Intraocular implant containing a tyrosine kinase inhibitor

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 The present invention is related 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 Patent 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 The disclosure is incorporated herein 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 AMD"). 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 an enzyme inhibitor (e.g., axitinib) Treatment is by administering an intravenous (intracellular) injection. [Background technology]

[0003] Macular diseases (including AMD) cause 40% of vision impairments and irreversible vision loss in people over the age of 50 worldwide. Specifically, AMD was the most popular It is one of the retinal diseases, with approximately 16.9 million people affected. By 2024, This is expected to grow 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 according to the stage of the disease. Early AMD is characterized by a small number (less than 20) of medium-sized dorsal ventricles. Intermediate AMD is characterized by the appearance of glaucoma or pigmentary abnormalities in the retina. At least one large drusen not reaching 10 mm, numerous 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 central 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 an increase in vascular endothelial growth factor (VEGF). The researchers say that increased VEGF causes tumors 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 blood vessels and underneath the To disrupt this pathway, we develop inhibitors of vascular endothelial growth factor subtypes, i.e. VEGF inhibitors. The inhibitor was originally used to treat a variety of 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 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 8 million people are affected, and this number 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 and 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 and 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. The aim of this study was to determine whether anti-VEGF therapy could be used to treat VEGF-related diseases (Browning et al., supra). It is now the standard treatment for DME because it has been shown to be less effective and less damaging than other treatments. It is considered the first-line therapy (Schmidt-Erfurth et al. (ibid.) The pharmacological pathway specifically targets the VEGF pathway and is 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 localized laser therapy. 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 1.3 million people in the United States by 2024. It is estimated that 1.4 million people will be affected by the disease (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 who have pre-existing conditions such as hypertension, diabetes, and glaucoma. RVO can cause a rapid deterioration of vision in some patients or remain asymptomatic. The prognosis of RVO and associated treatment options are not known. Although these diseases have similar behaviors, they have different risk factors and thus the classification of the disease is not dependent on the disease. The disease is classified into branch retinal vein occlusion (BRVO) and branch retinal vein occlusion (BRVO) according to the location of the retinal circulatory disorder. ), hemiretinal vein occlusion (HRVO), and central retinal vein occlusion (CRVO). BRVO is more common, affecting 0.4% of people worldwide, compared with 0.5% for CRVO. 0.8% of Americans are affected. Studies have shown that BRVO is more prevalent in Asian and Hispanic people than in Caucasians. It has been shown that the prevalence is high in panic disorder (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 can temporarily improve vision. These include chemotherapy, steroids, and surgery (Pierru et al., supra).

[0009] Currently, anti-VEGF agents are considered the standard of care for wet AMD, DME, and RVO. The first FDA-approved treatment for wet AMD in 2004 was MA CUGEN® (Pegaptanib Sodium Injection, manufactured by Bausch & Lomb) ) was subsequently developed into LUCENTIS (registered trademark) (Genentech's Ranibis In 2006, Regeneron Pharmaceuticals released EYLEA® (Regeneron Pharmaceuticals Injection) Aflibercept injection (manufactured by Aceuticals, Inc.) was launched in 2011 as a wet 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 Bruxella 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] Despite these advances, however, anti-VEGF treatments have limitations. Most patients will essentially require multiple (e.g., monthly) injections for the rest of their lives. This is due to the rapid clearance of the vitreous. Furthermore, all patients received anti-VEGF In addition, these treatment options have additional risks 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 photosensitivity. In addition to the burden on patients and the risks associated with frequent injections, Potential risks of vascular disease, complex manufacturing requirements for 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 a family of tyrosine protein kinases that act against receptor tyrosine kinases. It was developed as a chemotherapy drug that inhibits the signal transduction of retinoic acid kinase (RTK). K spans the cell membrane with an intracellular (inside) portion and an extracellular (outside) portion. Upon binding of the ligand to the extracellular portion, the receptor tyrosine kinase dimerizes and transmits the coenzyme message. It is driven by autophosphorylation with the enzyme adenosine triphosphate (ATP). Many of the RTK ligands activate VEGF and other cellular signaling pathways. VEGF is a type of VEGF receptor (VEGFR) that acts on the 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 vasculitic acid kinases) Platelet-derived growth factor receptor (PDGFR), or stem cell factor-activated stem cell formation The long-term factor receptor / type III receptor tyrosine kinase (c-Kit) also induces angiogenesis. It is known that

[0012] Several TKIs have been evaluated for the treatment of AMD via different routes of administration. Such TKIs include 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 be effective in preventing vitreous penetration. They have poor permeability and limited distribution to the retina. This is because they tend to have low aqueous solubility. This is due to the low concentration of TKI in solution and the short residence time on the ocular surface. Additionally, it is difficult to control the drug concentration during topical administration due to user error. For systemic administration of TKIs, it is important to achieve effective concentrations of the drug in the desired tissue, especially in the eye. This is impractical because of the high doses required to achieve this, which can lead to high systemic exposure. In addition, drug concentrations are difficult to control. Alternatively, intravitreal injection of TKI suspensions has been performed. Injections should be frequent (e.g., daily or at least once a day) to result in rapid clearance of the drug. In addition, some TKIs have low solubility, so When injected intravitreously, aggregates form, which then migrate or settle on the retina and localize This can lead to potential contact toxicity and holes (e.g., macular or retinal holes).

