Ocular hydrogel tyrosine kinase inhibitor implants

Abstract

Provided herein are sustained-release biodegradable ocular hydrogel implants useful for treating certain ocular conditions.

Description

[0001] Related Applications

[0002] This application claims priority to U.S. Provisional Application No. 62 / 838,796 filed on April 25, 2019, U.S. Provisional Application No. 62 / 838,998 filed on April 26, 2019, and U.S. Provisional Application No. 62 / 994,391 filed on March 25, 2020, the entire contents of each of which are incorporated herein by reference. Background Art

[0003] Macular degeneration, also known as age-related macular degeneration (AMD), is the leading cause of vision loss, affecting more than 10 million Americans. AMD is caused by the deterioration of the central part of the retina, the macula, which is responsible for focusing and controlling the central vision of the eye. AMD is diagnosed as dry (non-neovascular) or wet (neovascular) AMD. With dry AMD, macular tissue gradually thins and stops working properly. Approximately 90% of people with AMD are diagnosed with the dry form. Wet AMD occurs when fluid leaks from newly formed blood vessels under the macula. Although wet AMD represents a smaller population of AMD diagnoses, wet AMD poses a greater threat because vision loss can be more rapid and severe.

[0004] Tyrosine kinase inhibitors (TKIs) have recently shown promise for treating AMD. See, e.g., JAMA Ophthalmol, 2017 Jul 1;135(7):676-768 and Exp Eye Res. 2018 Mar;168:2-11. However, the problem with TKIs is that systemic administration is not ideal because high levels of systemic administration are required to achieve effective intraocular concentrations. This leads to an increased incidence of unacceptable side effects. Similarly, ocular instillation of TKIs and other drugs is ineffective most of the time because therapeutic levels are often not achieved in the middle or back of the eye, and drug concentrations are difficult to control due to cleaning, usage errors, and other factors. Other local treatment routes such as intravitreal injections have failed because such delivery routes often result in short half-lives and rapid clearance, and sustained release capabilities cannot be achieved. In addition, daily injections are often required to maintain therapeutic ocular drug levels, which is intolerable for many patients. Some TKIs, such as axitinib, have poor solubility and are injected as suspensions. However, these solid particles can aggregate, migrate, or settle onto the retina and cause local contact toxicity, holes, and floaters.

[0005] Drug delivery using ocular implants has many advantages over traditional drops or injections. These implants are typically placed in or near the target ocular tissue and offer better potential for drug release and duration of treatment. Although ocular implant devices have improved in recent years, they still have many shortcomings. First, not all ocular implants are biodegradable. The need for long-term treatment may lead to the accumulation of empty implants or may require cumbersome removal procedures after drug administration. In addition, most biodegradable implants do not dissolve completely or do not dissolve in a time consistent with drug release. Therefore, users are left with implant carrier residues, which are often called floaters. Secondly, most ocular implants are composed of complex multiple layers and require a large number of manufacturing processes. This leads to increased production costs and time, and increases the possibility of contamination caused by additional processing. In addition, formulations containing hydrophobic drugs with biodegradable matrices may result in high initial burst release of drugs or little or no drug release until network erosion occurs. This can lead to drug dumping, which has little benefit and causes toxicity problems. Summary of the invention

[0006] Provided herein are biodegradable ocular hydrogel implants comprising a tyrosine kinase inhibitor (TKI) and a polymer network and their use for treating ocular disorders.

[0007] The disclosed hydrogel implants can effectively deliver an effective dose of dissolved axitinib to the posterior segment of the eye, thereby successfully treating vascular endothelial growth factor (VEGF)-induced retinal leakage for at least six months. See, for example, the Examples section below, where leakage scores of eyes treated with hydrogel implants showed minimal or no vascular leakage within 12 months of TKI delivery.

[0008] In one aspect, the disclosed hydrogel implant is designed to include an interstitial zone on the implant surface that is free of particulate TKI (e.g., undissolved TKI particles) prior to drug release. In one aspect, the TKI is present in the hydrogel at or near saturation levels, provided that the TKI is not present in the interstitial zone. In one aspect, the interstitial zone provides a barrier between the TKI contained in the hydrogel and the retinal cells of the eye and prevents the release of undissolved drug substances into the eye.

[0009] In one aspect, the TKI is present in the interstitial regions of the hydrogel at or near saturation levels. When drug release occurs, the particulate TKI dissolves, passes through the interstitial regions, and is released into the eye.

[0010] In one aspect, the rate of TKI release from the hydrogel is controlled by the solubility of the drug in the hydrogel matrix, which is determined by the chemical properties (e.g., molecular weight, solubility, crystallinity, etc.) and structure (e.g., multi-armed, cross-linked, branched, etc.) of the polymer network, as well as the overall surface area of ​​the hydrogel.

[0011] In one aspect, the disclosed hydrogel implants are designed to be fully biodegradable, eg, residual particulate matter or floating matter is insignificant.

[0012] In one aspect, substantially all of the TKI is released from the hydrogel before hydrogel degradation occurs. BRIEF DESCRIPTION OF THE DRAWINGS

[0013] Figure 1 Shown is the dispersion of the TKI and the outer interstitial region of one aspect of the disclosed hydrogel.

[0014] Figure 2 Results of a PK / PD challenge of the hydrogel implant of the invention over a 12 month duration are shown. DETAILED DESCRIPTION

[0015] Provided herein are sustained-release biodegradable ocular hydrogel implants comprising a tyrosine kinase inhibitor (TKI), a polymer network, and an interstitial region.

[0016] 1. Definition

[0017] The term "biodegradable" refers to materials that degrade in vivo, such as the disclosed hydrogel implants. Degradation of the material occurs over time and may occur simultaneously with or subsequent to TKI release. In one aspect, "biodegradable" means that complete dissolution of the implant occurs, i.e., no residual hydrogel implant remains in the eye. In alternative aspects, degradation may occur independently of TKI release, such that, for example, residual TKI remains after degradation.

[0018] The term "polymer network" refers to a group of polymers comprising multiple branched structures (also called "arms") cross-linked with other polymer chains. The polymer chains can have the same or different chemical structures, for example, as in complementary or non-complementary repeat units.

[0019] References to synthetic precursors used to generate the disclosed polymer networks are named using the number of arms, followed by the MW of the PEG, and then the reactive group (e.g., electrophile or nucleophile). For example, 4a20K PEG SAZ refers to a 20,000 Da PEG with 4 arms having succinimidyl azelate end groups, 4a20K PEG SAP refers to a 20,000 Da PEG with 4 arms having succinimidyl adipate end groups, 4a20K PEG SG refers to a 20,000 Da PEG with 4 arms having succinimidyl glutarate end groups, and 4a20K PEG SS refers to a 20,000 Da PEG with 4 arms having succinimidyl succinate end groups. Similarly, 4a20K PEG NH2 means a 20,000 Da PEG with 4 arms having an amine terminal group, 8a20K PEG NH2 means a 20,000 Da PEG with 8 arms having an amine terminal group, and so on.

