basis; % w / w): about 30 wt% to about 80 wt%, or about 50 wt% to about 70 wt%, or about 55 wt% to about 70 wt% of axitinib, and about 20 wt% to about 60 wt%, or about 20 wt% to about 50 wt%, or about 25 wt% to about 35 wt% of PEG units. In some specific embodiments, the implant may have the following composition (wet basis; % w / w): about 10 wt% to about 22 wt%, or about 12 wt% to about 18 wt%, or about 14 wt% to about 17 wt% of axitinib, and about 2 wt% to about 12 wt%, or about 4 wt% to about 10 wt%, or about 5 wt% to about 8 wt% of PEG units. These compositions are particularly suitable for the implants of the present invention, which contain axitinib (i.e., axitinib free base in any of its polymorphs (e.g., polymorph IV) or in, for example, its cocrystal or prodrug form) in amounts corresponding to 200 µg to 1000 µg, 300 µg to 1000 µg, 300 µg to 800 µg, or about 480 µg to about 750 µg, or about 540 µg to about 660 µg, or about 600 µg of axitinib free base).

[0441] In some other embodiments, the implant of the present invention comprises at least two filaments (e.g., 2 to 10, or 3 to 7 filaments), and the implant or any filament constituting it may have the following composition (dry basis; % w / w): about 30 wt% to about 70 wt%, or about 30 wt% to about 60 wt% of axitinib, and about 20 wt% to about 60 wt%, or about 30 wt% to about 60 wt% of PEG units. In some specific embodiments, the implant of the present invention comprises at least two filaments (e.g., 2 to 10, or 3 to 7 filaments), and the implant may have the following composition (wet basis; % w / w): about 5 wt% to about 20 wt%, or about 5 wt% to about 15 wt% of axitinib, and about 3 wt% to about 20 wt%, or about 5 wt% to about 10 wt% of PEG units.

[0442] In some other embodiments, the implant of the present invention has a cross-sectional geometry that is not circular or rectangular, but specifically a cross-shaped or star-shaped (including but not limited to a 5-armed star) cross-sectional geometry. The implant may have the following composition (dry basis; % w / w): about 30 wt% to about 70 wt%, or about 40 wt% to about 70 wt% of axitinib, and about 20 wt% to about 60 wt%, or about 20 wt% to about 40 wt% of PEG units. In some specific embodiments, the implant of the present invention has a cross-sectional geometry that is not circular or rectangular, but specifically a cross-shaped or star-shaped (including but not limited to a 5-armed star) cross-sectional geometry. The implant may have the following composition (wet basis; % w / w): about 5 wt% to about 20 wt%, or about 8 wt% to about 18 wt% of axitinib, and about 3 wt% to about 20 wt%, or about 5 wt% to about 10 wt% of PEG units.

[0443] In some embodiments, the axitinib to PEG ratio in the implants of the present invention may be from about 1:1 to about 3:1 based on dry weight. In some embodiments, the maximum amount of drug in the formulation is about twice the amount of polymer (e.g., PEG) units, but may be higher in some cases, provided that the mixture comprising, for example, a precursor, a buffer, and the drug (in a state before complete hydrogel gelation) can be uniformly cast into a mold or tube (in the case where the implants of the present invention are produced by wet casting as further disclosed herein).

[0444] In some embodiments, the remaining portion of the implant in its dry state (i.e., the remainder of the formulation when the TKI (e.g., axitinib) and polymer units (e.g., PEG units) are taken into account) may be the salt remaining from the buffer solution disclosed above. In some embodiments, such salts are phosphates, borates, or carbonates (bicarbonates). In one embodiment, the buffer salt is sodium phosphate (sodium dihydrogen phosphate and / or disodium hydrogen phosphate).

[0445] In some embodiments, when forming the hydrogel of the implant of the present invention by wet casting as further disclosed herein, a solid content of about 10% to about 50%, or about 25% to about 50% (w / v) may be used in the wet composition (wherein “solid” means the combined weight of the polymer precursor, salt, and drug in the solution / suspension). Therefore, in some embodiments, the total solid content of the wet hydrogel composition to be cast into a mold or tube to form the hydrogel may not exceed about 60%, or about 50%, or about 40%, for example, equal to or less than about 35% (w / v). The content of a TKI (e.g., axitinib) may not exceed about 40% of the wet composition, or about 30%, for example, equal to or less than about 25% (w / v). The solid content may affect the viscosity of the wet hydrogel composition and therefore may also affect its castability.

[0446] In some embodiments, the water content of the hydrogel implant in its dry (dehydrated / dried) state (e.g., before loading into a needle, or while already loaded into a needle) may be extremely low, for example, no more than 1% by weight. In some embodiments, the water content may also be lower, possibly no more than 0.25% by weight or even no more than 0.1% by weight. In this invention, the term "implant" is used to refer to an implant in a hydrated state when in contact with water (e.g., immediately after the implant has been applied to the eye or otherwise immersed in an aqueous environment and then (re)hydrated), and an implant in a dry (dried / dehydrated) state, for example, when dried to a low water content, for example, no more than about 1% by weight, or when a drying step is not required to prepare such a low water content implant. In some embodiments, a dry implant is an implant that has been kept in a glove box in an inert nitrogen atmosphere (containing less than 20 ppm of oxygen and moisture) for at least about 7 days after production and before loading into a needle. The water content of the implant can be measured, for example, using the Karl Fischer coulometric method.

[0447] In some embodiments, the total weight of the implant of the present invention in its dry state (also referred to herein as "total mass") may be from about 200 µg (i.e., 0.2 mg) to about 1.5 mg, or from about 400 µg to about 1.2 mg, or from about 500 µg to about 1 mg. In specific embodiments, the total weight of the implant of the present invention in its dry state is from about 0.6 mg to about 1 mg, for example from about 600 µg to about 900 µg, or between about 600 µg and about 900 µg, for example from about 700 µg to about 875 µg. In the case where the implant is a composite (multifilament) implant, the total weight of the composite implant may be higher, depending on the number of individual filaments constituting the implant and the total weight of the filaments. In a particular embodiment, when the TKI in the implant is axitinib (e.g., axitinib polymorph IV) and is present in a dose of about 400 µg to about 500 µg, such as about 405 µg to about 495 µg, such as about 410 µg to about 490 µg, and wherein the axitinib particles are micronized particles as defined herein, the total weight of the implant may be about 0.6 mg to about 1 mg, or between about 0.6 mg and about 0.9 mg, and the hydrated surface area (as defined herein) of such implant may be at least 16 mm². 2 For example, 16.0 to 23.0 mm 2 .

[0448] In some embodiments, the implant of the present invention may contain about 200 µg to about 1000 µg of TKI (e.g., axitinib) / mm in its dry state. 3 (i.e., 1 mm) 3 (Dry implant). In some specific embodiments, the implant of the present invention may contain about 200 µg to about 300 µg axitinib / mm² in its dry state. 3 For example, in the case where the implant contains an amount of axitinib of about 160 µg to about 250 µg. In some other specific embodiments, the implant of the present invention may contain about 500 µg to about 800 µg of axitinib / mm in its dry state. 3 For example, in cases where the implant contains a quantity of axitinib ranging from approximately 480 µg to approximately 750 µg.

[0449] Therefore, the implants of the present invention can have different densities. The density of the final implant (i.e., in its dry state) can be controlled and determined by various factors, including (but not limited to) the concentration of the components in the wet composition during hydrogel formation (in the case of wet casting) and certain conditions during implant manufacturing. For example, in some embodiments, the density of the final implant can be increased by sonic treatment or degassing (e.g., using a vacuum) at certain points in the process. In some embodiments, the density of an implant produced by hot melt extrusion may be higher than that of a comparable implant produced by wet casting (in terms of its TKI and polymer content, respectively).

[0450] In some embodiments, the implant of the present invention contains a therapeutically effective amount of a TKI (e.g., axitinib) for release over an extended period of time, but its length and / or diameter are relatively small. This is advantageous in terms of ease of administration (injection) and reduction of potential damage to ocular tissues and potential impact on the patient's vision during implant placement. The implant of the present invention combines the benefits of an appropriately high dose of TKI (i.e., a therapeutically effective dose tailored to the specific needs of a particular patient) with a relatively small implant size. Furthermore, the implant of the present invention achieves a relatively high TKI release rate, particularly in the early stages of release, i.e., during the initial period after administration (or, in the case of in vitro release testing, during the initial period after the start of testing).

[0451] Exemplary implants of various aspects of the present invention are disclosed in the Embodiments section (including predictive examples of implants).

[0452] The size of the implant and its dimensional changes during hydration due to stretching:

[0453] Single implant:

[0454] Dry implants can have different geometries, depending on the manufacturing method, such as casting a mixture containing hydrogel precursors (including TKIs) into a mold or tube before complete gelation (in the case of manufacturing implants using wet casting methods as disclosed herein), or, depending on the shape and size of the die, extruding a molten mixture of polymer precursors and TKIs prepared in a hot melt extrusion process (also as disclosed herein).

[0455] The implants of the present invention may also be referred to herein as “fibers” (the term is used interchangeably with the term “rod”), wherein a fiber is an object that generally has an elongated shape. Implants (or fibers) may have different geometries and specific dimensions as disclosed herein. Implants (or fibers) are elongated objects that generally have a length and a width, wherein the width is the maximum cross-sectional dimension of the elongated object and the length is the longest elongation of the object. Typically, in the implants of the present invention, the length is longer than the width.

[0456] In one embodiment, the implant is cylindrical or has a substantially cylindrical shape. In this case, the implant has a circular or substantially circular cross-section. It has a length and a width / diameter. In other embodiments of the invention, the implant is non-cylindrical, wherein the implant is optionally elongated in its dry state.

[0457] Whether cylindrical or non-cylindrical, the length of the implant is generally greater than its width, where the width (also referred to as the "diameter" in implants with a circular or substantially circular cross-section) is the largest cross-sectional dimension substantially perpendicular to the length. The length is generally the longest elongation of the implant. In some embodiments, the width (or diameter) of the implant of the present invention in its dry state may be from about 0.1 mm to about 0.5 mm. Various geometries of the external implant shape or its cross-section can be used in the present invention. For example, cruciform fibers (i.e., where the cross-sectional geometry is cruciform) can also be used instead of circular diameter fibers (i.e., cylindrical implants). Other cross-sectional geometries can generally be used, such as oval, rectangular, elliptical, quadrilateral, square, rhomboid, cruciform, triangular, star-shaped (a star with any number of arms) or asterisk-shaped (again, with any number of arms), etc. The implant may also be in the form of a film or gear.

[0458] The cross-sectional geometry of an implant also determines its hydrated surface area. For example, an implant with a cruciform or star-shaped cross-sectional geometry has an increased hydrated surface area compared to an implant of the same length but with a circular or oval cross-section. For the purposes of this invention, the hydrated surface area of ​​the implant is calculated based on the hydrated size of the implant, as measured after 24 hours in phosphate-buffered saline (PBS) at pH 7.2 to 7.4 and 37°C.

[0459] In one aspect of the invention, the hydrated surface area of ​​the implant (as defined herein) is at least 25 mm². 2 For example, 25 mm 2 Up to 100 mm 2 or 25 mm 2 Up to 60 mm 2 In this aspect of the invention (i.e., wherein the hydrated surface area is at least 25 mm²), the hydrated surface area is... 2 In this context, TKIs (such as axitinib) may have any solubility, that is, a solubility greater than 0.3 µg / mL, for example greater than 0.4 µg / mL, or a solubility of 0.3 µg / mL or less, as measured after incubation for 5 days in phosphate-buffered saline (PBS) at pH 7.2 to 7.4 and 37°C.

[0460] In another aspect of the invention, the implant may have any hydrated surface area, provided that the solubility of the TKI (e.g., axitinib) contained therein is greater than 0.3 µg / mL, for example greater than 0.4 µg / mL, as measured after incubation for 5 days in phosphate-buffered saline (PBS) at pH 7.2 to 7.4 and 37°C (as disclosed herein). In embodiments of this aspect in which the TKI (e.g., axitinib) has the aforementioned greater solubility, including (but not limited to) embodiments where the TKI is axitinib in polymorph IV form, the hydrated surface area of ​​the implant (as defined herein) may be at least 10 mm². 2 For example, at least 15 mm 2 For example, at least 16 mm 2 For example, at least 19 mm 2 or at least 25 mm 2 Favorable 15 mm 2 Up to 100 mm 2 or 15mm 2 Up to 90 mm 2 or 16.0 mm 2 Up to 25.0 mm 2 or 16.0 mm 2 Up to 23.0 mm 2 Alternatively, if the solubility of a TKI (e.g., axitinib) in the implant of the present invention, as measured after incubation in phosphate-buffered saline (PBS) at pH 7.2 to 7.4 and 37°C for 5 days, is greater than 0.3 µg / mL, the hydrated surface area of ​​the implant may be 19 mm². 2 Up to 90mm 2 or 25 mm 2 Up to 90 mm 2 As measured after incubation for 24 hours in phosphate-buffered saline (PBS) at pH 7.2 to 7.4 and 37°C. In a particular embodiment, the hydrated surface area of ​​the implant of the present invention, for any of the two aspects just mentioned, may be 25 mm². 2 Up to 90 mm 2 or 25 mm 2 Up to 40 mm 2 As measured after incubation for 24 hours in phosphate-buffered saline (PBS) at pH 7.2 to 7.4 and 37°C.

[0461] In a specific embodiment of the invention, the solubility of the TKI (e.g., axitinib) contained in the implant is greater than 0.3 µg / mL, as measured after incubation for 5 days in phosphate-buffered saline (PBS) at pH 7.2 to 7.4 and 37°C, and in the case of a monofilament implant, the hydrated surface area can be 10 mm². 2 Up to 60 mm 2 For example, 15 mm 2 Up to 40 mm 2 or 16.0 mm 2 Up to 25.0 mm 2 or 16.0 mm 2 Up to 23.0 mm 2 The hydrated surface area is measured after incubation for 24 hours in phosphate-buffered saline (PBS) at pH 7.2 to 7.4 and 37°C, provided the implant cross-section is circular or substantially circular (i.e., the implant has a cylindrical or substantially cylindrical shape). In cases where the implant cross-section has an "arm" shape, such as a cross (4 arms) or a star (5 arms, 6 arms, or more arms), the hydrated surface area can be 30 mm². 2 Up to 90 mm 2 As measured after incubation for 24 hours in phosphate-buffered saline (PBS) at pH 7.2 to 7.4 and 37°C.

[0462] The hydrated surface area of ​​the implant is calculated using the formula for calculating the surface area of ​​the corresponding geometry (e.g., a cylinder in the case of a cylindrical implant) based on the corresponding hydrated size of the implant as defined herein (i.e., as measured after 24 hours of incubation in phosphate-buffered saline (PBS) at pH 7.2 to 7.4 and 37°C), where the surface area of ​​the cylinder 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 the diameter / width of the cylinder). Therefore, the hydrated dimensions (length and diameter / width) of the implant determine its hydrated surface area, which in particular controls the rate of release of the active agent from the implant. Generally speaking, a larger surface area provides faster release (if the drug / drug solubility and implant composition remain the same).

[0463] In the case of multifilament implants as further disclosed herein, the hydrated surface area of ​​the composite implant is the sum of the hydrated surface areas of each filament. For example, if the filaments are all of the same size, the hydrated surface area is the hydrated surface area of ​​a single filament multiplied by the number of filaments (this is because the filaments 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 filaments.

[0464] In the case of other implant geometries (e.g., other cross-sectional geometries), the corresponding hydration dimensions must also be used to calculate the hydration surface area. For example, for a 5-arm star-shaped cross-sectional geometry of the implant, such as... Figure 3 The hydrated surface area is calculated using the following formula, as shown in the figure:

[0465] "End face surface area" = arm width × arm length × 5 + center 2

[0466] Hydrated surface area (also known as total implant surface area) =

[0467] Perimeter × Implant length + 2 × "End face surface area"

[0468] "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 centerpiece. Irregular multi-arm shapes can also be used, and their hydrated surface area can be calculated accordingly.

