Intraocular implants containing tyrosine kinase inhibitors - Patents.com

Abstract

To provide methods for avoiding frequent injections in the treatment of ocular diseases using a tyrosine kinase inhibitor (TKI).SOLUTION: A sustained release biodegradable ocular implant comprises a hydrogel and at least about 150 μg of a tyrosine kinase inhibitor (TKI), wherein TKI particles are dispersed within the hydrogel, and wherein the implant in its dry state has a length of less than about 17 mm. There is also provided a method for the treatment of ocular diseases, comprising the administration of the implant.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This invention relates to U.S. Provisional Application No. 62 / 994,391 (filed March 25, 2020), International Application No. Application No. PCT / US2020 / 029827 (filed April 24, 2020), U.S. Provisional Application No. 63 / 106,276 (filed October 27, 2020), and U.S. Provisional Application No. 63 / 148,463 (filed February 11, 2021), all of which claim priority to The present application is incorporated by reference.

[0002] The present invention relates to a method for treating ocular diseases, such as neovascular age-related macular degeneration (AMD) (also known as "wet macular degeneration"). According to the present invention, the ocular disease is treated with a biodegradable tyrosine kinase inhibitor. Implants (e.g., vitreous) that provide sustained release of enzyme inhibitors (e.g., axitinib) Treatment is by administering an intravenous (intravenous) injection. [Background technology]

[0003] Macular diseases (including AMD) cause visual impairment and irreversible loss in people over the age of 50 worldwide. Specifically, AMD was the most popular processor in the United States (US) in 2019. It is one of the retinal diseases, affecting approximately 16.9 million people. This is expected to increase to 18.8 million (Market Scope.Oph thalmic Comprehensive Reports.2019 Retin al Pharmaceuticals Market Report:A Globa Analysis for 2018 to 2019,September 20 19) AMD is subdivided by stage. Early AMD is characterized by a small number (less than 20) of medium-sized discs. Intermediate AMD is characterized by the appearance of lucent or pigmentary abnormalities in the retina. At least one large drusen not reaching the periphery, multiple medium-sized drusen, or geographic Advanced or late AMD is characterized by non-neovascular (dry, atrophic, or Progressive non-exudative (non-exudative) or neovascular (wet or exudative). Developing AMD is characterized by drusen that extend into the center of the macula and geographic atrophy. Neovascular AMD is characterized by choroidal neovascularization and its sequelae (Jager et al. al.,Age-related macular degeneration.NE ngl J Med.2008;358(24):2606-17).

[0004] The more advanced form of wet AMD is characterized by increased vascular endothelial growth factor (VEGF) The increased VEGF causes the cells to grow under the retina and enter the macula and subretinal space. This promotes the growth of new blood vessels (angiogenesis) that leak blood and fluids into the arteries and underneath. To disrupt this pathway, we develop inhibitors of vascular endothelial growth factor subtypes, i.e., VEGF inhibitors. This inhibitor was originally used to treat various cancers. The combination of photodynamic therapy with anti-VEGF agents and steroids is currently It is reserved as second-line therapy for patients who do not respond to monotherapy with other drugs (Al- Zamil et al.,Recent developments in age- related macular degeneration:a review.Cl in Interv Aging.2017;12:1313-30).

[0005] Other common retinal diseases include diabetic macular edema (DME) and retinal vein occlusion (RVE). DME was one of the most common retinal diseases in the United States in 2019, with approximately It affects 8 million people and is expected to increase to 8.8 million by 2024. Market Scope 2019 (ibid.). This condition is caused by a decrease in retinal tension and VE Upregulation of GFs, autoregulation of retinal blood vessels (Browning et al., Diabetes ic macular edema:evidence-based manageme nt.2018 Indian journal of ophthalmology, 66(1), p.1736), and inflammatory cytokines and chemokines (Mille r et al., Diabetic macular edema:current understanding,pharmacologic treatment op tions,and developing therapies.2018,Asia -Pacific Journal of Ophthalmology,7(1):2 8-35) and the increase in vascular pressure caused by these inflammatory and the blood-retinal barrier (BRB) of the vascular endothelium as a result of changes resulting from angiogenic mediators. (Miller et al., supra) The hard exudate enters the extracellular space, This causes blurring and distortion of the central vision, resulting in a decrease in the patient's visual acuity (Sch midt-Erfurth et al., guidelines for the M anagement of Diabetic Macular Edema by t he European Society of Retina Specialist s(EURETINA).2017, Ophthalmologica.237(4): 185-222). On average, patients experience an 8% decrease in vision three years after the condition begins. Experience below.

[0006] The basis of all available treatments for DME is to attempt to control the metabolic functions of hyperglycemia and blood pressure. (Browning et al., supra). Anti-VEGF therapy is a method for preventing destructive It has been shown to be less harmful and less damaging than other treatments and is now considered the standard for DME. It is considered the first-line therapy for treatment (Schmidt-Erfurth et al. (ibid.) Pharmacological pathways specifically target the VEGF pathway and are associated with DME. This is beneficial because drugs can be manufactured to inhibit this regulation (Miller et al. (Ibid.) Other treatment options include intravitreal corticosteroid injections and topical laser. These include photocoagulation, and vitrectomy (Browning et al., supra).

[0007] RVO affected approximately 1.3 million people in the United States in 2019 and is expected to affect approximately 1.3 million people in the United States by 2024. It is estimated that 1.4 million people will be affected (Market Scope 2019 (ibid.) RVO is a chronic condition in which the retinal circulation becomes blocked, leading to leakage, retinal thickening, and visual impairment. (Ip and Hendrick, Retinal Vein Occlu sion Review.2018,Asia-Pacific Journal of Ophthalmology,7(1):40-45;Pierru et al., Occlusions veineuses retiniennes retinal Vein occlusions.2017, Journal Francais d Ophtalmologie, 40(8):696-705). This condition is typically is seen in patients over 55 years of age with pre-existing conditions such as high blood pressure, diabetes, and glaucoma RVO can cause a rapid deterioration of vision in some patients or can remain asymptomatic. The prognosis of RVO and associated treatment options are unclear. The classification of diseases is not dependent on the disease category because different types of patients have different risk factors despite similar behavior. The disease is classified into branch retinal vein occlusion (BRVO) according to the location of the retinal circulatory disorder. They are broadly divided into hemiretinal vein occlusion (HRVO), and central retinal vein occlusion (CRVO). BRVO is more common, affecting 0.4% of people worldwide, compared to 0.5% for CRVO. 0.8% of people. Studies have shown that BRVO is more prevalent in Asian and Hispanic people than in Caucasians. It has been shown that the prevalence of panic disorder is high (Ip and Hendrick, supra). )).

[0008] Currently, treatment for RVO involves avoiding further complications, macular edema, and neovascular glaucoma. Currently, anti-VEGF therapy is the standard treatment. Other treatment options include laser therapy, which may temporarily improve vision. These include steroids, and surgery (Pierru et al., supra).

[0009] Anti-VEGF agents are currently considered the standard of care for wet AMD, DME, and RVO. The first FDA-approved treatment for wet AMD in 2004 was MAMD. CUGEN® (pegaptanib sodium injection, manufactured by Bausch & Lomb) ) was subsequently used in LUCENTIS (registered trademark) (Genentech Ranibisma Injection) in 2006, EYLEA® (Regeneron Pharmaceuticals Aflibercept injection (manufactured by Aceuticals, Inc.) was released as a wet type in 2011. Approved for the treatment of AMD, DME, and macular edema following RVO. In addition, in October 2019, BEOVU (registered trademark) (Novartis Brolucizumab injection (manufactured by Pharmaceuticals Corp.) is a wet type A It has been approved by the FDA for the treatment of MD. Other developments include Amadio et al. l.,Targeting VEGF in eye neovascularization ion:What's new?:A comprehensive review o n current therapies and oligonucleotide- based interventions under development.20 16,Pharmacological Research,103:253-69 It has been reported.

[0010] However, despite these advances, anti-VEGF treatments have limitations. Most patients will require multiple (e.g., monthly) injections essentially for the rest of their lives. This is due to the rapid clearance of the vitreous. In addition, these treatment options have additional potential side effects associated with their administration. potential risks (infection, macular atrophy, loss of vision over time, retinal detachment, and intraocular pressure (IOP)) Patients' complaints include discomfort, eye pain, decreased vision, and light sensitivity. In addition to the burden on patients and the risks associated with frequent injections, potential risks of vasculitis, the complex manufacturing requirements of biologics, and current issues such as macular atrophy and retinal vasculitis. There are other limitations known to be associated with current anti-VEGF therapeutics. Importantly, Regardless of the number of medications, patients are currently expected to remain on treatment indefinitely.

[0011] Tyrosine kinase inhibitors are receptor tyrosine kinase inhibitors that act on receptors in the family of tyrosine protein kinases. It was developed as a chemotherapy drug that inhibits the signal transduction of RTK. K spans the cell membrane with an intracellular (inside) portion and an extracellular (outside) portion. When the ligand binds to the extracellular portion, the receptor tyrosine kinase dimerizes and transmits the coenzyme message. is driven by autophosphorylation with the enzyme adenosine triphosphate (ATP) Many of the RTK ligands initiate intracellular signaling cascades, such as VEGF. VEGF is a growth factor. VEGF is a type of VEGF receptor (VEGFR), i.e., VEGFR Related to a family of proteins that bind to RTKs 1-3 and induce angiogenesis VEGF-A, which binds to VEGFR2, is the target of the anti-VEGF drugs mentioned above. In addition to R1-3, several other RTKs (e.g., PDGF-activated erythrocytes) Platelet-derived growth factor receptor (PDGFR), or stem cell factor-activated stem cell formation Long-acting factor receptor / type III receptor tyrosine kinase (c-Kit) also induces angiogenesis It is known to do so.

[0012] Several TKIs have been evaluated for the treatment of AMD via different routes of administration. TKIs such as pazopanib (GlaxoSmithKline: NCT004 63320), regorafenib (Bayer: NCT02348359), and PAN9 0806 (PanOptica: NCT02022540) (both administered as eye drops) ), and oral X-82 (Tyrogenex; NCT01674569, NCT0 However, topically applied eye drops have been shown to penetrate the vitreous. They have poor permeability and limited distribution to the retina, which is due to their tendency to have low aqueous solubility. This is due to the low concentration of TKI solution and its short residence time on the ocular surface. Furthermore, it is difficult to control the drug concentration during topical administration due to user error. For systemic administration of TKIs, achieving effective drug concentrations in the desired tissue, especially in the eye, is essential. This is not practical because high doses are required to achieve this, which leads to high systemic exposure. This leads to unacceptable side effects. In addition, drug concentrations are difficult to control. Alternatively, intravitreal injection of TKI suspensions has been performed. However, this method of administration Injections should be given frequently (e.g., daily or at least once a day) to result in rapid clearance of the drug. In addition, the solubility of some TKIs is low, so Upon intravitreal injection, aggregates are formed, which then migrate or settle on the retina, causing local This may lead to potential contact toxicity and holes (e.g., macular or retinal holes).

[0013] Therefore, the treatment of ocular diseases (e.g., AMD, DME, and RVO) with TKIs is It is effective for a long period of time and does not require the frequent (every 24 hours) administration currently required for conventional anti-VEGF therapy. Improvements in avoiding monthly or even daily injections, especially in patients who respond to anti-VEGF therapy, urgently needed for individuals who do not (e.g., up to 33% of subjects with DME) There are.

[0014] All references disclosed herein are incorporated by reference in their entirety for all purposes. The specification is incorporated by reference. Summary of the Invention

[0015] An object of certain embodiments of the present invention is to provide a method for treating ocular diseases (e.g., neovascularized ocular diseases) in a patient. It is an effective long-term treatment for age-related macular degeneration (AMD), DME, and RVO. and an intraocular implant containing a thyroid kinase inhibitor (TKI) (e.g., axitinib). The purpose is to provide.

[0016] Another object of certain embodiments of the present invention is to provide a method for treating tyrosine kinase inhibitors (TKIs) (e.g., an intraocular implant containing a TKI (e.g., axitinib) that releases the TKI into the eye in a sustained manner; To provide an intraocular implant.

[0017] Another object of certain embodiments of the present invention is to provide ophthalmic solutions containing a TKI (e.g., axitinib). The intravenous implant is pre-loaded into a syringe, thereby eliminating further preparation steps. Provides intraocular implants that do not require a step, thus avoiding contamination of the implant before injection To do this.

[0018] Another object of certain embodiments of the present invention is to provide ophthalmic solutions containing a TKI (e.g., axitinib). and an intravenous implant that is sufficiently biodegradable, i.e., over a period of time consistent with TKI release. The implant is removed from the eye immediately after use, avoiding floaters (empty implant vehicle residue) in the patient's eye. and / or intraocularly, avoiding the need to remove the empty implant from the eye after the treatment period. The aim is to provide implants.

[0019] Another object of certain embodiments of the present invention is to provide ophthalmic solutions containing a TKI (e.g., axitinib). The implant is biodegradable, and during the degradation of the implant, the implant ( For example, intraocular implants that avoid breaking down into smaller particles (which may affect vision) The goal is to provide the runt.

[0020] Another object of certain embodiments of the present invention is to provide ophthalmic solutions containing a TKI (e.g., axitinib). Intraocular implants, wherein the stability of the intraocular implant is formed in situ after injection. Compared to conventional hydrogels, the vitreous humor is more resistant to various environments (e.g., vitreous humor viscosity, vitreous humor pH, Intraocular implants that are not affected by the composition of body fluids and / or intraocular pressure (IOP) The purpose of this project is to provide a

[0021] Another object of certain embodiments of the present invention is to provide ophthalmic solutions containing a TKI (e.g., axitinib). Intra-implants, whether the implant contains no components of animal or human origin and an intraocular implant that is biocompatible and non-immunogenic because it is or is substantially free of steroids. The purpose is to provide.

[0022] Another object of certain embodiments of the present invention is to provide ophthalmic solutions containing a TKI (e.g., axitinib). an intraocular implant that does not contain a preservative (e.g., an antimicrobial preservative); The purpose of this project is to provide a

[0023] Another object of certain embodiments of the present invention is to provide ophthalmic solutions containing a TKI (e.g., axitinib). The present invention provides an intraocular implant that is easy to inject, particularly to inject intravitreously. The purpose is to provide.

[0024] Another object of certain embodiments of the present invention is to provide ophthalmic solutions containing a TKI (e.g., axitinib). an intracellular implant comprising a therapeutically effective amount of said TKI, said implant having a length and / or diameter The object of the present invention is to provide an intraocular implant having a relatively small size.

[0025] Another object of certain embodiments of the present invention is to provide ophthalmic solutions containing a TKI (e.g., axitinib). an intraocular implant that is dimensionally stable in the dry state but that, upon hydration, e.g., administered to the eye The objective is to provide an intraocular implant that changes size after implantation.

[0026] Another object of certain embodiments of the present invention is to provide ophthalmic solutions containing a TKI (e.g., axitinib). It is an intraluminal implant that, in a dry state, fits inside the lumen of a small diameter needle (e.g., a 22- to 30-gauge needle). and upon hydration, e.g., after administration to the eye, increases in diameter and decreases in length. and thereby providing an intraocular implant that provides a minimally invasive method of administration. And so.

[0027] Another object of certain embodiments of the present invention is to provide ophthalmic solutions containing a TKI (e.g., axitinib). and intrathecal implants that are injected in dry form and that undergo in situ (i.e., The present invention provides an intraocular implant that hydrates (intraocularly).

[0028] Another object of certain embodiments of the present invention is to provide ophthalmic solutions containing a TKI (e.g., axitinib). It is an intraocular implant that has a low TKI concentration on the surface of the implant when placed in the eye. , whereby when the implant contacts cells or tissues of the eye (e.g., the retina), T The goal is to provide an intraocular implant that avoids the toxicity of KI.

[0029] Another object of certain embodiments of the present invention is to provide ophthalmic solutions containing a TKI (e.g., axitinib). an intraocular implant in a dry state before injection and in a hydrated state after injection (i.e., intraocularly); In either case, it is possible to provide an intraocular implant having a stable, defined shape and surface area. And so.

[0030] Another object of certain embodiments of the present invention is to provide ophthalmic solutions containing a TKI (e.g., axitinib). It is an intrathecal implant that is easy to handle and in particular does not easily spill or fragment. The present invention provides an intraocular implant that does not require a surgical procedure.

[0031] Another object of certain embodiments of the present invention is to provide ophthalmic solutions containing a TKI (e.g., axitinib). an intravenous implant that allows for precise administration of a dose (within a wide dose range) and thereby The objective of the present invention is to provide an intraocular implant that avoids the risk of over-dosing and under-dosing. .

[0032] Another object of certain embodiments of the present invention is to provide ophthalmic solutions containing a TKI (e.g., axitinib). and an intraocular implant that remains substantially within the region of the eye to which it is administered. To do this.

[0033] Another object of certain embodiments of the present invention is to provide ophthalmic solutions containing a TKI (e.g., axitinib). an intraocular implant that causes little or no visual impairment after administration; To provide an intraocular implant.

[0034] Another object of certain embodiments of the present invention is to provide ophthalmic solutions containing a TKI (e.g., axitinib). and to provide an intraocular implant that is safe and well tolerated. And so.

[0035] Another object of certain embodiments of the present invention is to provide ophthalmic solutions containing a TKI (e.g., axitinib). intraocular implants that do not induce serious adverse events (e.g., serious ocular adverse events) The present invention provides an intraocular implant.

[0036] Another object of certain embodiments of the present invention is to provide ophthalmic solutions containing a TKI (e.g., axitinib). an intravenous implant for sustained release of a therapeutically effective amount of a TKI (e.g., axitinib) for a prolonged period of time; Duration, e.g., up to 3 months or more, e.g., at least 6 months, at least 9 months 1 month, at least 11 months, or at least 13 months. The aim is to provide an implant.

[0037] Another object of certain embodiments of the present invention is to provide ophthalmic solutions containing a TKI (e.g., axitinib). an intravenous implant that provides sustained release of a TKI (e.g., axitinib) for an extended period of time, e.g. , up to 3 months or more, e.g., at least 6 months, at least 9 months, at least over a period of at least 11 months, or at least 13 months, so that frequent The object of the present invention is to provide an intraocular implant that avoids the need for administering a conventional intraocular implant.

[0038] Another object of certain embodiments of the present invention is to provide ophthalmic solutions containing a TKI (e.g., axitinib). an intravenous implant that provides sustained release of a TKI (e.g., axitinib) for an extended period of time, e.g. , up to 3 months or more, e.g., at least 6 months, at least 9 months, at least and for a period of 11 months, or at least 13 months, thereby enhancing angiogenesis. The object of the present invention is to provide an intraocular implant that inhibits the inflammatory process over this period.

[0039] Another object of certain embodiments of the present invention is to provide ophthalmic solutions containing a TKI (e.g., axitinib). an intravenous implant that provides sustained release of a TKI for an extended period of time, e.g., up to 3 months or longer; For example, at least 6 months, at least 9 months, at least 11 months, or less Both were provided over a 13-month period, and over this period, ocular tissues (e.g., retina and TKI levels in the choroid and vitreous humor are at therapeutically effective levels, especially To provide an intraocular implant that consistently maintains sufficient levels of inhibition of angiogenesis. is.

[0040] Another object of certain embodiments of the present invention is to provide ophthalmic solutions containing a TKI (e.g., axitinib). an intravenous implant that provides sustained release of a TKI (e.g., axitinib) for an extended period of time, e.g. , up to 3 months or more, e.g., at least 6 months, at least 9 months, at least over a period of at least 11 months, or at least 13 months, and over this period, Toxic concentrations of KI have been observed in ocular tissues (e.g., retina and choroid) and in the vitreous humor. The present invention provides an intraocular implant that does not require a surgical procedure.

[0041] Another object of certain embodiments of the present invention is to provide ophthalmic solutions containing a TKI (e.g., axitinib). an intravenous implant that provides sustained release of a TKI (e.g., axitinib) for an extended period of time, e.g. , up to 3 months or more, e.g., at least 6 months, at least 9 months, at least over a period of 11 months or at least 13 months, and the TKI accumulates in the anterior chamber. The aim is to provide an intraocular implant that does not

[0042] Another object of certain embodiments of the present invention is to provide ophthalmic solutions containing a TKI (e.g., axitinib). an intravenous implant that provides sustained release of a TKI for an extended period of time, e.g., up to 3 months or longer; For example, at least 6 months, at least 9 months, at least 11 months, or less Both were delivered over a 13-month period and were shown to be completely or substantially systemically absorbed. The object of the present invention is to provide an intraocular implant that substantially avoids systemic toxicity.

[0043] Another object of certain embodiments of the present invention is to provide a method for treating ocular diseases (e.g., AMD, DME, and Treatment of RVO for up to 3 months or longer in patients who require it For example, at least 6 months, at least 9 months, at least 11 months, or less The objective of the present invention is to provide a method for treating rheumatoid arthritis with rheumatoid arthritis, which can be performed for a treatment period of 13 months.

[0044] Another object of certain embodiments of the present invention is to provide a method for treating ocular diseases (e.g., AMD, DME, and Treatment of RVO for up to 3 months or longer in patients who require it For example, at least 6 months, at least 9 months, at least 11 months, or less Both methods are performed for a 13-month treatment period, during which rescue medication is administered. Rescue medications are not required or are administered infrequently during treatment (e.g., 1, The goal is to provide a way to stay in the same place for two or three times.

[0045] Another object of certain embodiments of the present invention is to provide a method for treating ocular diseases (e.g., AMD, DME, and Treatment of RVO in patients who require it (e.g., those previously treated with anti-VEGF agents) The present invention provides a method for performing this treatment in patients with VEGF-positive or anti-VEGF-naive tumors. And so.

[0046] Another object of certain embodiments of the present invention is to provide a method for treating ocular diseases (e.g., AMD, DME, and RVO) in patients who need it (e.g., those who have previously been treated with anti-VEGF The goal of this study is to provide a method for treating this condition in patients who have not responded to previous anti-VEGF therapy. do.

[0047] Another object of certain embodiments of the present invention is to provide a method for treating ocular diseases (e.g., AMD, DME, and RVO) in patients who need it (e.g., primary subfoveal hemorrhage secondary to AMD) The present invention provides a method for performing a vascular endothelial neoplasia (SFNV) treatment in a patient with a diagnosis of SFNV.

[0048] Another object of certain embodiments of the present invention is to provide a method for treating ocular diseases (e.g., AMD, DME, and Treatment of RVO in patients who need it (e.g., foveal-related leakage-associated neovascularization) Have a diagnosis of subfoveal neovascularization (SFNV) secondary to dry AMD and have previously been treated for the condition. and provide a method for performing this treatment in patients who have previously received anti-VEGF therapy. be.

[0049] Another object of certain embodiments of the present invention is to provide ophthalmic solutions containing a TKI (e.g., axitinib). The present invention provides a method for manufacturing an intravascular implant.

[0050] Another object of certain embodiments of the present invention is to provide an intraocular implant that can be rapidly and easily removed during storage and operation. 10. A method for protecting an intraocular implant from hydration, wherein the intraocular implant is moisture sensitive and therefore The object of the present invention is to provide a method for producing a polymeric nanoparticle that changes its dimensions, for example, upon hydration.

[0051] Another object of certain embodiments of the present invention is to provide a method for treating ocular disorders that may occur during injection of an intraocular implant. The object of the present invention is to provide a method for minimizing tissue damage.

[0052] Another object of certain embodiments of the present invention is to provide a method for treating rheumatoid arthritis with rheumatoid arthritis, including ... TKIs (e.g., axitinib). 1. A kit comprising one or more intraocular implants, optionally including an injection The present invention provides a kit comprising a means for:

[0053] Another object of certain embodiments of the present invention is to provide a method for treating ocular diseases associated with neovascularization in the central region of the eye. In patients with increased retinal thickness, for example by reducing retinal fluid, optical coherence tomography The present invention provides a method for reducing central retinal thickness as measured by MRI.

[0054] Another object of the present invention is to provide a method for treating retinal disorders in which central retinal thickness is increased due to ocular diseases associated with neovascularization. Patients showed a clinically significant increase in central retinal thickness as measured by optical coherence tomography. Essentially, the goal is to provide a method for maintaining or preventing retinal fluid buildup while not increasing it. .

[0055] Another object of certain embodiments of the present invention is to provide a method for treating ocular diseases associated with neovascularization in the central region of the eye. In patients with increased retinal thickness, central retinal thickness measured by optical coherence tomography Reduce, essentially maintain, or prevent clinically significant increases, while (e.g., maximum correction) A method that improves or at least does not impair a patient's vision (as measured by normal visual acuity) The purpose is to provide

[0056] Another object of certain embodiments of the present invention is to provide a method for treating patients with reduced vision due to ocular diseases associated with neovascularization. The present invention provides a method for improving the visual acuity of patients with glaucoma.

[0057] Another object of certain embodiments of the present invention is to detect the presence of retinal fluid (e.g., ocular tissue associated with neovascularization) a method for improving vision in patients with vision loss due to and reducing the amount of retinal fluid in the patient (which is, for example, a measure of the central nervous system in optical coherence tomography). The present invention provides a method for improving a patient's visual acuity by means of a reduction in cardiac retinal thickness. The purpose is to provide.

[0058] One or more of these objects of the present invention, as well as others, are disclosed and claimed herein. The above-described problems are solved by one or more embodiments.

[0059] Individual aspects of the invention are disclosed herein and claimed in the independent claims, while the dependent claims The present invention claims certain embodiments and variations of these aspects of the present invention. Further details of various aspects of the invention are provided in the detailed description below.

[0060] Throughout this application, various references are cited. The disclosures of these references No. 60 / 699,999, filed on Oct. 1, 2003, which is incorporated herein by reference. In case of conflict, the disclosure of this application will control. [Brief explanation of the drawings]