[0020] As used herein, "gap region" refers to a portion of an implant composed of hydrogel that is free of undissolved TKI particles before or after TKI release. "Gap region" and "region gap" are used interchangeably. Figure 1 An exemplary representation of the gap zone is depicted in FIG. As shown, the gap zone provides a protective barrier between the TKI contained in the hydrogel and the retinal cells in the eye. Without being bound by theory, this is because the water solubility of TKI is poor, which prevents the TKI concentration on the outer surface of the graft from being too high, which may contact the tissue. As the characteristics of the polymer network change, for example, as the polymer network slowly degrades, the TKI continues to be released from the hydrogel by first passing through the gap zone before being released and in direct contact with the eye. On the one hand, the release of TKI is solubility-driven and is not affected by changes in the polymer network, except for the size changes associated with polymer changes. In some aspects, as more TKI is released from the hydrogel, the overall size of the gap zone increases. On the one hand, it is desirable to match the size of the gap zone with the degradation rate of the hydrogel. For example, the polymer hydrolysis rate matches the TKI solubility, so as the size of the gap zone increases, the hydrogel degradation also increases, and thus the disappearance of the hydrogel is roughly consistent with the disappearance of the TKI.

[0021] The term "amorphous" refers to a polymer or polymer network that does not exhibit a crystalline structure in X-ray or electron scattering experiments.

[0022] The term "semi-crystalline" refers to a polymer or polymer network that has some crystalline characteristics, i.e., exhibits crystalline properties in thermal analysis, X-ray or electron scattering experiments. In some aspects, a "semi-crystalline" polymer or polymer network has a highly ordered molecular structure and a sharp melting point. In some aspects, a "semi-crystalline" polymer or polymer network does not gradually soften with increasing temperature, but instead remains in a solid state until a given amount of heat is absorbed, and then rapidly becomes rubbery or liquid.

[0023] As used herein, "homogeneously dispersed" means that a component, such as a TKI, is uniformly dispersed throughout the hydrogel or polymer network, except for portions that include interstitial regions.

[0024] As used herein, the terms "treat," "treating," and "treatment" refer to reversing, alleviating, delaying the onset of, or inhibiting the progression of an ocular disorder or one or more of its symptoms. In some aspects, treatment may be administered after one or more symptoms develop, i.e., therapeutic treatment. In other aspects, treatment may be administered in the absence of symptoms. For example, treatment may be administered to susceptible individuals prior to the onset of symptoms (e.g., based on a history of symptoms and / or based on exposure to a particular organism, or other susceptibility factors), i.e., prophylactic treatment. Treatment may also continue after symptoms disappear, e.g., to delay recurrence.

[0025] The term "ocular disorder" refers to a disease, illness or condition that affects the eye, a region of the eye or a part of the eye.

[0026] The terms "subject" and "patient" are used interchangeably and refer to mammals in need of treatment, such as companion animals (e.g., dogs, cats, etc.), livestock (e.g., cattle, pigs, horses, sheep, goats, etc.), and experimental animals (e.g., rats, mice, guinea pigs, etc.). Typically, the subject is a human in need of treatment.

[0027] 2. Sustained-release biodegradable ocular hydrogel implants

[0028] In a first embodiment, the interstitial region of the disclosed hydrogel implant is free of undissolved TKI particles prior to TKI release. For example, in one aspect of this embodiment, particulate TKI is contained in the polymer network of the hydrogel but is not present in the interstitial region. In one aspect, based on the design and properties of the polymer network, only dissolved TKI passes through the interstitial region and exits the hydrogel into the eye.

[0029] In a second embodiment, when a particulate TKI described herein is contained within a hydrogel implant, the particulate TKI does not contact retinal cells. The remaining features of the hydrogel implant are as described herein, for example, in the first embodiment.

[0030] In a third embodiment, a TKI described herein is dissolved prior to release into the eye, wherein the remaining features of the hydrogel implant are as described herein, eg, as in the first or second embodiment.

[0031] In a fourth embodiment, a TKI described herein becomes dissolved before it enters or passes through the interstitial region, wherein the remaining features of the hydrogel implant are as described herein, eg, as in the first, second, or third embodiment.

[0032] In a fifth embodiment, a TKI described herein dissolves as it enters or passes through the interstitial region, wherein the remaining features of the hydrogel implant are as described herein, eg, as in the first, second, third or fourth embodiment.

[0033] In a sixth embodiment, a solubilized TKI described herein is present in a hydrogel implant at or near its saturation level, wherein the remaining features of the hydrogel implant are as described herein, e.g., in the first, second, third, fourth or fifth embodiment.

[0034] In a seventh embodiment, the size of the interstitial region increases as a function of the amount of TKI released, wherein the remaining features of the hydrogel implant are as described herein, e.g., as in the first, second, third, fourth, fifth or sixth embodiment.

[0035] In an eighth embodiment, the hydrogel implant is completely degraded after the complete release of the TKI, wherein the remaining features of the hydrogel implant are described herein, for example, in the first, second, third, fourth, fifth, sixth, or seventh embodiments. Alternatively, as part of the eighth embodiment, the hydrogel implant is completely degraded after about 12 months, about 11 months, about 10 months, about 9 months, about 8 months, about 6 months, about 5 months, about 4 months, about 3 months, about 2 months, about 1 month (i.e., about 30 days) after the complete release of the TKI, wherein the remaining features of the hydrogel implant are described herein, for example, in the first, second, third, fourth, fifth, sixth, or seventh embodiments. Alternatively, as part of an eighth embodiment, the hydrogel implant completely degrades after at least 80%, at least 85%, or at least 90% (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) release of the TKI, wherein the remainder of the features of the hydrogel implant are as described herein, e.g., as described in the first, second, third, fourth, fifth, sixth, or seventh embodiment.

[0036] In a ninth embodiment, the polymer network of the disclosed hydrogel implant comprises a plurality of polyethylene glycol (PEG) units, wherein the remaining features of the hydrogel are as described herein, e.g., as in the first, second, third, fourth, fifth, sixth, seventh or eighth embodiment.

[0037] In a tenth embodiment, the polymer network of the disclosed hydrogel implant comprises a plurality of multi-arm PEG units, wherein the remaining features of the hydrogel are as described herein, e.g., as in the first, second, third, fourth, fifth, sixth, seventh, eighth or ninth embodiment.

[0038] In the eleventh embodiment, the polymer network of the disclosed hydrogel implant comprises a plurality of multi-arm PEG units having at least 2 arms, wherein the remaining features of the hydrogel are described herein, e.g., in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, or tenth embodiments. Alternatively, as part of the eleventh embodiment, the polymer network of the disclosed hydrogel implant comprises a plurality of multi-arm PEG units having 2 to 10 arms, wherein the remaining features of the hydrogel are described herein, e.g., in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, or tenth embodiments. In another alternative, as part of the eleventh embodiment, the polymer network of the disclosed hydrogel implant comprises a plurality of multi-arm PEG units having 4 to 8 arms, wherein the remaining features of the hydrogel are described herein, e.g., in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, or tenth embodiments. In another alternative, as part of the eleventh embodiment, the polymer network of the disclosed hydrogel implant comprises a plurality of 4-arm PEG units, wherein the remaining features of the hydrogel are as described herein, e.g., in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, or tenth embodiment. In another alternative, as part of the eleventh embodiment, the polymer network of the disclosed hydrogel implant comprises a plurality of 8-arm PEG units, wherein the remaining features of the hydrogel are as described herein, e.g., in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, or tenth embodiment.