[0469] In some implementations, 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 / TKI amount) × 100, may be at least 2, for example at least 3 or at least 5, or may be about 2 to about 10 mm. 2 / µg.

[0470] Generally, a larger hydration surface area provides an increased release rate of API from the implant (within certain limits). Increasing the hydration surface area by using different cross-sectional geometries or by, for example, combining multiple filaments into a combined strand as further disclosed herein, is another method (in vivo or in vitro) for increasing the daily release rate and / or the average daily release rate over a period of time, and / or the percentage of API released in one or more days, and / or the cumulative percentage of API released over a period of time (based on total released API or based on total API contained), and / or the absolute amount of API released in one or more days or over a period of time. Therefore, the present invention also relates to a method for increasing the release rate and / or average release rate and / or release amount of total TKI contained in an implant, and / or the release share of total TKI contained in the implant, or the total TKI released from the implant over a period of time, by increasing the hydration surface area of ​​the implant compared to known implants containing TKIs.

[0471] In some embodiments, the fibers may be twisted or coiled, both in the case of a single strand and in the case of multifilament fibers as disclosed herein. In other embodiments, the fibers are linear.

[0472] In embodiments where an implant is administered to the eye via a needle, the size of the implant (i.e., its length and diameter / width) and its cross-sectional geometry must allow the implant to be loaded into the needle, particularly a fine-diameter needle, such as a 25, 26, 27, or 30 gauge needle as further disclosed herein. A particularly suitable implant size is one that fits a 25 gauge needle. Therefore, when selecting an appropriate needle to inject the implant into the eye (e.g., vitreous fluid), the size of the implant in its dry state, specifically its width, is relevant. A smaller needle diameter generally means a lower likelihood of irritation and tissue trauma during injection.

[0473] In some embodiments of the present invention, the polymer network (e.g., a PEG network) of the hydrogel implant may be semi-crystalline in the dry state at or below room temperature and amorphous in the wet state. Even in stretched form, the dry implant may be dimensionally stable at or below room temperature, which may be advantageous for loading the implant into a needle and for quality control.

[0474] Once the implant is hydrated in the eye (which can be simulated by immersing the implant in PBS at 37°C for 24 hours at pH 7.2 to 7.4), the size of the implant may change: for example, the diameter of the implant may increase while its length may decrease or at least remain substantially the same. The advantage of this dimensional change is that, although the implant is thin enough in its dry state to fit into a fine-diameter needle (e.g., a 25 or 27 gauge needle, or in some cases even a smaller diameter needle, such as a 30 gauge needle) to be injected into the eye, it may immediately become shorter to better fit the limited volume of the eye after placement, for example, in vitreous fluid. In some embodiments, the needles (e.g., 25 or 27 gauge needles) for injecting the implants of the present invention, as disclosed herein, have a smaller diameter (and may, for example, have an inner diameter of about 0.4 mm). Because the implant also softens upon hydration, damage to any ocular tissue is prevented or minimized even when the implant comes into contact with any ocular tissue. In some embodiments, the dimensional change is achieved at least in part through a "shape memory" effect introduced into the implant during implant manufacturing by longitudinally stretching the implant (as also disclosed in the "Manufacturing Methods" section below). In some embodiments, stretching can be performed in a dry or wet state, i.e., after drying the hydrogel implant or before drying. It should be noted that if stretching is not performed and the hydrogel implant is simply dried and cut to the desired length, the diameter and length of the implant may increase upon hydration.

[0475] In a pre-formed dry hydrogel, the degree of molecular orientation can be imparted by “dry stretching” the material, then allowing it to solidify, promoting crystallization and locking the molecular orientation. In some embodiments, this can be accomplished by stretching the material (optionally while simultaneously heating the material to a temperature above the melting point of the crystallizable region of the material) and then allowing the crystallizable region to crystallize. Alternatively, in some embodiments, the glass transition temperature of the dry hydrogel can be used to lock the molecular orientation of a polymer (e.g., PVA) with a suitable glass transition temperature. Another alternative is to stretch the gel before it is fully dried (also known as “wet stretching”) and then dry the material under tension. Molecular orientation provides a mechanism for anisotropic swelling when introduced into a hydrating medium (e.g., a vitreous body). Upon hydration, implants in some embodiments will swell only in the radial dimension, while the length will decrease or remain substantially unchanged. The term “anisotropic swelling” means that swelling in one direction is preferred over swelling in another, such as in a cylinder that swells primarily in diameter but does not significantly expand (or even shrinks) in the longitudinal dimension.

[0476] The “locking” of molecular orientation is reversible upon (re)hydration. The extent of dimensional change during hydration is particularly dependent on the stretch factor. As an example, stretching with, for example, a low stretch factor (e.g., by wet stretching) may have a less significant effect or may not substantially alter the length during hydration. Conversely, stretching with a higher stretch factor of about 1.5 or greater, such as about 2 or greater, can produce a significantly shorter length during hydration. Stretching with a high stretch factor of 4 (e.g., by dry stretching) can produce an even shorter length during hydration (e.g., a reduction in length from 15 mm to 8 mm). In some cases, no stretching can maintain or even increase the implant length during hydration. Those skilled in the art will appreciate that factors other than stretching can also affect swelling behavior.

[0477] In one or more embodiments, the implant of the present invention is treated by wet stretching with a stretch factor of about 0.5 to about 5, or about 1 to about 4, or about 1.3 to about 3.5, or about 1.7 to about 3, or about 2 to about 2.5. In a particular embodiment, wet stretching is performed using a stretch factor of about 1.3 to about 1.5.

[0478] The composition of the polymer network is a significant factor influencing the potential for stretching the hydrogel and inducing dimensional changes in the implant upon hydration. When using PEG precursors, those with a lower number of arms (e.g., 4-arm PEG precursors) contribute to greater flexibility in the hydrogel compared to those with a higher number of arms (e.g., 8-arm PEG precursors). If the hydrogel contains more of the less flexible component (e.g., a higher amount of PEG precursors with a larger number of arms, such as 8-arm PEG units), the hydrogel may be stronger and less prone to stretching without breaking. On the other hand, hydrogels containing more flexible components (e.g., PEG precursors with a lower number of arms, such as 4-arm PEG units) may be more stretchable and softer, but may also swell more upon hydration. Therefore, the behavior and properties of the implant after placement in the eye (i.e., after the hydrogel becomes (re)hydrated) can be modulated by altering structural features and by improving the handling of the implant after initial formation (e.g., stretching).

[0479] The exemplary dimensions of the implants used in the following examples are provided in the Examples section. However, the dimensions of the implants (i.e., length and / or diameter) may also differ from those disclosed in the tables of the Examples, even when they contain similar TKI drug loadings. The dimensions of the dry implants are particularly determined by the amount of TKI incorporated and the ratio of TKI to polymer units, and may also be controlled by the diameter and shape of the mold or tube in which the hydrogel is gelled. In addition, the diameter of the implant is further affected, particularly, by the (wet or dry) stretching during the formation of the hydrogel strands. The dry strands (after stretching) are cut into segments of desired lengths to form the implants; therefore, the length can be selected as needed.

[0480] In some embodiments, the implant of the present invention has a high aspect ratio, i.e., a high length-to-width ratio (the width is the maximum cross-sectional dimension of the implant and the length is the maximum elongation of the implant). In some 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.

[0481] In some embodiments of the invention where the implant does not have a circular or substantially circular cross-section (e.g., where the implant is not cylindrical or substantially cylindrical), the corresponding cross-sectional dimension is referred to as the “width”. Where the implant is not cylindrical or substantially cylindrical, all values ​​and ranges of the implant diameter disclosed herein are explicit and equally applicable to the width of the implant.

[0482] In some embodiments, the implant of the present invention may have a length of less than about 17 mm in its dry state. In specific embodiments, the length of the implant in its dry state may be less than about 15 mm, or less than or equal to about 12 mm, or less than or equal to about 11 mm, or less than or equal to about 10 mm, or less than or equal to about 9 mm, or less than or equal to about 8.5 mm. In specific 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.

[0483] In some embodiments, the implant of the present invention may have a diameter / width of less than about 0.7 mm, 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 mm to about 0.40 mm, or about 0.31 mm to about 0.36 mm in its dry state.

[0484] In a particular embodiment, 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.

[0485] In other specific embodiments, the implant may have a length of about 6 mm to about 10 mm and a diameter of about 0.2 mm to about 0.5 mm in its dry state. In very specific embodiments, the implant may have a length of about 6 mm to about 9 mm and a diameter of about 0.25 mm to about 0.45 mm in its dry state.

[0486] In a more specific embodiment, 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 mm to 0.40 mm, for example 0.31 mm to 0.36 mm, in its dry state.

[0487] In some embodiments, the implant of the present invention may have a length of about 14 mm or less in its wet / hydrated state (i.e., after 24 hours in phosphate-buffered saline at pH 7.2-7.4 at 37°C).

[0488] In certain embodiments, the implant of the present invention may have a length equal to or less than about 12 mm, or equal to or less than about 11 mm, or equal to or less than about 10 mm in its wet / hydrated state; or it may have 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 are those with a hydrated length of less than about 11 mm, for example about 10 mm or less.

[0489] In some 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 particular 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 particular embodiments, the implant may have a length of about 7 mm to 10 mm and a diameter of about 0.5 mm to 0.9 mm in its wet / hydrated state.

[0490] In a more specific embodiment, 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.

[0491] Whenever the length or diameter / width (in mm) of the implant of the present invention is disclosed herein in a wet / hydrated state, this disclosure refers to the length or diameter / width of the implant, measured after 24 hours in PBS at 37°C and pH 7.2 to 7.4. While the implant is maintained under these conditions, the dimensions of the implant may further change over time (i.e., after 24 hours) (e.g., the length may increase slightly again). However, whenever the hydrated dimensions of the implant are reported herein, these dimensions are measured as disclosed above after 24 hours in PBS at 37°C and pH 7.2 to 7.4.

[0492] In embodiments of the invention, the diameter or width of the implant in its dry state is ideally such that the implant can be loaded into a fine-diameter needle (e.g., a 25-gauge or 27-gauge needle) as disclosed herein. Specifically, in one embodiment, an implant containing about 480 µg to about 750 µg of axitinib, or containing about 360 µg to about 562.5 µg of axitinib, such as 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 causing any damage to the implant during loading, and allows the implant to remain stably in the needle during further processing, including packaging, sterilization, transportation, etc.

[0493] When performing several measurements of the length or diameter of an implant, or collecting several data points during the measurement, the average (i.e., mean) value is reported as defined herein. The length and diameter of the implant of the present invention (whether in a dry or hydrated / wet state) can be measured, for example, by a microscope, or by a (optionally automatic) camera system as described in Example 6.1 of WO 2021 / 195163.

[0494] In some embodiments, the ratio of the diameter of the implant of the present invention in a hydrated state to its diameter in a dry state may be less than about 5 mm, or less than about 4 mm, or less than about 3.25 mm, or less than about 2.5 mm, or less than about 2.25 mm, or about 2.0 mm to about 2.5 mm.

[0495] In some identical or other embodiments, the ratio of the length of the implant in the dry state to its length in the hydrated state 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 length in the dry state to length in the hydrated state may be applied, either additionally or independently, to the ratio of diameter in the hydrated state to diameter in the dry state disclosed above.

[0496] In one embodiment, the implant of the present invention contains about 360 µg to about 562.5 µg of axitinib, or about 405 µg to about 495 µg, or about 450 µg of free axitinib base in polymorph IV form, in fibrous (cylindrical) form, and has a length of about 6 mm to about 9 mm and a diameter of about 0.25 mm to about 0.45 mm in a dry state. Such an implant may have a length of about 7 mm to about 9 mm and a diameter of about 0.65 mm to about 0.80 mm when in vivo in the eye (e.g., in vitreous fluid) or when in vitro hydrated (wherein in vitro hydration is measured after 24 hours at 37°C in phosphate-buffered saline at pH 7.2). In one embodiment, this dimensional change can be achieved by wet stretching as disclosed herein with a stretch factor between 1.25 and 3.

[0497] In another embodiment, the implant of the present invention contains about 360 µg to about 562.5 µg of axitinib, or about 400 µg to about 500 µg, or about 405 µg to about 495 µg, or about 450 µg of free axitinib base in polymorph IV form, and has a length of about 5 mm to about 11 mm and a diameter of about 0.28 mm to about 0.38 mm in the dry state. Such an implant may have a hydrated length of about 5 mm to about 11 mm and a hydrated diameter / width of about 0.4 mm to about 2 mm when in vivo in the eye (e.g., in vitreous fluid) or when hydrated in vitro (wherein in vitro hydration is measured after 24 hours at 37°C in phosphate-buffered saline at pH 7.2). In some embodiments, this dimensional variation can be achieved by wet stretching as disclosed herein with a stretch factor between 1.0 and 3.0.

[0498] In a particular embodiment, the implant of the present invention contains about 360 µg to about 562.5 µg of axitinib, or about 400 µg to about 500 µg, or about 405 µg to about 495 µg, or about 450 µg of free axitinib base in polymorph IV form, in fibrous (cylindrical) form, and has a length of about 6 mm to about 9 mm and a diameter of about 0.30 mm to about 0.35 mm in a dry state. Such an implant may have a hydrated length of about 6 mm to about 10 mm and a hydrated diameter of about 0.5 mm to about 0.90 mm when in vivo in the eye (e.g., in vitreous fluid) or when hydrated in vitro (wherein in vitro hydration is measured after 24 hours at 37°C in phosphate-buffered saline at pH 7.2). In one embodiment, this dimensional variation can be achieved by wet stretching as disclosed herein with a stretch factor between 1.2 and 1.5. Such an implant may have a diameter of about 17.0 to about 23.0 mm. 2 hydrated surface area.

[0499] In another embodiment, the implant of the present invention contains about 200 µg to 1000 µg, 300 µg to 1000 µg, 480 µg to about 750 µg, or about 540 µg to about 660 µg, or about 600 µg of free axitinib base in polymorph IV, in fibrous (cylindrical) form, and has a length of about 7 mm to less than 10 mm and a diameter of about 0.25 mm to about 0.45 mm in the dry state. Such an implant may have a length of about 8 mm to less than 10 mm and a diameter of about 0.65 mm to about 0.9 mm when in vivo in the eye (e.g., in vitreous fluid) or when in vitro hydrated (wherein in vitro hydration is measured after 24 hours at 37°C in phosphate-buffered saline at pH 7.2). In one embodiment, this dimensional variation can be achieved by wet stretching as disclosed herein with a stretch factor between 1.25 and 3.

[0500] In one embodiment, the length of the implant of the present invention containing about 300 μg to about 700 μg of axitinib, such as about 300 μg, about 450 μg or about 600 μg of axitinib, is not longer than 10 mm in the dry state, and is not longer than or significantly longer than about 11 mm, or not longer than about 10 mm, or not longer than about 9 mm in the hydrated state (e.g., measured after 24 hours in phosphate-buffered saline at pH 7.2 at 37°C).

[0501] In certain embodiments of the invention, specifically when the implant contains an amount of axitinib (e.g., axitinib polymorph IV) of about 400 µg to about 500 µg (or any subrange or dose within that range as disclosed herein), the implant has a diameter of at least 15.0 mm. 2 For example, at least 16.0 mm 2 For example, approximately 16.0 to approximately 25.0 mm 2 For example, approximately 16.0 to approximately 23.0 mm 2 The hydrated surface area (which is calculated based on the hydrated size as explained above, such as after 24 hours in vitro at 37°C in a phosphate-buffered saline solution at pH 7.2-7.4). In some other embodiments, the hydrated surface area may also be from about 17.0 to about 23.0 mm². 2 Especially from about 18.0 to about 22.5 mm 2 In any of these embodiments, the implant may be cylindrical or substantially cylindrical, i.e., having a circular or substantially circular cross-sectional area.