[0061] [Figure 1] Schematic of one embodiment of an implant package, in which the implant is pre-loaded into a thin-walled needle packaged separately from the injection device. An all-in-one device is also possible, with the injection needle already connected to the injection device. [Figure 2] Schematic of one embodiment of implant localization. After injection, the implant hydrates in situ while maintaining a cylindrical shape. The implant is localized in the posterior segment of the eye. [Figure 3] Schematic showing the biodegradation of a hydrogel over time. As the drug is released, the less soluble drug particles (white) gradually dissolve and the drug diffuses from the hydrogel into the surrounding aqueous environment (e.g., vitreous humor), forming a clearance zone (black). Over time, the gel degrades and is absorbed while the drug diffuses away. During the degradation process, the gel gradually swells until degradation reaches a level that causes shrinkage and distortion. [Figure 4] One embodiment of in vitro axitinib release per day for different implants. (A) In vitro axitinib release under non-sink dissolution conditions from different implants containing axitinib doses of 625, 716, 245, and 490 (2 x 245) μg. (B) In vitro accelerated axitinib release from a 556 μg implant. [Figure 5] One embodiment of a low-dose study in rabbits. (A) Infrared reflectance (IR) of one, two, and three implants in rabbits one month after injection. The overall shape of the implants was maintained regardless of the number of implants administered. (B) After one month, all three doses (15, 30, and 45 μg) effectively suppressed vascular leakage, while control animals without implants had more vascular leakage. Error bars represent standard deviation (SD; only the upper error bar is shown). [Figure 6]One embodiment of infrared reflectance (IR) and optical coherence tomography (OCT) imaging of a rabbit eye. IR / OCT images of retinal morphology 1 month, 3 months, and 6 months after implant injection. Retinal morphology was normal. [Figure 7] One example of implant biodegradation and inflammation. (A) Significant biodegradation of the implant's hydrogel component was observed over time in rabbit eyes. At 4 and 8 weeks after injection, the implant was still intact, but at 12 weeks, the early stages of hydrogel degradation were visible. At 16 weeks, the implant further narrowed due to loss of hydrogel structure. Finally, at 20 and 26 weeks, the hydrogel was absent, and free (undissolved) axitinib particles (small white specks) were visible near the site of the implant. (B) Histopathological analysis showed that at 26 weeks, inflammation was absent within the areas where axitinib had not dissolved. Images are presented at 20x magnification (scale: 1000 μm) and 200x magnification (scale: 100 μm). [Figure 8] Figure 1 shows an example of the inhibition of vascular leakage after administration of a 227 μg dose of axitinib implant in rabbits challenged with VEGF. Vascular leakage scores (0 (normal) to 4 (severe leakage)) are presented according to the time (months) after VEGF challenge in animals with and without implants. Effective inhibition of vascular leakage was observed in animals with implants for a duration of 6 months. Error bars represent standard deviation (SD; only the upper error bar is shown). [Figure 9] One embodiment of infrared reflectance (IR) imaging of two implants in a rabbit eye shows the implants degrading over time. The implants remained intact from 27 to 117 days, while narrowing of the implant was observed at 141 and 195 days due to hydrogel degradation. The remaining axitinib particles coalesced into a single monolithic structure at 141 and 195 days. After hydrogel degradation, free axitinib particles (small white specks) were observed near the site of the previous implant. [Figure 10]One example of infrared reflectance (IR) imaging of two implants in a rabbit eye. The implants remained intact 0.5 to 3 months after injection. After 6 months, the implants narrowed due to hydrogel degradation, and the remaining axitinib particles coalesced into a single monolithic structure. After 24 to 38 months, free axitinib particles (small white specks) were observed near the site of the implants after hydrogel degradation. [Figure 11] Figure 1 shows one embodiment of the inhibition of vascular leakage after administration of two axitinib implants at a total dose of 290 μg with (Group 1) and without (Group 2) Avastin® in rabbits challenged with VEGF. Vascular leakage scores (0 (normal) to 4 (severe leakage)) are presented according to the time (months) after VEGF challenge for animals in Groups 1 and 2, as well as for animals without implants. Significant inhibition of vascular leakage was observed in all animal groups that had implants. Error bars represent standard deviation. [Figure 12] One embodiment of fluorescein angiography (FA) images revealed significant leakage. Control animals showed active leakage from the vasculature immediately after fluorescein injection 48 hours after VEGF challenge (top panel), while leakage was completely inhibited from blood vessels in rabbit eyes containing implants (bottom panel). Images were collected after VEGF challenge one month after implant injection. [Figure 13] Figure 1 shows one embodiment of the mean vascular leakage scores in rabbits treated with neither implants nor anti-VEGF therapeutics (open squares and dashed line), rabbits treated with Avastin® alone (filled triangles, curve fit out to 3 months), rabbits treated with implants (filled squares, solid line out to 12 months), and rabbits treated with implants and Avastin® (striped squares, dashed line out to 12 months). Vascular leakage was effectively inhibited for 12 months for all animals receiving implants. Animals treated with anti-VEGF therapeutics alone showed a rapid onset of leakage inhibition for the first 2-4 weeks, but leakage recurred after 3 months. Values ​​represent the mean and standard error of the mean (SEM). [Figure 14] One embodiment of in vitro axitinib release from 200 μg implants. (A) In vitro real-time assay observed complete release of axitinib from 200 μg implants after 225 days. (B) In vitro accelerated assay observed complete release of axitinib from 200 μg implants after 12 days. The in vitro data did not demonstrate observed in vivo release. [Figure 15] One embodiment of an IR image of subject #1 in Cohort 2 (two implants, a total of 400 μg of axitinib per eye). On the day of injection, the implant is clearly visible and well-formed. After 9 months, the implant has completely degraded, while undissolved axitinib remains in the former implant location. The undissolved axitinib continues to release drug, but after 11 months, very little undissolved axitinib remains. [Figure 16] One embodiment of a spectral-domain optical coherence tomography (SD-OCT) image obtained from the study eye of subject #1 (one implant, 200 μg total axitinib per eye) in Cohort 1. In this treatment-naive subject, a significant decrease in central space retinal thickness (CSFT) was observed, while best-corrected visual acuity (BCVA) did not decline over 10.5 months. [Figure 17]One embodiment of central subretinal thickness (CSFT) in the study eyes of patients with neovascular age-related macular degeneration (wet AMD) treated with axitinib implants (one implant, 200 μg total dose: Cohort 1; two implants, 400 μg total dose: Cohort 2; three implants, 600 μg total dose: Cohort 3a; two implants, 400 μg total dose, and concurrent initial anti-VEGF: Cohort 3b). The chart presents the mean change in CSFT with the standard error of the mean (SEM) relative to baseline. In this chart, six patients in Cohort 1 were followed up to 9 months, seven in Cohort 2 to 12 months, five to 14 months, and two to 16 months. Six patients in Cohort 3a were followed to day 14, five to two months, two to 4.5 months, and one each to 6 and 7.5 months. Two patients in Cohort 3b were followed to three months and one to 4.5 months. Follow-up is ongoing. [Figure 18]One embodiment of best-corrected visual acuity (BCVA) in the study eyes of patients with neovascular age-related macular degeneration (wet AMD) treated with axitinib implants (one implant, 200 μg total dose: Cohort 1; two implants, 400 μg total dose: Cohort 2; three implants, 600 μg total dose: Cohort 3a; two implants, 400 μg total dose, and concurrent initial anti-VEGF: Cohort 3b). This chart presents the mean change in BCVA from baseline in the Early Treatment Diabetic Retinopathy Study (ETDRS) letter score (a representative number of letters that can be read correctly at a specific distance) along with the standard error of the mean (SEM). In this chart (similar to Figure 17 above), six patients from Cohort 1 were followed up to nine months. Seven patients in Cohort 2 were followed to 12 months, five to 14 months, and two to 16 months. Six patients in Cohort 3a were followed to 14 days, five to 2 months, two to 4.5 months, and one each to 6 and 7.5 months. Two patients in Cohort 3b were followed to 3 months and one to 4.5 months. Follow-up is ongoing. [Figure 19A] One embodiment of a spectral-domain optical coherence tomography (SD-OCT) image obtained from the study eye of subject #1 (who had a history of aflibercept treatment in the right eye (OD) 16 months prior to implant injection) in cohort 2 (two implants, a total of 400 μg of axitinib per eye). Subretinal fluid was clearly visible at baseline (pre-treatment). Importantly, the subretinal fluid resolved 2-3 months after implant injection and remained essentially in this state for 15.5 months (15.5 months is shown in Figure 19B, and earlier visits are shown in Figure 19A). Best-corrected visual acuity (BCVA) did not decline. [Figure 19B]One embodiment of a spectral-domain optical coherence tomography (SD-OCT) image obtained from the study eye of subject #1 (who had a history of aflibercept treatment in the right eye (OD) 16 months prior to implant injection) in cohort 2 (two implants, a total of 400 μg of axitinib per eye). Subretinal fluid was clearly visible at baseline (pre-treatment). Importantly, the subretinal fluid resolved 2-3 months after implant injection and remained essentially in this state for 15.5 months (15.5 months is shown in Figure 19B, and earlier visits are shown in Figure 19A). Best-corrected visual acuity (BCVA) did not decline. [Figure 20] One embodiment of a spectral-domain optical coherence tomography (SD-OCT) image from subject #7 in Cohort 2 (two implants, a total of 400 μg of axitinib per eye). Subject #7, who had been receiving aflibercept for 6 years prior to study initiation, demonstrated a significant reduction in CSFT and no decline in BCVA 9 months after implant injection. [Figure 21] One embodiment of a spectral-domain optical coherence tomography (SD-OCT) image from subject #1 of Cohort 3a (three implants, a total of 600 μg of axitinib per eye). In AMD treatment-naive subject #1 of Cohort 3a, a significant decrease in CSFT was observed at 2 months and maintained for 7.5 months. BCVA did not decline. [Figure 22] One embodiment of a spectral-domain optical coherence tomography (SD-OCT) image from subject #1 (who was anti-VEGF treatment naive) in cohort 3b (two implants, totaling 400 μg of axitinib per eye, including co-administration of an anti-VEGF agent). CSFT rapidly decreased within 7 days and further decreased, remaining low through month 3. [Figure 23] One embodiment of spectral-domain optical coherence tomography (SD-OCT) from subject #2 (who had been on anti-VEGF treatment for 7 months prior to implant injection) in cohort 3b (two implants, a total of 400 μg of axitinib per eye, including initial coadministration of an anti-VEGF agent). CSFT rapidly decreased within 7 days. Low CSFT values ​​were maintained through month 2. [Figure 24] 1 shows one embodiment of the aggregation tendency of axitinib when hydrogel implants according to embodiments of the present invention are prepared and cast using micronized and non-micronized axitinib under otherwise identical conditions. [Figure 25] 1A and 1B are one embodiment of a syringe according to the present invention for injecting an implant into a patient's vitreous humor. This illustrated syringe embodiment includes a Hamilton syringe body and a nitinol push wire for deploying the implant. 1A shows the Hamilton syringe body within an injection molded casing. 1B is a schematic diagram of the syringe components in this embodiment. [Figure 26A] 1 is an exploded view of one embodiment of a syringe according to the present invention made from an injection molded body. [Figure 26B] A photograph of the fully assembled syringe is shown. [Figure 26C] 1 shows an exploded view of a first assembly of a syringe according to the present invention. [Figure 26D] 1 shows an exploded view of a second assembly of a syringe according to the present invention. [Figure 26E] 1 shows that the first assembly and the second assembly can be aligned. [Figure 26F] 1 shows the cowl of the second assembly secured to the body of the first assembly. [Figure 26G] The needle shield is shown removed from the cowl of the second assembly and the plunger clip is shown removed from the body and plunger of the first assembly. [Figure 26H] The plunger of the first assembly is shown actuated to deploy the implant through the lumen of the needle of the second assembly. [Figure 27] Phase 1 study design using implants containing 200 μg of axitinib according to one embodiment of the present invention. [Figure 28] 1. Proposed Phase 2 study design using implants containing 600 μg of axitinib according to one embodiment of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0062] definition As used herein, the term "implant" (also sometimes referred to as "depot") The active agent, specifically a tyrosine kinase inhibitor (TKI) (e.g., axinoside) and other compounds disclosed herein, wherein the compounds are administered to a human or animal body. for example, into the vitreous humor of the eye (also called the "vitreous cavity" or "vitreous body"). refers to an object that remains there for a specific period of time while releasing an active agent into the surrounding environment. The implant may be in any predetermined shape (e.g., a shape as disclosed herein) prior to injection. This shape will have some effect once the implant is placed in the desired location. The implant dimensions (e.g., length and / or diameter) are maintained to the maximum extent permitted by the present specification. As further disclosed herein, this may be altered after administration by hydration. What is produced is not a solution or a suspension, but a coherent object that has already been formed. Thus, the implant must be fully formed as disclosed herein before administration. In embodiments of the present invention, the ophthalmic solution is administered (as would generally be possible with suitable formulations). It is not produced in situ at the desired location within the body. The implant will biodegrade over time (as disclosed below) in a physiological environment, thereby This causes the shape to change while its size decreases and it is eventually completely dissolved / absorbed. As used herein, the term "implant" refers to the hydrated state (as defined herein) when it contains water. Implants in their "wet" state (e.g., once the implant is in the eye) administered or otherwise immersed in an aqueous environment (e.g., in vitro) and hydrated or the implant after it has been rehydrated, and in its dry (dried / dehydrated) state. Implant in its pre-form (i.e., after the implant is manufactured and dried, loaded into the needle) Implantation immediately prior to or after loading into the needle as disclosed herein, or dehydration implants manufactured in a dry state without the need for sterilization) and Thus, in certain embodiments, in the context of the present invention, an implant is In its dried / dehydrated state, it may contain less than about 1% water by weight. The water content in the as-prepared state can be measured, for example, by Karl Fischer coulometry. As used herein, the dimensions (i.e., length, diameter, or volume) of an implant may be Whenever reported in a hydrated state, these dimensions are based on measurements taken after the implant was placed in phosphate buffered water at 37°C. The measurements were taken after 24 hours of immersion in buffered saline. Whenever implant dimensions are reported in a dry state, these dimensions are based on the implant being fully inserted. is thoroughly dried (and thus contains less than about 1% by weight of moisture in certain embodiments), and subsequently The measurements were taken after the needle was ready to be loaded for administration. In this state, the implant is placed in an inert atmosphere containing less than 20 ppm of both oxygen and moisture. Store in the glove box for at least about 7 days. is reported in Example 6.1.

[0063] As used herein, the term "ocular" refers to the eye in general, or the eye (The "intraocular implant" according to the present invention is, in principle, any part or site of the eye. or any disease of the eye (in one embodiment, In general, the present invention relates to the treatment of any eye disease ("ocular disease") of various origins and nature. In certain embodiments, the present invention refers to Thus, intravitreal injection of an intraocular implant (hence, in this case, "intraocular implant" It is intended for the treatment of ocular diseases affecting the posterior segment of the eye, including ocular diseases that affect the posterior segment of the eye. do.

[0064] As used herein, the term "patient" includes both human and animal patients. Therefore, the implant according to the invention is suitable for human or veterinary medical use. Patients enrolled in and treated in the clinical trials reported in 6 are referred to as "subjects." refers to a subject (human or animal) to which an implant according to the invention is administered (e.g., during a clinical trial). A "patient" is an individual (animal) who is in need of treatment due to a particular physiological or pathological condition. This refers to the object of consideration.

[0065] The term "biodegradable" refers to the ability to degrade in vivo, i.e., within the human or animal body. a material or object (e.g., an intraocular implant according to the present invention) that decomposes when exposed to light. In the context of the present invention, as disclosed in detail herein below, An implant comprising particles of a TKI (e.g., particles of axitinib) within a hydrogel. Once deposited in the eye (e.g., in the vitreous humor), the implant in which In certain embodiments, the biodegradation occurs at least in part. Specifically, this occurs via ester hydrolysis in the aqueous environment of the vitreous. It dissolves slowly and is eventually completely absorbed and becomes invisible in the vitreous.

[0066] A "hydrogel" is a material that swells in water and retains a certain amount of water while retaining, for example, individual polymers. Chemical or physical cross-linking of polymer chains to maintain or substantially maintain their structure three-dimensional networks of hydrophilic natural or synthetic polymers (as disclosed herein) that can Hydrogels are soft and flexible due to their high water content, making them suitable for natural In the present invention, the term "hydrogel" refers to a material that closely resembles natural tissue (e.g., Once the hydrogel has formed in aqueous solution, or once the hydrogel has been placed in the eye or elsewhere in the body, water (after being transplanted into a part of the body or otherwise immersed in an aqueous environment and (re)hydrated) Hydrogels in their hydrated state when loaded, and when dried to a low water content (e.g., 1% by weight or less). The term "hydrogel" is used to refer to both the hydrogel when it is dried and the hydrogel in its dry (dry / dehydrated) state. In the present invention, when the active ingredient is contained (e.g., dispersed) within the hydrogel, In this case, the hydrogel is sometimes referred to as a "matrix."

[0067] The term "polymer network" refers to polymer chains (having the same molecular structure) that are cross-linked to each other. It describes a structure formed from molecules (either the same or different, with the same or different molecular weights). The types of polymers suitable for the purposes of the present invention are disclosed herein. The network can also be formed using a crosslinking agent, as disclosed herein. do.

[0068] The term "non-crystalline" also applies to polymers that do not exhibit crystalline structure in X-ray or electron scattering experiments. The term "polymer" refers to a polymer network or other chemical substance or entity.

[0069] The term "semi-crystalline" refers to a material that has some crystalline properties, i.e., is sensitive to X-ray or electron scattering. Polymers or polymer networks or other chemical compounds that exhibit some crystalline properties in random experiments refers to a scientific substance or entity.

[0070] The term "crystalline" refers to a material having crystalline properties as evidenced by X-ray or electron scattering experiments. refers to a polymer or polymer network or other chemical substance or entity that is

[0071] As used herein, the term "precursors" refers to compounds that react with each other and thereby bond through crosslinks. to form a polymer network and thus a hydrogel matrix. The term refers to a compound or compound. Other materials, such as active agents or buffers, may be present within the hydrogel. Although there may be precursors, these are not referred to as "precursors."

[0072] The portion of the precursor molecule that is still present in the final polymer network is referred to herein as "single Therefore, the "units" are the polymer networks that form the hydrogel. For example, poly(ethylene glycol) copolymers suitable for use in the present invention are building blocks or constituents of polymers. The polymer network may be made of the same or different polyethylenes, as further disclosed herein. It may contain glycol units.

[0073] The molecular weights of the polymer precursors used for the purposes of the present invention and disclosed herein are determined by those skilled in the art. This can be quantified by analytical methods known in the art. The molecular weight of the recalled fragments can be determined by gel electrophoresis, e.g., SDS-PAGE (sodium dodecyl sulfate). Polyacrylamide gel electrophoresis), gel permeation chromatography (GPC) (dynamic including GPC with DLS), liquid chromatography (LC), and mass spectrometry analysis (e.g., matrix-assisted laser desorption / ionization time-of-flight (MALDI-TOF) spectroscopic or electrospray ionization (ESI) mass spectrometry) The amount of the polymer (the polymers disclosed herein) can be determined by any known method. The molecular weight of the polymer (including the ethylene glycol precursor) is the average molecular weight (based on the molecular weight distribution of the polymer). Therefore, various molecular weights, including weight average molecular weight (Mw) and number average molecular weight (Mn), are In the polyethylene glycol precursor used in the present invention, The molecular weights given herein are number average molecular weights (Mn).

[0074] In certain embodiments of the present invention, the term "fiber" (as used herein as "rod" (used interchangeably with the term "body") refers to an object having a generally elongated shape (i.e., The examples characterize the implants according to the invention. Specific dimensions are disclosed herein. The implant is cylindrical or essentially cylindrical. The cross-sectional area of ​​the fiber or implant may be cylindrical or non-cylindrical. may be circular or essentially circular, but in certain embodiments may be elliptical. or may be oval, or in other embodiments, may be cross-shaped as disclosed herein. The shape may have various forms such as a square, star, etc.

[0075] As used herein, the term "release" (and correspondingly "released"; "Releasing" refers to the release of a drug (e.g., The ambient environment refers to providing an in vitro API as described herein. In certain specific embodiments, The surrounding environment is the vitreous humor and / or ocular tissues (e.g., retina and choroid). Thus, as used herein, an implant "releases" a TKI (e.g., axitinib). Whenever it is stated that a hydrogel is "or provides (sustained) release," this means that the hydrogel is The TKI (e.g., axitinib) is released from the implant while it is not yet fully biodegraded. It not only refers to the direct delivery from the hydrogel, but also to the residual material that remains after the hydrogel has completely decomposed. The TKI may be present in the environment (e.g., in an aggregated form as further disclosed herein) for an extended period of time. TKIs (e.g., axitinib) are still present and continue to exert their therapeutic effects. The term "therapeutic" also refers to the continuous provision of a therapeutic agent to this environment. The "period" (i.e., the period during which a particular therapeutic effect as described herein is achieved) is As further disclosed herein, after the implant / hydrogel has completely biodegraded, However, it may be extended for a certain period.

[0076] The term "sustained release" for purposes of this invention means that a drug is available over an extended period of time. and thereby provide an immediate release dosage form (e.g., of the active ingredient injected into the eye). A product that can be administered less frequently than a solution (in the present invention, the product is an impregnated It may be used interchangeably herein with "sustained release." Other terms that may be used include "sustained release" or "controlled release." The API contained in the implant according to the present invention, specifically a TKI (e.g., axitinib) The term "sustained release" itself refers to the release of It is not associated with or limited to a particular rate of release (in vitro or in vivo). Although not all implants are specifically designed to be implantable, in certain embodiments of the present invention, the implant may be any of the implants disclosed herein. A specific average rate of release (in vitro or in vivo) or a specific The implants of the present invention may be characterized by a release profile of Whether commonly referred to as a "sustained release" implant or simply as an "implant," The implants of the present invention are referred to as "depots" because they provide sustained release of the API (regardless of whether the It is sometimes called.

[0077] As used herein, certain administrations or injections are used to refer to the administration or administration of implants according to the present invention. is "concurrently" or "simultaneously" with the injection. simultaneously or at the same time Whenever it is stated that two or more implants are injected individually or in combination, this does not include the injection of two or more implants. injection of one or more implant(s) (e.g., an anti-VEGF antibody disclosed herein) injection of a suspension or solution of the drug F, usually immediately alternating with This means that the drug is administered without significant delay. For example, a total dose of approximately 400 μg of axitinib The total dose was administered to one eye, with two implants according to the invention (approximately 200 μg each). When these two implants are included in the same treatment, Immediately alternate within a treatment session, of course, to safely and accurately inject into the desired area. By respecting all precautions in the The same applies to the use of one or more implant(s) according to the present invention in the This also applies when administered concurrently / simultaneously / simultaneously with the administration of an additional anti-VEGF agent. Additional anti-VEGF agents are administered by intravitreal injection of a suspension or solution containing the anti-VEGF agent. If administered, this injection also typically contains one or more injections according to the invention (as disclosed above). Immediately before or immediately after intravitreal injection of the implant(s), i.e., ideally one It is intended to be done during a therapy session.

[0078] However, under certain circumstances, for example, if you experience complications during administration of the first implant, and / or the injecting physician may administer a second injection during the same session on the same day or within a few days. If it is concluded that injection is not advisable, e.g., one or more implants from the first A second implant may be administered two weeks later. As disclosed in detail, the compounds are capable of being administered intravitreously in the vitreous of the human eye for extended periods of time (e.g., about 9 to about 12 hours). two implants, for example, one or two weeks apart, may remain in place for several months. are still considered "concurrent" in the context of the present invention. It also applies to the "concurrent" administration of an implant according to the invention and an anti-VEGF agent. Therefore, the anti-VEGF agent is administered simultaneously with the intravitreal administration of the implant of the present invention, i.e., That is, they can be administered simultaneously or nearly simultaneously as described herein.

[0079] However, in certain other embodiments, the anti-VEGF agent may be administered later (e.g., as an intravenous route in accordance with the present invention). It is administered one, two, or three months after the intravitreal injection of the implant. can also be administered in combination with the intravitreal implant of the present invention.

[0080] The term "rescue medication" generally refers to medication administered under predefined conditions (e.g., to a patient during a trial). are given to patients when they do not adequately respond to the investigational treatment, or to address emergencies. In the clinical trial disclosed in Example 6 of the present specification, a rescue drug was administered. The conditions for this are shown in Example 6 under the subheading "Rescue Drugs" (Rescue Drugs). (See especially Table 27 for % of drug administration.) In certain embodiments of the present invention "Rescue medication" refers to a solution or suspension of an anti-VEGF agent as disclosed herein. Refers to a single dose of an anti-VEGF agent administered as an intravitreal injection. In embodiments, rescue medication is administered as a single dose (2 mg) via intravitreal injection. The drug is aflibercept.

[0081] As used herein, the term "about" in connection with a measured quantity means that the measurement is made and It is expected by a person skilled in the art to exercise a level of care depending on the purpose of the measurement and the accuracy of the measurement equipment. This refers to the normal variation in the measured quantity that is measured.

[0082] The term "at least about" in connection with a measured quantity refers to the amount by which the measurement is made and the purpose and extent of the measurement. The measured results would be expected by a person skilled in the art, exercising a level of care commensurate with the accuracy of the measuring device. This refers to normal variations in the amount measured and amounts higher than those measured.

[0083] As used herein, the term "mean" refers to the central mean in a set of data (points). Or it refers to a typical value, calculated by dividing the sum of the data (points) in the set by the number of data (i.e., the mean value of a set of data).

[0084] As used herein, unless the context clearly dictates otherwise, the singular forms "a", " "an" and "the" have plural referents.

[0085] The term "and / or" used in expressions such as "A and / or B" in this specification The term "A and B" is intended to include both "A and B" as well as "A or B."

[0086] As used herein, "include" and "including" "ng")," "contain," "containing," etc. The open term means "comprising" and can include elements, method steps, etc. is intended to refer to an open-ended list or enumeration, such as a It is not limited to the recited elements, method steps, etc., but may include additional unrecited elements. It is intended to include elements, method steps, and the like.

[0087] The term "up to" when used in conjunction with a specific value or number herein , are intended to include the respective values ​​or numbers.

[0088] The terms "from A to B," "from A to B," and "A to B" are used herein to refer to are used interchangeably and both refer to a range from A to B, including the upper and lower limits of A and B. Point.

[0089] "API", "active (pharmaceutical) ingredient", "active (medicinal) drug", "active (pharmaceutical) ingredient", The terms "(active) therapeutic agent," "active," and "drug" are used interchangeably herein. and substances used in finished pharmaceutical products (FPPs), and in the preparation of such finished pharmaceutical products. refers to substances used in the manufacture of medicines and pharmaceuticals that produce pharmacological activity or other The method has a direct effect on the diagnosis, cure, mitigation, treatment, or prevention of disease; and is intended to have a direct effect on repairing, correcting, or modifying the patient's physiology. There are.

[0090] In certain embodiments, the TKI used in accordance with the present invention is axitinib Axitinib is a metastatic cancer drug indicated for the treatment of advanced renal cell carcinoma (Pf Axitinib is a small molecule (386.47 daltons) It is a synthetic tyrosine kinase inhibitor of the following: VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-β, and c-Kit ( Keating.Axitinib:a review in advanced re nal cell carcinoma.2015,Drugs,75(16):190 3-13;Kernt et al.,Inhibitory activity of ranibizumab, sorafenib, and pazopanib on light-induced overexpression of platelet -derived growth factor and vascular endo thereal growth factor A and the blood vessels endothelial growth factor receptors 1a nd 2 and neuropilin 1 and 2.2012,Retina, 32(8):1652-63) to inhibit angiogenesis (the formation of new blood vessels) These tyrosine kinases are known to be involved in pathological angiogenesis, tumor growth, and cancer progression. Therefore, axitinib inhibits both the VEGF and PDGF pathways. It is a multi-target inhibitor.

[0091] The molecular formula of axitinib is C 22 H 18 N4OS, whose IUPAC name is N-methyl-2 -[3-((E)-2-pyridin-2-yl-vinyl)-1H-indazol-6-yl Axitinib has the following chemical structure: [ka]

[0092] Axitinib was determined to have low solubility in biologically relevant media (PBS, pH 7.2, 37°C). Its partition coefficient (n-octanol) is approximately 0.4-0.5 μg / mL. / water) is 4.2 (logP; see DrugBank entry for "axitinib").

[0093] For purposes of this invention, active agents (including axitinib) are intended to be used in all their possible forms. In the form (any active agent polymorph, or pharmaceutically acceptable salt, anhydrate, hydrate, Other compounds (including other solvates or derivatives) may be used. In the range of Whenever possible, even in the absence of an explicit statement, such polymorphs of the active agent may be used in pharmaceutical preparations. It also refers to acceptable salts, anhydrates, solvates (including hydrates), or derivatives.

[0094] As used herein, the term "polymorph" refers to any of the active agents, such as axitinib. Active drugs that are solid at room temperature can exist in a variety of different crystalline forms, or polymorphs. often exist in a polymorphic form, with one polymorph being thermodynamically most stable at a given temperature and pressure. .

[0095] With respect to axitinib, preferred solid forms and polymorphs of axitinib (anhydrous and solvent forms) (including monohydrates) are described, for example, in AMCampeta et al., Journal of f Pharmaceutical Sciences,Vol.99,No.9,Se All axitinib is disclosed in Ptember 2010, 3874-3886. Polymorphs (whether anhydrous or solvated) may be used in conjunction with the compounds of interest according to certain embodiments of the present invention. Such polymorphs can be used in the preparation of plants, for example, those disclosed in US Pat. No. 8,791,1 40B2 contains the most thermodynamically stable polymorph of axitinib, designated XLI XLI is an anhydrous crystalline form of axitinib. In certain embodiments of the present invention, The axitinib used in the preparation of the implant according to the present invention is the anhydrous crystalline form XLI. In certain other embodiments, the crystalline form of axitinib suitable for use in the present invention is Anhydrous forms include (but are not limited to) polymorphs I, IV, VI, and XXV. In addition to the anhydrous form, various solvents are also used, as described in the cited art. There are many solvates of axitinib, all of which may be used in the preparation of implants according to the present invention. All of the above forms are well characterized in the art and can be used in the preparation of For example, see the Campeta et al. paper cited above, or the patent literature (including, but not limited to, However, US8,791,140B 2, US2006 / 0094763, and WO 2016 / 178150A1, and the like. The axes are known and disclosed in the documents cited herein (though not necessarily to be construed as limiting the scope of the invention). Any of the tinib polymorphs can be used in the present invention.

[0096] In certain specific embodiments, used in the preparation of implants according to the invention: and / or the axitinib 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, 21.0, 22.6, Selected from 23.1, 23.4, 24.1, and 26.0 (each value ±0.2 2θ°) It is characterized by an XRD pattern containing at least five characteristic 2θ peaks. In particular, it is used for the preparation of an implant according to the invention and / or for the preparation of an implant according to the invention. Axitinib present in the runt was 8.3, 9.3, 15.6, 16.5, 17.6, At least 5 selected from 21.0, 24.1 and 26.0 (each value ±0.2 2θ°) characterized by an XRD pattern containing two characteristic 2θ° peaks, and / or Chemical composition at 0.1, 114.7, 154.8, and 167.8 (each shift ±0.2 ppm) In DMSO solvent containing the chemical shift 13 C NMR and / or 171.1, 153.2 , 142.6, 139.5, 131.2, 128.1, and 126.3 (each shift ±0. 2 ppm) 13 C solid-state NMR and / or 213°C Contains two endothermic peaks between 17°C (Peak 1) and 219-224°C (Peak 2). Characterized by DSC isothermal method. In one specific embodiment, WO2016 The nonsolvated crystalline form SAB-I of axitinib disclosed in US Pat. No. 6,781,500 is The composition can be used for the preparation of implants according to

[0097] Axitinib inhibits VEGF signaling and also PDGF signaling In addition to inhibiting VEGF / PDGF, axitinib inhibits the growth of angiogenic survival factors, such as CK. It has a clearance half-life (t 1 / 2 ) inhibits (Rugo et al., Phase I trial of the oral antibiotics is agent AG-013736 in patients with adva nced solid tumors.2005,J clin Oncol.,23( 24):5474-83) (In contrast, ranibizumab and aflibercept 1 / 2 These large antibody molecules are capable of activating the t 1 / 2 If is long , can maintain effective tissue concentrations for several weeks, whereas small molecule antibodies However, axitinib has low solubility and is not readily absorbed for extended periods (e.g., several months). The hydrogel implant of the present invention remains in the vitreous humor (VH) for a period of time. Therefore, a therapeutically effective amount of axitinib is delivered for the duration of the implant's life in the VH. Therefore, intravitreal sustained delivery of axitinib is possible without the need for concomitant therapy. In principle, it can inhibit both the VEGF and PDGF pathways without the need for frequent intravitreal injections. The present invention provides a multi-target inhibitor that can inhibit the

[0098] As used herein, the term "therapeutically effective" refers to the production of a particular desired effect after administration. For example, in the context of the present invention, So, one desirable outcome of treatment is neovascular AMD, as measured by optical coherence tomography. The primary goal of this study is to reduce central space retinal thickness (CSFT) in patients with glaucoma. This is because CSFT is elevated in patients with neovascular AMD. A "therapeutically effective" amount of an active agent in a given substrate is the IC 50 multiples of, e.g., IC 50 For example, the TKI axitinib may be administered at a dose of 50 times or more. IC against angiogenesis-related RTKs 50 The values ​​are presented in Table 12.

[0099] As used herein, the abbreviation "PBS" means phosphate buffered saline.

[0100] As used herein, the abbreviation "PEG" means polyethylene glycol .

[0101] Detailed Description I. Implants Active ingredients: One aspect of the present invention is a sustained release biodegradable intraocular implant comprising a hydrogel and and at least about 150 μg of a tyrosine kinase inhibitor (TKI), and the TKI particles The sustained-release biodegradable intraocular implant is a vitreous sorbent dispersed in a hydrogel. In one embodiment, the present invention provides a method for treating a tyrosine kinase-inhibiting agent comprising administering to a subject a hydrogel and at least about 150 μg of a tyrosine kinase inhibitor. A sustained-release biodegradable intraocular implant containing a TKI, wherein the TKI particles are hydrogels. dispersed within a gel, the implant having a length in its dry state of less than about 17 mm. , provides sustained release biodegradable intraocular implants.

[0102] The active ingredient contained in the implant of this aspect of the present invention is a TKI. Examples include axitinib, sorafenib, sunitinib, nintedanib, pazopanib, and gorafenib, cabozantinib, and vandetanib. The TKI used in this and other aspects of the invention is axitinib. , details of its chemical structure, polymorphism, solvates, salts, etc., and properties such as solubility, etc. are defined above. As shown in Sect.

[0103] All the features (individually or optionally) disclosed herein regarding the implant according to the invention The combination of the features of (a) and (b) comprises a hydrogel and at least about 150 μg of a tyrosine kinase inhibitor. A sustained-release biodegradable intraocular implant containing a TKI, wherein the TKI particles are hydrogels. wherein the implant has a length in its dry state of less than about 17 mm. It can be used to characterize sustained release biodegradable intraocular implants.

[0104] In certain embodiments, the implant of the present invention is an intravitreal implant, i.e., That is, administered into the vitreous humor (also referred to herein as "intravitreally administered").

[0105] The TKI (e.g., axitinib) is administered in a dose of at least 150 μg, for example, from about 150 μg to about 1800μg, approximately 150μg to approximately 1200μg, or approximately 200μg to approximately 800μg Any TKI may be included in the implants of the present invention within the dosage ranges disclosed herein. (e.g., axitinib) may be administered in amounts within these ranges, e.g., about 150 μg, about 200 μg, g, approx. 300μg, approx. 400μg, approx. 500μg, approx. 600μg, approx. 700μg, approx. 80 Use 0 μg, approximately 900 μg, approximately 1000 μg, approximately 1100 μg, or approximately 1200 μg In an alternative embodiment, the TKI contained in the implant of the present invention (e.g., axitinib) doses up to about 1800 μg, e.g., about 1300 μg, 1400 μg, about 1500 μg, about 1600 μg, about 1700 μg, or about 1800 μg In a further alternative embodiment, the implant of the present invention may comprise the dose of the TKI (e.g., axitinib) administered is greater than about 1800 μg, or It may be higher than about 2000 μg, for example, up to about 3000 μg, up to about 6000 μg or up to about 10,000 μg. All values ​​given are subject to +25% and - This includes a 20% variation or + / - 10% variation.

[0106] In certain specific embodiments, the implants of the present invention comprise axitinib. The dosage is as follows: Approximately 160 μg to approximately 250 μg, or approximately 180 μg to approximately 220 μg, or approximately 2 00µg (i.e., +25% and -20% variation of 200µg, or + / -10% (including fluctuations) Approximately 320 μg to approximately 500 μg, or approximately 360 μg to approximately 440 μg, or approximately 4 00µg (i.e., +25% and -20% variation of 400µg, or + / -10% (including fluctuations) Approximately 375 μg to approximately 600 μg, or approximately 450 μg to approximately 550 μg, or approximately 5 00µg (i.e., +25% and -20% variation of 500µg, or + / -10% (including fluctuations) Approximately 480 μg to approximately 750 μg, or approximately 540 μg to approximately 660 μg, or approximately 6 00µg (i.e., +25% and -20% variation of 600µg, or + / -10% (including fluctuations) Approximately 640 μg to approximately 1000 μg, or approximately 720 μg to approximately 880 μg, or approximately 800 μg (i.e., +25% and -20% variation of 800 μg, or + / - 10% (including fluctuations in Approximately 800 μg to approximately 1250 μg, or approximately 900 μg to approximately 1100 μg, or Approximately 1000 μg (i.e., +25% and -20% variation of 1000 μg, or + / - (including 10% variation) Approximately 960 μg to approximately 1500 μg, or approximately 1080 μg to approximately 1320 μg, or is approximately 1200 μg (i.e., +25% and -20% variation of 1200 μg, or + / (including -10% fluctuation) Approximately 1440μg to approximately 2250μg, or approximately 1620μg to approximately 1980μg, or or approximately 1800 μg (i.e., +25% and -20% variation of 1800 μg, or (including + / -10% fluctuation)

[0107] In one preferred embodiment, the axitinib contained in one implant of the present invention The dose of the antibody is about 480 μg to about 750 μg, or about 540 μg to about 660 μg, or In a particular embodiment, it is about 600 μg.

