Intraocular implant containing an active agent - Patent application

Abstract

The present invention relates to sustained-release biodegradable intraocular implants comprising a tyrosine kinase inhibitor dispersed within a hydrogel for the long-term treatment of retinal diseases.

Description

Technical field

[0001] The present invention relates to the treatment of ocular diseases. According to the invention, ocular diseases are treated by administering an implant that is biodegradable and provides sustained release of active agents suitable for ocular treatment. [Background technology]

[0002] There are many ocular diseases that can be treated with drug therapy. The problem with drug therapy is that systemic administration is not ideal. This is because achieving effective intraocular concentrations requires high levels of systemic administration. This increases the incidence of unacceptable side effects. Similarly, ocular instillation of active agents (e.g., eye drops) often results in therapeutic levels of drug in the central or posterior part of the eye not being achieved, and control of drug concentration due to washout, misuse, and other factors. Because it is difficult, it is often ineffective. Other local therapy routes, such as intravitreal injections, have also been unsuccessful. This is because such delivery routes tend to have short half-lives, rapid clearance, and do not provide sustained release capabilities. Additionally, maintaining therapeutic intraocular drug levels often requires daily injections, which is not acceptable to many patients. Some active agents are poorly soluble and are injected as a suspension. However, these solid particles can settle on the retina, migrate into contact with the lens, or even migrate into the anterior chamber of the eye, leading to local toxic effects.

[0003] The use of intraocular implants for drug delivery offers many advantages over traditional eye drops or injections. These devices are typically placed in or adjacent to ocular tissue and have excellent potential for drug release and duration of treatment. Although intraocular implant devices have advanced over the years, there are still many deficiencies. First, not all intraocular implants are biodegradable, leaving behind permanent foreign material or requiring tedious removal procedures after drug administration. Additionally, most biodegradable implants do not completely dissolve long after their period of beneficial use. This leaves the user with implant residue that can accumulate with repeated treatments and / or interfere with vision. Second, some intraocular implants consist of complex multilayers and require extensive manufacturing processes. This increases the cost and time of production and increases the possibility of contamination due to additional operations. Also, formulations containing hydrophobic drugs with biodegradable matrices may release little or no active agent until erosion of the network results. This can lead to drug dumping, with little benefit and potential toxicity problems. Finally, when drug solubility is low, the delicate balance between long-term sustained release and the risk of unwanted particles floating or migrating to the center or back of the eye limits the use of intraocular implants. has proven difficult to succeed.

[0004] There is a continuing need in the art for intraocular implants to treat ocular diseases.

[0005] All references disclosed herein are incorporated by reference in their entirety for all purposes. [Summary of the invention]

[0006] It is an object of certain embodiments of the present invention to provide an eye treatment comprising an active agent effective for long-term treatment of ocular diseases (e.g., neovascular age-related macular degeneration (AMD), DME, and RVO) in a patient. is to provide endodontic implants.

[0007] Another object of certain embodiments of the present invention is to provide an intraocular implant containing an active agent that provides a sustained release of the active agent into the eye.

[0008] Another object of certain embodiments of the present invention is an intraocular implant containing an active agent that is preloaded into a syringe, thereby eliminating contamination of the implant prior to injection as no further preparation steps are required. The aim is to provide an intraocular implant that avoids.

[0009] Another object of certain embodiments of the present invention is an intraocular implant containing an active agent that is sufficiently biodegradable, i.e., removed from the eye in a time consistent with active agent release and An object of the present invention is to provide an intraocular implant that avoids intraocular floaters (empty implant vehicle residue) and / or avoids the need to remove an empty implant from the eye after a treatment period.

[0010] Another object of certain embodiments of the present invention is an intraocular implant containing an active agent that is biodegradable and that during degradation of the implant, the implant may It is an object of the present invention to provide an intraocular implant that avoids disintegration into small particles.

[0011] Another object of certain embodiments of the present invention is an intraocular implant containing an active agent, wherein the stability of the intraocular implant, compared to a hydrogel formed in situ after injection, is improved in various environments ( For example, it is an object to provide an intraocular implant that is less sensitive to vitreous humor viscosity, vitreous humor pH, vitreous humor composition, and / or intraocular pressure (IOP).

[0012] Another object of certain embodiments of the invention is an intraocular implant comprising an active agent, the implant being biocompatible because it is free or substantially free of components of animal or human origin. An object of the present invention is to provide an intraocular implant that is also non-immunogenic.

[0013] Another object of certain embodiments of the present invention is to provide an intraocular implant that includes an active agent and is free of preservatives (eg, antimicrobial preservatives).

[0014] Another object of certain embodiments of the present invention is to provide an intraocular implant containing an active agent that is easy to inject, particularly intravitreal injection.

[0015] Another object of certain embodiments of the invention is an intraocular implant comprising an active agent, the intraocular implant comprising a therapeutically effective amount of the active agent, but having a relatively small length and / or diameter. The goal is to provide the following.

[0016] Another object of certain embodiments of the present invention is an intraocular implant comprising an active agent that is dimensionally stable in the dry state but changes in dimension upon hydration, e.g. after administration to the eye. The purpose of the present invention is to provide an intraocular implant.

[0017] Another object of certain embodiments of the present invention is an intraocular implant containing an active agent that, when dry, has a small diameter that fits within the lumen of a small diameter needle (e.g., a 22-30 gauge needle). An object of the present invention is to provide an intraocular implant that increases in diameter and decreases in length upon hydration, eg, after administration to the eye, thereby providing a minimally invasive method of administration.

[0018] Another object of certain embodiments of the invention is an intraocular implant comprising an active agent, the intraocular implant being injected in dry form and hydrated in situ (i.e., within the eye) upon injection. The goal is to provide the following.

[0019] Another object of certain embodiments of the present invention is an intraocular implant containing an active agent that, when placed in the eye, has a low concentration of active agent on the surface of the implant, such that the implant or to provide an intraocular implant that avoids the toxicity of the active agent when it comes into contact with tissues (eg, the retina).

[0020] Another object of certain embodiments of the present invention is an intraocular implant containing an active agent that is stable and defined both in a dry state before injection and in a hydrated state after injection (i.e., intraocularly). An object of the present invention is to provide an intraocular implant having a shape and surface area.

[0021] It is another object of certain embodiments of the present invention to provide an intraocular implant containing an active agent that is easy to handle and, in particular, does not easily spill or fragment. .

[0022] Another object of certain embodiments of the invention is an intraocular implant containing an active agent that allows for the administration of precise doses (within a wide dose range), thereby preventing overdosing and underdosing. The objective is to provide an intraocular implant that avoids risks.

[0023] Another object of certain embodiments of the present invention is to provide an intraocular implant containing an active agent that generally remains within the area of ​​the eye into which it is administered.

[0024] Another object of certain embodiments of the invention is to provide an intraocular implant containing an active agent that causes little or no visual impairment after administration.

[0025] Another object of certain embodiments of the invention is to provide an intraocular implant containing an active agent that is safe and well tolerated.

[0026] Another object of certain embodiments of the invention is to provide an intraocular implant comprising an active agent that does not induce serious adverse events (e.g., serious ocular adverse events). It is to be.

[0027] Another object of certain embodiments of the invention is an intraocular implant containing an active agent that provides sustained release of a therapeutically effective amount of the active agent for an extended period of time, e.g., up to 3 months or more, e.g. To provide an intraocular implant for a period of at least 6 months, at least 9 months, at least 11 months, or at least 13 months.

[0028] Another object of certain embodiments of the present invention is an intraocular implant containing an active agent that provides sustained release of the active agent for an extended period of time, such as up to 3 months or more, such as at least 6 months. It is an object of the present invention to provide an intraocular implant that provides for a period of at least 9 months, at least 11 months, or at least 13 months, thereby avoiding the need for frequent implant administration.

[0029] Another object of certain embodiments of the present invention is an intraocular implant containing an active agent that provides sustained release of the active agent for an extended period of time, such as up to 3 months or more, such as at least 6 months. , for a period of at least 9 months, at least 11 months, or at least 13 months, thereby inhibiting angiogenesis over this period.

[0030] Another object of certain embodiments of the present invention is an intraocular implant containing an active agent that provides sustained release of the active agent for an extended period of time, such as up to 3 months or more, such as at least 6 months. , over a period of at least 9 months, at least 11 months, or at least 13 months, over which period the levels of the active agent in ocular tissues (e.g., retina and choroid) and vitreous humor are at therapeutic levels. It is an object of the present invention to provide an intraocular implant that is consistently maintained at an efficient level, particularly at a level sufficient to inhibit angiogenesis.

[0031] Another object of certain embodiments of the present invention is an intraocular implant containing an active agent that provides sustained release of the active agent for an extended period of time, such as up to 3 months or more, such as at least 6 months. , for a period of at least 9 months, at least 11 months, or at least 13 months, over which period no toxic concentrations of the active agent are observed in ocular tissues (e.g., retina and choroid) and in the vitreous humor; The present invention is to provide intraocular implants.

[0032] Another object of certain embodiments of the present invention is an intraocular implant containing an active agent that provides sustained release of the active agent for an extended period of time, such as up to 3 months or more, such as at least 6 months. , to provide an intraocular implant for a period of at least 9 months, at least 11 months, or at least 13 months, and in which the active agent does not accumulate in the anterior chamber of the eye.

[0033] Another object of certain embodiments of the present invention is an intraocular implant containing an active agent that provides sustained release of the active agent for an extended period of time, such as up to 3 months or more, such as at least 6 months. , for a period of at least 9 months, at least 11 months, or at least 13 months, wherein no or substantially no active agent is absorbed systemically, thereby substantially avoiding systemic toxicity. is to provide endodontic implants.

[0034] Another object of certain embodiments of the present invention is to provide treatment for ocular diseases (e.g., AMD, DME, and RVO) in patients in need thereof, for treatment periods of up to 3 months or more, e.g. , for a treatment period of at least 6 months, at least 9 months, at least 11 months, or at least 13 months.

[0035] Another object of certain embodiments of the present invention is to provide treatment for ocular diseases (e.g., AMD, DME, and RVO) in patients in need thereof, for treatment periods of up to 3 months or more, e.g. , for a treatment period of at least 6 months, at least 9 months, at least 11 months, or at least 13 months, and the rescue drug does not need to be administered during the treatment period, or during the treatment period. To provide a method in which rescue drugs need to be administered only infrequently (eg, once, twice, or three times).

[0036] Another objective of certain embodiments of the invention is to treat ocular diseases (e.g., AMD, DME, and RVO) in patients in need thereof (e.g., who have previously been treated with anti-VEGF). The purpose of the present invention is to provide a method for performing this in a patient (or a patient naive to anti-VEGF treatment).

[0037] Another objective of certain embodiments of the present invention is to provide treatment of ocular diseases (e.g., AMD, DME, and RVO) to patients in need thereof (e.g., who have previously been treated with anti-VEGF and who The purpose of the present invention is to provide a method for treating patients who have not responded to anti-VEGF therapy.

[0038] Another objective of certain embodiments of the invention is to provide treatment of ocular diseases (e.g., AMD, DME, and RVO) to patients in need thereof (e.g., primary subfoveal neovascularization secondary to AMD). (Patients with a diagnosis of SFNV).

[0039] Another object of certain embodiments of the invention is to provide treatment for ocular diseases (e.g., AMD, DME, and RVO) in patients in need thereof (e.g., neovascular types with foveal-related leakage). The purpose of the present invention is to provide a method for treating subfoveal neovascularization (SFNV) secondary to AMD in patients who have previously been diagnosed with subfoveal neovascularization (SFNV) and have previously been treated with anti-VEGF.

[0040] Another object of certain embodiments of the invention is to provide a method of manufacturing an intraocular implant containing an active agent.

[0041] Another object of certain embodiments of the present invention is a method of protecting intraocular implants from premature hydration during storage and handling, wherein the intraocular implants are sensitive to moisture and, therefore, e.g. The object of the present invention is to provide a method in which the dimensions change upon hydration.

[0042] Another objective of certain embodiments of the present invention is to provide a method of minimizing tissue damage that can occur during injection of an intraocular implant.

[0043] Another object of certain embodiments of the invention is a kit comprising one or more intraocular implants containing active agents, optionally comprising a means for injecting the intraocular implants. It is to provide.

[0044] Another object of certain embodiments of the invention is to reduce central retinal thickness as measured by optical coherence tomography in patients with increased central retinal thickness due to ocular disease involving neovascularization, for example by reducing retinal fluid. An object of the present invention is to provide a method for reducing regional retinal thickness.

[0045] Another object of the present invention is to essentially maintain clinically significant increases in central retinal thickness as measured by optical coherence tomography in patients with increased central retinal thickness due to ocular diseases involving neovascularization. Or to provide a method for preventing the retinal fluid while not increasing the retinal fluid.

[0046] It is another object of certain embodiments of the invention to improve clinically significant central retinal thickness as measured by optical coherence tomography in patients with increased central retinal thickness due to ocular disease associated with neovascularization. The objective is to provide a method that reduces, essentially maintains, or prevents the increase, while improving, or at least not reducing, a patient's visual acuity (eg, as measured by best-corrected visual acuity).

[0047] Another objective of certain embodiments of the present invention is to provide a method of improving visual acuity in patients whose visual acuity is impaired due to ocular disease involving neovascularization.

[0048] Another object of certain embodiments of the present invention is a method of improving visual acuity in a patient whose visual acuity is impaired due to the presence of retinal fluid (e.g., caused by an ocular disease involving neovascularization), It is an object of the present invention to provide a method of improving the visual acuity of a patient by means of reducing retinal fluid (as evidenced by a reduction in central area retinal thickness as measured by optical coherence tomography, for example).

[0049] One or more of these objects and others of the invention are solved by one or more embodiments as disclosed and claimed herein.

[0050] Individual aspects of the invention are disclosed herein and claimed in the independent claims. The dependent claims, on the other hand, claim particular embodiments and variations of these aspects of the invention. Details of various aspects of the invention are provided in the detailed description below.

[0051] Throughout this application, various references are cited. The disclosures of these references are incorporated into this disclosure by reference. In case of conflict, the disclosure of this application will control. [Brief explanation of drawings]

[0052]

Figure 1

Figure 2

[0053] Figures 12.1 to 12.4 show information and hypothetical data for Example 12.

[0054] definition As used herein, the term "implant" (sometimes referred to as "depot") is an object that contains an active agent within the body of a human or animal, such as the vitreous humor of the eye. Refers to an object that is administered into the vitreous cavity (also called the vitreous cavity or vitreous body) and remains there for a specified period of time, releasing the active agent into the surrounding environment. The implant can have any predetermined shape (e.g., as disclosed herein) before being injected, and this shape is maintained to some extent once the implant is placed in the desired location. However, the dimensions (eg, length and / or diameter) of the implant may change after administration due to hydration, as further disclosed herein. In other words, what is injected into the eye is not a solution or suspension, but a coherent object that has already been shaped. Thus, prior to administration, the implant is fully formed as disclosed herein, and in embodiments of the invention (generally as would be possible with a suitable formulation). ) are not produced in situ at the desired location within the eye. Once administered, the implant biodegrades in the physiological environment over time (as disclosed below), thereby changing its shape while its size decreases and eventually completely degrades. Dissolved / absorbed. As used herein, the term "implant" refers to an implant in a hydrated (also referred to herein as "wet") state when it contains water (e.g., once the implant has been administered to the eye or implants after being immersed in an aqueous environment (e.g. in vitro) and hydrated or rehydrated in a manner similar to Implants that have been manufactured and dried, just before being loaded into a needle, or as disclosed herein, after being loaded into a needle, or implants that are manufactured in a dry state without the need for dehydration); used to refer to both. Thus, in certain embodiments, in the context of the present invention, an implant may contain no more than about 1% water by weight in its dry / desiccated state. The moisture content of the implant in its dry / dried state can be measured, for example, by Karl Fischer coulometric method. Throughout this specification, whenever implant dimensions (i.e., length, diameter, or volume) are reported in the hydrated state, these dimensions are determined by placing the implant in phosphate-buffered saline at 37°C for 24 hours. Measurements were taken after immersion. Whenever dimensions of an implant are reported herein in a dry state, these dimensions indicate that the implant is completely dry (and therefore contains less than about 1% water by weight in certain embodiments). , measured after the needle was ready to be loaded for subsequent administration. In certain embodiments, the implant is stored in an inert atmosphere glove box containing less than 20 ppm of both oxygen and moisture for at least about 7 days. Details of one embodiment of dimensional measurements are reported in Example 6.1.

[0055] As used in the present invention, the term "ocular" generally refers to the eye, or any part or site of the eye (an "intraocular implant" according to the invention may in principle be administered to any part or site of the eye). or any disease of the eye (in one embodiment, the invention generally refers to the treatment of any disease of the eye (“ocular disease”) of various origin and nature). In certain embodiments, the present invention provides for intravitreal injection of an intraocular implant (therefore, in this case an "intraocular implant" is an "intravitreal implant"), and as further disclosed below. Intended for the treatment of ocular diseases that affect the eyes.

[0056] The term "patient" herein includes both human and animal patients. The implant according to the invention is therefore suitable for human or veterinary medical use. Patients enrolled and treated in the clinical trial reported in Example 6 are referred to as "subjects." Generally, a "subject" is an individual (human or animal) to whom an implant according to the invention is administered (eg, during a clinical trial). A "patient" is a subject in need of treatment due to a particular physiological or pathological condition.

[0057] The term "biodegradable" refers to a material or object (eg, an intraocular implant according to the invention) that degrades in vivo, ie, when placed within the human or animal body. In the context of the present invention, as disclosed herein below in detail, an implant comprising a hydrogel, wherein an active agent is dispersed within the hydrogel, is implanted once intraocularly (e.g., within the vitreous humor). When deposited, it biodegrades slowly over time. In certain embodiments, biodegradation occurs at least in part by ester hydrolysis in the aqueous environment of the vitreous. The implant slowly dissolves and is eventually completely absorbed and is no longer visible within the vitreous.

[0058] A "hydrogel" is one that is capable of swelling in water and retaining a certain amount of water while maintaining or substantially maintaining its structure, e.g., by chemical or physical cross-linking of individual polymer chains. A three-dimensional network of hydrophilic natural or synthetic polymers (as disclosed herein). Hydrogels are soft and flexible due to their high water content and therefore closely resemble natural tissue. In the present invention, the term "hydrogel" refers to the term "hydrogel" (e.g., after the hydrogel is formed in an aqueous solution, or once the hydrogel is implanted in the eye or other part of the body, or otherwise immersed in an aqueous environment). hydrogels in a hydrated state when containing water (after being (re)hydrated) and in a dry (dried / dehydrated) state when dried to a low water content (e.g., below 1% by weight); used to refer to both. In the present invention, when the active ingredient is contained (eg, dispersed) within a hydrogel, the hydrogel may also be referred to as a "matrix."

[0059] The term "polymer network" describes a structure formed from polymer chains (same or different molecular structures, same or different molecular weights) that are cross-linked to each other. The types of polymers suitable for the purposes of the present invention are disclosed herein. Polymer networks can also be formed using crosslinking agents, as also disclosed herein.

[0060] The term "amorphous" refers to a polymer or polymer network, or other chemical or entity, that does not exhibit a crystalline structure in X-ray or electron scattering experiments.

[0061] The term "semi-crystalline" refers to a polymer or polymer network, or other chemical substance or entity, that has some crystalline properties, ie, exhibits some crystalline properties in X-ray or electron scattering experiments.

[0062] The term "crystalline" refers to a polymer or polymer network or other chemical or entity that has crystalline properties as evidenced by X-ray or electron scattering experiments.

[0063] As used herein, the term "precursor" refers to molecules or compounds that react with each other and thereby bond through crosslinks to form a polymer network and thus a hydrogel matrix. Other materials such as active agents or buffers may be present within the hydrogel, but these are not referred to as "precursors."

[0064] The portions of the precursor molecules that are still present in the final polymer network are also referred to herein as "units." Thus, a "unit" is a building block or constituent of the polymer network that forms the hydrogel. For example, polymer networks suitable for use in the present invention can include the same or different polyethylene glycol units, as further disclosed herein.

[0065] The molecular weight of the polymer precursors used for the purposes of this invention and disclosed herein can be determined by analytical methods known in the art. For example, the molecular weight of polyethylene glycol can be determined by 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) spectroscopy or electrospray ionization (ESI) mass spectrometry). It can be quantified by the following method. The molecular weight of a polymer (including the polyethylene glycol precursors disclosed herein) is the average molecular weight (based on the molecular weight distribution of the polymer) and therefore varies, including weight average molecular weight (Mw) and number average molecular weight (Mn). can be represented by an average value. In the polyethylene glycol precursor used in the present invention, the molecular weight indicated herein is the number average molecular weight (Mn).

[0066] In certain embodiments of the invention, the term "fiber" (used interchangeably herein with the term "rod") refers to an object having a generally elongated shape (i.e., in this example, the term "rod" is used interchangeably with the term "rod"). The characteristics of implants according to Specific dimensions of the implants of the present invention are disclosed herein. The implant may have a cylindrical or essentially cylindrical shape, or it may have a non-cylindrical shape. The cross-sectional area of ​​the fiber or implant can be either circular or essentially circular, but in certain embodiments it can be oval or oblong, or in other embodiments as described herein. It may have various shapes such as a cross shape, a star shape, etc. as disclosed in .

[0067] As used herein, the term "release" (and corresponding terms "released," "releasing," etc.) refers to the release of a drug (e.g., API) from an implant of the present invention into the surrounding environment. It refers to providing. The ambient environment can be an in vitro environment or an in vivo environment, as described herein. In certain specific embodiments, the surrounding environment is the vitreous humor and / or ocular tissue (eg, retina and choroid). Therefore, whenever an implant is described herein as "releasing" or "providing a (sustained) release" of an active agent, this is meant while the hydrogel has not yet (fully) biodegraded. This does not only refer to the active agent being provided directly from the implant, but also that after the hydrogel is completely degraded, any remaining active agent may be present in the surrounding environment (e.g., in aggregated form as further disclosed herein). It also refers to the continuous provision of an active agent to this environment as it remains present for a period of time and continues to exert its therapeutic effect. Accordingly, the "treatment period" referred to herein (i.e., the period during which certain therapeutic effects as described herein are achieved) refers to the implant / hydrogel as further disclosed herein. can be extended to a certain period of time even after it has completely biodegraded.

[0068] The term "sustained release", for the purposes of the present invention, refers to formulations in which a drug is formulated to be available over an extended period of time, thereby making it available in an immediate release dosage form (e.g., a solution of the active ingredient injected into the eye). It is defined to refer to a product (in the case of the present invention, the product is an implant) that can reduce the frequency of administration compared to Other terms that may be used interchangeably with "sustained release" herein include "sustained release" or "controlled release." "Sustained release" therefore characterizes the release of the API contained in the implant according to the invention. Although the term "sustained release" itself is not associated with or limited to a particular rate of release (in vitro or in vivo), in certain embodiments of the invention, the implants described herein are may be characterized by a certain average rate of release (in vitro or in vivo) or a certain release profile as disclosed in . Because the implants of the present invention (whether expressly referred to herein as "sustained release" implants or simply as "implants") provide sustained release of API, the present invention An implant is sometimes referred to as a "depot."

[0069] As used herein, certain administrations or injections are carried out "concurrently" or "simultaneously" or "at the same time" with the administration or injection of an implant according to the invention. Whenever stated, this means that the injection of each of two or more implants or the injection of one or more implant(s) is an injection of a suspension or solution (e.g. of a different active agent). and usually means carried out immediately and alternately, i.e. without any noticeable delay. For example, if a total dose of about 400 μg of axitinib is administered to one eye and that total dose is contained in two implants according to the invention (each containing about 200 μg of axitinib), these two implants will typically be the same. Injected into the vitreous cavity immediately and alternately within the treatment session, respecting all precautions for safe and accurate injection at the desired site, but without unnecessary delays, of course. The same applies when administering one or more implant(s) according to the invention contemporaneously / simultaneously / simultaneously with the administration of, for example, an additional anti-VEGF agent as described herein. If the additional anti-VEGF agent is administered by intravitreal injection of a suspension or solution containing the anti-VEGF agent, this injection will also typically be combined with one or more implants according to the invention (as disclosed above). It is intended to occur immediately before or after the intravitreal injection(s), ie, ideally during one treatment session.

[0070] However, under certain circumstances, for example, if a complication is experienced during administration of the first implant, and / or the physician administering the injection may decide to administer the second injection on the same day, during the same session, or within a few days. If it is concluded that it is not advisable to do so, a second implant may be administered, for example, one or two weeks after the first implant. Because implants can remain within the vitreous of a human eye for an extended period of time (e.g., about 9 to about 12 months), two implants can be combined, e.g. Administration at weekly or biweekly intervals is still considered "concurrent" in the context of the present invention. Similar considerations apply to the "simultaneous" administration of an implant and an additional active agent according to the invention. Thus, another active agent can be administered concurrently with the administration of the implant of the invention, ie, at or near the same time as described herein.

[0071] However, in certain other embodiments, the invention provides that the additional active agent is administered at a later time (e.g., one month or two months or three months after administration of the implant according to the invention). It can also be administered in combination with an implant.

[0072] The term "rescue drug" generally refers to a medication that may be administered to a patient under predefined conditions (e.g., if a patient does not respond adequately to an investigational treatment during a trial) or to address an emergency situation. . Conditions for administering rescue drugs in clinical trials disclosed in Example 6 herein are set forth under the subheading "Rescue Drugs" within the description of Example 6 (for % of rescue drug administration). , see especially Table 27). In certain embodiments of the invention, "rescue agent" refers to a single dose of an active agent (e.g., an anti-VEGF agent) administered as an intravitreal injection of a solution or suspension of the anti-VEGF agent. . In certain specific embodiments, the rescue drug is a single dose (2 mg) of aflibercept administered by intravitreal injection.

[0073] As used herein, the term "about" in relation to a measured quantity is used as would be expected by one of ordinary skill in the art in making measurements and exercising the level of care that is appropriate to the purpose of the measurement and the accuracy of the measuring device. refers to the normal variation in that measured amount.

[0074] The term "at least about" in relation to a measured quantity refers to the normality of the measured quantity that would be expected by a person skilled in the art in making the measurement and exercising a level of care commensurate with the purpose of the measurement and the accuracy of the measuring device. refers to the variation in the amount and the amount that is higher than the measured amount.

[0075] As used herein, the term "average" refers to the central or typical value in a set of data (points), calculated by dividing the sum of the data (points) in the set by the number of data points. (i.e., it is the average value of the data set).

[0076] As used herein, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0077] The term "and / or" used herein in expressions such as "A and / or B" is intended to include both "A and B" and "A or B."

[0078] As used herein, open terms such as "include", "including", "contain", "containing", etc. '' and is intended to refer to an open-ended list or enumeration of elements, method steps, etc., and is therefore not limited to the listed elements, method steps, etc., but to additional unlisted elements, method steps, etc. It is also intended to include elements, method steps, etc.

[0079] The term "up to" when used herein with a particular value or number is intended to include the respective value or number.

[0080] The terms "from A to B", "from A to B", and "A to B" are used interchangeably herein, and each includes the upper and lower limits of A and B. Refers to the range from to B.

[0081] The terms "API", "active (pharmaceutical) ingredient", "active (pharmaceutical) agent", "active (pharmaceutical) ingredient", "(active) therapeutic agent", "active", and "drug" are used herein Used interchangeably in this document to refer to substances used in finished pharmaceutical products (FPPs) and substances used in the preparation of such finished pharmaceutical products, such substances are capable of producing pharmacological activity. or otherwise intended to have a direct effect on the diagnosis, cure, mitigation, treatment, or prevention of disease, or on the restoration, correction, or modification of the physiology of a patient. ing.

[0082] The active agent utilized herein can be any active agent suitable for ocular administration. In certain embodiments, the TKI used according to the invention is axitinib. Axitinib is the active ingredient in INLYTA® (Pfizer, NY), which is indicated for the treatment of advanced renal cell carcinoma. Axitinib is a small molecule (386.47 daltons) synthetic tyrosine kinase inhibitor. The main mechanism of action is receptor tyrosine kinases, mainly VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-β, and c-Kit (Keating.Axitinib:a review in advanced renal cell carcinoma.2015,Drugs ,75(16):1903-13;Kernt et al.,Inhibitory activity of ranibizumab,sorafenib,and pazopanib on light-induced overexpression of platelet-derived growth factor and vascular endothelial growth factor A and the vascular endothelial growth factor receptors 1 and 2 and neuropilin 1 and 2.2012, Retina, 32(8):1652-63), which inhibits angiogenesis (formation of new blood vessels). Involved in growth and cancer progression. Therefore, axitinib is a multi-target inhibitor that inhibits both the VEGF and PDGF pathways.

[0083] The molecular formula of axitinib is C 22 H 18 N 4 OS and its IUPAC name is N-methyl-2-[3-((E)-2-pyridin-2-yl-vinyl)-1H-indazol-6-ylsulfanyl]-benzamide. Axitinib has the following chemical structure. [ka]

[0084] The solubility of axitinib in biologically relevant media (PBS, pH 7.2, 37°C) has been determined to be low, approximately 0.4-0.5 μg / mL. Its partition coefficient (n-octanol / water) is 4.2 (logP; see: DrugBank "Axitinib" entry).