[0502] In an alternative embodiment, the implant of the present invention is produced in situ in the eye (e.g., in the vitreous humor). In this case, the solution containing precursors (e.g., those disclosed herein for manufacturing implants by wet casting) is assembled only shortly before the combined solution is injected into the eye. After the precursor (TKI and polymer precursor, and optionally buffer) solution has optionally been assembled in a syringe or another syringe element, the combined solution must be injected into the eye before the hydrogel has fully gelled (i.e., while the contents of the syringe are still a liquid sufficient for easy and complete injection without clogging the needle). Alternatively, in situ gelation may be triggered 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 intraocularly (e.g., in the vitreous humor), forming an implant having a generally spherical shape but without defined dimensions (e.g., defined length and diameter or defined hydrated surface area).

[0503] Multifilaments:

[0504] In some embodiments, the implant of the present invention comprises / includes at least two filaments. In specific embodiments, such an implant comprises at least three or four filaments, and / or up to 20, 15, or 12 filaments. In particular embodiments, the implant comprises two to eight or three to seven filaments, or comprises two, three, four, five, six, seven, or eight filaments. A single filament may have the composition (amount / percentage of TKI and PEG units, etc.) as disclosed herein for the (monostranded) implant of the present invention, and may also be produced in the same manner as the (monostranded) implant disclosed herein (i.e., by wet casting or by hot melt extrusion). The filaments included in a composite implant may be identical or may be different (including, but not limited to, differences in their composition and / or (wet and / or dry) dimensions and / or their geometry). A single filament may also contain, for example, different forms of the same active agent (including, but not limited to, different polymorphic forms) and / or different active agents.

[0505] In some embodiments, the monofilaments can then be combined into composite strands via a heat-stretch-twisting process illustrated in Example 3. In another embodiment, the monofilaments are braided to form a braided strand. In yet another embodiment, the monofilaments are connected to each other by other means, such as via adhesion to another material (e.g., linear PEG). The adhesive material may or may not dissolve after the implant is injected into a physiological environment (e.g., the eye, such as vitreous fluid). If the adhesive material dissolves, the monofilaments immediately detach from each other after the implant is placed in the physiological environment. Multiple filaments may also be connected to each other or formed into shapes connected to each other by other means.

[0506] The filaments can be combined into a composite implant by twisting them to form a twisted strand. The composite (twisted) strand in its dry state can have a diameter within the same range as that of a monofilament implant, as disclosed herein. In some embodiments, the composite diameter of the twisted strand in its dry state is 0.2 mm to 0.8 mm, or 0.2 mm to 0.5 mm, or 0.3 mm to 0.4 mm, or 0.33 mm to 0.38 mm. In some identical or other embodiments, the diameter of a single filament in its dry state 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 monofilament implants, multifilament implants can also be loaded into needles for injection into the eye, for example, into the vitreous humor, wherein the needle size is between 20 and 30, for example, between 25 and 27, or 25, 27, or 30.

[0507] In some embodiments, in the twisted composite implant of the present invention comprising at least two filaments, the twisted strands can be fully or partially unwound during hydration (in vivo or in vitro), thereby exposing the individual filaments. Thus, the multifilament implant effectively provides an increased hydration surface area (corresponding to the sum of the hydration surface areas of the individual filaments), thereby increasing the release rate of TKI from the implant. In certain embodiments, the hydration surface area of ​​the multifilament implant may be at least 2 times, for example at least 3 times, or at least 4 times larger than that of a single-strand implant containing the same TKI drug load and having substantially similar composite dimensions (composite diameter and length) in the dry state. Therefore, the release rate (amount of TKI released per day and / or the average daily release rate over a number of days) of the multifilament implant containing the same TKI drug load as the single-strand implant and having substantially similar composite dimensions (composite diameter and length) in the 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 can deliver multiple implants with a single injection, thereby increasing the API release rate.

[0508] In some embodiments of the twisted multifilament implant of 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.

[0509] Multifilament implants are produced from monofilaments (which are produced according to the manufacturing methods disclosed herein), as disclosed in the section "Manufacturing of Implants".

[0510] Multifilament implants can be used with any aspect of the invention, provided that the corresponding requirements are met, such as the solubility of the TKI being greater than 0.3 µg / mL, as measured after incubation for 5 days in phosphate-buffered saline (PBS) at pH 7.2 to 7.4 and 37°C (for this particular aspect of the invention), or provided that the hydrated surface area of ​​the implant is at least 25 mm². 2 This can be measured, as in the case of incubation for 24 hours in phosphate-buffered saline (PBS) at pH 7.2 to 7.4 and 37°C (for this particular aspect of the invention). In the case where the TKI incorporated into these multifilament implants is axitinib, it may contain axitinib in any form disclosed herein (again, provided the corresponding characteristics of this particular aspect of the invention are satisfied).

[0511] In some embodiments, the multifilament implant comprises 5% to 30% (w / w), for example 10% to 20% (w / w), of the dried implant with linear PEG.

[0512] In vitro release:

[0513] The in vitro release of TKIs (such as axitinib) from the implants of this invention can be determined by various in vitro methods (see also the Examples section and the Definitions section of this application for further explanation):

[0514] In a specific in vitro assay, the study implant is placed in a solvent mixture of 25% ethanol / 75% water (v / v) at a certain volume as disclosed herein and at a certain temperature (37°C or another temperature specifically mentioned). The release amount or percentage of the TKI (e.g., axitinib) is determined over predetermined days. The volume of solvent is calculated using a “leakage factor” as defined in the “Definitions” section. The in vitro assays reported in this invention can be performed under various leakage conditions. In some embodiments, the in vitro assay can be performed under 2× leakage conditions, or under 3× leakage conditions, or using a higher leakage factor, as disclosed herein. “2× leakage conditions” means that the volume of the solvent (mixture) impregnated with the implant of the invention (or several implants, if so indicated) for the specific test is twice the “leakage volume” (as defined above), i.e., in this case, the “leakage factor” will be 2. This also applies similarly to any other leakage factor. The leakage volume is the ratio of the amount of TKI contained in the implant [µg] to the solubility of TKI in the solvent (mixture) used, i.e., in 25% ethanol / 75% water (v / v), as defined in the "Definitions" section.

[0515] In some embodiments, for in vitro tests using 2× leak conditions (e.g., “Method A” mentioned in the examples) reported in this application, the leak volume is calculated by dividing the amount of axitinib contained in the study implant (in µg) by an average solubility value of 18.3 µg / mL. In these embodiments, this average solubility value is used regardless of which axitinib polymorph is used in the study implant, for example, whether polymorph IV or polymorph SAB-I is used.

[0516] In some embodiments, for in vitro testing using 3× leak conditions (e.g., “Method B” mentioned in the examples) reported in this application, the leak volume is calculated by dividing the amount of axitinib contained in the study implant (in µg) by a solubility value of 13.41 µg / mL (in the case of using axitinib polymorph SAB-I) or 20.09 µg / mL (in the case of using axitinib polymorph IV).

[0517] Specifically, the in vitro test of the present invention for implants containing axitinib is performed as follows (“Method A” or “Method B”): 1 L of a 25%:75% ethanol / water solvent mixture (also referred to herein as “buffer”) is prepared and equilibrated. The implant under study is placed in an amber-colored container. For 2× leak 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] (in some embodiments, this is the average solubility of the free base of axitinib, 18.3 µg / mL, as explained above). For 3× leak conditions, the volume of buffer added to the implant is equal to three times the volume corresponding to the TKI amount [µg] divided by the axitinib solubility [µg / mL] (in some embodiments, the solubility is 13.41 µg / mL (for the TKI being axitinib polymorph SAB-I) or 20.09 µg / mL (for the TKI being axitinib polymorph IV)). For example, if the implant contains 600 µg of axitinib polymorph SAB-I and is to be run as an in vitro assay under 3× leak conditions, 134 mL of a 25% / 75% ethanol / water mixture is used as the volume of the implant used for immersion in the study (i.e., 600 µg divided by 13.41 µg / mL multiplied by a factor of 3). During the in vitro assay run, the container containing the implant in the corresponding volume of buffer is stored in a 37°C incubator on a shaker to provide moderate agitation. 1 mL of buffer solution is removed and replenished on each sampling day. The buffer solution is analyzed using UV-VIS (in some embodiments, for testing under 2× leak conditions) or UPLC (in some embodiments, for testing under 3× leak conditions) against analytical standards prepared within the past 2 weeks.

[0518] In addition, the in vitro release of TKIs, specifically axitinib, from the implant of the present invention can also be determined by another accelerated in vitro method (“Method C”) as follows (see also the Examples section):

[0519] The solution medium used for this accelerated in vitro release test was 0.01N HCl containing 0.25% cetyltrimethylammonium bromide (CTAB). The test was performed in USP apparatus 4 at 35°C. Suitable test parameters are specified below:

[0520]

[0521] Sampling time points can be selected as needed, such as one or more of the following time points: 0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 16 hours, 24 hours, 36 hours, 48 ​​hours, 60 hours, and 83 hours. Samples are analyzed against analytical standards using UPLC. If several (e.g., n = 6) samples of a product (e.g., from the same production batch) are measured, the average release can be determined.

[0522] As disclosed in this article In vitro testing performed at 37°C in a 25% / 75% (v / v) ethanol / water mixture in 2x sink conditions In vitro testing performed at 37°C in a 25% / 75% (v / v) ethanol / water mixture in 2x sink conditions In vitro release of implants containing axitinib:

[0523] In certain embodiments of the invention, the implant contains axitinib as a TKI in any of the forms disclosed herein, and exhibits one or more of the following release characteristics in an in vitro release test performed at 37°C in a 25% / 75% (v / v) ethanol / water mixture under 2× leak conditions (this test is also referred to as "Method A" in the embodiments):

[0524] In some embodiments, the implant of the present invention releases axitinib at the following average rates: at least about 60 µg / day in the first day, and / or at least about 55 µg / day in the first two days, and / or at least about 45 µg / day in the first five days, and / or at least about 40 µg / day in the first seven days, and / or at least about 40 µg / day in the first ten days.

[0525] In some identical or other embodiments, the implant releases at least 40% or at least 44% of the total axitinib release within the first 3 days.

[0526] And / or release at least 70% of the total axitinib release within the first 7 days.

[0527] And / or release at least 90% of the total axitinib release within the first 10 days.

[0528] In certain specific embodiments, the amount of axitinib contained in the implant corresponds to approximately 480 µg to approximately 750 µg, or approximately 600 µg of free axitinib base, and First 3 days At least 40% of the total axitinib release is released internally, and / or

[0529] The amount of axitinib contained in the implant corresponds to approximately 360 µg to approximately 562.5 µg, or approximately 450 µg of free axitinib base, and releases at least 50% of the total axitinib released from the implant within the first 3 days, and / or

[0530] The amount of axitinib contained in the implant corresponds to approximately 240 µg to approximately 375 µg, or approximately 300 µg of free axitinib base, and releases at least 60% of the total axitinib release within the first 3 days, and / or

[0531] The amount of axitinib contained in the implant corresponds to about 120 µg to about 187.5 µg, or about 150 µg of axitinib free base, and releases at least 90% of the total axitinib release within the first 3 days.

[0532] In some identical or other specific embodiments, the amount of axitinib contained in the implant corresponds to approximately 480 µg to approximately 750 µg, or approximately 600 µg of free axitinib base, and First 7 days At least 70% of the total axitinib release is released internally, and / or

[0533] The amount of axitinib contained in the implant corresponds to approximately 360 µg to approximately 562.5 µg, or approximately 450 µg of free axitinib base, and releases at least 80% of the total axitinib release within the first 7 days, and / or

[0534] The amount of axitinib contained in the implant corresponds to approximately 240 µg to approximately 375 µg, or approximately 300 µg of free axitinib base, and releases at least 85% of the total axitinib release within the first 7 days, and / or

[0535] The amount of axitinib contained in the implant corresponds to about 120 µg to about 187.5 µg, or about 150 µg of axitinib free base, and releases at least 95% of the total axitinib release within the first 7 days.

[0536] In some identical or other specific embodiments, the amount of axitinib contained in the implant corresponds to approximately 480 µg to approximately 750 µg, or approximately 600 µg of free axitinib base, and First 10 days At least 90% of the total axitinib release is achieved internally, and / or

[0537] The amount of axitinib contained in the implant corresponds to approximately 360 µg to approximately 562.5 µg, or approximately 450 µg of free axitinib base, and releases at least 92% of the total axitinib release within the first 10 days, and / or

[0538] The amount of axitinib contained in the implant corresponds to approximately 240 µg to approximately 375 µg, or approximately 300 µg of free axitinib base, and releases at least 95% of the total axitinib release within the first 10 days, and / or

[0539] The amount of axitinib contained in the implant corresponds to about 120 µg to about 187.5 µg, or about 150 µg of axitinib free base, and releases at least 98% of the total axitinib release within the first 10 days.

[0540] In some implementations, the implant releases at least about 65 µg of axitinib within the first day and / or at least about 120 µg of axitinib within the first two days.

[0541] In certain specific embodiments, the axitinib contained in the implant of the present invention corresponds to approximately 480 µg to approximately 750 µg of axitinib, or About 600 µg The amount of free axitinib base, and the release of at least about 75 µg, or at least about 90 µg, or at least about 100 µg of axitinib within the first day, and / or

[0542] Release at least approximately 125 µg, or at least approximately 150 µg, or at least approximately 140 µg of axitinib within the first 2 days, and / or

[0543] Release at least approximately 150 µg, or at least approximately 180 µg, or at least approximately 200 µg of axitinib within the first 3 days, and / or

[0544] Release at least approximately 275 µg, or at least approximately 300 µg, or at least approximately 375 µg of axitinib within the first 7 days, and / or

[0545] Release at least approximately 350 µg, or at least approximately 400 µg, or at least approximately 450 µg of axitinib within the first 10 days.

[0546] In some other specific embodiments, the axitinib contained in the implant of the present invention corresponds to about 360 µg to about 562.5 µg of axitinib, or About 450 µg The amount of free axitinib base, and the release of at least about 60 µg, or at least about 70 µg, or at least about 80 µg of axitinib within the first 1 day, and / or

[0547] Release at least approximately 100 µg, or at least approximately 120 µg, or at least approximately 130 µg of axitinib within the first 2 days, and / or

[0548] Release at least approximately 130 µg, or at least approximately 150 µg, or at least approximately 180 µg of axitinib within the first 3 days, and / or

[0549] Release at least approximately 220 µg, or at least approximately 260 µg, or at least approximately 290 µg of axitinib within the first 7 days, and / or

[0550] Release at least approximately 275 µg, or at least approximately 300 µg, or at least approximately 350 µg of axitinib within the first 10 days.

[0551] In some other specific embodiments, the axitinib contained in the implant of the present invention corresponds to about 240 µg to about 375 µg of axitinib, or About 300 µg The amount of free axitinib base, and the release of at least about 60 µg, or at least about 65 µg, or at least about 70 µg of axitinib within the first 1 day, and / or

[0552] Release at least approximately 90 µg, or at least approximately 110 µg, or at least approximately 130 µg of axitinib within the first 2 days, and / or

[0553] Release at least approximately 120 µg, or at least approximately 140 µg, or at least approximately 180 µg of axitinib within the first 3 days, and / or

[0554] Release at least approximately 200 µg, or at least approximately 240 µg, or at least approximately 270 µg of axitinib within the first 7 days, and / or

[0555] Release at least approximately 250 µg, or at least approximately 275 µg, or at least approximately 300 µg of axitinib within the first 10 days.

[0556] In some other specific embodiments, the axitinib contained in the implant of the present invention corresponds to about 120 µg to about 187.5 µg of axitinib, or About 150 µg The amount of free base of axitinib, and the release of 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 within the first 1 day, and / or the release of at least about 90 µg, or at least about 100 µg, or at least about 115 µg of axitinib within the first 2 days.