[0013] Therefore, the use of TKIs to treat ocular diseases (e.g., AMD, DME, and RVO) is It is effective for a long period of time and does not require the frequent (every Improvements that avoid monthly or even daily injections are of particular concern, especially in patients who respond to anti-VEGF therapy. urgently needed for individuals who do not have There are.

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

[0015] The objective of certain embodiments of the present invention is to provide a method for treating ocular disease (e.g., neovascular disease) in a patient. It is an effective long-term treatment for age-related macular degeneration (AMD), DME, and RVO. The present invention provides an intraocular implant containing a thyroxine 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; An intraocular implant is provided.

[0017] Another object of certain embodiments of the present invention is to provide an ophthalmic solution comprising a TKI (e.g., axitinib). The intraoperative implant is preloaded into a syringe, thereby eliminating further preparation steps. Provides an intraocular implant that does not require a step, thus avoiding contamination of the implant before injection To do so.

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

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

[0020] Another object of certain embodiments of the present invention is to provide an ophthalmic solution comprising a TKI (e.g., axitinib). Intraocular implants, the stability of which 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 aim of the project is to provide

[0021] Another object of certain embodiments of the present invention is to provide an ophthalmic solution comprising a TKI (e.g., axitinib). Intraoperative implants, whether the implant contains no components of animal or human origin and providing an intraocular implant that is biocompatible and non-immunogenic by virtue of being free of, or substantially free of, The purpose is to provide.

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

[0023] Another object of certain embodiments of the present invention is to provide an ophthalmic solution comprising 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 an ophthalmic solution comprising a TKI (e.g., axitinib). an intracellular implant comprising a therapeutically effective amount of said TKI, said intracellular implant having a length and / or diameter of The object of the present invention is to provide an intraocular implant that is relatively small in size.

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

[0026] Another object of certain embodiments of the present invention is to provide an ophthalmic solution comprising 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., 22-30 gauge needle). and upon hydration, e.g., after administration to the eye, increases in diameter and decreases in length. and 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 an ophthalmic solution comprising a TKI (e.g., axitinib). and an intrathecal implant that is injected in dry form and that acts in situ (i.e., The object of the present invention is to provide an intraocular implant that is hydrated (intraocularly).

[0028] Another object of certain embodiments of the present invention is to provide an ophthalmic solution comprising 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 ocular cells or tissues (e.g., the retina), T The objective of the present invention 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 an ophthalmic solution comprising a TKI (e.g., axitinib). Intraocular implants in a dry state before injection and in a hydrated state after injection (i.e., intraocularly). In any case, it is possible to provide an intraocular implant having a stable and defined shape and surface area. And so.

[0030] Another object of certain embodiments of the present invention is to provide an ophthalmic solution comprising 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

[0031] Another object of certain embodiments of the present invention is to provide an ophthalmic solution comprising a TKI (e.g., axitinib). An intravenous implant that allows for precise administration of a dose (within a wide dose range) and thereby The present invention aims to provide an intraocular implant that avoids the risks of overdosing and underdosing. .

[0032] Another object of certain embodiments of the present invention is to provide an ophthalmic solution comprising 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 so.

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

[0034] Another object of certain embodiments of the present invention is to provide an ophthalmic solution comprising a TKI (e.g., axitinib). 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 an ophthalmic solution comprising a TKI (e.g., axitinib). and 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 an ophthalmic solution comprising a TKI (e.g., axitinib). An intravenous implant that provides sustained release of a therapeutically effective amount of a TKI (e.g., axitinib) for an extended 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 of the project is to provide a plant.

[0037] Another object of certain embodiments of the present invention is to provide an ophthalmic solution comprising a TKI (e.g., axitinib). and an intrathecal implant for delivering 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 Provide for 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 which avoids the need for administering a therapeutically effective amount of an implant to the eye.

[0038] Another object of certain embodiments of the present invention is to provide an ophthalmic solution comprising a TKI (e.g., axitinib). and an intrathecal implant for delivering 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 providing the antibody for a period of 11 months, or at least 13 months, thereby The object of the present invention is to provide an intraocular implant that inhibits the retinal hyperplasia (eg, retinal hyperplasia) over this period.

[0039] Another object of certain embodiments of the present invention is to provide an ophthalmic solution comprising a TKI (e.g., axitinib). and an intravenous implant that provides sustained release of a TKI for an extended period of time, e.g., up to 3 months or more. For example, at least 6 months, at least 9 months, at least 11 months, or less The ocular tissues (e.g., retina and The levels of TKIs in the choroid and vitreous humor are at therapeutically effective levels, particularly To provide an intraocular implant that consistently maintains sufficient levels of inhibition of neovascularization It is.