[0085] For the purposes of this invention, the active agent (including axitinib) is defined in all possible forms thereof (any active agent polymorph, or a pharmaceutically acceptable salt of the active agent, anhydride, hydrate, (including other solvates or derivatives) can be used. In this description or in the claims, whenever an active agent is referred to by name, e.g. "axitinib," such polymorphs of the active agent, even in the absence of an explicit recitation, Also refers to pharmaceutically acceptable salts, anhydrides, solvates (including hydrates), or derivatives.

[0086] As used herein, the term "polymorph" refers to any crystalline form of an active agent, such as axitinib. Active agents that are solid at room temperature often exist in a variety of different crystalline forms, or polymorphs, with one polymorph being thermodynamically most stable at a given temperature and pressure.

[0087] Regarding axitinib, suitable solid forms and polymorphs (including anhydrous forms and solvates) of axitinib are described, for example, by A.M. Campeta et al., Journal of Pharmaceutical Sciences, Vol. 99, No. 9, September 2010, 3874 -3886. All axitinib polymorphs (whether anhydrous or solvated) can be used in the preparation of implants according to certain embodiments of the invention; such polymorphs include, for example, US 8,791,140 The most thermodynamically stable polymorph of axitinib, designated XLI in B2, is included. XLI is the anhydrous crystalline form of axitinib. In certain embodiments of the invention, axitinib used in the preparation of implants according to the invention is anhydrous crystalline form XLI. In certain other embodiments, crystalline anhydrous forms of axitinib suitable for use in the present invention include (but are not limited to) polymorphs I, IV, VI, and XXV. In addition to the anhydrous form, as also described in the cited art, there are numerous solvates of axitinib with different solvents, all of which can also be used to prepare implants according to the present invention. . All of the forms mentioned above are well characterized in the art, for example in the paper by Campeta et al. cited above, or in the patent literature (including, but not limited to, US 8,791,140B 2, US 2006 / 0094763). , and WO2016 / 178150A1). Any of the axitinib polymorphs known and disclosed in the art, including, but not limited to, the documents cited herein, can be used in the present invention.

[0088] In certain specific embodiments, the axitinib used in the preparation of and / or present in the implant according to the invention is 8.3, 9.3, 13.7, 15.6, 16.1, 16.5, 17.6, 18.6, Characterized by an XRD pattern containing at least five characteristic 2θ peaks selected from 21.0, 22.6, 23.1, 23.4, 24.1, and 26.0 (each value ±0.2 2θ°). In particular, axitinib used for the preparation of the implant according to the invention and / or present in the implant according to the invention is 8.3, 9.3, 15.6, 16.5, 17.6, 21.0, 24.1 and 26.0 (each value ± 0.2 2θ° ) in DMSO solvent characterized by an XRD pattern containing at least five characteristic 2θ° peaks selected from 13 C NMR and / or chemical shifts at 171.1, 153.2, 142.6, 139.5, 131.2, 128.1, and 126.3 (each shift ±0.2 ppm) 13 Characterized by C solid-state NMR and / or DSC isotherm including two endothermic peaks between 213°C-217°C (peak 1) and 219°C-224°C (peak 2). In one specific embodiment, the unsolvated crystalline form of axitinib SAB-I disclosed in WO2016 / 178150 can be used for the preparation of implants according to the present invention.

[0089] Axitinib inhibits VEGF signaling and also inhibits PDGF signaling. In addition to inhibiting VEGF / PDGF, axitinib inhibits the blood vessel-generating survival factor c-kit with a clearance half-life (t) of several hours. 1 / 2 ) (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) (in contrast, ranibizumab and aflibercept t 1 / 2 (each takes several days in the human eye). These large antibodies are t 1 / 2 Longer antibodies can maintain effective tissue concentrations over several weeks, while small molecule antibodies are cleared more quickly. However, axitinib has low solubility and is contained within the hydrogel implants of certain embodiments of the present invention, where it remains in the vitreous humor (VH) for extended periods of time (e.g., several months), thus ensuring that the implant remains in the VH. A therapeutically effective amount of axitinib is delivered for a period of time that lasts during the treatment period. Therefore, sustained intravitreal delivery of axitinib provides a multi-target inhibitor that can in principle inhibit both VEGF and PDGF pathways without the need for combination therapy and without the need for frequent intravitreal injections. .

[0090] As used herein, the term "therapeutically effective" refers to the amount of drug or active agent necessary to produce a certain desired therapeutic result after administration. For example, in the context of one embodiment of the invention, one desired therapeutic outcome is to reduce central zone retinal thickness (CSFT) in patients with neovascular AMD, as measured by optical coherence tomography. Conceivable. This is because patients with neovascular AMD have elevated CSFT. A "therapeutically effective" amount of an active agent in the context of the present invention also refers to the IC that this active agent provides for a particular substrate. 50 A multiple of, e.g., IC 50 It may be 50 times or more. For example, the IC of TKI axitinib against angiogenesis-related RTKs 50 The values ​​are presented in Table 12.

[0091] As used herein, the abbreviation "PBS" means phosphate buffered saline.

[0092] As used herein, the abbreviation "PEG" means polyethylene glycol.

[0093] I. Implant Active ingredients and methods: In certain embodiments, the implants disclosed herein are, for example, punctal, intravitreal, subconjunctival, intrascleral, subretinal, suprachoroidal, periocular, peribulbar, retrobulbar, intracorneal, posterior. Suitable for ocular delivery to a route selected from sub-Tenon's delivery, anterior sub-Tenon's delivery, conjunctival sac delivery, or fornix delivery. Administration can be accomplished, for example, by injection with a needle or insertion with a delivery device into the selected ocular delivery route.

[0094] The needle may be, for example, 18 gauge, 19 gauge, 20 gauge, 21 gauge, 22 gauge, 23 gauge, 24 gauge, 25 gauge, 26 gauge, 27 gauge, 28 gauge, 29 gauge, 30 gauge, 31 gauge, 32 gauge or The gauge can be selected from 33 gauges.

[0095] In certain embodiments, the administration is performed in accordance with US Pat. No. 8,808,225; US Pat. No. 10,722,396; US Pat. No. 10,390,901; US ​​Pat. No. 2019 / 0290485, US Patent Application Publication No. 2019 / 0000669, and US Patent Application Publication No. 2018 / 0042767.

[0096] In alternative embodiments in which the intraocular delivery route is accessible from outside the eye, administration is optionally performed without a needle (e.g., manually or utilizing forceps, applicators, or other delivery aids). ) can be implemented.

[0097] The active agents administered by the implants of the invention can be, for example, less than about 2,000 μg / mL, less than about 1,500 μg / mL, less than about 1,000 μg / mL, less than about 800 μg / mL, less than about 600 μg / mL, about 500 μg / mL Less than mL, less than about 400 μg / mL, less than about 300 μg / mL, less than about 200 μg / mL, less than about 100 μg / mL, less than about 75 μg / mL, less than about 50 μg / mL, less than about 25 μg / mL, less than about 10 μg / mL, Water solubility of less than about 5 μg / mL, less than about 1 μg / mL, less than about 0.5 μg / mL, less than about 0.4 μg / mL, less than about 0.3 μg / mL, less than about 0.2 μg / mL, or less than about 0.1 μg / mL can have.

[0098] In other embodiments, the active agent administered by the device of the invention is sparingly soluble (30-100 parts solvent to 1 part solute) as described in Remington, The Science and Practice of Pharmacy 22nd Edition 2012. ), sparingly soluble (100-1000 parts of solvent required for 1 part solute), very sparingly soluble (1000-10000 parts solvent required for 1 part solute), or barely soluble (1 part solute required) of solute (10,000 parts of solvent required).

[0099] Ocular diseases that can be treated with the implants and methods of the invention can include any ocular disease (eg, an anterior eye disease or a posterior eye disease).

[0100] Anterior ocular conditions may be related to cellular or subcellular components of the anterior ocular anatomy, such as the acellular tear film layer and its corresponding lipid-aqueous mucin components. . The condition of the front part of the eye also includes the upper and lower eyelids (meibomian glands and their corresponding cellular and tissue components, such as muscles, lipid-producing holocrine glands, exocrine glands, and endocrine glands, as well as blood vessels and connective tissue components). and the condition of the conjunctiva and its corresponding cells (including goblet cells, fibroblasts, vascular cells and components). Conditions in the anterior part of the eye may also be related to the corneal layers of the eye, including epithelial cells, stromal cells, fibroblasts, corneal endothelial cells, corneal nerves and their associated cells, and layers of the stroma. . Conditions of the anterior part of the eye may also include inflammation, diffuse lamellar keratitis, corneal disease, edema, or opacification with an exudative or inflammatory component, ocular conditions related to systemic autoimmune diseases, and dry eye. Ocular surface disorders from the eye (e.g., keratoconjunctivitis (e.g., vernal keratoconjunctivitis, atopic keratoconjunctivitis, and sicca keratoconjunctivitis)), lid margin disease, meibomian gland conditions, dysfunctional lacrimal syndrome, anterior and posterior eyelids inflammation, staphylococcal blepharitis, microbial infections, conjunctivitis (e.g., persistent allergic, macropapillary, seasonal intermittent allergic, perennial allergic, toxic, and infectious conjunctivitis), conjunctival edema, anterior Uveitis, inflammatory conditions, edema, hereditary diseases of the cornea (e.g. corneal dystrophies (e.g. keratoconus, posterior polymorphic corneal dystrophy), Fuchs' dystrophy, aphakic and pseudophakic bullous keratopathy, scleral diseases , ocular cicatricial pemphigoid, and pterygium may also be mentioned.

[0101] The condition of the posterior part of the eye may concern the cellular or subcellular components of the posterior part of the eye's anatomy, including the retina and all cells of the retinal layers, e.g., the outer and inner photoreceptor cells. may be associated with the nucleocytic layer, amacrine and ganglion cells, ganglion cells, macula, fovea, and vitreous. Additional components of the posterior part of the eye include the ciliary body, iris, uvea, and retinal pigment cells. Conditions of the posterior part of the eye include conditions of the optic nerve (including corresponding cellular and subcellular components, e.g., axons and associated innervation), glaucoma (e.g., primary open-angle glaucoma, acute and chronic Clinical macular edema or angiographic cysts resulting from conditions such as angle-closure glaucoma (as well as secondary glaucoma), myopic retinopathy, and macular edema (diabetes, exudative macular degeneration, and macular edema associated with laser treatment of the retina) (including macular edema), diabetic retinopathy, age-related macular degeneration, retinopathy of prematurity, retinal ischemia and choroidal neovascularization, genetic diseases of the retina, pars planitis, Posner-Schlossman syndrome, Behçet disease, Vogt-Koyanagi-Harada syndrome, hypersensitivity reaction, Toxoplasma chorioretinitis, orbital inflammatory pseudotumor, conjunctival edema, conjunctival venous congestion, periorbital cellulitis, acute dacryocystitis, nonspecific vasculitis, sarcoidosis, and cytotoxicity. One example is megalovirus infection.

[0102] Specific active agents that can be utilized in the implants and methods of the invention include, but are not limited to, immunosuppressants, complement protein C5 agents (e.g., eculizumab or avasincaptadopegol), Anti-inflammatory agents such as steroids, steroidal and non-steroidal anti-inflammatory agents (e.g. COX1 or COX2 inhibitors), antivirals, antibiotics, anti-glaucoma agents, anti-VEGF agents, analgesics, and combinations thereof. It will be done.

[0103] Immunosuppressants include, but are not limited to, cyclosporine, mTOR inhibitors (e.g., rapamycin, tacrilimus, temsirolimus, sirolimus, everolimus, KU-0063794, WYE-354, AZD8055, metformin, or Torin- 2), cyclophosphamide, atoposide, thiotepa, methotrexate, azathioprine, mercaptopurine, interferon, infliximab, etanercept, mycophenolate mofetil, 15-deoxyspargarin, thalidomide, glatiramer, leflunomide, vincristine, cytarabine, its pharmaceutical Included are acceptable salts, and combinations thereof.

[0104] Nonsteroidal anti-inflammatory compounds include inhibitors of cyclooxygenase (COX) enzymes, such as cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) isoenzymes. General classes of nonsteroidal anti-inflammatory compounds include salicylates, propionic acid derivatives, acetic acid derivatives, enolic acid derivatives, and anthranilic acid derivatives. Examples of nonsteroidal anti-inflammatory drugs include acetylsalicylic acid, diflunisal, salsalate, ibuprofen, dexibuprofen, naproxen, fenoprofen, ketoprofen, dexketoprofen, flubiprofen, oxaprozin, loxoprofen, indomethacin, tolmetin, sulindac, etodolac, Ketorolac, diclofenac, aceclofenac, nabumetone, piroxicam, tenoxicam, loroxicam, phenylbutazone, mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid, celecoxib, pharmaceutically acceptable salts thereof, and combinations thereof. Can be mentioned.

[0105] Anti-inflammatory agents that can be utilized in the implants and methods of the invention include agents that target inflammatory cytokines (e.g., TNFα, IL-1, IL-4, IL-5 or IL-17, or CD20). can be mentioned. Such agents can include etanercept, infliximab, adalimumab, daclizumab, rituximab, tocilizumab, certolizumab pegol, golimumab, pharmaceutically acceptable salts thereof, and combinations thereof.

[0106] Analgesics that can be utilized in the implants and methods of the present invention include acetaminophen, acetaminosaol, aminochlortenoxazine, acetylsalicyl 2-amino-4-picolinic acid, acetylsalicylsalicylic acid, anilelidine, benoxa Profen, benzylmorphine, 5-bromosalicylacetic acid, busetin, buprenorphine, butorphanol, capsaicin, cinchophen, silamadol, clomethacin, clonixin, codeine, desomorphine, dezocine, dihydrocodeine, dihydromorphine, dimefeptanol, dipyrocetyl, eptazocin, etoxazene, Ethylmorphine, eugenol, froctafenine, phosphosar, graphenine, hydrocodone, hydromorphone, hydroxypethidine, ibufenac, p-lactofenetide, levorphanol, meptazinol, metazosine, metopone, morphine, nalbuphine, nicomorphine, norlevorphanol, normorphine, oxycodone, Oxymorphone, pentazocine, phenazocine, phenocol, fenoperidine, phenylbutazone, phenyl salicylate, phenylamidol, salicin, salicylamide, thiorphan, tramadol, diacerein, actarit, pharmaceutically acceptable salts thereof, and combinations thereof. can be mentioned.

[0107] Antibiotics that can be utilized in the implants and methods of the invention include aminoglycosides, penicillins, cephalosporins, fluoroquinolones, macrolides, and combinations thereof. Aminoglycosides include tobramycin, kanamycin A, amikacin, dibekacin, gentamicin, sisomicin, netilmicin, neomycin B, neomycin C, neomycin E, streptomycin, paramomycin, pharmaceutically acceptable salts thereof, and combinations thereof. can be mentioned. Penicillins include amoxicillin, ampicillin, bacampicillin, carbenicillin, cloxacillin, dicloxacillin, flucloxacillin, mezlocillin, nafcillin, oxacillin, penicillin G, penicillin V, piperacillin, pivampicillin, pivmecillinum, ticarcillin, and pharmaceutically acceptable salts thereof. , and combinations thereof. Cephalosporins include cefacetril, cefadroxil, cephalexin, cephaloglycin, cephalonium, cephaloridine, cephalothin, cefapirin, cefatridine, cefazaflu, cefazedone, cefazolin, cefrazine, cefuroxazine, ceftesol, cefaclor, cefamandole, cefmetazole, cefoniside, cefotetan. , cefoxitin, cefprozil, cefuroxime, cefzonam, cefcapene, cefdaloxime, cefdinir, cefditoren, cefetameth, cefixime, cefmenoxime, cefodizime, cefotaxime, cefpimizole, cefpodoxime, ceftelam, ceftibuten, ceftiofur, ceftiolene, ceftizoxime, ceftriaxone, cefti perazon, ceftazidime, cefclizine , cefepime, cefluprenam, cefoselis, cefozopran, cefpirome, cefquinome, ceftobiprole, ceftaroline, cefaclomedine, cephalolam, cefparol, cefcanel, cefdrolol, cefemipidone, cefemipidone, cefemitril, cefimatylene, cefmepidium, cefvecin, cefoxazole, cefrotil, cefsumide Do, cefuracetim, Mention may be made of ceftioxide, pharmaceutically acceptable salts thereof, and combinations thereof. Fluoroquinolones can include ciprofloxacin, levofloxacin, gatifloxacin, moxifloxacin, ofloxacin, norfloxacin, pharmaceutically acceptable salts thereof, and combinations thereof. Macrolides can include azithromycin, erythromycin, clarithromycin, dirithromycin, oxythromycin, telithromycin, pharmaceutically acceptable salts thereof, and combinations thereof.

[0108] Antiviral agents that can be utilized in the implants and methods of the invention include nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, fusion inhibitors, integrase inhibitors, nucleoside analogs, protease inhibitors, and Includes reverse transcriptase inhibitors. Examples of antiviral agents include, but are not limited to, abacavir, acyclovir, adefovir, amantadine, amprenavir, ampligen, arbidol, atazanavir, boceprevir, cidofovir, darunavir, delavirdine, didanosine, docosanol, edoxudine, efavirenz. , emtricitabine, enfuvirtide, entecavir, famciclovir, fomivirsen, fosamprenavir, foscarnet, phosphonet, ganciclovir, ivacitabine, immunovir, idoxuridine, imiquimod, indinavir, inosine, interferon type III, interferon type II, interferon I Types, interferon, lamivudine, lopinavir, loviride, maraviroc, moloxidine, metisazone, nelfinavir, nevirapine, nexavir, oseltamivir, peginterferon alfa-2a, penciclovir, peramivir, pleconaril, podophyllotoxin, raltegravir, ribavirin, rimantadine, ritonavir, pyramide pyramiding saquinavir, stavudine, tenofovir, tenofovir disoproxil, tipranavir, trifluridine, tridivir, tromantadine, truvada, valacyclovir, valganciclovir, vicriviroc, vidarabine, viramidine, zalcitabine, zanamivir, zidovudine, pharmaceutically acceptable and combinations thereof.

[0109] Steroidal anti-inflammatory agents that can be utilized in the implants and methods of the present invention include dexamethasone, budesonide, triamcinolone, hydrocortisone, loteprednol, prednisolone, mometasone, fluticasone, rimexolone, fluorometholone, beclomethasone, flunisolide, and the like. Included are pharmaceutically acceptable salts, and combinations thereof.

[0110] Anti-glaucoma agents that can be utilized in the implants and methods of the invention include beta-blockers such as atenolol, propranolol, methiplanolol, betaxolol, carteolol, levobetaxolol, levobunolol, timolol, Acceptable salts, and combinations thereof; adrenergic agonists or sympathomimetics, such as epinephrine, dipivefrin, clonidine, aparclonidine, brimonidine, pharmaceutically acceptable salts thereof, and combinations thereof; ; parasympathomimetic agents or cholinergic agonists, such as pilocarpine, carbachol, phosphorous iodide, physostigmine, pharmaceutically acceptable salts thereof, and combinations thereof; carbonic anhydrase inhibitors (topical or systemic agents); mydriatic-cycloplegic agents, such as atropine, cyclopentolate , succinylcholine, homatropine, phenylephrine, scopolamine, tropicamide, pharmaceutically acceptable salts thereof, and combinations thereof; prostaglandins, such as prostaglandin F2 alpha, anti-prostaglandins, prostaglandin precursors, or prostaglandin analogs, such as bimatoprost, latanoprost, travoprost, unoprostone, tafluprost, pharmaceutically acceptable salts thereof, and combinations thereof.

[0111] Anti-VEGF agents that can be utilized in the implants and methods of the invention include bevacizumab, pegaptanib, ranibizumab, brolucizumab, pharmaceutically acceptable salts thereof, and combinations thereof.

[0112] One embodiment of the invention is a sustained release biodegradable intraocular implant comprising a hydrogel and an active agent (e.g., at least about 150 μg of a tyrosine kinase inhibitor (TKI)), wherein the active agent particles are within the hydrogel. A dispersed, sustained release, biodegradable intraocular implant. In one embodiment, the present invention provides a sustained release biodegradable intraocular implant comprising a hydrogel and an active agent, wherein the active agent particles are dispersed within the hydrogel and the implant has a diameter of about 17 mm in its dry state. Provided are sustained release biodegradable intraocular implants having a length of less than or equal to

[0113] In certain embodiments, the active ingredient included in the implant of this aspect of the invention is a TKI. Examples of suitable TKIs include axitinib, sorafenib, sunitinib, nintedanib, pazopanib, regorafenib, cabozantinib, and vandetanib. In certain embodiments, the TKI used in this and other aspects of the invention is axitinib. Details of axitinib, its chemical structure, polymorphs, solvates, salts, etc., and properties such as solubility are shown in the Definitions section above.

[0114] All the features disclosed herein (individually or in any combination of features) with respect to the implant according to the invention provide a sustained release biodegradable intraocular implant comprising a hydrogel and an active agent, wherein the TKI particles are present within the hydrogel. can be used to characterize sustained release biodegradable intraocular implants where the implant has a length in its dry state of less than about 17 mm.

[0115] In certain embodiments, the implants of the invention are intravitreal implants, ie, administered into the vitreous humor (also referred to herein as "intravitreally administered").

[0116] In embodiments using a TKI (e.g., axitinib), the active agent is present at a dose as disclosed herein of at least 150 μg, such as from about 150 μg to about 1800 μg, from about 150 μg to about 1200 μg, or from about 200 μg to about 800 μg. It is included within the scope of the implant of the present invention. Any TKI (e.g., axitinib) may be present in an amount within these ranges, such as about 150 μg, about 200 μg, about 300 μg, about 400 μg, about 500 μg, about 600 μg, about 700 μg, about 800 μg, about 900 μg, about 1000 μg, about 1100 μg, or about 1200 μg can be used. In alternative embodiments, the dose of TKI (e.g., axitinib) included in an implant of the invention is up to about 1800 μg, such as about 1300 μg, about 1400 μg, about 1500 μg, about 1600 μg, about 1700 μg, or about 1800 μg. It's okay. In further alternative embodiments, the dose of TKI (e.g., axitinib) included in the implants of the invention may be even higher than about 1800 μg, or higher than about 2000 μg, e.g., up to about 3000 μg, up to about It may be 6000 μg, or up to about 10000 μg. All listed values ​​also include +25% and -20% variation, or + / -10% variation.

[0117] In certain specific embodiments, the doses of axitinib included in the implants of the invention are as follows: ●A range of about 160 μg to about 250 μg, or about 180 μg to about 220 μg, or about 200 μg (i.e., including +25% and -20% variation of 200 μg, or + / -10% variation) ●A range of approximately 320μg to approximately 500μg, or approximately 360μg to approximately 440μg, or approximately 400μg (i.e., including +25% and -20% variation of 400μg, or + / -10% variation) ●A range of approximately 375μg to approximately 600μg, or approximately 450μg to approximately 550μg, or approximately 500μg (i.e., including +25% and -20% variation of 500μg, or + / -10% variation) ●A range of about 480 μg to about 750 μg, or about 540 μg to about 660 μg, or about 600 μg (i.e., including +25% and -20% variation of 600 μg, or + / -10% variation) ●A range of about 640 μg to about 1000 μg, or about 720 μg to about 880 μg, or about 800 μg (i.e., including +25% and -20% variation of 800 μg, or + / -10% variation) ●A range of approximately 800μg to approximately 1250μg, or approximately 900μg to approximately 1100μg, or approximately 1000μg (i.e., including +25% and -20% variation of 1000μg, or + / -10% variation) ●A range of approximately 960μg to approximately 1500μg, or approximately 1080μg to approximately 1320μg, or approximately 1200μg (i.e., including +25% and -20% variation of 1200μg, or + / -10% variation) ●A range of approximately 1440μg to approximately 2250μg, or approximately 1620μg to approximately 1980μg, or approximately 1800μg (i.e., including +25% and -20% variation of 1800μg, or + / -10% variation)

[0118] In one embodiment, the dose of axitinib included in one implant of the invention is about 480 μg to about 750 μg, or about 540 μg to about 660 μg, or in certain embodiments about 600 μg.

[0119] The disclosed amount (including any mentioned variations) of the active agent (e.g. axitinib) is based on the final content of active ingredient within the implant and the active ingredient used as a starting component per implant in manufacturing the implant. amount, refers to both of these. The doses disclosed herein may also be applicable to other active agents in certain embodiments.

[0120] As disclosed in more detail hereinbelow and as made clear from the Examples section, in certain embodiments of the invention, the total dose of active agent administered to a patient is It may be included in two, three, or more implants that are administered. For example, a dose of about 400 μg of active agent may be administered in one implant containing about 400 μg axitinib, two implants (eg, each containing about 200 μg axitinib), etc. Naturally, two or more identical implants (or implants containing the same dose) can be combined, as well as two or more different implants (or implants containing different doses) to reach the desired total dose. You can also do it. In certain embodiments, about 480 μg to about 750 μg, or about 540 μg to about 660 μg, or a total dose of about 600 μg of axitinib is included in one implant, and such only one implant is used for such treatment according to the present invention. administered to patients in need. In another embodiment, the total dose is higher than about 600 μg, such as from about 800 μg to about 1250 μg, or from about 900 μg to about 1100 μg, or about 1000 μg, or from about 960 μg to about 1500 μg, or from about 1080 μg to about 1320 μg, or about 1200 μg. or a total dose of about 1440 μg to about 2250 μg, or about 1620 μg to about 1980 μg, or about 1800 μg is included in one implant, and only one such implant requires such treatment according to the present invention. administered to patients. In other embodiments, the total dose administered to a patient according to the invention may be comprised in two or more implants (containing the same or different amounts of API) that are administered simultaneously.

[0121] The active agent is contained in the implant of the invention and is dispersed or distributed within a hydrogel that is composed of a polymer network. In certain embodiments, the particles are homogeneously or essentially homogeneously dispersed within the hydrogel. Hydrogels can prevent the particles from agglomerating and can also provide a matrix for the particles that holds them in the desired location within the eye while slowly releasing the drug.

[0122] In certain embodiments of the invention, active agents may be microencapsulated. The term "microcapsule" (also referred to as "microparticle") may be defined as a generally spherical particle having a size varying between, for example, about 50 nm to about 2 mm. Microcapsules have at least one active agent domain (or core) encapsulated within a surrounding material (sometimes referred to as a shell). One suitable agent for microencapsulating active agents for purposes of the present invention (without limiting this disclosure) is poly(lactic-co-glycolic acid).

[0123] In other embodiments, the active agent is not microencapsulated and is therefore in situ, i.e., admixed with another material, such as (but not limited to) poly(lactic-co-glycolic acid). dispersed within the hydrogel, and thus within the implant of the present invention, without being attached to or adjacent to or microencapsulated with another material.

[0124] In one embodiment, the active agent particles (eg, axitinib particles) may be micronized particles. In another embodiment, the active agent particles (eg, axitinib particles) may not be micronized. Micronization refers to the process of reducing the average diameter of particles of a solid material. Particles with reduced diameter can, among other things, have higher dissolution and erosion rates, which increases the bioavailability of the active pharmaceutical ingredient and, in certain embodiments, positively impacts release kinetics. obtain. Additionally, micronized particles may have a reduced tendency to agglomerate during manufacturing operations (see also Figure 24). In the composites field, particle size is known to influence mechanical properties when combined with a matrix, with smaller particles providing better reinforcement for a given mass fraction. Therefore, hydrogel matrices loaded with micronized TKI particles may have improved mechanical properties (e.g., brittleness, strain to failure, etc.) compared to similar mass fractions of larger TKI particles. Such properties are important during manufacturing, implantation, and disassembly of the implant. Micronization can also promote a more homogeneous distribution of the active ingredient within the selected dosage form or matrix. Particle size distribution can be measured by methods known in the art, including sieving, laser diffraction, or dynamic light scattering. In certain embodiments of the invention, the active agent (e.g., axitinib) particles used in preparing the implants of the invention have a d90 of less than about 100 μm and / or a d50 of less than about 50 μm as determined by laser diffraction. , or may have a d90 of less than about 75 μm and / or a d50 of less than about 20 μm. In specific embodiments, the d90 of the active agent (eg, axitinib) can be less than about 30 μm, less than about 20 μm, as determined by laser diffraction. In very specific embodiments, the active agent (eg, axitinib) has a d90 of less than about 10 μm as determined by laser diffraction. In these or other embodiments, the active agent (eg, axitinib) particles used in preparing the implants of the invention may have a d50 of less than about 5 μm as determined by laser diffraction. In these or other embodiments, the active agent (eg, axitinib) particles used in the invention can have a d10 of less than about 3 μm as determined by laser diffraction. In certain embodiments, the active agent (eg, axitinib) particles used in the preparation of the implants of the invention can have a d100 of less than about 20 μm as determined by laser diffraction. The "d90" (also referred to herein as "D90") value is the indicated value of 90% by volume of all particles in a measured bulk material (having a certain particle size distribution). means having a particle size less than the value. For example, a d90 particle size of less than about 10 μm means that 90% by volume of the particles in the measured bulk material have a particle size of less than about 10 μm. Corresponding definitions may apply to other "d" values ​​(e.g., "d10", "d50", or "d100" values ​​(also referred to herein as "D10", "D50", and "D100" values, respectively)). )) also applies. In certain other embodiments, TKI (eg, axitinib) particles having diameters exceeding this specification can also be used.