[0557] In some embodiments, the implant contains about 240 µg to about 375 µg of axitinib, and releases at least about 90% of the total amount of axitinib within the first 7 days or the first 10 days.

[0558] In some embodiments, the implant contains about 480 µg to about 750 µg of axitinib, and releases at least about 90% of the total amount of axitinib within the first 10 days or the first 14 days.

[0559] In some embodiments, the implant contains about 120 µg to about 187.5 µg of axitinib, and releases at least about 90% of the total axitinib release within the first 2 or 3 days.

[0560] In some embodiments, the implant contains about 360 µg to about 562.5 µg of axitinib, and releases at least about 90% of the total axitinib release within the first 8 or 9 days.

[0561] In some embodiments, for the release characteristics determined in in vitro tests under 2× leak conditions as reported above in this section, the volume of the 25% / 75% (v / v) ethanol / water solvent mixture is twice the volume calculated based on the ratio of the amount of axitinib contained in the implant [µg] to the average solubility value of axitinib [µg / mL] of 18.3 µg / mL.

[0562] As disclosed in this article In vitro testing performed at 37°C in a 25% / 75% (v / v) ethanol / water mixture in 3x sink conditions In vitro testing performed at 37°C in a 25% / 75% (v / v) ethanol / water mixture in 2x sink conditions In vitro release of implants containing axitinib:

[0563] In certain embodiments of the invention, the implant contains axitinib as a TKI in any of the forms disclosed herein, and exhibits one or more of the following release characteristics in an in vitro release test performed at 37°C in a 25% / 75% (v / v) ethanol / water mixture under 3× leak conditions (this test is also referred to as "Method B" in the embodiments):

[0564] In some embodiments, the implant of the present invention comprises axitinib and releases axitinib at the following average rates: at least about 40 µg / day in the first day, and / or at least about 35 µg / day in the first two days, and / or at least about 30 µg / day in the first four days, and / or at least about 25 µg / day in the first seven days.

[0565] In some embodiments, the implant of the present invention comprises axitinib and releases at least 25%, at least 30%, or at least 34% of the total amount of axitinib released within the first 4 days.

[0566] In some embodiments, the amount of axitinib contained in the implant of the present invention corresponds to about 480 µg to about 750 µg, or about 600 µg of free axitinib base, and initially... 4 days At least 35% of the total axitinib release is produced internally, and / or

[0567] The amount of axitinib contained in the implant corresponds to approximately 360 µg to approximately 562.5 µg, or approximately 450 µg of free axitinib base, and releases at least 30% of the total axitinib release within the first 4 days, and / or

[0568] The amount of axitinib contained in the implant corresponds to approximately 240 µg to approximately 375 µg, or approximately 300 µg of free axitinib base, and releases at least 30% of the total axitinib release within the first 4 days, and / or

[0569] The amount of axitinib contained in the implant corresponds to about 120 µg to about 187.5 µg, or about 150 µg of axitinib free base, and releases at least 60% of the total axitinib release within the first 4 days.

[0570] In some embodiments, the implant of the present invention contains axitinib and releases at least 40% or at least 50% of the total amount of axitinib within the first 7 or 9 days.

[0571] In some embodiments, the amount of axitinib contained in the implant corresponds to approximately 480 µg to approximately 750 µg, or approximately 600 µg of free axitinib base, and First 7 days or first 9 days At least 50% of the total axitinib release is released internally, and / or

[0572] The amount of axitinib contained in the implant corresponds to approximately 360 µg to approximately 562.5 µg, or approximately 450 µg of free axitinib base, and releases at least 50% of the total axitinib release within the first 7 or first 9 days, and / or

[0573] The amount of axitinib contained in the implant corresponds to approximately 240 µg to approximately 375 µg, or approximately 300 µg of free axitinib base, and releases at least 50% of the total axitinib release within the first 7 or first 9 days, and / or

[0574] The amount of axitinib contained in the implant corresponds to about 120 µg to about 187.5 µg, or about 150 µg of axitinib free base, and releases at least 90% of the total axitinib release within the first 7 or first 9 days.

[0575] In some implementations, the amount of axitinib contained in the implant corresponds to approximately 480 µg to approximately 750 µg, or approximately 600 µg The amount of free axitinib base, and the release of at least about 40 µg, or at least about 50 µg, or at least about 55 µg of axitinib within the first 1 day, and / or

[0576] Release at least approximately 80 µg, or at least approximately 100 µg, or at least approximately 120 µg of axitinib within the first 2 days, and / or

[0577] Release at least approximately 160 µg, or at least approximately 190 µg, or at least approximately 200 µg of axitinib within the first 4 days, and / or

[0578] Release at least approximately 290 µg, or at least approximately 300 µg, or at least approximately 350 µg of axitinib within the first 7 days, and / or

[0579] Release at least approximately 300 µg, or at least approximately 330 µg, of axitinib within the first 9 days.

[0580] In some implementations, the amount of axitinib contained in the implant corresponds to approximately 360 µg to approximately 562.5 µg, or approximately 450 µg The amount of free base of axitinib, and the release of at least about 35 µg, or at least about 40 µg, or at least about 45 µg of axitinib within the first 1 day, and / or

[0581] Release at least approximately 60 µg, or at least approximately 70 µg, or at least approximately 80 µg of axitinib within the first 2 days, and / or

[0582] Release at least approximately 100 µg, or at least approximately 120 µg, or at least approximately 150 µg of axitinib within the first 4 days, and / or

[0583] Release at least approximately 180 µg, or at least approximately 200 µg, or at least approximately 240 µg of axitinib within the first 7 days, and / or

[0584] Release at least approximately 200 µg, or at least approximately 250 µg, or at least approximately 270 µg of axitinib within the first 9 days.

[0585] In some implementations, the amount of axitinib contained in the implant corresponds to approximately 240 µg to approximately 375 µg, or approximately 300 µg The amount of free axitinib base, and the release of at least about 30 µg, or at least about 35 µg, or at least about 40 µg of axitinib within the first day, and / or

[0586] Release at least approximately 50 µg, or at least approximately 60 µg, or at least approximately 70 µg of axitinib within the first 2 days, and / or

[0587] Release at least approximately 80 µg, or at least approximately 100 µg, or at least approximately 120 µg of axitinib within the first 4 days, and / or

[0588] Release at least approximately 150 µg, or at least approximately 160 µg, or at least approximately 180 µg of axitinib within the first 7 days, and / or

[0589] Release at least approximately 160 µg, or at least approximately 180 µg, or at least approximately 200 µg of axitinib within the first 9 days.

[0590] In some embodiments, the amount of axitinib contained in the implant corresponds to approximately 120 µg to approximately 187.5 µg, or approximately 150 µg of free axitinib base, and releases at least approximately 60 µg, or at least approximately 70 µg, or at least approximately 80 µg of axitinib within the first day, and / or

[0591] Release at least approximately 90 µg, or at least approximately 100 µg, or at least approximately 120 µg of axitinib within the first 2 days.

[0592] In some implementations, the implant contains about 240 µg to about 375 µg of axitinib and releases at least about 85% or at least about 90% of the total axitinib release within the first 14 days.

[0593] In some embodiments, the implant contains about 480 µg to about 750 µg of axitinib, and releases at least about 90% of the total amount of axitinib within the first 16 days or the first 18 days.

[0594] In some implementations, the implant contains about 120 µg to about 187.5 µg of axitinib and releases at least about 90% of the total axitinib release within the first 7 days.

[0595] In some implementations, the implant contains about 360 µg to about 562.5 µg of axitinib, and releases at least about 90% of the total axitinib release over the first 14 to 16 days.

[0596] In some embodiments, for the release characteristics determined in in vitro tests under 3× leak conditions as reported above in this section, the volume of the 25% / 75% (v / v) ethanol / water solvent mixture is three times the volume determined based on the amount of axitinib contained in the implant [µg] divided by the ratio of the solubility of 13.41 µg / mL of axitinib polymorph SAB-I (if polymorph SAB-I is used) and the solubility of 20.09 µg / mL of axitinib polymorph IV (if polymorph IV is used) in the solvent mixture.

[0597] In particular, any in vitro release test, especially the accelerated in vitro release test described herein, can be used to compare different implants (e.g., different production batches, different compositions, and different dose intensities), for purposes such as quality control or other qualitative evaluation.

[0598] As disclosed in this article Accelerated in vitro testing performed in USP Apparatus 4 at 35°C ± 0.5°C in 0.01N HCl containing 0.25% CTAB In vitro release of axitinib-containing implants (“Method C”):

[0599] In some embodiments of the invention, the axitinib-containing implant is characterized by the following percentage of axitinib released from the implant in an in vitro test conducted in the USP device 4 at 35°C ± 0.5°C in 0.01N HCl containing 0.25% cetyltrimethylammonium bromide (CTAB):

[0600] After 0.5 hours, it is approximately 10% to approximately 25%.

[0601] After 2 hours, it is approximately 30% to approximately 50%.

[0602] After 6 hours, it is approximately 60% to approximately 90%.

[0603] After 10 hours, it is approximately 79% to approximately 100%.

[0604] At least approximately 90% after 12 hours.

[0605] And / or at least approximately 92% after 16 hours;

[0606] Or, characterized in that, in an in vitro test conducted in the USP device 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:

[0607] After 0.5 hours, it is approximately 10% to approximately 25%.

[0608] After one hour, it was approximately 19% to approximately 35%.

[0609] After 2 hours, it is approximately 30% to approximately 50%.

[0610] After 4 hours, it is approximately 55% to approximately 70%.

[0611] After 6 hours, it is approximately 60% to approximately 90%.

[0612] After 8 hours, it is approximately 78% to approximately 95%.

[0613] After 10 hours, it is approximately 79% to approximately 100%.

[0614] At least approximately 90% after 12 hours.

[0615] And / or at least approximately 92% after 16 hours.

[0616] In certain embodiments of the invention, the axitinib-containing implant is characterized by the following percentage of axitinib released from the implant in an in vitro test conducted in the USP device 4 at 35°C ± 0.5°C in 0.01N HCl containing 0.25% cetyltrimethylammonium bromide (CTAB):

[0617] After 0.5 hours, it is approximately 10% to approximately 18%.

[0618] After 2 hours, it is approximately 30% to approximately 45%.

[0619] After 6 hours, it is approximately 60% to approximately 80%.

[0620] After 10 hours, it was approximately 79% to approximately 98%.

[0621] At least approximately 90% after 12 hours.

[0622] And / or at least approximately 92% after 16 hours;

[0623] Or, characterized in that, in an in vitro test conducted in the USP device 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:

[0624] After 0.5 hours, it is approximately 10% to approximately 18%.

[0625] One hour later, it was approximately 19% to approximately 27%.

[0626] After 2 hours, it is approximately 30% to approximately 45%.

[0627] After 4 hours, it is approximately 55% to approximately 65%.

[0628] After 6 hours, it is approximately 60% to approximately 80%.

[0629] After 8 hours, it is approximately 78% to approximately 90%.

[0630] After 10 hours, it was approximately 79% to approximately 98%.

[0631] At least approximately 90% after 12 hours.

[0632] And / or at least approximately 92% after 16 hours.

[0633] In certain embodiments of the invention, the axitinib-containing implant is characterized by the following percentage of axitinib released from the implant in an in vitro test conducted in the USP device 4 at 35°C ± 0.5°C in 0.01N HCl containing 0.25% cetyltrimethylammonium bromide (CTAB):

[0634] After 0.5 hours, it is approximately 12% to approximately 17%.

[0635] After 2 hours, it was approximately 32% to approximately 42%.

[0636] After 6 hours, it was approximately 62% to approximately 78%.

[0637] After 10 hours, it was approximately 83% to approximately 97%.

[0638] And / or at least approximately 94% after 16 hours;

[0639] Or, characterized in that, in an in vitro test conducted in the USP device 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:

[0640] After 0.5 hours, it is approximately 12% to approximately 17%.

[0641] After 1 hour, it is approximately 23% to approximately 25%.

[0642] After 2 hours, it was approximately 32% to approximately 42%.

[0643] After 4 hours, it was approximately 57% to approximately 62%.

[0644] After 6 hours, it was approximately 62% to approximately 78%.

[0645] After 8 hours, it is approximately 80% to approximately 88%.

[0646] After 10 hours, it was approximately 83% to approximately 97%.

[0647] After 12 hours, it is at least approximately 94%.

[0648] And / or at least approximately 94% after 16 hours.

[0649] In certain embodiments of the invention, the axitinib-containing implant is characterized by the following percentage of axitinib released from the implant in an in vitro test conducted in the USP device 4 at 35°C ± 0.5°C in 0.01N HCl containing 0.25% cetyltrimethylammonium bromide (CTAB):

[0650] After 0.5 hours, it is approximately 12% to approximately 16%.

[0651] After 2 hours, it was approximately 34% to approximately 41%.

[0652] After 6 hours, it was approximately 66% to approximately 77%.

[0653] After 10 hours, it is approximately 85% to approximately 96%.

[0654] And / or at least approximately 95% after 16 hours;

[0655] Or, characterized in that, in an in vitro test conducted in the USP device 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:

[0656] After 0.5 hours, it is approximately 12% to approximately 16%.

[0657] After 1 hour, it is approximately 23% to approximately 25%.

[0658] After 2 hours, it was approximately 34% to approximately 41%.

[0659] After 4 hours, it was approximately 57% to approximately 62%.

[0660] After 6 hours, it was approximately 66% to approximately 77%.

[0661] After 8 hours, it is approximately 80% to approximately 88%.

[0662] After 10 hours, it is approximately 85% to approximately 96%.

[0663] After 12 hours, it is at least approximately 94%.

[0664] And / or at least approximately 95% after 16 hours.

[0665] In all the above-described implant embodiments for in vitro release, as measured according to Method C and defined by the percentage of axitinib released, the axitinib contained in the implant is a free axitinib base and is or contains axitinib polymorph IV. In a particular embodiment, the axitinib contained in the implant is axitinib polymorph IV. In embodiments where the implant contains axitinib polymorph IV, at least 90% by weight of the free axitinib base contained in the implant is polymorph IV. In some embodiments, the amount of axitinib contained in these implants is from about 300 µg to about 600 µg, for example from about 400 µg to about 500 µg, for example from about 450 µg. In a specific embodiment, the implant is a monofilament implant, for example a monofilament implant having a substantially cylindrical shape and having a diameter of at least 16 mm. 2 For example, approximately 16.0 to approximately 23.0 mm 2 Hydrated surface area (as measured after 24 hours of incubation in PBS at pH 7.2 to 7.4 and 37°C).

[0666] In certain embodiments of these implementations, the implant contains an amount of about 400 µg to about 500 µg, for example, about 450 µg, of axitinib polymorph IV, and the percentage of axitinib released is based on the maximum amount of axitinib representing 100% released from the implant (also referred to herein as “normalized release %”), as explained in Example 7.3 for in vitro method C. In other specific embodiments, the implant contains an amount of about 400 µg to about 500 µg, for example, about 450 µg, of axitinib polymorph IV, and the percentage of axitinib released is based on the theoretical (labeled) amount representing 100% of 450 µg of axitinib. This means that if the theoretical (labeled) amount of axitinib in the implant is 450 µg, but the actual axitinib content (analyzed) is, for example, slightly higher than 450 µg, then the percentage (%) of axitinib released after a certain period of time, as indicated above, still refers to the theoretical / labeled content of 450 µg, as also explained in Example 7.3 for Method C.

[0667] In some embodiments of the invention, the axitinib-containing implant is characterized in that, in an in vitro test conducted in the USP device 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:

[0668] After 0.5 hours, it is approximately 50 µg to approximately 80 µg.

[0669] After 2 hours, it was approximately 140 µg to approximately 200 µg.

[0670] After 6 hours, it was approximately 270 µg to approximately 360 µg.

[0671] After 10 hours, it was approximately 350 µg to approximately 450 µg.