[0108] The disclosed amounts (including the stated variations) of TKIs (e.g., axitinib) are The final content of the active ingredient in the implant and the amount of active ingredient per implant when manufacturing the implant It refers to both the amount of active ingredient used as the starting component and the amount of active ingredient used.

[0109] As disclosed in more detail herein below and as will become apparent from the Examples section, In certain embodiments of the present invention, a TKI (e.g., axitinib) is administered to a patient. The total dose of the implant may be increased by two, three, or more implants administered simultaneously. For example, a dose of about 400 μg of a TKI (e.g., axitinib) may be Although administered in one implant containing 400 μg of axitinib, For example, each containing about 200 μg of axitinib. While combining two or more identical implants (or implants containing the same dose), Not only can two or more different implants (or implants containing different doses) be combined, In certain embodiments, the total dose may be achieved by combining the active ingredient(s) of the compound(s) in the active ingredient(s). In the case of about 480 μg to about 750 μg, or about 540 μg to about 660 μg, or total use Approximately 600 μg of axitinib is contained in one implant, and only one such implant The implant is administered to a patient in need of such treatment according to the present invention. In some embodiments, a total dose greater than about 600 μg, for example, about 800 μg to about 1250 μg, may be used. or about 900 μg to about 1100 μg, or about 1000 μg, or about 960 μg to Approximately 1500 μg, or approximately 1080 μg to approximately 1320 μg, or approximately 1200 μg Total dose, or about 1440 μg to about 2250 μg, or about 1620 μg to about 1980 A total dose of approximately 1800 μg, or 1800 μg, is contained in one implant. Such implants are administered to patients in need of such treatment according to the present invention. In some embodiments, the total dose administered to a patient in accordance with the present invention is The present invention may include two or more implants (containing the same or different amounts of API).

[0110] The TKI (e.g., axitinib) is included in the implant of the present invention, and the polymer network In certain embodiments, the hydrogel is dispersed or distributed within the hydrogel. In the hydrogel, the particles are dispersed homogeneously or essentially homogeneously within the hydrogel. The drug can be prevented from agglomerating and can be released slowly while delivering a drug to the eye. A matrix for the particles can be provided that holds the particles in a desired position within the cavity.

[0111] In certain embodiments of the invention, the TKI particles (e.g., axitinib particles) are They may be microencapsulated. "Microcapsules" (also called "microparticles") The term "spherical particles" refers to particles having a size that varies, for example, between about 50 nm and about 2 mm. Microcapsules are sometimes defined as particles that are separated from the surrounding material (sometimes called a shell). at least one active agent domain (or core) encapsulated within For purposes of the present invention, a TKI (e.g., axitinib) is microencapsulated. One suitable agent for polymerizing (without limiting the disclosure thereto) is poly(lactic acid -co-glycolic acid).

[0112] In other embodiments, the TKI particles (e.g., axitinib particles) are microcapsules. It is not modified and therefore may be used as is, i.e., without the need for other materials (e.g., but not limited to) blended with or adjacent to (but not limited to) poly(lactic-co-glycolic acid); or dispersed within the hydrogel without being microencapsulated in another material, thus Dispersed within the implant of the invention.

[0113] In one embodiment, the TKI particles (e.g., axitinib particles) are micronized particles. In another embodiment, the TKI particles (e.g., axitinib particles) may be It does not have to be powdered. Micronization is the process of reducing the average diameter of the particles of a solid material. Particles with reduced diameter may, among other things, have higher dissolution and erosion rates. This increases the bioavailability of the active pharmaceutical ingredient, and in certain embodiments In addition, micronized particles can be agglomerated during manufacturing operations, which can positively affect release kinetics. In the field of composite materials, particle size can be a key factor in determining the tendency for particles to aggregate (see also Figure 24). It is known that small particles affect the mechanical properties of the compound when combined with other compounds. The smaller the mass fraction, the better the reinforcement obtained at a given mass fraction. The hydrogel matrix exhibited mechanical properties similar to those of larger TKI particles. Properties (e.g., brittleness, strain to fracture, etc.) may be improved. Such properties may be improved by manufacturing, Micronization is important during implantation and during the degradation of the implant. Micronization is also important in the selected dosage form or It can also promote a more homogeneous distribution of the active ingredient in the matrix. The method may be performed by methods known in the art, including sieving, laser diffraction, or dynamic light scattering. In certain embodiments of the present invention, the present invention can be measured by The TKI (e.g., axitinib) particles used in preparing the implant are laser- Diffraction determination of d90 less than about 100 μm and / or d50 less than about 50 μm Alternatively, it may have a d90 of less than about 75 μm and / or a d50 of less than about 20 μm. In a specific embodiment, the d90 of the TKI (e.g., axitinib) is measured by laser diffraction. In very particular embodiments, the particle size may be less than about 30 μm, or less than about 20 μm, as determined by the method. In this study, the d90 of TKI (e.g., axitinib) was determined by laser diffraction. In these or other embodiments, the implants of the present invention are prepared The d50 of the TKI (e.g., axitinib) particles used in the preparation was measured by laser diffraction. In these or other embodiments, the present invention The d10 of TKI (e.g., axitinib) particles used in In certain embodiments, the implants of the present invention may have a thickness of less than about 3 μm. The d100 of the TKI (e.g., axitinib) particles used in the preparation of The "d90" (also referred to herein as "D90") may be less than about 20 μm as determined by The particle size distribution (also called the particle size distribution) of all particles in the measured bulk material is This means that 90% by volume of the particles have a particle size less than the indicated value. For example, if the d90 particle size is less than about 10 μm, the 90% of particles in the measured bulk material % by volume have a particle size of less than about 10 μm. Corresponding definitions apply to other "d" values ​​(e.g., "d10", "d50", or "d100" values ​​(referred to herein as "d10", "d50", or "d100", respectively) Also applies to the "D10", "D50", and "D100" values). In other embodiments, a TKI (e.g., axitinib) having a diameter greater than this specification. ) particles can also be used.

[0114] Micronized TKIs (e.g., axitinib particles) may be purchased exactly as specified from the supplier, For example, the following exemplary axitinib procedure (WO2016 / 183296A1, Example 1 3) in 1800 mL of sterile water for injection (WFI). Weigh into a 2 L beaker, place on a stir plate and stir at 600 RPM with a stir bar. Create a large vortex in the center of the WFI beaker. Place two 60 mL BD syringes into the syringe holders clamped above the WFI beaker. A hypodermic needle (21G, BD) was connected to the syringe, and the axitinib solution was injected. Place the target directly at the center of the vortex for dispensing. Then add the axitinib solution dropwise into the WFI. Run the syringe pump at 7.5 mL / min to precipitate the micronized axitinib. After micronization, axitinib is filtered (e.g., through a 0.2 μm vacuum filter) and washed with WFI. After filtration, rinse the axitinib powder (e.g., by using a spatula) through the filter. Collect the solution from the filter and allow it to stand for a long period of time (e.g., about 12 hours or about 2 hours) to remove excess solvent. Another exemplary method for micronizing axitinib is described in WO2017 / The micronization method described is limited. Instead, other methods of micronizing the active agent (e.g., axitinib) may be used as well. Furthermore, the disclosed micronization method (or other methods) can be used to produce other drugs besides axitinib. It can also be used for active substances such as:

[0115] Another aspect of the invention is a method for producing a composition comprising a hydrogel and at least about 150 μg of a tyrosine kinase inhibitor. A sustained-release biodegradable intraocular implant containing a TKI, wherein the TKI particles are hydrogels. The total weight of the implant in its dry state is about 0.2 mg to about 1.5 mg. In certain embodiments, the sustained-release biodegradable intraocular implant has an amount The TKI is axitinib or another TKI disclosed herein.

[0116] In certain embodiments, the total weight of the implant according to the present invention (referred to herein as "total") The dry mass (also referred to as "mass") can be about 400 μg to about 1.2 mg. In certain specific embodiments, the total weight of an implant according to the present invention is The dry weight is about 0.3 mg to about 0.6 mg, for example, about 0.4 mg to about 0.5 mg. or about 0.8 mg to about 1.1 mg, for example, about 0.9 mg to about 1.0 mg. It is possible.

[0117] All the features (individually or in any combination) disclosed herein relating to the implant according to the invention are The combination of any of the features comprises a hydrogel and at least about 150 μg of a tyrosine kinase inhibitor. A sustained-release biodegradable intraocular implant containing a TKI, wherein the TKI particles are hydrogels. The implant weighs approximately 0.2 mg to 1.5 mg in its dry state. Use to characterize sustained-release biodegradable intraocular implants having a total weight can be done.

[0118] Polymer Network: In certain embodiments, the hydrogel may be formed by crosslinking to form a polymer network. They can be formed from precursors that have functional groups that form between polymer strands or These crosslinks between the arms may be chemical (i.e., covalent) and / or covalent in nature. or physical (eg, ionic bonds, hydrophobic associations, hydrogen bridges, etc.).

[0119] Polymer networks can be prepared from or reacted with one type of precursor. The precursors may be prepared from two or more types of precursors that can be used to obtain the resulting hydrochloride. The gel is selected based on the desired properties. Suitable precursors exist: generally any pharmaceutically acceptable crosslinker that will form a hydrogel. Any polymer that can be used for the purposes of the present invention can be used. The components incorporated (including the polymers used to create the polymer network) are: For example, it should be physiologically safe so as not to induce an immune response or other adverse effects. Hydrogels are formed from natural, synthetic, or biosynthetic polymers. It is possible.

[0120] Natural polymers include glycosaminoglycans, polysaccharides (e.g., dextran), polysaccharides (e.g., cellulose), and polysaccharides (e.g., cellulose). This may include amino acids, proteins, or mixtures or combinations thereof.

[0121] Synthetic polymers are generally produced by different types of polymerization (free radical, anionic or Various polymerizations are possible through polymerization, including thiol polymerization, chain growth or addition polymerization, condensation polymerization, and ring-opening polymerization. Polymerization can be any polymer that is synthetically produced from a suitable feedstock. The reaction can be initiated by an agent, light and / or heat, and can also be mediated by a catalyst.

[0122] Generally, for the purposes of the present invention, a group comprising one or more units of polyalkylene glycol one or more synthetic polymers, such as polyethylene glycol (PEG), polypropylene Poly(ethylene glycol), poly(ethylene glycol)-block-poly(propylene glycol) Copolymer, or polyethylene oxide, polypropylene oxide, polyvinyl alcohol Poly(vinylpyrrolidinone), polylactic acid, polylactic-co-glycolic acid, random or block copolymers, or any combination / blend of these. (However, this list is not intended to be exhaustive.)

[0123] Precursors are covalently linked to each other to form a covalently crosslinked polymer network. In certain embodiments, the polymer may be associatively crosslinked (e.g., free radicals). In polymerization, precursors with at least two reactive centers are those in which each reactive group is capable of reacting with a different compound. They can participate in the formation of long polymer chains and therefore function as cross-linking agents.

[0124] The precursor may have a biologically inert and hydrophilic portion, e.g., a core. In this case, the core refers to the continuous portion of the molecule connected to the arms extending from the core. , where the arms often have functional groups at the ends of the arms or branches. A polymerized PEG precursor is an example of such a precursor, and is further disclosed herein below.

[0125] Thus, hydrogels for use in the present invention may comprise, for example, a first functional group (a set of )(s) and a second functional group(s) ) can be prepared from another multi-arm precursor. The precursor comprises a hydrophilic arm (e.g., a polyethylene glycol unit) terminated with a primary amine. ) (nucleophilic) or may have activated ester end groups (electrophilic) The polymer network according to the present invention is made up of the same or different polymers crosslinked to each other. It may contain mer units.

[0126] Certain functional groups can be made more reactive through the use of activating groups. Such activating groups include (but are not limited to) carbonyldiimidazole , sulfonyl chlorides, aryl halides, sulfosuccinimidyl esters, N- Hydroxysuccinimidyl esters, succinimidyl esters, epoxides, aldehydes Examples include hydrides, maleimides, imide esters, and acrylates. Succinimide esters (NHS) are used to prepare nucleophilic polymers (e.g., primary amine-terminated or thiol-terminated). The NHS-amine crosslinking reaction is useful for crosslinking NHS-terminated polyethylene glycols. In aqueous solution, buffer solutions (e.g., phosphate buffer (pH 5.0-7.5), triethanolamine, Amine buffer (pH 7.5-9.0), borate buffer (pH 9.0-12), or bicarbonate The reaction can be carried out in the presence of a sodium chloride buffer solution (pH 9.0 to 10.0).

[0127] In certain embodiments, each precursor may comprise both a nucleophilic precursor and an electrophilic precursor. As used in reactions, they may contain only nucleophilic or only electrophilic functional groups. Thus, for example, if the crosslinker has only nucleophilic functional groups (e.g., amines), The precursor polymer must have electrophilic functional groups (e.g., N-hydroxysuccinimide). On the other hand, when the crosslinking agent has an electrophilic functional group such as sulfosuccinimide, The polymer can have nucleophilic functional groups such as amines and thiols. functional polymers (e.g., proteins, poly(allylamine), or amine-terminated bifunctional or multifunctional poly(ethylene glycol)) to form the polymer network of the present invention. It is also possible to prepare a sachet.

[0128] In one embodiment, the first reactive precursors each contain from about 2 to about 16 nucleophilic functional groups (functional groups). The polymer network is formed by reacting with the first reactive precursor. The second reactive precursors each have from about 2 to about 16 electrophilic functional groups. The number of reactive (nucleophilic or electrophilic) groups is a multiple of 4, so for example, 4, 8, and 16 reactive groups. Reactive precursors having reactive groups are particularly suitable for the present invention. while ensuring sufficient functionality for proper crosslinked network formation. To do this, any number of functional groups (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 1 2, 13, 14, 15, or 16).

[0129] PEG hydrogel: In certain embodiments of the present invention, the polymer network forming the hydrogel is , which contain polyethylene glycol (PEG) units. PEG forms hydrogels when crosslinked. These PEG hydrogels are known in the art to be useful in pharmaceutical applications, e.g. For example, a matrix of a drug intended to be administered to any part of the human or animal body. It is suitable for use as a custard.

[0130] The polymer network of the hydrogel implant of the present invention may have 2 to 10 arms, or 4 to 8 arms, or one or more multi-arm Ps with 4, 5, 6, 7, or 8 arms The PEG units may have different numbers of arms or may contain the same number of arms. In certain embodiments, the PEG used in the hydrogels of the present invention may have a The units have 4 and / or 8 arms. In certain embodiments, the units have 4 and 8 arms. A combination of PEG units is utilized.

[0131] The number of PEG arms used controls the flexibility or softness of the resulting hydrogel. For example, hydrogels formed by crosslinking four-arm PEGs They are generally softer and more flexible than those formed from 8-arm PEG of the same molecular weight. The implant may be pre-dried or pre-assembled as disclosed later in this specification in the section on implant manufacture. If it is desired to stretch the hydrogel after drying, a more flexible hydrogel, e.g. For example, a four-arm PEG, optionally with another multi-arm PEG (e.g., as disclosed above). It can be used in combination with an 8-arm PEG.

[0132] In certain embodiments of the present invention, polyethylene glycol is used as a precursor. The molecular units are in the range of about 2,000 to about 100,000 daltons, or about 10,000 to about 100,000 daltons. Within the range of about 60,000 daltons, or within the range of about 15,000 to about 50,000 daltons In certain specific embodiments, the polyethylene glycol The molecular weight ranges from about 10,000 to about 40,000 daltons, or about 20,000 daltons. Even if PEG precursors of the same average molecular weight are used, different average PEG precursors of different molecular weights may be combined with each other. The average molecular weight is given as the number average molecular weight (Mn), which in certain embodiments is M This can be determined by ALDI.

[0133] In a 4-arm PEG, each arm has an average arm length (or Therefore, one of the precursors that can be used in the present invention is A 4a20k PEG precursor has four arms each with an average molecular weight of approximately 5,000 daltons. In addition to the 4a20kPEG precursor, the 8a20kP precursor can be used in the present invention. The EG precursor therefore has eight arms each with an average molecular weight of 2,500 daltons. Longer arms may be more flexible than shorter arms. EG may swell more than PEG with shorter arms. PEG with fewer arms may swell more and be more flexible than PEG with more arms. In certain specific embodiments, P Combinations of PEG precursors (e.g., a combination of a 4-arm PEG precursor and an 8-arm PEG precursor) are used in this study. In addition, the longer PEG arms have a higher melting point when dried, which This may increase dimensional stability during storage. For example, trilysine crosslinked molecular weight polymers The 15,000 dalton 8-arm PEG may not be able to maintain an extended configuration at room temperature. whereas a 4-arm 20,000 dalton PEG crosslinked with an 8-arm 20,000 dalton PEG PEG may be dimensionally stable in an oriented configuration at room temperature.

[0134] PEG precursors with a certain average molecular weight (e.g., 15k PEG or 20k PEG) When referring to the G precursors, the average molecular weights indicated (i.e., 15,000 and 15,000, respectively) are used. where Mn is 20,000) refers to the precursor PEG moiety before the end groups are added (here "20k" means 20,000 daltons, and "15k" means 15,000 daltons. The same abbreviation is used for other average molecular weights of PEG precursors herein. In certain embodiments, the Mn of the precursor PEG moiety is determined by MALDI. The degree of substitution with the end groups disclosed herein is determined by the following: 1 HN It can be quantified by MR.

[0135] In certain embodiments, PEG precursors are used in conjunction with the hydrogels of the present invention. The electrophilic end group for use in Such esters include, but are not limited to, "SAZ" (succinic acid esters). "SAP" (referring to succinimidyl adipate end groups) "SG" (referring to succinimidyl glutarate end groups), and "SS" (referring to succinimidyl glutarate end groups). (referring to a cinimidyl succinate end group).

[0136] In certain embodiments, PEG precursors are used in conjunction with the hydrogels of the present invention. The nucleophilic end group for use in is an amine (denoted as "NH") end group. A hydroxyl (-SH) or other nucleophilic end group is also possible.

[0137] In certain preferred embodiments, the average molecular weight is about 20,000 daltons and 4-arm PEG with electrophilic end groups as disclosed in and about 20,000 Daltons The average molecular weight of the polymer and the 8-arm PEG having a nucleophilic end group as disclosed above are used to form the polymer. To form a polymer network and thus a hydrogel according to the present invention, It is cross-linked.

[0138] Nucleophile-containing PEG units and electrophile-containing PEG units (e.g., amine-terminated PEG units and activated ester group-containing PEG units) to form multiple PEG units of the formula: [ka] wherein m is an integer of 0 to 10, and Typically, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In the above formula, for example, when a PEG containing an SAZ end group is used, m is 6. For SG end groups, m is 3, for SS end groups, m is 2, and for SS end groups, m is 1. All of the crosslinks within the polymer network can be the same or different.

[0139] In certain preferred embodiments, the present invention utilizes SAZ end groups. The end group can increase the duration of persistence in the eye, and in certain embodiments of the present invention Implants comprising hydrogels containing PEG-SAZ units can be implanted into the eye, e.g., the human eye. in the vitreous humor after an extended period of time (e.g., 9-12 months), as further disclosed below. The SAZ group is biodegradable depending on the number of carbon atoms in the chain. Since m is 6, the total number of carbon atoms between the amide group and the ester group is 7. ), which are more hydrophobic than, for example, SAP, SG, or SS end groups.

[0140] In certain preferred embodiments, the four-arm 20,000 dalton PEG precursor is , combined with an 8-arm 20,000 dalton PEG precursor, e.g., a SAZ group (see above). A four-arm 20,000 dalton PEG precursor having an amine group (as defined above) is ) and an 8-arm 20,000 dalton PEG precursor. The precursors are herein designated 4a20kPEG-SAZ and 8a20kPEG-NH It is also abbreviated as 2. The chemical structure of 4a20kPEG-SAZ is as follows: [ka] In the formula, R represents the pentaerythritol core structure. The chemical structure of α-glucan (with a glycerol core) is as follows: [ka] In the above formula, n is determined by the molecular weight of each PEG arm.

[0141] In certain embodiments, the molar ratio of nucleophilic and electrophilic end groups that react with each other is It is about 1:1, i.e., one amine group is provided per SAZ group. In the case of 0kPEG-SAZ and 8a20kPEG-NH2, this means that the 8-arm PEG is 4 Since it contains twice the amount of terminal groups as arm PEG, the weight ratio is about 2:1. of nucleophilic (e.g., NHS end groups such as SAZ) or nucleophilic (e.g., amine) end groups Either may be used in excess. In particular, precursors containing nucleophilic groups, e.g., amine end groups, The body can be used in excess, i.e., 4a20kPEG-SAZ and 8a20kP The weight ratio of EG-NH2 can also be less than 2:1.

[0142] Each and any combination of PEG precursors containing electrophilic and nucleophilic groups disclosed herein is can be used to prepare implants according to the present invention. Any 4-arm or 8-arm PEG-NH (with SAP, SG, or SS end groups) The S precursor can be any 4-arm or 8-arm PEG-NH precursor (or a nucleophilic group-containing precursor). In addition, electrophilic group-containing precursors can be combined with other PEG precursors. The PEG units of the nucleophilic group-containing precursor may have the same average molecular weight or different average molecular weights. You may do so.

[0143] Other nucleophilic group-containing crosslinkers may be used in place of PEG-based crosslinkers. a molecular amine linker, such as trilysine (or a salt or derivative of trilysine, e.g., trilysine acetate) or other low molecular weight multi-arm amine linkers. It is possible.

[0144] In certain embodiments, the nucleophilic group-containing crosslinker may be attached to the visualization agent or may interact with the visualization agent. A visualization agent is an agent that contains a fluorescent group or other group that allows visualization. Fluorophores, such as fluorescein, rhodamine, coumarin, and cyano The visualization agent can be, for example, one of the nucleophilic groups of the crosslinker. It can be conjugated to a cross-linking agent via the nucleophilic group. Therefore, in general, "conjugated" or "conjugation" includes partial conjugation, and This means that only a portion of the nucleophilic groups are used for conjugation with the visualization agent, e.g., crosslinked About 1% to about 20%, or about 5% to about 10%, or about 8% of the nucleophilic groups on the crosslinker are linked to the visualization agent. In other embodiments, the visualization agent may be conjugated to, for example, a specific It may be conjugated to a polymer precursor via a reactive (eg, electrophilic) group.

[0145] Further ingredients: The implants of the present invention comprise polymers that form a polymer network as disclosed above. In addition to the mer unit and the active ingredient, other additional ingredients may be included. Such additional ingredients include: For example, salts resulting from buffers used in the preparation of the hydrogel, such as phosphates, boron Other buffering agents include acid salts, bicarbonates, or triethanolamine. In certain embodiments, sodium phosphate buffers (e.g., sodium phosphate monobasic and dibasic sodium phosphate) are used.

[0146] Optionally, preservatives may be used in the implants of the present invention. In certain embodiments, the present invention provides an implant comprising axitinib as the active agent. The implant may contain a preservative, such as an antimicrobial preservative (including but not limited to, benzyl chloride). Benzalkonium (BAK), chlorobutanol, sodium perborate, and stabilized oxy (including chloro complexes (SOC)) or are substantially free of such preservatives stomach.

[0147] In one embodiment of the present invention, where in situ gelation is preferred, possible additional components include: The component may be any other agent used during the preparation of the hydrogel, such as (but not limited to) ) viscosity-influencing agents (e.g., hyaluronic acid, etc.), surfactants, etc.

[0148] In certain embodiments, the inserts of the present invention can include a visualization agent. Visualization agents that can be used in this context are conjugated to components of the hydrogel or or encapsulated in a hydrogel, and may be visible or, for example, All agents that can be visualized when exposed to long-term light or are contrast agents Visualization agents suitable 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, triazapentalene, The visualization agent is a polymer network, as disclosed above. Conjugation with either a nucleophilic group-containing precursor or an electrophilic group-containing precursor results in a network. Alternatively, a visualization agent may be added during the manufacture of the implant and present within the hydrogel. The compound may also be a separate (unconjugated) agent.

[0149] formulation: In certain embodiments, the implant according to the present invention comprises a TKI and a hydrogel a polymer prepared from one or more polymer precursors disclosed hereinabove, in the form - network and optionally additional components (e.g. from the production process to the implant and salts remaining in the solution (e.g., phosphates used as buffers). In certain preferred embodiments, the TKI is axitinib.

[0150] In certain embodiments, the implant according to the present invention has a viscosity of about 1500 saturations in its dry state. % to about 80% by weight (e.g., about 25% to about 75% by weight) of a TKI and about 15% by weight % to about 80% by weight (e.g., about 20% to about 60% by weight) of polymer units, or In this embodiment, about 35% to about 65% by weight of a TKI and about 25% to about 50% by weight of a In a specific embodiment, the polymeric units according to the present invention may comprise: The plant contains about 45% to about 55% by weight of a TKI and about 37% to about 47% by weight of The TKI and the polymer unit may comprise a polymeric unit (dry composition), as described herein above. In another specific embodiment, an implant according to the invention is selected from those shown. In its dry state, it contains about 55% to about 75% by weight of TKI and about 20% to about 40% by weight of PEG-40 % of the polymer unit (dry composition), and the TKI and the polymer unit may be In another specific embodiment, the present invention provides a method for the treatment of a pulmonary arthritis. The implants according to the invention contain, in their dry state, about 30% to about 45% by weight of a TKI and about 47% by weight of a soluble fiber. % to about 70% by weight of the polymer unit (dry composition), The mer units are selected from those disclosed herein above.

[0151] In one particular embodiment, the implant according to the invention has, in its dry state, a viscosity of about 2 5% to about 75% by weight of axitinib and about 20% to about 60% by weight of PEG units; or about 35% to about 65% by weight of axitinib and about 25% to about 50% by weight of P EG units, or about 45% to about 55% by weight of axitinib and about 37% to about 47% by weight of % by weight of PEG units, or about 48% by weight to about 52% by weight of axitinib and about 40% by weight of % to about 44% by weight of PEG units (dry composition). In the dry state, the implant according to the present invention has a content of about 55% to about 75% by weight. axitinib and about 20% to about 40% by weight of PEG units, or about 60% to about 75% by weight axitinib and about 21% to about 31% by weight PEG units (dry composition) may include:

[0152] In one further particular embodiment, the dry weight of the implant according to the invention The standard axitinib to PEG ratio was approximately 40% by weight or less of PEG. It may be 50% or more by weight of axitinib, with the remainder being phosphate. Thus, the ratio of axitinib:PEG on a dry weight basis in the implant according to the present invention is The ratio can be about 1:1 to about 3:1.

[0153] In certain embodiments, the remaining portion of the dry implant (i.e., the TKI ( Axitinib) and polymer hydrogels (e.g., PEG hydrogels) have already been considered. The remainder of the formulation (when considered) is the remaining salt from the buffer solution as disclosed above. In certain embodiments, such salts are phosphates, borates, or In one embodiment, the buffer salt is sodium phosphate (monobasic and and / or dibasic).

[0154] The amounts of TKI and polymer(s) can be varied, and other amounts of TKI and polymer can be used. The merhydrogel can be used to prepare implants according to the present invention.

[0155] In certain embodiments, the maximum amount of drug in the formulation is determined by the polymer (e.g., PEG). Approximately twice the amount of the unit, but may be higher in certain cases, e.g. The mixture containing the precursor, buffer solution, and drug (before the hydrogel was completely gelled) was It is desirable to be able to cast uniformly into the mold or tube.

[0156] In one embodiment of the invention, the hydrogel is, after it is formed and before it is dried, That is, in a wet state, about 3% to about 20% polyethylene glycol (polyethylene glycol In one embodiment, the wet state may include a weight of the gel divided by the weight of the fluid × 100. The hydrogel may be about 5% to about 15%, for example, about 7.5% to about 15% or about 5% to about 10%. % polyethylene glycol (weight of polyethylene glycol ÷ weight of fluid × 100) (including the current

[0157] In one embodiment of the present invention, a wet hydrogel composition (i.e., a hydrogel composition After the composition is formed, i.e., after all the components that form the hydrogel are mixed, The composition contains about 5% to about 50% by weight of an active ingredient (e.g., axitinib) and about 5% by weight of % to about 50% by weight or about 5% to about 30% by weight of PEG units.

[0158] In certain embodiments, when forming an implantable hydrogel according to the present invention, In the wet composition, the solids content (w / v) is about 10% to about 50% or about 25% to about 50%. Here, "solids" refers to the total of the polymer precursor(s), salts, and drug in the solution / suspension. Thus, in certain embodiments, A wet hydrogel composition is cast into a mold or tube to form the hydrogel. The total solids content of the composition is about 60% or less, or about 50% or less, or about 40% or less, e.g., It may be equal to or lower than about 35% (w / v). The content of nibs is about 40% or less, or about 30% or less, for example about 25% (w The solids content can be equal to or less than 1000 ppm (v / v). The solids content can affect the viscosity. This may also affect the flexibility of the wet hydrogel composition.

[0159] In certain embodiments, the hydrogel implant (e.g., before being loaded into the needle, or loaded into the needle) is its dry (dehydrated / dried) state. The water content may also be very low, for example, less than 1% by weight of water. In certain embodiments, it may be lower, in some cases 0.25% by weight or less, or In the present invention, the term "implant" means a water-soluble polymer. The hydrated implant (e.g., once the implant is administered to the eye) (implants after being immersed or otherwise immersed in an aqueous environment and (re)hydrated), and Implants in a dry (dried / dehydrated) state (e.g. When dried to a low moisture content (less than about 1% by weight), or by preparation, the drying step implants when such low water content implants are obtained without the need for In certain embodiments, the implant is After manufacturing, the needles were stored in an inert nitrogen atmosphere in a glove box for at least approximately 7 days before being loaded into the needles. Implants stored under a clean atmosphere (containing less than 20 ppm of both oxygen and moisture) The water content of the implant can be measured, for example, using the Karl Fischer coulometry method. This can be done.

[0160] In certain embodiments, the total weight of the implant according to the present invention (referred to herein as "total") The dry mass of the cellulose acetate solution is about 200 μg (i.e., 0.2 mg) to about 100 μg (i.e., 0.2 mg). The amount can be 1.5 mg, or about 400 μg to about 1.2 mg. In one embodiment, the total weight of an implant according to the present invention, in its dry state, is about 0.3 mg to about 0.6 mg, for example, about 0.4 mg to about 0.5 mg (for example, when the implant In one embodiment, the amount of xitinib is about 160 μg to about 250 μg. In certain other specific embodiments, the total mass of an implant according to the invention is In this state, about 0.75 mg to about 1.25 mg, or about 0.8 mg to about 1.1 mg, or about 0.9 mg to about 1.0 mg (for example, if the implant contains axitinib, about 480 μg to about 7 (When contained in an amount of 50 μg)

[0161] In one particular embodiment, the implant according to the invention has a thickness of 1 mm in its dry state. 3 per (i.e., 1 mm of dry implant) 3 (per volume) Approx. 200 μg to Approx. 100 0 μg of a TKI (e.g., axitinib). In terms of shape, the implant according to the invention has a thickness of 1 mm in its dry state. 3 Approximately 200 per μg to approximately 300 μg of axitinib (e.g., the implant delivers axitinib to approximately 160 μg) In certain other specific embodiments, the amount of the hydroxybenzoate may be in the range of 1000 to 1500 μg. In the dry state, the implant according to the invention has a thickness of 1 mm 3 Approximately 500μg per serving Approximately 800 μg of axitinib (e.g., implants containing approximately 480 μg to approximately 750 μg) It may contain axitinib).