[0125] Micronized TKIs (eg, axitinib particles) may be purchased as specified from a supplier or prepared, for example, according to the exemplary axitinib procedure (disclosed in WO2016 / 183296A1, Example 13) below. Briefly, measure 1800 mL of sterile water for injection (WFI) in a 2 L beaker, place it on a stir plate, and stir at 600 RPM using a stir bar to create a large WFI vortex in the center of the beaker. Place one 60 mL BD syringe containing axitinib in ethanol into a syringe pump that is clamped above the WFI beaker. Connect a hypodermic needle (21G, BD) to the syringe and center the target directly on the vortex for dispensing the axitinib solution. The syringe pump is then run at 7.5 mL / min to drop the axitinib solution into the WFI to precipitate the micronized axitinib. After micronization, filter the axitinib (e.g., with a 0.2 μm vacuum filter) and rinse with WFI. After filtration, the axitinib powder is collected from the filter (eg, by using a spatula) and vacuum dried for an extended period of time (eg, about 12 hours or about 24 hours) to remove excess solvent. Another exemplary method of micronizing axitinib is disclosed in Example 9 of WO2017 / 091749. The methods of micronization described are not limiting, and other methods of micronizing the active agent (eg, axitinib) can be used as well. Additionally, the disclosed micronization method (or other methods) can be used with active substances other than axitinib.

[0126] Another embodiment of the present invention is a sustained release biodegradable intraocular implant comprising a hydrogel and an active agent, wherein the TKI particles are dispersed within the hydrogel and the implant contains from about 0.2 mg to about 1.5 mg in its dry state. A sustained release biodegradable intraocular implant with a total weight of .

[0127] In certain embodiments, the total weight (also referred to herein as "total mass") of an implant according to the present invention can be from about 400 μg to about 1.2 mg in its dry state. In certain specific embodiments, the total weight of an implant according to the invention in its dry state can be from about 0.3 mg to about 0.6 mg, such as from about 0.4 mg to about 0.5 mg, or about 0.8 mg. ~about 1.1 mg, for example, about 0.9 mg to about 1.0 mg.

[0128] All the features (individually or in any combination of features) disclosed herein with respect to the implant according to the present invention provide a sustained release biodegradable intraocular implant comprising a hydrogel and an active agent, wherein the active agent particles are contained in a hydrogel. can be used to characterize sustained release biodegradable intraocular implants, wherein the implant has a total weight in its dry state of about 0.2 mg to about 1.5 mg.

[0129] Polymer network: In certain embodiments, hydrogels can be formed from precursors having functional groups that form crosslinks to form a polymer network. These crosslinks between polymer strands or arms can be chemical (ie, may be covalent) and / or physical (eg, ionic bonds, hydrophobic associations, hydrogen bridges, etc.) in nature.

[0130] Polymer networks can be prepared from one type of precursor or from two or more types of precursors that can be reacted. Precursors are selected with consideration to the desired properties of the resulting hydrogel. There are a variety of suitable precursors for use in making hydrogels. In general, any pharmaceutically acceptable crosslinkable polymer that forms a hydrogel can be used for purposes of the present invention. Hydrogels and the components incorporated therein, including the polymers used to create the polymer network, should be physiologically safe, eg, not eliciting immune responses or other adverse effects. Hydrogels can be formed from natural, synthetic, or biosynthetic polymers.

[0131] Natural polymers can include glycosaminoglycans, polysaccharides (eg, dextran), polyamino acids, proteins, or mixtures or combinations thereof.

[0132] Synthetic polymers are generally any polymers that are synthetically produced from various feedstocks by different types of polymerization (including free radical polymerization, anionic or cationic polymerization, chain growth or addition polymerization, condensation polymerization, ring-opening polymerization, etc.). It can be a polymer. Polymerization can be initiated by certain initiators, light and / or heat, and can also be catalyst-mediated.

[0133] Generally, for the purposes of the present invention, one or more synthetic polymers of the group comprising one or more units of polyalkylene glycol, such as polyethylene glycol (PEG), polypropylene glycol, poly(ethylene glycol)-block-poly(propylene glycol) copolymers, or polyethylene oxide, polypropylene oxide, polyvinyl alcohol, poly(vinylpyrrolidinone), polylactic acid, polylactic-co-glycolic acid, random or block copolymers, or combinations / mixtures of any of these. (However, this list is not intended to be exhaustive).

[0134] The precursors can be covalently crosslinked to each other to form a covalently crosslinked polymer network. In certain embodiments, precursors with at least two reactive centers (e.g., in free radical polymerization) function as crosslinkers because each reactive group can participate in the formation of a different growing polymer chain. can do.

[0135] The precursor may have a biologically inert and hydrophilic portion, such as a core. In the case of branched polymers, the core refers to a continuous portion of the molecule linked to arms extending from the core, where the arms often have functional groups at the ends of the arms or branches. Multi-arm PEG precursors are examples of such precursors and are further disclosed herein below.

[0136] Thus, hydrogels for use in the present invention may include, for example, one multi-arm precursor having a first functional group(s)(s) and a second functional group(s)(s). can be made from another multi-armed precursor with By way of example, multi-arm precursors may have hydrophilic arms (e.g. polyethylene glycol units) terminated with primary amines (nucleophilic) or may have activated ester end groups. Good (electrophilic). The polymer network according to the invention may contain identical or different polymer units crosslinked to each other.

[0137] The reactivity of certain functional groups can be increased by using activating groups. Such activating groups include (but are not limited to) carbonyldiimidazole, sulfonyl chloride, aryl halide, sulfosuccinimidyl ester, N-hydroxysuccinimidyl ester, succinimidyl ester, epoxide, Examples include aldehydes, maleimides, imidoesters, and acrylates. N-Hydroxysuccinimide ester (NHS) is a useful group for crosslinking nucleophilic polymers, such as primary amine-terminated or thiol-terminated polyethylene glycols. The NHS-amine crosslinking reaction is carried out in an aqueous solution using a buffer solution (e.g., phosphate buffer (pH 5.0~7.5), triethanolamine buffer (pH 7.5~9.0), borate buffer (pH 9.0~ 12) or sodium bicarbonate buffer (pH 9.0 to 10.0)).

[0138] In certain embodiments, each precursor can contain only nucleophilic functional groups or only electrophilic functional groups, so long as both nucleophilic and electrophilic precursors are used in the crosslinking reaction. Thus, for example, if the crosslinker has only nucleophilic functionality (eg, amine), the precursor polymer can have electrophilic functionality (eg, N-hydroxysuccinimide). On the other hand, if the crosslinking agent has an electrophilic functional group such as sulfosuccinimide, the functional polymer can have a nucleophilic functional group such as an amine or a thiol. Thus, functional polymers such as proteins, poly(allylamine), or amine-terminated bifunctional or multifunctional poly(ethylene glycol) can also be used to prepare the polymer networks of the invention.

[0139] In one embodiment, the first reactive precursors each have from about 2 to about 16 nucleophilic functional groups (referred to as functionalities) and are reacted with the first reactive precursor to form the polymer network. The second reactive precursors that can be formed each have from about 2 to about 16 electrophilic functional groups. Reactive precursors in which the number of reactive (nucleophilic or electrophilic) groups is a multiple of 4, thus for example 4, 8, and 16 reactive groups, are particularly suitable for the present invention. Any number of functional groups (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16).

[0140] PEG hydrogel: In certain embodiments of the invention, the polymer network forming the hydrogel includes polyethylene glycol (PEG) units. PEG is known in the art to form hydrogels when cross-linked, and these PEG hydrogels can be used for pharmaceutical purposes, e.g. drugs intended to be administered to any part of the human or animal body. suitable for use as a matrix.

[0141] The polymer network of the hydrogel implant of the invention can include one or more multi-arm PEG units having 2 to 10 arms, or 4 to 8 arms, or 4, 5, 6, 7 or 8 arms. PEG units may have different or the same number of arms. In certain embodiments, the PEG units used in the hydrogels of the invention have 4 and / or 8 arms. In certain embodiments, a combination of 4- and 8-arm PEG units is utilized.

[0142] The number of PEG arms used contributes to controlling the flexibility or softness of the resulting hydrogel. For example, hydrogels formed by crosslinking 4-arm PEG are generally softer and more flexible than those formed from 8-arm PEG of the same molecular weight. In particular, as disclosed later in the section on implant manufacturing herein, if it is desired to stretch the hydrogel before or after drying, a more flexible hydrogel, such as a 4-arm PEG, can optionally be used. , in combination with another multi-arm PEG (eg, an 8-arm PEG as disclosed above).

[0143] In certain embodiments of the invention, the polyethylene glycol units used as precursors are in the range of about 2,000 to about 100,000 Daltons, or in the range of about 10,000 to about 60,000 Daltons, or in the range of about 15,000 to about 50,000 Daltons. It has an average molecular weight within the range. In certain specific embodiments, the polyethylene glycol units have an average molecular weight in the range of about 10,000 to about 40,000 Daltons, or about 20,000 Daltons. PEG precursors of the same average molecular weight may be used or PEG precursors of different average molecular weights may be combined with each other. The average molecular weight of the PEG precursor used in the present invention is given as the number average molecular weight (Mn), which can be determined by MALDI in certain embodiments.

[0144] In a four-arm PEG, each arm can have an average arm length (or molecular weight) that is the total molecular weight of the PEG divided by four. Accordingly, one of the precursors that can be utilized in the present invention, the 4a20k PEG precursor, has four arms each having an average molecular weight of about 5,000 daltons. The 8a20kPEG precursor that can be used in the present invention in addition to the 4a20kPEG precursor thus has eight arms each with an average molecular weight of 2,500 daltons. Longer arms may be more flexible than shorter arms. PEGs with long arms can swell more than PEGs with short arms. Also, PEGs with fewer arms may swell more and may be more flexible than PEGs with more arms. In certain specific embodiments, combinations of PEG precursors with different numbers of arms (eg, a combination of a 4-arm PEG precursor and an 8-arm PEG precursor) can be utilized in the present invention. In addition, longer PEG arms have a higher melting point upon drying, which may increase dimensional stability during storage. For example, an 8-arm PEG with a molecular weight of 15,000 daltons cross-linked with trilysine may not be able to maintain the stretched configuration at room temperature, whereas a 4-arm 20,000 dalton PEG cross-linked with an 8-arm 20,000 dalton PEG may not be able to maintain its stretched configuration at room temperature. The configuration may be dimensionally stable.

[0145] When referring to a PEG precursor with a certain average molecular weight (e.g., 15kPEG or 20kPEG precursor), the average molecular weight indicated (i.e., 15,000 or 20,000 Mn, respectively) refers to the precursor before end groups are added. (herein, "20k" means 20,000 Daltons and "15k" means 15,000 Daltons. The same abbreviations are also used herein for other average molecular weights of PEG precursors. ). In certain embodiments, the Mn of the PEG moiety of the precursor is quantified by MALDI. The degree of substitution with the end groups disclosed herein is such that after functionalization of the end groups, 1 It can be quantified by H-NMR.

[0146] In certain embodiments, the electrophilic end group for use with the PEG precursor for the preparation of the hydrogels of the invention is an N-hydroxysuccinimidyl (NHS) ester, such esters include: Without limitation, "SAZ" (refers to succinimidyl azelate end group), "SAP" (refers to succinimidyl adipate end group), "SG" (succinimidyl glutarate end group), (refers to the succinimidyl succinate end group), and "SS" (refers to the succinimidyl succinate end group).

[0147] In certain embodiments, the nucleophilic end group for use with the PEG precursor for the preparation of the hydrogels of the invention is an amine (“NH 2 ”) is the terminal group. Thiol (-SH) or other nucleophilic end groups are also possible.

[0148] In certain preferred embodiments, a four-arm PEG having an average molecular weight of about 20,000 Daltons and an electrophilic end group as disclosed above and a 4-arm PEG also having an average molecular weight of about 20,000 Daltons and a nucleophilic end group as disclosed above. is crosslinked to form a polymer network and thus a hydrogel according to the invention.

[0149] When a nucleophilic group-containing PEG unit and an electrophilic group-containing PEG unit (e.g., an amine end group-containing PEG unit and an activated ester group-containing PEG unit) are reacted, a plurality of PEG units form the formula: [ka] where m is an integer from 0 to 10, specifically 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In one particular embodiment, m is 6, for example when a PEG containing SAZ end groups is used. For SAP end groups, m is considered to be 3, for SG end groups, m is 2, and for SS end groups, m is considered to be 1. All crosslinks within the polymer network may be the same or different.

[0150] In certain preferred embodiments, the present invention utilizes SAZ end groups. This end group can increase intraocular duration, and implants comprising hydrogels containing PEG-SAZ units in certain embodiments of the invention can be used intraocularly, e.g., in the vitreous humor of the human eye. Within the scope of the invention, it only biodegrades after an extended period of time (eg, 9 to 12 months), as further disclosed below, and may last even longer in certain circumstances. The SAZ group has a 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) than, for example, the SAP, SG, or SS end groups. is also hydrophobic.

[0151] In certain preferred embodiments, a 4-arm 20,000 Dalton PEG precursor is combined with an 8-arm 20,000 Dalton PEG precursor, e.g., a 4-arm 20,000 Dalton PEG precursor with a SAZ group (as defined above) has an amine group. (defined above) is combined with an 8-arm 20,000 Dalton PEG precursor. These precursors are herein referred to as 4a20kPEG-SAZ and 8a20kPEG-NH, respectively. 2 Also abbreviated as The chemical structure of 4a20kPEG-SAZ is as follows, [ka] In the formula, R represents a pentaerythritol core structure. 8a20kPEG-NH 2 The chemical structure (with hexaglycerol core) is as follows: [ka] In the above formula, n is determined by the molecular weight of each PEG arm.

[0152] In certain embodiments, the molar ratio of nucleophilic and electrophilic end groups that react with each other is about 1:1, ie, one amine group is provided per SAZ group. 4a20kPEG-SAZ and 8a20kPEG-NH 2 In the case of , this results in a weight ratio of approximately 2:1 since the 8-arm PEG contains twice the amount of end groups as the 4-arm PEG. However, either electrophilic end groups (eg, NHS end groups such as SAZ) or nucleophilic (eg, amine) end groups may be used in excess. In particular, precursors containing nucleophilic groups, e.g. amine end groups, can be used in excess, i.e. 4a20kPEG-SAZ and 8a20kPEG-NH 2 The weight ratio of can also be less than 2:1.

[0153] Each and any combination of PEG precursors containing electrophilic and nucleophilic groups disclosed herein can be used to prepare implants according to the invention. For example, any 4-arm or 8-arm PEG-NHS precursor (with e.g. SAZ, SAP, SG or SS end groups) can be converted into any 4-arm or 8-arm PEG-NHS 2 precursor (or any other PEG precursor with a nucleophilic group). Furthermore, the PEG units of the electrophile-containing precursor and the nucleophile-containing precursor may have the same or different average molecular weights.

[0154] Other nucleophile-containing crosslinkers may be used in place of the PEG-based crosslinker. For example, a low molecular weight amine linker such as trilysine (or a salt or derivative of trilysine, such as trilysine acetate) or other low molecular weight multi-arm amine linker can be used.

[0155] In certain embodiments, the nucleophile-containing crosslinker may be attached to or conjugated with a visualization agent. A visualization agent is an agent that includes a fluorescent group or other group that allows visualization. Fluorophores such as fluorescein, rhodamine, coumarin, cyanine can be used as visualization agents. The visualization agent can be conjugated with the crosslinking agent, for example, via a portion of the nucleophilic group of the crosslinking agent. Because crosslinking requires a sufficient amount of nucleophile, "conjugated" or "conjugation" generally includes partial conjugation, which means that a portion of the nucleophile is For example, about 1% to about 20%, or about 5% to about 10%, or about 8% of the nucleophilic groups of the crosslinking agent are used for conjugation with the visualization agent. can be conjugated with agents. In other embodiments, the visualization agent may be conjugated to the polymer precursor, eg, through certain reactive (eg, electrophilic) groups on the polymer precursor.

[0156] Further ingredients: In addition to the polymeric units forming the polymer network and the active ingredients as disclosed above, the implants of the invention may also contain other additional ingredients. Such additional components are, for example, salts resulting from the buffers used during the preparation of the hydrogel, such as phosphates, borates, bicarbonates, or other buffers such as triethanolamine. In certain embodiments of the invention, sodium phosphate buffers (specifically monobasic sodium phosphate and dibasic sodium phosphate) are used.

[0157] Optionally, preservatives can be used in the implants of the invention. However, in certain embodiments, implants of the present invention, including implants containing axitinib as an active agent, may contain preservatives, such as antimicrobial preservatives such as, but not limited to, benzalkonium chloride (BAK), chlorobutanol, sodium perborate, and stabilized oxychloro complex (SOC)) or substantially free of such preservatives.

[0158] If in situ gelation is preferred in one embodiment of the invention, possible additional components include other agents used during the production of the hydrogel, such as (but not limited to) influencing the viscosity. It can be a drug (eg, hyaluronic acid, etc.), a surfactant, and the like.

[0159] In certain embodiments, inserts of the invention can include a visualization agent. Visualizing agents that can be used in the context of the present invention can be conjugated with components of the hydrogel or encapsulated within the hydrogel and are visible or sensitive to light of a certain wavelength, for example. Any drug that can be visualized or is a contrast agent when exposed. Suitable visualization agents for use in the present invention include (but are not limited to) fluorescein, rhodamine, coumarin, cyanine, europium chelate complex, boron dipyrromethene, benzofurazan, dansyl, bimane, acridine, triaza These are pentalene, pyrene, and their derivatives. The visualization agent may be conjugated with either the nucleophilic group-containing precursor or the electrophilic group-containing precursor from which the polymer network is formed, as disclosed above, or the visualization agent may be conjugated during manufacture of the implant. It may also be a separate (unconjugated) drug that is added and present within the hydrogel.

[0160] formulation: In certain embodiments, an implant according to the invention comprises an active agent, a polymer network made from one or more polymer precursors disclosed herein above in the form of a hydrogel, and optional additions. components (e.g., salts remaining on the implant from the production process (e.g., phosphates used as buffering agents, etc.)).

[0161] In certain embodiments, an implant according to the invention, in its dry state, contains from about 15% to about 80% (e.g., from about 25% to about 75%) of the active agent and from about 15% to about 80% by weight (e.g., about 20% to about 60%) of polymer units, or in certain embodiments, about 35% to about 65% by weight of active agent and about 25% to about 50% by weight of polymer units. (dry composition). In a specific embodiment, an implant according to the invention may comprise from about 45% to about 55% by weight of active agent and from about 37% to about 47% by weight of polymer units (dry composition), wherein the active agent and The polymer units are selected from those disclosed here above. In other specific embodiments, an implant according to the invention comprises, in its dry state, about 55% to about 75% active agent and about 20% to about 40% polymer units (dry composition). The active agent and the polymer unit are selected from those disclosed hereinabove. In other specific embodiments, an implant according to the invention comprises, in its dry state, about 30% to about 45% active agent and about 47% to about 70% polymer units (dry composition). wherein the active agent and the polymer unit are selected from those disclosed herein above.

[0162] In one particular embodiment, an implant according to the invention comprises, in its dry state, about 25% to about 75% active agent and about 20% to about 60% PEG units, or about 35% by weight ~ about 65% by weight active agent and about 25% to about 50% by weight PEG units, or about 45% to about 55% by weight active agent and about 37% to about 47% by weight PEG units, or It can include from about 48% to about 52% by weight of active agent and from about 40% to about 44% by weight of PEG units (dry composition). In other specific embodiments, the implant according to the invention comprises, in its dry state, about 55% to about 75% active agent and about 20% to about 40% PEG units, or about 60% by weight The composition can include from about 75% by weight axitinib and from about 21% to about 31% by weight PEG units (dry composition).

[0163] In one further specific embodiment, the ratio of active agent to PEG on a dry weight basis in an implant according to the invention can be about 40% by weight or less PEG to about 50% active agent or more; The remainder is phosphate. Alternatively, the ratio of active agent:PEG on a dry weight basis in an implant according to the invention can be from about 1:1 to about 3:1.

[0164] In certain embodiments, the remainder of the dry implant (i.e., the remainder of the formulation when the active agent and polymeric hydrogel (e.g., PEG hydrogel) have already been taken into account) is in a buffered solution as disclosed above. It can be residual salt from. In certain embodiments, such salts are phosphates, borates, or (bi)carbonates. In one embodiment, the buffer salt is sodium phosphate (monobasic and / or dibasic).

[0165] The amounts of active agent and polymer(s) can be varied, and other amounts of active agent and polymer hydrogels can be used to prepare implants according to the invention.

[0166] In certain embodiments, the maximum amount of drug within the formulation is about twice the amount of polymer (eg, PEG) units, but may be higher in certain cases. However, it is desirable to be able to uniformly cast a mixture containing, for example, a precursor, a buffer, and a drug (before the hydrogel is completely gelled) into a mold or tube.

[0167] In one embodiment of the invention, the hydrogel, after being formed and before being dried, i.e., in the wet state, contains about 3% to about 20% polyethylene glycol (equivalent to the weight of polyethylene glycol divided by the weight of the fluid x 100). ) may be included. In one embodiment, the wet hydrogel comprises about 5% to about 15%, such as about 7.5% to about 15% or about 5% to about 10% polyethylene glycol (weight of polyethylene glycol divided by weight of fluid x 100). (equivalent to).

[0168] In one embodiment of the invention, the wet hydrogel composition (i.e., the composition after the hydrogel composition is formed, i.e., after all the components forming the hydrogel have been mixed) is about 5% by weight ~50% by weight active agent and from about 5% to about 50% or from about 5% to about 30% PEG units.

[0169] In certain embodiments, when forming implant hydrogels according to the present invention, the solids content (wherein "Solid content" can be utilized to mean the total weight of polymer precursor(s), salt, and drug in a solution / suspension. Thus, in certain embodiments, the total solids content of a wet hydrogel composition that is cast into a mold or tube to form a hydrogel is about 60% or less, or about 50% or less, or about 40% or less , for example, equal to or lower than about 35% (w / v). The content of active agent can be less than or equal to about 40%, or less than or equal to about 30%, such as less than or equal to about 25% (w / v) of the wet composition. Solids content can affect the viscosity and therefore the flexibility of the wet hydrogel composition.

[0170] In certain embodiments, the water content of the hydrogel implant (e.g., before or when loaded into the needle) is very low in its dry (dehydrated / dried) state. For example, it may be 1% by weight or less of water. Moisture content may also be lower in certain embodiments, in some cases less than or equal to 0.25% by weight, or less than or equal to 0.1% by weight. In the present invention, the term "implant" refers to an implant in a hydrated state when it contains water (e.g., once the implant has been administered to the eye or otherwise immersed in an aqueous environment and is (re)hydrated) implants in a dry (dried / dehydrated) state (e.g., when the implant is dried to a low moisture content (e.g., below about 1% by weight), or by preparation, after the drying step). used to refer to both when an implant with such a low water content is obtained without the need for an implant). In certain embodiments, the implant is in its dry state under an inert nitrogen atmosphere (containing less than 20 ppm of both oxygen and moisture) in a glove box for at least about 7 days after manufacture and before being loaded into a needle. This is an implant that will be stored. The water content of the implant can be measured using, for example, Karl Fischer coulometric method.

[0171] In certain embodiments, the total weight (also referred to herein as "total mass") of an implant according to the invention, in its dry state, is from about 200 μg (i.e., 0.2 mg) to about 1.5 mg, or about The amount can be 400 μg to about 1.2 mg. In certain specific embodiments, the total weight of an implant according to the invention in its dry state can be from about 0.3 mg to about 0.6 mg, such as from about 0.4 mg to about 0.5 mg. In certain other specific embodiments, the total weight of an implant according to the invention in its dry state is from about 0.75 mg to about 1.25 mg, or from about 0.8 mg to about 1.1 mg, or from about 0.9 mg to about 1.0 mg. It can be mg.

[0172] In certain embodiments, the implant according to the invention has a diameter of 1 mm in its dry state. 3 per (i.e. 1 mm of dry implant 3 From about 200 μg to about 1000 μg (per volume) of active agent. In certain specific embodiments, the implant according to the invention has a diameter of 1 mm in its dry state. 3 from about 200 μg to about 300 μg of active agent per implant (eg, where the implant includes an amount of active agent from about 160 μg to about 250 μg). In certain other specific embodiments, the implant according to the invention has a diameter of 1 mm in its dry state. 3 about 500 μg to about 800 μg axitinib per patient (eg, if the implant includes axitinib in an amount of about 480 μg to about 750 μg).

[0173] Implants of the invention can therefore have different densities. The density of the final implant (i.e., in its dry state) is determined by a variety of factors, including, but not limited to, the concentration of the components in the wet composition when forming the hydrogel, and the concentration of the components during the manufacture of the implant. (including specific conditions). For example, the density of the final implant in certain embodiments can be increased at certain points during the manufacturing process by sonication or degassing (eg, using a vacuum).

[0174] In certain embodiments, implants according to the invention contain a therapeutically effective amount of active agent for release over an extended period of time, yet are relatively small in length and / or diameter. This is important both in terms of ease of administration (injection) and in reducing the chance of damaging ocular tissue and affecting the patient's vision while the implant is in place. It is advantageous in In certain embodiments, the implants of the present invention suitably combine the advantages of high doses of active agent (i.e., therapeutically effective doses tailored to the needs of a particular patient) with the advantages of relatively small implant size. It is combined with

[0175] Exemplary implants according to the invention include hypothetical examples of implants according to the invention containing high amounts of TKI, as disclosed in Tables 1, 6, 21.1, 21.2, and 29 of the Examples section (Table 29). ) is disclosed.

[0176] Implant dimensions and dimensional changes upon hydration due to stretching: Dried implants have a variety of geometries, depending on the manufacturing method (e.g., use of a mold or tube to cast a mixture containing a hydrogel precursor containing the active agent prior to complete gelation). be able to. Implants according to the invention are also referred to as "fibers" (this term is used herein interchangeably with the term "rod"), where fibers are objects having a generally elongated shape. The implant (or fiber) can have different geometries with specific dimensions as disclosed herein.

[0177] In one embodiment, the implant is cylindrical or has an essentially cylindrical shape. In this case, the implant has a circular or essentially circular cross section.

[0178] In other embodiments of the invention, the implant is non-cylindrical, the implant is optionally elongated in its dry state, the length of the implant is greater than the width of the implant, and the width is substantially equal to the length. It is the largest cross-sectional dimension that is vertical. In certain embodiments, the width can be about 0.1 mm to about 0.5 mm. Various geometries of outer implant shapes or cross-sections thereof may be used in the present invention. For example, instead of circular diameter fibers (ie, cylindrical implants), cruciform fibers (ie, cross-sectional geometry that is cross-like) may be used. Other cross-sectional geometries, such as elliptical or oval, rectangular, triangular, star-shaped, etc., generally can also be used. In certain embodiments, the fibers may be twisted. In embodiments where the implant is administered to the eye by a needle, the dimensions of the implant (i.e., its length and diameter) as well as its cross-sectional geometry are such that the implant can be administered to the eye by a needle, particularly as further disclosed herein. It must be able to be loaded into fine diameter needles such as 25 or 27 gauge needles.

[0179] The polymer network (eg, the PEG network of a hydrogel implant according to certain embodiments of the invention) can be semi-crystalline in the dry state and amorphous in the wet state below room temperature. Even in the stretched form, the dry implant can be dimensionally stable below room temperature, which can be advantageous for implant needle loading and quality control.

[0180] Once the implant is hydrated within the eye (which can be simulated by immersing the implant in PBS at 37°C and pH 7.2), the dimensions of the implant according to the invention may change, and in general the diameter of the implant increases. while the length may be reduced or at least remain essentially the same. The advantage of this dimensional change is that, in its dry state, the implant can be used with fine diameter needles (e.g., even smaller diameter needles such as 25 gauge, 27 gauge, or even 30 gauge needles) for intraocular injection. Once placed within the eye, e.g. within the vitreous humor, the implant can be further shortened to better fit within the limited small volume of the eye. . The needles used for injection of the inventive implants disclosed herein (e.g., 25 gauge or 27 gauge needles in certain embodiments) may have a small diameter (e.g., an inner diameter of about 0.4 mm). ). The implant may also soften upon hydration, thereby preventing or minimizing any ocular tissue damage when the implant contacts ocular tissue. In certain embodiments, the dimensional change is enabled, at least in part, by a "shape memory" effect introduced by longitudinally stretching the implant during manufacture of the implant (see "Methods of Manufacturing" below). section). In certain embodiments, stretching can be performed in either dry or wet conditions, ie, after or before drying the hydrogel implant. Note that if no stretching is performed and the hydrogel implant is only dried and cut to the desired length, both the diameter and length of the implant may increase upon hydration. If this is not desired, the hydrogel fibers can be dry drawn or wet drawn.

[0181] In the case of preformed dry hydrogels, some degree of molecular orientation can be imparted by dry stretching the material and then solidifying to fix the molecular orientation. This is accomplished in certain embodiments by stretching the material (optionally while heating the material to a temperature above the melting point of the crystallizable regions of the material) and then crystallizing the crystallizable regions. can do. Alternatively, in certain embodiments, the glass transition temperature of the dry hydrogel may be used to fix the molecular orientation of a polymer, such as PVA, that has a suitable glass transition temperature. Yet another alternative is to stretch the gel before it is completely dry (also referred to as "wet stretching") and then dry the material under tension. This molecular orientation provides one mechanism for anisotropic swelling when introduced into a hydration medium such as the vitreous. Upon hydration, the implants of certain embodiments swell only in the radial dimension, while length decreases or remains essentially unchanged. The term "anisotropic swelling" refers to preferential swelling in one direction and swelling in another direction, such that in a cylindrical shape, the diameter swells predominantly, but the longitudinal dimension swells little (or even contracts). This means that it does not swell.