[0672] And / or at least about 410 µg after 16 hours;

[0673] Or, characterized in that, in an in vitro test conducted in the USP device 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:

[0674] After 0.5 hours, it is approximately 50 µg to approximately 80 µg.

[0675] After 1 hour, it was approximately 100 µg to approximately 120 µg.

[0676] After 2 hours, it was approximately 140 µg to approximately 200 µg.

[0677] After 4 hours, it was approximately 240 µg to approximately 295 µg.

[0678] After 6 hours, it was approximately 270 µg to approximately 360 µg.

[0679] After 8 hours, it was approximately 350 µg to approximately 410 µg.

[0680] After 10 hours, it was approximately 350 µg to approximately 450 µg.

[0681] After 12 hours, it is at least approximately 400 µg.

[0682] And / or at least about 410 µg after 16 hours.

[0683] In certain embodiments of the invention, the axitinib-containing implant is characterized in that, in an in vitro test conducted in the USP device 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:

[0684] After 0.5 hours, it was approximately 55 µg to approximately 72 µg.

[0685] After 2 hours, it was approximately 147 µg to approximately 190 µg.

[0686] After 6 hours, it was approximately 280 µg to approximately 350 µg.

[0687] After 10 hours, it was approximately 360 µg to approximately 440 µg.

[0688] And / or at least approximately 420 µg after 16 hours;

[0689] Or, characterized in that, in an in vitro test conducted in the USP device 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:

[0690] After 0.5 hours, it was approximately 55 µg to approximately 72 µg.

[0691] After 1 hour, it was approximately 105 µg to approximately 112 µg.

[0692] After 2 hours, it was approximately 147 µg to approximately 190 µg.

[0693] After 4 hours, it was approximately 250 µg to approximately 280 µg.

[0694] After 6 hours, it was approximately 280 µg to approximately 350 µg.

[0695] After 8 hours, it was approximately 360 µg to approximately 400 µg.

[0696] After 10 hours, it was approximately 360 µg to approximately 440 µg.

[0697] After 12 hours, it was at least approximately 420 µg.

[0698] And / or at least about 420 µg after 16 hours.

[0699] In certain embodiments of the invention, the axitinib-containing implant is characterized in that, in an in vitro test conducted in the USP device 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:

[0700] After 0.5 hours, it was approximately 57 µg to approximately 70 µg.

[0701] After 2 hours, it was approximately 150 µg to approximately 180 µg.

[0702] After 6 hours, it was approximately 290 µg to approximately 345 µg.

[0703] After 10 hours, it was approximately 370 µg to approximately 430 µg.

[0704] And / or at least approximately 420 µg after 16 hours;

[0705] Or, characterized in that, in an in vitro test conducted in the USP device 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:

[0706] After 0.5 hours, it was approximately 57 µg to approximately 70 µg.

[0707] After 1 hour, it was approximately 105 µg to approximately 112 µg.

[0708] After 2 hours, it was approximately 150 µg to approximately 180 µg.

[0709] After 4 hours, it was approximately 250 µg to approximately 280 µg.

[0710] After 6 hours, it was approximately 290 µg to approximately 345 µg.

[0711] After 8 hours, it was approximately 360 µg to approximately 400 µg.

[0712] After 10 hours, it was approximately 370 µg to approximately 430 µg.

[0713] After 12 hours, it was at least approximately 420 µg.

[0714] And / or at least about 420 µg after 16 hours.

[0715] In all the above-described implant embodiments of in vitro release, as measured according to Method C and defined by the amount of axitinib released (in µg), the axitinib contained in the implant is a free axitinib base and is or contains axitinib polymorph IV. In a particular embodiment, the axitinib contained in the implant is axitinib polymorph IV. In embodiments where the implant contains axitinib polymorph IV, at least 90% by weight of the free axitinib base contained in the implant is polymorph IV. In some embodiments, the amount of axitinib contained in these implants is from about 300 µg to about 600 µg, for example from about 400 µg to about 500 µg, for example from about 450 µg. In a particular embodiment of these embodiments, the implant contains an amount of about 400 µg to about 500 µg, for example from about 450 µg, of axitinib polymorph IV. In specific embodiments of these implementations, the implant is a monofilament implant, such as a monofilament implant having a substantially cylindrical shape and having a diameter of at least 16 mm. 2 For example, approximately 16.0 to approximately 23.0 mm 2 Hydrated surface area (as measured after 24 hours of incubation in PBS at pH 7.2 to 7.4 and 37°C).

[0716] In certain specific embodiments of the invention, the implant contains about 400 µg to about 500 µg of axitinib in the form of polymorph IV (e.g., micronized axitinib polymorph IV particles as defined herein), optionally with a hydrated surface area (as measured after incubation in PBS at pH 7.2 to 7.4 and 37°C for 24 hours) of at least 16 mm². 2 For example, approximately 16.0 to approximately 23.0 mm 2 The implant is a single-stranded implant, and optionally has a total weight of about 0.6 mg to about 1 mg in the dry state, wherein the implant is further characterized in that, in an in vitro test performed in the USP device 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:

[0717] After 0.5 hours, it is at least about 50 µg, for example, at least about 51 µg.

[0718] After 2 hours, it is at least approximately 140 µg, for example, at least approximately 150 µg.

[0719] After 6 hours, it is at least approximately 270 µg, for example, at least approximately 290 µg.

[0720] After 10 hours, it is at least approximately 350 µg, for example, at least approximately 370 µg.

[0721] After 12 hours, it is at least approximately 400 µg, for example, at least approximately 410 µg.

[0722] And / or after 16 hours it is at least about 410 µg, for example at least about 430 µg.

[0723] The implant is further characterized by the amount of axitinib released from the implant in an in vitro test conducted in the USP device 4 at 35°C ± 0.5°C in 0.01N HCl containing 0.25% cetyltrimethylammonium bromide (CTAB):

[0724] After 0.5 hours, it is at least about 50 µg, for example, at least about 51 µg.

[0725] After 1 hour, it is at least approximately 90 µg, for example, at least approximately 95 µg.

[0726] After 2 hours, it is at least approximately 140 µg, for example, at least approximately 150 µg.

[0727] After 4 hours, it is at least approximately 230 µg, for example, at least approximately 240 µg.

[0728] After 6 hours, it is at least approximately 270 µg, for example, at least approximately 290 µg.

[0729] After 8 hours, it is at least approximately 340 µg, for example, at least approximately 350 µg.

[0730] After 10 hours, it is at least approximately 350 µg, for example, at least approximately 370 µg.

[0731] After 12 hours, it is at least approximately 400 µg, for example, at least approximately 410 µg.

[0732] And / or after 16 hours it is at least about 410 µg, for example at least about 430 µg.

[0733] In these or other specific embodiments, the implant contains approximately 400 µg to approximately 500 µg, for example, approximately 450 µg, of axitinib in the form of polymorph IV (e.g., micronized axitinib polymorph IV particles as defined herein), having a hydrated surface area (as measured after 24 hours of incubation in PBS at pH 7.2 to 7.4 and 37°C) of at least 16 mm². 2 For example, approximately 16.0 to approximately 23.0 mm 2 The implant is a single-stranded implant, and has a total weight of approximately 0.6 mg to approximately 1 mg in the dry state. The implant is further characterized by the percentage of axitinib released from the implant in an in vitro test performed in the USP device 4 at 35°C ± 0.5°C in 0.01N HCl containing 0.25% cetyltrimethylammonium bromide (CTAB) (wherein the percentage of axitinib released is based on the maximum amount of axitinib released from the implant representing 100%).

[0734] After 0.5 hours, it is at least approximately 10%, for example, at least approximately 12%.

[0735] After 2 hours, it is at least approximately 30%, for example, at least approximately 32%.

[0736] After 6 hours, it is at least approximately 58%, for example, at least approximately 60%.

[0737] After 10 hours, it is at least approximately 75%, for example, at least approximately 80%.

[0738] After 12 hours, it is at least approximately 80%, for example, at least approximately 85%.

[0739] And / or after 16 hours it is at least approximately 90%, for example at least approximately 95%;

[0740] The implant is further characterized by the percentage of axitinib released from the implant in an in vitro test performed in the USP device 4 at 35°C ± 0.5°C in 0.01N HCl containing 0.25% cetyltrimethylammonium bromide (CTAB) (wherein the percentage of axitinib released is based on the maximum amount of axitinib released from the implant representing 100%):

[0741] After 0.5 hours, it is at least approximately 10%, for example, at least approximately 12%.

[0742] After one hour, it is at least approximately 19%, for example, at least approximately 20%.

[0743] After 2 hours, it is at least approximately 30%, for example, at least approximately 32%.

[0744] After 4 hours, it is at least approximately 45%, for example, at least approximately 50%.

[0745] After 6 hours, it is at least approximately 58%, for example, at least approximately 60%.

[0746] After 8 hours, it is at least approximately 70%, for example, at least approximately 74%.

[0747] After 10 hours, it is at least approximately 75%, for example, at least approximately 80%.

[0748] After 12 hours, it is at least approximately 80%, for example, at least approximately 85%.

[0749] And / or after 16 hours it is at least about 90%, for example at least about 95%.

[0750] In some more specific embodiments, the implant contains about 400 µg to about 500 µg of axitinib in the form of polymorph IV (e.g., micronized axitinib polymorph IV particles as defined herein), optionally with a hydration surface area (as measured after incubation in PBS at pH 7.2 to 7.4 and 37°C for 24 hours) of at least 16 mm². 2 For example, approximately 16.0 to approximately 23.0 mm 2 The implant is a single-stranded implant, and optionally has a total weight of about 0.6 mg to about 1 mg in the dry state, wherein the implant is further characterized in that, in an in vitro test performed in the USP device 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:

[0751] After 0.5 hours, it is approximately 50 µg to approximately 80 µg, for example, approximately 55 µg to approximately 75 µg, for example, approximately 57 µg to approximately 72 µg.

[0752] After 1 hour, it is approximately 90 µg to approximately 130 µg, for example, approximately 95 µg to approximately 120 µg, for example, approximately 100 µg to approximately 120 µg.

[0753] After 2 hours, it is approximately 140 µg to approximately 210 µg, for example, approximately 140 µg to approximately 200 µg, for example, approximately 147 µg to approximately 195 µg.

[0754] After 4 hours, it is approximately 230 µg to approximately 290 µg, for example, approximately 235 µg to approximately 290 µg, for example, approximately 240 µg to approximately 280 µg.

[0755] After 6 hours, it is approximately 270 µg to approximately 380 µg, for example, approximately 295 µg to approximately 370 µg, for example, approximately 300 µg to approximately 360 µg.

[0756] After 8 hours, it is approximately 340 µg to approximately 440 µg, for example, approximately 350 µg to approximately 430 µg, for example, approximately 355 µg to approximately 420 µg.

[0757] After 10 hours, it is approximately 350 µg to approximately 470 µg, for example, approximately 380 µg to approximately 460 µg, for example, approximately 390 µg to approximately 450 µg.

[0758] After 12 hours, it is at least approximately 400 µg, for example, at least approximately 410 µg.

[0759] And / or after 16 hours it is at least about 410 µg, for example at least about 430 µg.

[0760] In these or other more specific embodiments of the invention, the implant contains about 400 µg to about 500 µg, for example about 450 µg, of axitinib in the form of polymorph IV (e.g., micronized axitinib polymorph IV particles as defined herein), having a hydrated surface area (as measured after incubation in PBS at pH 7.2 to 7.4 and 37°C for 24 hours) of at least 16 mm². 2 For example, approximately 16.0 to approximately 23.0 mm 2 The single-stranded implant, having a total weight of approximately 0.6 mg to approximately 1 mg, is further characterized by the percentage of axitinib released from the implant in an in vitro test performed in the USP device 4 at 35°C ± 0.5°C in 0.01N HCl containing 0.25% cetyltrimethylammonium bromide (CTAB) (wherein the percentage of axitinib released is based on the maximum amount of axitinib representing 100% released from the implant):

[0761] After 0.5 hours, the percentage is approximately 10% to 20%, for example, approximately 10% to 18%, or approximately 12% to 17%.

[0762] After one hour, it is approximately 19% to 30%, for example, approximately 20% to 27%, for example, approximately 20% to 26%.

[0763] After 2 hours, it is approximately 30% to approximately 45%, for example, approximately 31% to approximately 43%, for example, approximately 32% to approximately 41%.

[0764] After 4 hours, it is approximately 45% to approximately 65%, for example, approximately 48% to approximately 63%, or approximately 49% to approximately 60%.

[0765] After 6 hours, it is approximately 58% to approximately 81%, for example, approximately 60% to approximately 80%, for example, approximately 62% to approximately 78%.

[0766] After 8 hours, it is approximately 70% to 90%, for example, approximately 73% to 87%, for example, approximately 74% to 86%.

[0767] After 10 hours, it is approximately 75% to approximately 98%, for example, approximately 78% to approximately 95%, for example, approximately 80% to approximately 95%.

[0768] After 12 hours, it is at least approximately 80%, for example, at least approximately 85%.

[0769] And / or after 16 hours it is at least about 90%, for example at least about 95%.

[0770] In vivo release and hydrogel durability:

[0771] In embodiments of the invention, when the dry implant of the invention is applied to the eye (e.g., vitreous fluid), it becomes hydrated and changes size as disclosed herein, and the hydrogel subsequently biodegrades over time until it is completely reabsorbed. As the implant biodegrades, for example via ester hydrolysis, it may gradually swell and soften, then become smaller, softer, and more fluid until it is completely dissolved and no longer visible. After the hydrogel has completely degraded, undissolved TKI particles may remain at the original site of the implant and, in some cases, may aggregate, i.e., merge into a single monolithic structure. These remaining undissolved axitinib particles may continue to dissolve slowly at a rate sufficient to provide a therapeutically effective TKI level. If two or more implants are applied in some embodiments to achieve the desired total dose, they biodegrade equally over time, and the remaining axitinib particles also merge into a single monolithic structure.

[0772] In some embodiments, the hydrogel implant softens over time as it degrades, which can be particularly determined by the structure of the linkers of the crosslinked PEG units in the hydrogel (i.e., the hydrophilicity or hydrophobicity of the carbon chains adjacent to the degradable ester groups). For example, in the implants used in the embodiments herein, the carbon chains contain 7 carbon atoms when they originate from the SAZ functional group of a PEG (e.g., 4a20k PEG) precursor. This carbon chain can provide extended durability of up to about 9 months or up to about 12 months in the human eye, compared to shorter carbon chains when using, for example, SG functional groups that provide shorter carbon chains in the linkers.

[0773] In the human eye, such as in vitreous fluid, the implants of the present invention, in some embodiments, biodegrade (i.e., hydrogel dissolution) within about 2 to 15 months after application, or within about 4 to 13 months after application, or within about 6 to 12 months after application, or within about 6 to 18 months after application, specifically within about 6 to 9 months after application, for example within about 8 months after application, or within about 9 to 12 months after application. In certain embodiments (e.g., in embodiments where the hydrogel comprises cross-linked PEG units, such as cross-linked 4a20kPEG-SAZ and 8a20kPEG-NH2 units), the hydrogel degrades (bioresorbs) within about 8 to 9 months after injection into human vitreous fluid. In other species, the implants of the present invention may biodegrade later or earlier than in human vitreous fluid. For example, in non-human primates, such as monkeys, specifically cynomolgus monkeys, the hydrogel dissolves within approximately 5 to 6 months (specifically, in embodiments where the hydrogel contains cross-linked PEG units, such as cross-linked 4a20kPEG-SAZ and 8a20kPEG-NH2 units); and in rabbits, specifically Dutch Black rabbits, the hydrogel dissolves within approximately 4 to 5 months (specifically, in embodiments where the hydrogel contains cross-linked PEG units, such as cross-linked 4a20kPEG-SAZ and 8a20kPEG-NH2 units). Unwilling to be limited by theory, the degradation of the hydrogel (e.g., via ester hydrolysis) is largely determined by the temperature within the vitreous body. The vitreous temperature is approximately 33°C in humans, approximately 35°C in monkeys, and approximately 37°C in rabbits (F. Lorget et al., Molecular pharmaceutics, 13(9), pp. 2891-2896; and MB Landers III et al., Retina 32(1), pp. 172-176 (1 / 2012)), which provides some variation in hydrogel persistence among different species (e.g., rabbits, monkeys, and humans). The solubility of drugs (e.g., TKIs, such as axitinib) is affected to varying degrees by these temperature differences.