[0162] Thus, the implants of the present invention can have different densities. The density of the plant (i.e., in its dry state) can be affected by a variety of factors, including but not limited to: However, the concentration of the components in the wet composition when forming the hydrogel and during the manufacture of the implant For example, certain conditions can be controlled and determined by The final implant density in certain embodiments may vary at certain points during the manufacturing process. , can be increased by sonication or degassing (e.g., using a vacuum).

[0163] In certain embodiments, implants according to the present invention provide extended release. a therapeutically effective amount of a TKI (e.g., axitinib) for the treatment of rheumatoid arthritis, but nevertheless Relatively small length and / or diameter. This is beneficial from the standpoint of ease of administration (injection) and This reduces the chance of damaging the eye tissue and improves the patient's vision while the implant is in place. This is advantageous both in terms of reducing the possibility of affecting the Runt is a suitable high-dose TKI (i.e., tailored to the needs of the particular patient). It combines the advantages of a high therapeutically effective dose with the advantages of a relatively small implant size.

[0164] Exemplary implants according to the present invention are listed in Tables 1, 6, 21.1, 21.2, and 21.3 in the Examples section. 1, 2, and 29 (Table 29, which discloses implants according to the present invention containing high doses of TKI) The present invention is disclosed in the following patent application (including a hypothetical example of the present invention).

[0165] Implant dimensions and dimensional changes upon hydration due to stretching: Dried implants may be prepared by the manufacturing method (e.g., by adding a TKI-containing hydroxybenzoate to the implant prior to complete gelation). Various methods are available depending on the type of gel (e.g., the use of molds or tubes to cast the mixture containing the gel precursor). The implant according to the invention can have any geometric shape. The term is also referred to herein interchangeably with the term "rod"), where: Fibers are generally objects having an elongated shape. The present invention can have different geometries with specific dimensions as disclosed in.

[0166] In one embodiment, the implant is cylindrical or essentially cylindrical in shape. In this case, the implant has a circular or essentially circular cross section.

[0167] In another embodiment of the invention, the implant is non-cylindrical and the implant in a dry state, optionally elongated, the length of the implant being greater than the width of the implant; The width is the largest cross-sectional dimension substantially perpendicular to the length. The width can be about 0.1 mm to about 0.5 mm. A circular diameter fiber (or a cross section thereof) may be used. Instead of a cylindrical implant, the cross-shaped fibers (i.e., the cross-sectional geometry Other cross-sectional geometries, e.g., oval or cross-shaped, may also be used. In general, oval, rectangular, triangular, star, etc. shapes may also be used. In some embodiments, the fibers may be twisted. In embodiments, the dimensions of the implant (i.e., its length and diameter) and its cross-section The geometry of the implant allows for the insertion of needles, particularly 25 gauge needles as further disclosed herein. The needle must be capable of being loaded into a fine diameter needle, such as a 27-gauge or 28-gauge needle.

[0168] Polymer networks (e.g., hydrogel impregnation according to certain embodiments of the present invention) The PEG network of the PEG polymer is semi-crystalline in the dry state below room temperature and amorphous in the wet state. Even in the expanded form, the dry implant remains dimensionally stable at or below room temperature. , which can be advantageous for needle loading and quality control of the implant.

[0169] Once the implant is hydrated in the eye (this is done by placing the implant in PBS at 37°C, pH 7.2), The dimensions of the implant according to the invention can be varied (this can be simulated by immersing the implant in water). Generally, the diameter of the implant may increase while the length decreases, or The advantage of this dimensional change is that the implant can In the dry state, a fine diameter needle (e.g., 25 gauge, 27 gauge, or thin enough to be loaded into needles of smaller diameter (such as a 30 gauge needle) However, once placed in the eye, for example in the vitreous humor, the implant penetrates the limited area of ​​the eye. It can be even shorter to better fit within a small volume. The needles used to inject the implants of the disclosed invention (e.g., in certain embodiments 25-gauge or 27-gauge needles) have a small diameter (e.g., an inner diameter of about 0.4 mm) The implant can also soften during hydration, allowing the implant to penetrate the eyeball. Even when tissue is contacted, damage to any ocular tissue can be prevented or minimized. In certain embodiments, the dimensional change is due, at least in part, to the manufacturing of the implant. The "shape memory" effect introduced by longitudinally stretching the implant during This is possible (also disclosed in the "Method of Manufacturing" section below). In this case, stretching can be performed either in a dry state or in a wet state, i.e., in a hydrogel implant. It should be noted that stretching can be performed after or before drying the polymer. If the hydrogel implant is simply dried and cut to the desired length without further treatment, the implant will not be able to withstand hydration. The advantage is that both the diameter and length of the implant can be increased. The hydrogel fibers can be dry stretched or wet stretched.

[0170] In the case of preformed dry hydrogels, the material is dry stretched and then solidified, resulting in molecular orientation. By fixing the polymer, it is possible to impart a certain degree of molecular orientation. In this embodiment, the material is stretched (optionally above the melting point of the crystallizable region of the material). This is achieved by heating the material to a temperature where the crystallizable regions are then crystallized. Alternatively, in certain embodiments, the glass of the dried hydrogel can be The glass transition temperature is used to orient the molecules of a polymer such as PVA, which has a suitable glass transition temperature. Yet another alternative is to stretch the gel before it is completely dried ("wet stretching"). The process involves stretching the material (also called "stretching") and then drying the material under tension. This molecular orientation This provides one mechanism for anisotropic swelling when introduced into a hydrated medium such as the body. Certain embodiments of the implant swell only in the radial dimension while decreasing in length. The term "anisotropic swelling" refers to a cylindrical shape with a diameter The longitudinal dimension swells predominantly, but the longitudinal dimension swells very little (or even shrinks). This means that the polymer swells preferentially in one direction and not in another.

[0171] The extent of the dimensional change upon hydration may depend, among other things, on the stretch factor. When stretched with a stretch factor of 1.3 (e.g., by wet stretching), the effect is not significant or the water In contrast, for example, the length may not change significantly during the synthesis. When stretched (e.g., by wet stretching) with a stretch factor of For example, stretching with a stretch factor of 4 (e.g., by dry stretching) may be much shorter in length (e.g., reduced from 15 mm to 8 mm in length). Those skilled in the art will appreciate that factors other than stretching may also affect swelling behavior. It would be.

[0172] Stretching the hydrogel affects its ability to change dimensions of the implant upon hydration Other factors include the composition of the polymer network. When used, precursors with fewer arms (e.g., 4-arm PEG precursors) have fewer arms. This results in more flexible hydrogels than precursors with a higher number of PEGs (e.g., 8-arm PEG precursors). When the hydrogel contains many components with low flexibility (e.g., When the amount of PEG precursor containing a higher number of arms (e.g., 8-arm PEG units) is large, In this case, the hydrogel may become stiffer and less easily stretched without breaking. On the other hand, more flexible components (e.g., PEG precursors containing fewer arms (e.g., For example, hydrogels containing 4-arm PEG units are easier to stretch and softer. However, it is possible that the implant may swell more during hydration. Behavior and properties once placed in the eye (i.e., once the hydrogel is (re)hydrated) by changing the structural characteristics and by altering the implant after it is initially formed. Adjustments can be made by modifying the plant's processes.

[0173] Exemplary dimensions of the implants used in the following examples are provided, inter alia, in the Examples section. Tables 6, 21.1, and 21.2 of the FDA's FDA Approval Guidelines for the Use of Acute Toxic Substances (ATOs) are shown in Tables 6, 21.1, and 21.2 of the FDA Approval Guidelines for the Use of Acute Toxic Substances (ATOs). Specific implants containing citinib are disclosed in Tables 21.1 and 21.2. However, implants containing approximately 200 μg or approximately 600 μg of axitinib were It may have dimensions (i.e., length and / or diameter) different from those disclosed in the table. The dimensions of the dried implant depend, among other things, on the amount of TKI incorporated and the TKI The diameter of the mold or tube that allows the hydrogel to gel depends on the ratio of the polymer units to the Furthermore, the diameter of the implant can be controlled by, among other things, This is further determined by (wet or dry) stretching of the formed hydrogel strands. The dried strands (after stretching) are cut into segments of the desired length and then impregnated. Therefore, the length can be selected as needed.

[0174] Disclosed below are embodiments of implants with specific dimensions. Whenever the dimension range or value is related to the length and diameter of the implant, The implant is cylindrical or essentially cylindrical, provided that the length and diameter of the cylindrical implant are All values ​​and ranges disclosed herein for non-cylindrical inks as also disclosed herein. The same can be used for the length and width of the implant, respectively.

[0175] In one particular embodiment, the implant of the present invention has a size of about 17 mm in its dry state. In a specific embodiment, the length of the implant is less than the length of its dry state. In this state, it is about 15 mm or less, or about 12 mm or less, or about 10 mm or less, or about 8.5 In a specific embodiment, the implant of the present invention can be In its dry state, it may have a length of about 12 mm to about 17 mm, or in its dry state, it may have a length of about 6 mm to about 17 mm. The length may be from about 6 mm to about 10 mm, or specifically from about 6 mm to about 9 mm.

[0176] In certain embodiments, the implant of the present invention has a thickness of about 0.1 mm in its dry state. In certain other embodiments, the implant may have a diameter of from about 0.5 mm to about 0.5 mm. In its dry state, it may have a diameter of about 0.2 mm to about 0.5 mm. In this case, the implant, in its dry state, is approximately 0.2mm to 0.4mm, or approximately 0. In a specific embodiment, the implant of the present invention may have a diameter of 3 mm to about 0.4 mm. The thickness of the material is approximately 0.2mm to 0.3mm, or approximately 0.3mm to 0.4mm when dry. The diameter of the axial length of the axial groove may be 0.05 mm.

[0177] In certain embodiments, the implant, in its dry state, has a diameter of about 6 mm to about 10 mm. It may have a length and a diameter of about 0.2 mm to about 0.4 mm.

[0178] In certain embodiments, the implant of the present invention, in its wet / hydrated state, has a viscosity of about 6 In certain other embodiments, the implants of the present invention may have a length of from about 12 mm to about 15 mm. The runt, in its wet / hydrated state, is about 10 mm or less in length, or about 6 mm to about 10 mm in length. In a specific embodiment, the implant of the present invention may have, in its wet / hydrated state: and may have a length of about 6 mm to about 8 mm.

[0179] In certain embodiments, the implant of the present invention, in its wet / hydrated state, has a viscosity of about 0. 0.8mm or less, or about 0.5mm to about 0.8mm, or about 0.65mm to about 0.8mm In a specific embodiment, the implant of the present invention may have a diameter of 100 mm. In a hydrated state, it may have a diameter of about 0.7 mm to about 0.8 mm.

[0180] In certain embodiments, the implant has a thickness of about 10 mm or less in its wet / hydrated state. It may have a length and a diameter of about 0.8 mm or less.

[0181] In an embodiment of the present invention, the diameter of the implant in the dry state is The implant can be loaded into a small diameter needle (e.g., 25-gauge or 27-gauge needle). Specifically, in one embodiment, the diameter of the particle is about 480 μg. ~The diameter of the implant containing approximately 750 μg of axitinib can be loaded into a 25-gauge needle or loaded into a 27 gauge needle without causing any damage to the implant during loading diameter and further handling (including packaging, sterilization, shipping, etc.) The diameter may be such that the implant can remain stably within the needle.

[0182] Disclosed herein are lengths or diameters of the wet / hydrated implants of the present invention. Wherever measurements are made (units: mm), this disclosure is based on measurements made after 24 hours at 37°C and pH 7.2. In this context, pH 7.2 refers to the length or diameter of the implant, respectively. This should be understood to include a pH range of 0.2 to about 7.4.

[0183] When the implant remains under these conditions, the implant dimensions decrease over time. (i.e., after 24 hours) may further change (e.g., the length may change slightly again) However, when the implant hydrated dimensions are reported herein, Invariably, these were measured after 24 hours at 37°C in PBS, pH 7.2, as disclosed above. This has been determined.

[0184] If multiple measurements of the length or diameter of a single implant are taken, or if multiple measurements are taken during the measurement, If multiple data points are collected, the average, as defined herein, ) (i.e., mean) values ​​are reported. The diameter and diameter can be determined, for example, by microscopy or by (optionally automatically) measuring the diameter as described in Example 6.1. Measurements can be made using a camera system (automated).

[0185] In certain embodiments, the hydrated diameter of the implant of the present invention versus the direct diameter of the dry state The ratio of the diameters is less than about 5 mm, or less than about 4 mm, or less than about 3.25 mm, or less than about 2 It can be less than 0.5mm, or less than about 2.25mm, or less than about 2.10mm do.

[0186] In certain of the same or other embodiments, the dry length of the implant of the present invention The ratio of the length to the hydrated state is greater than about 0.7, or greater than about 0.8, or greater than about 0.9, or In certain specific embodiments, the dry impregnation The ratio of runt length to hydrated implant length is greater than about 1.5, or even about 2. This dry length to hydrated length ratio can be greater than 0. Applies in addition to or regardless of the ratio of hydrated diameter to dry diameter It is also possible.

[0187] The small dry diameter makes it possible to use the small diameter injection needles disclosed herein (e.g., 2 This may be advantageous as the implant may fit into a 27-gauge or 5-gauge needle. In addition, the swelling during hydration must be kept to a moderate level to prevent the implant from becoming excessively voided in the vitreous humor. The relatively short length of the implant can be advantageous in that it does not occupy space. , which can be advantageous in reducing the chance of contact with the retina.

[0188] In one embodiment, the implant of the present invention has a weight of about 160 μg to about 250 μg, or or about 180 μg to about 220 μg, or about 200 μg of axitinib, When dried, it has a shape of about 14.5 mm to about 17 mm or about 1 It has a length of 5 mm to about 16.5 mm and a diameter of about 0.20 mm to about 0.30 mm. Such implants, upon in vivo hydration within the eye (e.g., in the vitreous humor), or in vitro hydration (where in vitro hydration is at 37°C, p The length ranges from about 6.5 mm to about 8 mm (measured after 24 hours in phosphate buffered saline at H7.2). mm or about 7 mm to about 8.5 mm, and the diameter is reduced to about 0.65 mm to about 0.8 mm or may increase to about 0.70 to about 0.80 mm. In one embodiment, this dimensional change is , a stretch factor of about 2 to about 5, or a stretch factor of about 3 to about 4.5, as disclosed herein This can be achieved by dry stretching.

[0189] In another embodiment, the implant of the present invention comprises from about 480 μg to about 750 μg, contains about 540 μg to about 660 μg, or about 600 μg of axitinib, and the fiber (cylindrical When dried, it takes the shape of about 6 mm or about 7 mm to about 12 mm. The inner length and diameter are about 0.25 mm to about 0.50 mm, or about 7 mm to about 10 mm. The device may have a length of about 8 mm to about 11 mm and a diameter of about 0.3 mm to about 0.4 mm. In particular embodiments, the implants of the present invention have a weight of about 480 μg to about 750 μg, contains about 540 μg to about 660 μg, or about 600 μg of axitinib, and the fiber (cylindrical and in its dried state, it has a size of about 7 mm to about 10 mm (for example, about 7 mm to about 10 mm). about 9 mm) and 0.3 mm to 0.4 mm (for example, about 0.35 mm to about 0.39 mm) The diameter of the slit may be 1 / 4 m.

[0190] Such implants, upon in vivo hydration within the eye (e.g., in the vitreous humor), , or upon in vitro hydration (where in vitro hydration is at 37°C, (measured after 24 hours in phosphate buffered saline at pH 7.2) The length may be essentially maintained, reduced, or slightly It may increase, for example, to about 6 mm or about 9 mm to about 12 mm in its hydrated state. Lengths within the range and diameters from about 0.5 mm to about 0.8 mm, or from about 9.5 mm to about 11.5 mm The length is about 0.65 mm to about 0.75 mm or about 0.8 mm. In particular embodiments, the implants of the present invention have a weight of about 480 μg to about 750 μg, The composition contains about 540 μg to about 660 μg, or about 600 μg of axitinib, and its hydrated form The fibers (cylindrical shape) were grown at room temperature (i.e., after 24 hours at 37°C and pH 7.2 as described above). ) and has a length of about 6 mm to about 10.5 mm (for example, about 6.5 mm to about 8.5 mm). The length may be about 0.7 mm to about 0.8 mm and the diameter may be about 0.7 mm to about 0.8 mm.

[0191] In one embodiment, 480 μg to about 750 μg, or about 540 μg to about 660 μg The length of the implant of the present invention containing 100 μg, or about 600 μg, of axitinib is dried. The length of the sample is 10 mm or less when it is frozen and when it is hydrated (at 37°C, pH 7.2 phosphate buffer solution). Even after 24 hours in saline solution, the length is approximately 10 mm or less or substantially longer. or about 9 mm or less, or about 8 mm or less in length.

[0192] In one or more embodiment(s), the dimensional change is a stretch factor of about 0.5 to about 5. number, 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. This can be achieved by wet stretching at a stretch factor of 7 to about 3, or at a stretch factor of about 2 to about 2.5. In other embodiments, about 480 μg to about 750 μg, or about 540 μg Implants of the invention containing about 660 μg, or about 600 μg, of axitinib are In the dry state, it may be longer than about 12 mm, but in the hydrated state it may be longer than about 10 mm or about 9 mm. It can be shorter.

[0193] In certain embodiments, this stretching results in shape memory, i.e. This is because the implant regains its original shape upon hydration when administered intraocularly, for example, into the vitreous cavity. The length contracts until it (approximately) approaches the equilibrium size determined by the dimensional and compositional variables. This means that the diameter will increase. Narrowing the drying dimension will allow for the use of smaller gauge needles. While this makes administration easier, the expanded diameter and shortened length after administration prevent the The implant becomes shorter in the chamber relative to the diameter of the eye (e.g., approximately 9-10 mm in length, or at least not significantly more than that), minimizing the possibility of contact with surrounding eye tissue. Thus, in one embodiment, the present invention provides a method for treating an inflammatory bowel disease in which an active agent (e.g., axitinib) A method of imparting shape memory to a hydrogel fiber comprising: and stretching the hydrogel fibers longitudinally to impart shape memory. In another aspect, the present invention relates to a method for treating a rheumatoid arthritis (RA) comprising administering to a subject an active agent (e.g., a TKI, e.g., axillary steroid) to treat a rheumatoid arthritis (RA) associated with a rheumatoid arthritis (RA). and a method for preparing an intraocular implant comprising a hydrogel having dispersed therein an anti-inflammatory drug (anti-inflammatory drug) The implant changes dimensions upon administration to the eye, and the method comprises dissolving the hydrogel fibers. and longitudinally stretching the fiber.

[0194] In vitro release: The in vitro release of TKIs from the implants of the present invention is disclosed in detail in Example 2. This can be quantified by a variety of methods.

[0195] Briefly, one method measures the in vitro release of TKIs from implants. The method is a non-sink simulated PBS (phosphate buffered saline, pH 7.2) at 37°C. Under physiological conditions, PBS was replaced daily with a volume equivalent to the vitreous volume of the human eye. The results of an exemplary implant are shown in Figure 4A. As described in Example 2, PEG hydrochloride was added to the implant. In the test implants containing axitinib in a Rogel matrix, the higher the dose strength, the , resulting in a higher concentration of axitinib in the release medium.

[0196] Generally, in an embodiment of the present invention, the implants according to the present invention are stored at 37°C, pH 7. In vitro, the average daily dose was approximately 0.1 μg to approximately 10 μg / day in 2% PBS for a 30-day period. 3 μg, or about 0.25 μg to about 2.5 μg, or about 0.1 μg to about 2 μg Alternatively, about 0.25 μg to about 1.5 μg can be released.

[0197] In one embodiment, an implant according to the invention comprising about 200 μg of axitinib. The test was performed in vitro at 37°C in phosphate buffered saline at pH 7.2 for a period of 30 days. It can release an average of about 0.01 μg to about 0.15 μg of axitinib per day. do.

[0198] In one embodiment, an implant according to the invention comprising about 600 μg of axitinib. The test was performed in vitro at 37°C in phosphate buffered saline at pH 7.2 for a period of 30 days. It is possible to release an average of about 0.3 μg to about 0.5 μg of axitinib per day.

[0199] In accelerated in vitro studies, detailed in Example 2, TKI release was quantified in a 25:75 ethanol / water mixture (v / v) at 37°C. This accelerated in vitro test can be completed in approximately two weeks. Figure 14 B is an accelerated in vitro study of an implant according to the invention containing about 200 μg of axitinib. FIG. 4B shows the release data of an injectable bolus containing approximately 556 μg of axitinib according to the present invention. Accelerated in vitro release data for the plant is presented.

[0200] In one embodiment, an implant according to the invention comprising about 200 μg of axitinib. The rats were incubated in a 25:75 ethanol / water mixture (v / v) at 37°C for 3 days to axenicize the rats. Approximately 35% to 45% of that of nibromide in 7 days, approximately 65% ​​to 75% of that of axitinib in 12 to 13 days Approximately 90% to 100% of axitinib is released in vitro.

[0201] In one embodiment, an implant according to the invention comprising about 600 μg of axitinib. The rats were incubated in a 25:75 ethanol / water mixture (v / v) at 37°C for 2 days to axenicize the rats. Approximately 40% to 60% of axitinib in 4 days, approximately 65% ​​to 85% of axitinib in 6 days Approximately 75% to 90% of the nib is released in vitro. Implants according to the invention containing tinib were incubated in a 25:75 ethanol / water mixture ( v / v), approximately 45% to 55% of axitinib was lost in 2 days, and approximately 45% to 55% of axitinib was lost in 4 days. Approximately 70% to 80% of axitinib was released in vitro in 6 days, and approximately 80% to 90% of axitinib was released in 1 day. Sometimes it is issued.

[0202] Finally, the release of TKI from the implants of the present invention was also demonstrated as detailed in Example 2. In addition, real-time sinks may be quantified under simulated physiological conditions. In the experiment, octadecanoate was placed on PBS (pH 7.2) / 0.01% NaF at 37°C. The release of TKI from the implant into the vitreous humor was measured with and without the Nol overlay. Qualitatively simulate the release of TKIs into the ocular tissue and their absorption into the ocular tissue. One method for achieving this is to administer an implant according to the present invention containing about 200 μg of axitinib. An exemplary real-time release profile is shown in Figure 14A.

[0203] In one embodiment, an implant according to the invention comprising about 200 μg of axitinib. The rats were incubated at 37°C, pH 7.2, in phosphate-buffered saline with an octanol overlay for 2 months. Approximately 25% to 35% of citrinib at 3 months, approximately 47% to 57% of axitinib at 5 months Approximately 70% to 80% of axitinib was achieved in 7 months, and approximately 90% to 100% of axitinib was achieved in Release in vitro.

[0204] In vitro release testing, particularly the accelerated in vitro release testing described herein, For example, for purposes of quality control or other qualitative evaluation, it is possible, inter alia, to compare different implants (e.g. To compare different products (e.g., different production batches, different compositions, and different dosage strengths) with each other It can be used.

[0205] In vivo release and sustained release: In one embodiment of the present invention, the dry implant of the present invention is administered to the eye (e.g., the vitreous humor). ), the implant hydrates and changes dimensions as disclosed above, and then The implant will biodegrade over time and eventually be completely absorbed. When biodegraded (through hydrolysis), the implant gradually swells and softens, and then It becomes smaller, softer, more liquid, and eventually dissolves completely and becomes invisible. The inventors have recognized from animal studies presented in the Examples section herein below. Thus, implants according to the present invention can be used in rabbit eyes for about 2 to about 6 months, or for about 5 to about 10 months. It can last for 6 months (see Figures 7A, 9, and 10). After complete degradation of the implant, dissolution Undissolved axitinib particles may remain at the site of the implant and may agglomerate. These remainders have been observed to merge, i.e., to form a monolithic structure. Undissolved axitinib particles provide therapeutically effective axitinib levels In certain embodiments, dissolution can continue slowly at a rate sufficient to Two or more implants may be administered to achieve the desired total dose, and they may be administered over time. The remaining axitinib particles are integrated into a single monolithic structure. (See Figure 9.)

[0206] In certain embodiments, the present invention can be used in the human eye (e.g., in the vitreous humor). The implant is administered within approximately 2 to 15 months, or within approximately 4 to 13 months, or is biodegraded within about 9 to 12 months after administration, specifically within about 9 to 10.5 months after administration. This is achieved by administering one or two implant(s) (each containing 200 μg of axin). This has been demonstrated in clinical trials using nibs (including nibs). See the Examples section, specifically Example 6. See also FIG.

[0207] In one embodiment, the implant after administration to the vitreous humor is administered with a TKI, e.g., At least about 3 months after administration of a therapeutically effective amount of a TKI (e.g., a therapeutically effective amount of axitinib) , at least about 6 months, at least about 9 months, at least about 10 months, at least about 11 months, or at least about 12 months, or at least about 13 months, or longer In certain embodiments, the implant releases the The agent releases the TKI (eg, axitinib) for a period of about 6 to about 9 months.

[0208] In one embodiment of the invention, the implant is provided to the patient (i.e., a single implant). After administration of the plant into the vitreous humor, the At least about 10 months, at least about 11 months, at least about 12 months, or at least about 1 This results in a treatment period of 3 months or more.

[0209] In one embodiment of the invention, the TKI (e.g., axitinib) is administered by implantation. to about 0.1 μg / day to about 10 μg / day, or about 0.5 μg / day to about 7 μg / day, or Nitrogen is released at an average rate of about 0.5 μg / day to about 2 μg / day, or about 1 μg / day to about 5 μg / day. in the body fluids of the fetus for at least 3 months, or at least 6 months, or at least 9 months, or or a period of at least 11 months, or at least 12 months, or at least 13 months In certain embodiments, the release of the TKI (e.g., axitinib) The effect is maintained for approximately 6 to 9 months after administration of the implant.

[0210] As presented in the Examples section herein, preclinical studies in animals and in humans have Clinical trials in humans have demonstrated that the implant of the present invention delivers therapeutically effective doses of TKIs over a long period of time. It was shown that the drug could be released continuously until the implant was completely biodegraded. Residual undissolved TKI particles (if present) remain at the site of the implant. essentially remain, coherently forming essentially monolithic structures (see Figures 7A, 9, and 10 ) and this structure can be distributed in the vitreous at levels sufficient to achieve a therapeutic effect. However, in certain embodiments, the release of the TKI into the implant may continue. Before the biodegradation of the implant is complete, the entire amount of TKI contained in the implant is released from the implant. In this case, the undissolved TKI particles are released after the complete biodegradation of the implant. Remain near the implant site or elsewhere in the eye (and / or clump together) It is unlikely that this will occur.

[0211] In one embodiment, the persistence of the hydrogel in an aqueous environment and in the human eye is In particular, it depends on the hydrophobicity of the carbon chain adjacent to the degradable ester group. In the case of implants prepared using PEG, this carbon chain is attached to the SAZ functional group of the 4a20k PEG precursor. It contains seven carbon atoms, which allows it to survive in the human eye for up to about 9 months to about 12 months. months, or from about 9 months to about 10.5 months. In this study, different precursors from 4a20kPEG-SAZ and 8a20kPEG-NH2 were used. and biodegrade in the human eye, similar to or different from the implants exemplified in the examples. Hydrogel implants can be prepared that have a long-lasting effect.

[0212] In certain embodiments, the hydrogel implant softens over time as it degrades. This may depend, among other things, on the structure of the linker that bridges the PEG units within the hydrogel. 4a20kPEG-SAZ and 8a20kPEG- Implants formed from NH2 soften fairly slowly over time.

[0213] Mechanism of release: Without wishing to be bound by theory, it is believed that the TKI is released from the implant of the present invention. The mechanism by which this occurs can be explained as follows: In an embodiment of the present invention, intraocular and vitreous The release of TKI into the fluid is determined by diffusion and drug clearance. An exemplary TKI is axitinib. Axitinib has a very high solubility in physiological media. It has been determined that the concentration is low (about 0.4 to about 0.5 μg / mL in PBS at pH 7.2). According to the disclosure, TKIs (e.g., axitinib) have specific geometric shapes and surfaces. Confined within a biodegradable hydrogel. The fluid in the posterior chamber is viscous and has slow clearance. Flow is relatively stagnant (at least compared to the anterior chamber).

[0214] In certain embodiments, the implants of the present invention are made from a polymer network. The hydrogel contains a drug dispersed within the hydrogel. The drug gradually dissolves. This allows the hydrogel to diffuse into the eye, as it is in contact with the liquid environment of the vitreous. This may occur first in the outer regions of the hydrogel (i.e., the drug located in the outermost region of the hydrogel). (The outermost particles dissolve and diffuse first, the innermost regions last). In this embodiment, the outer region of the hydrogel is devoid of drug particles. Also called the "clearance zone," this is limited to dissolved drug only and does not exceed the drug's solubility. In certain embodiments, this low surface concentration is Physical separation of drug particles from tissue (retina or other cells) upon contact with the tissue This can protect such tissues from potential drug toxicity. In this context, the "clearance zone" refers to the active substance within the inner region of the hydrated hydrogel upon hydration. An outer region has a lower concentration of the active agent than the active agent.

[0215] In embodiments with a clearance zone, the region of the hydrogel is the area where the drug is cleared. As the drug dissolves and diffuses from the barrier zone, cavities form, making the drug even softer and more brittle. Concurrently with diffusion from the gel, the hydrogel may, for example, release esters into the aqueous environment of the eye. It can also slowly degrade by hydrolysis, which occurs uniformly throughout the bulk of the hydrogel. As degradation progresses, distortion and erosion of the hydrogel begins to occur. As this occurs, the hydrogel becomes softer and more liquid (thus distorting its shape). Eventually, the hydrogel dissolves and is completely absorbed. This process is shown schematically in Figure 3. This has been demonstrated by infrared reflectance (IR) imaging, e.g., in Figure 10. It has been done.

[0216] Axitinib is a relatively poorly soluble drug, and therefore, in certain embodiments, After the implant has already completely degraded, the undissolved axitinib particles remain in the implant. These remaining undissolved axitinib particles may They are not fixed or separated by a hydrogel and therefore aggregate into a substantially monolithic This monolithic axitinib structure has yet to be and axitinib at a rate sufficient to achieve a therapeutic effect (specifically, reduction in CSFT). The release can continue.

[0217] However, in one embodiment, the entire amount of axitinib is removed before the hydrogel is completely degraded. The hydrogel holds the axitinib particles in place and prevents them from clumping together. Therefore, axillary activity from the hydrogel can be prevented while the hydrogel is not yet completely degraded. When the hydrogel is completely degraded, the remaining axillae may be released more rapidly. The axitinib particles form a monolithic structure from which axitinib slowly dissolves. Therefore, axitinib is completely released before the hydrogel is completely degraded. In one embodiment of the present invention, it is desirable to

[0218] This overall process, in certain embodiments, enhances the therapeutic efficacy of the implants of the present invention. The results are obtained over a long period of time, for example, at least 3 months, or at least 6 months, or at least 9 months, or at least 11 months, or at least 12 months, or at least for at least 13 months, or at least 14 months, or even longer, say up to 15 months. The present inventors believe that this is because the neovascularized age-related macula can be effectively maintained. This has proven to be a significant benefit for patients undergoing treatment for degenerative disorders. In contrast, the present invention involves the very frequent intravitreal injection of anti-VEGF agents. The implants that follow only need to be injected at much larger time intervals, which is already As disclosed in the "Objectives and Overview" section above, there are many reasons why be.