[0039] In a twelfth embodiment, the polymer network of the disclosed hydrogel implant comprises a plurality of PEG units having a number average molecular weight (Mn) of at least 10,000 Daltons, wherein the remaining features of the hydrogel are as described herein, e.g., in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, or eleventh embodiments. Alternatively, as part of the twelfth embodiment, the polymer network of the disclosed hydrogel implant comprises a plurality of PEG units having an Mn of at least 15,000 Daltons, wherein the remaining features of the hydrogel are as described herein, e.g., in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, or eleventh embodiments. In another alternative, as part of the twelfth embodiment, the polymer network of the disclosed hydrogel implant comprises a plurality of PEG units having an Mn of at least 20,000 Daltons, wherein the remaining features of the hydrogel are as described herein, e.g., in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, or eleventh embodiments. In another alternative, as part of the twelfth embodiment, the polymer network of the disclosed hydrogel implant comprises a plurality of PEG units having an Mn of at least 40,000 Daltons, wherein the remaining features of the hydrogel are as described herein, e.g., in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, or eleventh embodiments. In another alternative, as part of the twelfth embodiment, the polymer network of the disclosed hydrogel implant comprises a plurality of PEG units having an Mn in the range of 10,000 Daltons to 50,000 Daltons, wherein the remaining features of the hydrogel are as described herein, e.g., in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, or eleventh embodiments. In another alternative, as part of the twelfth embodiment, the polymer network of the disclosed hydrogel implant comprises a plurality of PEG units having an Mn in the range of 10,000 Daltons to 40,000 Daltons, wherein the remaining features of the hydrogel are as described herein, e.g., in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, or eleventh embodiments. In another alternative, as part of a twelfth embodiment, the polymer network of the disclosed hydrogel implant comprises a plurality of PEG units having an Mn ranging from 30,000 Daltons to 50,000 Daltons, wherein the remainder of the features of the hydrogel are as described herein, e.g., as in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth or eleventh embodiment.In another alternative, as part of the twelfth embodiment, the polymer network of the disclosed hydrogel implant comprises a plurality of PEG units having an Mn in the range of 35,000 Daltons to 45,000 Daltons, wherein the remaining features of the hydrogel are as described herein, e.g., in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, or eleventh embodiment. In another alternative, as part of the twelfth embodiment, the polymer network of the disclosed hydrogel implant comprises a plurality of PEG units having an Mn in the range of 15,000 Daltons to 30,000 Daltons, wherein the remaining features of the hydrogel are as described herein, e.g., in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, or eleventh embodiment. In another alternative, as part of the twelfth embodiment, the polymer network of the disclosed hydrogel implant comprises a plurality of PEG units having an Mn in the range of 15,000 Daltons to 25,000 Daltons, wherein the remaining features of the hydrogel are as described herein, e.g., in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, or eleventh embodiments. In another alternative, as part of the twelfth embodiment, the polymer network of the disclosed hydrogel implant comprises a plurality of PEG units having an Mn of about 20,000 Daltons, wherein the remaining features of the hydrogel are as described herein, e.g., in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, or eleventh embodiments. In another alternative, as part of the twelfth embodiment, the polymer network of the disclosed hydrogel implant comprises a plurality of PEG units having an Mn of about 40,000 Daltons, wherein the remaining features of the hydrogel are as described herein, e.g., in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, or eleventh embodiments.

[0040] In a thirteenth embodiment, the polymer network of the disclosed hydrogel implant comprises a plurality of PEG units cross-linked by a hydrolyzable linker, wherein the remaining features of the hydrogel are as described herein, e.g., in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, or twelfth embodiment. Alternatively, as part of the thirteenth embodiment, the polymer network of the disclosed hydrogel implant comprises a plurality of PEG units cross-linked by a hydrolyzable linker having the formula: wherein m is an integer from 1 to 9, wherein the remaining features of the hydrogel are as described herein, e.g., in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, or twelfth embodiment. In another alternative, the polymer network of the disclosed hydrogel implant comprises a plurality of PEG units cross-linked by a hydrolyzable linker having the formula: wherein m is an integer from 2 to 6, wherein the remaining features of the hydrogel are as described herein, e.g., in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, or twelfth embodiment. In another alternative, as part of the thirteenth embodiment, the polymer network of the disclosed hydrogel implant comprises a plurality of PEG units having the formula:

[0041]

[0042] wherein n represents an ethylene oxide repeating unit and the wavy lines represent dots of repeating units of the polymer network, wherein the remaining features of the hydrogel are as described herein, e.g., in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, or twelfth embodiment. In another alternative, as part of the thirteenth embodiment, the polymer network of the disclosed composition comprises a plurality of PEG units having the formula shown above, but having an 8-arm PEG scaffold.

[0043] In a fourteenth embodiment, the polymer network of the disclosed hydrogel implant is formed by reacting a plurality of polyethylene glycol (PEG) units comprising groups susceptible to nucleophilic attack with one or more nucleophilic groups to form a polymer network, wherein the remaining features of the hydrogel are herein, e.g., as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh or twelfth embodiment. Examples of suitable groups susceptible to nucleophilic attack include, but are not limited to, activated esters (e.g., thioesters, succinimidyl esters, benzotriazole esters, acrylates, etc.). Examples of suitable nucleophilic groups include, but are not limited to, amines and thiols.

[0044] In the fifteenth embodiment, the polymer network of the disclosed hydrogel implant is formed by reacting a plurality of polyethylene glycol (PEG) units with one or more nucleophilic groups to form a polymer network, each polyethylene glycol (PEG) unit having a molecular weight as described above in the twelfth embodiment and comprising a group susceptible to nucleophilic attack, wherein the remaining features of the hydrogel are described herein, for example, in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, or fourteenth embodiment. Alternatively, as part of the fifteenth embodiment, the polymer network of the disclosed hydrogel implant is formed by reacting a plurality of polyethylene glycol (PEG) units with one or more nucleophilic groups to form a polymer network, each polyethylene glycol (PEG) unit having a molecular weight as described above in the twelfth embodiment and comprising a succinimide ester group, wherein the remaining features of the hydrogel are described herein, for example, in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, or fourteenth embodiment. In another alternative, as part of the fifteenth embodiment, the polymer network of the disclosed hydrogel implant is formed by reacting a plurality of polyethylene glycol (PEG) units selected from 4a20K PEG SAZ, 4a20K PEG SAP, 4a20K PEG SG, 4a20K PEG SS, 8a20K PEG SAZ, 8a20K PEG SAP, 8a20K PEG SG, and 8a20K PEG SS, wherein the remainder of the hydrogel features are as described herein, e.g., as in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, or fourteenth embodiment.