[0774] In one embodiment, the implant, after administration to the vitreous fluid, releases a TKI (as defined herein), such as a therapeutically effective amount of a TKI, such as axitinib, over a period of at least about 3 months, at least about 6 months, at least about 9 months, at least about 10 months, at least about 11 months, or at least about 12 months, or at least about 13 months or even longer after administration (i.e., injection). In a specific embodiment, the implant releases a TKI (e.g., axitinib) over a period of about 6 months to about 9 months after administration.

[0775] In one embodiment of the invention, after the implant (i.e., a single implant) is administered (injected) into the patient's vitreous fluid, the implant provides a therapeutic 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. In some embodiments, the implant of the invention provides a therapeutic period of about 6 months to about 12 months (e.g., about 8 months to about 11 months, or about 6 months). In a particular embodiment, the implant of the invention provides a therapeutic period of about 9 months. After one therapeutic period, a fresh implant of the invention may be injected as disclosed herein, and this sequence may be repeated as needed. For example, a second fresh implant may be injected about 9 months after the injection of the first implant. Specifically, in embodiments of the present invention, the hydrogel comprises cross-linked PEG units, such as an implant obtained by cross-linking 4a20kPEG-SAZ and 8a20kPEG-NH2 precursors, and wherein the amount of TKI (e.g., axitinib, specifically axitinib polymorph IV) contained in the implant is from about 400 µg to about 500 µg, and a new implant can be injected into the vitreous fluid about 9 months after the injection of the first implant, because by then the hydrogel has been completely biodegraded and the remaining axitinib has been released into the vitreous for delivery to the retina and / or choroid / RPE.

[0776] In one embodiment of the invention, a TKI (e.g., axitinib) is typically released from the implant into the vitreous humor at the following average rates: 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 specific embodiment of the invention, over a period of at least 3 months, e.g., at least 6 months, or at least 9 months, or at least 10 months post-injection, the TKI (e.g., axitinib) is released from the implant (in the vitreous humor, e.g., in human vitreous humor) at the following average release rates: 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. In a specific embodiment, such release of the TKI (e.g., axitinib) after implantation is sustained for at least about 3 months, e.g., about 6 months to about 9 months, or about 6 months to about 12 months. In some embodiments, the mentioned average release rate applies to the vitreous body of non-human primates (e.g., monkeys, specifically but not limited to cynomolgus monkeys). In some embodiments, the mentioned average release rate applies to the vitreous body of humans. In a particular embodiment, the implant of the present invention (e.g., an implant comprising a hydrogel and axitinib particles, wherein the hydrogel comprises cross-linked PEG units obtained by cross-linking 4a20kPEG-SAZ and 8a20kPEG-NH2 precursors, and wherein the amount of axitinib contained in the implant (specifically, axitinib polymorph IV) is from about 400 µg to about 500 µg) provides axitinib release into the human vitreous body at the following average rates: from about 0.8 µg / day to about 1.5 µg / day, for example from about 0.9 µg / day to about 1.3 µg / day, or from about 1.0 µg / day to about 1.2 µg / day, for example from about 1.0 µg / day). In some implementations, the release rate remains substantially constant for at least about 3 months, or during the first quarter or first half of the treatment period.

[0777] In vivo release and preclinical studies in non-human primates (NHP)

[0778] Especially with axitinib containing approximately 300 µg in polymorph IV form and having a hydrated surface area of ​​approximately 20 mm² 2Preclinical studies of the implant were conducted in non-human primates (NHPs). Briefly, in this ocular distribution and pharmacokinetic study, in vivo release of the implant following a single intravitreal injection was determined in cynomolgus monkeys and compared with results obtained using a reference implant containing the following doses of axitinib in the form of polymorph SAB-I: approximately 600 µg, approximately 300 µg, and three implants each containing approximately 200 µg of axitinib. The results of these studies are reported and compared in Example 10. It was found that 3 months after intravitreal injection of the single implant of the present invention containing approximately 300 µg of axitinib polymorph IV, axitinib levels in the retina, choroid, and retinal pigment epithelium (RPE) were higher than those in the reference implant (containing axitinib polymorph SAB-I). Not wishing to be limited by this theory, it is argued that these increased axitinib levels in the mentioned ocular tissues are attributable to the solubility of axitinib polymorph IV, which is approximately twice that of axitinib polymorph SAB-I, as disclosed herein, and thus provides for more rapid release of axitinib from the implant into the vitreous fluid. Based on IC50 values ​​from VEGFR-2 derived from cell-based analysis... 50 The value is 0.077 ng / mL, and considering that the vitreous half-life of axitinib is 2 hours, it has been determined (in paragraphs

[0048] to

[0050] of US 2020 / 0375889 A1) that 256 ng / day of axitinib must be released from the vitreous implant to provide a therapeutically effective concentration of axitinib in the vitreous. To date, in this study at NHP, a release rate of 986 ng / day has been measured from an implant containing approximately 300 µg of axitinib (polymorph IV), which is almost four times the required release rate of 256 ng / day.

[0779] Example 10 also provides further data on in vivo release of the implant of the present invention in NHP (specifically, cynomolgus monkeys) for more than 3 months, i.e., at 6 months and 9 months. In this example, it has been demonstrated that implants containing axitinib polymorph IV (e.g., implant 10D in Example 10, containing a dose of approximately 300 µg of axitinib) can effectively release the retina and choroid / RPE. max It appeared during the sustained release period at 3 months, and for implants containing the axitinib polymorph SAB-I (implants 10A, 10B, and 10C), retinal and choroidal / RPE t maxThis occurs at 6 or 9 months. The hydrogel of the implant of the present invention used in this study biodegrades in NHP within approximately 5 to 6 months. This means that, in some embodiments of the present invention, for implants containing a more soluble form of axitinib (e.g., axitinib polymorph IV), a larger portion of the drug payload contained in the implant is released prior to the final release that occurs during the eventual biodegradation of the hydrogel, compared to the release of comparative implants containing a poorly soluble form of axitinib (e.g., axitinib polymorph SAB-I) but otherwise comparable to the implant of the present invention (e.g., in terms of implant composition and the dosage of drug contained in the implant). Therefore, in certain embodiments of the invention, the axitinib contained in the sustained-release biodegradable ocular implant is axitinib (e.g., axitinib polymorph IV) with a solubility of at least 0.3 µg / mL (as measured after incubation for 5 days in phosphate-buffered saline (PBS) at pH 7.2 to 7.4 and 37°C). The maximum axitinib concentration in the retina and / or choroid / RPE upon final hydrogel degradation provided by the sustained-release biodegradable ocular implant is less than the maximum axitinib concentration in the retina and / or choroid / RPE upon final hydrogel degradation provided by the comparative implant, wherein the solubility of axitinib in the comparative implant is less than 0.3 µg / mL, as measured after incubation for 5 days in phosphate-buffered saline (PBS) at pH 7.2 to 7.4 and 37°C. In some of these embodiments, the total amount of axitinib contained in the comparative implant differs from the total amount of axitinib contained in the sustained-release biodegradable ocular implant by no more than 10%.

[0780] Therefore, in certain embodiments of the invention, specifically, when the implant contains an amount of about 400 µg to about 500 µg of axitinib polymorph IV, the cumulative amount of axitinib released before the biodegradation of the hydrogel is higher than the final amount of axitinib released upon biodegradation. In some embodiments, the final amount of axitinib released upon biodegradation of the hydrogel in the vitreous fluid is not higher than or not significantly higher than the cumulative amount of axitinib released by the implant while the implant remains intact before biodegradation. In some embodiments, the amount of axitinib retained in the vitreous fluid 6 months after implantation (including the amount of axitinib present in the implant residing in the vitreous fluid) is 250 µg or less, for example, 200 µg or less. In some embodiments, the concentration of axitinib in the retina or choroid / RPE provided during the final release of the hydrogel upon injection into the vitreous fluid is not higher or significantly higher than the maximum concentration of axitinib in the retina or choroid / RPE provided by the implant at any time after injection and before the implant is still intact, for example, not exceeding about 25% higher, or for example, not exceeding about 10% higher.

[0781] In some embodiments of the invention, prior to hydrogel biodegradation, implants of the present invention containing a more soluble TKI (e.g., axitinib polymorph IV, for example, in amounts of about 400 µg to about 500 µg) achieve maximum TKI (specifically, axitinib) concentrations in the NHP retina and choroid / RPE, while in implants containing a poorly soluble TKI (e.g., axitinib polymorph SAB-I), maximum TKI concentrations in the NHP retina and choroid / RPE are only reached during / after hydrogel degradation (which occurs in the NHP at about 5 to 6 months, as explained herein). See, for example, Example 10, implant 10D containing about 0.3 mg of axitinib polymorph IV, compared with implants 10A to 10C containing different amounts of axitinib polymorph SAB-I. The implant of the present invention (sample 10D) containing approximately 0.3 mg of axitinib in the more soluble axitinib polymorph IV form reached steady state earlier than the implant containing the poorly soluble axitinib polymorph SAB-I and maintained its release without any increase during hydrogel biodegradation. In Example 10, after hydrogel biodegradation, the implant containing the more soluble axitinib polymorph IV (implant 10D) showed ...

Claims

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

2. The sustained-release biodegradable ocular implant of claim 1, comprising about 410 µg to about 490 µg of axitinib polymorph IV.

3. The continuously releasing biodegradable ocular implant as described in claim 1 or 2, wherein the hydrated surface area of ​​the implant is at least 15 mm². 2 As measured after incubation for 24 hours in phosphate-buffered saline (PBS) at pH 7.2 to 7.4 and 37°C.

4. The sustained-release biodegradable ocular implant as claimed in any of the preceding claims, wherein the hydrated surface area of ​​the implant is approximately 16.0 mm². 2 To approximately 23.0 mm 2 As measured after incubation for 24 hours in phosphate-buffered saline (PBS) at pH 7.2 to 7.4 and 37°C.

5. The sustained-release biodegradable ocular implant as claimed in any of the preceding claims, wherein the axitinib particles have a d10 particle size of less than 0.25 µm, a d50 particle size of less than 2.6 µm, and a d90 particle size of less than 8 µm, as determined by laser diffraction.

6. The sustained-release biodegradable ocular implant as claimed in any of the preceding claims, wherein the total weight of the implant in a dry state is about 0.6 mg to about 1 mg.

7. The continuously releasing biodegradable ocular implant as claimed in any of the preceding claims, wherein the implant is an elongated object having a length and a width, wherein the width is the maximum cross-sectional dimension of the object and the length is the maximum elongation of the object.

8. The continuously releasing biodegradable ocular implant as claimed in any of the preceding claims, wherein the implant is cylindrical or substantially cylindrical.

9. A continuously releasing biodegradable ocular implant as claimed in any of the preceding claims, wherein the implant has a length of 11 mm or less in its dry state, such as 6 mm to 10 mm or 6 mm to 9 mm, and / or has a width of less than 0.7 mm, such as 0.1 mm to 0.65 mm or 0.20 mm to 0.45 mm.

10. The continuously releasing biodegradable ocular implant as claimed in any of the preceding claims, wherein the implant has a length of 6.7 mm to 7.8 mm and / or a width of 0.30 mm to 0.40 mm in its dry state.

11. A continuously releasing biodegradable ocular implant as claimed in any of the preceding claims, wherein the implant, in its hydrated state (after 24 hours in phosphate-buffered saline at pH 7.2 to 7.4 at 37°C), has a length of 4 mm to 12 mm, or 4 mm to 11 mm, or 6 mm to 11 mm, or 6 mm to 10 mm, and / or has a width of 0.5 mm to 0.9 mm, or 0.5 mm to 0.8 mm.

12. The sustained-release biodegradable ocular implant as claimed in any of the preceding claims, wherein the implant has a length of 7 mm to 10 mm and a width of 0.5 mm to 0.9 mm in its hydrated state (after 24 hours in PBS at pH 7.2 to 7.4 at 37°C).

13. The sustained-release biodegradable ocular implant as claimed in any of the preceding claims, wherein the hydrogel comprises a synthetic polymer network.

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

15. A sustained-release biodegradable ocular implant as claimed in any of the preceding claims, wherein the hydrogel comprises multi-arm PEG units, such as 4-arm and / or 8-arm PEG units, the units being identical or different, and having a number-average molecular weight of about 10,000 Daltons to about 60,000 Daltons, or about 15,000 Daltons to about 40,000 Daltons, such as about 20,000 Daltons.

16. The sustained-release biodegradable ocular implant of any one of claims 13 to 15, wherein the polymer network is formed by reacting an electrophilic PEG precursor with a nucleophilic crosslinking agent, wherein the crosslinking agent is a nucleophilic PEG precursor or another nucleophilic crosslinking agent.

17. The sustained-release biodegradable ocular implant of claim 16, wherein the nucleophilic group is an amino group, for example, wherein the crosslinking agent containing the nucleophilic group is trilysine or a salt or derivative thereof, and the electrophilic group is an activated ester group, such as N-hydroxysuccinimide (NHS).

18. The sustained-release biodegradable ocular implant of any one of claims 16 or 17, wherein the electrophilic group is one or more of the following: succinimide azelaate (SAZ) group, succinimide adipate (SAP) group, succinimide glutarate (SG) group, succinimide glutaramide (SGA) group, succinimide carbonate (SC) group, or succinimide succinate (SS) group, especially succinimide azelaate (SAZ) group.

19. A sustained-release biodegradable ocular implant as claimed in any of the preceding claims, wherein the hydrogel comprises cross-linked PEG units, and the cross-linking between the PEG units comprises groups represented by the following formula. Where m is an integer from 0 to 10, for example m is 1, 2, 3 or 6, especially m is 6.

20. The sustained-release biodegradable ocular implant of any one of claims 13 to 19, wherein the polymer network is formed by crosslinking 4a20kPEG-SAZ and 8a20kPEG-NH2.

21. The sustained-release biodegradable ocular implant as claimed in any of the preceding claims, comprising (dry basis; % w / w): about 30 wt% to about 70 wt%, or about 40 wt% to about 70 wt%, or about 45 wt% to about 65 wt% of axitinib, and about 20 wt% to about 50 wt%, or about 25 wt% to about 45 wt%, or about 30 wt% to about 43 wt% of PEG units; or comprising (dry basis; % w / w): about 60 wt% to about 70 wt% of axitinib and about 25 wt% to about 35 wt% of PEG units.

22. The sustained-release biodegradable ocular implant as claimed in any of the preceding claims, having the following composition (wet basis; in % w / w): about 5 wt% to about 20 wt%, or about 6 wt% to about 15 wt% of axitinib, and about 4 wt% to about 12 wt%, or about 5 wt% to about 10 wt% of PEG units.

23. The continuously releasing biodegradable ocular implant as described in any of the preceding claims, characterized in that... In an in vitro test conducted in USP device 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 (wherein the percentage of axitinib released is based on the maximum amount of axitinib representing 100% released from the implant): After 0.5 hours, it is at least about 10%. After 2 hours, it is at least about 30%. After 6 hours, it is at least about 58%. After 10 hours, it is at least about 75%. After 12 hours, it is at least about 80%. And / or at least approximately 90% after 16 hours; For example: After 0.5 hours, it is at least about 10%. After one hour, it is at least about 19%. After 2 hours, it is at least about 30%. After 4 hours, it is at least about 45%. After 6 hours, it is at least about 58%. After 8 hours, it is at least about 70%. After 10 hours, it is at least about 75%. After 12 hours, it is at least about 80%. And / or at least about 90% after 16 hours.