[0182] The degree of dimensional change upon hydration may depend, among other things, on the stretch factor. As an example, stretching (e.g., by wet stretching) with a stretch factor of, for example, about 1.3 may not have a significant effect or change the length significantly during hydration. In contrast, stretching (eg, by wet stretching), for example, with a stretch factor of about 1.8, can result in significant length shortening during hydration. For example, stretching with a stretch factor of 4 (eg, by dry stretching) can result in a much shorter length upon hydration (eg, length reduced from 15 mm to 8 mm). Those skilled in the art will appreciate that other factors besides stretching can also affect swelling behavior.

[0183] Other factors that influence the ability of the hydrogel to stretch and change the dimensions of the implant upon hydration include the composition of the polymer network. When PEG precursors are used, precursors with a lower number of arms (e.g., a 4-arm PEG precursor) will result in a more flexible hydrogel than those with a higher number of arms (e.g., an 8-arm PEG precursor). Contribute to further increasing the If the hydrogel contains more components that are less flexible (e.g., a higher amount of PEG precursor containing a higher number of arms (e.g., 8-arm PEG units)), the hydrogel will become stiffer and will not break. It may not be easy to stretch the film. On the other hand, hydrogels containing more flexible components (e.g., PEG precursors containing fewer arms (e.g., 4-arm PEG units)) are easier to stretch and may be softer, but , and may swell upon hydration. Therefore, the behavior and properties of the implant once placed in the eye (i.e., when the hydrogel is (re)hydrated) can be modified by changing the structural characteristics and after the implant is initially formed. can be adjusted by changing the treatment of the implant.

[0184] Exemplary dimensions of the implants used in the examples below are shown in Tables 6, 21.1, and 21.2 in the Examples section, among others. Specific implants containing about 200 μg and about 600 μg of axitinib are disclosed in Tables 21.1 and 21.2. However, the implants of the present invention may have different dimensions (ie, length and / or diameter) than those disclosed in these tables. The dimensions of the dried implant depend, among other things, on the amount of active agent incorporated and the ratio of active agent to polymer units, and can also be controlled by the diameter and shape of the mold or tube in which the hydrogel is gelled. Furthermore, the diameter of the implant is further determined, inter alia, by the stretching (wet or dry) of the hydrogel strands once formed. The dried strand (after stretching) is cut into segments of desired length to form the implant. Therefore, the length can be selected as required.

[0185] In the following, embodiments of the implant with specific dimensions are disclosed. Whenever the dimensional ranges or values ​​disclosed herein relate to the length and diameter of the implant, the implant is cylindrical or essentially cylindrical. However, all values ​​and ranges disclosed herein for lengths and diameters of cylindrical implants may be similarly used for lengths and widths, respectively, of non-cylindrical implants as also disclosed herein. can.

[0186] In certain embodiments, the implants of the present invention may have a length in its dry state of less than about 17 mm. In specific embodiments, the length of the implant, in its dry state, can be about 15 mm or less, or about 12 mm or less, or about 10 mm or less, or about 8.5 mm or less. In specific embodiments, the implants of the invention may have a length in its dry state of about 12 mm to about 17 mm, or in its dry state of about 6 mm to about 10 mm, or specifically about 6 mm. ~Can have a length of about 9mm.

[0187] In certain embodiments, the implants of the present invention can have a diameter in its dry state of about 0.1 mm to about 0.5 mm. In certain other embodiments, the implant may have a diameter in its dry state of about 0.2 mm to about 0.5 mm. In specific embodiments, the implant may have a diameter in its dry state of about 0.2 mm to about 0.4 mm, or about 0.3 mm to about 0.4 mm. In specific embodiments, the implants of the invention may have a diameter in the dry state of about 0.2 mm to about 0.3 mm, or about 0.3 mm to about 0.4 mm.

[0188] In certain embodiments, the implant may have a length of about 6 mm to about 10 mm and a diameter of about 0.2 mm to about 0.4 mm in its dry state.

[0189] In certain embodiments, the implants of the present invention can have a length of about 6 mm to about 12 mm in its wet / hydrated state. In certain other embodiments, the implants of the present invention may have a length in its wet / hydrated state of about 10 mm or less, or from about 6 mm to about 10 mm. In specific embodiments, the implants of the present invention may have a length of about 6 mm to about 8 mm in its wet / hydrated state.

[0190] In certain embodiments, the implants of the present invention can have a diameter in its wet / hydrated state of no more than about 0.8 mm, or from about 0.5 mm to about 0.8 mm, or from about 0.65 mm to about 0.8 mm. In a specific embodiment, the implant of the present invention may have a diameter of about 0.7 mm to about 0.8 mm in its wet / hydrated state.

[0191] In certain embodiments, the implant, in its wet / hydrated state, can have a length of about 10 mm or less and a diameter of about 0.8 mm or less.

[0192] In embodiments of the invention, the diameter of the dry implant must be such that it can be loaded into small diameter needles (eg, 25 gauge or 27 gauge needles) as disclosed herein. Specifically, in one embodiment, the diameter of the implant is such that it can be loaded into a 25 gauge needle or loaded into a 27 gauge needle without causing any damage to the implant during loading, and further The diameter may be such that the implant can remain stably within the needle during handling (including packaging, sterilization, shipping, etc.).

[0193] In this specification, whenever the length or diameter of a wet / hydrated implant of the present invention is disclosed (in mm), this disclosure is determined after 24 hours at 37°C and pH 7.2. Refers to the length or diameter of the implant, respectively. In this context, pH 7.2 is understood to include the pH range of about 7.2 to about 7.4.

[0194] When the implant remains under these conditions, the dimensions of the implant may change further over time (i.e. after 24 hours) (e.g. the length may increase slightly again). However, whenever the hydration dimensions of the implant are reported herein, these were measured after 24 hours at 37° C., pH 7.2 in PBS as disclosed above.

[0195] If one implant length or diameter measurement is made multiple times, or if multiple data points are collected during a measurement, the average (i.e., mean )) value is reported. The length and diameter of an implant according to the invention can be measured, for example, by microscopy or by an (optionally automated) camera system as described in Example 6.1.

[0196] In certain embodiments, the hydrated to dry diameter ratio of implants of the invention is 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 about 2.25. mm or less than about 2.10 mm.

[0197] In certain same or other embodiments, the dry length to hydrated length ratio of the implants of the invention is greater than about 0.7, or greater than about 0.8, or greater than about 0.9, or greater than about 1.0. It can be done. In certain specific embodiments, the ratio of dry implant length to hydrated implant length can be greater than about 1.5, or even greater than about 2.0. This dry length to hydrated length ratio may be applied in addition to or independent of the hydrated diameter to dry diameter ratio disclosed above.

[0198] In certain embodiments, a small dry diameter is advantageous because it allows the implant to be compatible with the small diameter injection needles disclosed herein (e.g., 25 gauge or 27 gauge needles). obtain. Also, a moderate degree of swelling upon hydration may be advantageous so that the implant does not take up too much space in the vitreous humor. A relatively short length of the implant may be advantageous in reducing the possibility of contacting the retina.

[0199] In one embodiment, the implant of the invention comprises from about 160 μg to about 250 μg, or from about 180 μg to about 220 μg, or about 200 μg of active agent, and is in the form of a fiber (or cylinder) in a dried state. , has a length of about 14.5 mm to about 17 mm, or about 15 mm to about 16.5 mm, and a diameter of about 0.20 mm to about 0.30 mm. Such implants can be hydrated either in vivo, within the eye (e.g., in the vitreous humor), or in vitro, where in vitro hydration is at 37°C, pH 7. (measured after 24 hours in phosphate-buffered saline at 2), the length decreases to about 6.5 mm to about 8 mm or about 7 mm to about 8.5 mm, and the diameter decreases to about 0.65 mm to about 0.8 mm or about 0.70 to about Can be increased to 0.80mm. In one embodiment, this dimensional change can be achieved by dry stretching as disclosed herein with a stretch factor of about 2 to about 5 or a stretch factor of about 3 to about 4.5.

[0200] In another embodiment, the implant of the invention comprises about 480 μg to about 750 μg, or about 540 μg to about 660 μg, or about 600 μg of active agent, and is in the form of a fiber (cylindrical) in its dried state. , a length in the range of about 6 mm or about 7 mm to about 12 mm and a diameter of about 0.25 mm to about 0.50 mm, or a length of about 7 mm to about 10 mm or about 8 mm to about 11 mm and a diameter of about 0.3 mm to about 0.4 mm. It can have a diameter. In a specific embodiment, the implant of the invention comprises about 480 μg to about 750 μg, or about 540 μg to about 660 μg, or about 600 μg of axitinib, in the form of a fiber (cylindrical), in its dried state. , may have a length of about 7 mm to about 10 mm (eg, about 7 mm to about 9 mm) and a diameter of 0.3 mm to 0.4 mm (eg, about 0.35 mm to about 0.39 mm).

[0201] Such implants can be used during hydration in vivo within the eye (e.g., in the vitreous humor) or during hydration in vitro (where in vitro hydration is at 37°C, pH 7.2). (measured after 24 hours in phosphate-buffered saline), but its length may be essentially maintained, reduced, or slightly increased. For example, in its hydrated state, it has a length in the range of about 6 mm or about 9 mm to about 12 mm and a diameter of about 0.5 mm to about 0.8 mm, or a length of about 9.5 mm to about 11.5 mm and about 0.65 mm. ~The diameter will be approximately 0.75mm or approximately 0.8mm. In specific embodiments, the implants of the present invention contain about 480 μg to about 750 μg, or about 540 μg to about 660 μg, or about 600 μg of active agent, and the implant is in its hydrated state (i.e., at 37° C. as described above). , after 24 hours at pH 7.2) to take the form of fibers (cylindrical), with a length of about 6 mm to about 10.5 mm (for example, about 6.5 mm to about 8.5 mm) and a diameter of about 0.7 mm to about 0.8 mm. may have.

[0202] In one embodiment, the length of the implant of the invention containing from 480 μg to about 750 μg, or from about 540 μg to about 660 μg, or about 600 μg is 10 mm or less in length in a dry state and less than or substantially less than about 10 mm, or less than or equal to about 9 mm, or less than or equal to about 8 mm in length, even under normal conditions (measured after 24 hours in phosphate-buffered saline at 37°C and pH 7.2). .

[0203] In one or more embodiment(s), the dimensional change described above is a stretch factor of about 0.5 to about 5, or a stretch factor of about 1 to about 4, or a stretch factor of about 1.3 to about 3.5, or about 1.7. This can be achieved by wet stretching with a stretch factor of ~3, or a stretch factor of about 2 to about 2.5. In other embodiments, implants of the invention comprising about 480 μg to about 750 μg, or about 540 μg to about 660 μg, or about 600 μg of active agent can be longer than about 12 mm in the dry state, but about It can be shorter than 10mm or about 9mm.

[0204] In certain embodiments, such stretching results in shape memory, which means that upon hydration when the implant is administered intraocularly, e.g., into the vitreous cavity, it retains its original shaped dimensions and compositional variables. This means that the length contracts and the diameter increases until (approximately) it approaches the equilibrium dimension determined by . While the narrower dry dimension facilitates product administration through smaller gauge needles, the expanded diameter and shorter length after administration allows the implant to remain in the posterior chamber of the eye relative to the diameter of the eye. be short (e.g., approximately 9-10 mm in length, or at least not significantly more) to minimize the possibility of contact with surrounding ocular tissue. Accordingly, in one embodiment, the present invention provides a method of imparting shape memory to hydrogel fibers containing an active agent, the active agent being dispersed within the hydrogel and the hydrogel fibers being longitudinally stretched to provide shape memory. It also relates to a method of imparting memory. In another aspect, the invention relates to a method of manufacturing an intraocular implant comprising a hydrogel having an active agent dispersed therein, the implant changes its dimensions upon administration to the eye, and the method comprises It includes preparing the fibers and longitudinally drawing the fibers.

[0205] In vitro release: In vitro release of active agents from implants of the invention can be quantified by various methods as disclosed in detail in Example 2.

[0206] Briefly, one method to measure the in vitro release of active agents from implants is to measure the in vitro release of active agents from implants under non-sink simulated physiological conditions in PBS (phosphate buffered saline, pH 7.2) at 37°C. It should be replaced every day in a volume comparable to the vitreous volume of the human eye. Exemplary implant results are shown in Figure 4A. As described in Example 2, for test implants containing the active agent in a PEG hydrogel matrix, higher dose strengths resulted in higher active agent concentrations in the release medium.

[0207] In certain embodiments of the present invention, implants according to the present invention average about 0.1 μg to about 3 μg, or about 0.25 μg per day in vitro for a period of 30 days at 37° C. in PBS, pH 7.2. ~about 2.5 μg, or from about 0.1 μg to about 2 μg, or from about 0.25 μg to about 1.5 μg.

[0208] In one embodiment, an implant according to the invention containing about 200 μg of active agent averages from about 0.01 μg to about Capable of releasing 0.15 μg of active drug.

[0209] In one embodiment, an implant according to the invention containing about 600 μg of active agent averages from about 0.3 μg to about Capable of releasing 0.5μg of active drug.

[0210] In an accelerated in vitro study, also detailed in Example 2, the release of TKI from the implant can be quantified in a 25:75 ethanol / water mixture (v / v) at 37°C. This accelerated in vitro study can be completed in approximately two weeks. FIG. 14B shows accelerated in vitro release data for an implant according to the invention containing about 200 μg axitinib, and FIG. 4B shows accelerated in vitro release data for an implant according to the invention containing about 556 μg axitinib.

[0211] In one embodiment, an implant according to the invention containing about 200 μg of active agent loses about 35% to about 45% of the active agent in 3 days in a 25:75 ethanol / water mixture (v / v) at 37°C. %, about 65% to about 75% of the active drug in 7 days, and about 90% to about 100% of the active drug in 12 to 13 days in vitro.

[0212] In one embodiment, an implant according to the invention containing about 600 μg of active agent loses about 40% to about 60 μg of active agent in 2 days in a 25:75 ethanol / water mixture (v / v) at 37°C. %, about 65% to about 85% of the active drug in 4 days, and about 75% to about 90% of the active drug in 6 days in vitro. Implants according to the present invention containing about 600 μg of active agent also contain about 45% to about 55% of the active agent in 2 days and 4 days in a 25:75 ethanol / water mixture (v / v) at 37°C. In some cases, about 70% to about 80% of the active drug is released in vitro, and about 80% to about 90% of the active drug is released in 6 days.

[0213] Finally, active agent release from the implants of the invention may be quantified under real-time sink simulated physiological conditions, as also detailed in Example 2. In this real-time test, the release of active agent is measured in PBS (pH 7.2) / 0.01% NaF at 37°C with an octanol overlay on PBS. This is one way to qualitatively simulate the release of the active agent from the implant into the vitreous humor and absorption of the active agent from there into the ocular tissues. An exemplary real-time release profile of an implant according to the invention containing approximately 200 μg of axitinib is shown in FIG. 14A.

[0214] In one embodiment, an implant according to the invention containing about 200 μg of active agent loses about 25% to about 35% of the active agent in 2 months in phosphate buffered saline with an octanol overlayer at 37° C. and pH 7.2. , about 47% to about 57% of the active drug in 3 months, about 70% to about 80% of the active drug in 5 months, and about 90% to 100% of the active drug in 7 months in vitro. .

[0215] In vitro release studies, particularly the accelerated in vitro release studies described herein, can be used, for example, for quality control or other qualitative evaluation purposes, inter alia, to test different implants (e.g., different production batches, different compositions, and different strength, etc.) can be used to compare them with each other. The release rates disclosed herein can also be obtained with different amounts of active agent.

[0216] In vivo release and persistence: In one embodiment of the invention, when a dry implant of the invention is administered to the eye (e.g., vitreous humor), the implant hydrates and changes dimensions as disclosed above, and then over time It is biodegraded and eventually completely absorbed. As the implant biodegrades (e.g., through ester hydrolysis), it gradually swells and softens, then becomes smaller, softer, more liquefied, and finally dissolves completely and becomes invisible. become. As the inventors have recognized from the animal studies presented in the Examples section hereinbelow, implants according to the present invention remain in the eye of rabbits for about 2 to about 6 months, or about 5 to about 6 months. It can last up to 6 months (see Figures 7A, 9, and 10). After complete disintegration of the implant, undissolved axitinib particles may remain at the site where the implant was and have been observed to aggregate, ie, coalesce into a monolithic structure. These remaining undissolved active agent particles can continue to slowly dissolve at a rate sufficient to provide therapeutically effective axitinib levels. In certain embodiments, two or more implants are administered to achieve the desired total dose, and they biodegrade evenly over time, with any remaining active agent particles also integrated into a single monolithic structure (see Figure 9).

[0217] Within the human eye (e.g., in the vitreous humor), the implants of the invention in certain embodiments are within about 2 to about 15 months after administration, or within about 4 to about 13 months after administration, or within about 4 to about 13 months after administration, or It biodegrades within about 9 to about 12 months after administration, specifically within about 9 to about 10.5 months after administration. This has been demonstrated in clinical trials using one or two implant(s), each containing 200 μg of active agent. See the Examples section, Example 6 and FIG. 15 for details.

[0218] In one embodiment, the implant after administration to the vitreous humor is at least about 3 months, at least about 6 months after administration of the active ingredient (e.g., a therapeutically effective amount of a TKI, e.g., axitinib), Release (as defined herein) over a period of 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 more. In certain embodiments, the implant releases the active agent for a period of about 6 months to about 9 months.

[0219] In one embodiment of the invention, the implant is administered for at least about 3 months, at least about 9 months, at least about 10 months after administration of the (i.e., single) implant to the patient, e.g., into the vitreous humor. , resulting in a treatment period of at least about 11 months, at least about 12 months, or at least about 13 months, or longer.

[0220] In one embodiment of the invention, the active agent is from about 0.1 μg / day to about 10 μg / day, or from about 0.5 μg / day to about 7 μg / day, or from about 0.5 μg / day to about 2 μg / day, from the implant. or at an average rate of about 1 μg / day to about 5 μg / day, e.g. in the vitreous humor, for at least 3 months, or at least 6 months, or at least 9 months, or at least 11 months, or at least 12 months, or released over a period of at least 13 months. In certain embodiments, release of the active agent is maintained for about 6 to about 9 months after administration of the implant.

[0221] As presented in the Examples section herein, preclinical studies in animals and clinical studies in humans demonstrate that the implants of the present invention receive therapeutically effective doses of active agents over extended periods of time and that the implants are completely biodegradable. It has been shown that it can be released continuously until the Any remaining undissolved active agent particles (if any) essentially remain at the site where the implant was and aggregate to form an essentially monolithic structure (see Figures 7A, 9, and 10). This structure can continue to release the TKI into the vitreous at levels sufficient to achieve a therapeutic effect. However, in certain embodiments, the entire amount of active agent contained in the implant is released from the implant before biodegradation of the implant is complete. In this case, undissolved active agent particles would not remain (and / or aggregate) near the site of the implant or elsewhere in the eye after complete biodegradation of the implant.

[0222] In one embodiment, the persistence of the hydrogel in an aqueous environment and in the human eye depends, among other things, on the hydrophobicity of the carbon chains in close proximity to the degradable ester groups. In the case of the implant used in the examples herein, this carbon chain contains 7 carbon atoms as it is derived from the SAZ functionality of the 4a20k PEG precursor. This can result in long-term persistence in the human eye of up to about 9 months to about 12 months, or about 9 months to about 10.5 months. In other embodiments, 4a20kPEG-SAZ and 8a20kPEG-NH 2 Different precursors can be used to prepare hydrogel implants that biodegrade within the human eye and have similar or different persistence than the implants exemplified in the Examples.

[0223] In certain embodiments, the hydrogel implant softens over time as it degrades, which may depend, among other things, on the structure of the linker that crosslinks the PEG units within the hydrogel. 4a20kPEG-SAZ and 8a20kPEG-NH as used in the examples of this application 2 Implants formed from soften fairly slowly over time.

[0224] Mechanism of release: Without wishing to be bound by theory, the mechanism by which active agents are released from the implants of the present invention may be explained as follows. In embodiments of the invention, release of the active agent into the eye and into the vitreous humor is defined by diffusion and drug clearance. An exemplary active agent according to the invention is axitinib. The solubility of axitinib has been determined to be very low in physiological media (about 0.4 to about 0.5 μg / mL in PBS at pH 7.2). According to the invention, the active agent is confined within a biodegradable hydrogel having a specific geometry and surface. The fluid in the posterior chamber is viscous, has slow clearance, and relatively sluggish flow (at least compared to the anterior chamber).

[0225] In certain embodiments, the implants of the invention include a hydrogel made from a polymer network and a drug dispersed within the hydrogel. The drug gradually dissolves and diffuses from the hydrogel into the eye. This may occur first in the outer regions of the hydrogel that are in contact with the fluid environment of the vitreous (i.e., drug particles located in the outermost regions of the hydrogel dissolve and diffuse first, and the innermost regions last). become). Thereby, in certain embodiments, the outer region of the hydrogel is free of drug particles. Therefore, this region is also called the "clearance zone", which is limited only to dissolved drug and has a concentration below the solubility of the drug. In certain embodiments, this low surface concentration protects such tissues from potential drug use by physically separating the drug particles from the tissue (retina or other cells) when the implant contacts the tissue. Can protect against toxicity. In other embodiments, the "clearance zone" is an outer region that, upon hydration, has a lower concentration of active agent than the active agent in the inner region of the hydrated hydrogel.

[0226] In embodiments with a clearance zone, this region of the hydrogel becomes cavitated and further softens and becomes brittle as the drug dissolves and diffuses out of the clearance zone. Simultaneously as the drug diffuses out of the hydrogel, the hydrogel may also be slowly degraded, for example, by ester hydrolysis within the aqueous environment of the eye. This degradation occurs uniformly throughout the bulk of the hydrogel. At an advanced stage of decomposition, distortion and erosion of the hydrogel begins to occur. As this happens, the hydrogel becomes softer and more liquefied (thus distorting its shape) until it dissolves and is completely absorbed. This process is shown schematically in Figure 3 and demonstrated by infrared reflectance (IR) imaging, for example in Figure 10.

[0227] With active agents that have relatively low solubility drugs, in certain embodiments, undissolved axitinib particles may remain at the site of the implant, even after the implant has completely degraded. . These remaining undissolved active agent particles are not anchored or held apart by the hydrogel and can aggregate to form a substantially monolithic structure. This monolithic active agent structure can still continue to release the active agent at a rate sufficient to achieve a therapeutic effect, specifically a reduction in CSFT.

[0228] However, in one embodiment, the entire amount of active agent is released before the hydrogel is completely degraded. Since the hydrogel can hold the active agent particles in place and prevent particle agglomeration, the release of active agent from the hydrogel can be faster while the hydrogel is not yet completely degraded. When the hydrogel is completely degraded, the remaining axitinib particles form a monolithic structure from which the active agent can slowly dissolve. Therefore, complete release of the active agent before the hydrogel completely degrades is desired in one embodiment of the invention.

[0229] This entire process, in certain embodiments, allows the therapeutic effects of the implants of the invention to last for an extended period of time, such as at least 3 months, or at least 6 months, or at least 9 months, or at least 11 months. or for at least 12 months, or at least 13 months, or at least 14 months, or even longer, such as up to 15 months. The inventors have demonstrated that this is a major advantage for patients undergoing treatment for neovascular age-related macular degeneration. This treatment has traditionally involved very frequent intravitreal injections of anti-VEGF agents. In contrast, the implant according to the invention only needs to be injected at much larger time intervals, which is advantageous to the patient for a number of reasons, as already disclosed in the "Purpose and Summary" section above.

[0230] Specific implants of certain embodiments: In certain embodiments, the polymer network comprises polyethylene glycol units that include multi-arm polyethylene glycol units (e.g., 4-arm and / or 8-arm polyethylene glycol units having an average molecular weight within the range of about 10,000 Daltons to about 60,000 Daltons). including. In this embodiment, the polymer network of this implant consists of 4a20kPEG-SAZ, 8a20kPEG-NH 2 It is formed by reacting it with a weight ratio of about 2:1. In this embodiment, the hydrogel (i.e., wet composition) as formed and before drying contains about 6.5% to about 7.5% polyethylene glycol (equivalent to weight of polyethylene glycol divided by weight of fluid x 100). include. In this embodiment, the implant also comprises from about 45% to about 55% active agent and from about 37% to about 47% polyethylene glycol units, or from about 47% to about 52% by weight on a dry basis. of axitinib and about 40% to about 45% by weight polyethylene glycol units (e.g., about 49% to about 50% by weight active agent and about 42% by weight PEG units, or about 47% by weight active agent and about 44% by weight PEG units) (dry composition), the remainder being sodium phosphate. Further, the implant can contain less than about 1% water by weight in its dry state, or less than about 0.25% water by weight.

[0231] In this embodiment, the implant containing the active agent releases an average of about 0.01 μg to about 0.15 μg of active agent per day in vitro in phosphate buffered saline at 37° C. for a period of 30 days. Additionally, in this embodiment, the implants contain about 35% to about 45% of the active agent at 3 days and about 45% of the active agent at 7 days in a 25:75 ethanol / water (v / v) mixture at 37°C. Releases approximately 65% ​​to approximately 75% and approximately 90% to approximately 100% of axitinib in 12 to 13 days in vitro. In this embodiment, the implants are injected in phosphate-buffered saline with an octanol overlayer at 37°C, pH 7.2, from about 25% to about 35% of the active agent at 2 months and about 47% of the active agent at 3 months. It can also release ~57% of the active drug in vitro, about 70% to about 80% of the active drug in 5 months, and about 90% to 100% of the active drug in 7 months.

[0232] In this embodiment, the implant containing the active agent can take the form of a fiber (or cylinder) that in its dry state has a length of less than about 20 mm, or less than about 17 mm, or from about 15 mm to about 16.5 mm, and about It can have a diameter of 0.20 mm to about 0.30 mm and upon hydration in vivo or in vitro in the vitreous humor (wherein vitro hydration is defined as hydration in phosphate buffered saline at 37°C and pH 7.2). (measured after 24 hours) decreases in length and increases in diameter, and in the hydrated state can be about 6.5 mm to about 8 mm long and about 0.70 mm to about 0.80 mm in diameter. This dimensional change upon hydration is such that the implant can be longitudinally dry-dried with a stretch factor of about 2 to about 5, or a stretch factor of about 3 to about 4.5, as described in more detail elsewhere herein. This can be achieved by imparting shape memory to the implant by stretching. In other embodiments, the implant may be non-cylindrical.

[0233] In this embodiment, the hydrated diameter to dry diameter ratio of the active agent-containing implant is less than about 3.25 mm, and / or the dry length to hydrated length ratio is greater than about 1.5. It can be done.

[0234] The total weight of the implant disclosed in this embodiment in its dry state can be about 0.3 mg to about 0.6 mg, such as about 0.4 mg to about 0.5 mg. Such implants can contain from about 10 μg to about 15 μg of active agent per mm of final length in the dry state; 3 from about 200 μg to about 300 μg of active agent per drug.

[0235] In this embodiment, prior to administration, the implant containing the active agent is loaded into a 25-gauge or 27-gauge needle (or even a smaller gauge needle (e.g., a 30-gauge needle)) for injection into the vitreous humor. be done.

[0236] To summarize and to illustrate, specific characteristics of the implants of the invention disclosed with respect to the embodiments described in this section (including the implant used in the clinical trial presented in Example 6) can be found in the Examples section. It is shown in Table 21.1 and is reproduced here. [Table 1-1] [Table 1-2]

[0237] In certain embodiments, the sustained release biodegradable intraocular implant is an intravitreal implant that is cylindrical and has a length in its dry state of 17 mm or less and a diameter of about 0.2 mm to about 0.3 mm. In its hydrated state (after 24 hours in phosphate buffered saline at 37°C and pH 7.2), the hydrogel has a length of about 6.5 mm to about 8 mm and a diameter of about 0.7 mm to about 0.8 mm. Contains cross-linked 4a20k and 8a20k PEG units, where the cross-linking between the PEG units is as follows: [ka] (wherein m is 6).

[0238] Alternatively, the implant of this particular embodiment may be non-cylindrical as disclosed herein.

[0239] Specific implants of certain embodiments: In another embodiment of the implant, the polyethylene glycol units include multi-arm polyethylene glycol units (eg, 4-arm and / or 8-arm polyethylene glycol units having an average molecular weight within the range of about 10,000 Daltons to about 60,000 Daltons). In this embodiment, the polymer network of the implant includes 4a20kPEG and 8a20kPEG units, and 4a20kPEG-SAZ and 8a20kPEG-NH 2 It is formed by reacting it with a weight ratio of about 2:1.

[0240] In this embodiment, the implant can comprise from about 45% to about 55% active agent and from about 37% to about 47% polyethylene glycol units, or from about 60% to about 75% by weight active agent and about 21% to about 31% polyethylene glycol units (e.g., about 63% to about 72% by weight active agent and about 23% to about 27% polyethylene glycol units) (dry composition) and the remainder is sodium phosphate. In certain specific embodiments, the implant can include about 68% to about 69% active agent and about 26% polyethylene glycol units (dry composition), with the remainder being sodium phosphate. The implant can contain up to about 1% water, or up to about 0.25% water by weight.