[0219] A specific example includes about 160 μg to about 250 μg (e.g., about 200 μg) of axitinib. Plant: In one particular embodiment, the present invention provides a method for treating a pulmonary artery disease comprising administering to a subject a dose of about 160 μg to about 180 μg of erythrocyte colony-stimulating factor (EGF) dispersed in a hydrogel. Approximately 250 μg, or approximately 180 μg to approximately 220 μg, particularly approximately 200 μg. For sustained release biodegradable intraocular implants containing xitinib, the hydrogel is polyethylene. The implant contains a polymer network of glycol units, and is in a dried state. In this embodiment, the polymer network is a multi-arm polyethylene Recall unit (e.g., average value within the range of about 10,000 Daltons to about 60,000 Daltons) Polyethylene glycol containing 4-arm and / or 8-arm polyethylene glycol units having an average molecular weight In this embodiment, the polymer of the implant comprises polyethylene glycol units. The network is composed of 4a20kPEG-SAZ and 8a20kPEG-NH2 with a weight ratio of approximately 2:1. In this embodiment, when formed, The hydrogel (i.e., wet composition) before drying is about 6.5% to about 7.5% poly(ethylene glycol) copolymer. Contains ethylene glycol (equivalent to weight of polyethylene glycol ÷ weight of fluid × 100) In this embodiment, the implant contains about 45% to about 55% by weight of the total weight of the dried material. % by weight of axitinib and about 37% to about 47% by weight of polyethylene glycol units, or about 47% to about 52% by weight of axitinib and about 40% to about 45% by weight of poly(vinyl alcohol). ethylene glycol units (e.g., about 49% to about 50% by weight of axitinib and about 4 2% by weight of PEG units, or about 47% by weight of axitinib and about 44% by weight of PEG units The remainder is sodium phosphate. It may contain less than about 1% water by weight, or less than about 0.25% water by weight in its dry state. do.

[0220] In this embodiment, axitinib is administered in a dose of about 160 μg to about 250 μg, or about 180 μg. Implants containing an amount in the range of 200 μg to about 220 μg, specifically about 200 μg, are phosphate buffered saline solution in vitro for a period of 30 days, averaging approximately 0.0 The amount of axitinib released is 1 μg to about 0.15 μg. The implants were incubated in a 25:75 ethanol / water (v / v) mixture at 37°C for 3 days. Approximately 35% to 45% of axitinib at 7 days, approximately 65% ​​to 75% of axitinib at 12 days, Approximately 90% to 100% of axitinib is released in vitro in 13 days. In the formulation, the implants were buffered with phosphate buffer with an octanol overlay at 37°C, pH 7.2. In saline, the effect was approximately 25% to 35% of axitinib at 2 months and approximately 4% of axitinib at 3 months. 7% to approximately 57% of axitinib at 5 months, approximately 70% to approximately 80% of axitinib at 7 months Approximately 90% to 100% can be released in vitro.

[0221] In this embodiment, the implant containing about 200 μg of axitinib is made of fibers (or or cylinder) and in its dry state is less than about 20 mm, or about 17 mm or less than about 15 mm to about 16.5 mm in length and about 0.20 mm to about 0.30 mm in width diameter in the vitreous humor in vivo or upon hydration in vitro ( In vitro hydration was measured after 24 hours in phosphate buffered saline at 37°C and pH 7.2. The length decreases and the diameter increases (measured in millimeters), reaching a length of about 6.5 mm to about 8 mm in the hydrated state. The diameter of the hydrated particles can be about 0.70 mm to about 0.80 mm. As described in more detail elsewhere in this document, the implant may be stretched to a stretch factor of about 2 to about 5, or The implant is shaped by dry stretching in the longitudinal direction with a stretch factor of about 3 to about 4.5. This can be achieved by providing memory. The tube may be non-cylindrical.

[0222] In this embodiment, the hydrated state of the implant containing about 200 μg of axitinib The ratio of diameter to dry diameter is less than about 3.25 mm, and / or the ratio of dry length to hydrated length is less than about 3.25 mm. The ratio of the lengths of the two phases can be greater than about 1.5.

[0223] The total weight of the implant disclosed in this embodiment in its dry state is about 0.3 mg to about 0 Such an impact may be about 0.6 mg, for example, about 0.4 mg to about 0.5 mg. The runt contains approximately 10 μg to 15 μg of axitinib per 1 mm of final length in a dry state. can be mm 3 Each tablet may contain about 200 μg to about 300 μg of axitinib. do.

[0224] In this embodiment, prior to administration, an implant containing a dose of about 200 μg of axitinib is administered. The needle is inserted into the vitreous humor using a 25-gauge or 27-gauge needle (or even smaller). It is loaded into a small gauge needle (e.g., a 30 gauge needle).

[0225] To summarize and illustrate, the disclosed embodiments in this section are Implants of the present invention containing a dose of 0.00 μg (as used in the clinical trial presented in Example 6) The specific characteristics of the implants (including those implanted in the experimental setting) are listed in Table 21.1 in the Examples section. It has been shown and is reproduced here. [Table 1-1] [Table 1-2]

[0226] The implant is an intravitreal implant, and contains approximately 180 μg to approximately 220 μg of axin. It includes a nib and is cylindrical, and has a length of 17 mm or less and a length of about 0.2 mm to about 0.05 mm in its dry state. It has a diameter of 0.3 mm and in its hydrated state (24°C in phosphate buffered saline at pH 7.2 at 37°C). After 2 hours, the length is about 6.5 mm to about 8 mm and the diameter is about 0.7 mm to about 0.8 mm. The hydrogel contains crosslinked 4a20k and 8a20k PEG units, and the PEG units The bridge of the formula [ka] 2. The sustained release biodegradable polymer of claim 1, comprising a group represented by the formula: (wherein m is 6). Sexual intraocular implants.

[0227] Alternatively, the implant of this particular embodiment may be a non- It may be cylindrical.

[0228] A specific example includes about 480 μg to about 750 μg (e.g., about 600 μg) of axitinib. Plant: In another specific embodiment, the present invention provides axitinib dispersed in a hydrogel. A sustained-release biodegradable intraocular implant comprising: wherein the hydrogel is a polymer comprising cross-linked polyethylene glycol units. The implant contains a network of approximately 540 μg to 100 μg of axitinib. It may be in the range of about 660 μg, or specifically about 600 μg.

[0229] In this implant, the polyethylene glycol units are multi-arm polyethylene glycol units. Recall unit (e.g., average value within the range of about 10,000 Daltons to about 60,000 Daltons) The polyethylene glycol comprises 4-arm and / or 8-arm polyethylene glycol units having an average molecular weight. In this embodiment, the polymer network of the implant is composed of 4a20kPEG and 8a20kPEG-N, containing 8a20kPEG units, and 4a20kPEG-SAZ It is formed by reacting it with H2 in a weight ratio of about 2:1.

[0230] In this embodiment, the implant is about 45% to about 55% by weight of anionic surfactants, on a dry basis. The composition may comprise xitinib and about 37% to about 47% by weight of polyethylene glycol units. or about 60% to about 75% by weight of axitinib and about 21% to about 31% of poly(Axitinib). ethylene glycol units (e.g., about 63% to about 72% by weight of axitinib and about 23% The dry composition may contain up to about 27% polyethylene glycol units, with the remainder being polyethylene glycol units. In certain specific embodiments, the implant comprises about 68% ~about 69% axitinib and about 26% polyethylene glycol units (dry composition) The implant may contain less than about 1% by weight of water, with the remainder being sodium phosphate. , or may contain about 0.25% by weight or less of water.

[0231] In this embodiment, axitinib is administered in a dose of about 480 μg to about 750 μg, or about 540 μg. This implant contains an amount ranging from about 600 μg to about 660 μg, or specifically about 600 μg. was observed in vitro at approximately 1000 kJ / day for a period of 30 days in phosphate buffered saline at 37°C. The implant releases 0.3 μg to approximately 0.5 μg of axitinib. Approximately 100% of axitinib was detected in 25:75 (v / v) ethanol / water mixture at 7°C over 2 days. 40% to approximately 60% of axitinib in 4 days, approximately 65% ​​to approximately 85% of axitinib in 6 days In this embodiment, the implant releases 75% to about 90% of the active ingredient in the formulation in vitro. The cells were incubated in a 25:75 ethanol / water (v / v) mixture at 37°C for 2 days to axonalize the cells. Approximately 45% to 55% of axitinib in 4 days, approximately 70% to 80% of axitinib in 6 days In some cases, approximately 80% to 90% of tinib is released in vitro.

[0232] In this embodiment, the implant containing about 600 μg of axitinib is made of fibers (or or cylindrical) and in its dried state, may be less than about 20 mm, or less than about 17 mm. Less than mm, or less than about 15 mm, or less than about 12 mm (for example, about 7 mm to about 1 2 mm) and a diameter of about 0.25 mm to about 0.50 mm, or about 7 mm or It may have a length of 8 mm to about 11 mm and a diameter of about 0.3 mm to about 0.4 mm, and may be absorbed into the vitreous humor. may increase in diameter upon hydration in vivo or in vitro (where In vitro hydration was measured after 24 hours in phosphate-buffered saline at 37°C and pH 7.2. In a specific embodiment, an implant containing about 600 μg of axitinib The dry size of the material is 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 in length and about 0.3 mm to about 0.4 mm (e.g. The diameter of the slit may be about 0.35 mm to about 0.39 mm.

[0233] The dimensions of this implant after in vivo or in vitro hydration (herein In vitro hydration was measured after 24 hours in phosphate buffered saline at pH 7.2 at 37°C. The length of the slit is about 10 mm or less (for example, about 6 mm or about 9 mm to about 12 mm). and a diameter of about 0.5 mm to about 0.8 mm, or a length of about 9.5 mm to about 11.5 mm. Or a length of about 10 mm or less or about 9 mm or less and a length of about 0.65 mm to about 0.75 mm Or it can be about 0.80 mm in diameter. In a specific embodiment, it can be about 600 Implants containing μg of axitinib in their hydrated state (here, in vitro Hydration at 37°C in phosphate buffered saline at pH 7.2 is measured after 24 hours, approximately Length of 6 mm to about 10.5 mm (for example, about 6.5 mm to about 8.5 mm) and about 0.7 m In certain embodiments, the diameter of the vitreous humor of the eye may be between 0.5 mm and about 0.8 mm. A length of about 10 mm or less (e.g., about 9 mm or less) when inserted is considered to be within the limited volume of the eye. Considering this, it is an acceptable length.

[0234] This dimensional change upon hydration is approximately 0.5 mm before drying, as disclosed in more detail below. a stretch factor of about 1 to about 5, or a stretch factor of about 1 to about 4, or a stretch factor of about 1.3 to about 3.5 or a stretch factor of about 1.7 to about 3, or a stretch factor of about 2 to about 2.5. This can be achieved by stretching.

[0235] In this embodiment, the hydrated state of the implant contains about 600 μg of axitinib. The ratio of diameter to dry diameter is less than about 2.25 mm, and / or the ratio of dry length to hydrated length is less than about 2.25 mm. The ratio of the lengths of the two states may be greater than 0.75.

[0236] The total weight of an implant as disclosed herein comprises about 600 μg of axitinib. is about 0.8 mg to about 1.1 mg, for example, about 0.9 mg to about 1.0 mg in a dry state. In the dry state, such implants have a density of approximately 70 μg per mm of final length. ~ about 85 μg of axitinib, mm 3 Approximately 500μg to 800μg per serving g of axitinib.

[0237] In this embodiment, the preferred implant shape is cylindrical or essentially cylindrical. (sometimes referred to as fibers). In other embodiments, the implant is non-cylindrical. Prior to administration, the implant containing a dose of about 600 μg of axitinib may be 25 gauge (or smaller gauge, e.g., 2 7 gauge needle.

[0238] In summary, approximately 600 μg of the disclosed embodiments in this section The specific properties of the implants of the present invention, including the dose of axitinib, are described in the Examples section. This is shown in Table 21.2 in the previous section and is reproduced here. [Table 2-1] [Table 2-2]

[0239] In certain embodiments, the sustained release biodegradable intraocular implant of the present invention is administered intravitreally. The implant contains about 540 μg to about 660 μg of axitinib and is cylindrical in shape. In its dry state, it has a length of 10 mm or less and a diameter of about 0.3 mm to about 0.4 mm, In the hydrated state (after 24 hours in phosphate buffered saline at 37°C, pH 7.2), the The hydrogel has a length of 0.5 mm and a diameter of about 0.6 mm to about 0.8 mm, and is crosslinked. The PEG units comprise 4a20k and 8a20k PEG units, and the crosslinks between the PEG units are of the formula [ka] wherein m is 6.

[0240] Alternatively, the implant of this particular embodiment may be a non- It may be cylindrical.

[0241] II. Implant Manufacturing Manufacturing Process: In certain embodiments, the present invention provides the sustained-release biodegradable intraocular The present invention also relates to a method for producing an implant. Generally, the method comprises forming a polymer network and and a hydrogel comprising TKI particles, wherein the TKI particles are dispersed within the hydrogel. Forming the Hydrogel, Shaping the Hydrogel, and Drying the Hydrogel In certain embodiments, the method includes the step of: , polymer networks from precursors containing reactive groups (e.g., containing PEG units), and forming a hydrogel comprising TKI particles dispersed within the hydrogel; and drying the hydrogel. The polymer network is formed by coupling electrophilic-group-containing multi-arm PEG precursors with nucleophilic-group-containing multi-arm PEG precursors. a multi-arm PEG precursor or another nucleophilic group-containing crosslinker (the "polymer network" herein). and the precursors and crosslinkers disclosed in the "PEG Hydrogel" and "PEG Hydrogel" sections) with TKI particles. It is formed by mixing and reacting in a buffer solution in the presence of an alkyl group, causing the mixture to gel. In an embodiment of the present invention, the hydrogel is formed by the addition of the hydrogel. Prior to complete gelation, the mixture was cast into a tube to allow for the formation of the hyaluronic acid-containing polymers disclosed herein. In certain embodiments, the hydrogel strands are formed into hydrogel strands. is longitudinally stretched before or after drying as further disclosed herein.

[0242] In certain embodiments, the TKI in the method of manufacture according to the present invention is In one embodiment, the TKI (e.g., axitinib) tinib) is used in micronized form to prepare the implants as disclosed herein. and may have a particle size as also disclosed in the "Active Ingredients" section of this specification. In certain specific embodiments, axitinib may have a particle size of less than about 30 μm, Or may have a d90 of less than about 10 μm. Micronized TKIs, particularly micronized axitinib By using a sieve, during the casting of the hydrogel strands, as shown in Figure 24, It is believed that this will have the effect of reducing the tendency of TKI (specifically axitinib) particles to aggregate. In another embodiment, the TKI (e.g., axitinib) is used to prepare the implant. It may also be used in non-micronized form for the purpose of

[0243] The precursors for forming the hydrogel of certain embodiments are the implants themselves. PEG crosslinked using PEG precursors is disclosed in detail in the section on When preparing the network, in certain embodiments, a method for manufacturing an implant is an electrophilic group-containing polymer precursor (e.g., electrophilic group-containing multi-arm polyethylene glycol). Cole, e.g., 4a20kPEG-SAZ), is added to a nucleophilic group-containing polymer precursor or other Crosslinkers (e.g., nucleophilic group-containing multi-arm polyethylene glycols, e.g., 8a20k PEG-NH2) in the presence of a tyrosine kinase inhibitor in a buffer solution. and allowing the mixture to gel. In certain embodiments, PEG The molar ratio of electrophilic groups to nucleophilic groups in the precursor is about 1:1, but the nucleophilic groups (e.g., amines) groups) may be used in excess of the electrophilic groups. As disclosed in the "PEG Hydrogel" section and the "PEG Hydrogel" section, other precursors (e.g., other and other nucleophilic group-containing precursors or crosslinkers) may be used. .

[0244] In certain embodiments, the electrophilic group-containing precursor and the nucleophilic group-containing precursor or other crosslinking precursor are The bridge agent, TKI, and optionally a buffer (and optionally, the components listed in the "Additional Ingredients" section) are included. A mixture of the above ingredients (and additional ingredients as indicated) is prepared. This can be done in a variety of orders, The procedure is not limited to the following, but may be carried out first by reacting an electrophilic group-containing precursor and a nucleophilic group-containing precursor. Separate mixtures of each of the precursors were prepared in buffer, and then one of the buffer / precursor mixtures ( For example, a buffer / nucleophile-containing precursor mixture) is combined with a TKI, followed by The electrophile-containing buffer / precursor mixture can then be mixed with another buffer / precursor mixture (in this case, buffer / electrophile-containing The mixture of all components is Once prepared (i.e., after all components are combined to form the wet composition) The mixture is then mixed prior to complete gelation of the hydrogel to obtain the desired final shape of the hydrogel. The mixture is then cast into a suitable mold or tube. The mixture is then allowed to gel. The resulting hydrogel is then dried.

[0245] The viscosity of the wet hydrogel composition cast into a mold or tube is particularly The viscosity may depend on the concentration and solids content of the gel composition, but may also depend on external conditions such as temperature. of wet hydrogel compositions, especially when the compositions are cast into fine diameter tubes. Flexibility can be improved by reducing the viscosity of the wetting composition. This may involve reducing the concentration of the components in the solvent and / or reducing the solids content. or other measures (e.g., increasing the temperature) may be taken (but are not limited to) Suitable solids are disclosed in the "Formulations" section herein.

[0246] If the implant is to have the final shape of the fiber (e.g., cylindrical), the elongated circle To obtain a cylindrical shape, the reactive mixture is poured into a fine diameter tube such as a PU or silicone tube. The hydrogel can be cast into a tube (for example, with an inner diameter of about 1.0 mm to about 1.5 mm). The desired final cross-sectional geometry of the gel fiber, its initial diameter (which may be further expanded by stretching), may decrease) and also depending on the ability of the reactive mixture to fill the tube uniformly. A variety of tube geometries and diameters can be used.

[0247] Thus, the interior of the tube may have a circular geometry, but may also have a non-circular geometry. It may have a shape (e.g., a cross (or other) geometric shape). The shape of the implant can increase the surface area of ​​the implant. In this configuration, the amount of TKI incorporated into the implant is determined by the geometric shape of this cross. The overall effect is increased by using a cross-shaped geometry. thereby increasing the release of the API from the implant in certain embodiments. Other cross-sectional geometries of the implant may be used as disclosed herein. You may do so.

[0248] In certain embodiments, the hydrogel is formed and allowed to cure until fully gelled. The hydrogel strands are then hydrated as described herein (e.g., dimensional changes of the implant upon hydration). As disclosed in detail in the section on chemistry, the In certain embodiments, the stretch factor (stretching factor) is g factor) (also referred to herein as "stretch factor" (also referred to as "the ratio of the molecular weight of the polymer to the total molecular weight of the polymer") is about 1 to about 4.5, or about 1.3 to about 3.5, or about 2 to about 2.5 or within other ranges disclosed herein (e.g., limited Although not included in the "Implant Dimensions and Dimensional Changes Upon Hydration Due to Stretching" section The stretch factor may be the value of the stretched hydrogel strand after stretching. The stretch factor of the hydrogel strand is the ratio of the length of the hydrogel strand to the length of the hydrogel strand before stretching. The number 2 means that the length of the dry hydrogel strand after (dry) stretching is the same as that of the dry hydrogel strand before stretching. This means that the length is twice the length of the dry hydrogel strand. The same applies to wet stretching. In certain embodiments, when dry stretching is performed, the hydrogel is first In certain embodiments, when wet stretching is performed, the The rogel is stretched in the wet (undried) state and then dried under tension. Heat may be applied during stretching. Optionally, the hydrogel fibers may be further twisted. In certain embodiments, stretching and / or drying may be performed while the hydrogel is still in the form of a tube. Alternatively, the hydrogel may be stretched while it is in the tube. In certain embodiments, the implant may be placed at room temperature or below. As long as it is stored dry, it will maintain its dimensions even after stretching.

[0249] After stretching and drying, the hydrogel strands (if still in the tube) are removed from the tube. and dried to the desired length for the final implant as disclosed herein. (If cutting inside the tube, the cut segments are (The implant is then removed from the tube immediately after the procedure.) For the purposes of the present invention, a dry implant is particularly preferred. Preferred lengths are, for example, about 12 mm or less or about 10 mm or less as disclosed herein. is the length of

[0250] In certain embodiments, the prepared final implant is then passed through a fine diameter needle. In certain embodiments, the needle gauge size is 22-30, e.g., Gauge 22, Gauge 23, Gauge 24, Gauge 25, Gauge 26, Gauge 27, Gauge 2 8, gauge 29, or gauge 30. In specific embodiments, the needle is dry (and 25 gauge or 27 gauge depending on the diameter of the implant (and optionally stretched) needle, or even smaller gauge needle (e.g., 30 gauge needle).

[0251] In certain embodiments, the needles containing the implants are then packaged separately. and sterilized, for example by gamma irradiation.

[0252] In certain embodiments, an injection device (e.g., a syringe or another injection device) The device) can be packaged separately and is referred to below as a kit (another embodiment of the present invention, For example, gamma spectroscopy may be used as disclosed in the "Injection Devices and Kits" section. Sterilization can be achieved by irradiation.

[0253] A particular embodiment of the manufacturing process according to the present invention is disclosed in detail in Example 1.

[0254] Needle (PEG) tipping: In one embodiment, after the implant is loaded into the needle, the tip of the needle is Alternatively, molten PEG can be injected into the lumen of the needle tip. This low molecular weight PEG is liquid (molten) at body temperature, but at room temperature The molten PEG is applied to the tip of the needle by dipping or dripping, and then the needle is cooled. and a droplet or segment of hardened PEG at the tip of the needle and within the tip (referred to herein as the tip). The tip / plug (also called the tip plug) remains in place and blocks the needle lumen. Shown in Figure 25B.

[0255] The low molecular weight PEG used in this embodiment can be a linear PEG and has a maximum molecular weight of about 1500 Or may have an average molecular weight of up to about 1000, or about 400, about 600, about 800, Alternatively, the polymer may have an average molecular weight of about 1000. Also, as disclosed, different average molecular weights may be used. A mixture of PEG in a quantity of 100 mg / ml can also be used. The average molecular weight of the PEG used for this purpose is about 1000. PEG with a molecular weight of k(1000) has a melting point of about 33°C to about 40°C, and is suitable for intraocular injection with a needle. It melts at body temperature when heated.

[0256] Instead of PEG materials, water-soluble and biocompatible (i.e., compatible with the human or animal body) They can be used in contact with the body and do not induce local or systemic adverse effects (e.g. , non-irritating), solid or hard at room temperature but liquid or or any other material that is substantially liquid, or at least soft, may be used to treat the tip of the needle. Instead of PEG, the following materials may also be used (including: (non-limiting): poloxamers or poloxamers that melt / are liquid at body temperature -blend, crystallized sugar or salt (e.g., trehalose or sodium chloride), Gallose, cellulose, polyvinyl alcohol, poly(lactic-co-glycolic acid), U V A combination of a cured polymer, chitosan, or a mixture thereof.

[0257] The plug or tip keeps the implant in place within the needle during packaging, storage, and shipping. This helps to keep the needle in a stable position and also occludes the needle lumen, preventing premature hydration during the procedure. It also protects the implant from the effects of the injection during the administration procedure, i.e. when the doctor is using the needle and syringe to administer the injection. While preparing the injector or when the needle is inserted into the eye during injection (implant Immediately prior to the actual injection of the implant, positive intraocular pressure may be exerted to induce at least some early hydration of the implant. Prevent premature hydration of the implant in the needle due to moisture ingress, which may cause The tip or plug can also be heated by body heat or exposed to moisture. and lubrication, which allows for successful placement of the implant. Furthermore, by blocking the needle lumen, needle tip treatment can prevent tissue damage, i.e., tissue core formation. the possibility of needle swabbing (the process by which pieces of tissue are removed by the needle as it passes through the tissue) Minimize sexuality.

[0258] One procedure is to apply a PEG (or other material) tip / plug to the lumen of the needle. In this configuration, the needle containing the implant is filled with molten PEG (or other materials). The needle can be dipped into the molten material manually or by an automatic device. Hold the needle immersed for 2 seconds to allow the molten material to flow upward into the needle by capillary action. Depending on the dwell time, immersion depth and temperature of the molten material, The final size or length of the tip / plug will be determined. The length of the PEG (or other) tip / plug at the top of the needle is about 1 to about 5 mm (e.g. In certain embodiments, 1k PEG may be When used, the tip / plug weighs about 0.1 mg to about 0.6 mg (e.g., about 0. The implant according to the present invention can be used in a range of dosages from 15 mg to about 0.55 mg. and in vivo from a syringe with a needle with a 1k PEG tip as disclosed in the document. It has been demonstrated that it can be successfully deployed in vitro.

[0259] Furthermore, the tip treatment of the injection needle disclosed in this specification is effective in preventing the needle from penetrating the human or animal body (eye) other implants that are injected into the body (including other locations within the body or other areas or tissues of the body) implant (or other medicine or vaccine) the protective effect of the implant (or medicine or vaccine) from moisture and Other implants or other medical devices where a protective effect on the tissue being treated is desirable and advantageous. It can also be used to inject medicines or vaccines.

[0260] Stretching: The shape memory effect due to stretching has already been discussed in detail above in relation to the properties of implants. In certain embodiments, the degree of shrinkage upon hydration is, inter alia, as already described above. Depends on the stretch factor as disclosed.

[0261] Thus, in certain embodiments, the present invention provides a method for preparing a hydrogel comprising administering to a subject a subject a subject, the method comprising administering to a subject ... The present invention also relates to a method of imparting shape memory to a hydrogel strand containing an active agent, the method comprising: This is done by stretching the hydrogel strands longitudinally.

[0262] Similarly, therefore, in certain embodiments, the present invention provides a method for dissolving an active agent within a hydrogel. 1. A method for making an intraocular implant comprising a hydrogel having an agent dispersed therein, the method comprising: The present invention also relates to a method for administering a hydrogel to an eye, the method comprising administering a hydrogel to an eye, the hydrogel being capable of changing its size when administered to the eye. It involves preparing a strand of gel and stretching it longitudinally.

[0263] The stretch factors for use in these methods of the present invention are utilized as already disclosed above. The described manufacturing method (including the extension method) can be used to Implants containing hydroxybenzoates, including but not limited to hydroxybenzoates, may also contain other active pharmaceutical agents. The present invention also provides a method for preparing a hydrogel-forming polymer, which is not formed from gels or PEG units, but can form hydrogels. Implants containing hydrogels formed from other polymeric units as disclosed above can also be used.

[0264] The implant contains axitinib in an amount ranging from about 160 μg to about 250 μg or about 20 In embodiments containing 0 μg of stretched hydrogel, the stretching is performed after drying the hydrogel for about 2 to about 5 minutes. The stretching can be carried out at a stretch factor of about 3 to about 4.5 (dry stretching).

[0265] The implant contains axitinib in an amount ranging from about 480 μg to about 750 μg or about 60 μg. In certain embodiments comprising an amount of 0 μg, stretching is performed by wetting the hydrogel before drying. In this state, the stretch factor is about 0.5 to about 5, or about 1 to about 4, or about 1.3 to about A stretch factor of 3.5, or a stretch factor of about 1.7 to about 3, or a stretch factor of about 2.0 to about 2.5 It can be carried out by a factor of 1 (wet stretching).

[0266] III. Injection Devices and Kits In certain embodiments, the present invention further provides a method for treating a pulmonary arthritis, as disclosed above or as described above. One or more sustained-release biodegradable intraocular implants prepared according to the methods as disclosed. and one or more needles for injection (referred to as a "system"). wherein each of the one or more needles is in a dried state. In one embodiment, the sustained-release biodegradable intraocular implant is preloaded. In some embodiments, the needle(s) have a gauge size of 22 to 30, e.g., 22, 23, 24, 25, 26, 27, 28, 29, or 30 gauge. The needles can be 25 or 27 gauge needle(s), or 30 The diameter of the needle may be smaller than the gauge of the dry needle. The implant is selected based on the final diameter of the implant in its expanded (and optionally expanded) state. The active agent contained in the implant is generally a TKI (e.g., axitinib).

[0267] In one embodiment, the kit contains axitinib in the range of about 180 μg to about 220 μg. or about 200 μg of PEG-10 ... of, for example, two or three 22-30 gauge, for example, 25 gauge or 27 gauge Includes needle(s).

[0268] In yet another embodiment, the kit contains about 540 μg to about 660 μg of axitinib. One 25-gauge implant loaded with an amount within the range, or approximately 600 μg In another embodiment, the kit contains about 540 μg to about 660 μg of axitinib. g range, or approximately 600 μg of one 27-gauge implant. Includes a marker needle.

[0269] If two or more implants are included in the kit, they must be identical. The TKIs may be present or different and may include the same or different doses of TKIs.

[0270] In certain embodiments, the lumen of the needle containing the implant is referred to herein as an "implant needle." This is explained in detail in the section "Manufacturing of the Needle," especially in the subsection "Needle (PEG) Tip Treatment." As shown, materials that are solid at room temperature but soft or liquid at body temperature (e.g., 1k The endothelial cells may be occluded by a PEG material.

[0271] The kit further includes a device for placing the implant(s) in the patient's eye (e.g., in the patient's vitreous humor). In certain embodiments, the injection device may include an injection device for injecting the The device is provided separately from one or more needle(s) into which the implant is loaded and In such an embodiment, the injection device is packaged in Before implantation, it must be connected to one or more needles that are loaded. stomach.

[0272] In certain embodiments, the number of injection devices provided separately in the kit may be The number of implants provided in the slot is equal to the number of loaded needles. Thus, the injection device is used only once for the injection of one implant.

[0273] In other embodiments, the kit may include a method for administering the implant into the patient's eye (e.g., the patient's vitreous). one or more injection devices for injecting into a liquid, wherein each injection device The chair may be pre-connected to a needle loaded with an implant or may be unconnected. Therefore, in one aspect, the present invention provides a needle-loaded sustained-release biodegradable intraocular A pharmaceutical product comprising an implant and an injection device, wherein a needle is pre-connected to the injection device. If the needle is not pre-connected to the injection device, the impregnation The physician administering the implant must remove both the needle and the injection device containing the implant from the packaging. and connect the needle to an injection device so that the implant can be injected into the patient's eye. There is a need.

[0274] In some embodiments, the injection device dispenses the implant from the needle into the vitreous humor. The push wire includes a nitinol push wire. or stainless steel / Teflon push wire. The wire allows for easier deployment of the implant from the needle.

[0275] In other embodiments, the injection device and / or needle may include a stop to control the depth of injection. It may include a stop function.

[0276] In some embodiments, the injection device is housed within a plastic syringe housing ( For example, a modified Hamilton that can be placed inside an injection molded housing A push wire (e.g., a Nitinol wire) is or includes a glass syringe. The ear is inserted into the syringe and is then inserted into the syringe plunger during implant placement. To facilitate the Nitinol push wire entering the needle, A hub insert may be added to the tube. Figures 25A and 25B show the tube inserted into the vitreous humor of a patient. 1 shows one embodiment of a syringe according to the present invention for injecting an implant. The syringe embodiment includes a Hamilton syringe body and a syringe for placing the implant. and a Nitinol push wire. Figure 25A shows the Hammer inside the injection molded casing. Figure 25B shows the silton syringe body. 1 is a schematic diagram of a Hamilton syringe body and a syringe pump according to a specific embodiment. The syringe, including the syringe housing, is pre-assembled in a kit according to the invention. The injector is ready to use (no needles containing implants or needle attachments). In an embodiment, the syringe is assembled by the physician before attaching the needle containing the implant. It must be erected.

[0277] In other embodiments, the injection device is an injection molded syringe. A schematic exploded view of one embodiment of an extruded syringe is shown in Figure 26. In this case, the patient is implanted with This reduces the number of assembly steps that the physician must perform immediately prior to administering the agent.

[0278] The kit may further comprise one or more ready-to-inject doses, particularly a single dose of an anti-VEGF agent. Anti-VEGF agents include aflibercept, bevacizumab, and pegaptanib. , ranibizumab, and brolucizumab. In one embodiment, the anti-VEGF agent is bevacizumab. The anti-VEGF agent is aflibercept. The anti-VEGF agent is administered via a separate injection device connected to a needle. It may be provided in a dish or as a solution or suspension in a sealed vial. The solution or suspension may be dispensed from the vial through a needle into a syringe or syringe prior to administration. can be aspirated into other injection devices.

[0279] The kit also includes instructions for the physician who will inject the intraocular implant(s). The kit may further include a package insert with product-related information. .