24. The continuously releasing biodegradable ocular implant as described in any of the preceding claims, characterized in that... In an in vitro test conducted in USP device 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 (wherein the percentage of axitinib released is based on the maximum amount of axitinib representing 100% released from the implant): After 0.5 hours, it is approximately 10% to approximately 20%. After 2 hours, it is approximately 30% to approximately 45%. After 6 hours, it was approximately 58% to approximately 81%. After 10 hours, it is approximately 75% to approximately 98%. After 12 hours, it is at least about 80%. And / or at least approximately 90% after 16 hours. For example: After 0.5 hours, it is approximately 10% to approximately 20%. After one hour, it was approximately 19% to approximately 30%. After 2 hours, it is approximately 30% to approximately 45%. After 4 hours, it is approximately 45% to approximately 65%. After 6 hours, it was approximately 58% to approximately 81%. After 8 hours, it is approximately 70% to approximately 90%. After 10 hours, it is approximately 75% to approximately 98%. After 12 hours, it is at least about 80%. And / or at least about 90% after 16 hours.

25. The sustained-release biodegradable ocular implant as described in any of the preceding claims, characterized in that... In an in vitro test conducted in USP device 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 (wherein the percentage of axitinib released is based on the maximum amount of axitinib representing 100% released from the implant): After 0.5 hours, it is approximately 10% to approximately 18%. After 2 hours, it was approximately 31% to approximately 43%. After 6 hours, it is approximately 60% to approximately 80%. After 10 hours, it is approximately 78% to approximately 95%. After 12 hours, it is at least about 85%. And / or at least approximately 95% after 16 hours. For example: After 0.5 hours, it is approximately 12% to approximately 17%. After 2 hours, it was approximately 32% to approximately 41%. After 6 hours, it was approximately 62% to approximately 78%. After 10 hours, it is approximately 80% to approximately 95%. After 12 hours, it is at least about 85%. And / or at least approximately 95% after 16 hours.

26. The sustained-release biodegradable ocular implant as described in any of the preceding claims, characterized in that... In an in vitro test conducted in USP device 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: After 0.5 hours, it is at least about 50 µg. After 2 hours, it is at least approximately 140 µg. After 6 hours, it was at least approximately 270 µg. After 10 hours, it is at least approximately 350 µg. After 12 hours, it is at least approximately 400 µg. And / or at least approximately 410 µg after 16 hours, For example: After 0.5 hours, it is at least about 50 µg. After 1 hour, it is at least approximately 90 µg. After 2 hours, it is at least approximately 140 µg. After 4 hours, it was at least approximately 230 µg. After 6 hours, it was at least approximately 270 µg. After 8 hours, it was at least approximately 340 µg. After 10 hours, it is at least approximately 350 µg. After 12 hours, it is at least approximately 400 µg. And / or at least about 410 µg after 16 hours.

27. The continuously releasing biodegradable ocular implant as described in any of the preceding claims, characterized in that... In an in vitro test conducted in USP device 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: After 0.5 hours, it is approximately 50 µg to approximately 80 µg. After 2 hours, it was approximately 140 µg to approximately 210 µg. After 6 hours, it was approximately 270 µg to approximately 380 µg. After 10 hours, it was approximately 350 µg to approximately 470 µg. After 12 hours, it is at least approximately 400 µg. And / or at least approximately 410 µg after 16 hours, For example: After 0.5 hours, it is approximately 50 µg to approximately 80 µg. After 1 hour, it was approximately 90 µg to approximately 130 µg. After 2 hours, it was approximately 140 µg to approximately 210 µg. After 4 hours, it was approximately 230 µg to approximately 290 µg. After 6 hours, it was approximately 270 µg to approximately 380 µg. After 8 hours, it was approximately 340 µg to approximately 440 µg. After 10 hours, it was approximately 350 µg to approximately 470 µg. After 12 hours, it is at least approximately 400 µg. And / or at least about 410 µg after 16 hours.

28. The continuously releasing biodegradable ocular implant as described in any of the preceding claims, characterized in that... In an in vitro test conducted in USP device 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: After 0.5 hours, it was approximately 55 µg to approximately 75 µg. After 2 hours, it was approximately 140 µg to approximately 200 µg. After 6 hours, it was approximately 295 µg to approximately 370 µg. After 10 hours, it was approximately 350 µg to approximately 460 µg. After 12 hours, it was at least approximately 410 µg. And / or at least approximately 430 µg after 16 hours, For example: After 0.5 hours, it was approximately 57 µg to approximately 72 µg. After 2 hours, it was approximately 147 µg to approximately 195 µg. After 6 hours, it was approximately 300 µg to approximately 360 µg. After 10 hours, it was approximately 390 µg to approximately 450 µg. After 12 hours, it was at least approximately 410 µg. And / or at least about 430 µg after 16 hours.

29. A sustained-release biodegradable ocular implant as claimed in any of the preceding claims, wherein the axitinib polymorph IV in the implant contains, upon exposure to visible light, 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 than the powdered form of axitinib polymorph IV under the same exposure time and conditions.

30. A sustained-release biodegradable ocular implant as claimed in any of the preceding claims, wherein the axitinib polymorph IV in the implant contains, upon exposure to UV light, at least about 10% less total impurities than, 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 in powder form of axitinib polymorph IV under the same exposure time and conditions.

31. The continuously releasing biodegradable ocular implant as claimed in any of the preceding claims, wherein the implant is an intravitreal implant.

32. The sustained-release biodegradable ocular implant of claim 1, wherein the hydrogel comprises a number of cross-linked multi-arm PEG units with an average molecular weight of about 20,000 Daltons, wherein the cross-linking between the PEG units comprises groups represented by the following formula. Where m is 6. The implant is cylindrical and has a length of 10 mm or less and a diameter of 0.25 mm to 0.45 mm in its dry state, and / or has a length of 10 mm or less and a diameter of 0.5 mm to 0.9 mm in its hydrated state (after 24 hours in PBS at pH 7.2 to 7.4 at 37°C), and the axitinib particles have a d90 particle size of less than 10 µm, for example less than 8 µm, and / or a d50 particle size of less than 3 µm.

33. The sustained-release biodegradable ocular implant of claim 1, wherein the implant is an intravitreal implant and has the following composition: about 30% to about 75% axitinib, about 20% to about 50% PEG units and about 0.5% to about 15% sodium phosphate on a dry basis (in % w / w), and about 5% to about 17% axitinib, about 4% to about 12% PEG units and about 0.2% to about 5% sodium phosphate on a wet basis (in % w / w). The hydrogel comprises a PEG hydrogel network formed by crosslinking 4a20kPEG-SAZ and 8a20kPEG-NH2 units. The implant is longer than its width and has a length of 11 mm or less, for example 5 mm to 11 mm, and a width of 0.2 mm to 0.4 mm, for example 0.28 mm to 0.38 mm, in its dry state, and / or has a length of 11 mm or less, for example 5 mm to 11 mm, and a width of 0.4 mm to 2 mm, in its hydrated state (after 24 hours in PBS at pH 7.4 at 37°C). Furthermore, the axitinib particles described herein have a d90 particle size of less than 8 µm and a d50 particle size of less than 3 µm.

34. The sustained-release biodegradable ocular implant of claim 1, wherein the implant is an intravitreal implant and has the following composition: about 30% to about 75% axitinib, about 20% to about 50% PEG units and about 0.5% to about 15% sodium phosphate on a dry basis (in % w / w), and about 5% to about 17% axitinib, about 4% to about 12% PEG units and about 0.2% to about 5% sodium phosphate on a wet basis (in % w / w). The hydrogel comprises a PEG hydrogel network formed by crosslinking 4a20kPEG-SAZ and 8a20kPEG-NH2 precursors. The implant has a width of 0.20 mm to 0.40 mm in its dry state and a length of 11 mm or less in its hydrated state (after 24 hours in PBS at pH 7.4 at 37°C). And the implant described herein has a diameter of 10 to 30 mm. 2 Hydrated surface area (as measured after 24 hours of incubation in phosphate-buffered saline (PBS) at pH 7.2 to 7.4 and 37°C).

35. The sustained-release biodegradable ocular implant as described in claim 34, The implant has a width of 0.30 mm to 0.36 mm in its dry state and a length of 10.5 mm or less in its hydrated state (after 24 hours in PBS at pH 7.4 at 37°C). And the implant described therein has a diameter of 16 to 25 mm. 2 For example, 16 to 23 mm 2 Hydrated surface area (as measured after 24 hours of incubation in phosphate-buffered saline (PBS) at pH 7.2 to 7.4 and 37°C).

36. The sustained-release biodegradable ocular implant of claim 1, wherein the implant is an intravitreal implant and has the following composition: about 30% to about 75% axitinib, about 20% to about 50% PEG units and about 0.5% to about 15% sodium phosphate on a dry basis (in % w / w), and about 5% to about 17% axitinib, about 4% to about 12% PEG units and about 0.2% to about 5% sodium phosphate on a wet basis (in % w / w). The hydrogel comprises a PEG hydrogel network formed by crosslinking 4a20kPEG-SAZ and 8a20kPEG-NH2 units. The implant has a length of 5 mm to 11 mm and a width of 0.28 mm to 0.38 mm in its dry state, and / or a length of 5 mm to 11 mm and a width of 0.4 mm to 2 mm in its hydrated state (after 24 hours in PBS at pH 7.4 at 37°C).

37. The sustained-release biodegradable ocular implant of claim 1, wherein the implant is an intravitreal implant and has the following composition on a dry basis (% w / w): The composition includes approximately 54% to approximately 69% axitinib, a PEG hydrogel network formed by crosslinking approximately 17% to approximately 26% 4a20kPEG-SAZ and approximately 8% to approximately 13% 8a20kPEG-NH2, approximately 3% to approximately 5% disodium hydrogen phosphate, and approximately 1% to approximately 3% sodium dihydrogen phosphate.

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

39. The sustained-release biodegradable ocular implant of claim 1, wherein the hydrogel comprises a PEG hydrogel, and wherein the implant has a width of about 0.30 mm to about 0.36 mm in its dry state. Furthermore, the implant provides axitinib release in an in vitro test conducted in the USP device 4 at 35°C ± 0.5°C in 0.01N HCl containing 0.25% cetyltrimethylammonium bromide (CTAB), characterized in that... The percentage of axitinib released from the implant (wherein the percentage of axitinib released is based on the maximum amount of axitinib released, representing 100% of the total amount released from the implant): After 0.5 hours, it is at least about 10%. After 2 hours, it is at least about 30%. After 6 hours, it is at least about 58%. After 10 hours, it is at least about 75%. After 12 hours, it is at least about 80%. And / or at least approximately 90% after 16 hours; For example: After 0.5 hours, it is at least about 10%. After one hour, it is at least about 19%. After 2 hours, it is at least about 30%. After 4 hours, it is at least about 45%. After 6 hours, it is at least about 58%. After 8 hours, it is at least about 70%. After 10 hours, it is at least about 75%. After 12 hours, it is at least about 80%. And / or at least about 90% after 16 hours.

40. The sustained-release biodegradable ocular implant of claim 1, wherein the hydrogel comprises a hydrogel network formed by crosslinking 4a20kPEG-SAZ and 8a20kPEG-NH2 units. The implant described herein has the following composition (dry basis; % w / w): approximately 60% to approximately 70% axitinib and approximately 25% to approximately 35% PEG units. The implant, in its dry state, has a width of about 0.30 mm to about 0.36 mm and a total weight of about 0.6 mg to about 1 mg. Furthermore, the implant provides axitinib release in an in vitro test conducted in the USP device 4 at 35°C ± 0.5°C in 0.01N HCl containing 0.25% cetyltrimethylammonium bromide (CTAB), characterized in that... The percentage of axitinib released from the implant (wherein the percentage of axitinib released is based on the maximum amount of axitinib released, representing 100% of the total amount released from the implant): After 0.5 hours, it is approximately 10% to approximately 20%. After 2 hours, it is approximately 30% to approximately 45%. After 6 hours, it was approximately 58% to approximately 81%. After 10 hours, it is approximately 75% to approximately 98%. After 12 hours, it is at least about 80%. And / or at least approximately 90% after 16 hours. For example: After 0.5 hours, it is approximately 10% to approximately 20%. After one hour, it was approximately 19% to approximately 30%. After 2 hours, it is approximately 30% to approximately 45%. After 4 hours, it is approximately 45% to approximately 65%. After 6 hours, it was approximately 58% to approximately 81%. After 8 hours, it is approximately 70% to approximately 90%. After 10 hours, it is approximately 75% to approximately 98%. After 12 hours, it is at least about 80%. And / or at least about 90% after 16 hours.

41. The sustained-release biodegradable ocular implant of claim 1, wherein the hydrogel comprises a PEG hydrogel, and wherein the implant has a width of about 0.30 mm to about 0.36 mm in its dry state. Furthermore, the implant is characterized in that, in an in vitro test conducted in the USP device 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: After 0.5 hours, it is at least about 50 µg. After 2 hours, it is at least approximately 140 µg. After 6 hours, it was at least approximately 270 µg. After 10 hours, it is at least approximately 350 µg. After 12 hours, it is at least approximately 400 µg. And / or at least approximately 410 µg after 16 hours, For example: After 0.5 hours, it is at least about 50 µg. After 1 hour, it is at least approximately 90 µg. After 2 hours, it is at least approximately 140 µg. After 4 hours, it was at least approximately 230 µg. After 6 hours, it was at least approximately 270 µg. After 8 hours, it was at least approximately 340 µg. After 10 hours, it is at least approximately 350 µg. After 12 hours, it is at least approximately 400 µg. And / or at least about 410 µg after 16 hours.

42. The sustained-release biodegradable ocular implant of claim 1, wherein the hydrogel comprises a PEG hydrogel network formed by crosslinking 4a20kPEG-SAZ and 8a20kPEG-NH2 units. The implant described herein has the following composition (dry basis; % w / w): approximately 60% to approximately 70% axitinib and approximately 25% to approximately 35% PEG units. The implant, in its dry state, has a width of about 0.30 mm to about 0.36 mm and a total weight of about 0.6 mg to about 1 mg. Furthermore, the implant is characterized in that, in an in vitro test conducted in the USP device 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: After 0.5 hours, it is approximately 50 µg to approximately 80 µg. After 2 hours, it was approximately 140 µg to approximately 210 µg. After 6 hours, it was approximately 270 µg to approximately 380 µg. After 10 hours, it was approximately 350 µg to approximately 470 µg. After 12 hours, it is at least approximately 400 µg. And / or at least approximately 410 µg after 16 hours, For example: After 0.5 hours, it is approximately 50 µg to approximately 80 µg. After 1 hour, it was approximately 90 µg to approximately 130 µg. After 2 hours, it was approximately 140 µg to approximately 210 µg. After 4 hours, it was approximately 230 µg to approximately 290 µg. After 6 hours, it was approximately 270 µg to approximately 380 µg. After 8 hours, it was approximately 340 µg to approximately 440 µg. After 10 hours, it was approximately 350 µg to approximately 470 µg. After 12 hours, it is at least approximately 400 µg. And / or at least about 410 µg after 16 hours.

43. The sustained-release biodegradable ocular implant of claims 39 to 42, wherein the implant has a diameter of at least 16 mm. 2 For example, 16 to 23 mm 2 The surface area of ​​the monofilament implant was hydrated (after 24 hours in PBS at pH 7.2 to 7.4 at 37°C).

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

45. The sustained-release biodegradable ocular implant of claim 1, wherein the hydrogel comprises cross-linked PEG units. The amount of axitinib released when the hydrogel eventually degrades in vitreous fluid is less than 200 µg. The implant has a width of about 0.3 mm to about 0.4 mm and a length of less than about 11 mm in its dry state (before injection) and a length of less than about 11 mm in its hydrated state (after 24 hours in PBS at pH 7.4 at 37°C).