[0241] In this embodiment, the implant containing the active agent releases about 0.3 μg to about 0.5 μg of axitinib per day in vitro for a period of 30 days in phosphate buffered saline at 37°C. Additionally, the implant was tested in a 25:75 (v / v) ethanol / water mixture at 37°C to contain approximately 40% to approximately 60% of the active agent in 2 days and approximately 65% ​​to approximately 40% of the active agent in 4 days. 85%, releasing about 75% to about 90% of the active drug in 6 days in vitro. In this embodiment, the implant contains about 45% to about 55% of the active agent in 2 days and about 70% of the active agent in 4 days in a 25:75 ethanol / water (v / v) mixture at 37°C. % to about 80%, and may release about 80% to about 90% of the active drug in vitro in 6 days.

[0242] In this embodiment, the implant may take the form of a fiber (or cylindrical) and in its dry state is less than about 20 mm, or less than about 17 mm, or less than about 15 mm, or less than about 12 mm (e.g., about 7 mm to 12 mm) and a diameter of about 0.25 mm to about 0.50 mm, or about 7 mm or about 8 mm to about 11 mm and a diameter of about 0.3 mm to about 0.4 mm, in vivo in the vitreous humor. The diameter may increase upon hydration at or in vitro (where in vitro hydration is measured after 24 hours in phosphate buffered saline at 37°C and pH 7.2). In specific embodiments, an implant containing about 600 μg of active agent has a length in its dry state of about 10 mm or less, or about 8.5 mm or less, or about 7 mm to about 9 mm, or about 7 mm to about 8.5 mm, and about It can have a diameter of 0.3 mm to about 0.4 mm (eg, about 0.35 mm to about 0.39 mm).

[0243] The dimensions of this implant after hydration in vivo or in vitro (where in vitro hydration is measured after 24 hours in phosphate-buffered saline at 37°C and pH 7.2) are approximately 10 mm or less. (e.g., about 6 mm or about 9 mm to about 12 mm) in length and about 0.5 mm to about 0.8 mm in diameter, or about 9.5 mm to about 11.5 mm in length or about 10 mm or less or about 9 mm or less and about The diameter can be from 0.65 mm to about 0.75 mm or about 0.80 mm. In a specific embodiment, the implant, in its hydrated state (wherein in vitro hydration is measured after 24 hours in phosphate buffered saline, pH 7.2 at 37°C), is approximately 6 mm It can have a length of about 10.5 mm (eg, about 6.5 mm to about 8.5 mm) and a diameter of about 0.7 mm to about 0.8 mm. In certain embodiments, a length of about 10 mm or less (e.g., about 9 mm or less) when hydrated in the vitreous humor of the eye is an acceptable length given the limited volume of the eye. .

[0244] This dimensional change upon hydration is determined by a stretch factor of about 0.5 to about 5, or a stretch factor of about 1 to about 4, or a stretch factor of about 1.3 to about 3.5, as disclosed in more detail below. This can be achieved by wet stretching in the longitudinal direction with a stretch factor, or a stretch factor of about 1.7 to about 3, or a stretch factor of about 2 to about 2.5.

[0245] In this embodiment, the hydrated diameter to dry diameter ratio of the implant can be less than about 2.25 mm, and / or the dry length to hydrated length ratio can be greater than 0.75. .

[0246] The total weight of an implant as disclosed herein can be from about 0.8 mg to about 1.1 mg, such as from about 0.9 mg to about 1.0 mg, dry. Such implants in the dry state can contain from about 70 μg to about 85 μg of active agent per mm of final length, with 3 from about 500 μg to about 800 μg of active agent per dose.

[0247] In this embodiment, the preferred implant shape is cylindrical or essentially cylindrical (sometimes referred to as fibrous). In other embodiments, the implant may be non-cylindrical. Prior to administration, the implant is loaded into a 25 gauge (or smaller gauge, eg, 27 gauge) needle for injection into the eye, eg, the vitreous humor.

[0248] In summary, the individual characteristics of the implant of the present invention, including a dose of approximately 600 μg of axitinib, disclosed for the embodiments described in this section, are shown in Table 21.2 of the Examples section, but also here: Reproduce it. [Table 2-1] [Table 2-2]

[0249] In certain embodiments, the sustained release biodegradable intraocular implants of the present invention are intravitreal implants that are cylindrical and have a length of less than 10 mm in their dry state and a diameter of about 0.3 mm to about 0.4 mm. having a length of about 6 mm to about 10.5 mm and a diameter of about 0.6 mm to about 0.8 mm in its hydrated state (after 24 hours in phosphate buffered saline at 37° C. and pH 7.2); The hydrogel contains crosslinked 4a20k and 8a20k PEG units, and the crosslinking between PEG units is as follows: [ka] (wherein m is 6).

[0250] Alternatively, the implant of this particular embodiment may be non-cylindrical as disclosed herein.

[0251] II. Manufacturing of implants Manufacturing process: In certain embodiments, the invention also relates to methods of manufacturing the sustained release biodegradable intraocular implants disclosed herein. Generally, the method comprises forming a hydrogel comprising a polymer network and active agent particles, the active agent particles being dispersed within the hydrogel, shaping the hydrogel, and drying the hydrogel. including. In certain embodiments, the method comprises a hydrogel comprising a polymer network from a precursor comprising reactive groups (e.g., comprising PEG units) and active agent particles dispersed within the hydrogel. forming a hydrogel, and drying the hydrogel, and more specifically, the polymer network comprises forming an electrophilic group-containing multi-arm PEG precursor into a nucleophilic group-containing multi-arm PEG precursor. a precursor or another nucleophile-containing crosslinker (precursors and crosslinkers disclosed in the "Polymer Networks" and "PEG Hydrogels" sections herein) in the presence of active agent particles in a buffered solution. and gelling the mixture to form a hydrogel. In embodiments of the invention, the hydrogel is shaped into the hydrogel strands disclosed herein by casting the mixture into a tube prior to complete gelation of the hydrogel. In certain embodiments, the hydrogel strands are longitudinally stretched before or after drying, as further disclosed herein.

[0252] In one embodiment, the active agent may be used in micronized form to prepare an implant as disclosed herein and also as disclosed in the "Active Ingredients" section herein. It may have a particle size. In certain specific embodiments, the active agent may have a d90 of less than about 30 μm, or less than about 10 μm. The use of micronized active agents is believed to have the effect of reducing the tendency of TKI (specifically axitinib) particles to agglomerate during casting of hydrogel strands, as shown in FIG. 24. In another embodiment, the active agent may be used in non-micronized form to prepare the implant.

[0253] Precursors for forming certain embodiments of hydrogels are disclosed in detail in the section regarding the implant itself above. When preparing a crosslinked PEG network using a PEG precursor, the method of making an implant in certain embodiments involves using an electrophilic group-containing polymer precursor (e.g., an electrophilic group-containing multi-arm polyethylene glycol, e.g. , 4a20kPEG-SAZ) with a nucleophile-containing polymer precursor or other crosslinking agent (e.g., a nucleophile-containing multi-arm polyethylene glycol, e.g., 8a20kPEG-NH 2 ), mixing and reacting in a buffer in the presence of a tyrosine kinase inhibitor, and gelling the mixture. In certain embodiments, the molar ratio of electrophilic groups to nucleophilic groups in the PEG precursor is about 1:1, although nucleophilic groups (e.g., amine groups) may be used in excess of electrophilic groups. can. Other precursors, including other electrophilic group-containing precursors and other nucleophilic group-containing precursors or crosslinkers, as disclosed in the "Polymer Networks" and "PEG Hydrogels" sections herein. ) may be used.

[0254] In certain embodiments, an electrophilic group-containing precursor, a nucleophilic group-containing precursor or other crosslinking agent, an active agent, and optionally a buffer (and optionally, in the "Additional Ingredients" section) (additional components disclosed) are prepared. This can be done in various orders including, but not limited to, first adding separate mixtures of each of the electrophile-containing precursor and the nucleophile-containing precursor in a buffer solution. and then combining one of the buffer / precursor mixtures (e.g., a buffer / nucleophile-containing precursor mixture) with an active agent; Examples include combinations with other buffer / precursor mixtures (in this case, buffer / electrophilic group-containing precursor mixtures). After the mixture of all components has been prepared (i.e., after all components have been combined to form a wet composition), prior to complete gelation of the hydrogel to obtain the desired final shape of the hydrogel. Cast the mixture into a suitable mold or tube. The mixture is then allowed to gel. The resulting hydrogel is then dried.

[0255] The viscosity of a wet hydrogel composition cast into a mold or tube may depend, among other things, on the concentration and solids content of the hydrogel composition, but may also depend on external conditions such as temperature. The flexibility of wet hydrogel compositions, particularly when the compositions are cast into fine-diameter tubes, can be improved by reducing the viscosity of the wet composition, which includes reducing the viscosity in a solvent. including (but not limited to) reducing the concentration of the components of and / or reducing the solids content or other measures (such as increasing the temperature). Suitable solids contents are disclosed in the "Formulation" section herein.

[0256] If the implant is to have a fibrous final shape (e.g. cylindrical), the reactive mixture is poured into a fine diameter tube such as a PU or silicone tube (e.g. about 1.0 mm to about 1.5 mm) to obtain an elongated cylindrical shape. Can be cast inside (inner diameter). Depending on the desired final cross-sectional geometry of the hydrogel fibers, their initial diameter (which can be further reduced by stretching), and also on the ability of the reactive mixture to uniformly fill the tube, various Tube geometry and diameter can be used.

[0257] Thus, the interior of the tube may have a circular geometry or a non-circular geometry, such as a cruciform (or other) geometry. The cruciform geometry allows the surface area of ​​the implant to be increased. Also, in certain embodiments, the amount of active agent incorporated into the implant can be increased by such a cruciform geometry. Overall, the use of a cruciform geometry can, in certain embodiments, increase the release of API from the implant. Other cross-sectional geometries of implants may be used as disclosed herein.

[0258] In certain embodiments, after forming the hydrogel and curing until fully gelled, the hydrogel strands are removed from the hydrogel as already disclosed in detail herein (e.g., in the section on dimensional changes of the implant upon hydration). It can be longitudinally stretched in the wet or dry state, as shown in FIG. In certain embodiments, the stretching factor (also referred to herein as "stretch factor") is from about 1 to about 4.5, or from about 1.3 to about 3.5, or from about 2 to 2.5, or within other ranges disclosed herein (for example, but not limited to, in the "Implant Dimensions and Dimensional Changes Upon Hydration Due to Stretching" section) (within a certain range). The stretch factor indicates the ratio of the stretched length of a particular hydrogel strand to the unstretched length of that hydrogel strand. For example, a stretch factor of 2 for dry stretching means that the length of the dry hydrogel strand after (dry) stretching is twice the length of the dry hydrogel strand before stretching. The same applies to wet stretching. When dry stretching is performed in certain embodiments, the hydrogel is first dried and then stretched. When wet stretching is performed in certain embodiments, the hydrogel is stretched in a wet (not dried) state and then dried under tension. Optionally, heat may be applied during stretching. Additionally, the hydrogel fibers may optionally be further twisted. In certain embodiments, stretching and / or drying can be performed while the hydrogel is still within the tube. Alternatively, the hydrogel may be removed from the tube before stretching. In certain embodiments, the implant maintains its dimensions even after stretching as long as it is stored dry at or below room temperature.

[0259] After stretching and drying, the hydrogel strands are removed from the tube (if still within the tube) and cut into segments of the desired length for the final implant in the dry state as disclosed herein. When cutting with , the cut segment is removed from the tube after cutting). Particularly desirable lengths of dry implants for purposes of the present invention are, for example, lengths of about 12 mm or less, or about 10 mm or less, as disclosed herein.

[0260] In certain embodiments, the final prepared implant is then loaded into a fine diameter needle. In certain embodiments, the gauge size of the needle is between 22 and 30, such as 22 gauge, 23 gauge, 24 gauge, 25 gauge, 26 gauge, 27 gauge, 28 gauge, 29 gauge, or 30 gauge. In specific embodiments, the needle is a 25 gauge or 27 gauge needle, or an even smaller gauge needle (eg, a 30 gauge needle), depending on the diameter of the dried (and optionally stretched) implant.

[0261] In certain embodiments, the needle containing the implant is then packaged separately and sterilized, such as by gamma irradiation.

[0262] In certain embodiments, the injection device (e.g., a syringe or another injection device) can be packaged separately, and is described below in a kit (another aspect of the invention, in the "Injection Devices and Kits" section). It can be sterilized, for example by gamma irradiation, as disclosed in Reference).

[0263] A specific embodiment of the manufacturing process according to the invention is disclosed in detail in Example 1.

[0264] Needle (PEG) tipping: In one embodiment, after the implant is loaded into the needle, the tip of the needle is dipped into molten low molecular weight PEG. Alternatively, molten PEG may be injected or placed / dropped into the needle tip lumen. This low-molecular-weight PEG is liquid (molten) at body temperature, but solid at room temperature. After applying molten PEG to the needle tip by dipping or dropping, cooling the needle creates a droplet or piece of hardened PEG (also referred to herein as the tip) on and within the tip of the needle. It remains and this blocks the needle lumen. The location of this tip / plug is shown in Figure 25B.

[0265] The low molecular weight PEG used in this embodiment can be a linear PEG and have an average molecular weight of up to about 1500 or up to about 1000, or an average molecular weight of about 400, about 600, about 800, or about 1000. may have. Also, mixtures of PEGs of different average molecular weights can be used as disclosed. In a specific embodiment, the average molecular weight of the PEG used for this purpose of tipping the needle is about 1000. This 1k (1000) molecular weight PEG has a melting point of about 33°C to about 40°C and melts at body temperature when the needle is injected into the eye.

[0266] Alternatives to PEG materials that are water-soluble and biocompatible (i.e., can be used in contact with the human or animal body and do not induce local or systemic adverse effects (e.g., are not irritating) ), any other material that is solid or hard at room temperature but liquid, or substantially liquid, or at least soft at body temperature, may be used to tip the needle. Instead of PEG, the following materials can also be used, for example (but not limited to): poloxamers or poloxamer blends that melt / are liquid at body temperature, crystallized sugars or salts (e.g. , trehalose or sodium chloride), agarose, cellulose, polyvinyl alcohol, poly(lactic-co-glycolic acid), UV-curable polymers, chitosan, or combinations of mixtures thereof.

[0267] The plug or tip helps keep the implant in place within the needle during packaging, storage, and shipping, and additionally occludes the needle lumen, protecting the implant from early hydration during manipulation. protect Also, during the administration procedure, when the doctor prepares the needle and syringe for administration, and when the needle is inserted into the eye to inject the implant (just before the implant is actually injected), positive intraocular pressure is created. Premature hydration of the implant within the needle due to ingress of moisture may be prevented (which may cause premature hydration of at least some of the implant). The tip or plug also provides lubricity when warmed to body temperature or exposed to moisture, thereby allowing successful placement of the implant. Furthermore, by occluding the lumen of the needle, needle tipping increases the possibility of tissue damage, i.e. tissue coring (the process by which fragments of tissue are removed by the needle as it passes through the tissue). minimize.

[0268] In one embodiment, the needle containing the implant is placed in a container of melted PEG (or the respective other material) in order to apply the tip / plug of PEG (or other material) to the lumen of the needle. It can be soaked manually or by automatic equipment. The needle may be held submerged in the molten material for a few seconds to allow the molten material to flow upwardly into the needle by capillary action. Residence time, depth of immersion, and temperature of the molten material determine the final size or length of the tip / plug. In certain embodiments, the length of the PEG (or other) tip / plug at the top of the needle can be about 1 to about 5 mm (eg, about 2 to about 4 mm). In certain embodiments, when 1k PEG is used, the weight of the tip / plug can be about 0.1 mg to about 0.6 mg (eg, about 0.15 mg to about 0.55 mg). It has been demonstrated that implants according to the invention can be successfully deployed in vivo and in vitro from a syringe with a needle with a 1k PEG tip as disclosed herein.

[0269] The needle tip treatments disclosed herein also apply to other implants or other materials injected into the human or animal body (including elsewhere within the eye or other areas or tissues of the body) by the needle. other implants or vaccines in which the protective effect of the implant (or the medicament or vaccine) against moisture and the protective effect on the tissue into which the implant (or the medicament or vaccine) is injected is desirable and advantageous. It can also be used for injection of other medicines or vaccines.

[0270] Stretching: The shape memory effect due to stretching has already been disclosed in detail above in connection with the properties of the implant. In certain embodiments, the degree of shrinkage upon hydration depends, among other things, on the stretch factor as already disclosed above.

[0271] Accordingly, in certain embodiments, the invention also relates to a method of imparting shape memory to a hydrogel strand comprising an active agent dispersed within the hydrogel, the method comprising longitudinally stretching the hydrogel strand. carried out by

[0272] Accordingly, in certain embodiments, the present invention also provides a method of manufacturing an intraocular implant comprising a hydrogel having an active agent dispersed within the hydrogel, the implant comprising: Also directed to a method of varying dimensions, the method includes preparing a strand of hydrogel and longitudinally stretching it.

[0273] Stretching factors for use in these methods of the invention can be utilized as already disclosed above. The described manufacturing methods (including stretching methods) are not limited to implants containing TKI inhibitors or axitinib, but rather hydrogels containing other active pharmaceutical agents, or formed from PEG units. Implants containing hydrogels formed from other polymeric units, such as those disclosed hereinabove that are capable of forming hydrogels, can also be used.

[0274] In embodiments where the implant includes axitinib in an amount within the range of about 160 μg to about 250 μg or in an amount of about 200 μg, stretching is performed after drying the hydrogel by a stretch factor of about 2 to about 5 or a stretch of about 3 to about 4.5. It can be carried out with a coefficient (dry stretching).

[0275] In certain embodiments where the implant includes axitinib in an amount within the range of about 480 μg to about 750 μg or in an amount of about 600 μg, stretching comprises a stretch factor of about 0.5 to about 5 in the wet state before drying the hydrogel; Alternatively, it can be carried out with a stretching coefficient of about 1 to about 4, or a stretching coefficient of about 1.3 to about 3.5, or a stretching coefficient of about 1.7 to about 3, or a stretching coefficient of about 2.0 to about 2.5 (wet stretching).

[0276] III. Injection devices and kits In certain embodiments, the invention further provides one or more sustained release biodegradable intraocular implant(s) as disclosed above or made according to a method as disclosed above; A kit (sometimes referred to as a "system") comprising one or more needle(s) for injection, wherein each of the one or more needle(s) is dried. One sustained release biodegradable intraocular implant is preloaded with In certain embodiments, the needle(s) have a gauge size of 22-30, such as 22, 23, 24, 25, 26, 27, 28, 29, or 30 gauge. In specific embodiments, the needle can be a 25 gauge or 27 gauge needle(s), or a smaller gauge, such as a 30 gauge needle(s). The diameter of the needle is selected based on the final diameter of the implant in the dry (and optionally stretched) state.

[0277] In one embodiment, the kit comprises one or more, e.g., two or three, 22 to Includes 30 gauge, eg, 25 gauge or 27 gauge needle(s).

[0278] In yet another embodiment, the kit includes one 25 gauge needle loaded with an implant comprising axitinib in an amount within the range of about 540 μg to about 660 μg, or in an amount of about 600 μg. In another embodiment, the kit includes one 27 gauge needle loaded with an implant containing the active ingredient.

[0279] If more than one implant is included in the kit, the implants may be the same or different and may contain the same or different doses of the active agent.

[0280] In certain embodiments, the lumen of the needle containing the implant is as disclosed in detail in the "Implant Fabrication" section herein, particularly in the subsection "Needle (PEG) Tip Processing." It may be occluded by a material that is solid at room temperature but soft or liquid at body temperature (eg, a 1k PEG material).

[0281] The kit can further include an injection device for injecting the implant(s) into the patient's eye (eg, into the patient's vitreous humor). In certain embodiments, the injection device is provided and / or packaged separately from the implant-loaded needle(s). In such embodiments, the injection device must be connected to one or more needle(s) loaded with the implant prior to injection.

[0282] In certain embodiments, the number of injection devices provided separately within the kit is equal to the number of implant-loaded needles provided within the kit. In such embodiments, the injection device is used only once for injection of one implant.

[0283] In other embodiments, the kit includes one or more injection device(s) for injecting the implant into a patient's eye (e.g., into the patient's vitreous humor), where each injection device The implant may be pre-connected to a loaded needle or not. Accordingly, in one aspect, the present invention provides a pharmaceutical product comprising a needle-loaded sustained release biodegradable intraocular implant and an injection device, the needle being pre-connected to the injection device. Also related. If the needle is not pre-connected to the injection device, the physician administering the implant removes both the needle containing the implant and the injection device from the package and connects the needle to the injection device so that the implant can be injected into the patient's eye. There is a need.

[0284] In some embodiments, the injection device includes a push wire to place the implant from the needle into the vitreous humor. The push wire may be a nitinol push wire or a stainless steel / Teflon push wire. A push wire allows for easier placement of the implant from the needle.

[0285] In other embodiments, the injection device and / or needle can include a stop feature to control the depth of injection.

[0286] In some embodiments, the injection device is or includes a modified Hamilton glass syringe that can be placed within a plastic syringe housing (eg, inside an injection molded housing). A push wire (eg, a nitinol wire) is inserted into the syringe and advanced with the plunger of the syringe during placement of the implant. A hub insert may be added to the needle hub to facilitate entry of the Nitinol push wire into the needle. Figures 25A and 25B illustrate one embodiment of a syringe according to the present invention for injecting an implant into the vitreous humor of a patient. This illustrated syringe embodiment includes a Hamilton syringe body and a nitinol push wire for placing the implant. Figure 25A shows the Hamilton syringe body inside the injection molded casing. FIG. 25B is a schematic diagram of the components in this syringe embodiment. In certain embodiments, the syringe, including the Hamilton syringe body and the plastic housing part, is preassembled in a kit according to the invention, and the syringe is ready for use (without needle containing implant or without needle attachment). . In other embodiments, the syringe must be assembled by the physician before attaching the needle containing the implant.

[0287] In other embodiments, the injection device is an injection molded syringe. A schematic exploded view of one embodiment of such an injection molded syringe is shown in FIG. In this case, the number of assembly steps performed by the physician immediately before administering the implant to the patient is reduced.

[0288] The kit can further contain one or more ready-to-inject doses, particularly a single dose, of an additional active agent, such as an anti-VEGF agent. The anti-VEGF agent can be selected from the group consisting of aflibercept, bevacizumab, pegaptanib, ranibizumab, and brolucizumab. In certain embodiments, the anti-VEGF agent is bevacizumab. In other embodiments, the anti-VEGF agent is aflibercept. The additional active agent may be provided in a separate injection device connected to the needle or as a solution or suspension in a sealed vial, the solution or suspension being ready for administration. The vial can then be drawn through a needle into a syringe or other injection device.

[0289] The kit can further include an operating manual for a physician injecting the intraocular implant(s). The kit can further include a package insert with product-related information.

[0290] In addition to the kit, the invention in one aspect is also directed to an injection device itself suitable for injecting into the eye a sustained release biodegradable intraocular implant according to the invention. The injection device may include means for connecting the injection device to a needle preloaded with an implant. The injection device may further include a push wire for placing the implant from the needle into the eye when the injection device is connected to the needle, the push wire being made of Nitinol or stainless steel / Teflon or other suitable material. It can be made from various materials. The injection device can also be obtained by affixing a wire to the plunger, placing it between two snap-fit ​​syringe body parts, and securing the plunger with a clip. An injection device and a needle preloaded with an implant according to certain embodiments of the invention are illustrated in FIG.

[0291] As shown in FIG. 1, in some embodiments, an injection device (e.g., an implant injection device) includes a first assembly and a second assembly that are packaged separately (e.g., in separate housings). May include assembly. FIG. 26C is an exploded view of the first assembly and FIG. 26D is an exploded view of the second assembly.

[0292] Referring to FIG. 26C, the first assembly includes a body forming a first internal volume, a plunger including a first distal end disposed within the first internal volume, and a first distal end of the plunger. a wire including a first distal end secured to the distal end of the wire; and a plunger clip. The plunger clip is configured to connect to the plunger and the body to prevent actuation of the plunger. The body can include a first body half and a second body half configured to interconnect each other. The body can include a living hinge that connects to the protrusion of the plunger in response to actuation of the plunger. The living hinge can actuate the plunger in response to application of a threshold force.

[0293] Referring to FIG. 26D, the second assembly includes a cowl forming a second interior volume, a needle including a base and a lumen, a cowl cap disposed within the base, and a needle secured relative to the cowl and having an inner diameter. and a needle shield configured to be disposed about a portion of the cavity. The implant is configured to be disposed within the lumen of the needle. The cowl can include a first cowl half and a second cowl half configured to interconnect with each other. The second assembly can further include a polymeric tip (eg, a PEG tip) disposed at the second distal end of the lumen. The implant is secured within the lumen between the cowl cap and the polymer tip. The polymeric tip is configured to liquefy (eg, dissolve) within the user's body, allowing the user to inject the implant.

[0294] In some embodiments, to prevent the implant from absorbing moisture, the second assembly is made from a less moisture-containing material and / or subjected to conditioning (e.g., Nitrogen conditioning). In some embodiments, because the implant is not included in the housing with the first assembly, the first assembly is made from a moisture-rich material and / or conditioned before being sealed within the housing. I don't receive it.

[0295] The first assembly can be removed from the first housing of FIG. 1, and the second assembly can be removed from the second housing of FIG. Referring to FIG. 26E, the first assembly and the second assembly may be aligned. One or more outer recesses of the first assembly may be aligned with one or more inner protrusions of the second assembly. The first assembly and the second assembly can include indicia (eg, an arrow) indicating how to align the first assembly and the second assembly. Referring to FIG. 26F, the cowl of the second assembly is secured to the body of the first assembly (eg, by a protrusion on the inside of the cowl recessed into a recess on the outside of the body). Referring to FIG. 26G, the needle shield has been removed from the cowl of the second assembly and the plunger clip has been removed from the body and plunger of the first assembly. Referring to FIG. 26H, the plunger of the first assembly is actuated (eg, pushed into the body of the first assembly) to deploy the implant from the lumen of the needle of the second assembly. In some embodiments, the body has a living hinge that allows actuation of the plunger in response to a threshold force applied to the plunger. In some embodiments, the lumen of the needle has a polymeric tip (e.g., a polymer (e.g., PEG) disposed at least at the distal end of the lumen) that blocks an implant that is placed from the lumen. . Inserting a lumen with a polymeric tip into the user allows coring of the user's tissue (e.g., a piece of tissue is cut at the internal diameter of the lumen to be later placed within the user's body). ) can be prevented. The lumen can be inserted into the user for a threshold amount of time (eg, 1-5 seconds) to liquefy (eg, dissolve) the polymer tip. After the polymer tip is liquefied, the implant can be deployed from the lumen by actuation of the plunger.

[0296] IV. Therapy In certain embodiments, the present invention is further directed to a method of treating an ocular disease in a patient in need thereof, the method comprising administering to the patient a sustained release drug comprising a hydrogel as disclosed above and an active agent. and administering a biodegradable intraocular implant.

[0297] In a specific embodiment, the invention is directed to a method of treating an ocular disease in a patient in need thereof, the method comprising administering to the patient a sustained release biodegradable intraocular implant containing an active agent. wherein the active agent particles are dispersed within the hydrogel.

[0298] In embodiments, the dose per eye administered once during a treatment period of at least 3 months is at least about 150 μg, such as from about 150 μg to about 1800 μg, or from about 150 μg to about 1200 μg of active agent.

[0299] In certain embodiments, the dose of active agent per eye administered once during the treatment period (ie, during the treatment period) is within the range of about 200 μg to about 800 μg. In certain embodiments, the dose is within the range of about 160 μg to about 250 μg, or about 180 μg to about 220 μg, or about 200 μg. In still other specific embodiments, the dose is within the range of about 320 μg to about 500 μg, or about 360 μg to about 440 μg, or about 400 μg. In yet other embodiments, the dose is within the range of about 480 μg to about 750 μg, or about 540 μg to about 660 μg, or about 600 μg. In still other embodiments, the dose is within the range of about 640 μg to about 1000 μg, or about 720 μg to about 880 μg, or about 800 μg. In still other embodiments, the dose is within the range of about 800 μg to about 1250 μg, or about 900 μg to about 1100 μg, or about 1000 μg. In yet other embodiments, the dose is within the range of about 960 μg to about 1500 μg, or about 1080 μg to about 1320 μg, or about 1200 μg.

[0300] In certain embodiments, the treatment period for the treatment of ocular diseases disclosed herein using the implants of the present invention is at least 3 months, at least 4.5 months, at least 6 months, at least 9 months. , can be at least 11 months, at least 12 months, at least 13 months, at least 14 months, or even longer, eg, from about 6 to about 9 months.

[0301] In certain embodiments, the ocular disease involves angiogenesis.

[0302] In other embodiments, the ocular disease is mediated by one or more receptor tyrosine kinases (RTKs), e.g., VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-α / β, and / or c-Kit. can be done.

[0303] In some embodiments, the ocular disease includes choroidal neovascularization, diabetic retinopathy, diabetic macular edema, retinal vein occlusion, acute macular neuroretinopathy, central serous chorioretinopathy, and cystoid macular edema. retinal diseases including acute multifocal patchy pigment epitheliopathy, Behcet's disease, birdshot chorioretinopathy, infectious (syphilis, Lyme disease, tuberculosis, toxoplasmosis), intermediate uveitis ( pars planitis), multifocal choroiditis, multiple effacement white dot syndrome (MEWDS), ocular sarcoidosis, posterior scleritis, serpentine choroiditis, subretinal fibrosis, uveitis syndrome, or Vogt syndrome. Koyanagi-Harada syndrome, ocular disease, vascular disease or exudative disease (Coats disease, parafoveal telangiectasia, papillary vasculitis, frosty branch vasculitis, sickle cell retinopathy and other hemoglobin ophthalmopathy, retinitis pigmentosa, and familial exudative vitreoretinopathy), or the ocular disease results from trauma or surgery (sympathetic ophthalmia, uveitis retinal disease, retinal detachment). , trauma, photodynamic laser therapy, photocoagulation, intraoperative hypoperfusion, radiation retinopathy, bone marrow transplant retinopathy, retinopathy, rhodopsin-mediated autosomal dominant retinitis pigmentosa, Best1-related retinal disease, Leber congenital amaurosis, including Stargardt macular dystrophy, or inherited retinal diseases).