[0280] In addition to the kit, the present invention in one embodiment provides a sustained release biodegradable intraocular Also of interest is the injection device itself, suitable for injecting the implant into the eye. The device includes a means for connecting an injection device to a needle that is preloaded with an implant. The injection device may further comprise a needle-insertion device for injecting a liquid into the needle when the injection device is connected to the needle. A push wire may be included for positioning the implant within the eye, and the push wire may be included for positioning the implant within the eye. The wires are made of Nitinol or stainless steel / Teflon or other suitable material The injection device further comprises a wire attached to the plunger and connecting it to two Insert it between the snap-fit ​​syringe body and secure the plunger with a clip. Injection devices and implants according to certain embodiments of the present invention are obtainable. A needle pre-loaded with the drug is shown in FIG.

[0281] As shown in FIG. 1, in some embodiments, an injection device (e.g., an impingement device) The pharmacy injection device is packaged separately (e.g., in separate housings). The first assembly and the second assembly can be included. Figure 26C shows the first assembly. 26A is an exploded view of the first assembly, and FIG. 26D is an exploded view of the second assembly.

[0282] Referring to FIG. 26C, the first assembly includes a body defining a first interior volume; a plunger including a first distal end disposed within the interior volume of the plunger; The plunger clip includes a wire having a first distal end fixed to the distal end. The plunger clip connects to the plunger and body to prevent the plunger from operating. The body is configured with a first body half and a second body half configured to interconnect with each other. The body may include a body half configured to move the plunger in response to actuation of the plunger. The living hinge may include a living hinge that connects to the protrusion. The living hinge may be configured to provide a threshold force upon application of the living hinge. The plunger can be actuated in response to the

[0283] Referring to FIG. 26D, the second assembly includes a cowl defining a second interior volume and a base. a needle including a base and a lumen; a cowl cap disposed within the base; and a needle fixed to the cowl and having an inner lumen. and a needle shield configured to be disposed about a portion of the cavity. The cowls are configured to be disposed within the lumen of the needle. The second assembly may include a first cowl half and a second cowl half formed therein. further comprising a polymer tip (e.g., a PEG tip) disposed at a second distal end of the lumen. The implant may include a cap between the cowl cap and the polymer tip within the lumen. The polymer tip liquefies (e.g., dissolves) within the user's body, providing an The implant is configured to be injected.

[0284] In some embodiments, a second The assembly is made from materials that retain less moisture and / or is sealed in an enclosure. Before use, the material is conditioned (e.g., nitrogen conditioned). In some embodiments, the implant is not included in the housing with the first assembly, so the first The assembly is made from materials with a higher moisture content and / or is sealed in an enclosure. Do not undergo conditioning before the race.

[0285] The first assembly can be removed from the first housing of FIG. 1. Referring to FIG. 26E, the first assembly The first and second assemblies may be aligned. The recess may be aligned with one or more inner protrusions of the second assembly. The first assembly and the second assembly are aligned The assembly may include markings (e.g., arrows) to indicate how to attach the second assembly. The cowl of the assembly (for example, the protrusion on the inside of the cowl fits into the recess on the outside of the body) 26G, the needle sleeve is secured to the body of the first assembly. The cord is removed from the cowl of the second assembly and the plunger clip is attached to the first assembly. Referring to Figure 26H, the first assembly is removed from its body and plunger. The plunger of the first assembly is actuated (e.g., pushed into the body of the first assembly). ), and the implant is deployed through the lumen of the needle of the second assembly. wherein the body is capable of actuating the plunger in response to a threshold force applied to the plunger. In some embodiments, the needle lumen has a living hinge that allows the needle to move freely. a polymer tip (e.g., at least the distal portion of the lumen) that blocks the implant from being placed The lumen has a polymer (e.g., PEG) attached to the end. By inserting it into the user, it can coring the user's tissue (e.g., tissue fragments that later The lumen can be placed in the body and prevent the internal diameter of the lumen from being cut. A threshold time (e.g., 1–5 s) is required to liquefy (e.g., dissolve) the polymer tip. After the polymer tip has liquefied, the implant can be inserted into the It can be deployed from the lumen by actuation of the plunger.

[0286] IV. Therapy In certain embodiments, the present invention further provides for the treatment of an ocular disorder in a subject in need thereof. The invention is directed to a method for performing a method in a patient, the method comprising administering to the patient a hydrogel as disclosed above and The method includes administering a sustained-release biodegradable intraocular implant containing a tyrosine kinase inhibitor. nothing.

[0287] In a specific embodiment, the present invention provides a method for treating an ocular disease in a patient in need thereof. The method comprises administering to a patient a hydrogel and at least about 150 μg Patients were administered sustained-release biodegradable intraocular implants containing tyrosine kinase inhibitors (TKIs). wherein the TKI particles are dispersed within the hydrogel.

[0288] In this treatment, the dose per eye is administered once during a treatment period of at least 3 months. The amount is at least about 150 μg, for example, from about 150 μg to about 1800 μg, or from about 15 0 μg to about 1200 μg of a tyrosine kinase inhibitor. In this case, the tyrosine kinase inhibitor is axitinib.

[0289] In certain embodiments, the compound is administered once during the treatment period (i.e., during the treatment period). The dose of TKI (specifically axitinib) per eye is approximately 200 μg to approximately 800 μg. In certain embodiments, the dose is in the range of about 160 μg to about 250 μg. Or in the range of about 180 μg to about 220 μg, or about 200 μg. In particular embodiments, the dose is about 320 μg to about 500 μg, or about 360 μg. In other embodiments, the amount is in the range of 100 μg to about 440 μg, or about 400 μg. The dose is in the range of about 480 μg to about 750 μg, or about 540 μg to about 660 μg, or about 600 μg. In yet other embodiments, the dose is from about 640 μg to about 1000 μg, or within the range of about 720 μg to about 880 μg, or about 800 μg In other embodiments, the dose is about 800 μg to about 1250 μg, or about 9 In other embodiments, the range is from 00 μg to about 1100 μg, or about 1000 μg. In this case, the dose is about 960 μg to about 1500 μg, or about 1080 μg to about 132 μg. In certain embodiments, the dose is within the range of 0 μg or about 1200 μg during the treatment period. The dose administered once per eye is about 600 μg of axitinib. In some embodiments, the 600 μg dose is contained in a single implant.

[0290] In certain embodiments, the implants of the present invention are used to treat the eyeballs disclosed herein. The duration of treatment for the treatment of the disease should be at least 3 months, at least 4.5 months, or at least 6 months, at least 9 months, at least 11 months, at least 12 months, at least 13 It can be for at least 14 months, or even longer, for example, from about 6 to about It can be nine months.

[0291] In certain embodiments, the ocular disease involves neovascularization.

[0292] In other embodiments, the ocular disease is caused by one or more receptor tyrosine kinases (RTKs), For example, VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-α / β, and and / or may be mediated by c-Kit.

[0293] In some embodiments, the ocular disease is choroidal neovascularization, diabetic retinopathy, diabetes macular edema, retinal vein occlusion, acute macular neuroretinopathy, central serous chorioretinopathy, and cysts retinal diseases including acute multifocal macular pigment epitheliopathy, vitreous edema, Birdshot chorioretinopathy, infectious diseases (syphilis, Lyme disease, tuberculosis, toxoplasmosis) uveitis), intermediate uveitis (pars planitis), multifocal choroiditis, multiple vanishing white dots syndrome Group (MEWDS), ocular sarcoidosis, posterior scleritis, serpiginous choroiditis, subretinal fibrosis, Uveitis syndrome or Vogt-Koyanagi-Harada syndrome, or eye disease, vascular Diseases or exudative diseases (Coats' disease, parafoveal telangiectasia, papillary vasculitis, frosty branch vessels) retinitis, sickle cell retinopathy and other hemoglobinopathies, angioid streaks, and familial edema ocular disease is due to trauma or surgery (including exudative vitreoretinopathy) or Sensitive ophthalmia, uveitis, retinal disease, retinal detachment, trauma, photodynamic laser therapy, photocoagulation, surgery (including hypoperfusion during thoracoabdominal surgery, radiation retinopathy, or bone marrow transplant retinopathy).

[0294] In an alternative embodiment, a hydrogel of the present invention and a tyrosine kinase inhibitor are included. Sustained-release biodegradable intraocular implants have potential applications in the treatment of tumor-related ocular conditions. Such conditions include, for example, tumor-associated retinal disease, solid tumors, tumor metastasis, and metastasis, benign tumors (e.g., hemangiomas, neurofibromas, trachoma, and pyogenic granulomas), RPE Congenital hypertrophy of the retina, posterior uveal melanoma, choroidal hemangioma, choroidal osteoma, choroidal metastasis, retinal and Complex hamartoma of the retinal pigment epithelium, retinoblastoma, angioproliferative tumor of the fundus, retinal astrocytoma, Examples include intraocular lymphatic tumors.

[0295] Generally, the intraocular implants of the present invention are applicable to the treatment of any ophthalmic disease involving vascular leakage. It is possible.

[0296] In certain embodiments, the ocular disease is neovascular age-related macular degeneration (AMD), diabetes Selected from the list consisting of: pathological macular edema (DME), and retinal vein occlusion (RVO) In certain embodiments, the ocular disease is neovascular age-related macular degeneration.

[0297] In some embodiments, the treatment is for patients with increased central retinal thickness. and is effective in reducing central zone retinal thickness (CSFT) as measured by optical coherence tomography. Elevated in this context means that the level of ocular disease is higher than that of other individuals who do not have the specific eye disease. This means that the patient has a higher CSFT. It may be caused by retinal fluid, such as intraretinal fluid. Reduction of CSFT in patients with treatment A baseline measured in the patient before initiation, i.e., before administration of the implant of the present invention. The implants of the present invention can be evaluated based on the CSFT of a cohort of patients. In this study, we aimed to reduce CSFT and maintain the reduced CSFT for a long period of time, or The ability to maintain quality is demonstrated in Examples 6.3 and 6.4. Therefore, treatment according to the present invention, including administration of an implant according to the present invention, can be used to treat ocular diseases associated with neovascularization. In patients with elevated CSFT due to pulmonary disease, the CSFT is not considered to be a given level. Qualitatively maintain or prevent a clinically significant increase in CSFT in patients, and On the other hand, subretinal or intraretinal fluid does not increase significantly (i.e., is essentially maintained). It is also said that.

[0298] In certain embodiments, CSFT is reduced for at least 3 months, at least 4.5 months, at least 6 months, at least 9 months months, at least 11 months, at least 12 months, at least 13 months, at least 14 It is maintained at a reduced level for a period of months or longer. In some embodiments, CSFT is measured as the patient's baseline CSFT before administration of the implant. The criteria were at least 6 months, or at least 9 months, or at least 1 month after implant administration. In certain other embodiments, the reduction in retinal fluid volume and / or The reduction in CSFT or CSFT may reduce the need for rescue medication (e.g., anti-VEGF injections). or infrequent administration of rescue medication during treatment (e.g., 1, 2, or 3 times) and the patient's blood pressure remains at least 4.5 times higher for at least 3 months after administration of the implant of the present invention. months, at least 6 months, at least 9 months, at least 11 months, at least 12 months , for a treatment period of at least 13 months, at least 14 months, or longer, patients Therefore, in this embodiment, the implant according to the present invention During treatment with steroids, patients may not need any rescue medication. or the need to administer rescue medication infrequently during treatment (e.g., 1, 2, or 3 times).

[0299] In certain embodiments, the rescue medication is an anti-VEGF agent (e.g., aflivercone). bevacizumab), which is administered by intravitreal injection in the form of a suspension or solution. In certain specific embodiments, the rescue medication is aflivercone. A single dose (2 mg) of acetaminophen is administered by intravitreal injection. Therefore, in accordance with another embodiment of the present invention disclosed herein, an anti-VEG Concurrent (i.e., planned) administration of F medication does not qualify as a "rescue medication." In a further particular embodiment, (which is reduced by administration of an implant according to the present invention) Fluid and / or CSFT levels are maintained without (or at low frequency with) rescue medication. The duration of treatment that is maintained or essentially maintained (with rescue medications only) is In certain embodiments, the period is about 6 to about 9 months after administration of the lant. Patients treated with dental implants should be given steroids (e.g., dexamethasone) during the treatment period. Concomitant administration of steroids (or prednisolone drops) is not required.

[0300] In another embodiment, a treatment according to the present invention comprising administration of an implant according to the present invention In patients with elevated CSFT due to angiogenesis, CSFT is reduced or essentially Maintain or prevent a clinically significant increase in CSFT while improving the patient's visual acuity (For example, visual acuity as represented by best corrected visual acuity (also referred to herein as "BCVA")) In certain embodiments, the present invention provides Treatment according to the present invention, including administration of an implant according to the present invention, can improve the quality of life (e.g., as indicated by BCVA). the patient's visual acuity (if the patient's visual acuity is impaired by neovascular ocular disease) at least 3 months, at least 6 months, at least 9 months, at least 11 months, improvement during at least 12 months, at least 13 months, or at least 14 months of treatment It is possible.

[0301] Thus, in certain embodiments, the present invention provides a method for treating conditions in which vision is impaired (e.g., associated with angiogenesis). The present invention provides a method for improving vision in patients with impaired vision due to retinal fluid produced by ocular disease. The method comprises administering to a patient an implant according to the invention, for example by intravitreal injection. The improvement in the patient's vision can be assessed, for example, by BCVA. Improvement in visual acuity was defined as an increase in the patient's BCVA, e.g., an increase in the ETDRS word count by at least 10 words. or at least 15 characters, or at least 20 characters. can be.

[0302] In certain embodiments, a TKI (e.g., axitidine) administered once during the treatment period The total dose per eye of nib may be contained in one or more implants. In some embodiments, the dose administered per eye during the treatment period is one implant. (e.g., one implant containing a dose of about 600 μg or about 200 μg of axitinib) In another embodiment, the total amount of acetaminophen administered per eye during the treatment period is The dose is contained in, for example, two implants, where each implant contains, for example, about 200 The dose of axitinib is approximately 400 μg (total dose of approximately 400 μg). In embodiments, the dose administered per eye during the treatment period may be, for example, 3 in. plant, wherein each implant contains, for example, a dose of about 200 μg of axitinib. (which results in a total dose of about 600 μg). Specific embodiments of the treatment method of the present invention In this study, the dose of axitinib administered to one eye was approximately 600 μg, and this dose was administered in one eye. Included in implants.

[0303] Implants according to the invention can be used to treat ocular diseases, such as retinal diseases (including AMD). Injection into the patient's eye (e.g., into the vitreous humor) during the The injection method makes administration easier and reduces the possibility of damaging the ocular tissue. A relatively small size is used to reduce the possibility of affecting the patient's vision while the device is in place. Therapeutic effective doses of TKIs (i.e., specific to the patient type and condition) are delivered into the small implant. The present invention provides an implant with a dose appropriate for the severity of the condition. The implant is preferably administered with a high dose of a TKI (i.e., tailored to the needs of the specific patient). It advantageously combines the advantages of a relatively small implant size with the advantages of a high therapeutically effective dose. It's matched.

[0304] In certain embodiments, the implant is an implant as disclosed herein. The drug may be administered by an injection device according to the invention connected to a pre-loaded needle. or connected to a needle pre-loaded with an implant as disclosed herein. The drug may be administered by another injection device (e.g., a (modified) Hamilton syringe) suitable for the administration of the drug. In other embodiments, the compounds of US Pat. No. 8,808,225 (incorporated herein by reference) may be administered. As disclosed in the above reference, hollow microneedles can be used for suprachoroidal administration. This can be done.

[0305] In embodiments in which more than one implant is administered, the implants generally comprise Concurrently administered implants are administered as disclosed above in the specification. The agents may be the same or different. If administration during the same session is not possible, e.g. Due to the complexity of the administration or patient-related reasons, sequential administration during two or more different sessions ( For example, two implants administered 7 days apart may alternatively be applied. It can still be considered "concurrent" administration in the context of the invention.

[0306] In certain embodiments, the dry implant can be inserted into a needle for injection, e.g., a gauge size. Use a needle with a size of 22-23, e.g., a 25-gauge or 27-gauge needle, or a smaller gauge needle. The drug is loaded into a needle in a syringe and administered through the needle into the eye (e.g., into the vitreous humor). In embodiments, the syringe used to inject the implant into the eye is the syringe described above. 1 is an injection device according to another aspect of the present invention, suitable for therapeutic use according to the present application. Implants containing 200 μg and 600 μg are shown in Tables 21.1 and 21.2, respectively. Illustratively.

[0307] Implants are generally injected intravitreally, subconjunctivally, subtenonally, suprachoroidally, or into the anterior chamber. In certain embodiments, the implant can be administered intravitreously. For example, the implant is administered intravitreally into the posterior vitreous humor. In embodiments, the implant is delivered by hollow microneedles, e.g., US8, 808,225 (incorporated herein by reference) It is administered intrasclerally into the eye at the site of insertion into the space.

[0308] In certain embodiments, the treatment period is at least 3 months, but at least 4. 5 months, at least 6 months, at least 9 months, at least 11 months, or at least In certain embodiments, the treatment period is at least 6 months, at least 12 months. at least 9 months, at least 11 months, at least 12 months, at least 13 months, or The treatment period is at least 14 months. In certain embodiments, the treatment period may be longer. A "treatment period" according to one embodiment of the present invention is a period of time during which a person The specific therapeutic effect of the implant of the present invention administered each time is maintained over that period. In other words, the term "maintained" as used herein means that the Therapeutic strategies to reduce or essentially maintain CSFT over an extended period of time, referred to as the "treatment period," are also included. To maintain therapeutic efficacy in preventing or preventing a clinically significant increase in the Only one injection (of the implant of the present invention) is required. This is advantageous over more frequent administration. This represents a significant advantage over currently available anti-VEGF drugs for AMD, which require additional treatment. Therefore, it improves the quality of life of the patient. The need for and / or frequency of rescue medication during the treatment period is very low. In certain embodiments, the treatment period (e.g., about 6 months to about 9 months after administration of the implant) In certain other embodiments, rescue medication is not required during the treatment period. Rescue medications are only needed infrequently (e.g., 1, 2, or 3 times) during this period The patient's visual acuity may be improved, for example, by an increase in BCVA (e.g., For example, the ETDRS character count must be at least 10 characters, at least 15 characters, or at least 2 This can be improved as evidenced by the increase of 0 characters.

[0309] In one particular embodiment, the present invention provides a method for treating neovascular age-related macular degeneration, The invention relates to a method for administering a polymer net to a patient in need thereof, the method comprising administering to the patient a polymer net. A hydrogel containing the workpiece and a sustained-release biosensor containing approximately 200 μg of a tyrosine kinase inhibitor were prepared. This involves administering a degradable intraocular implant, with one implant per eye at a time. Both were administered once during a 9-month treatment period, and patients had a history of anti-VEGF therapy. In embodiments, the treatment may include reducing the central area as measured by optical coherence tomography during the treatment period. This results in a reduction in central retinal thickness (CSFT), or at least a preservation of CSFT. In this embodiment, the TKI can further be axitinib, wherein axitinib is 4a20 Poly(kPEG-SAZ) was formed by reacting 8a20kPEG-NH2 The implant is dispersed within a hydrogel comprising a polymer network, where the implant is dried prior to administration. In this embodiment, the hydrogel is in a state where it is formed and dried. Before use, add approximately 7.5% polyethylene glycol (weight of polyethylene glycol divided by the weight of the fluid) Alternatively, if the patient undergoing treatment has not undergone anti-VEGF therapy, Patients do not need to have a history of AMD (naive to AMD treatment).

[0310] In another specific embodiment, the present invention provides for the treatment of neovascular age-related macular degeneration in a subject requiring such treatment. The invention relates to a method for administering to a patient in need thereof a polymer network. and a sustained-release biodegradable hydrogel containing about 200 μg of a tyrosine kinase inhibitor. 2 intraocular implants per eye forming a total dose of approximately 400 μg One implant at least once during a treatment period of at least 3 months or at least 9 months The patient has a history of anti-VEGF treatment or has a history of anti-VEGF treatment. In this embodiment, the treatment is not performed during the treatment period. Additionally, there is a reduction (or less) of central zone retinal thickness (CSFT) as measured by optical coherence tomography. In this embodiment, the TKI is further axitinib. Axitinib was synthesized by combining 4a20kPEG-SAZ with 8a20kPEG-NH2. dispersed within a hydrogel containing a polymer network formed by reacting In this embodiment, the implant is in a dried state prior to administration. The gel, when formed and before drying, contained approximately 7.5% polyethylene glycol ( (weight of polyethylene glycol ÷ weight of fluid × 100)

[0311] In yet another specific embodiment, the present invention provides a method for treating neovascular age-related macular degeneration, comprising administering to the retina a The invention relates to a method for administering a polymer network to a patient in need thereof, the method comprising administering to the patient a polymer network. A hydrogel containing a tyrosine kinase inhibitor and a sustained-release biologic containing approximately 200 μg of a tyrosine kinase inhibitor. and administering a dissolvable intraocular implant to each eye forming a total dose of about 600 μg. Three implants in a treatment period of at least three months or at least nine months It is administered once and the patient has a history of anti-VEGF treatment or has a history of anti-VEGF treatment. In this embodiment, the treatment is performed in a treatment phase. During this time, there was a reduction (or less) in central zone retinal thickness (CSFT) as measured by optical coherence tomography. In this embodiment, the TKI further comprises axitinib. Axitinib can be synthesized by dissolving 4a20kPEG-SAZ in 8a20kPEG-NH Dispersed within the hydrogel containing the polymer network formed by reacting 2 wherein the implant is in a dried state prior to administration. The hydrogel, when formed and before drying, contained approximately 7.5% polyethylene glycol. (equivalent to weight of polyethylene glycol ÷ weight of fluid × 100)

[0312] In yet another embodiment, the present invention provides a method for treating neovascular age-related macular degeneration in a subject in need thereof. The present invention relates to a method for administering to a patient a polymer network comprising administering to the patient a polymer network. Axitinib dispersed in a hydrogel containing the compound in the range of about 480 μg to about 750 μg the implant comprises administering a sustained release biodegradable intraocular implant comprising and administered once during a treatment period of at least 3 months. In certain cases, axitinib is administered at a dose of about 560 μg to about 660 μg, or about 600 μg. The specific properties of the implant are described in in an amount ranging from about 480 μg to about 750 μg, or in an amount ranging from about 560 μg to about 660 μg, or about 600 μg. The implant may be inserted, for example, by a fine diameter (e.g., 25 gauge) needle. The treatment period as defined above must be at least 4.5 months, or at least 6 months, or at least 9 months, or at least 11 months, or at least 12 months, or at least 13 months, or at least 14 months, or or even longer, for example, up to about 15 months. The duration of treatment is at least 6 months, or at least 9 months, or at least 12 months, Or about 6 to 9 months.

[0313] In some embodiments, a sustained-release biodegradable intraocular implant (including a combination of or a sustained-release biodegradable intraocular implant containing axitinib according to the present invention. Concurrently with treatment with the plant(s), an anti-VEGF agent is administered to the patient. EGF agents include aflibercept, bevacizumab, pegaptanib, ranibizumab, and bronchodilator. In certain embodiments, the anti-VEGF receptor antagonist can be selected from the group consisting of lucizumab, methicillin-resistant Staphylococcus aureus (STA), ... and methicillin-resistant Staphylococcus aureus (STA). In certain embodiments, the anti-VEGF agent is aflibercept. In certain embodiments, the anti-VEGF agent is administered intravitreously in a sustained release form. Concurrently (as defined above) with the administration of the exudative biodegradable intraocular implant, optionally at the same time Anti-VEG The administration of the F agent and the implant of the present invention may be affected by, for example, complications of administration or patient-related reasons. If this is not possible, administer the test in two or more different sessions consecutively ( For example, two implants administered 7 days apart can alternatively be applied. can still be considered "concurrent" administration in the context of the present invention.

[0314] In other embodiments, an anti-VEGF agent is used in combination with an implant of the present invention. However, not simultaneously (i.e., not concurrently), during the treatment period of the implant of the present invention. In certain embodiments, the anti-V EGF agents should be administered within approximately one month, two months, or three months of implant administration. or more months, i.e., before or after implant. This combined (and planned) co-administration of anti-VEGF agents can be is distinct from a rescue medication as defined herein.

[0315] In certain embodiments of the invention, the patient has primary subfoveal lesions (e.g., ulcerative colitis) secondary to AMD. For example, active subfoveal or juxtafoveal CNV with leakage involving the fovea) neovascularization ( Has a diagnosis of SFNV.

[0316] In certain embodiments of the invention, the patient has neovascularization with leakage involving the fovea. Patients with a diagnosis of subfoveal neovascularization (SFNV) secondary to type 2 AMD have previously been treated. In these patients, prior treatment was with an anti-VEGF agent.

[0317] In some embodiments, the patient is at least 50 or at least 60 years old. Patients may be male or female. Patients may present with retinal or subretinal fluid. It may have a membrane solution.

[0318] In some embodiments, the patient receiving the implant is receiving an anti-VEGF treatment (e.g., , LUCENTIS® and / or EYLEA® treatment history In certain embodiments, the patient receiving the implant has a history of anti-VEGF therapy. The patient had a history of VEGF-positive leukemia but did not respond to this anti-VEGF treatment. The patient was not improved by anti-VEGF treatment. In embodiments with a history of anti-VEGF treatment prior to initiation of treatment, Administration may be over an extended period (e.g., over the treatment period defined above) and may be in combination with a prior anti-VEG In another embodiment, the patient receiving the implant may be The subjects had no history of anti-VEGF treatment (anti-VEGF naive, AMD treatment naive).

[0319] In certain embodiments, the systemic plasma concentration of the TKI (e.g., axitinib) is 1 Less than ng / ml, or less than 0.5ng / ml, or less than 0.3ng / ml, or 0 The TKI systemic concentration is minimal. This minimizes the risk of drug-drug interactions or systemic toxicity. In one embodiment, the additional medication(s) taken by the patient poses no significant risk. This is especially true for elderly patients who frequently suffer from eye diseases and take other medications. This is particularly effective for

[0320] Once injected, certain embodiments of the present invention (including the hydrogel and drug) The implants, as disclosed above, may be used for extended periods of time, e.g., within about 9-12 months. In certain embodiments, once the hydrogel is completely degraded, , undissolved axitinib particles remained localized at the site of the implant. These undissolved particles may become viscous when the hydrogel is degraded. This allows the TKI delivery rate to be maintained at a sufficient rate for therapeutic effect (i.e., inhibition of vascular leakage). Figure 15 shows the absorption of the hydrogel in one patient up to 11 months after administration and the effect of the hydrogel on the intestinal wall. The figure shows an example of axitinib particles remaining in the location of the implant. In certain embodiments, the entire amount of the TKI dissolves before the hydrogel completely degrades.

[0321] In certain embodiments, mild or moderate adverse events (e.g., ocular adverse events) ) are observed over the course of treatment. In certain embodiments, serious ocular adverse events are observed. No events were observed, and no treatment-related serious ocular adverse events were observed. Table 23 and Table 2 5 is a clinical study whose results (to the extent available) are presented in Example 6.4. The incidence of adverse events in subjects in cohorts 1 and 2, and cohorts 3a and 3b, respectively, is shown. There are.

[0322] In certain embodiments, the present invention further relates to ocular diseases centered around neovascularization. Clinical significance of central retinal thickness measured by optical coherence tomography in patients with high regional retinal thickness The present invention relates to a method for reducing, essentially maintaining, or preventing a clinically significant increase in a patient's The present invention provides a method for treating ophthalmic use comprising administering to a subject a sustained-release biodegradable eye patch comprising the tyrosine kinase inhibitor of the present invention disclosed herein. In certain embodiments, the method comprises administering an intraocular implant to the ocular tissue associated with neovascularization. In another embodiment, the ocular disease is neovascular age-related macular degeneration. After administration to patients with high central retinal thickness due to disease (e.g., neovascular age-related macular degeneration) , at least 3 months, at least 4.5 months, at least 6 months, at least 9 months, at least 11 months, at least 12 months, at least 13 months, or at least 14 months A decrease in central retinal thickness for a period of months or longer (e.g., at least 15 months) Reduce, essentially maintain, or prevent a clinically significant increase in central retinal thickness In certain embodiments, the patient's visual acuity (e.g., as represented by BCVA) does not decrease substantially during treatment. In certain other embodiments, (e.g., BCV The patient's vision may even be improved. In the present invention, the present invention is directed to a patient suffering from reduced vision (e.g., caused by an ocular disease involving neovascularization). Also covered is a method for improving vision in a patient (caused by retinal fluid) comprising administering an IVF injection according to the present invention. The method includes administering the implant to the patient, for example, by intravitreal injection.