46. ​​A sustained-release biodegradable ocular implant comprising a hydrogel and a tyrosine kinase inhibitor (TKI), wherein the tyrosine kinase inhibitor particles are dispersed within the hydrogel, the implant being characterized in that the solubility of the tyrosine kinase inhibitor is 0.3 µg / mL or greater, as measured after incubation for 5 days in phosphate-buffered saline (PBS) at pH 7.2 to 7.4 and 37°C.

47. A sustained-release biodegradable ocular implant comprising a hydrogel and a tyrosine kinase inhibitor, wherein tyrosine kinase inhibitor particles are dispersed within the hydrogel, the implant being characterized in that the hydrated surface area of ​​the implant is at least 25 mm². 2 As measured after incubation for 24 hours in phosphate-buffered saline (PBS) at pH 7.2 to 7.4 and 37°C.

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

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

50. The sustained-release biodegradable ocular implant of any one of claims 46 to 49, wherein the TKI is axitinib, and the axitinib particles are dispersed within the hydrogel, wherein after incubation for 5 days in phosphate-buffered saline (PBS) at pH 7.2 to 7.4 and 37°C, the solubility of the axitinib in the sustained-release biodegradable ocular 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 ocular implant of claim 50, wherein the TKI in the sustained-release biodegradable ocular implant is axitinib, and the axitinib is in the form of its free base, solvate, salt, cocrystal, derivative, prodrug, or a mixture thereof.

52. The sustained-release biodegradable ocular implant of any one of claims 46 to 50, wherein the sustained-release biodegradable ocular implant contains axitinib free base in the form of one or more axitinib polymorphs.

53. The sustained-release biodegradable ocular implant as claimed in any of the preceding claims, wherein the axitinib polymorph contained in the sustained-release biodegradable ocular implant is characterized by having a powder X-ray diffraction pattern comprising at least one, for example at least two, at least three, or at least four, peaks at the following diffraction angles (2θ): 8.90, 9.50, 12.0, 14.60, 15.25, 15.75, 17.80, 19.30, 20.65, 24.95, 26.10 (all ± 0.2).

54. The sustained-release biodegradable ocular implant according to any one of claims 1 to 52, wherein the axitinib polymorph contained in the sustained-release biodegradable ocular implant is characterized by a powder X-ray diffraction pattern containing peaks at the following diffraction angles (2θ): 8.90, 12.0, 14.60, 15.75, and 19.30 (all ± 0.2).

55. The sustained-release biodegradable ocular implant according to any one of claims 1 to 52, wherein the axitinib polymorph contained in the sustained-release biodegradable ocular implant is characterized by a powder X-ray diffraction pattern comprising peaks at the following diffraction angles (2θ): 8.9, 14.6, 15.7 and 19.2 (all ± 0.1), or 8.9 and 15.7 (all ± 0.1).

56. A cassette comprising one or more continuously releasing biodegradable ocular implants as claimed in any one of claims 1 to 55 and one or more injection needles, wherein each implant is loaded in a needle of gauge 25 or finer.

57. The cassette of claim 56, further comprising one or more syringe components, wherein each needle is pre-connected to a syringe component.

58. The pillbox of claim 56, further comprising one or more syringe components, wherein the one or more needles are not pre-connected to the syringe components.

59. A method of treating an eye disease in a patient in need, the method comprising administering to the patient's eye a continuously releasing biodegradable ocular implant as claimed in any one of claims 1 to 55, wherein the implant is administered via intravitreal injection.

60. The method of claim 59, wherein the ocular 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 wherein the ocular disease is acute multifocal squamous pigment epithelial lesion, Bechtel's disease, shotgun retinochoroidal lesion, infectious diseases (syphilis, Lyme disease, tuberculosis, toxoplasmosis), intermediate uveitis (paris plaque inflammation), multifocal choroiditis, multiple transient white spot syndrome (MEWDS), ocular nodules. Diseases, posterior scleritis, creeping choroiditis, subretinal fibrosis, uveitis syndrome, or Vogt-Koyanagi-Harada syndrome; or wherein the ocular disease is a vascular or exudative disease, including Coats' disease, parafoveal telangiectasia, papillary phlebitis, frost-like dendritic retinal vasculitis, sickle cell retinopathy and other hemoglobinopathies, angiostriate syndrome, and familial exudative vitreoretinopathy; or wherein the ocular disease is caused by trauma or surgery, including sympathetic ophthalmia, uveitis-related retinal disease, retinal detachment, trauma, photodynamic laser therapy, photocoagulation, inadequate perfusion during surgery, radiation retinopathy, or bone marrow transplant retinopathy.

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

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

63. The method of any one of claims 59 to 62, wherein the treatment period using an implant lasts for at least about 3 months, or at least about 6 months, or at least about 9 months, or at least about 12 months.

64. The method of any one of claims 59 to 62, wherein the treatment period using an implant lasts from about 6 months to about 12 months after application, or from about 6 months to about 9 months after application.

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

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

25.

67. The method of any one of claims 59 to 66, wherein, upon completion of a treatment period using an implant, a new implant of any one of claims 1 to 55 is administered to the patient for a subsequent treatment period.

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

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

70. The method of any one of claims 59 to 69, wherein the new implant as claimed in any one of claims 1 to 55 is applied about 6 months, or about 9 months, or about 12 months after the application of the aforementioned implant.

71. The method of any one of claims 59 to 70, wherein the new implant as described in any one of claims 1 to 55 is applied every 6 to 12 months.

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

73. The method of 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 mitigation of VEGF-induced retinal vascular leakage during the treatment period.

74. The method of any one of claims 59 to 73, wherein the patient is diagnosed with extrafoveolar choroidal neovascularization (CNV) or subfoveolar neovascularization (SFNV) secondary to neovascular AMD (nAMD).

75. The method of any one of claims 59 to 74, wherein the patient has not received nAMD treatment.

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

77. The method of any one of claims 59 to 76, wherein the treatment with the continuously releasing biodegradable ocular implant maintains or substantially maintains visual acuity (BCVA) during the treatment period.

78. The method of any one of claims 59 to 76, wherein treatment with the continuously releasing biodegradable ocular implant prevents or substantially prevents a decrease in visual acuity (BCVA) during the treatment period.

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

80. The method of claim 79, wherein, without administration or administration of no more than one emergency medication, at 9 or 12 months after injection of the implant, the patient experiences a BCVA loss of fewer than 15 ETDRS letters compared to baseline.

81. The method of any one of claims 59 to 80, wherein the implant provides an average axitinib release rate of more than about 0.8 µg / day, for example, at least about 1.0 µg / day, in vitreous fluid for a period of at least 3 months after injection.

82. The method of 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 higher than or significantly higher than the cumulative amount of axitinib released by the implant while the implant was still intact before biodegradation.

83. The method of 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 about 130 µg or less.

84. The method of any one of claims 59 to 83, wherein the amount of axitinib retained in the vitreous fluid at 6 months after implantation (including the amount of axitinib in the implant residing in the vitreous fluid) is 250 µg or less, for example 200 µg or less.

85. The method of any one of claims 59 to 84, wherein the concentration of axitinib in the retina or choroid / RPE provided during the final release of the hydrogel upon injection into the vitreous fluid is not higher than or significantly higher than the maximum concentration of axitinib provided by the implant in the retina or the choroid / RPE at any time after injection and before the implant is still intact, for example, not exceeding about 25% higher, for example, not exceeding about 10% higher.

86. The method of any one of claims 59 to 85, wherein, after injection into the vitreous fluid, the maximum axitinib concentration is achieved in the retina and / or the choroid / RPE by the sustained release of the biodegradable ocular implant prior to the eventual biodegradation of the hydrogel.

87. The method of any one of claims 59 to 86, wherein after injecting the implant into the eye of a cynomolgus monkey, and after injecting it into the vitreous fluid, axitinib is injected into the retina or the choroid / RPE. max Earlier than about 6 months, for example, earlier than about 5 months, for example, earlier than about 4 months, for example, at about 3 months or earlier than about 3 months, for example, earlier than about 2 months; or In the case of injecting the implant into the eye of a Dutch Black Belt rabbit, axitinib in the retina or the choroid / RPE... max Earlier than about 6 months, for example, at about 5.5 months or earlier, or earlier than about 5 months, for example, earlier than about 4 months, for example, at about 3 months or earlier than about 3 months, for example, earlier than about 2 months, for example, earlier than about 1 month; or In human patients, after injection into the eye, axitinib showed t in the retina or choroid / RPE. max Earlier than about 9 months, for example, earlier than about 8 months, for example, earlier than about 7 months, for example, earlier than about 6 months, for example, earlier than about 5 months, for example, earlier than about 4 months.

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

89. The method of any one of claims 59 to 88, wherein, after injection into the vitreous fluid and before the biodegradation of the hydrogel, the sustained release of the biodegradable ocular implant provides C-level concentrations of axitinib in the retina or the choroid / RPE. max Higher than that of axitinib provided by comparative implants. max , The total amount of axitinib contained in the comparative implant is within + / - 10% of the total amount of axitinib contained in the sustained-release biodegradable ocular implant, for example, within + / - 5%, and differs from the sustained-release biodegradable ocular implant in that (e.g., only) the solubility of the form of axitinib contained in the comparative implant is lower than that of axitinib polymorph IV, as measured after incubation in PBS at pH 7.2 to 7.4 and 37°C for 5 days, and the hydrated surface area of ​​the comparative implant (as measured after incubation in phosphate-buffered saline (PBS) at pH 7.2 to 7.4 and 37°C for 24 hours) is within + / - 20% of the hydrated surface area of ​​the sustained-release biodegradable ocular implant, for example, within + / - 10%.

90. The method of any one of claims 59 to 89, wherein, after injection into the vitreous fluid, the continuously releasing biodegradable ocular implant provides axitinib in the retina or the choroid / RPE. max Earlier than axitinib provided by comparative implants, t max , The total amount of axitinib contained in the comparative implant is within + / - 10% of the total amount of axitinib contained in the sustained-release biodegradable ocular implant, for example, within + / - 5%, and differs from the sustained-release biodegradable ocular implant in that (e.g., only) the solubility of the form of axitinib contained in the comparative implant is lower than that of axitinib polymorph IV, as measured after incubation in PBS at pH 7.2 to 7.4 and 37°C for 5 days, and the hydrated surface area of ​​the comparative implant (as measured after incubation in phosphate-buffered saline (PBS) at pH 7.2 to 7.4 and 37°C for 24 hours) is within + / - 20% of the hydrated surface area of ​​the sustained-release biodegradable ocular implant, for example, within + / - 10%.

91. The method of any one of claims 59 to 90, wherein, after injection into the vitreous fluid, the geometric mean amount (in µg) of axitinib in the vitreous fluid (which includes the amount of axitinib in the continuously releasing biodegradable ocular implant remaining in the vitreous fluid after injection is lower than the geometric mean amount (in µg) of axitinib in the vitreous fluid at any time point selected from 3 months, 6 months, or 9 months after injection of the comparative implant. The comparative implant differs from the sustained-release biodegradable ocular implant in that (e.g., only in that) the solubility of axitinib contained in the comparative implant is lower than that of axitinib polymorph IV, as measured after incubation in PBS at pH 7.2 to 7.4 and 37°C for 5 days.

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

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

94. The method of any one of claims 59 to 86, wherein, after the implant is injected into the vitreous fluid, respectively, the geometric mean concentration (in ng / g) of axitinib in the retina and / or the choroid / RPE at week 6 after injection of the sustained-release biodegradable ocular implant is higher than that at week 6 after injection of the comparative implant. The comparative implant differs from the sustained-release biodegradable ocular implant in that (e.g., only) the solubility of axitinib in the comparative implant is lower than that of axitinib polymorph IV, as measured after incubation in PBS at pH 7.2 to 7.4 and 37°C for 5 days.

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

96. The method of claim 94 or 95, wherein the subject is a rabbit, such as a Dutch black-banded rabbit, and the concentration of axitinib in the retina and / or the choroid / RPE is measured in the rabbit.

97. The method of any one of claims 88 to 96, wherein the sustained-release biodegradable ocular implant comprises axitinib polymorph IV, and wherein the comparative implant differs from the sustained-release biodegradable ocular implant only in that... (a) The solubility of the axitinib contained in the comparative implant was lower than that of axitinib polymorph IV, as measured after incubation in PBS at pH 7.2 to 7.4 and 37°C for 5 days. (b) The difference between the hydrated surface area and that of the comparative implant (as measured after incubation in phosphate-buffered saline (PBS) at pH 7.2 to 7.4 and 37°C for 24 hours) does not exceed 5%, and (c) The total amount of axitinib contained in the comparative implant does not differ by more than 5%; or is in the range of (a) The solubility of the axitinib contained in the comparative implant was lower than that of axitinib polymorph IV, as measured after incubation in PBS at pH 7.2 to 7.4 and 37°C for 5 days. (b) The total amount of axitinib contained in the comparative implant is at least 1.5 times higher, and (c) The difference between the hydrated surface area and that of the comparative implant (as measured after incubation in phosphate-buffered saline (PBS) at pH 7.2 to 7.4 and 37°C for 24 hours) does not exceed 10%; or is greater than or equal to the hydrated surface area of ​​the comparative implant. (a) The solubility of the axitinib contained in the comparative implant was lower than that of axitinib polymorph IV, as measured after incubation in PBS at pH 7.2 to 7.4 and 37°C for 5 days. (b) The difference between the hydrated surface area and that of the comparative implant (as measured after incubation in phosphate-buffered saline (PBS) at pH 7.2 to 7.4 and 37°C for 24 hours) does not exceed 10%, and (c) The total amount of axitinib contained in the comparative implant is at least twice as high.

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

99. The method of any one of claims 59 to 98, wherein the treatment is characterized in that, compared with VEGF-induced retinal leakage at the corresponding same time period after administration of bevacizumab (Avastin), VEGF-induced retinal vascular leakage is reduced or delayed for at least about 1 month, for example at least about 2 months, for example at least about 3 months, as measured in a VEGF stimulation study in rabbits (e.g., Holland Black rabbits), said study comprising intravitreal injection of the continuous-release biodegradable ocular implant into the rabbit eye, wherein the rabbit eye is subsequently administered at least three doses of 1 µg of VEGF over a 3-month period, compared with administration of 50 µL of 25 mg / mL bevacizumab under the same conditions including said VEGF stimulation.

100. The implant as claimed in any one of claims 1 to 55, used in the method as claimed in any one of claims 59 to 99.

101. The use of the implant as claimed in any one of claims 1 to 55 for manufacturing a medicament for use in any one of claims 59 to 99.

102. A method for manufacturing a sustained-release biodegradable ocular implant as claimed in any one of claims 1 to 55, the method comprising the following steps: A hydrogel is formed, the hydrogel comprising a polymer network and axitinib particles dispersed within the hydrogel, the hydrogel is shaped, and the hydrogel is dried.

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

104. The method of claim 102 or 103, the method comprising casting the mixture into a tube to form a hydrogel strand before the hydrogel is fully gelled, drying the hydrogel strand, and cutting the strand.

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

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

107. The method of any one of claims 105 to 106, further comprising the step of: Cool the stock, solidify the stock, stretch the stock, and / or dry the stock.

108. The method of claim 103 or any one of claims 105 to 107, wherein the nucleophilic crosslinking agent is a nucleophilic salt, such as an amine salt or a polyamine salt, wherein the extrusion is carried out in the absence of water and the curing comprises exposing the extruded composition to moisture and / or elevated temperatures, and forming the polymer network by crosslinking the polymer precursor during curing in a humid atmosphere.

109. The method of claim 108, wherein the curing At temperatures above ambient temperature, such as approximately 25°C to approximately 50°C, or approximately 30°C to approximately 40°C, and The duration of the treatment is at least 0.5 hours, at least 1 hour, or at least 2 hours in an atmosphere with 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 of any one of claims 102 to 109, comprising longitudinally stretching the hydrogel strand (wet stretching or dry stretching) before or after drying the hydrogel, wherein the stretching factor 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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