[0304] In an alternative embodiment, sustained release biodegradable intraocular implants containing the hydrogels and active agents of the present invention can be applied in the treatment of ocular conditions associated with tumors. Such conditions include, for example, tumor-associated retinal diseases, solid tumors, tumor metastases, benign tumors (e.g., hemangiomas, neurofibromas, trachomas, and pyogenic granulomas), congenital hypertrophy of the RPE, posterior Uveal melanoma, choroidal hemangioma, choroidal osteoma, choroidal metastasis, combined hamartoma of the retina and retinal pigment epithelium, retinoblastoma, vascular proliferative tumor of the fundus, retinal astrocytoma, or intraocular lymphoid tumor. Can be mentioned.

[0305] In general, the intraocular implant of the present invention can also be applied in the treatment of any ophthalmological disease involving vascular leakage.

[0306] In certain embodiments, the ocular disease is a disease selected from the list consisting of neovascular age-related macular degeneration (AMD), diabetic macular edema (DME), and retinal vein occlusion (RVO). In certain embodiments, the ocular disease is neovascular age-related macular degeneration.

[0307] In some embodiments, the treatment is effective in reducing central zone retinal thickness (CSFT) as measured by optical coherence tomography in patients with increased central zone retinal thickness. Elevated within this context means that the patient's CSFT is higher when compared to other individuals who do not suffer from the particular ocular disease. Elevated CSFT can be caused by retinal fluids, such as subretinal fluid or intraretinal fluid. A reduction in CSFT in a patient can be determined with reference to the baseline CSFT measured in that patient before the initiation of treatment, ie, before administration of the implant of the invention. The ability of the implants of the invention to reduce CSFT and maintain or substantially maintain reduced CSFT over time in a cohort of patients is demonstrated in Examples 6.3 and 6.4. In other embodiments, treatment according to the invention comprising administration of an implant according to the invention essentially maintains the CSFT at a certain given level in a patient whose CSFT is elevated due to an ocular disease involving neovascularization. clinically significant increase in CSFT in the patient is prevented, while subretinal or intraretinal fluid does not increase significantly (i.e., is also essentially maintained).

[0308] In certain embodiments, CSFT is reduced in a patient after administration of an implant of the invention for at least 3 months, at least 4.5 months, at least 6 months, at least 9 months, at least 11 months, at least 12 months. maintained at a reduced level for a period of at least 13 months, at least 14 months, or longer. In very specific embodiments, CSFT is reduced for at least 6 months, or at least 9 months, or at least 12 months after implant administration, relative to the patient's baseline CSFT before implant administration. In certain other embodiments, the reduction in retinal fluid volume and / or the reduction in CSFT occurs without the need to administer a rescue drug (e.g., injection of an anti-VEGF agent) or with reduced administration of a rescue drug during the treatment period. at least 3 months, at least 4.5 months, at least 6 months, at least 9 months, at least 11 months, at least maintained in the patient for a treatment period of 12 months, at least 13 months, at least 14 months, or longer. Thus, in this embodiment, during the period of treatment with the implant according to the invention, the patient being treated may not require any rescue drug, or the need to administer rescue drug during the treatment period may be infrequent (e.g. 1, 2, or 3 times).

[0309] In certain embodiments, the rescue drug is an anti-VEGF agent (eg, aflibercept or bevacizumab), which is administered by intravitreal injection in the form of a suspension or solution. In certain specific embodiments, the rescue drug is a single dose (2 mg) of aflibercept, administered by intravitreal injection. As defined herein, concurrent (ie, scheduled) administration of an anti-VEGF agent with an implant according to another embodiment of the invention disclosed herein does not constitute a "rescue drug." In further particular embodiments, the levels of body fluids and / or CSFT (reduced by administration of an implant according to the invention) are maintained without (or with only infrequent administration of rescue drugs) the administration of rescue drugs, or The essentially sustained treatment period is about 6 months to about 9 months after administration of the implant. In certain embodiments, patients treated with implants according to the invention do not require concomitant administration of steroids (eg, dexamethasone or prednisolone instillations) during the treatment period.

[0310] In another embodiment, treatment according to the invention comprising administration of an implant according to the invention reduces or essentially maintains CSFT in a patient whose CSFT is elevated due to angiogenesis, or the clinical a significant increase in visual acuity is prevented, while the patient's visual acuity (e.g., visual acuity as expressed by best-corrected visual acuity (also referred to herein as "BCVA") is not decreased or is not significantly decreased. . In certain embodiments, treatment according to the invention comprising administration of an implant according to the invention improves the patient's visual acuity (e.g., as expressed by BCVA), if the patient's visual acuity is impaired by an ocular disease involving neovascularization. ) may improve during a treatment period of at least 3 months, at least 6 months, at least 9 months, at least 11 months, at least 12 months, at least 13 months, or at least 14 months.

[0311] Accordingly, in certain embodiments, the present invention provides a method of improving visual acuity in a patient whose visual acuity is impaired (e.g., due to retinal fluid caused by an ocular disease involving neovascularization); involves administering an implant according to the invention to a patient, eg, by intravitreal injection. Improvement in a patient's visual acuity can be assessed by, for example, BCVA. Improvement in visual acuity is manifested by an increase in the patient's BCVA, eg, an increase in the number of ETDRS characters by at least 10 characters, or at least 15 characters, or at least 20 characters.

[0312] In certain embodiments, one or more implants may contain a total per eye dose of active agent administered once during a treatment period. In certain embodiments, the dose per eye administered once during the treatment period is contained in one implant. In other embodiments, the total dose per eye administered once during the treatment period is included in, for example, two implants. In yet other embodiments, the dose per eye administered once during the treatment period includes, for example, three implants.

[0313] For injecting an implant according to the invention into a patient's eye (e.g. into the vitreous humor) in the course of the treatment of ocular diseases (e.g. retinal diseases including AMD), it is generally desirable to treatment of the active agent within a relatively small implant to facilitate treatment and reduce the chance of damaging ocular tissue and impacting the patient's vision while the implant is in place. The goal is to use an implant that has an effective dose (ie, a dose that is appropriate in light of the particular patient type and severity of symptoms). In certain embodiments, the implants of the present invention suitably combine the advantages of high doses of active agent (i.e., therapeutically effective doses tailored to the needs of a particular patient) with the advantages of relatively small implant size. It is advantageously combined with

[0314] In certain embodiments, the implant may be administered by an injection device according to the present invention, in which the implant as disclosed herein is connected to a preloaded needle, or as disclosed herein. Such an implant may be administered by another injection device suitable for connection to a preloaded needle, such as a (modified) Hamilton syringe. In other embodiments, hollow microneedles can be used for suprachoroidal administration, as disclosed in US 8,808,225 (herein incorporated by reference).

[0315] In embodiments where more than one implant is administered, the implants are generally administered simultaneously as disclosed herein above. Implants administered simultaneously may be the same or different. If administration during the same session is not possible, e.g. due to complexity of administration or patient-related reasons, sequential administration during two or more different sessions (e.g., administration of two implants 7 days apart) is recommended. May be applied alternatively. This can still be considered "concurrent" administration in the context of the present invention.

[0316] In certain embodiments, the dry implant is loaded into a needle for injection, such as a needle having a gauge size of 22-23, such as a 25- or 27-gauge needle, or a smaller gauge needle. Administered into the eye (eg, into the vitreous humor). In one embodiment, the syringe used to inject the implant into the eye is an injection device according to another aspect of the invention as disclosed above. Implants suitable for therapeutic use according to the present application are exemplarily shown in Tables 21.1 and 21.2.

[0317] Implants generally can be administered by intravitreal, subconjunctival, subtenon, suprachoroidal, or intracameral injection. In certain embodiments, the implant is administered into the vitreous humor. For example, the implant is administered intravitreally posterior to the vitreous humor. In other embodiments, the implant is inserted into the sclera of the eye at the site of insertion into the suprachoroidal space of the eye as disclosed, for example, in US 8,808,225 (herein incorporated by reference) by means of a hollow microneedle. Administered intravenously.

[0318] In certain embodiments, the treatment period is at least 3 months, but may be at least 4.5 months, at least 6 months, at least 9 months, at least 11 months, or at least 12 months. In certain embodiments, the treatment period is at least 6 months, at least 9 months, at least 11 months, at least 12 months, at least 13 months, or at least 14 months. In certain embodiments, the duration of treatment may be longer (eg, up to about 15 months). A "treatment period" according to one embodiment of the present invention refers to the period during which certain therapeutic effects of the implant of the present invention, once administered, are maintained, essentially maintained, or partially maintained over that period of time. means. In other words, to maintain a therapeutic effect that reduces or essentially maintains CSFT, or prevents a clinically significant increase thereof, over an extended period of time, referred to herein as the "treatment period," In certain embodiments, only one injection (of the implant of the invention) is required. This is a major advantage over currently used anti-VEGF treatments for AMD, which require more frequent dosing, thus improving patient quality of life. Another advantage is that the need and / or frequency of administering rescue drugs during the treatment period is very low. In certain embodiments, no rescue drug is required during the treatment period (eg, a treatment period of about 6 months to about 9 months after administration of the implant). In certain other embodiments, the need to administer the rescue drug is less frequent (eg, 1, 2, or 3 times) during the treatment period. A patient's visual acuity may be improved, for example, as evidenced by an increase in BCVA (eg, an increase in ETDRS letters of at least 10 letters, at least 15 letters, or at least 20 letters) after administering an implant of the invention.

[0319] In one particular embodiment, the invention is directed to a method of treating neovascular age-related macular degeneration in a patient in need thereof, the method comprising: administering to the patient a hydrogel comprising a polymer network; comprising administering a sustained-release biodegradable intraocular implant containing a suitable active agent, one implant per eye administered once during a treatment period of at least 9 months, and the patient receiving anti-VEGF treatment. Has a history. In this embodiment, the treatment results in a reduction in central zone retinal thickness (CSFT), or at least maintenance of CSFT, as measured by optical coherence tomography, during the treatment period. In this embodiment, the active agent is 4a20kPEG-SAZ, 8a20kPEG-NH 2 The implant is in a dry state before administration. In this embodiment, the hydrogel, as formed and before drying, comprises about 7.5% polyethylene glycol (equivalent to weight of polyethylene glycol divided by weight of fluid x 100). Alternatively, the patient undergoing treatment may have no history of anti-VEGF treatment (AMD treatment naïve).

[0320] In another specific embodiment, the invention is directed to a method of treating neovascular age-related macular degeneration in a patient in need thereof, the method comprising administering to the patient a hydrogel comprising a polymer network and a suitable administering a sustained release biodegradable intraocular implant containing an active agent, two implants per eye administered once during a treatment period of at least 3 months, or at least 9 months; Patients either have a history of anti-VEGF therapy or have no history of anti-VEGF therapy (AMD treatment naïve). In this embodiment, the treatment results in a reduction (or at least maintenance thereof) of central zone retinal thickness (CSFT) as measured by optical coherence tomography during the treatment period. In this embodiment, the active agent is 4a20kPEG-SAZ, 8a20kPEG-NH 2 The implant is in a dry state prior to administration. In this embodiment, the hydrogel, as formed and before drying, comprises about 7.5% polyethylene glycol (equivalent to weight of polyethylene glycol divided by weight of fluid x 100).

[0321] In yet another specific embodiment, the invention is directed to a method of treating neovascular age-related macular degeneration in a patient in need thereof, the method comprising: administering to the patient a hydrogel comprising a polymer network; 3 implants per eye are administered once during a treatment period of at least 3 months, or at least 9 months, and the patient have a history of anti-VEGF treatment or no history of anti-VEGF treatment (AMD treatment naïve). In this embodiment, the treatment results in a reduction (or at least maintenance thereof) of central zone retinal thickness (CSFT) as measured by optical coherence tomography during the treatment period. In this embodiment, the active agent is dispersed within a hydrogel comprising a polymer network formed by reacting 4a20kPEG-SAZ with 8a20kPEG-NH2, and the implant is dry prior to administration. In this embodiment, the hydrogel, as formed and before drying, comprises about 7.5% polyethylene glycol (equivalent to weight of polyethylene glycol divided by weight of fluid x 100).

[0322] In still other embodiments, the invention is directed to a method of treating neovascular age-related macular degeneration in a patient in need thereof, the method comprising administering to the patient a hydrogel dispersion in a hydrogel comprising a polymer network. a sustained release biodegradable intraocular implant containing a suitable active agent, the implant being administered once during a treatment period of at least 3 months. The implant can be administered into the vitreous humor, for example, through a fine diameter (eg, 25 gauge) needle. The treatment period as defined above is at least 4.5 months, or at least 6 months, or at least 9 months, or at least 11 months, or at least 12 months, or at least 13 months, or at least 14 months, or It can be even longer, for example up to about 15 months. In certain embodiments, the treatment period is at least 6 months, or at least 9 months, or at least 12 months, or about 6 months to about 9 months.

[0323] In some embodiments, treatment with sustained release biodegradable intraocular implant(s) containing an active agent or treatment with sustained release biodegradable intraocular implant(s) containing an active agent according to the present invention Concurrently, an anti-VEGF agent is administered to the patient. The anti-VEGF agent can be selected from the group consisting of aflibercept, bevacizumab, pegaptanib, ranibizumab, and brolucizumab. In certain embodiments, the anti-VEGF agent is bevacizumab. In certain embodiments, the anti-VEGF agent is aflibercept. In certain embodiments, the anti-VEGF agent is administered by intravitreal injection contemporaneously and optionally simultaneously with the administration (as defined above) of the sustained release biodegradable intraocular implant, i.e. It is administered in one session as already disclosed in detail. If administration of the anti-VEGF agent and the implant of the invention is not possible in the same session, e.g. due to complications of administration or patient-related reasons, consecutive administration in two or more different sessions (e.g. 7 days apart) (Administering two implants) can be applied alternatively. This can still be considered "concurrent" administration in the context of the present invention.

[0324] In other embodiments, the anti-VEGF agent is administered in combination with the implant of the present invention, but not simultaneously (i.e., not concurrently), at an earlier or later time during the treatment period of the implant of the present invention. be able to. In certain embodiments, the anti-VEGF agent can be administered within about 1 month, within about 2 months, or within about 3 months, or more months of administration of the implant, i.e., It can be administered before or after the implant. This combined (and deliberate) co-administration of anti-VEGF agents is distinct from rescue drugs as defined herein.

[0325] In certain embodiments of the invention, the patient has primary subfoveal (e.g., active subfoveal or juxtafoveal CNV with leakage involving the fovea) secondary to AMD (SFNV). have a diagnosis.

[0326] In certain embodiments of the invention, the patient has a previously treated diagnosis of subfoveal neovascularization (SFNV) secondary to neovascular AMD with leakage involving the fovea. In these patients, prior treatment was with anti-VEGF agents.

[0327] In some embodiments, the patient is at least 50 years old or at least 60 years old. Patients can be male or female. Patients may have retinal fluid, such as intraretinal fluid or subretinal fluid.

[0328] In some embodiments, the patient receiving the implant has a history of anti-VEGF treatment (eg, treatment with LUCENTIS® and / or EYLEA®). In certain embodiments, the patient receiving the implant has a history of anti-VEGF therapy, but has not responded to this anti-VEGF therapy. That is, the patient's disease status was not improved by anti-VEGF treatment. In embodiments where the patient has a history of anti-VEGF treatment prior to the initiation of treatment with an implant according to the invention, administration of the implant of the invention may be administered over an extended period of time (e.g., over the treatment period defined above), prior to anti-VEGF treatment. The effects of VEGF treatment can be prolonged. In other embodiments, the patient receiving the implant has no history of anti-VEGF treatment (anti-VEGF naive, AMD treatment naive).

[0329] In certain embodiments, the systemic plasma concentration of the active agent is less than 1 ng / ml, or less than 0.5 ng / ml, or less than 0.3 ng / ml, or less than 0.1 ng / ml (or below the limit of quantitation). Because systemic concentrations of TKIs are minimized, the risk of drug-drug interactions or systemic toxicity is also minimized. Therefore, in one embodiment, the additional drug(s) taken by the patient do not pose a significant risk. This is particularly useful for elderly patients who frequently suffer from ocular diseases and are additionally taking other medications.

[0330] Once injected, the implants of certain embodiments of the invention (including the hydrogel and drug) biodegrade over time, e.g., within about 9 to 12 months, as disclosed above. do. In certain embodiments, once the hydrogel is completely degraded, undissolved active agent particles may remain localized at the site where the implant was. These undissolved particles can further maintain active agent delivery rates sufficient for therapeutic effect (ie, inhibition of vascular leakage) when the hydrogel is degraded. Figure 15 exemplarily presents the absorption of the hydrogel and axitinib particles remaining where the implant was in one patient up to 11 months after administration. However, in certain embodiments, the entire amount of active agent dissolves before the hydrogel completely degrades.

[0331] In certain embodiments, only mild or moderate adverse events (eg, ocular adverse events) are observed over the treatment period. In certain embodiments, no serious ocular adverse events are observed, and no serious ocular adverse events related to treatment are observed. Tables 23 and 25 show the occurrence of adverse events for subjects in Cohorts 1 and 2, Cohorts 3a and 3b, respectively, in the clinical trials whose results are presented (to the extent available) in Example 6.4.

[0332] In certain embodiments, the invention further provides the method of reducing clinically significant increases in central retinal thickness as measured by optical coherence tomography in patients with elevated central retinal thickness due to ocular disease involving neovascularization; The present invention is directed to a method of maintaining or preventing in nature, the method comprising administering to a patient a sustained release biodegradable intraocular implant containing a suitable active agent. In certain embodiments, the ocular disease involving neovascularization is neovascular age-related macular degeneration. In other embodiments, at least 3 months, at least 4.5 months, at least 6 months after administration to a patient with elevated central retinal thickness due to an ocular disease involving neovascularization (e.g., neovascular age-related macular degeneration). , reduced central region retinal thickness for a period of at least 9 months, at least 11 months, at least 12 months, at least 13 months, or at least 14 months, or longer (e.g., at least 15 months). or essentially maintained or clinically significant increase in central area retinal thickness is prevented. In certain embodiments, the patient's visual acuity (eg, as expressed by BCVA) does not substantially decrease during treatment. In certain other embodiments, the patient's visual acuity (eg, as expressed by BCVA) may even be improved. Accordingly, in certain embodiments, the invention is also directed to a method of improving the visual acuity of a patient with impaired visual acuity (e.g., due to retinal fluid caused by an ocular disease involving neovascularization), the method comprising: It includes administering an implant according to the invention to a patient, for example by intravitreal injection.