[0045] In the sixteenth embodiment, the polymer network of the disclosed hydrogel implant is formed by reacting a plurality of polyethylene glycol (PEG) units comprising a group susceptible to nucleophilic attack with one or more amine groups to form a polymer network, wherein the remaining features of the hydrogel are described herein, for example, in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, fourteenth, or fifteenth embodiment. Alternatively, as part of the sixteenth embodiment, the polymer network of the disclosed hydrogel implant is formed by reacting a plurality of polyethylene glycol (PEG) units comprising a group susceptible to nucleophilic attack with one or more PEG or lysine-based amine groups to form a polymer network, wherein the remaining features of the hydrogel are described herein, for example, in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, fourteenth, or fifteenth embodiment. In another embodiment, as part of the sixteenth embodiment, the polymer network of the disclosed hydrogel implant is formed by reacting a plurality of polyethylene glycol (PEG) units comprising a group susceptible to nucleophilic attack with one or more PEG or lysine-based amine groups selected from 4a20K PEG NH2, 8a20K PEG NH2, and trilysine or a salt thereof to form a polymer network, wherein the remaining features of the hydrogel are described herein, e.g., in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, fourteenth, or fifteenth embodiment. In another alternative, as part of the sixteenth embodiment, the polymer network of the disclosed hydrogel implant is formed by reacting 4a20K PEG-SAZ with 8a20K PEG NH2, wherein the remaining features of the hydrogel are described herein, e.g., in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth or eleventh, twelfth, fourteenth, or fifteenth embodiment. In another alternative, as part of a sixteenth embodiment, the polymer network of the disclosed hydrogel implant is formed by reacting 2 parts of 4a20K PEG-SAZ with 1 part of 8a20K PEG NH2, wherein the remaining characteristics of the hydrogel are as described herein, e.g., as in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth or eleventh, twelfth, fourteenth or fifteenth embodiment.

[0046] In a seventeenth embodiment, the ocular hydrogel implant is amorphous (e.g., under aqueous conditions, such as in vivo), wherein the remainder of the characteristics of the hydrogel are as described herein, e.g., as in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth or eleventh, twelfth, thirteenth, fourteenth, fifteenth, or sixteenth embodiment.

[0047] In an eighteenth embodiment, the ocular hydrogel implant is semi-crystalline (e.g., in the absence of water), wherein the remainder of the characteristics of the hydrogel are as described herein, e.g., as in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth or eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, or seventeenth embodiment.

[0048] In a nineteenth embodiment, the disclosed hydrogel implant has a tyrosine kinase inhibitor as particles uniformly dispersed within a polymer network, wherein the remaining features of the hydrogel are as described herein, e.g., as in the first, second, third, fourth, fifth, sixth, seventeenth, or eighteenth embodiment.

[0049] In the twentieth embodiment, the tyrosine kinase inhibitor of the hydrogel is released over a period of at least 15 days, wherein the remaining characteristics of the hydrogel are described herein, for example, in the first, second, third, fourth, fifth, sixth, seventeenth, eighteenth, or nineteenth embodiments. Alternatively, as part of the twentieth embodiment, the tyrosine kinase inhibitor of the disclosed hydrogel implant is released over a period of at least 30 days, wherein the remaining characteristics of the hydrogel are described herein, for example, in the first, second, third, fourth, fifth, sixth, seventeenth, eighteenth, or nineteenth embodiments. In another alternative, as part of the twentieth embodiment, the tyrosine kinase inhibitor of the disclosed hydrogel implant is released over a period of at least 60 days, wherein the remaining characteristics of the hydrogel are described herein, for example, in the first, second, third, fourth, fifth, sixth, seventeenth, eighteenth, or nineteenth embodiments. In another alternative, as part of the twentieth embodiment, the tyrosine kinase inhibitor of the disclosed hydrogel implant is released over a period of at least 90 days, wherein the remaining characteristics of the hydrogel are described herein, for example, in the first, second, third, fourth, fifth, sixth, seventeenth, eighteenth, or nineteenth embodiments. In another alternative, as part of the twentieth embodiment, the tyrosine kinase inhibitor of the disclosed hydrogel implant is released over a period of at least 120 days, wherein the remaining characteristics of the hydrogel are described herein, e.g., in the first, second, third, fourth, fifth, sixth, seventeenth, eighteenth, or nineteenth embodiment. In another alternative, as part of the twentieth embodiment, the tyrosine kinase inhibitor of the disclosed hydrogel implant is released over a period of at least 150 days, wherein the remaining characteristics of the hydrogel are described herein, e.g., in the first, second, third, fourth, fifth, sixth, seventeenth, eighteenth, or nineteenth embodiment. In another alternative, as part of the twentieth embodiment, the tyrosine kinase inhibitor of the disclosed hydrogel implant is released over a period of at least 180 days, wherein the remaining characteristics of the hydrogel are described herein, e.g., in the first, second, third, fourth, fifth, sixth, seventeenth, eighteenth, or nineteenth embodiment. In another alternative, as part of the twentieth embodiment, the tyrosine kinase inhibitor of the disclosed hydrogel implant is released over a period of at least 210 days, wherein the remaining characteristics of the hydrogel are as described herein, e.g., in the first, second, third, fourth, fifth, sixth, seventeenth, eighteenth, or nineteenth embodiment. In another alternative, as part of the twentieth embodiment, the tyrosine kinase inhibitor of the disclosed hydrogel implant is released over a period of at least 240 days, wherein the remaining characteristics of the hydrogel are as described herein, e.g., in the first, second, third, fourth, fifth, sixth, seventeenth, eighteenth, or nineteenth embodiment.In another alternative, as part of the twentieth embodiment, the tyrosine kinase inhibitor of the disclosed hydrogel implant is released over a period of at least 270 days, wherein the remaining characteristics of the hydrogel are described herein, e.g., in the first, second, third, fourth, fifth, sixth, seventeenth, eighteenth, or nineteenth embodiments. In another alternative, as part of the twentieth embodiment, the tyrosine kinase inhibitor of the disclosed hydrogel implant is released over a period of at least 300 days, wherein the remaining characteristics of the hydrogel are described herein, e.g., in the first, second, third, fourth, fifth, sixth, seventeenth, eighteenth, or nineteenth embodiments. In another alternative, as part of the twentieth embodiment, the tyrosine kinase inhibitor of the disclosed hydrogel implant is released over a period of at least 330 days, wherein the remaining characteristics of the hydrogel are described herein, e.g., in the first, second, third, fourth, fifth, sixth, seventeenth, eighteenth, or nineteenth embodiments. In another alternative, as part of the twentieth embodiment, the tyrosine kinase inhibitor of the disclosed hydrogel implant is released over a period of at least 365 days, wherein the remainder of the characteristics of the hydrogel are as described herein, e.g., as in the first, second, third, fourth, fifth, sixth, seventeenth, eighteenth or nineteenth embodiment.

[0050] In a twenty-first embodiment, the tyrosine kinase inhibitor of the disclosed hydrogel implant is in the form of encapsulated microparticles, wherein the remaining features of the hydrogel are as described herein, e.g., as in the first, second, third, fourth, fifth, sixth, seventeenth, eighteenth, nineteenth or twentieth embodiment.

[0051] In a twenty-second embodiment, the tyrosine kinase inhibitor of the disclosed hydrogel implant has a water solubility suitable for a desired release rate, wherein the remainder of the characteristics of the hydrogel are as described herein, e.g., as in the first, second, third, fourth, fifth, sixth, seventeenth, eighteenth, nineteenth, twentieth or twenty-first embodiment.