[0040] Another object of certain embodiments of the present invention is to provide an ophthalmic solution comprising a TKI (e.g., axitinib). and an intrathecal implant for delivering 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 Provide for a period of at least 11 months, or at least 13 months, and over that 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

[0041] Another object of certain embodiments of the present invention is to provide an ophthalmic solution comprising a TKI (e.g., axitinib). and an intrathecal implant for delivering 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 The TKIs were administered for a period of 11 months or at least 13 months, and the TKIs accumulated in the anterior chamber. The present invention provides an intraocular implant that does not

[0042] Another object of certain embodiments of the present invention is to provide an ophthalmic solution comprising a TKI (e.g., axitinib). and an intravenous implant that provides sustained release of a TKI for an extended period of time, e.g., up to 3 months or more. 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 demonstrated no or virtually no systemic absorption of TKIs. , thereby substantially avoiding 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 need 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 bronchitis, in which both treatments are 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 need 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. No need or infrequent need for rescue medication during treatment (e.g., 1, The aim of the study is to provide a way for people to stay in the same place for at least two or three years.

[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 need it (e.g., those who have previously been treated with anti-VEGF The present invention provides a method for performing the method in patients who have a history of VEGF therapy or who are naïve to anti-VEGF therapy. 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 Treatment of RVO in patients who need it (e.g., those who have previously been treated with anti-VEGF The objective of this study is to provide a method for treating VEGF-positive 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 Treatment of RVO in patients who need it (e.g., primary subfoveal hemorrhage secondary to AMD) The present invention provides a method for treating pulmonary artery disease in patients 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., neovascularization with leakage involving the fovea) Have a diagnosis of subfoveal neovascularization (SFNV) secondary to dry AMD and have previously been treated for the condition. By providing a method to perform this treatment in patients who have previously been treated with anti-VEGF agents, be.

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

[0050] Another object of certain embodiments of the present invention is to provide an intraocular implant that can be used for early detection and treatment during storage and manipulation. The method of claim 1, wherein the intraocular implant is sensitive to moisture 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 the treatment of 1, 2, or 3, 3-HTLV-1 deficiency, including TKIs (e.g., axitinib). A kit comprising one or more intraocular implants, optionally including a step of injecting the intraocular implant. The object of the present invention is to provide a kit comprising:

[0053] Another object of certain embodiments of the present invention is to provide a method for treating ocular diseases involving neovascularization in the central region. In patients with increased retinal thickness, for example by reducing retinal fluid, The present invention provides a method for reducing central area retinal thickness as measured by vitreous stimulatory spectroscopy.

[0054] Another object of the present invention is to provide a method for treating ocular diseases in which central retinal thickness is increased due to ocular diseases involving neovascularization. Patients showed a clinically significant increase in central retinal thickness as measured by optical coherence tomography. The objective of the present invention is to provide a method for essentially 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 involving neovascularization in the central region. In patients with increased retinal thickness, central retinal thickness as measured by optical coherence tomography Reduce, essentially maintain, or prevent a clinically significant increase while (e.g., A method to improve, or at least not impair, a patient's visual acuity (as measured by normal visual acuity) The purpose of this project is to provide

[0056] Another object of certain embodiments of the present invention is to provide a method for treating eye diseases caused by ocular diseases involving neovascularization. The objective of the present invention is to provide a method for improving the vision of patients suffering from 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 a patient suffering from impaired vision due to a disease 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 vision by means of a method for treating atherosclerosis, the method comprising: The purpose is to provide.

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

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

[0060] Throughout this application, various references are cited. The disclosures of these references are No. 60 / 339,933 filed on Oct. 23, 2003, which is incorporated herein by reference. In case of conflict, the disclosure of this application will control. [Brief description of the drawings]