[0333] Additional disclosures In addition to the above disclosure, the present invention also discloses the following items and list of items. 1st item list 1. A sustained release biodegradable intraocular implant comprising a hydrogel and about 150 μg to about 1200 μg of a tyrosine kinase inhibitor. 2. The sustained release biodegradable intraocular implant of item 1, wherein the tyrosine kinase inhibitor is axitinib. 3. The sustained release biodegradable intraocular implant of claim 1 or 2, comprising the tyrosine kinase inhibitor in an amount within the range of about 200 μg to about 800 μg. 4. The sustained release biodegradable intraocular implant according to item 1 or 2, comprising the tyrosine kinase inhibitor in an amount within the range of about 160 μg to about 250 μg. 5. The sustained release biodegradable intraocular implant of claim 4, comprising the tyrosine kinase inhibitor in an amount within the range of about 180 μg to about 220 μg. 6. The sustained release biodegradable intraocular implant of item 5, comprising said tyrosine kinase inhibitor in an amount of about 200 μg. 7. The sustained release biodegradable intraocular implant of claim 1 or 2, comprising the tyrosine kinase inhibitor in an amount within the range of about 320 μg to about 500 μg. 8. The sustained release biodegradable intraocular implant of item 7, comprising the tyrosine kinase inhibitor in an amount within the range of about 360 μg to about 440 μg. 9. The sustained release biodegradable intraocular implant of claim 8, comprising said tyrosine kinase inhibitor in an amount of about 400 μg. 10. The sustained release biodegradable intraocular implant of item 1 or 2, comprising the tyrosine kinase inhibitor in an amount within the range of about 480 μg to about 750 μg. 11. The sustained release biodegradable intraocular implant of claim 10, comprising the tyrosine kinase inhibitor in an amount of about 540 μg to about 660 μg. 12. The sustained release biodegradable intraocular implant of item 11, comprising said tyrosine kinase inhibitor in an amount of about 600 μg. 13. The sustained release biodegradable intraocular implant of item 1 or 2, comprising the tyrosine kinase inhibitor in an amount within the range of about 640 μg to about 1000 μg. 14. The sustained release biodegradable intraocular implant of item 13, comprising the tyrosine kinase inhibitor in an amount of about 720 μg to about 880 μg. 15. The sustained release biodegradable intraocular implant of item 14, comprising said tyrosine kinase inhibitor in an amount of about 800 μg. 16. A sustained release biodegradable intraocular implant according to any of the preceding items, wherein said implant is used for administration to the posterior segment of the eye. 17. The sustained release biodegradable intraocular implant of item 16, wherein said administration is in the vitreous humor. 18. A sustained release biodegradable intraocular implant according to any of the preceding items, wherein particles of said tyrosine kinase inhibitor are dispersed within a hydrogel. 19. The sustained release biodegradable intraocular implant of item 18, wherein the particles of the tyrosine kinase inhibitor are micronized particles. 20. A sustained release biodegradable intraocular implant according to any of the preceding items, wherein the implant is dry before administration and becomes hydrated once administered intraocularly. 21. The hydrogel may be one of polyethylene glycol, polyethylene oxide, polypropylene oxide, polyvinyl alcohol, poly(vinylpyrrolidinone), polylactic acid, polylactic-co-glycolic acid, random or block copolymers or combinations or mixtures of any of these. A sustained release biodegradable intraocular implant according to any of the preceding items, comprising a polymer network comprising one or more units or one or more units of polyamino acids, glycosaminoglycans, polysaccharides, or proteins. 22. The sustained release biodegradable intraocular implant of item 21, wherein the hydrogel comprises a polymer network comprising identical or different crosslinked polymer units. 23. The sustained release biodegradable intraocular implant of item 22, wherein said crosslinked polymer units are one or more crosslinked polyethylene glycol units. 24. The sustained release biodegradable intraocular implant according to any of items 21 to 23, wherein the polymer network comprises polyethylene glycol units having an average molecular weight within the range of about 2,000 to about 100,000 Daltons. 25. The sustained release biodegradable intraocular implant of item 24, wherein the polyethylene glycol units have an average molecular weight within the range of about 10,000 to about 60,000 Daltons. 26. The sustained release biodegradable intraocular implant of item 25, wherein the polyethylene glycol units have an average molecular weight within the range of about 20,000 to about 40,000 Daltons. 27. The sustained release biodegradable intraocular implant of item 26, wherein said polyethylene glycol units have an average molecular weight of about 20,000 Daltons. 28. The sustained release biodegradable intraocular implant according to any of items 21 to 27, wherein the polymer network comprises one or more crosslinked multi-arm polymer units. 29. The sustained release biodegradable intraocular implant of item 28, wherein the multi-arm polymer unit comprises one or more 2-10 arm polyethylene glycol units. 30. The sustained release biodegradable intraocular implant of item 29, wherein the multi-arm polymer unit comprises one or more 4-8 arm polyethylene glycol units. 31. The sustained release biodegradable intraocular implant of item 30, wherein said multi-arm polymer unit comprises one or more four-arm polyethylene glycol units. 32. The sustained release biodegradable intraocular implant according to any of items 21 to 31, wherein the polymer network comprises both 4-arm and 8-arm polyethylene glycol units. 33. The sustained release biodegradable device according to any one of items 21 to 32, wherein the polymer network is formed by reacting an electrophilic group-containing multi-arm polymer precursor with a nucleophilic group-containing multi-arm polymer precursor. sexual intraocular implants. 34. The sustained-release biodegradable intraocular implant according to any one of items 21 to 33, wherein the nucleophilic group is an amine group. 35. The sustained release biodegradable intraocular implant according to any one of items 21 to 34, wherein the electrophilic group is an activated ester group. 36. The sustained release biodegradable intraocular implant according to item 35, wherein the electrophilic group is an N-hydroxysuccinimidyl (NHS) group. 37. The sustained release biodegradable intraocular implant according to item 36, wherein the electrophilic group is a succinimidyl azelate (SAZ) group. 38. The sustained release biodegradable intraocular implant according to any of items 32 to 37, wherein the 4-arm polyethylene glycol units are 4a20kPEG units and the 8-arm polyethylene glycol units are 8a20kPEG units. 39. The polymer network is 4a20kPEG-SAZ and 8a20kPEG-NH 2 39. A sustained release biodegradable intraocular implant according to item 38, obtained by reacting in a weight ratio of about 2:1 or less. 40. Any of items 1 to 39, wherein the implant comprises, in a dry state, from about 25% to about 75% by weight of a tyrosine kinase inhibitor and from about 20% to about 60% by weight of polymer units. A sustained release biodegradable intraocular implant as described. 41. The sustained release of item 40, wherein the implant comprises, in a dry state, from about 35% to about 65% by weight of the tyrosine kinase inhibitor and from about 25% to about 50% by weight of polymer units. Biodegradable intraocular implant. 42. The sustained release of item 41, wherein the implant comprises, in a dry state, from about 45% to about 55% by weight tyrosine kinase inhibitor and from about 37% to about 47% by weight polymer units. Biodegradable intraocular implant. 43. A sustained release biodegradable intraocular implant according to any of the preceding items, wherein said implant comprises one or more phosphate, borate, or carbonate(s). 44. The sustained release biodegradable intraocular implant of item 43, wherein the implant comprises phosphate derived from the phosphate buffer used during the preparation of the hydrogel. 45. The sustained release biodegradable eye according to any of the preceding items, wherein the hydrogel comprises, in wet state, from about 3% to about 20% polyethylene glycol (equivalent to polyethylene glycol weight ÷ fluid weight x 100). Internal implant. 46. ​​The sustained release biodegradable intraocular implant of item 45, wherein the hydrogel comprises about 7.5% to about 15% polyethylene glycol (equivalent to weight of polyethylene glycol divided by weight of fluid x 100). 47. A sustained release biodegradable intraocular implant according to any of the preceding items, wherein said implant comprises less than or equal to about 1% water by weight in its dry state. 48. A sustained release biodegradable intraocular implant according to any of the preceding items, wherein said implant has an essentially cylindrical shape or another shape, such as a cruciform shape. 49. A sustained release biodegradable intraocular implant according to any of the preceding items, wherein said implant is in the form of a fiber. 50. A sustained release biodegradable intraocular implant according to any of the preceding items, wherein said implant is administered to the eye by means of a needle. 51. The sustained release biodegradable intraocular implant of item 50, wherein the needle is a 25 gauge or 27 gauge needle. 52. Any of the preceding items, wherein hydration in the eye in vivo or in vitro increases the diameter of said implant, or increases the diameter of said implant and shortens the length of said implant. Sustained-release biodegradable intraocular implant. 53. The sustained release biodegradable intraocular implant of item 52, wherein hydration is measured in vitro after 24 hours in phosphate buffered saline at 37°C and pH 7.2. 54. The sustained release biodegradable intraocular implant of any of items 17-53, wherein the implant biodegrades in the vitreous humor within about 2 to about 15 months after administration. 55. The sustained release biodegradable intraocular implant of item 54, wherein the implant biodegrades in the vitreous humor within about 4 to about 13 months after administration. 56. The sustained release biodegradable intraocular implant of item 55, wherein the implant biodegrades in the vitreous humor within about 9 to about 12 months after administration. 57. The implant, after being administered to the vitreous humor, delivers a therapeutically effective amount of axitinib for at least about 3 months, at least about 6 months, at least about 9 months, at least about 10 months, at least about 57. The sustained release biodegradable intraocular implant of any of items 2-56, which releases over a period of 11 months, at least about 12 months, at least about 13 months, or at least about 14 months. 58. The sustained release biodegradable intraocular implant of item 57, wherein the implant releases a therapeutically effective amount of axitinib over a period of at least about 6 months after being administered to the vitreous humor. 59. The sustained release biodegradable intraocular implant of item 57, wherein the implant releases a therapeutically effective amount of axitinib over a period of at least about 9 months after being administered to the vitreous humor. 60. The sustained release biodegradable intraocular implant of any of items 17-59, wherein axitinib is released from the implant at an average rate of about 0.1 μg / day to about 10 μg / day after administration. 61. The sustained release biodegradable intraocular implant of item 60, wherein axitinib is released from the implant at an average rate of about 0.5 μg / day to about 7 μg / day. 62. The sustained release biodegradable intraocular implant of item 61, wherein axitinib is released from the implant at an average rate of about 1 μg / day to about 5 μg / day. 63. The sustained release biodegradable eye according to any of items 17 to 62, wherein the implant biodegrades in the vitreous humor before complete solubilization of the tyrosine kinase inhibitor particles contained in the implant. Internal implant. 64. The sustained release biodegradable according to any of items 17 to 63, wherein the entire amount of the tyrosine kinase inhibitor contained in the implant is released before the implant completely degrades in the vitreous humor. Intraocular implant. 65. The implant comprises preparing a mixture comprising a hydrogel precursor and a tyrosine kinase inhibitor, filling a tube with the mixture, and gelling the hydrogel within the tube to obtain a hydrogel shaped as a fiber; Sustained-release biodegradable intraocular implant according to any of the preceding items, obtainable by stretching hydrogel fibers. 66. Sustained release biodegradable intraocular implant according to item 65, wherein the fibers are stretched and / or twisted before or after drying. 67. The sustained release biodegradable intraocular implant of item 66, wherein the fibers are longitudinally stretched with a stretch factor of about 1.0 to about 4.5. 68. A sustained release biodegradable intraocular implant comprising 160 μg to about 250 μg, or about 180 μg to about 220 μg, or about 200 μg of axitinib dispersed within a hydrogel, wherein the hydrogel comprises polyethylene glycol units. The sustained-release biodegradable intraocular implant comprises a polymer network comprising: wherein the implant is in a dry state prior to administration. 69. The polymer network consists of 4a20kPEG-SAZ and 8a20kPEG-NH 2 The sustained release biodegradable intraocular implant of item 68, formed by reacting with. 70. The sustained release biodegradable intraocular system of item 69, wherein the hydrogel, when formed and before being dried, comprises 7.5% polyethylene glycol (equivalent to polyethylene glycol weight ÷ fluid weight x 100). implant. 71. The implant according to any of items 68 to 70, wherein the implant comprises from about 45% to about 55% by weight of axitinib and from about 37% to about 47% by weight of polyethylene glycol units. Sustained-release biodegradable intraocular implant. 72. The sustained release biodegradable intraocular implant according to any of items 68 to 71, wherein the implant contains about 1% or less water by weight in a dry state. 73. The polymer network consists of 4a20kPEG-SAZ and 8a20kPEG-NH 2 73. The sustained release biodegradable intraocular implant of any of items 68 to 72, formed by reacting with a weight ratio of about 2:1 or less. 74. The implant according to any of items 68-73, wherein the implant releases about 0.01 μg to about 0.15 μg axitinib per day in vitro for a period of 30 days in phosphate buffered saline at 37°C. Sustained-release biodegradable intraocular implant. 75. The implant is capable of producing about 35% to about 45% of the axitinib in 3 days and about 65% to about 7 days of the axitinib in a 25:75 ethanol / water mixture (v / v) at 37°C. 75. The sustained release biodegradable intraocular implant according to any of items 68 to 74, which releases about 90% to about 100% of the axitinib in vitro in 12 to 13 days. 76. The implant is capable of producing about 25% to about 35% of the axitinib at 2 months and about 47% of the axitinib at 3 months in phosphate buffered saline with an octanol overlayer at 37° C. and pH 7.2. The sustained release agent according to any one of items 68 to 75, which releases about 57% of the axitinib in vitro, about 70% to about 80% of the axitinib in 5 months, and about 90% to 100% of the axitinib in 7 months in vitro. Release biodegradable intraocular implant. 77. Any of items 68 to 76, wherein the implant, in its dried state, takes the form of fibers having an average length of about 15 mm to about 16.5 mm and an average diameter of about 0.20 mm to about 0.30 mm. A sustained release biodegradable intraocular implant as described. 78. Hydration in the eye in vivo or in vitro decreases length and increases diameter, and in vitro hydration is measured after 24 hours in phosphate-buffered saline at 37°C and pH 7.2. 77. The sustained release biodegradable intraocular implant of item 77. 79. The sustained release biodegradable intraocular implant of item 77 or 78, wherein said implant has an average length in its hydrated state of about 6.5 to about 8 mm and an average diameter of about 0.70 to about 0.80 mm. 80. The implant comprises preparing a mixture comprising a hydrogel precursor and axitinib, filling a tube with the mixture, gelling the hydrogel in the tube to obtain a hydrogel shaped as fibers, and forming the hydrogel fibers into a hydrogel. 79. The sustained-release biodegradable intraocular implant according to any of items 68 to 79, which is obtainable by stretching. 81. The sustained release biodegradable intraocular implant of item 80, wherein the fibers are dry stretched by a factor of about 2 to about 5 after drying. 82. The sustained release biodegradable intraocular implant of item 81, wherein the fibers are dry-stretched after drying by a factor of about 3 to about 4.5. 83. Sustained release according to any of items 68 to 82, wherein said implant is loaded in a dry state into a needle, such as a 25 gauge needle or a 27 gauge needle, for injection into the vitreous humor. Biodegradable intraocular implant. 84. A sustained release biodegradable intraocular implant comprising axitinib dispersed within a hydrogel in an amount ranging from about 480 μg to about 750 μg, the sustained release biodegradable intraocular implant comprising a polymer network. Intraocular implant. 85. The sustained release biodegradable intraocular implant of item 84, wherein the polymer network comprises crosslinked polyethylene glycol units. 86. The sustained release biodegradable intraocular implant of item 85, wherein said axitinib is included in an amount within the range of about 540 μg to about 660 μg. 87. The sustained release biodegradable intraocular implant of item 86, wherein said axitinib is included in an amount of about 600 μg. 88. The sustained release product according to any of items 84 to 87, wherein the polyethylene glycol units comprise 4-arm and / or 8-arm polyethylene glycol units having an average molecular weight within the range of about 10,000 Daltons to about 60,000 Daltons. Degradable intraocular implants. 89. The sustained release biodegradable intraocular implant of item 88, wherein said polyethylene glycol units comprise 4a20kPEG units. 90. The polymer network consists of 4a20kPEG-SAZ and 8a20kPEG-NH 2 A sustained release biodegradable intraocular implant according to item 89, formed by reacting with. 91.4a20kPEG-SAZ vs 8a20kPEG-NH 2 91. The sustained release biodegradable intraocular implant of item 90, wherein the weight ratio of is about 2:1 or less. 92. The implant according to any of items 84 to 91, wherein the implant comprises from about 45% to about 55% by weight axitinib and from about 37% to about 47% by weight polyethylene glycol units. Sustained-release biodegradable intraocular implant. 93. The sustained release biodegradable intraocular implant according to any of items 84 to 92, wherein the implant contains less than or equal to about 1% water by weight in its dry state. 94. According to any of items 84 to 93, the implant, in its dry state, takes the form of fibers having an average length of about 7 mm to about 12 mm and an average diameter of about 0.25 mm to about 0.50 mm. sustained release biodegradable intraocular implant. 95. The sustained release product of item 94, wherein said implant, in its dry state, is in the form of fibers having an average length of about 8 mm to about 11 mm and an average diameter of about 0.3 mm to about 0.4 mm. Degradable intraocular implants. 96. The sustained release biodegradable intraocular implant according to any of items 84 to 95, wherein the implant is for administration into the vitreous humor. 97. Diameter increases upon hydration in the eye in vivo or in vitro, with in vitro hydration measured after 24 hours in phosphate buffered saline at 37°C and pH 7.2, Item 94 The sustained release biodegradable intraocular implant described in ~96. 98. The sustained release biodegradable intraocular implant of item 97, wherein said implant has an average length in its hydrated state of about 9 mm to about 12 mm and an average diameter of about 0.5 mm to about 0.8 mm. 99. The implant has an average length in its hydrated state of from about 9.5 mm to about 11.5 mm and an average diameter of from about 0.65 mm to about 0.75 mm, or less than or equal to about 10 mm or less than or equal to about 9 mm in its hydrated state. 99. A sustained release biodegradable intraocular implant according to item 98, having an average length of. 100. Items 84-99, wherein said implant comprises about 600 μg axitinib and releases about 0.3 μg to about 0.5 μg axitinib per day in vitro for a period of 30 days in phosphate buffered saline at 37° C. A sustained release biodegradable intraocular implant according to any one of . 101. The implant is capable of producing about 40% to about 60% of the axitinib in 2 days and about 65% to about 65% of the axitinib in 4 days in a 25:75 ethanol / water mixture (v / v) at 37°C. 101. The sustained release biodegradable intraocular implant of any one of items 84 to 100, which releases about 75% to about 90% of the axitinib in vitro in 6 days. 102. The implant is capable of producing about 45% to about 55% of the axitinib in 2 days and about 70% to about 4 days of the axitinib in a 25:75 ethanol / water mixture (v / v) at 37°C. 102. The sustained release biodegradable intraocular implant of item 101, which releases about 80% to about 90% of said axitinib in vitro in 6 days. 103. The implant comprises preparing a mixture comprising a hydrogel precursor and axitinib, filling a tube with the mixture, gelling the hydrogel in the tube to obtain a hydrogel shaped as fibers, and forming the hydrogel fibers into a hydrogel. The sustained release biodegradable intraocular implant according to any one of items 84 to 102, which is obtainable by stretching. 104. The sustained release biodegradable intraocular implant of item 103, wherein the fibers are wet stretched by a factor of about 0.5 to about 5 before drying. 105. The sustained release biodegradable intraocular implant of item 104, wherein the fibers are wet stretched by a factor of about 1 to about 4 before drying. 106. The sustained release biodegradable intraocular implant of item 105, wherein the fibers are wet stretched by a factor of about 1.5 to about 3.5 before drying. 107. The sustained release biodegradable intraocular implant of item 106, wherein the fibers are wet-stretched by a factor of about 1.7 to about 3 before drying. 108. The sustained release biodegradable intraocular implant according to any of items 84 to 107, wherein the implant is loaded in a dry state into a needle for injection into the vitreous humor. 109. The sustained release biodegradable intraocular implant of item 108, wherein the implant is loaded in a dry state into a 25 gauge or 27 gauge needle. 110. The sustained release biodegradable intraocular implant according to any of items 1 to 109, wherein the hydrogel comprises a polymer network that is semicrystalline in a dry state below room temperature and amorphous in a wet state. . 111. According to any of items 1 to 110, wherein said implant is subjected to wet or dry stretching during manufacture and said implant in stretched form is dimensionally stable when in a dry state at or below room temperature. A sustained release biodegradable intraocular implant as described. 112. A method of treating an ocular disease in a patient in need thereof, comprising administering to said patient a sustained release biodegradable intraocular implant comprising a hydrogel and a tyrosine kinase inhibitor according to any of the preceding items. wherein the dose per eye administered once during a treatment period of at least 3 months is from about 150 μg to about 1200 μg of the tyrosine kinase inhibitor. 113. The method of item 112, wherein the tyrosine kinase inhibitor is axitinib. 114. The method of item 112 or 113, wherein the dose per eye administered once during the treatment period is in the range of about 200 μg to about 800 μg. 115. The method of item 112 or 113, wherein the dose is in the range of about 160 μg to about 250 μg, or about 180 μg to about 220 μg. 116. The method of item 115, wherein said dose is about 200 μg. 117. The method of item 112 or 113, wherein the dose is in the range of about 320 μg to about 500 μg, or about 360 μg to about 440 μg. 118. The method of item 117, wherein said dose is about 400 μg. 119. The method of item 112 or 113, wherein the dose is in the range of about 480 μg to about 750 μg, or about 540 μg to about 660 μg. 120. The method of item 119, wherein said dose is about 600 μg. 121. The method of item 112 or 113, wherein the dose is in the range of about 640 μg to about 1000 μg, or about 720 μg to about 880 μg. 122. The method of item 121, wherein said dose is about 800 μg. 123. The method according to any one of items 112 to 122, wherein the ocular disease is accompanied by angiogenesis. 124. Said ocular disease is mediated by one or more receptor tyrosine kinases (RTKs), in particular VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-α / β, and / or c-Kit. The method described in any of items 112 to 123. 125. The ocular disease is a retinal disease including choroidal neovascularization, diabetic retinopathy, diabetic macular edema, retinal vein occlusion, acute macular neuroretinopathy, central serous chorioretinopathy, and cystoid macular edema. The ocular diseases include acute multifocal patchy pigment epitheliopathy, Behcet's disease, birdshot chorioretinopathy, infectious diseases (syphilis, Lyme disease, tuberculosis, toxoplasmosis), intermediate uveitis (spas plana), inflammation), multifocal choroiditis, multiple effacement white spot syndrome (MEWDS), ocular sarcoidosis, posterior scleritis, tortuous choroiditis, subretinal fibrosis, uveitis syndrome, or Vogt-Koyanagi-Harada syndrome. or the ocular disease is a vascular disease or an exudative disease (Cotes' disease, parafoveal telangiectasia, papillary vasculitis, frosty branch vasculitis, sickle cell retinopathy and other hemoglobinopathies, retinal or the ocular disease is due to trauma or surgery (sympathetic ophthalmia, uveitis retinal disease, retinal detachment, trauma, 125. The method according to any one of items 112 to 124, wherein the ocular disease is the ocular disease (including photodynamic laser therapy, photocoagulation, intraoperative hypoperfusion, radiation retinopathy, or bone marrow transplant retinopathy). 126. The method according to any one of items 112 to 124, wherein the ocular disease is neovascular age-related macular degeneration, diabetic macular edema, or retinal vein occlusion. 127. The method according to item 126, wherein the disease is neovascular age-related macular degeneration. 128. The treatment is effective in reducing, essentially maintaining, or preventing a clinically significant increase in central retinal thickness as measured by optical coherence tomography in a patient with elevated central retinal thickness; The method described in any of items 112 to 127. 129.Item 112, wherein said dose per eye administered once during said treatment period is included in one implant, or in two, three or more implants administered simultaneously. The method described in any of ~128. 130. The method of any of items 112-129, wherein the implant is administered by injection into the vitreous humor. 131. The treatment period is at least about 3 months, at least about 4.5 months, at least about 6 months, at least about 9 months, at least about 11 months, at least about 12 months, at least about 13 months, or The method of any of items 112-130, wherein the period is at least about 14 months. 132. The method of item 131, wherein the treatment period is at least 6 months, at least about 9 months, or at least about 12 months. 133. An anti-VEGF agent is administered to the patient concurrently with said treatment with said sustained release intraocular implant, or an anti-VEGF agent is administered within about 1, about 2, or about 3 minutes from said administration of said implant. The method according to any of items 112 to 132, which is administered within a month. 134. The method of item 133, wherein the anti-VEGF agent is selected from the group consisting of aflibercept, bevacizumab, pegaptanib, ranibizumab, and brolucizumab. 135. The method of item 134, wherein the anti-VEGF agent is bevacizumab. 136. The method according to any one of items 133 to 135, wherein the anti-VEGF agent is administered by intravitreal injection. 137. The method of any of items 112-136, wherein the patient receiving the implant has a history of anti-VEGF treatment. 138. The method according to any of items 112 to 136, wherein the patient receiving the implant has no history of anti-VEGF treatment (is anti-VEGF naive). 139. A method of treating neovascular age-related macular degeneration in a patient in need thereof, comprising administering to the patient a sustained release product comprising a hydrogel comprising a polymer network and about 200 μg of a tyrosine kinase inhibitor. said method comprising administering a degradable intraocular implant, one implant per eye being administered once during a treatment period of at least 9 months, said patient having a history of anti-VEGF treatment. 140. A method of treating neovascular age-related macular degeneration in a patient in need thereof, comprising administering to the patient a sustained release product comprising a hydrogel comprising a polymer network and about 200 μg of a tyrosine kinase inhibitor. 2 implants per eye forming a total dose of approximately 400 μg are administered once during a treatment period of at least 3 months, said patient receiving anti-VEGF therapy. Said method, with or without history. 141. The method of item 139 or 140, wherein the treatment results in a reduction in central zone retinal thickness (CSFT) as measured by optical coherence tomography during the treatment period. 142. The tyrosine kinase inhibitor is axitinib, and the tyrosine kinase inhibitor is 4a20kPEG-SAZ or 8a20kPEG-NH 2 142. The method of any one of items 139-141, wherein the implant is in a dry state prior to administration. 143. The method of item 142, wherein the hydrogel comprises about 7.5% polyethylene glycol (equivalent to weight of polyethylene glycol divided by weight of fluid x 100) when formed and before being dried. 144. The method according to any of items 140 to 143, wherein the treatment period is at least 9 months. 145. A method of treating neovascular age-related macular degeneration in a patient in need thereof, the patient receiving in the range of about 480 μg to about 750 μg of axitinib dispersed within a hydrogel comprising a polymer network. said method comprising administering a sustained release biodegradable intraocular implant comprising an amount of 0.05 to 0.05, wherein said implant is administered once during a treatment period of at least 3 months. 146. The method of item 145, wherein said axitinib is included in said implant in an amount of about 560 μg to about 660 μg. 147. The method of item 146, wherein said axitinib is included in said implant in an amount of about 600 μg. 148. The method according to any of items 145-147, wherein the implant is as defined in items 84-111. 149. The method of any of items 145-148, wherein the implant is administered into the vitreous humor. 150. The treatment period is at least about 3 months, at least about 6 months, at least about 9 months, at least about 11 months, at least about 12 months, at least about 13 months, or at least about 14 months. The method described in any of items 145 to 149. 151. The method of any of items 145-150, wherein the implant is administered by injection into the vitreous humor with a 25 gauge or 27 gauge needle. 152. The method according to any of items 145 to 151, wherein the patient receiving the implant has a history of anti-VEGF treatment or has no history of anti-VEGF treatment (is anti-VEGF naive). 153. The method according to any one of items 145 to 152, wherein the anti-VEGF agent is administered to the patient simultaneously with the implant. 154. The method of item 153, wherein the anti-VEGF agent is selected from the group consisting of aflibercept, bevacizumab, pegaptanib, ranibizumab, and brolucizumab. 155. The method of item 154, wherein the anti-VEGF agent is bevacizumab. 156. The method according to any one of items 153 to 155, wherein the anti-VEGF agent is administered by intravitreal injection. 157. The method according to any one of items 112 to 156, wherein the number of adverse events is low during administration of the sustained release biodegradable intraocular implant. 158. The method of item 157, wherein the number of treatment-related ocular adverse events is low during administration of the sustained release biodegradable intraocular implant. 159. A method of producing a sustained release biodegradable intraocular implant comprising a hydrogel according to any of items 1 to 111 and from about 150 μg to about 1200 μg of a tyrosine kinase inhibitor, the hydrogel comprising a polymer network. and tyrosine kinase inhibitor particles dispersed within the hydrogel, forming the hydrogel, and drying the hydrogel. 160. The method of item 159, wherein the tyrosine kinase inhibitor is axitinib. 161. The method of item 159 or 160, wherein said tyrosine kinase inhibitor particles are micronized and / or homogeneously dispersed within said hydrogel. 162. The method according to any of items 159 to 161, wherein the polymer network is formed by crosslinking multi-arm polyethylene glycol units in a buffer solution. 163. The hydrogel is mixed and reacted with an electrophilic group-containing multi-arm polyethylene glycol and a nucleophilic group-containing multi-arm polyethylene glycol in a buffer solution in the presence of the tyrosine kinase inhibitor, and the mixture is gelled. 163. The method according to any one of items 159 to 162, comprising a polymer network formed by. 164.4a20kPEG-SAZ to 8a20kPEG-NH 2 The method of item 163, comprising reacting with the compound in a weight ratio of about 2:1. 165. The method includes filling a mold or tube with the mixture prior to complete gelling, allowing the mixture to gel, and forming the hydrogel in order to provide the desired final shape of the hydrogel. and drying. The method of item 163 or 164. 166. The method of item 165, wherein the mixture is filled into fine diameter tubes to prepare hydrogel fibers. 167. The method of item 166, wherein the interior of the tube has a circular geometry. 168. The method of item 166, wherein the interior of the tube has a geometric shape other than circular. 169. The method of item 168, wherein the interior of the tube has a cruciform geometry. 170. The method according to any one of items 166 to 169, further comprising drawing the fibers and / or twisting the fibers. 171. The method of item 170, wherein said stretching is performed before or after drying said hydrogel. 172. The method of item 171, wherein the fiber is drawn with a draw factor of about 1 to about 4.5. 173. The implant comprises axitinib in an amount of about 200 μg, and the stretching is performed after drying the hydrogel at a stretch factor of about 2 to about 5 or a stretch factor of about 3 to about 4.5. the method of. 174. The implant comprises axitinib in an amount of about 600 μg, and the stretching comprises a stretch factor of about 0.5 to about 5, or a stretch factor of about 1 to about 4, or about 172. The method of item 171, carried out with a stretch factor of 1.3 to about 3.5, or a stretch factor of about 1.7 to about 3. 175. The method according to any of items 159-174, wherein the method further comprises loading the implant in a dry state into a needle. 176. The method of item 175, wherein the needle is a 25 gauge or 27 gauge needle. 177. A method of imparting shape memory to hydrogel fibers, the hydrogel fibers comprising an active agent dispersed within the hydrogel, and imparting shape memory by longitudinally stretching the hydrogel fibers. Method. 178. A method of manufacturing an intraocular implant comprising a hydrogel having an active agent dispersed therein that changes size upon administration to the eye, comprising preparing fibers of the hydrogel and longitudinally extending the fibers. and stretching. 179. The method of item 177 or 178, wherein the method comprises drying the hydrogel, and the fibers are longitudinally stretched (wet or dry stretching) before or after the drying. 180. The fibers of items 177-179, wherein the fibers are drawn by a factor of about 0.5 to about 5, or about 1 to about 4.5, or about 3 to about 4.5, or about 1 to about 2. Any method described. 181. The method of any of items 177-180, wherein the active agent is a tyrosine kinase inhibitor (eg, axitinib). 182. The method according to any of items 177-181, wherein the hydrogel comprises a polymer network comprising crosslinked polyethylene glycol units. 183. The method according to any of items 177-182, wherein the fiber, upon hydration, fully or partially returns to its approximate original length and / or original diameter that it had before said drawing. 184. The method according to any one of items 177 to 183, wherein the dimensional change is an increase in diameter or an increase in diameter accompanied by a decrease in length. 185. A kit comprising one or more sustained release biodegradable intraocular implant(s) manufactured according to any of items 1-111 or according to the method described in any of items 159-176. one or more needle(s), each of said one or more needle(s) being dry preloaded with one sustained release biodegradable intraocular implant; The said kit. 186. The kit of item 185, wherein the needle(s) are 25 gauge or 27 gauge needle(s). 187. The kit includes one or more 25 gauge or 27 gauge needle(s), each of the needles being loaded with an implant comprising axitinib in an amount in the range of about 180 μg to about 220 μg. , the kit described in item 185 or 186. 188. The kit of item 187, wherein the implant comprises axitinib in an amount of about 200 μg. 189. The kit of item 185 or 186, wherein the kit comprises one 25 gauge or 27 gauge needle loaded with an implant comprising axitinib in an amount in the range of about 540 μg to about 660 μg. 190. The kit of item 189, wherein said implant comprises axitinib in an amount of about 600 μg. 191. The kit according to any of items 185 to 190, further comprising an injection device for injecting the implant into the patient's eye. 192. The kit of item 191, wherein said injection device is provided in a kit separately from said one or more needle(s) loaded with an implant. 193. The kit of item 191, wherein the injection device is pre-connected to a needle loaded with an implant. 194. The kit of item 191 or 192, wherein the injection device includes a push wire for placing the implant into the eye from an injection needle. 195. The kit of any of items 185-194, further comprising a single dose of a ready-to-inject anti-VEGF agent. 196. An injection device suitable for intraocularly injecting a sustained release biodegradable intraocular implant according to any of items 1 to 111. 197. The injection device of item 196, comprising means for connecting said injection device to a needle. 198. The injection device of item 196 or 197, wherein the needle is preloaded with the implant. 199. The injection device of any of items 196-198, including a push wire for positioning the implant from the needle into the eye when the injection device is connected to the needle. 200. The injection device according to item 199, wherein said push wire is made of Nitinol or stainless steel / Teflon. 201. Injection device according to item 199 or 200, obtainable by affixing said wire to a plunger, placing it between two snap-fit ​​syringe body parts and securing said plunger with a clip. 202. A pharmaceutical product comprising a sustained release biodegradable intraocular implant according to any of items 1 to 111 loaded in a needle and an injection device according to any of items 196 to 201, Said medicament, wherein a needle is pre-connected to said injection device. 203. Treatment of the ocular disease described in any of Items 112 to 138 in a patient in need of treatment, or neovascular age-related macular according to any of Items 139 to 158, 210, or 211. A sustained release biodegradable intraocular implant comprising a tyrosine kinase inhibitor according to any of items 1 to 111 for use in the treatment of said neovascular age-related macular degeneration in a patient in need of treatment for degeneration. . 204. For the treatment of an ocular disease according to any of items 112 to 138 in a patient in need thereof, or to the angiogenic aging according to any of items 139 to 158, 210, or 211. Use of a sustained release biodegradable intraocular implant comprising a tyrosine kinase inhibitor according to any of items 1 to 111 in the preparation of a medicament for the treatment of macular degeneration in a patient in need thereof. 205. Reduce, essentially maintain, or prevent a clinically significant increase in central retinal thickness as measured by optical coherence tomography in patients with increased central retinal thickness due to ocular disease with neovascularization. 112. The method, the method comprising administering to the patient a sustained release biodegradable intraocular implant comprising a tyrosine kinase inhibitor according to any of items 1-111. 206. The method according to item 205, wherein the ocular disease is neovascular age-related macular degeneration. 207. The central region retinal thickness of the patient is at least about 3 months, at least about 6 months after administration of the implant, relative to the patient's baseline central region retinal thickness measured before administration of the implant; reduced, essentially maintained, or said central region retinal thickness for at least about 9 months, at least about 11 months, at least about 12 months, at least about 13 months, or at least about 14 months. The method of item 205 or 206, wherein a clinically significant increase in is prevented. 208. In patients with increased central retinal thickness due to an ocular disease associated with angiogenesis described in any of items 205 to 207, 210, or 211, clinical central retinal thickness as measured by optical coherence tomography. A sustained release biodegradable intraocular implant comprising a tyrosine kinase inhibitor according to any of items 1 to 111 for use in reducing, essentially maintaining, or preventing a significant increase in. 209. In patients with increased central retinal thickness due to ocular disease associated with angiogenesis described in any of items 205 to 207, 210, or 211, the clinical central retinal thickness as measured by optical coherence tomography Use of a sustained release biodegradable intraocular implant comprising a tyrosine kinase inhibitor according to any of items 1 to 111 in the preparation of a medicament for reducing, essentially maintaining, or preventing a significant increase in 210. The method of any of items 128-158 or any of items 205-207, wherein the patient's visual acuity, as expressed by best-corrected visual acuity, is not decreased or is improved. 211. No rescue drug needs to be administered during the treatment period, or the rescue drug needs to be administered only infrequently (e.g., 1, 2, or 3 times) during the treatment period, item 128~ 158, any of items 205 to 207, or the method described in item 210. 212. The method of item 211, wherein the duration of the treatment period is about 6 months to about 9 months after administration of the sustained release biodegradable intraocular implant. 213. A method for improving the visual acuity of a patient whose visual acuity has decreased due to an ocular disease associated with angiogenesis, the method comprising: administering to said patient a sustained release drug comprising a tyrosine kinase inhibitor according to any one of items 1 to 111; The method comprising administering a degradable intraocular implant. 214. The method according to item 213, wherein the ocular disease is neovascular age-related macular degeneration, diabetic macular edema, or retinal vein occlusion. 215. The method of item 213 or item 214, wherein the patient's visual acuity is reduced by the presence of retinal fluid. 216. The method according to any of items 213-215, wherein said improvement in visual acuity is manifested by an increase in best-corrected visual acuity. 217. The method of item 216, wherein the best-corrected visual acuity is increased by at least 10 characters, at least 15 characters, or at least 20 ETDRS characters. 218. The method according to any of items 1 to 111 for use in improving the visual acuity of a patient whose vision is impaired by an ocular disease involving neovascularization by the method described in any of items 213 to 217. Extended release biodegradable intraocular implant containing a tyrosine kinase inhibitor. 219. Tyrosine according to any of items 1 to 111 in the preparation of a medicament for improving the visual acuity of a patient whose vision has decreased due to an ocular disease accompanied by angiogenesis, by the method according to any of items 213 to 217. Use of sustained-release biodegradable intraocular implants containing kinase inhibitors. 220. Any of the above, wherein said TKI or axitinib is replaced with a different active agent. second item list 1. A sustained release biodegradable intraocular hydrogel implant comprising a tyrosine kinase inhibitor, a polymer network, and a clearance zone, wherein the clearance zone is free of the TKI prior to release of the TKI. Degradable intraocular hydrogel implant. 2. The intraocular hydrogel of item 1, wherein the TKI does not contact retinal cells when included within the hydrogel implant. 3. The intraocular hydrogel of item 1 or 2, wherein said TKI is present within the hydrogel implant at or near its saturation level. 4. The intraocular hydrogel implant according to any one of items 1 to 3, wherein the size of the clearance zone increases as a function of the amount of TKI released. 5. The intraocular hydrogel implant according to any one of items 1 to 4, wherein the intraocular hydrogel implant is completely degraded after the TKI is released, or after at least 90% of the TKI is released. . 6. The intraocular hydrogel implant according to any one of items 1 to 5, wherein the intraocular hydrogel implant is completely degraded about 30 days or about 3 months after the TKI is completely released. 7. The intraocular hydrogel implant according to any one of items 1 to 4, wherein degradation of the intraocular hydrogel occurs before release of the TKI. 8. The intraocular hydrogel implant according to any one of items 1 to 7, wherein the polymer network comprises a plurality of polyethylene glycol (PEG) units. 9. The intraocular hydrogel implant according to any one of items 1 to 8, wherein the polymer network comprises a plurality of multi-arm PEG units. 10. The intraocular hydrogel implant according to any one of items 1 to 9, wherein the polymer network comprises a plurality of 4-arm or 8-arm PEG units. 11. The polymer network has the following formula: [ka] Intraocular hydrogel implant according to any one of items 1 to 9, comprising a plurality of PEG units having the formula: (wherein n represents a repeating unit of ethylene oxide and the wavy line represents a point of a repeating unit of the polymer network) . 12. The polymer network is 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. 4a20k PEG-NH 2 ,8a20k PEG-NH 2 , and one or more PEG- or lysine-based amine-bearing groups selected from , and trilysine, or a salt thereof. 13. The polymer network consists of 4a20k PEG-SAZ to 8a20k PEG-NH 2 The intraocular hydrogel implant according to any one of items 1 to 12, formed by reacting with. 14. The intraocular hydrogel implant according to any one of items 1 to 13, wherein the polymer network is amorphous (under aqueous conditions). 15. The intraocular hydrogel implant according to any one of items 1 to 14, wherein the polymer network is semi-crystalline in the absence of water. 16. The intraocular hydrogel implant according to any one of items 1 to 15, wherein said tyrosine kinase inhibitor is homogeneously distributed within said polymer network. 17. The intraocular hydrogel implant according to any one of items 1 to 16, wherein said tyrosine kinase inhibitor is released over a period of at least 15 days. 18. The intraocular hydrogel implant according to any one of items 1 to 17, wherein said tyrosine kinase inhibitor is released over a period of at least 30 days. 19. The intraocular hydrogel implant according to any one of items 1 to 18, wherein said tyrosine kinase inhibitor is released over a period of at least 60 days. 20. The intraocular hydrogel implant according to any one of items 1 to 19, wherein said tyrosine kinase inhibitor is released over a period of at least 90 days. 21. The intraocular hydrogel implant according to any one of items 1 to 20, wherein said tyrosine kinase inhibitor is released over a period of at least 180 days. 22. The intraocular hydrogel implant according to any one of items 1 to 21, wherein said tyrosine kinase inhibitor is released over a period of at least 365 days. 23. The intraocular hydrogel implant according to any one of items 1 to 22, wherein said tyrosine kinase inhibitor is in the form of encapsulated microparticles. 24. The intraocular hydrogel implant according to any one of items 1 to 23, wherein the tyrosine kinase inhibitor is in the form of encapsulated microparticles comprising poly(lactic-co-glycolic acid). 25. The tyrosine kinase inhibitor is abemaciclib, acalabrutinib, afatinib, alectinib, axitinib, balictinib, binimetinib, brigatinib, cabozantinib, ceritinib, cobrumetinib, crizotinib, dabrafenib, dacomitinib, dasatinib, encalafenib, erlotinib, verolimus, fostamatinib, gefitinib , gilteritinib, gilteritinib, ibrutinib, imatinib, larotrectinib, lenvatinib, lorlatinib, axitinib, idelalisib, lenvatinib, midostaurin, neratinib, netarsudil, nilotinib, nintedanib, osimertinib, palbociclib, pazopanib, ponatinib, regorafenib ribociclib, luxolitinib, sirolimus, sorafenib, sunitinib , temsirolimus, tofacitinib, trametinib, vandetanib, and vemurafenib. 26. The intraocular hydrogel implant according to item 1 or 25, wherein the tyrosine kinase inhibitor is axitinib. 27. Any one of items 1 to 26, wherein the intraocular hydrogel implant is injected into the vitreous humor, injected into the anterior chamber of the eye, or applied to the upper or lower punctum of the eye. Intraocular hydrogel implants as described in. 28. A method for treating an ocular condition in a subject in need thereof, the method comprising injecting or applying an intraocular hydrogel implant according to any one of items 1 to 27 to the subject. , said method. 29. The eye condition is maculopathy, retinal degeneration, uveitis, retinitis, choroiditis, vascular disease, exudative disease, trauma, proliferative disease, infectious disease, genetic disorder, retinal tear, retinal hole, and a tumor. 30.The eye condition is age-related macular degeneration, choroidal neovascularization, diabetic retinopathy, acute macular neuroretinopathy, central serous chorioretinopathy, cystoid macular edema, diabetic macular edema, acute multifocal macular pigmentation. Epitheliopathy, Behcet's disease, Birdshot chorioretinopathy, intermediate uveitis, multifocal choroiditis, multiple effacement white dot syndrome (MEWDS), ocular sarcoidosis, posterior meningitis, tortuous choroiditis, subretinal fibers and uveitis syndrome, Vogt-Koyanagi-Harada syndrome, Coats disease, parafoveal telangiectasia, papillary vasculitis, frosty branch vasculitis, sickle cell retinopathy, retinitis pigmentosa, familial Exudative vitreoretinopathy, sympathetic ophthalmitis, uveitis retinal disease, retinal detachment, proliferative diabetic retinopathy, ocular histoplasmosis, ocular toxoplasmosis, viral retinitis, acute retinal necrosis, ocular syphilis, ocular tuberculosis , congenital non-progressive night blindness, cone dystrophy, retinal detachment, macular hole, giant retinal tear, solid tumor, posterior uveal melanoma, choroidal hemangioma, choroidal osteoma, choroidal metastasis, retinoblastoma, blood vessels of the fundus. The method according to item 28 or 29, selected from proliferative tumors, retinal astrocytomas, and intraocular lymphoid tumors. 31. The method according to item 29 or 30, wherein the condition is age-related macular degeneration. 32. The method according to any one of items 29 to 31, wherein the subject has been treated with anti-VEGF therapy in the past. 33. Any of the above, wherein said TKI or axitinib is replaced with a different active agent.