[0052] In a twenty-third embodiment, the tyrosine kinase inhibitor of the disclosed hydrogel implant is in the form of encapsulated microparticles comprising poly(lactic-co-glycolic acid), wherein the remainder of the features of the hydrogel are as described herein, e.g., in the first, second, third, fourth, fifth, sixth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first or twenty-second embodiment.

[0053] In a twenty-fourth embodiment, the tyrosine kinase inhibitor of the disclosed hydrogel implant is selected from abemaciclib, acalabrutinib, afatinib, alectinib, axitinib, barictinib, binimetinib, brigatinib, cabozantinib, ceritinib, coblmetinib, crizotinib , dabrafenib, dacomitinib, dasatinib, encorafenib, erlotinib, everolimus, fostamatinib, gefitinib, gilteritinib, ibrutinib, imatinib, larotrectinib, lenvatinib, lorlatinib ib), axitinib, idelalisib, lenvatinib, midostaurin, neratinib, netarsudil, nilotinib, nintedanib, osimertinib, palbociclib, pazopanib, ponatinib, regorafenib, ribociclib ib), ruxolitinib, sirolimus, sorafenib, sunitinib, temsirolimus, tofacitinib, trametinib, vandetanib and vemurafenib, wherein the remaining features of the hydrogel are described herein, e.g., as in the first, second, third, fourth, fifth, sixth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second or twenty-third embodiment.Alternatively, the tyrosine kinase inhibitor of the hydrogel is sunitinib, nintedanib, regorefanib or axitinib, wherein the remaining features of the hydrogel are described herein, for example, in the first, second, third, fourth, fifth, sixth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second or twenty-third embodiment. In another alternative, the tyrosine kinase inhibitor of the hydrogel is axitinib, wherein the remaining features of the hydrogel are described herein, for example, in the first, second, third, fourth, fifth, sixth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second or twenty-third embodiment. In another alternative, the tyrosine kinase inhibitor of the hydrogel is an inhibitor targeting VEGFR1, wherein the remaining features of the hydrogel are described herein, for example, in the first, second, third, fourth, fifth, sixth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second or twenty-third embodiment. In another alternative, the tyrosine kinase inhibitor of the hydrogel is an inhibitor that targets VEGFR2, wherein the remaining features of the hydrogel are as described herein, e.g., as in the first, second, third, fourth, fifth, sixth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second or twenty-third embodiment.

[0054] In a twenty-fifth embodiment, the ophthalmic hydrogel described herein is formulated as an intravitreal implant that can be delivered to the eye, e.g., via needle injection, wherein the remaining features of the hydrogel are as described herein, e.g., in the first, second, third, fourth, fifth, sixth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, or twenty-fourth embodiment.

[0055] In a twenty-sixth embodiment, the ophthalmic hydrogel described herein is attached to the lower lacrimal punctum of the eye, wherein the remaining features of the hydrogel are as described herein, e.g., as in the first, second, third, fourth, fifth, sixth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, or twenty-fifth embodiment.

[0056] In a twenty-seventh embodiment, the ophthalmic hydrogel described herein is injected into the vitreous humor, injected into the anterior chamber, or attached to the upper or lower punctum of the eye, wherein the remaining features of the hydrogel are as described herein, e.g., as in the first, second, third, fourth, fifth, sixth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, or twenty-fifth embodiment.

[0057] 2. Methods, Process and Purpose

[0058] The disclosed hydrogel implants can be used to treat eye disorders. Thus, provided herein are methods of treating one or more eye disorders described herein, the methods comprising attaching the disclosed hydrogel implants to an eye of a subject, such as to the lower lacrimal punctum of the eye. Also provided are uses of the disclosed hydrogel implants in the manufacture of a medicament for treating one or more eye disorders described herein.

[0059] In one aspect, the disclosed hydrogel implants can be used to treat eye conditions associated with macular degeneration / retinal degeneration. Such conditions include, for example, age-related macular degeneration (AMD) (such as wet or dry AMD), choroidal neovascularization, diabetic retinopathy, acute macular neuroretinopathy, central serous chorioretinopathy, cystoid macular edema, and diabetic macular edema.

[0060] In one aspect, the disclosed hydrogel implants can be used to treat ocular disorders associated with uveitis / retinitis / choroiditis. Such disorders include, for example, acute multifocal ichthyosphagoid pigment epitheliopathy, Behcet's disease, birdshot retinochoroidopathy, infectious diseases (syphilis, Lyme disease, tuberculosis, toxoplasmosis), intermediate uveitis (Pars Planitis), multifocal choroiditis, multiple transient white dot syndrome (MEWDS), ocular sarcoidosis, posterior scleritis, serpiginous choroiditis, subretinal fibrosis and uveitis syndrome, and Vogt-Koyanagi-Harada Syndrome.

[0061] In one aspect, the disclosed hydrogel implants can be used to treat ocular disorders associated with vascular / exudative diseases. Such disorders include, for example, Coat's Disease, Parafoveal Telangiectasis, Papillophlebitis, Frosted Branch Angitis, Sickle Cell Retinopathy and other hemoglobinopathies, Angioid Streaks, and Familial Exudative Vitreoretinopathy.

[0062] In one aspect, the disclosed hydrogel implants can be used to treat eye disorders associated with trauma / surgery. Such disorders include, for example, sympathetic ophthalmia, uveitic retinal disease, retinal detachment, trauma, photodynamic laser therapy, photocoagulation, hypoperfusion during surgery, radiation retinopathy, and bone marrow transplant retinopathy.

[0063] In one aspect, the disclosed hydrogel implants can be used to treat ocular disorders associated with proliferative conditions. Such disorders include, for example, proliferative vitreoretinopathy and epiretinal membranes, proliferative diabetic retinopathy, and retinopathy of prematurity (posterior lenticular fibroplasia).

[0064] In one aspect, the disclosed hydrogel implants can be used to treat ocular disorders associated with infectious conditions. Such disorders include, for example, ocular histoplasmosis, ocular toxocariasis, suspected ocular histoplasmosis syndrome (POHS), endophthalmitis, toxoplasmosis, HIV infection-related retinal disease, HIV infection-related choroidal disease, HIV infection-related uveitis disease, viral retinitis, acute retinal necrosis, progressive outer retinal necrosis, fungal retinal disease, ocular syphilis, ocular tuberculosis, diffuse unilateral subacute neuroretinitis, and myiasis.

[0065] In one aspect, the disclosed hydrogel implants can be used to treat ocular disorders associated with genetic disorders. Such disorders include, for example, Systemic Disorders with Associated Retinal Dystrophies, Congenital Stationary Night Blindness, Cone Dystrophy, Fundus Xanthophy, Best's Disease, Retinal Pigment Epithelial Pattern Dystrophy, X-linked Retinoschisis, Sorsby's Fundus Dystrophy, Benign Concentric Maculopathy, Bietti's Crystalline Dystrophy, Pseudoxanthoma Elasticus, Osier Weber syndrome.