[0061] [Figure 1] Schematic diagram of one embodiment of an implant package, in which the implant is preloaded 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. [Diagram 2] Schematic of one embodiment of implant localization. After injection, the implant hydrates in situ while maintaining a cylindrical shape. The implant is localized to the posterior segment of the eye. [Diagram 3] Schematic diagram 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 out of the hydrogel into the aqueous surroundings (e.g., vitreous humor) with the formation of a clearance zone (black). Over time, the gel degrades and is absorbed while the drug diffuses out. During the degradation process, the gel gradually swells until degradation reaches a level that shrinks and distorts. [Figure 4] One embodiment of the in vitro axitinib release per day of 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. [Diagram 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) efficiently 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, 3, and 6 months after implant injection. Retinal morphology was normal. [Figure 7] One embodiment of implant biodegradation and inflammation. (A) Significant biodegradation of the hydrogel component of the implant was observed over time in rabbit eyes. At 4 and 8 weeks after injection, the implant was still intact, but at 12 weeks, 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 not occurring within the areas where axitinib was not dissolved. Images are presented at magnifications of 20× (scale: 1000 μm) and 200× (scale: 100 μm). [Figure 8] One embodiment of the inhibition of vascular leakage after administration of a 227μg 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 presented). [Figure 9] One embodiment of infrared reflectance (IR) imaging of two implants in a rabbit eye. The implants show degradation over time. The implants were intact from 27 to 117 days, while narrowing of the implant was observed due to hydrogel degradation observed at 141 and 195 days. 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 embodiment of infrared reflectance (IR) imaging of two implants in a rabbit eye. The implants were intact 0.5-3 months after injection. After 6 months, the implants had narrowed due to degradation of the hydrogel, and the remaining axitinib particles had coalesced into a single monolithic structure. After 24-38 months, free axitinib particles (small white specks) were found near the site of the implants after hydrogel degradation. [Figure 11] One embodiment of 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 time (months) after challenge with VEGF for animals in groups 1 and 2, as well as animals without implants. Significant inhibition of vascular leakage was observed in all animal groups with 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), whereas 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] One embodiment of the average vascular leakage scores in rabbits treated with neither implants nor anti-VEGF therapeutics (open squares and dashed line), rabbits treated with Avastin® only (filled triangles, curve fit to 3 months), rabbits treated with implants (filled squares, solid line to 12 months), and rabbits treated with implants and Avastin® (striped squares, dashed line to 12 months). Vascular leakage was effectively inhibited for 12 months for all animals receiving implants. Animals treated with anti-VEGF therapeutics only 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. In vitro data did not show observed in vivo release. [Figure 15] One embodiment of an IR image of subject #1 in cohort 2 (two implants, totaling 400 μg axitinib per eye). On the day of injection, the implant is clearly visible and well formed. After 9 months, the implant is completely degraded, while undissolved axitinib remains where the implant was. 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, total of 200 μg 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 zone retinal thickness (CSFT) in study eyes of patients with neovascular age-related macular degeneration (wet AMD) treated with axitinib implant (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 first anti-VEGF administered concomitantly: Cohort 3b). In this figure, the mean change in CSFT is presented with the standard error of the mean (SEM) relative to the baseline value. In this figure, six patients from Cohort 1 were followed up to 9 months, seven from Cohort 2 to 12 months, five to 14 months, and two to 16 months. Six patients in cohort 3a were followed up 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 up to three months and one to 4.5 months. Follow-up is ongoing. [Figure 18]One embodiment of best corrected visual acuity (BCVA) in study eyes of patients with neovascular age-related macular degeneration (wet AMD) treated with axitinib implant (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 initial anti-VEGF administered concomitantly: Cohort 3b). In this chart, the mean change in BCVA from baseline in Early Treatment Diabetic Retinopathy Study (ETDRS) letter count score (representative of letters that can be read correctly at a particular distance) is presented along with the standard error of the mean (SEM). In this chart (similar to FIG. 17 above), six patients from Cohort 1 were followed up to 9 months. Seven patients in cohort 2 were followed up to 12 months, five to 14 months, and two to 16 months. Six patients in cohort 3a were followed up 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 up 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 (previous aflibercept treatment in the right eye (OD) 16 months prior to implant injection) in cohort 2 (2 implants, total of 400 μg axitinib per eye). Subretinal fluid was clearly visible at baseline (pre-treatment). Importantly, the subretinal fluid resolved 2-3 months after implant injection and this stage was essentially maintained over 15.5 months (after 15.5 months is shown in FIG. 19B, prior visits are shown in FIG. 19A). There was no decline in best corrected visual acuity (BCVA). [Figure 19B]One embodiment of a Spectral Domain Optical Coherence Tomography (SD-OCT) image obtained from the study eye of subject #1 (previous aflibercept treatment in the right eye (OD) 16 months prior to implant injection) in cohort 2 (2 implants, total of 400 μg axitinib per eye). Subretinal fluid was clearly visible at baseline (pre-treatment). Importantly, the subretinal fluid resolved 2-3 months after implant injection and this stage was essentially maintained over 15.5 months (after 15.5 months is shown in FIG. 19B, prior visits are shown in FIG. 19A). There was no decline in best corrected visual acuity (BCVA). [Figure 20] One embodiment of a spectral domain optical coherence tomography (SD-OCT) image from subject #7 in cohort 2 (two implants, totaling 400 μg axitinib per eye). Subject #7, who had been receiving aflibercept for 6 years prior to study initiation, showed 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, total 600 μg axitinib per eye). In AMD treatment-naive cohort 3a subject #1, a significant reduction in CSFT was observed at 2 months and was 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 axitinib per eye, including coadministration of an anti-VEGF agent). CSFT rapidly decreased within 7 days and further decreased and remained low through month 3. [Diagram 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 (2 implants, total of 400 μg axitinib per eye, including initial coadministration of an anti-VEGF agent). CSFT rapidly decreased within 7 days. Low CSFT values ​​were maintained through the second month. [Figure 24] 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. [Diagram 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. A shows the Hamilton syringe body within an injection molded casing. B is a schematic diagram of the syringe components in this embodiment. [Figure 26A] FIG. 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 illustrates that the first assembly and the second assembly can be aligned. [Figure 26F] 1 shows the cowl of the second assembly being 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. [Fig. 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 with implants containing 200 μg of axitinib according to one embodiment of the present invention. [Figure 28] Proposed Phase 2 study design with implants containing 600 μg of axitinib according to one embodiment of the present invention. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0062] definition As used herein, the term "implant" (also sometimes referred to as "depot") The active agents, specifically tyrosine kinase inhibitors (TKIs) (e.g., axin and other compounds disclosed herein, in a human or animal body. For example, into the vitreous humor of the eye (also called the "vitreous cavity" or "vitreous body"). It refers to an object that remains there for a certain period of time while releasing an active agent into the surrounding environment. The implant may be in any desired shape (e.g., a shape as disclosed herein) prior to injection. The implant may have a shape that, once placed in the desired location, The implant dimensions (e.g., length and / or diameter) are maintained at the maximum allowable implantable diameter. As further disclosed herein, the ocular What is produced is not a solution or a suspension, but a coherent object that has already been formed. Thus, the implant is fully formed as disclosed herein prior to administration. In an embodiment of the invention, the drug is administered to the eye (as would generally be possible with a suitable formulation). They are not produced in situ at the desired location within the body. The implant is biodegradable over time (as disclosed below) in a physiological environment, thereby This causes the capsule to change shape while decreasing in size and eventually dissolve / absorb completely. In the present specification, the term "implant" refers to the hydration (as used herein) of the implant when it contains water. The implant is in its “wet” state (e.g., once the implant is in the eye) The drug is administered or otherwise immersed in an aqueous environment (e.g., in vitro) and becomes hydrated or or rehydrated implants) and in their dry (dried / dehydrated) state. Implants in their original state (i.e., after the implants are manufactured and dried, and loaded into the needles) Implantation immediately prior to or after loading into the needle as disclosed herein, or dehydration. The term refers to both implants that are manufactured in a dry state without the need for pre-treatment and implants that are manufactured in a dry state without the need for pre-treatment. Thus, in certain embodiments, in the context of the present invention, an implant is In its dry / dried state, it may contain less than about 1% water by weight. The water content in the dried 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 measured after the implant is 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% moisture by weight in certain embodiments) and subsequently The measurements were taken after the needle was ready to be loaded for administration of the drug. In this embodiment, the implant is placed in an inert atmosphere containing less than 20 ppm of oxygen and moisture. The container is stored in the glove box for at least about 7 days. This is reported in Example 6.1.