[0323] Additional Disclosures In addition to the above disclosure, the present invention also discloses the following items and item lists: . First item list 1. A composition comprising a hydrogel and about 150 μg to about 1200 μg of a tyrosine kinase inhibitor; Sustained-release biodegradable intraocular implant. 2. The sustained-release biologic according to item 1, wherein the tyrosine kinase inhibitor is axitinib. Dissolvable intraocular implants. 3. A composition comprising the tyrosine kinase inhibitor in an amount ranging from about 200 μg to about 800 μg. 3. The sustained-release biodegradable intraocular implant according to claim 1 or 2. 4. The tyrosine kinase inhibitor is contained in an amount ranging from about 160 μg to about 250 μg. 3. The sustained-release biodegradable intraocular implant according to item 1 or 2. 5. A composition comprising the tyrosine kinase inhibitor in an amount ranging from about 180 μg to about 220 μg. 5. The sustained-release biodegradable intraocular implant according to claim 4. 6. The sustained-release formulation according to item 5, comprising the tyrosine kinase inhibitor in an amount of about 200 μg. Biodegradable intraocular implants. 7. A composition comprising the tyrosine kinase inhibitor in an amount ranging from about 320 μg to about 500 μg. 3. The sustained-release biodegradable intraocular implant according to claim 1 or 2. 8. The tyrosine kinase inhibitor is contained in an amount ranging from about 360 μg to about 440 μg. 7. A sustained-release biodegradable intraocular implant as described in item 7. 9. The sustained release formulation of claim 8, comprising the tyrosine kinase inhibitor in an amount of about 400 μg. Biodegradable intraocular implant. 10. The tyrosine kinase inhibitor is contained in an amount ranging from about 480 μg to about 750 μg. 3. The sustained-release biodegradable intraocular implant according to item 1 or 2. 11. The composition of claim 1, comprising the tyrosine kinase inhibitor in an amount of about 540 μg to about 660 μg. 10. A sustained-release biodegradable intraocular implant according to claim 0. 12. The sustained-release formulation according to item 11, comprising the tyrosine kinase inhibitor in an amount of about 600 μg. Biodegradable intraocular implant. 13. The tyrosine kinase inhibitor is contained in an amount ranging from about 640 μg to about 1000 μg. 3. The sustained-release biodegradable intraocular implant according to item 1 or 2. 14. Item 13, which contains the tyrosine kinase inhibitor in an amount of about 720 μg to about 880 μg. 10. A sustained release biodegradable intraocular implant according to claim 1. 15. The sustained-release formulation according to item 14, comprising the tyrosine kinase inhibitor in an amount of about 800 μg. Biodegradable intraocular implant. 16. The method of claim 1, wherein the implant is used for administration to the posterior segment of the eye. Sustained-release biodegradable intraocular implant. 17. The sustained-release biodegradable intraocular implant according to item 16, wherein the administration is into the vitreous humor. plant. 18. The method of the preceding paragraph, wherein the particles of the tyrosine kinase inhibitor are dispersed within a hydrogel. The sustained-release biodegradable intraocular implant according to any one of the preceding claims. 19. The sustained-release formulation according to item 18, wherein the particles of the tyrosine kinase inhibitor are micronized particles. Biodegradable intraocular implant. 20. The implant is in a dry state before administration and once administered into the eye 4. The sustained-release biodegradable intraocular implant of any of the preceding items, wherein the sustained-release biodegradable intraocular implant becomes hydrated with 21. The hydrogel is made of polyethylene glycol, polyethylene oxide, polypropylene Polyethylene oxide, polyvinyl alcohol, poly(vinylpyrrolidinone), polylactic acid, poly(milk) acid-co-glycolic acid, random or block copolymers of any of these, or is one or more units of a combination or mixture of polyamino acids, glycosaminoglycans , polysaccharide, or protein, including a polymer network containing one or more units of the preceding Item 10. A sustained-release biodegradable intraocular implant according to any one of items 1 to 4. 22. The hydrogel comprises a polymer network comprising identical or different crosslinked polymer units. 22. The sustained-release biodegradable intraocular implant according to item 21, comprising a network. 23. The cross-linked polymer unit is one or more cross-linked polyethylene glycol units. 23. The sustained-release biodegradable intraocular implant according to item 22, wherein the implant is in the form of a hydroxybenzoate. 24. The polymer network has a molecular weight in the range of about 2,000 to about 100,000 daltons. Any of items 21 to 23, containing polyethylene glycol units having an average molecular weight of A sustained release biodegradable intraocular implant as described. 25. The polyethylene glycol unit is about 10,000 to about 60,000 daltons. 25. The sustained-release biodegradable intraocular implant according to item 24, having an average molecular weight within the range. 26. The polyethylene glycol unit is about 20,000 to about 40,000 daltons. 26. The sustained-release biodegradable intraocular implant according to item 25, having an average molecular weight within the range. 27. The polyethylene glycol units have an average molecular weight of about 20,000 daltons. 27. The sustained-release biodegradable intraocular implant according to Item 26. 28. The polymer network comprises one or more crosslinked multi-arm polymer units. 28. The sustained-release biodegradable intraocular implant according to any one of items 21 to 27, comprising 29. The multi-arm polymer unit is one or more 2-10 arm polyethylene glycols. 29. The sustained-release biodegradable intraocular implant according to item 28, comprising a hydroxyl group unit. 30. The multi-arm polymer unit is one or more 4- to 8-arm polyethylene glycols. 30. The sustained-release biodegradable intraocular implant according to item 29, comprising a hydroxyl unit. 31. The multi-arm polymer unit comprises one or more four-arm polyethylene glycol units. 31. The sustained-release biodegradable intraocular implant according to item 30, comprising a 32. The polymer network comprises 4-arm and 8-arm polyethylene glycol units. 32. The sustained-release biodegradable intraocular implant according to any one of Items 21 to 31, to. 33. The polymer network is formed by converting an electrophilic group-containing multi-arm polymer precursor into a nucleophilic group. 2. The multi-arm polymer precursor of claim 1, wherein the multi-arm polymer precursor is a hydroxy group-containing polymer. 10. The sustained-release biodegradable intraocular implant according to any one of the preceding claims. 34. The sustained-release bioparticle according to any one of items 21 to 33, wherein the nucleophilic group is an amine group. Dissolvable intraocular implants. 35. The sustained release agent according to any one of items 21 to 34, wherein the electrophilic group is an activated ester group. Releasing biodegradable intraocular implant. 36. The method according to item 35, wherein the electrophilic group is an N-hydroxysuccinimidyl (NHS) group. A sustained release biodegradable intraocular implant as described. 37. The electrophilic group according to item 36, wherein the electrophilic group is a succinimidyl azelate (SAZ) group. Sustained-release biodegradable intraocular implant. 38. The 4-arm polyethylene glycol unit is a 4a20kPEG unit, and the 8 Any of items 32 to 37, wherein the arm polyethylene glycol unit is 8a20kPEG unit. 2. The sustained-release biodegradable intraocular implant according to claim 1, wherein the intraocular implant is a biodegradable intraocular implant. 39. The polymer network comprises 4a20kPEG-SAZ and 8a20kPEG- 39. The support according to item 38, which is obtained by reacting NH2 with HCl in a weight ratio of about 2:1 or less. Sustained-release biodegradable intraocular implant. 40. The implant, when dried, contains about 25% to about 75% by weight of tyrosine. 39. The method according to any one of items 1 to 39, comprising a kinase inhibitor and about 20% by weight to about 60% by weight of polymer units. The sustained-release biodegradable intraocular implant according to any one of the preceding claims. 41. The implant, when dried, contains about 35% to about 65% by weight of tyrosine. Item 40, comprising a kinase inhibitor and about 25% by weight to about 50% by weight of polymer units. Sustained-release biodegradable intraocular implant. 42. The implant, when dried, contains about 45% to about 55% by weight of tyrosine. 41. The method according to claim 41, comprising a kinase inhibitor and about 37% to about 47% by weight of polymer units. Sustained-release biodegradable intraocular implant. 43. The implant contains one or more phosphates, borates, or carbonates. 10. The sustained-release biodegradable intraocular implant of any of the preceding items. 44. The implant is derived from the phosphate buffer used during the preparation of the hydrogel. 44. The sustained-release biodegradable intraocular implant according to item 43, comprising a phosphate salt. 45. The hydrogel, in a wet state, contains about 3% to about 20% polyethylene glycol (PEG). (equivalent to polyethylene glycol weight ÷ fluid weight × 100) The sustained-release biodegradable intraocular implant. 46. ​​The hydrogel is made of about 7.5% to about 15% polyethylene glycol (polyethylene glycol). Item 45. A sustained-release bioavailable composition comprising the sustained-release bioavailable composition according to Item 45, which contains the sustained-release bioavailable composition (equivalent to the weight of glycol divided by the weight of fluid × 100). Dissolvable intraocular implants. 47. The method of claim 1, wherein the implant contains, in a dried state, about 1% by weight or less of water. The sustained-release biodegradable intraocular implant according to any one of the preceding claims. 48. The implant has an essentially cylindrical shape or another shape, such as a cross shape. A sustained-release biodegradable intraocular implant according to any of the line items. 49. The sustained release bioavailable composition according to any of the preceding claims, wherein the implant is in the form of a fiber. Degradable intraocular implants. 50. The sustained release device according to any of the preceding items, wherein the implant is administered to the eye by means of a needle. Releasing biodegradable intraocular implant. 51. The sustained release biodegradable preparation according to item 50, wherein the needle is a 25-gauge or 27-gauge needle. Degradable intraocular implants. 52. The implant, when hydrated in vivo or in vitro in the eye, or the diameter of the implant increases and the length of the implant 8. The sustained-release biodegradable intraocular implant of any preceding item, wherein the implant shortens. 53. Hydration was measured in vitro after 24 hours in phosphate buffered saline at 37°C, pH 7.2. 53. The sustained-release biodegradable intraocular implant according to item 52, wherein the ocular surface area is measured at 0.05°C. 54. The implant biodegrades in the vitreous humor within about 2 to about 15 months after administration. 54. The sustained-release biodegradable intraocular implant according to any one of Items 17 to 53. 55. The implant biodegrades in the vitreous humor within about 4 to about 13 months after administration. 55. The sustained-release biodegradable intraocular implant according to item 54. 56. The implant biodegrades in the vitreous humor within about 9 to about 12 months after administration. 56. The sustained-release biodegradable intraocular implant according to item 55. 57. The implant, after administration to the vitreous humor, contains a therapeutically effective amount of axitinib. , at least about 3 months, at least about 6 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least about 13 months, and 57. The sustained release method according to any one of items 2 to 56, wherein the sustained release agent is released over a period of at least about 14 months. Sustained-release biodegradable intraocular implant. 58. The implant, after administration to the vitreous humor, contains a therapeutically effective amount of axitinib. 58. The sustained-release biodegradable ophthalmic solution according to item 57, which releases over a period of at least about 6 months. Intra-implant. 59. The implant, after administration to the vitreous humor, contains a therapeutically effective amount of axitinib. 58. The sustained-release biodegradable ophthalmic solution according to item 57, which releases over a period of at least about 9 months. Intra-implant. 60. Axitinib is administered from the implant at a dose of about 0.1 μg / day to about 10 μg / day. 59. The sustained-release biodegradable intraocular formulation according to any one of items 17 to 59, which is released at an average rate of 1 day. Implant. 61. Axitinib is delivered from the implant at an average rate of about 0.5 μg / day to about 7 μg / day. 61. The sustained-release biodegradable intraocular implant according to item 60, wherein the sustained-release biodegradable intraocular implant is released at a constant rate. 62. Axitinib is administered from the implant at an average rate of about 1 μg / day to about 5 μg / day. 62. The sustained-release biodegradable intraocular implant according to item 61, wherein the sustained-release biodegradable intraocular implant is released. 63. The implant comprises tyrosine kinase inhibitor particles contained in the implant. 63. The method according to any one of items 17 to 62, which is biodegraded in the vitreous humor before complete solubilization. Sustained-release biodegradable intraocular implant. 64. The total amount of the tyrosine kinase inhibitor contained in the implant is 63. The method according to claim 17, wherein the compound is released before it is completely decomposed in the vitreous humor. The sustained-release biodegradable intraocular implant. 65. The implant comprises a mixture comprising a hydrogel precursor and a tyrosine kinase inhibitor. The mixture is filled into a tube, and the hydrogel is allowed to gel in the tube. The hydrogel fibers are stretched to obtain a hydrogel formed into fibers. 2. The sustained release biodegradable intraocular implant of any of the preceding items, wherein the sustained release biodegradable intraocular implant is obtainable. 66. The fibers are stretched and / or twisted before or after drying. Item 66. The sustained-release biodegradable intraocular implant according to item 65. 67. Item 6, wherein the fibers are stretched in the longitudinal direction with a stretch factor of about 1.0 to about 4.5. 7. The sustained-release biodegradable intraocular implant according to claim 6. 68. 160 μg to approximately 250 μg of axitinib dispersed within a hydrogel, or A sustained-release biodegradable intraocular implant containing about 180 μg to about 220 μg, or about 200 μg. The implant, wherein the hydrogel is a polymer chain comprising polyethylene glycol units. the sustained release network, wherein the implant is in a dried state prior to administration. Biodegradable intraocular implant. 69. The polymer network is 4a20kPEG-SAZ and 8a20kPEG-N 69. The sustained-release biodegradable intraocular implant according to item 68, which is formed by reacting with H Plant. 70. The hydrogel, when formed and before drying, is coated with 7.5% polyethylene. Glycol (equivalent to polyethylene glycol weight ÷ fluid weight × 100), item 69 10. A sustained release biodegradable intraocular implant according to claim 1. 71. The implant, when dried, has an axial content of about 45% to about 55% by weight. Item 68 to 69, comprising nibs and about 37% to about 47% by weight of polyethylene glycol units. 70. A sustained-release biodegradable intraocular implant according to any one of claims 70 to 70. 72. The implant according to items 68 to 72, wherein the implant contains about 1% by weight or less of water in a dried state. 71. A sustained-release biodegradable intraocular implant according to any one of 71. 73. The polymer network is 4a20kPEG-SAZ and 8a20kPEG-N Any of items 68-72 formed by reacting with H2 in a weight ratio of about 2:1 or less. 2. The sustained-release biodegradable intraocular implant according to claim 1, wherein the intraocular implant is a biodegradable intraocular implant. 74. The implant is in v in phosphate buffered saline at 37°C for a period of 30 days. The drug releases approximately 0.01 μg to approximately 0.15 μg of axitinib per day in vitro. 74. The sustained-release biodegradable intraocular implant according to any one of 68 to 73. 75. The implant is placed in a 25:75 ethanol / water mixture (v / v) at 37°C. In the case of the above, about 35% to about 45% of the axitinib was detected in 3 days, and about 65% of the axitinib was detected in 7 days. and about 90% to about 100% of the axitinib in 12 to 13 days. 75. A sustained-release biodegradable intraocular implant according to any one of Items 68 to 74, which is released by ro. to. 76. The implant is placed in a phosphate buffered saline solution with an octanol overlay at 37°C, pH 7.2. In saline, the axitinib concentration was approximately 25% to 35% of the axitinib concentration at 2 months and approximately 10% of the axitinib concentration at 3 months. about 47% to about 57% of the axitinib at 5 months, about 70% to about 80% of the axitinib at 7 months Any of items 68 to 75 that release approximately 90% to 100% of axitinib in vitro 2. The sustained-release biodegradable intraocular implant according to claim 1, wherein the intraocular implant is a biodegradable intraocular implant. 77. The implant has an average diameter of about 15 mm to about 16.5 mm in its dried state. Item 6, in the form of fibers having a length and an average diameter of about 0.20 mm to about 0.30 mm. 77. The sustained-release biodegradable intraocular implant according to any one of 8 to 76. 78. Hydration in vivo or in vitro in the eye reduces the length and diameter Increased in vitro hydration was observed in phosphate buffered saline at 37°C, pH 7.2, for 24 h. 78. The sustained-release biodegradable intraocular implant of item 77, measured after 2 hours. 79. The implant has an average length in its hydrated state of about 6.5 to about 8 mm and a length of about 0.7 79. The sustained-release biodegradable polymer according to item 77 or 78, having an average diameter of 0 to about 0.80 mm. Sexual intraocular implants. 80. The implant comprises preparing a mixture comprising a hydrogel precursor and axitinib; The mixture is filled into a tube, and the hydrogel is allowed to gel within the tube to form fibers. The hydrogel fiber can be obtained by stretching the hydrogel fiber. 80. The sustained-release biodegradable intraocular implant according to any one of Items 68 to 79. 81. The method according to item 80, wherein the fibers are dry stretched by a factor of about 2 to about 5 after drying. Releasing biodegradable intraocular implant. 82. The method according to item 81, wherein the fibers are dry stretched by a factor of about 3 to about 4.5 after drying. Sustained-release biodegradable intraocular implant. 83. The implant, in its dried state, is inserted into a 25 gauge tube for injection into the vitreous humor. 83. The sustained release agent according to any one of items 68 to 82, which is loaded into a needle such as a 27-gauge needle or a 27-gauge needle. Releasing biodegradable intraocular implant. 84. Axitinib dispersed in a hydrogel in a range of about 480 μg to about 750 μg. a sustained release biodegradable intraocular implant comprising an amount of The sustained-release biodegradable intraocular implant comprises a network. 85. The polymer network comprises cross-linked polyethylene glycol units. A sustained-release biodegradable intraocular implant as described in eye 84. 86. The axitinib is contained in an amount ranging from about 540 μg to about 660 μg. 85. A sustained-release biodegradable intraocular implant according to claim 85. 87. The sustained-release formulation according to item 86, wherein the axitinib is contained in an amount of about 600 μg. Biodegradable intraocular implants. 88. The polyethylene glycol unit has a molecular weight of about 10,000 daltons to about 60,000 daltons. 4-arm and / or 8-arm polyethylene glycols having an average molecular weight in the range of 100 kJ / kg. 88. The sustained-release biodegradable intraocular implant according to any one of items 84 to 87, comprising a steroid unit. to. 89. The polyethylene glycol unit according to item 88, wherein the polyethylene glycol unit comprises 4a20kPEG units. Sustained-release biodegradable intraocular implant. 90. The polymer network is 4a20kPEG-SAZ and 8a20kPEG-N 89. The sustained-release biodegradable intraocular implant according to claim 89, which is formed by reacting with H Plant. 91.4a20kPEG-SAZ to 8a20kPEG-NH2 weight ratio is approximately 2:1 or less Item 90. The sustained-release biodegradable intraocular implant according to Item 90. 92. The implant, when dried, has an axial content of about 45% to about 55% by weight. Item 84 - nib and about 37% to about 47% by weight of polyethylene glycol units 91. A sustained-release biodegradable intraocular implant according to any one of claims 91 to 91. 93. The implant according to items 84 to 88, wherein the implant contains about 1% by weight or less of water in a dried state. 92. A sustained-release biodegradable intraocular implant according to any one of 92. 94. The implant has an average length of about 7 mm to about 12 mm in its dried state. and items 84 to 9, which are in the form of fibers having an average diameter of about 0.25 mm to about 0.50 mm. 4. A sustained-release biodegradable intraocular implant according to any one of 3. 95. The implant has an average length of about 8 mm to about 11 mm in its dried state. Item 95. The composition according to Item 94, which is in the form of fibers having an average diameter of about 0.3 mm to about 0.4 mm. Sustained-release biodegradable intraocular implant. 96. The method according to any one of items 84 to 95, wherein the implant is for administration into the vitreous humor. Sustained-release biodegradable intraocular implant. 97. Hydration in vivo or in vitro increases the diameter of the eye, In vitro hydration measured after 24 hours in phosphate buffered saline, pH 7.2, at 37°C 97. The sustained-release biodegradable intraocular implant according to items 94 to 96. 98. The implant has an average length in its hydrated state of about 9 mm to about 12 mm and a length of about 0. Item 97. The sustained-release biodegradable intraocular implant according to item 97, having an average diameter of 5 mm to about 0.8 mm. Plant. 99. The implant has an average length of about 9.5 mm to about 11.5 mm in its hydrated state and and has an average diameter of about 0.65 mm to about 0.75 mm, or has an average diameter of about 10 mm in its hydrated state. 99. The sustained-release biodegradable composition according to item 98, having an average length of less than or equal to about 9 mm. Sexual intraocular implants. 100. The implant contains about 600 μg of axitinib and is maintained in a phosphate-buffered saline solution at 37°C. Approximately 0.3 μg to approximately 0.5 μg per day in vitro for a period of 30 days in saline 99. The sustained-release biodegradable intraocular drug according to any one of Items 84 to 99, which releases axitinib of Implant. 101. The implant is placed in a 25:75 ethanol / water mixture (v / v) at 37°C. In this study, about 40% to about 60% of the axitinib was detected in 2 days, and about 60% of the axitinib was detected in 4 days. In vitro release of axitinib was observed in 5 days to approximately 85% of the active ingredient in the compound, and in 6 days, approximately 75% to approximately 90% of the active ingredient in the compound was released. The sustained-release biodegradable intraocular implant according to any one of Items 84 to 100, . 102. The implant is placed in a 25:75 ethanol / water mixture (v / v) at 37°C. In this study, the axitinib concentration was approximately 45% to 55% in 2 days and approximately 75% in 4 days. In vitro release of axitinib was observed in 0% to about 80% of the active ingredient in the compound in 6 days, and in vitro release of axitinib was observed in 1 day to about 80% to about 90% of the active ingredient in the compound in 6 days. Item 102. The sustained-release biodegradable intraocular implant according to Item 101. 103. The implant comprises preparing a mixture containing a hydrogel precursor and axitinib. The mixture is filled into a tube, and the hydrogel is allowed to gel within the tube to form fibers. and stretching the hydrogel fiber. 103. The sustained-release biodegradable intraocular implant according to any one of Items 84 to 102. 104. The method according to item 103, wherein the fibers are wet stretched by a factor of about 0.5 to about 5 before drying. The sustained-release biodegradable intraocular implant. 105. The method according to item 104, wherein the fibers are wet-stretched by a factor of about 1 to about 4 before drying. Sustained-release biodegradable intraocular implant. 106. Item 105, wherein the fibers are wet stretched by a factor of about 1.5 to about 3.5 before drying. 10. A sustained release biodegradable intraocular implant according to claim 1. 107. The method according to item 106, wherein the fibers are wet stretched by a factor of about 1.7 to about 3 before drying. The sustained-release biodegradable intraocular implant. 108. The implant is loaded in a dried state into a needle for injection into the vitreous humor. The sustained-release biodegradable intraocular implant according to any one of Items 84 to 107. 109. The implant, in its dried state, is inserted into a 25-gauge or 27-gauge needle. Item 109. The sustained-release biodegradable intraocular implant according to item 108, wherein the implant is loaded with a hydroxybenzoate. 110. The hydrogel is semi-crystalline in a dry state at or below room temperature and non-crystalline in a wet state. 109. The sustained-release composition according to any one of items 1 to 109, comprising a polymer network that is crystalline. Biodegradable intraocular implants. 111. The implant is subjected to wet or dry stretching during manufacture and is in the stretched form before The implant is dimensionally stable when in a dry state at or below room temperature. 11. A sustained-release biodegradable intraocular implant according to any one of 10. 112. A method for treating an ocular disease in a patient in need thereof, comprising administering a hydrogel and a sustained-release biodegradable ophthalmic solution comprising a tyrosine kinase inhibitor according to any of the preceding items. administering to said patient an intravenous implant for at least 3 months of treatment The dose of the tyrosine kinase administered once per eye is about 150 μg to about 1200 μg. The method according to any one of claims 1 to 4, wherein the compound is an enzyme inhibitor. 113. The method of item 112, wherein the tyrosine kinase inhibitor is axitinib. 114. The dose administered per eye during the treatment period is about 200 μg to about 114. The method according to item 112 or 113, wherein the amount of the serotonin-containing compound is in the range of 800 μg. 115. The dose is about 160 μg to about 250 μg, or about 180 μg to about 220 μg 114. The method according to item 112 or 113, wherein the range is 116. The method of item 115, wherein the dose is about 200 μg. 117. The dose is about 320 μg to about 500 μg, or about 360 μg to about 440 μg 114. The method according to item 112 or 113, wherein the range is 118. The method of item 117, wherein the dose is about 400 μg. 119. The dose is about 480 μg to about 750 μg, or about 540 μg to about 660 μg 114. The method according to item 112 or 113, wherein the range is 120. The method of item 119, wherein the dose is about 600 μg. 121. The dose is about 640 μg to about 1000 μg, or about 720 μg to about 880 μg. 114. The method of claim 112 or 113, wherein the range is within g. 122. The method of item 121, wherein the dose is about 800 μg. 123. The method according to any one of items 112 to 122, wherein the ocular disease is accompanied by neovascularization. 124. The ocular disease is characterized by the involvement of one or more receptor tyrosine kinases (RTKs), particularly V EGFR-1, VEGFR-2, VEGFR-3, PDGFR-α / β, and / or c - The method according to any one of items 112 to 123, wherein the method is mediated by Kit. 125. The ocular disease is choroidal neovascularization, diabetic retinopathy, diabetic macular edema, retinal stasis, Retinopathy, including venous occlusion, acute macular neuroretinopathy, central serous chorioretinopathy, and cystoid macular edema The ocular disease is an ocular disease, such as acute multifocal macular pigment epitheliopathy, Behcet's disease, Bard's disease, Schott chorioretinopathy, infectious diseases (syphilis, Lyme disease, tuberculosis, toxoplasmosis), intermediate bud Uveitis (pars planitis), multifocal choroiditis, multiple vanishing white dot syndrome (MEWDS), eye Sarcoidosis, posterior scleritis, serpiginous choroiditis, subretinal fibrosis, uveitis syndrome, or Vogt-Koyanagi-Harada syndrome, or the eye disease is a vascular disease or an exudative Diseases (Coats' disease, parafoveal telangiectasia, papillary vasculitis, frosty branch vasculitis, sickle cell reticulitis) Membranopathy and other hemoglobinopathies, angioid streaks, and familial exudative vitreoretinopathy or the eye disease is due to trauma or surgery (including sympathetic ophthalmia, Uveitic retinal disease, retinal detachment, trauma, photodynamic laser therapy, photocoagulation, intraoperative hypoperfusion, radiation retinopathy, or bone marrow transplant retinopathy), or the ocular disease. 5. A method according to any one of claims 4 to 4. 126. The ocular disease is neovascular age-related macular degeneration, diabetic macular edema, or retinal vein atherosclerosis. 125. The method according to any one of items 112 to 124, wherein the condition is obstructive. 127. The method according to item 126, wherein the disease is neovascular age-related macular degeneration. 128. The treatment is effective in patients with high central retinal thickness, as measured by optical coherence tomography. and (iii) a method for reducing, essentially maintaining, or preventing a clinically significant increase in central retinal thickness in patients with glaucoma. The method according to any one of Items 112 to 127, which is effective. 129. The dose per eye administered once during the treatment period is one implant. or in two, three, or more implants administered simultaneously The method according to any one of items 112 to 128, 130. The implant is administered by injection into the vitreous humor. 29. A method according to any one of claims 1 to 29. 131. The treatment period is at least about 3 months, at least about 4.5 months, or at least about 6 months, at least about 9 months, at least about 11 months, at least about 12 months, at least At least about 13 months, or at least about 14 months, as described in any of items 112-130 How to post. 132. The treatment period is at least 6 months, at least about 9 months, or at least about Item 132. The method according to item 131, wherein the period is 12 months. 133. Concurrently with the treatment with the sustained-release intraocular implant, an anti-VEGF agent or an anti-VEGF agent is administered to said patient within about 1 day of said administration of said implant. 133. The method according to any one of items 112 to 132, wherein the administration is within about 2, or about 3 months. . 134. The anti-VEGF agent is aflibercept, bevacizumab, pegaptanib, ranibizumab, or 134. The method of claim 133, wherein the medicament is selected from the group consisting of izumab, and brolucizumab. 135. The method of item 134, wherein the anti-VEGF agent is bevacizumab. 136. Any of items 133 to 135, wherein the anti-VEGF agent is administered by intravitreal injection. The method according to any one of the preceding claims. 137. Item 1, wherein the patient receiving the implant has a history of anti-VEGF treatment. 12 to 136. A method according to any one of claims 12 to 136. 138. The patient receiving the implant has no history of anti-VEGF treatment (anti-V The method according to any one of items 112 to 136, wherein the cells are EGF-naive. 139. Method for treating neovascular age-related macular degeneration in a patient in need thereof The patient is administered a hydrogel comprising a polymer network and about 200 μg of tyrosine. administering a sustained-release biodegradable intraocular implant containing a synthase kinase inhibitor; One implant per eye will be administered once over a treatment period of at least 9 months, The method, wherein the patient has a history of anti-VEGF treatment. 140. Method for treating neovascular age-related macular degeneration in a patient in need thereof The patient is administered a hydrogel comprising a polymer network and about 200 μg of tyrosine. administering a sustained-release biodegradable intraocular implant containing a synthase kinase inhibitor; Two implants per eye forming a total dose of approximately 400 μg were administered for at least 3 months of treatment. and the patient may or may not have a history of anti-VEGF therapy. , the method. 141. The treatment comprises: a central area retinal defect measured by optical coherence tomography during the treatment period; 141. The method of claim 139 or 140, which results in a reduction in thickness (CSFT). 142. The tyrosine kinase inhibitor is axitinib, The agent was synthesized by reacting 4a20kPEG-SAZ with 8a20kPEG-NH2. Dispersed within the hydrogel comprising the formed polymer network, the implant 142. The method according to any one of items 139 to 141, wherein the composition is in a dried state before administration. 143. The hydrogel, when formed and before drying, contains about 7.5% polyethylene. polyethylene glycol (equivalent to polyethylene glycol weight ÷ fluid weight × 100) 142. 144. The method according to any one of items 140 to 143, wherein the treatment period is at least 9 months. How to do it. 145. A method for treating neovascular age-related macular degeneration in a patient in need thereof. The patient is then administered an axial graft that is dispersed within a hydrogel comprising a polymer network. A sustained-release biodegradable intraocular implant containing nib in an amount ranging from about 480 μg to about 750 μg. and administering to the patient a therapeutically effective amount of the implant for at least three months. The method according to claim 1, wherein the 146. The axitinib is contained in the implant in an amount of about 560 μg to about 660 μg. Item 145. The method of claim 145, 147. Item 1, wherein the axitinib is contained in the implant in an amount of about 600 μg. 46. ​​The method according to claim 46. 148. The implant is as defined in items 145 to 111. 147. A method according to any one of claims 147 to 147. 149. Any of items 145 to 148, wherein the implant is administered into the vitreous humor. The method described. 150. The treatment period is at least about 3 months, at least about 6 months, at least about 9 months, months, at least about 11 months, at least about 12 months, at least about 13 months, or less 149. The method according to any one of items 145 to 149, wherein the period is at most about 14 months. 151. The implant is inserted into the vitreous humor using a 25-gauge or 27-gauge needle. 151. The method according to any of items 145 to 150, wherein the compound is administered by injection of 152. The patient receiving the implant has a history of anti-VEGF treatment, or have no history of anti-VEGF treatment (anti-VEGF naive), items 145-151 A method according to any one of the preceding claims. 153. The anti-VEGF agent is administered to the patient concurrently with the implant. The method according to any one of items 145 to 152. 154. The anti-VEGF agent is aflibercept, bevacizumab, pegaptanib, ranibizumab, or 154. The method of claim 153, wherein the medicament is selected from the group consisting of izumab, and brolucizumab. 155. The method of item 154, wherein the anti-VEGF agent is bevacizumab. 156. Any of items 153 to 155, wherein the anti-VEGF agent is administered by intravitreal injection. The method according to any one of the preceding claims. 157. A low number of adverse events during administration of the sustained-release biodegradable intraocular implant; The method according to any one of items 112 to 156. 158. The incidence of treatment-related ocular adverse events during administration of the sustained-release biodegradable intraocular implant The method described in item 157, which has a small number of cases. 159. A hydrogel according to any one of items 1 to 111 and about 150 μg to about 1,200 μg Method for producing sustained-release biodegradable intraocular implants containing tyrosine kinase inhibitors of g A hydrogel comprising a polymer network and a polymer dispersed within the hydrogel. forming the hydrogel containing tyrosine kinase inhibitor particles; The method includes the steps of shaping a hydrogel and drying the hydrogel. Law. 160. The method of item 159, wherein the tyrosine kinase inhibitor is axitinib. 161. The tyrosine kinase inhibitor particles are micronized and / or uniformly dispersed within the hydrogel. 161. The method according to item 159 or 160, wherein the particles are dispersed evenly. 162. The polymer network is a multi-arm polyethylene glycol in a buffer solution. 162. The method according to any one of items 159 to 161, wherein the polymer is formed by crosslinking a methyl group unit. . 163. The hydrogel is electrophilically reacted in a buffer solution in the presence of the tyrosine kinase inhibitor. Nucleophilic group-containing multi-arm polyethylene glycol and nucleophilic group-containing multi-arm polyethylene glycol a polymer formed by mixing and reacting with lycohol and gelling the mixture The method according to any one of items 159 to 162, including a network. 164.4a20kPEG-SAZ was reacted with 8a20kPEG-NH2 in a weight ratio of approximately 2:1. Item 164. The method of item 163, comprising reacting 165. The method further comprises: filling the mixture into a mold or tube before it is completely gelled; and drying the hydrogel. 4. The method described in 4. 166. The mixture is filled into a fine diameter tube to prepare a hydrogel fiber. Item 165. The method according to item 165. 167. The method according to item 166, wherein the interior of the tube has a circular geometric shape. 168. The method according to item 166, wherein the interior of the tube has a geometric shape other than circular. Law. 169. The method according to item 168, wherein the interior of the tube has a cross-shaped geometric shape. . 170. Further comprising drawing the fibers and / or twisting the fibers. 169. The method according to any one of Items 166 to 169. 171. The method according to item 170, wherein the stretching is performed before or after drying the hydrogel. The method described. 172. The method according to item 171, wherein the fiber is drawn at 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 comprises 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 Item 171, wherein the method is carried out as described in Item 171. 174. The implant comprises axitinib in an amount of about 600 μg, and the stretching comprises The hydrogel has a stretch factor of about 0.5 to about 5, or about 1 to about 4, in a wet state before drying. A stretch factor of about 1.3 to about 3.5, or a stretch factor of about 1.7 to about 3 Item 171, wherein the method is performed. 175. The method further includes loading the implant into a needle in a dry state. The method according to any one of Items 159 to 174. 176. The method of item 175, wherein the needle is a 25-gauge or 27-gauge needle. 177. A method for imparting shape memory to a hydrogel fiber, the method comprising: The hydrogel fiber includes an active agent dispersed within the hydrogel, and the hydrogel fiber is stretched in the longitudinal direction. The method of imparting shape memory by 178. A device containing a hydrogel with an active agent dispersed therein that changes dimensions upon administration to the eye. 1. A method for producing an intraocular implant comprising the steps of: preparing fibers of said hydrogel; and stretching the fiber longitudinally. 179. The method includes a step of drying the hydrogel, and the fiber is Stretched longitudinally (wet or dry stretching) before or after item 177 or 178 The method described below. 180. The fiber has a coefficient of about 0.5 to about 5, or a coefficient of about 1 to about 4.5, or a coefficient of about 3 Stretched by a factor of about 4.5 or about 1 to about 2, Any of the methods described above. 181. Item 181, wherein the active agent is a tyrosine kinase inhibitor (e.g., axitinib). 177 to 180. A method according to any one of claims 177 to 180. 182. The hydrogel comprises a polymer network comprising cross-linked polyethylene glycol units. 182. The method according to any one of items 177 to 181, comprising a network. 183. The fiber, upon hydration, retains approximately its original length that it had before stretching and / or 183. The method of any of items 177 to 182, wherein the original diameter is fully or partially restored. 184. The dimensional change is an increase in diameter or an increase in diameter accompanied by a decrease in length. 184. The method according to any one of Items 177 to 183. 185. A kit according to any one of items 1 to 111 or items 159 to 17 6. One or more sustained-release biodegradable intraocular implants manufactured according to any one of the methods described above. and one or more needles, Each of the ocular implants was pre-loaded with one sustained-release biodegradable intraocular implant in a dry state. The kit. 186. Item 1, wherein the needle(s) are 25-gauge or 27-gauge needle(s). 85. A kit according to claim 85. 187. The kit includes one or more 25-gauge or 27-gauge needle(s); Each of the needles contains an implant containing axitinib in an amount ranging from about 180 μg to about 220 μg. 187. The kit of item 185 or 186, wherein the kit is loaded with a runt. 188. The method according to item 187, wherein the implant contains axitinib in an amount of about 200 μg. Kit included. 189. The kit contains axitinib in an amount ranging from about 540 μg to about 660 μg. Item 185 or 186 contains one 25-gauge or 27-gauge needle loaded with an implant. or 186. 190. The method according to item 189, wherein the implant contains axitinib in an amount of about 600 μg. Kit included. 191. Item 191 further includes an injection device for injecting the implant into the patient's eye. 185 to 190. A kit according to any one of 185 to 190. 192. The injection device includes one or more needles loaded with an implant. The kit according to item 191, provided separately within the kit. 193. Item 193. The injection device is pre-connected to a needle loaded with an implant. 191. A kit according to claim 191. 194. The injection device includes a push button for placing the implant from the injection needle into the eye. 193. The kit according to item 191 or 192, comprising Schweyer. 195. A method according to items 185 to 194, further comprising administering a single dose of a ready-to-inject anti-VEGF agent. The kit according to any one of the above. 196. A sustained-release biodegradable intraocular implant according to any one of items 1 to 111. 2. An injection device suitable for injecting into a patient. 197. The injection device according to item 196, comprising means for connecting the injection device to a needle. Vice. 198. The method according to item 196 or 197, wherein the needle is preloaded with the implant. The injection device. 199. When the injection device is connected to the needle, the injection is delivered from the needle into the eye. Includes a push wire for placing the plant, and is described in any of items 196-198. The injection device. 200. The push wire is made of Nitinol or stainless steel / Teflon. Item 199. An injection device according to item 199, 201. Affix the wire to the plunger and attach it to two snap-fit ​​syringes. and securing the plunger with a clip. 199 or 200. An injection device according to item 199 or 200. 202. A pharmaceutical product, a sustained release drug according to any one of items 1 to 111, loaded into a needle. A biodegradable intraocular implant and an injection device according to any one of items 196 to 201. wherein the needle is pre-connected to the injection device. 203. In a patient requiring treatment for an ocular disease described in any of items 112 to 138 or any of items 139 to 158, 210, or 211. The method for treating neovascular age-related macular degeneration according to the present invention is described below. 112. A tyrosine kinase inhibitor according to any one of items 1 to 111 for use in the treatment of macular degeneration. A sustained-release biodegradable intraocular implant containing an enzyme inhibitor. 204. Treatment of an ocular disease according to any one of items 112 to 138 is carried out for a patient in need thereof. or any of items 139-158, 210, or 211 A medical device for treating neovascular age-related macular degeneration according to the present invention in a patient in need thereof. A method for preparing a drug comprising administering a tyrosine kinase inhibitor according to any one of items 1 to 111 to a patient. Use of sustained-release biodegradable intraocular implants. 205. In patients with increased central retinal thickness due to neovascular ocular disease, Essentially reduces clinically significant increases in central retinal thickness as measured by optical coherence tomography A method for maintaining or preventing the occurrence of a disease comprising administering to the patient a chemotherapy drug according to any one of items 1 to 111. administering a sustained-release biodegradable intraocular implant containing a rosin kinase inhibitor. , the method. 206. The method according to item 205, wherein the ocular disease is neovascular age-related macular degeneration. 207. The method of claim 1, wherein the central retinal thickness of the patient is measured before administration of the implant. a decrease in central retinal thickness relative to the patient's baseline central retinal thickness of at least about 3 days after administration of the implant; month, at least about 6 months, at least about 9 months, at least about 11 months, at least about 1 reduced, essentially, for 2 months, at least about 13 months, or at least about 14 months Item 20. The method of claim 20, wherein the central retinal thickness is maintained at or prevented from increasing clinically significant. 5 or 206. 208. A tumor associated with angiogenesis according to any of items 205 to 207, 210, or 211. Optical coherence tomography measurements in patients with increased central retinal thickness due to ocular disease Reduce, essentially maintain, or prevent clinically significant increases in central retinal thickness in and a tyrosine kinase inhibitor according to any one of items 1 to 111 for use in 1. A sustained-release biodegradable intraocular implant comprising: 209. A tumor associated with angiogenesis according to any of items 205 to 207, 210, or 211. Optical coherence tomography measurements in patients with increased central retinal thickness due to ocular disease To reduce, essentially maintain, or prevent a clinically significant increase in central retinal thickness in 112. A tyrosine kinase inhibitor according to any one of items 1 to 111, in the preparation of a pharmaceutical for 1. Use of a sustained-release biodegradable intraocular implant comprising: 210. The patient's visual acuity, as measured by best corrected visual acuity, is not reduced or improved. The method according to any one of Items 128 to 158 or any one of Items 205 to 207. 211. No rescue medication is required during the treatment period, or Rescue medications need to be administered only infrequently (e.g., 1, 2, or 3 times), Any of items 128 to 158, any of items 205 to 207, or any of items 210 How to post. 212. The duration of the treatment period is Item 212. The method according to Item 211, wherein the period is about 6 months to about 9 months. 213. Method for improving visual acuity in patients with impaired visual acuity due to neovascular ocular disease wherein the patient is administered a tyrosine kinase inhibitor according to any one of items 1 to 111. The method comprises administering a sustained-release biodegradable intraocular implant comprising: 214. The ocular disease is neovascular age-related macular degeneration, diabetic macular edema, or retinal vein atherosclerosis. Item 214. The method of item 213, wherein the obstruction is 215. The patient's vision is reduced due to the presence of retinal fluid, item 213 or item 21 4. The method described in 4. 216. The improvement in visual acuity is manifested by an increase in best-corrected visual acuity, items 213 to 215. A method according to any one of claims 215 to 215. 217. The best corrected visual acuity is at least 10 letters, at least 15 letters, or less. Item 217. The method of item 216, wherein the number of ETDRS characters is increased by 20 characters. 218. A method for treating an ocular disease accompanied by neovascularization, according to any one of items 213 to 217. Items 1 to 11 for use in improving the vision of patients with reduced vision due to 1. A sustained-release biodegradable intraocular implant comprising the tyrosine kinase inhibitor according to any one of claims 1 to 9. to. 219. A method for treating ocular diseases associated with neovascularization using a method according to any one of items 213 to 217. Therefore, in the preparation of a medicine for improving the vision of a patient with reduced vision, items 1 to 111 1. A sustained-release biodegradable intraocular implant comprising the tyrosine kinase inhibitor according to any one of claims 1 to 9. Use of. Second item list 1. A polymer network containing a tyrosine kinase inhibitor and a clearance zone. A sustained-release biodegradable intraocular hydrogel implant, wherein the clearance zone is The sustained-release biodegradable intraocular hydrogel implant is free of the TKI prior to the release of the KI. Runt. 2. When the TKI is contained within the hydrogel implant, the TKI Item 1. The intraocular hydrogel of item 1, which is not in contact with membrane cells. 3. The TKI is present in the hydrogel implant at or near its saturation level. 3. The intraocular hydrogel according to item 1 or 2. 4. Items 1 to 3, wherein the size of the clearance zone increases as a function of the amount of TKI released. 10. The intraocular hydrogel implant according to any one of claims 1 to 9. 5. The intraocular hydrogel implant is used after the TKI has been released or after the TKI has been released. Completely decomposed after at least 90% of the Intraocular hydrogel implants. 6. The intraocular hydrogel implant is about 30 days after the TKI has been completely released. or an intraocular hydrogel according to any one of items 1 to 5, which is completely degraded after about 3 months. Lu implant. 7. Any of items 1 to 4, wherein the degradation of the intraocular hydrogel occurs before the release of the TKI. 1. An intraocular hydrogel implant according to claim 1. 8. The polymer network comprises a plurality of polyethylene glycol (PEG) units; 8. The intraocular hydrogel implant according to any one of items 1 to 7. 9. Any of items 1 to 8, wherein the polymer network comprises a plurality of multi-arm PEG units. An intraocular hydrogel implant according to any one of the above. 10. The polymer network comprises a plurality of 4-arm or 8-arm PEG units. The intraocular hydrogel implant according to any one of items 1 to 9. 11. The polymer network has the following formula: [ka] (wherein n represents a repeating unit of ethylene oxide, and the wavy lines represent repeating units of the polymer network.) PEG units having a PEG-1 unit point) Intraocular hydrogel implants. 12. The polymer network is 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, 4a20 k PEG-NH2, 8a20k PEG-NH2, and trilysine, or a salt thereof By reacting one or more selected PEG or lysine-based amine-containing groups 12. The intraocular hydrogel implant according to any one of items 1 to 11, formed thereby. 13. The polymer network is a 4a20k PEG-SAZ polymer. 13. The eye according to any one of items 1 to 12, formed by reacting with —NH Intracellular hydrogel implant. 14. Any of items 1 to 13, wherein the polymer network is amorphous (under aqueous conditions). An intraocular hydrogel implant according to any one of the above. 15. Any of items 1 to 14, wherein the polymer network is semi-crystalline in the absence of water. 1. An intraocular hydrogel implant according to any one of claims 1 to 10. 16. The tyrosine kinase inhibitor is homogeneously dispersed within the polymer network. 16. The intraocular hydrogel implant according to any one of items 1 to 15, 17. The tyrosine kinase inhibitor is released over a period of at least 15 days. 17. The intraocular hydrogel implant according to any one of items 1 to 16. 18. The tyrosine kinase inhibitor is released over a period of at least 30 days. 18. An intraocular hydrogel implant according to any one of items 1 to 17. 19. The tyrosine kinase inhibitor is released over a period of at least 60 days. 19. The intraocular hydrogel implant according to any one of items 1 to 18. 20. The tyrosine kinase inhibitor is released over a period of at least 90 days. 20. The intraocular hydrogel implant according to any one of items 1 to 19. 21. The tyrosine kinase inhibitor is released over a period of at least 180 days. 21. The intraocular hydrogel implant according to any one of items 1 to 20. 22. The tyrosine kinase inhibitor is released over a period of at least 365 days. 22. The intraocular hydrogel implant according to any one of items 1 to 21. 23. Any of items 1 to 22, wherein the tyrosine kinase inhibitor is in the form of encapsulated microparticles. An intraocular hydrogel implant according to any one of the above. 24. The tyrosine kinase inhibitor is a capsule comprising poly(lactic-co-glycolic acid). 24. The intraocular hydrogel implant according to any one of items 1 to 23, which is in the form of crystalline microparticles. nt. 25. The tyrosine kinase inhibitor is abemaciclib, acalabrutinib, afatinib alectinib, axitinib, barictinib, binimetinib, brigatinib, caboza entinib, ceritinib, cobrametinib, crizotinib, dabrafenib, dacomitinib , dasatinib, encarafenib, erlotinib, everolimus, fostamatinib, gefitinib Fritinib, gilteritinib, gilteritinib, ibrutinib, imatinib, larotrek tinib, lenvatinib, lorlatinib, axitinib, idelalisib, lenvatinib, Dostaurin, neratinib, netarsudil, nilotinib, nintedanib, osimertinib , palbociclib, pazopanib, ponatinib, regorafenib, ribociclib, ruxoli tinib, sirolimus, sorafenib, sunitinib, temsirolimus, tofacitinib, Any of items 1 to 24 selected from lametinib, vandetanib, and vemurafenib 1. An intraocular hydrogel implant according to any one of claims 1 to 10. 26. The ophthalmic solution according to item 1 or 25, wherein the tyrosine kinase inhibitor is axitinib. Intracellular hydrogel implant. 27. The intraocular hydrogel implant is injected into the vitreous humor or into the anterior chamber of the eye. or applied to the upper or lower punctum of the eye, according to any one of items 1 to 26. 1. An intraocular hydrogel implant as described. 28. A method of treating an ocular condition in a subject in need thereof, comprising: The animals were injected or affixed with an intraocular hydrogel implant according to any one of items 1 to 27. The method further comprising: 29. The ocular condition is maculopathy, retinal degeneration, uveitis, retinitis, choroiditis, vascular disease, Exudative diseases, trauma, proliferative diseases, infectious diseases, genetic disorders, retinal tears, retinal holes, and tumors 29. The method of claim 28, wherein the tumor is selected from the group consisting of tumors. 30. The ocular condition is age-related macular degeneration, choroidal neovascularization, diabetic retinopathy, acute macular neuropathy, Retinopathy, central serous chorioretinopathy, cystoid macular edema, diabetic macular edema, acute multifocal macular edema Pigment epitheliopathy, Behçet's disease, birdshot chorioretinopathy, intermediate uveitis, multifocal venous ulcers Ocular ocular inflammation, multiple disappearing white dot syndrome (MEWDS), ocular sarcoidosis, posterior meningitis, tortuosity Choroiditis, subretinal fibrosis and uveitis syndrome, Vogt-Koyanagi-Harada syndrome, Coe Tuberous sclerosis, parafoveal telangiectasia, papillary vasculitis, frosty branch vasculitis, sickle cell retinopathy, retinal Angioid streaks, familial exudative vitreoretinopathy, sympathetic ophthalmia, 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. Sepsis, macular hole, giant retinal tear, solid tumor, posterior uveal melanoma, choroidal hemangioma, choroidal bone tumors, choroidal metastases, retinoblastoma, angioproliferative tumors of the fundus, retinal astrocytomas, and intraocular lymphomas 30. The method of claim 28 or 29, wherein the tumor is selected from the group consisting of thyroid tumors, ... and thyroid tumors. 31. The method according to item 29 or 30, wherein the condition is age-related macular degeneration. 32. Any of items 29 to 31, wherein the subject has previously been treated with anti-VEGF therapy. The method described in one. [Example]