[0066] In one aspect, the disclosed hydrogel implants can be used to treat ocular disorders associated with retinal tears / holes. Such disorders include, for example, detachments, macular holes, and giant retinal tears.

[0067] On the one hand, the disclosed hydrogel implants can be used to treat eye disorders associated with tumors. Such disorders include, for example, tumor-related retinal diseases, solid tumors, tumor metastases, benign tumors (e.g., hemangiomas, neurofibromas, trachoma, and pyogenic granulomas), congenital hypertrophy of the RPE, posterior uveal melanoma, choroidal hemangiomas, choroidal osteomas, choroidal metastases, retinal and retinal pigment epithelial combined hamartomas, retinoblastomas, fundus vascular proliferative tumors, retinal astrocytomas, and intraocular lymphomas.

[0068] In one aspect, the disclosed hydrogel implants can be used to treat punctate inner choroidopathy, acute posterior ichthyosis pigment epitheliopathy, myopic retinal degeneration, acute retinal pigment epitheliitis, ocular inflammatory and immune disorders, ocular vascular dysfunction, corneal graft rejection, and neovascular glaucoma.

[0069] The specific dosage and treatment regimen for any particular patient will depend on a number of factors, including the activity of the specific compound employed, age, weight, health status, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated.

[0070] Various techniques can be used to produce the implants described herein. Available techniques include, but are not necessarily limited to, solvent evaporation, phase separation, interfacial methods, molding, injection molding, extrusion, coextrusion, Carver press method, die cutting, and the like.

[0071] Example

[0072] Preparation of in situ gelling TKI implant formulations

[0073] A series of TKI formulations were prepared as detailed in the table below.

[0074]

[0075]

[0076] Provisc: Each ml of PROVISC (OVD) contains 10.0 mg sodium hyaluronate; 2.0 mg anhydrous disodium hydrogen phosphate; 0.45 mg sodium dihydrogen phosphate, monohydrate; 7.5 mg sodium chloride; hydrochloric acid and / or sodium hydroxide to adjust the pH, and water for injection. The sodium hyaluronate used in PROVISC (OVD) is derived from bacterial fermentation and has an average molecular weight of 2,500,000 Daltons. The weight-gram molecular osmotic concentration of PROVISC (OVD) is 310±50mOsm / kg; the pH range is 6.8 to 7.5. Buffer modifier: 0.5 mg / ml sodium borate pH6.8

[0077] In vivo testing of in situ gelling TKI implant formulations

[0078] The samples prepared in Examples 1-5 were tested in rabbit eyes. Briefly, on day 0, rabbits were injected with 10 uL of the test articles listed below in the left and right eyes (OU). Animals were euthanized at the time points listed in the study design table below. Eyes were removed and fixed in Davidson's solution for histopathological analysis.

[0079] A total of 10 left and right eyes from 5 rabbits were examined. Sutures were placed at the 12 o'clock position for positioning during extraction. Typically, the eye is cut in half along the midline through the lens and optic nerve in the 12 o'clock to 6 o'clock plane. This captures as many optical structures as possible in one plane. The pruned eye is carefully examined and abnormalities are recorded. Each half of the pruned eyeball is embedded in its own box. For each block, 6 slides stained with hematoxylin and eosin (H&E) are prepared, which are 1000 microns (1 mm) apart. Each slide contains 2 serial sections.

[0080] All slides were evaluated by a board-certified veterinary pathologist. Tissues were scored on a semiquantitative scale of 0-5 for any abnormalities. See table on page 5. The presence or absence of any injected material was also recorded.

[0081] score describe 0 No change; normal 1 Sparsely changing focus; minimal 2 Mild diffuse changes or more obvious focal changes 3 Moderate diffusion changes 4 Significant diffusion changes 5 Severe diffusion changes

[0082]

[0083] Under the conditions studied, intravitreal injection of the hydrogel depot formulation containing the tyrosine kinase inhibitor into rabbit eyes resulted in continued presence of hydrogel in the vitreous cavity of at least one eye in each group 14 days after injection, but no hydrogel material was found in any eye in Groups 1 and 3.

[0084] No inflammation was observed around any injected material in any eye from Groups 2, 4, and 6. Minimal inflammation consisting primarily of macrophages within the vitreous cavity and / or attached to the retina was occasionally observed in samples from Groups 1 and 3 but was not associated with the injected material. Likewise, no injected material was observed in any eye from Groups 1 and 3.

[0085] Minimal inflammation and fibrosis were observed in some slide samples from groups 3 and 4. These were generally small linear areas of fibrosis with a few macrophages mixed in. They were interpreted as sequelae of the needle injection.

[0086] One or a few small areas of retinal breaks or retinal folds were observed in at least 1 eye of Groups 1, 3, 4, and 6. These were probably due to retinal invaginations caused by the needle injection. One eye had a very small retinal detachment of 100 microns in length at the site of the small retinal break (Group 3). No other retinal detachments were found in any eye of any group.

[0087] Mild histiocytes and multinucleated inflammatory foci were observed in the vitreous cavity of one eye in Group 3, surrounding small displaced foci of lens fibers. This was considered to be lens-induced granulomatous endophthalmitis, probably due to slight nicking of the lens by the needle during injection. No other such lesions were observed in any eye in any group.

[0088] General synthetic methods

[0089] The ocular hydrogel implant of the present invention was prepared by the following procedure. This hydrogel implant contained axitinib as the active pharmaceutical ingredient (API) and a 4-arm polyethylene glycol (PEG)-based hydrogel serving as an inactive delivery platform.

[0090] Implant manufacturing

[0091]

[0092]

[0093] Implant inspection / packaging and yield calculation

[0094]

[0095]

[0096] Clinical investigation

[0097] A. Reduce vascular leakage in rabbits

[0098] Micronized TKI particles were formulated in the hydrogel matrix of the present invention according to the above procedure. On day 0, hydrogel implants were administered bilaterally to 30 eyes of naive Dutch belted rabbits (n=15). Over the course of 12 months, the eyes were challenged by injection of vascular endothelial growth factor (VEGF) at predetermined time points, and leakage was assessed by fluorescein angiography (FA) and dilated fundus examination. At each VEGF challenge time point, eyes treated with the implant of the present invention were compared with untreated control eyes (n=4). Ocular tissues were collected immediately after FA assessments for up to 6 months, and pharmacokinetic (PK) analysis was performed by liquid chromatography / mass spectrometry (LC / MS). Tolerability was assessed by MacDonald Shadduck scoring and clinical observations.

[0099] When challenged with a VEGF suspension, eyes treated with the hydrogel implant of the invention had significant inhibition of leakage at 3, 6, 9, and 12 months. Leakage scores for eyes treated with the hydrogel implant showed minimal or no vascular leakage over the 12 months. Untreated control eyes exhibited high tortuosity and leakage at all time points. Figure 2 In treated animals, retinal tissue showed high drug concentrations (>2800X IC50) over 6 months. MacDonald Shadduck scores showed that the treatment was well tolerated. Other clinical observations did not raise safety concerns.