[0063] As used herein, the term "ocular" refers generally to the eye, or In principle, the "intraocular implant" according to the present invention can be applied to any part or site of the eye. or any disease of the eye (in one embodiment, the administration may be to any part or site of the eye). 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 relates to a method for the treatment of osteoporosis, as further disclosed below. Thus, the intravitreal injection of an intraocular implant (hence, in this case, the "intraocular implant" The company is targeting the treatment of ocular diseases that affect the posterior segment of the eye, as well as ocular diseases that affect the posterior segment of the eye. do.

[0064] As used herein, the term "patient" includes both human and animal patients. The implant according to the invention is therefore 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 "Patient" means an individual (animal) who is in need of treatment due to a particular physiological or pathological condition. This refers to the object of study.

[0065] The term "biodegradable" refers to the ability of a substance to be degraded 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 degrades when exposed to heat. In the context of the present invention, as disclosed in detail herein below, hydrogels are 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 disperses Slowly biodegrades over time. In certain embodiments, 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 no longer visible in the vitreous.

[0066] A "hydrogel" is a polymer that swells in water and retains a certain amount of water while retaining individual polymers, e.g. 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 ideal for use in applications where In the present invention, the term "hydrogel" refers to a material that is highly similar to natural tissue (e.g., After the hydrogel is formed in an aqueous solution, or once the hydrogel is placed in the eye or other part of the body, after being transplanted into a part of the Hydrogels in their hydrated state when loaded, and when dried to low water content (e.g., 1 wt. % or less). The term is used to refer to both hydrogels when they are dried and in their 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 may be referred to as a "matrix."

[0067] The term "polymer network" refers to polymer chains that are cross-linked with each other (i.e., polymers with the same molecular structure). The term describes a structure formed from a mixture of 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 show crystalline structure in X-ray or electron scattering experiments. The term 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. The term 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, thus forming a hydrogel matrix. Within the hydrogel, there may be other materials, such as active agents or buffers. Although it is possible that 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 Thus, the "units" are the polymer networks that form the hydrogel. For example, poly(ethylene glycol) is a building block or constituent of a polymer that is suitable for use in the present invention. 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 within the skill of the art. The amount of the polysaccharide can be determined 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). -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) spectroscopy or electrospray ionization (ESI) mass spectrometry) The amount of the polymer (the polymers disclosed herein) can be quantified 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 "strip") generally refers to an object having an elongated shape (i.e., The examples characterize the implants according to the invention. Specific dimensions are disclosed herein. The implants are 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 oval, or in other embodiments, cross-shaped as disclosed herein. The shape may have various configurations such as circles, stars, 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 In certain specific embodiments, The surrounding environment is the vitreous humor and / or ocular tissues (e.g., the retina and choroid). Thus, as used herein, the implant "releases" the TKI (e.g., axitinib). Whenever it is stated that the hydrogel is "adhesive" or "provides for (sustained) release", this means that the hydrogel is also The TKI (e.g., axitinib) is released from the implant while it is not yet (completely) biodegraded. This not only refers to the direct delivery from the hydrogel, but also to the residual hydrogel that remains after the hydrogel is 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 effect. The term "therapeutic agent" also refers to the continuous provision of a therapeutic agent to this environment. The time 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 liquid 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." Thus, "sustained release" refers to 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 The drug is not associated with or limited to a particular rate of release (in tro or in vivo). However, in certain embodiments of the invention, the implant may be A specific average rate of release (in vitro or in vivo) or a specific The implants of the invention may be characterized by a release profile of Whether commonly referred to as a "sustained release" implant or simply as an "implant," Since the implants of the present invention provide sustained release of the API, regardless of whether the API is administered intravenously or intramuscularly, the implants are referred to as "depots." It is also sometimes referred to as.