Example

[0334] The following examples are included to demonstrate certain aspects and embodiments of the claimed invention. However, those skilled in the art will appreciate that the following description is illustrative only and should not be construed as limiting the invention in any way.

[0335] Example 1: Preparation of axitinib implant The axitinib implant of the present application is (essentially) cylindrical (also referred to herein as a "fiber"), and the axitinib is uniformly dispersed and encapsulated within a PEG-based hydrogel matrix to provides sustained release of axitinib based on its low aqueous solubility in the vitreous humor.

[0336] Two parts of 4a20K PEG-SAZ (4-armed 20kDa PEG with N-hydroxysuccinimidyl reactive end groups; sometimes referred to as "NHS" end groups) were replaced by two parts of 8a20K PEG NH2 (with amine end groups). The polymer network of the implant was formed by reacting with 1 part of 8-armed 20 kDa PEG). Therefore, the polyurethane tube was cut into pieces of appropriate length. A 8a20K PEG NH2 dibasic sodium phosphate solution was then prepared and sterile filtered to remove endotoxin and particles larger than 0.2 μm (filter pore size). The desired volume of PEG amine solution was then weighed into the syringe. A corresponding amount of solid axitinib depending on the desired final axitinib dose in the implant was then weighed into a separate syringe. The powdered axitinib syringe and the PEG amine syringe were carefully mixed to suspend and disperse the particles. The syringe containing the suspension was then sonicated to break up any powder agglomerates. A 4a20K PEG SAZ monobasic sodium phosphate solution was then prepared and sterile filtered as described for PEG amine solutions. The desired amount of PEG SAZ solution was then weighed into a separate syringe. In the next step, the components of both syringes (4a20K PEG SAZ monobasic sodium phosphate solution and axitinib-8a20K PEG NH2 mixture) were mixed to initiate the reaction leading to gelation. This liquid suspension was cast into a prepared polyurethane tube before the material crosslinked and solidified. Gel time was confirmed by performing a gel tap test. The tube containing the gel was then placed in a high humidity curing chamber for 2 hours to prevent premature drying of the hydrogel before gelation. In the chamber, the hydrogel axitinib suspension in the tube was crosslinked to complete the creation of a highly reactive homogeneous gel to form hydrogel strands.

[0337] After curing, various implant stretching methods were performed as disclosed herein. Implants were either dry-stretched or wet-stretched as outlined below. For dry stretching, the strands were cut into short segments after curing, and the strands were dried for 48-96 hours. After drying, the dried strand segments were removed from the tube and placed in the clamps of a custom stretcher. The strands were then slowly dry drawn at a controlled rate to achieve the desired diameter to fit small gauge needles (stretch factor from about 2 to about 5, or from about 3 to about 4.5). The stretching step was performed in an oxygen and moisture free environment to protect the product. For wet stretching, the strands were placed in the clamps of a custom stretcher. The strands were then slowly wet drawn at a controlled rate to achieve the desired diameter to fit small gauge needles (stretch factor from about 1 to about 3, or from about 1.3 to about 2.6). After drawing, the strands were dried under tension under conditions as described for the dry drawing process.

[0338] This stretching causes shape memory. This means that upon hydration, when the implant is administered into the vitreous cavity of the eye, it rapidly shrinks in length and expands in diameter until it approaches its original wet cast dimensions. A narrower dry dimension makes it easier to administer the product with a smaller gauge needle and increases the diameter and shortens the length after administration, allowing the implant to remain relative to the diameter of the eye in the posterior chamber of the eye. It is short (in certain embodiments, not much more than about 10 mm in length) to minimize the potential for contact with surrounding ocular tissue. Generally, the degree of shrinkage upon hydration depends, among other things, on the stretch factor. For example, stretching with a stretching factor of about 1.3 (wet stretching) will result in no significant effect or significant change in length during hydration. In contrast, for example, stretching with a stretch factor of about 1.8 (wet stretching) can result in a significant shortening in length during hydration. For example, stretching (dry stretching) with a stretch factor of about 4 can result in much shorter lengths upon hydration (eg, length reduction from about 15 mm to about 8 mm).

[0339] The stretched hydrogel strands were removed from the stretcher and cut to the desired final length. The implant fibers were then placed in the testing station. If the implant passes quality control, use a customized vacuum device to insert a 25-gauge or 27-gauge needle (e.g., FDA-approved 25G UTW 1 / 2 inch, or 25G UTW 1 inch, or 27G TW with approximately 0.4 mm inner diameter). A 1.25 inch needle) was loaded and capped securely to avoid any needle tip damage.

[0340] The loaded needles were placed in a glove box for 6 to 9 days to remove moisture (it is intended that the residual moisture content within the implant does not exceed 1%). All subsequent steps were performed in a glovebox. The tip of the loaded needle was treated by immersing it in molten low molecular weight 1kPEG. Upon cooling, the hardened PEG droplet (which provides lubrication) stays in place, holding the implant in place within the needle, allowing for successful placement, and allowing for early rehydration of the implant within the needle during administration. prevent Additionally, PEG tipping minimizes tissue damage, ie, tissue coring, a process in which tissue fragments are removed by the needle as it passes through the tissue. The PEG-tipped needles were then inspected again and those that did not meet quality requirements were discarded. Passing needles were re-capped to ensure that the needles did not sustain any additional damage. The needles were then individually sealed in pouches to protect them from moisture and maintain sterility. The injection device, eg, a modified Hamilton glass syringe, had a push wire (eg, a nitinol push wire) to make implant placement from the needle easier. The needle can include a stop feature to control the depth of injection. The injection device can be individually packaged and sealed under nitrogen in a foil pouch, as described for the needle (Figure 1), or it can be pre-assembled with an implant-loaded needle or can be pre-loaded. It is conceivable that it may be assembled in a syringe. The packaged needles and injection devices were removed from the glove box and stored refrigerated (2-8 °C) before sterilization using gamma irradiation. After sterilization, the packages were stored refrigerated (2–8 °C) or frozen, protected from light, before use and equilibrated to room temperature for 30 min before injection.

[0341] Administration of the implant is performed by intravitreal injection, where the implant is localized in the posterior segment of the eye (Figure 2). After injection, the implant is hydrated in situ. When hydrated upon contact with the vitreous, the implant softens, increases in diameter, and may also shorten in length. Entrapping axitinib within a hydrogel may result in defined and limited localization of axitinib within the eye. The hydrogel matrix of the implant is formulated to biodegrade by ester hydrolysis in the aqueous environment of the vitreous. Based on its low solubility under physiological conditions, axitinib is released over a sustained period of time by diffusion from the hydrogel into the vitreous and then into the surrounding ocular tissues (Figure 3). Diffusion, drug clearance, vitreous viscosity, concentration gradients within and near the implant, implant dose, implant surface area and geometry, and the number and number of implants influence the rate of drug release from the implant, among others. It is located within the vitreous body.

[0342] Example 2: Axitinib release in vitro In the next step, the release rate of axitinib from implants of different formulations was quantified by in vitro studies. In vitro assays can further be used for implant quality control.

[0343] In vitro axitinib release under non-sink simulated physiological conditions In one set of in vitro assays, axitinib release was evaluated under non-sink simulated physiological conditions in a daily exchange volume comparable to the vitreous volume of the human eye.

[0344] Three exemplary implant formulations were tested (Table 1). Implant variants #1 and 2 were tested using one implant, and implant variant #3 was tested using one and two implants (4 conditions in total). All conditions were performed in duplicate. [Table 3]

[0345] Before performing in vitro release assays, the starting drug content of the implants was determined by liquid chromatography coupled to fragmentation-based mass spectrometry (LC-MS / MS) using ethanol as the extraction solvent (Table 2; Implant Dissolution and details regarding LC-MS / MS are mentioned in Example 3.5). The quantified axitinib amount was in good agreement with the formulated amount. [Table 4]

[0346] In vitro released and unreleased axitinib was quantified for each group without (control) and with daily release medium sampling.

[0347] Samples were placed in tubes for the control implant release group. On day 0, 5 mL of PBS (pH 7.2) was added to each tube and the tubes were covered with lids. The samples were then placed in a 37° C. incubator with gentle rocking for 20 days (1× implant #3) or 30 days (implants #1 and #2, 2× implant #3). At the end of the test period, the PBS was removed (1 mL of PBS remained for testing). 1 mL of ethanol was added to the remaining sample. Both PBS and residual samples were tested for the amount of axitinib released.

[0348] Samples were placed in tubes for the daily implant release group. On day 0, 5 mL of PBS was added to each tube and the tubes were covered with lids. The samples were then placed in a 37°C incubator and gently rocked. After 24 hours, 4 mL of PBS was removed from each sample, of which 1 mL was used for testing and the remaining 3 mL was discarded. 4 mL of fresh PBS was added to each tube. This process was repeated for 20 days (1x implant #3) or 30 days (implants #1 and #2, 2x implant #3). On the last day of testing, 1 mL of PBS was used to test each sample and the remaining 4 mL was discarded. 1 mL of ethanol was added to the remaining residual implant and tested for total residual axitinib.

[0349] The axitinib concentration in PBS from each control implant release measurement after 20 or 30 days provides a quantification of the maximum solubility of axitinib after prolonged incubation in the release medium (Table 3). Higher dose intensities resulted in higher axitinib concentrations in the release medium. The apparent maximum axitinib solubility ranged from 0.24 to 0.40 μg / mL, which was consistent with the results reported in the INLYTA® [NDA202324] literature. [Table 5]

[0350] The study results demonstrated that the two high dose samples (implants #1 and 2) released more axitinib per day than the low dose group (Table 4). Axitinib release per day over the duration of the study is shown in Figure 4A. Total axitinib release was higher in the group in which PBS was removed and replaced daily than in the group without PBS replacement (control). Implants #1 and #2 released more axitinib per day than the two implants #3. Although the mean total amount of axitinib released was slightly different in both high-dose groups, the median amount released per day was similar, indicating that there were no obvious differences between both high-dose groups. Shown. [Table 6]

[0351] The results of this study showed that a single dose of an implant containing approximately 0.6-0.7 mg of axitinib delivered more axitinib per day than the combined strength of one or two lower doses to represent the vitreous volume of the eye. This is to demonstrate that the volume is released into solution under simulated physiological conditions. The two implants (each containing approximately 0.2 mg) did not release as much axitinib under these conditions as the higher dose single implant. These in vitro results demonstrate that a single implant with a higher dose may release more axitinib into the eye per day under nonsink conditions than two implants with a lower total dose. .

[0352] Real-time sink in vitro axitinib release under simulated physiological conditions In another in vitro setting, we evaluated axitinib release under real-time sink-simulating physiological conditions.

[0353] Therefore, the implants were placed in 5 mL of a physiologically relevant medium, i.e., PBS containing 0.01% NaF, pH 7.2, with a layer of 1-octanol on top of the solution to allow the transfer of axitinib to the octanol layer. Provided a sink phase that allows. Implants were incubated in an air chamber at 37°C with gentle agitation. Axitinib was measured at predetermined sampling points in the octanol layer by using UV absorbance at 333 nm. The amount of axitinib released at each time point is quantified by comparison to a standard curve prepared from an axitinib reference material. Accelerated in vitro release profiles are quantified as a percentage of cumulative release of axitinib. The duration of complete drug release was several months.

[0354] An exemplary release profile under real-time sink conditions is shown in Figure 14A.

[0355] In vitro axitinib release under accelerated conditions In a further in vitro setting, axitinib release was evaluated under accelerated conditions.

[0356] Therefore, the implants were placed in a mixture of ethanol and water (25:75 ratio, v / v) at 37°C in an air chamber with gentle stirring to increase the solubility of axitinib. The solubility of axitinib in pure ethanol is 1.4 mg / mL, and the solubility in a 25% ethanol / 75% water mixture (v / v; a non-physiologically relevant medium) is approximately 19 μg / mL. Aliquots are removed at predetermined sampling points and analyzed for axitinib using UV at 332 nm. The amount of axitinib released at each time point is quantified by comparison to a standard curve prepared from an axitinib reference material. Accelerated in vitro release profiles are quantified as a percentage of cumulative release of axitinib. The duration of release under accelerated conditions is approximately 2 weeks.

[0357] See FIG. 14B (200 μg implant) and FIG. 4B (556 μg implant) for exemplary release profiles under accelerated conditions.

[0358] Example 3: Evaluation of axitinib implant in rabbits Several preclinical studies were conducted in Dutch Belted rabbits to evaluate the safety, tolerability, drug release, and efficacy of axitinib implantation. A wide range of doses delivered by either single or multiple implants was tested. A summary of the various rabbit studies performed is presented in Table 5. Further studies were also conducted in beagles and African green monkeys. [Table 7]

[0359] Table 6 provides an exemplary summary of the formulation, composition, and dimensions of the implants used in the animal studies (see Examples 3.2-6). The dimensions of the hydrated implants were examined after 24 hours in biorelevant medium (PBS, 37°C, pH 7.2). Although implant #5 showed a slight increase in length, the length after hydration was still less than 10 mm. [Table 8-1] [Table 8-2]

[0360] Prior to implant administration, animals were anesthetized with an intramuscular injection of ketamine hydrochloride (20 mg / kg) and xylazine (5 mg / kg). The eye and surrounding area were irrigated with 5% betadine solution and rinsed with balanced salt solution. One to two drops of topical proparacaine hydrochloride anesthetic (0.5%) were applied. The eye was draped, a sterile wire speculum was placed, and the eyelids were retracted. The needle was placed approximately 3-5 mm from the limbus and was placed in a single stroke.

[0361] In summary, axitinib implants showed a good safety profile, were well tolerated, and had high efficacy regardless of dose (with one or more implants) or delivery method. Furthermore, the drug was efficiently released into target tissues, while systemic blood concentrations remained very low or undetectable.

[0362] Example 3.1: Primary low-dose screening of axitinib implants To investigate the primary safety, tolerability, and efficacy of axitinib-containing implants, a low dose of 15 μg of axitinib per implant was administered using a 30G 0.5-inch needle in rabbits (including control animals receiving saline). Depending on the intravitreal injection used, either one (Group 1, n=5), two (Group 2, n=5), or three (Group 3, n=5) per eye. It was administered bilaterally as an implant. The implants used in this study had a diameter of 0.15±0.13 mm and a length of 6.9±0.1 mm in the dry state. After hydration for 24 hours in biorelevant medium (PBS, pH 7.2, 37 °C), the diameter was 0.42 ± 0.02 mm and the length was 10.6 ± 0.4 mm.

[0363] General health status, weight, and intraocular pressure (IOP) were recorded for one month. Clinical ophthalmological examination was performed at baseline and at 1 month according to the modified McDonald-Shadduck scoring system (McDonald, T.O., and Shadduck, J.A. “Eye irritation.” Advances in Modern Toxicology, IV: Dermatotoxicology and Pharmacology, 1977). Scored. In infrared reflectance (IR) imaging, representative images of one, two, and three implants in the vitreous were collected at 1 month. The intraocular distribution of axitinib was investigated using LC-MS / MS essentially as described in Example 3.5. To assess the efficacy of the implants, rabbits with and without implants were challenged with repeated intravitreal injections of VEGF to induce retinal vascular leakage essentially as described in Example 3.2.

[0364] No significant effect on body weight was observed in either group. Furthermore, IOP values ​​were normal and comparable in all groups. There were no or only mild effects on ocular health, indicating overall safety and tolerability. Ophthalmic clinical examination at 1 month showed no ocular findings in any of the animals receiving a single implant. Mild corneal opacification was observed in one eye of animals receiving two or three implants. Mild and moderate ocular discharge was observed in two eyes of animals receiving three implants.

[0365] IR imaging revealed that the overall shape of the implant remained intact regardless of the number administered (Figure 5A).

[0366] The pharmacokinetic results of axitinib concentration in ocular tissue at 1 month in each group are presented in Table 7. One eye in the second group of retinal tissue samples and one eye in the third group of choroid / RPE (retinal pigment epithelium) samples were treated with preferential treatment in the extraction organic solvent system used prior to LC-MS / MS analysis. These two eyes were excluded from the analysis as they may have contained parts of the implant that resulted in falsely high concentrations in these two tissue samples due to dissolution (see Example 3.5). The solubility of axitinib in PBS at 37°C, pH 7.2 is approximately 0.5 μg / mL, and any tissue value significantly higher than this may indicate either tissue accumulation or sample contamination. Axitinib concentrations were lower or absent in AH compared to other ocular tissues, indicating that there was little axitinib transfer from the posterior chamber to the anterior chamber. From the intraocular distribution results, it appears that the single implant dose (Group 1) was almost completely depleted at 1 month, with only 0.3 μg remaining in the VH during the first month. A starting dose of 30 μg (2 implants, group 2) released 25.5 μg, resulting in a daily release rate of approximately 0.8 μg / day. In the first month, 33.8 μg was released from the starting dose of 45 μg (3 implants, group 3), resulting in a daily release rate of approximately 1.1 μg / day. Median axitinib levels in the retina were 31 ng / g in group 1, 65 ng / g in group 2, and 148 ng / g in group 3, indicating that release into retinal tissue was dose-dependent. Shown. Saturation was not achieved in this test. [Table 9]

[0367] Of note, all three doses showed inhibition of vascular leakage at 1 month after VEGF challenge compared to control animals without implants (n=3), with the lowest dose (15 μg) They also showed good efficacy after a short period of 1 month (Figure 5B).

[0368] In summary, in primary low-dose studies, TKI implants administered as either 1, 2, or 3 per eye were successfully validated for safety, tolerability, and axitinib release and efficacy. .

[0369] Example 3.2: Tolerability, Safety, and Efficacy Study with One Axitinib Implant To test the tolerability, safety, and efficacy of one implant per eye with a higher dose of axitinib, rabbits were administered 227 μg axitinib per eye by intravitreal injection using a 25G ultrathin-walled needle. One implant with a dose was administered bilaterally. Implant dimensions are mentioned in Table 6 (implant type #3). Tolerability and safety

[0370] For tolerability and safety studies, 9 animals were tested over 6 months for general health (daily), body weight (0, 1, 3, 6 months), and IOP and ophthalmological examination (0.5 each). monitoring was conducted at monthly intervals). Clinical ophthalmological examinations were scored according to the modified McDonald-Shadduck scoring system. Electroretinogram (ERG) and fluorescein angiography (FA) were performed at 1, 3, and 6 months to assess retinal function and ocular vasculature, respectively. Optical coherence tomography (OCT) was performed monthly to obtain cross-sectional images of the retina. IR imaging was performed monthly to monitor implant biodegradation and axitinib persistence within the vitreous over time.

[0371] At sacrifice (3 animals at 1, 3, and 6 months), whole eyes were prepared for histopathological analysis. Therefore, the suture was placed at the 12 o'clock position for orientation and harvesting. Typically, the eye was cut in half in the 12 o'clock to 6 o'clock plane along the midline and through the lens and optic nerve. This allows as many visual structures as possible to be captured in one plane. The removed eyeballs were visually examined and any abnormalities noted. Hematoxylin and eosin (H&E) stained slides separated by 1 mm were prepared. Each slide contained two serial sections. Histopathological evaluation at each time point included vitreous, retinal, scleral, or episcleral inflammation, retinal destruction, and fibrosis around the injection area. Scoring was performed for any abnormality on a semi-quantitative scale from 0 to 5. 0 means no change (normal), 1 means rare focal changes (minor), 2 means mild diffuse changes or more prominent focal changes, 3 means moderate diffuse changes 4 means marked disseminated change and 5 means severe disseminated change.

[0372] No significant effects on daily health status or body weight were observed. IOP was normal throughout the duration of the study. Based on electroretinogram (ERG) measurements, no significant effect of the implant was observed. Fluorescein angiography (FA) and OCT images did not show any pathology during the study. For example, normal retinal morphology was maintained over 6 months (Figure 6). In addition, ophthalmological examination findings were normal or mild. IR imaging at 4 and 8 weeks showed an intact implant, but at 12 weeks it showed early stages of hydrogel degradation (Figure 7A). Images at 16 weeks showed narrowing of the implant due to loss of hydrogel structure. Finally, images at 20 and 26 weeks showed the absence of hydrogel, but undissolved axitinib particles remained close to the site of the implant, forming a single monolithic structure. . However, any undissolved axitinib remaining at the implant site has been shown to continue to release axitinib at levels sufficient to inhibit vascular leakage (e.g., as demonstrated in a 21-month VEGF challenge study and Similarly, see Example 3.4). Additionally, no inflammation was observed within the area of ​​undissolved axitinib particles (Figure 7B).

[0373] The amount of axitinib in histopathological sections decreased over time, indicating bioabsorption of the injected material. No macroscopic lesions in the sections were observed over the duration of the study. The mean values ​​and standard deviations of the histopathological examination results are presented in Table 8. The average inflammation score indicates that retinal, scleral, or episcleral, vitreous cavity, and chronic subcorneal (limbal lymphocytes and phagocytes) inflammation scores are normal to minimal over the duration of the study. Shown. The average fibrosis score around the injected test article was normal to minimal over the duration of the study. Average retinal destruction scores were minimal over the duration of the study. The mean retinal vacuolization score was minimal over the duration...

Claims

1. A sustained release biodegradable intraocular implant comprising an active agent and a polymer network in the form of a hydrogel, the polymer network comprising one or more crosslinked polyethylene glycol (PEG) units which are 4-arm and / or 8-arm PEG units having a number average molecular weight of 10,000 to 60,000 Daltons, the crosslinks between the PEG units being represented by the formula: 【Chemistry 1】 wherein m is an integer from 0 to 10; the active agent is a complement protein C5 agent; The sustained release biodegradable intraocular implant.

2. A sustained-release biodegradable intraocular implant as described in claim 1, wherein the active agent is an active agent suitable for treating age-related macular degeneration.

3. A sustained release biodegradable intraocular implant as described in claim 1, wherein the active agent is avacincaptad pegol.

4. The sustained release biodegradable intraocular implant of claim 1, wherein the active agent is eculizumab.

5. The sustained release biodegradable intraocular implant of claim 1, wherein the implant is an in situ implant.

6. The sustained release biodegradable intraocular implant of claim 1, wherein the implant is cylindrical in its dry state and has a length of less than about 17 mm.

7. The sustained release biodegradable intraocular implant of claim 6, having a diameter of 0.1 mm to 0.5 mm in its dry state.

8. The sustained release biodegradable intraocular implant of claim 6, wherein the implant, in its dry state, has a total weight of 0.2 mg to 1.5 mg.

9. The sustained release biodegradable intraocular implant of claim 6, wherein the implant has a length of 10 mm or less and a diameter of 0.8 mm or less in its hydrated state, the hydrated state being the hydrated state after 24 hours in phosphate buffered saline at 37°C and pH 7.

2.

10. The sustained release biodegradable intraocular implant of claim 1, wherein the implant is an intravitreal implant.

11. The sustained release biodegradable intraocular implant of claim 1, wherein the implant provides release of the active agent for a period of at least 3 months after administration, at least 6 months after administration, at least 9 months after administration, or at least 12 months after administration.

12. The sustained release biodegradable intraocular implant of claim 11, wherein the polymer network is formed by reacting an electrophilic group-containing multi-arm PEG precursor with a nucleophilic group-containing multi-arm PEG precursor or another nucleophilic group-containing crosslinker.

13. The sustained release biodegradable intraocular implant of claim 12, wherein the electrophilic group is an N-hydroxysuccinimidyl (NHS) ester terminal group and the nucleophilic group is an amine group.

14. The sustained release biodegradable intraocular implant of claim 13, wherein the electrophilic groups are succinimidyl azelate (SAZ) end groups, succinimidyl adipate (SAP) end groups, succinimidyl glutarate (SG) end groups, and / or succinimidyl succinate (SS) end groups or any combination thereof.

15. A sustained release biodegradable intraocular implant described in any one of claims 1 to 14 for the treatment of age-related macular degeneration.

Images