[0100] B. Other clinical studies / data in rabbits

[0101] The hydrogel implant test articles of the invention were formulated to contain approximately 110 μg of axitinib drug substance per implant. The implants were hydrated in a biorelevant medium (PBS, pH 7.2, 37° C.) to a size of approximately 0.5×9.2 mm for 24 hours.

[0102] A single hydrogel implant was administered to each eye (bilaterally) of 14 female Dutch black-belted rabbits via intravitreal injection, for a total of 28 eyes. Two rabbits were euthanized at the 1st, 45th, 90th, 137th, 180th, 225th, and 270th day study time points. At the euthanasia time point, plasma samples were collected, both eyes were removed and frozen in liquid nitrogen. Frozen eye tissues and plasma were stored at -80 ° C until bioanalysis testing was performed. Samples were tested after the study midpoint (137th day) and at the end of the study (270th day). Due to the experimental error determined, 4 of the 28 eyes were excluded from statistical analysis.

[0103] The concentrations of axitinib in rabbit AH samples during the study (see Table 1) were considered lower than those observed in the VH, retina, and choroid, indicating a lower level of migration of axitinib from the posterior chamber to the anterior chamber. The median axitinib concentration reached a maximum value (5.9 ng / mF) on day 45 and decreased to zero on day 225.

[0104] Table 1. Summary of axitinib concentrations in aqueous humor A

[0105]

[0106] na means not suitable for statistical calculations. A LLOQ of the method for assaying axitinib in AH = 0.100 ng / mL

[0107] The median axitinib concentration of soluble axitinib in rabbit VH samples during the study (see Table 2) reached a maximum value (264.0 ng / mL) on Day 180. Individual samples ranged from a low of 2.9 ng / mL (Days 225 and 270) to a high of 571.0 ng / mL (Day 180).

[0108] Table 2. Summary of soluble axitinib concentrations in vitreous humor A

[0109]

[0110] A LLOQ of the method for determining soluble axitinib in VH = 0.100 ng / mL

[0111] The median axitinib concentrations in rabbit retinal samples during the study (see Table 3) reached a maximum value at day 137 (206.0 ng / g). Individual samples ranged from a low of 9.6 ng / g (day 270) to a high of 522.1 ng / g (day 180) at the end of the study. The median axitinib concentrations in the retina were similar from day 1 to day 180, after which a decrease to 14.6 ng / g was noted at day 225. This suggests that axitinib is rapidly and continuously transported from the hydrogel implant to the target retinal tissue from 1 day to approximately 6 months after administration. In retinal tissue samples, there was a significant decrease in axitinib concentrations from day 180 to day 225, with an approximate 10-fold decrease (147.1 to 14.6 ng / g).

[0112] Table 3. Summary of axitinib concentrations in the retina A

[0113]

[0114] A LLOQ of the method for determining axitinib in the retina = 0.100 ng / mL

[0115] The median axitinib concentrations in rabbit choroidal samples during the study (see Table 4) reached a maximum value at day 190 (306.5 ng / g). Individual samples ranged from a minimum of 15.2 ng / g (day 270) to a maximum of 581.6 ng / g (day 90) at the end of the study. The median axitinib concentrations in the choroid were similar from day 1 to day 180, after which a decrease to 33.3 ng / g was noted at day 225. This suggests that axitinib is rapidly and continuously transported from the hydrogel implant to the choroidal tissue from 1 day to approximately 6 months after administration. In choroidal tissue samples, there was a significant decrease in axitinib concentrations from day 180 to day 225, with an approximate 3-fold decrease (98.4 to 33.3 ng / g).

[0116] Table 4. Summary of axitinib concentrations in the choroid A

[0117]

[0118] AMethod for determining axitinib in the retina LLOQ = 0.100 ng / mL on Days 1, 45, 90, and 137, LLOQ = 0.200 ng / mL on Days 180, 225, and 270

[0119] The solubility of axitinib in (internal communication) in vitro biorelevant media was measured at 540 ng / mL under physiological conditions (PBS, pH 7.2, 37°C). This solubility value is similar to the maximum individual sample concentrations of axitinib observed in soluble VH (571.0 ng / mL), retina (522.1 ng / g), and choroid (581.6 ng / g). If axitinib accumulates in these tissues during the study, the maximum values ​​may be higher than the solubility observed in in vitro biorelevant media.

[0120] The hydrogel implant test article was formulated to contain approximately 110 μg of axitinib drug substance per implant. The insoluble (undissolved) axitinib in the VH containing the implant was measured at different time points, and the release of axitinib from the hydrogel implant over time can be assessed, Table 5. The results show that 90.0 μg of axitinib (109.4 μg-19.4 μg) was released within 180 days. The amount released within this 180-day period is similar to the amount observed in the hydrogel implant ocular distribution study conducted on beagle dogs using the same hydrogel implant test article. Assuming sustained release within 6 months, based on the consistency of retinal tissue concentrations during this period, this is equivalent to a rate of release of approximately 0.5 μg of axitinib from the hydrogel implant per day. The rate of release of axitinib from the implant of the present invention slowed down from day 180 to the completion of the study, which may be due to the almost complete biodegradation of the hydrogel in DB rabbits between 5 and 6 months, resulting in the localization of undissolved axitinib in VH.

[0121] Table 5. Summary of insoluble axitinib in VH containing hydrogel implants A

[0122]

[0123] A The LLOQ of the method used to determine insoluble axitinib in the VH containing hydrogel implants = 0.100 ng / mL. B Due to incomplete drug extraction, all insoluble axitinib in the VH of the hydrogel implant samples on Days 1, 45, 90, and 137 was excluded from analysis, and the method was refined with a modified extraction procedure for the Days 180, 225, and 270 samples.

[0124] in conclusion

[0125] The hydrogel test articles of the present invention contained approximately 109 pg of axitinib and were hydrated in a biologically relevant medium to a size of approximately 0.5 mm diameter x 9.2 mm length.

[0126] Axitinib plasma concentrations were < LLOQ (0.0500 ng / mL) for all DB rabbit samples, indicating little systemic axitinib exposure in the rabbit model following hydrogel implant administration.

[0127] The concentration of axitinib in rabbit AH samples during the study was low relative to other ocular tissues, indicating that axitinib migrated little from the posterior chamber to the anterior chamber. The median axitinib concentrations in the retina and choroid increased (98.4 to 306.5 ng / g) from 1 day to approximately 6 months after administration, indicating that axitinib was rapidly and continuously transported from the hydrogel implant to the target tissues, which then diminished over the next 3 months.

[0128] The maximum concentrations observed in individual samples in the VH, retina, and choroid were similar to the maximum solubility in biologically relevant media in vitro, indicating that there was no appreciable accumulation of axitinib in tissues during the study period.

[0129] After the hydrogel degraded and disappeared after about 4.5 months, residual undissolved drug was observed to remain in the vitreous humor, having coagulated into aggregated clumps. Although axitinib concentrations in the vitreous humor remained high at days 180 and 225, concentrations in the retina and choroid declined after 137 days, roughly corresponding to the disappearance of the hydrogel. This suggests that the hydrogel helps maintain a faster drug release rate by preventing drug particles from aggregating into coagulated clumps.