[0077] As used herein, certain administrations or injections are used to refer to administrations or injections of implants according to the present invention. "concurrently" or "simultaneously" with the injection "aneously" or "at the same time" Whenever it is stated that a single injection is required, this includes the injection or administration of two or more implants. In one embodiment, the injection of one or more implants (e.g., an anti-VEGF Injection of a suspension or solution of the drug F is usually given immediately, i.e., immediately followed by an injection of any This means that the drug will be administered without significant delay. For example, a total dose of about 400 μg of axitinib The total dose was administered to one eye, with two implants according to the invention (each about 200 μg These two implants are usually used in the same treatment Alternate immediately within a treatment session, of course, to safely and accurately inject into the desired area. By respecting all precautions in accordance with the FDA, but without unnecessary delays, The same can be said for the case in which one or more implants according to the present invention are used 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 comprises 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 treatment session.

[0078] However, under certain circumstances, for example, if a complication is experienced 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 injections are not advisable, e.g., one or two implants from the first A second implant may be administered two weeks later. As disclosed in detail, the compound is capable of being administered to humans for an extended period of time (e.g., about 9 to about 12 hours) in the vitreous of the human eye. Two implants may be administered, for example, one or two weeks apart, so that the remaining would still be 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. The administration can be simultaneous or near simultaneous as described herein.

[0079] However, in certain other embodiments, the anti-VEGF agent may be administered later (e.g., in accordance with the present invention). The drug is administered 1, 2, or 3 months after the intravitreal injection of the implant. may also be administered in combination with the intravitreal implant of the present invention.

[0080] The term "rescue medication" generally refers to a drug that is administered under predefined conditions (e.g., to treat a patient during a study). are given to patients when they do not respond adequately to the investigational treatment, or to address emergency situations. In the clinical trial disclosed in Example 6 of the present specification, a rescue drug is administered. The conditions for this are shown in Example 6 under the subheading "Rescue Drugs" (see Table 1). (See especially Table 27 for percentage of drug administration.) In certain embodiments of the present invention "Rescue agent" 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 first is aflibercept.

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

[0082] The term "at least about" in connection with a measured amount refers to the amount by which the measurement was made and the purpose and quantity of the measurement. The measured results are expected by one of ordinary skill in the art to exercise a level of caution commensurate with the accuracy of the measuring device. This refers to normal variations in the amounts measured and amounts higher than those measured.

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

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

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

[0086] As used herein, "include", "inclusion" and "contain" mean "ing," "contain," "containing," etc. Open terms mean "comprising" and include elements, method steps, is intended to refer to an open-ended list or enumeration, such as a The present invention is not limited to the recited elements, method steps, etc., and 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 particular value or number herein , each value or number is intended to be inclusive.

[0088] The terms "from A to B," "from A to B," and "of A to B" are used herein. 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 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 a substance used in the manufacture of medicines that is intended to produce pharmacological activity or have other properties. 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 the repair, correction, or modification of a patient's physiology. There are.

[0090] In certain embodiments, the TKI used according to the present invention is axitinib. Axitinib is a vasodilator used in patients with advanced renal cell carcinoma (Pf Axitinib is a small molecule (386.47 daltons) It is a synthetic tyrosine kinase inhibitor of the 1,2-dihydropyridine-2-phosphate phosphatase inhibitor ... 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 1 a 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 N 4 OS, 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). The partition coefficient (n-octanol / 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 any form (including any active agent polymorph, or pharma- ceutical acceptable salt, anhydrate, hydrate, Other solvates or derivatives may be used. In the range of In all cases, even if there is no explicit statement, such polymorphism of an active drug, 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. An active drug that is solid at room temperature can exist in a variety of different crystalline forms, or polymorphs. with one polymorph that is 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 solvates) 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 indole derivatives of the instant invention according to certain embodiments. Such polymorphs can be used in the preparation of plants, for example those described in US 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, as described in the cited art, it can be prepared in various solvents. 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 mentioned forms are well characterized in the art and can be used for the preparation of For example, see the above-cited Campeta et al. paper, or the patent literature (including, but not limited to, However, US8,791,140B2, US2006 / 0094763, and WO The present invention is described in the art, particularly (but not limited to) US Pat. The present invention relates to a method for producing a cyclic axial tangled ... Any of the tinib polymorphs can be used in the present invention.