[0324] The following examples illustrate certain aspects and embodiments of the claimed invention. However, those skilled in the art will appreciate that the following description is merely exemplary and that It should be understood that these terms should not be construed as limiting the invention in any way.

[0325] Example 1: Preparation of Axitinib Implants The axitinib implant of the present application is (essentially) cylindrical (referred to herein as "fiber"). Axitinib is distributed uniformly within the PEG-based hydrogel matrix. The drug is dispersed and encapsulated in a vitreous humor of the eye, allowing for sustained release of axitinib based on its low aqueous solubility in the vitreous humor of the eye. Provide an outlet.

[0326] 4a20K PEG-SAZ (with N-hydroxysuccinimidyl reactive end groups) Two moieties of 4-armed 20 kDa PEG (sometimes referred to as "NHS" end groups) , 8a20K PEG NH2 (20 kDa PEG with 8 arms and amine end groups) The polymer network of the implant was formed by reacting with 1 part EG. Therefore, the polyurethane tubing was cut into small pieces of appropriate length. PEG-NH2 dibasic sodium phosphate solution was prepared and sterile filtered to prepare the endotoxin. Toxins and particles larger than 0.2 μm (pore size of the filter) were removed. The volume of PEG amine solution was weighed into a syringe. The corresponding amount of solid axitinib according to the final axitinib dose was weighed into a separate syringe. The syringe of powdered axitinib and the syringe of PEG amine were carefully mixed to separate the particles. The syringe containing the suspension was then sonicated to remove any powder agglomerates. Then, 4a20K PEG SAZ monobasic sodium phosphate solution was prepared. and sterile filtered as described for the PEG amine solution. A quantity of PEG SAZ solution was weighed into a separate syringe. The ingredients of the syringe (4a20K PEG SAZ monobasic sodium phosphate solution and axit Nib-8a20K PEG NH2 mixture) was mixed to initiate the reaction leading to gelation. This liquid suspension was cast into a prepared polyurethane tube before the material crosslinked and solidified. The gelation time was confirmed by performing a gel tap test. The tube containing the hydrogel was placed in a high humidity curing chamber for 2 hours to allow for early drying before gelation. In the chamber, the hydrogel axitinib suspension in the tube was crosslinked. This completes the creation of a highly reacted, uniform gel, forming hydrogel strands.

[0327] After hardening, various implant expansion methods were carried out as disclosed herein. The plants performed either dry stretching or wet stretching as outlined below. For elongation, the strands are cut into short segments after hardening, and the strands are stretched to 48-50°C. After drying for 96 hours, the dried strand segments were removed from the tube and The strand was then placed in the clamps of a stamstretcher. The needle was then dry stretched slowly to achieve the desired diameter to fit into the small gauge needle (stretch factor of approximately 2). The stretching step is performed to protect the product from oxygen and moisture. For wet stretching, the stretcher was placed in the clamps of a custom stretcher. The strand was then slowly wet stretched at a controlled rate to form a small The desired diameter was achieved (stretch factor of about 1 to about 3, or about 1.3 to about 1.5) to fit a needle of suitable gauge. After drawing, the strands are dried under conditions as described for the dry drawing process. , dried under tension.

[0328] This stretching creates a shape memory, meaning that the implant remains in the vitreous cavity of the eye. Upon hydration when administered, the length rapidly shrinks until it approaches the original wet cast dimensions. Narrowing the dry dimension means that the needle will be smaller in diameter. This allows for easier administration of the product and, once administered, the diameter expands and the length shortens. In the posterior chamber of the eye, the implant shortens relative to the diameter of the eye (in certain embodiments, the implant lengthens). (thickness not much more than approximately 10 mm), minimizing the possibility of contact with surrounding eye tissue. Generally, the degree to which it shrinks upon hydration depends, among other things, on the stretch factor. For example, about 1. When stretched with a stretch factor of 3 (wet stretching), the effect is not significant or the length increases during hydration. In contrast, when stretched (wet stretched) at a stretch factor of about 1.8, This can lead to significant length reduction during hydration. For example, stretching ( Dry stretching) results in a much shorter length upon hydration (e.g., from about 15 mm to about 8mm).

[0329] The stretched hydrogel strand is removed from the stretcher and stretched to the desired final length. The implant fibers were then placed on an inspection station. If quality control is passed, a customized vacuum device is used to remove the 25 gauge or 27 gauge gauge needle (e.g., FDA-approved 25G UTW 1 / 2 inch with an inner diameter of approximately 0.4 mm, or or 25G UTW 1 inch, or 27G TW 1.25 inch needle) Cap securely to avoid any needle tip damage.

[0330] The loaded needles were placed in a glove box for 6–9 days to remove moisture (Implant (The residual moisture content in the container is intended not to exceed 1%). The needle was immersed in molten small molecule 1kPEG. Upon cooling, small droplets of hardened PEG (which provide lubrication) formed on the needle tip. This retains the implant in place within the needle, allowing for successful placement and during administration. This prevents the implant from prematurely rehydrating within the needle. tissue damage...

Claims

1. A hydrogel and a carrier comprising at least about 150 μg of a tyrosine kinase inhibitor (TKI). A sustained release biodegradable intraocular implant, comprising a hydrogel having TKI particles dispersed therein. wherein the implant has a length in its dry state of less than about 17 mm. Biodegradable intraocular implants.

2. The implant is cylindrical and has a diameter in its dry state of about 0.1 mm to about 0.5 mm.

2. The sustained release biodegradable intraocular implant of claim 1, comprising:

3. 10. The sustained release biodegradable intraocular implant of claim 1, wherein the implant is non-cylindrical. Runt.

4. The sustained release biodegradable composition according to any one of claims 1 to 3, wherein the TKI is axitinib. Sexual intraocular implants.

5. The implant is in an amount of about 150 μg to about 1800 μg, preferably about 150 μg to about 1800 μg. An amount of about 1200 μg, more preferably about 480 μg to about 750 μg, or about 160 μg The sustained release biodegradable intraocular implant of claim 4, comprising axitinib in an amount of about 250 μg. Plant.

6. The implant has a total dry weight of about 0.2 mg to about 1.5 mg, preferably The sustained release agent according to any one of the preceding claims has a total weight of about 0.75 mg to 1.25 mg. Releasing biodegradable intraocular implants.

7. The sustained release agent according to any of the preceding claims, wherein the implant is for administration to the posterior segment of the eye. Releasing biodegradable intraocular implants.

8. 13. The method according to any of the preceding claims, wherein the implant is an intravitreal implant. Releasing biodegradable intraocular implants.

9. The implant is cylindrical and has a length in its dry state of about 6 mm to about 10 mm.

2. A sustained release biodegradable intraocular implant according to any of the preceding claims.

10. The implant is cylindrical and has a diameter in its dry state of about 0.2 mm to about 0.4 mm.

2. The sustained release biodegradable intraocular implant according to any of the preceding claims, comprising:

11. The implant is cylindrical in shape and its hydration state (at 37° C. in a phosphate buffered saline solution at pH 7.2) is After 24 hours in salt water, the tip has a length of about 10 mm or less and a diameter of about 0.8 mm or less.

2. A sustained release biodegradable intraocular implant according to claim 1 .

12. the implant is cylindrical, and the diameter in the hydrated state versus the diameter in the dry state 5. The sustained release agent according to claim 1, wherein the ratio of Releasing biodegradable intraocular implants.

13. the implant is cylindrical, and the length in the dry state versus the length in the hydrated state The ratio of is greater than about 0.7, preferably greater than about 0.

8. The sustained release biodegradable intraocular implant described above.

14. The TKI is axitinib and the implant is a non-sink simulated physiological Axitinib was administered in phosphate buffered saline at pH 7.2 at 37° C. for a period of 30 days under the following conditions: of about 0.25 μg to about 2.5 μg per day, preferably about 0.25 μg per day. and more preferably at an average rate of about 0.3 μg to about 0.5 μg per day.

4. A sustained release biodegradable intraocular implant according to any of the preceding claims.

15. The implant regulates the release of the TKI for a period of at least three months after administration or for a period of at least three months after administration. For a period of at least 6 months after administration, or for a period of at least 9 months after administration, or The prior claim provides for a period of at least 12 months, or for a period of about 6 months to about 9 months after administration. Item 10. The sustained release biodegradable intraocular implant according to any one of items 1 to 7.

16. The implant is administered within about 2 to about 15 months, preferably about Any of the preceding claims, which biodegrades within 4 to about 13 months, or within about 9 to about 12 months.

2. A sustained release biodegradable intraocular implant as described in claim 1.

17. The hydrogel may be a polyalkylene glycol, a polyethylene glycol, a polyethylene Polyvinyl oxide, polypropylene oxide, polyvinyl alcohol, poly(vinylpyrrolidino polylactic acid, polylactic acid-co-glycolic acid, any of these random or One or more units of a block copolymer or a combination or mixture, or a polyamino acid A polymer chain containing one or more units of glycosaminoglycan, polysaccharide, or protein.

4. A sustained release biodegradable intraocular implant according to any of the preceding claims, comprising a 。

18. 18. The hydrogel of claim 17, wherein the hydrogel comprises polyethylene glycol (PEG) units. Sustained release biodegradable intraocular implants.

19. The hydrogels may be the same or different, having a molecular weight of about 10,000 to about 60,000 Daltons, preferably or a multi-arm PEG unit having a number average molecular weight of about 20,000 Daltons; 20. The sustained release biodegradable intraocular implant of claim 18.

20. The hydrogel comprises crosslinked PEG units, the crosslinks between the PEG units being Formula 【Chemistry 1】 (wherein m is an integer from 0 to 10, preferably m is 6).

20. The sustained release biodegradable intraocular implant of claim 18 or 19.

21. The PEG units are 4-arm and / or 8-arm PEG units, preferably 4a20k and The sustained release biosynthetic composition according to any one of claims 18 to 20, comprising 8a20k PEG units. Dissolvable intraocular implants.

22. The implant comprises, in its wet state, about 40% or less of a TKI by weight of the wet composition.

10. A sustained release biodegradable intraocular implant according to any of the preceding claims.

23. The implant comprises, by weight of the dry state, about 25% to about 75% TKI and about 20% % to about 60% by weight of PEG units (dry composition) Sustained release biodegradable intraocular implant.

24. The implant comprises, by weight in its dry state, about 60% to about 75% TKI and about 21% % to about 31% by weight of PEG units, or about 45% to about 55% by weight of TK I and about 37% to about 47% by weight of PEG units (dry composition). The sustained release biodegradable intraocular implant described above.

25. The implant has a thickness of 1 mm in its dry state. ３ About 200 μg to about 1000 μg per TKI, preferably 1 mm ３ about 500 μg to about 800 μg of axitinib per dose, 10. A sustained release biodegradable intraocular implant according to any of the preceding claims.

26. The implant is an intravitreal implant, comprising about 480 μg to about 750 μg of axitinib, preferably about 540 μg to about 660 μg of axitinib, more preferably about It contains 600 μg of axitinib, is cylindrical, and has a length of 10 mm or less in its dry state. and a diameter of about 0.3 mm to about 0.4 mm, and After 24 hours in acid-buffered saline, the length is about 6 mm to about 10.5 mm and about 0.6 mm to about 0.8 mm in diameter, the hydrogel being crosslinked 4a20k and 8a20k P EG units, and the crosslinks between the PEG units are represented by the formula 【Chemistry 2】 2. The sustained release biodegradable composition according to claim 1, comprising a group represented by the formula: Sexual intraocular implants.

27. The implant is an intravitreal implant, comprising about 160 μg to about 250 μg of axitinib, preferably about 180 μg to about 220 μg of axitinib, more preferably about containing 200 μg of axitinib, being cylindrical in shape and having a length of less than about 17 mm in its dry state; and a diameter of about 0.2 mm to about 0.3 mm, and After 24 hours in phosphate buffered saline, the length is about 6.5 mm to about 8 mm and the length is about 0.7 mm to about 0.8 mm in diameter, the hydrogel being crosslinked 4a20k and 8a20k P EG units, and the crosslinks between the PEG units are represented by the formula 【Chemistry 3】 2. The sustained release biodegradable composition according to claim 1, comprising a group represented by the formula: Sexual intraocular implants.

28. The TKI particles have a d90 particle size of less than about 30 μm as determined by laser diffraction.

2. The sustained release biodegradable intraocular implant according to any of the preceding claims, comprising a

29. The implant is free or substantially free of antimicrobial preservatives.

20. The sustained release biodegradable intraocular implant of claim 19.

30. A method of treating an ocular disorder in a patient in need thereof, comprising administering to the patient and a sustained release drug comprising at least about 150 μg of a tyrosine kinase inhibitor (TKI). and administering to the patient a biodegradable intraocular implant, the biodegradable intraocular implant comprising a hydrogel having TKI particles disposed therein. The method, wherein the

31. The sustained release biodegradable intraocular implant is according to any one of claims 1 to 29. The method of claim 30 .

32. 31. The method of claim 30, wherein the implant is administered by injection into the vitreous humor. The method according to

33. The implant has a shelf life of at least 3 months, or at least 6 months, or at least 33. The method of claim 30, wherein the method is administered once during a treatment period of 9 months or at least 12 months. Any method as described above.

34. 34. The method of claim 33, wherein the treatment period is from about 6 months to about 9 months.

35. the TKI is axitinib, and The dose of axitinib is about 150 μg to about 1800 μg, preferably about 150 μg to about 120 0 μg, said dose being one implant or two, three or four doses administered simultaneously.

35. The method of claim 33 or 34, wherein the implant is comprised in one or more implants.

36. The axitinib dose is about 160 μg to about 250 μg, preferably about 200 μg. The method of claim 35.

37. The dose of axitinib is about 480 μg to about 750 μg, preferably about 600 μg. The method of claim 35 .

38. The method according to any one of claims 30 to 37, wherein the ocular disease is a retinal disease.

39. The disease is retinal vein occlusion (RVO), diabetic macular edema (DME), or neovascular 39. The method of claim 38, wherein the disease is dry age-related macular degeneration (AMD).

40. 40. The method of claim 39, wherein the disease is AMD.

41. The treatment was shown to be effective in patients with increased central retinal thickness, as measured by optical coherence tomography. and (b) reducing, essentially maintaining, or preventing a clinically significant increase in central retinal thickness in patients with glaucoma. The method according to any one of claims 30 to 40, which is effective.

42. Concurrently with the treatment with the sustained release intraocular implant, an anti-VEGF agent is administered The method according to any one of claims 30 to 41, wherein the method is administered to a patient.

43. An anti-VEGF agent is administered in combination with the implant and 41. The method of claim 30, wherein the administration is within about 1 month, about 2 months, or about 3 months of the administration.

2. The method according to claim 1 ,

44. The anti-VEGF agent is aflibercept, bevacizumab, pegaptanib, ranibizumab and brolucizumab, and is administered by intravitreal injection; 44. The method of claim 42 or 43.

45. A hydrogel and at least one component thereof for use in the method according to any one of claims 30 to 44. The tyrosine kinase inhibitor (TKI) particles contain at least about 150 μg of the tyrosine kinase inhibitor (TKI), A sustained release biodegradable intraocular implant, comprising the above-mentioned components dispersed within a rogel, or the above-mentioned components according to claims 1 to 2.

10. The sustained release biodegradable intraocular implant according to any one of 9.

46. For the preparation of a medicament for use in the method according to any one of claims 30 to 44, A method for treating a tyrosine kinase disease comprising administering to a patient a therapeutically effective amount of at least about 150 μg of a tyrosine kinase inhibitor (TKI), comprising administering to the patient a therapeutically effective amount of at least about 150 μg of a tyrosine kinase inhibitor (TKI), a sustained release biodegradable intraocular implant, wherein KI particles are dispersed within said hydrogel; Or use of a sustained release biodegradable intraocular implant according to any one of claims 1 to 29.

47. A method for producing the sustained release biodegradable intraocular implant according to any one of claims 1 to 29. A method for producing a hydrogel comprising the steps of: forming a hydrogel, wherein the hydrogel has dispersed therein I particles; The method includes the steps of: casting the hydrogel; and drying the hydrogel. method.

48. The polymer network comprises a multi-arm PEG precursor having an electrophilic group attached to a TKI particle. In a buffer solution in the presence of a nucleophile-containing multi-arm PEG precursor or another nucleophile-containing crosslinker, by mixing and reacting with a crosslinking agent and gelling the mixture to form said hydrogel. The method of claim 47, wherein

49. Before the hydrogel is completely gelled, the mixture is cast into a tube to form a hydrogel.

5. The method of claim 4, further comprising shaping the hydrogel by forming gel strands. 7 or 48. The method according to claim 7 or 48.

50. The hydrogel strands are dried at about 1 to about 4.

5. The method of claim 1, further comprising stretching the film in the longitudinal direction (wet stretching or dry stretching) with a stretch factor of 5.

50. The method according to claim 49.

51. 51. The method according to claim 50, wherein the stretch factor is from about 1.3 to about 3.5, preferably from about 2 to about 2.

5. The method described.

52. One or more sustained release biodegradable intraocular implants according to any one of claims 1 to 29. and one or more injection needles, each of the implants being inserted into the needle. The kit,

53. 53. The kit of claim 52, wherein the needle(s) have a gauge size of 22 to 30.

54. The lumen of each needle is occluded with a material that is solid at room temperature and soft or liquid at body temperature.

54. The kit of claim 52 or 53,

55. The method further includes an injection device, wherein each needle is pre-connected or pre-assembled to the injection device. The kit according to any one of claims 52 to 54, wherein the kit is not connected to the

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