[0130] Safety, tolerability and activity in humans

[0131] Subjects with neovascular age-related macular degeneration (nAMD, both untreated and with a history of anti-VEGF therapy) were enrolled and the hydrogel of the invention was administered in a single study eye. Two groups were enrolled and evaluated: 200 μg axitinib in 7.5% PEG hydrogel (formed from 2 parts 4a20K PEG-SAZ and 1 part 8a20K PEG amine), where 7.5% represents the weight of PEG divided by the weight of liquid x 100 (1 implant; n=6); and 400 pg axitinib (2 implants; n=7). Spectral domain optical coherence tomography (SD-OCT) imaging was performed at baseline for assessment of retinal fluid and central subfield thickness (CSFT). Injection visits occurred on days 3, 7, and 14, and at months 1, 2, 3, 4.5, 6, 7.5, and 9, approximately monthly until the implant was no longer visible. The implant of the invention was visible at each visit.Safety assessments included: adverse event collection, vital signs, best corrected visual acuity (BCVA), slit lamp biomicroscopy, intraocular pressure measurement, indirect and direct ophthalmoscopy, and safety lab.

[0132] In the 400pg group, a mean reduction in central subfield thickness (CSFT) of 89.8±22.5pm (mean±SEM) was observed at 2 months and generally remained unchanged at the 3-month time point (ongoing follow-up). For some subjects with a history of anti-VEGF treatment, the duration of anti-VEGF treatment was extended to >9 months in the 200pg group and to >3 months in the 400pg group (ongoing follow-up). Best corrected visual acuity (BCVA) was maintained and no serious ocular adverse events were reported. The most common adverse events observed in the study eyes included fine pigmented posterior corneal deposits (3 / 13), subretinal hemorrhages (2 / 13) and subconjunctival hemorrhages (3 / 13), and pain (2 / 13) following implant injection. In the 200μg group, there was little migration of the implant within the vitreous and it was no longer visible after 9-10.5 months.

[0133] The implants of the present invention were generally well tolerated and had a good safety profile. Minimal migration and consistent resorption of the implants were observed over a period of up to 10.5 months.

[0134] Although we have described many embodiments of the present disclosure, it is apparent that our basic examples can be altered to provide other embodiments utilizing the compounds and methods of the present disclosure. It should be understood, therefore, that the scope of the present disclosure will be defined by the appended claims rather than by the specific embodiments that have been represented by way of example.

Claims

1. A sustained-release biodegradable ophthalmic hydrogel implant, comprising: a tyrosine kinase inhibitor, which is axitinib; and a polymer network which is a 4-arm polyethylene glycol-based hydrogel; wherein upon hydration, the ocular hydrogel implant comprises an outer interstitial region, wherein the outer interstitial region is free of undissolved axitinib particles prior to release of the axitinib, and The ocular hydrogel implant is in a solid state before administration.

2. The ocular hydrogel implant of claim 1, wherein particulate axitinib does not contact retinal cells when the axitinib is contained within the hydrogel implant.

3. The ocular hydrogel implant of claim 1, wherein dissolved axitinib is present in the hydrogel implant at a saturation level.

4. The ocular hydrogel implant of claim 1, wherein the size of the outer interstitial region increases as a function of the amount of axitinib released.

5. The ocular hydrogel implant of claim 1, wherein the ocular hydrogel implant completely degrades after at least 90% release of axitinib.

6. The ocular hydrogel implant of claim 1, wherein the ocular hydrogel implant completely degrades after about 3 months after complete release of axitinib.

7. The ocular hydrogel implant of claim 1, wherein degradation of the ocular hydrogel occurs prior to release of axitinib.

8. The ocular hydrogel implant of claim 1, comprising axitinib in the form of micronized particles.

9. The ocular hydrogel implant of any one of claims 1 to 8, wherein the polymer network is formed by reacting 4a20K PEG-SAZ with 8a20K PEG NH2.

10. The ocular hydrogel implant of any one of claims 1 to 8, wherein the polymer network is amorphous under aqueous conditions.

11. The ocular hydrogel implant of any one of claims 1 to 8, wherein the polymer network is semi-crystalline in the absence of water.

12. The ocular hydrogel implant of any one of claims 1 to 8, wherein the tyrosine kinase inhibitor is uniformly dispersed within the polymer network.

13. The ocular hydrogel implant of any one of claims 1 to 8, wherein the tyrosine kinase inhibitor is released over a period of at least 15 days.

14. The ocular hydrogel implant of any one of claims 1 to 8, wherein the tyrosine kinase inhibitor is released over a period of at least 30 days.

15. The ocular hydrogel implant of any one of claims 1 to 8, wherein the tyrosine kinase inhibitor is released over a period of at least 60 days.

16. The ocular hydrogel implant of any one of claims 1 to 8, wherein the tyrosine kinase inhibitor is released over a period of at least 90 days.

17. The ocular hydrogel implant of any one of claims 1 to 8, wherein the tyrosine kinase inhibitor is released over a period of at least 180 days.

18. The ocular hydrogel implant of any one of claims 1 to 8, wherein the tyrosine kinase inhibitor is released over a period of at least 365 days.

19. The ocular hydrogel implant of any one of claims 1 to 8, wherein the ocular hydrogel implant is injected into the vitreous humor, injected into the anterior chamber, or attached to the upper or lower punctum of the eye.

20. Use of the ocular hydrogel implant of any one of claims 1 to 19 for the preparation of a medicament for treating an ocular disorder in a subject in need thereof.

21. The use of claim 20, wherein the ocular disorder is selected from maculopathy, retinal degeneration, uveitis, retinitis, choroiditis, vascular disease, exudative disease, trauma, proliferative disease, infectious disorders, genetic disorders, retinal tears, holes and tumors.

22. The use of claim 20, wherein the ocular disorder is selected from age-related macular degeneration, choroidal neovascularization, diabetic retinopathy, acute macular neuroretinopathy, central serous chorioretinopathy, cystoid macular edema, diabetic macular edema, acute multifocal ichthyosphaeroides, Behcet's disease, birdshot choroidopathy, intermediate uveitis, multifocal choroiditis, multiple transient white dot syndrome (MEWDS), ocular sarcoidosis, posterior scleritis, serpiginous choroiditis, subretinal fibrosis and uveitis syndrome, Vogt-Koyanagi-Harada syndrome, outer exudative retinopathy, central paramacular Foveal telangiectasia, papillary phlebitis, frosty dendritic vasculitis, sickle cell retinopathy, angioid streaks, familial exudative vitreoretinopathy, sympathetic ophthalmia, uveitic retinal disease, retinal detachment, proliferative diabetic retinopathy, ocular histoplasmosis, ocular toxocariasis, viral retinitis, acute retinal necrosis, ocular syphilis, ocular tuberculosis, congenital stationary night blindness, cone dystrophy, macular hole, giant retinal tear, solid tumors, posterior uveal melanoma, choroidal hemangioma, choroidal osteoma, choroidal metastasis, retinoblastoma, fundus vascular proliferative tumors, retinal astrocytoma, and intraocular lymphoma.

23. The use according to claim 20, wherein the eye disorder is age-related macular degeneration.

24. The use of any one of claims 20 to 23, wherein the subject has been previously treated with anti-VEGF therapy.

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