[0096] In certain specific embodiments, for the preparation of an implant 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°) They are characterized by XRD patterns 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°) and / or characterized by an XRD pattern containing two characteristic 2θ° peaks; Chemical composition at 1.1, 114.7, 154.8, and 167.8 (each shift ±0.2 ppm) 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 to 2 Contains two endothermic peaks between 17°C (peak 1) and 219°C-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. 6,317,350 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 survival factor ck, which promotes blood vessel development. It has a clearance half-life (t 1 / 2 ) (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 t 1 / 2 If is long , which 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., 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. Thus, sustained intravitreal delivery of axitinib is possible without the need for concomitant therapy. In principle, it is possible to 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

[0098] As used herein, the term "therapeutically effective" refers to the production of a particular desired effect following administration. For example, in the context of the present invention, So, one desirable outcome of treatment is to reduce neovascular AMD as measured by optical coherence tomography. The primary goal of this study is to reduce central subretinal 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 defined as the IC 50 A multiple of, for example, IC 50 For example, the TKI axitinib may be 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), The sustained release biodegradable intraocular implant is a biodegradable intraocular implant in which the ophthalmic solution is dispersed within 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 comprising administering to said subject a tyrosine kinase-inhibiting agent. A sustained release biodegradable intraocular implant containing a TKI, dispersed within a gel, the implant having a length in its dry state of less than about 17 mm. Abstract: A sustained release biodegradable intraocular implant is provided.

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

[0103] All the features disclosed herein with respect to the implant according to the invention (individually or optionally) The combination of features comprises a hydrogel and at least about 150 μg of a tyrosine kinase inhibitor. A sustained release biodegradable intraocular implant comprising a TKI, the TKI particles being hydrogel-based. 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 a particular embodiment, 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, e.g., about 150 μg to about 1800μg, about 150μg to about 1200μg, or about 200μg to about 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 0μg, approx. 900μg, approx. 1000μg, approx. 1100μg, or approx. 1200μg In an alternative embodiment, the TKI contained in the implant of the present invention (e.g., axitinib) doses may range 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 include The dose of 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 also subject to +25% and - This includes a 20% variation or + / - 10% variation.

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

[0108] The disclosed amounts (including the variations noted) of TKI (e.g., axitinib) are The final content of the active ingredient in the implant and the amount of active ingredient per implant during the manufacture of the implant It refers to both the amount of active ingredient used as a starting component and the amount of active ingredient used as a starting component.

[0109] As disclosed in more detail herein below and as will become apparent from the Examples section, In certain embodiments of the invention, the TKI administered to the patient (e.g., axitinib) The total dose of the drug may be increased by up to 2, 3 or more implants administered simultaneously. For example, a dose of about 400 μg of a TKI (e.g., axitinib) may be Although axitinib was administered in one implant containing 400 μg, For example, each of the two may contain 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 above-mentioned components may be combined to arrive at a desired total dose. In the case of about 480 μg to about 750 μg, or about 540 μg to about 660 μg, or total 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, the total dose is greater than about 600 μg, for example, from about 800 μg to about 1250 μg. or about 900μg to about 1100μg, or about 1000μg, or about 960μg to Approximately 1500μg, or approximately 1080μg to approximately 1320μg, or approximately 1200μg 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 1,800 μg, is contained in one implant. Such implants are administered to patients in need of such treatment according to the present invention. In one embodiment, the total dose administered to a patient according to the present invention is administered concurrently. 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 composed of a zeolite and a zeolite. In the present invention, the particles are homogeneously or essentially homogeneously dispersed within the hydrogel. The drug can be prevented from agglomerating and can be delivered to the eye slowly while releasing the drug. A matrix can be provided for the particles 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. The term "microcapsules" (also called "microparticles") The term refers to roughly spherical particles having sizes ranging, for example, from about 50 nm to about 2 mm. Microcapsules are sometimes defined as particles that are surrounded by a surrounding material (also called a shell). At least one active agent domain (or core) is encapsulated within the 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 addition of other materials (e.g., but not limited 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 the release kinetics. In the field of composite materials, the particle size is important for the matrix. It is known that small particles affect the mechanical properties of the The smaller the mass fraction, the better the reinforcement obtained at a given mass fraction. The hydrogel matrix was mechanically stable compared to a similar mass fraction of larger TKI particles. Properties (e.g., brittleness, strain to fracture, etc.) may be improved. Such properties may be improved by manufacturing, Micronization is also important during implantation and during the degradation of the implant. It can also promote a more homogeneous distribution of the active ingredient in the matrix. The method may be performed using 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 method of the present invention. The TKI (e.g., axitinib) particles used in preparing the implant are laser-induced Quantification by diffraction: 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 determined by laser diffraction. In very specific embodiments, the diameter of the particle may be less than about 30 μm, or less than about 20 μm, as determined by the method described above. In this study, the d90 of TKI (e.g., axitinib) was quantified by laser diffraction. In these or other embodiments, the implants of the invention are prepared The d50 of the TKI (e.g., axitinib) particles used in the preparation of the drug was determined by laser diffraction. In these or other embodiments, the present invention The d10 of TKI (e.g., axitinib) particles used in was quantified by laser diffraction In certain embodiments, the implant 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 (having a particular particle size distribution) 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, then 90% of the particles in the measured bulk material % by volume have a particle size of less than about 10 μm. Corresponding definitions are given for other "d" values ​​(e.g., "d10", "d50", or "d100" values ​​(referred to herein as "d100", respectively) This also applies to the "D10", "D50", and "D100" values. In other embodiments, a TKI having a diameter above this specification (e.g., axitinib ) 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) as disclosed in Example 1. Weigh into a 2 L beaker, place on a stir plate and stir at 600 RPM with a stir bar. 1. Add 1 mL of axitinib in ethanol to the beaker. Insert two 60mL BD syringes into the syringe positions 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 in the center of the vortex for dispensing. Then add the axitinib solution dropwise into the WFI. The syringe pump is operated at 7.5 mL / min to precipitate the micronized axitinib. After micronization, the 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. The cells are then collected from the filter and incubated for an extended 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. In addition, the disclosed micronization method (or other methods) can be used to produce other drugs besides axitinib. It can also be used for the following active substances:

[0115] Another aspect of the invention is a method for producing a composition 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, The total weight of the implant in its dry state is about 0.2 mg to about 1.5 mg. In certain embodiments, the present invention is a sustained release biodegradable intraocular implant having a 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 mass (also referred to as "mass") of the dried product may be about 400 μg to about 1.2 mg. In certain specific embodiments, the total weight of the implant according to the present invention is About 0.3 mg to about 0.6 mg, for example, about 0.4 mg to about 0.5 mg in a dry state. 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 disclosed herein relating to the implant according to the invention (individually or in any combination) The combination of any one 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, 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 is formed by forming crosslinks to form a polymer network. They can be formed from precursors that have functional groups that form between the polymer strands or These crosslinks between the arms may be chemical (i.e., covalent) and / or covalent in nature. or it can be physical (eg, ionic bonds, hydrophobic associations, hydrogen bridges, etc.).

[0119] Polymer networks can be prepared or reacted from 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. A variety of hydrogels for use in making hydrogels are selected based on the properties desired for the gel. Suitable precursors exist. In general, any pharma- ceutically acceptable crosslinker that will form a hydrogel. Any possible polymer can be used for the purposes of the present invention. The components to be 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., glycerol), and polysaccharides (e.g., glycerol). 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 cationic). Various polymerizations are possible using polymerizations such as 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 a chemical 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)-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 / mixture of these. (However, this list is not intended to be limiting.)

[0123] The precursors are covalently linked to each other to form a covalently crosslinked polymer network. In certain embodiments, (e.g., free radicals) can be associatively crosslinked. In the case of cyclohexane polymerization, a precursor having at least two reactive centers is one 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 the present case, the core refers to the continuous portion of the molecule connected to the arms extending from the core. , where the arms often have a functional group at the end of the arm or branch. A polymeric 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, for example, comprise a first functional group (a set of ) and a second functional group (set of) ) can be prepared from another multi-arm precursor having the multi-arm 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 comprise mer units.

[0126] Certain functional groups can be made more reactive through the use of an activating group. 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 synthesize nucleophilic polymers (e.g., primary amine-terminated or thiol-terminated). The NHS-amine crosslinking reaction is useful for crosslinking aryl-terminated polyethylene glycols. In aqueous solution, buffer solutions (e.g., phosphate buffer (pH 5.0 to 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 is a crosslinked precursor, both the nucleophilic precursor and the electrophilic precursor. To the extent that they are 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 has electrophilic functional groups (e.g., N-hydroxysuccinimide). On the other hand, when the crosslinking agent has an electrophilic functional group such as sulfosuccinimide, The functional 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 .

[0128] In one embodiment, the first reactive precursors each contain from about 2 to about 16 nucleophilic functional groups (functional groups). The first reactive precursor reacts with the second reactive precursor to form a polymer network. 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 Reactive precursors having reactive groups are particularly suitable for the present invention. while ensuring sufficient functionality for proper crosslinked network formation. To achieve 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 groups are possible.

[0129] PEG hydrogel: In certain embodiments of the present invention, the polymer network that forms the hydrogel is , which contain polyethylene glycol (PEG) units. PEG forms hydrogels when crosslinked. It is known in the art that these PEG hydrogels can be used 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 tool.

[0130] The polymer network of the hydrogel implant of the present invention may have 2 to 10 arms, or 4-8 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 have 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. As disclosed later in this specification in the section on the manufacture of implants, 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 such as

[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 has an average molecular weight within the range. The molecular weight units are in the range of about 10,000 to about 40,000 daltons, or about 20,000 daltons. The average molecular weight of the PEG precursors is 100%. 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 Thus, one of the precursors that can be used in the present invention is The 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 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 short arms. PEG with fewer arms may swell more and be less flexible than PEG with more arms. In certain specific embodiments, P Combinations of EG 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, This may increase dimensional stability during storage. For example, trilysine crosslinked molecular weight The 15,000 dalton 8-arm PEG may not be able to maintain an extended conformation at room temperature. whereas 4-arm 20,000 dalton PEG crosslinked with 8-arm 20,000 dalton PEG PEG may be dimensionally stable in an oriented configuration at room temperature.

[0134] PEG precursors having a certain average molecular weight (e.g., 15kPEG or 20kPEG) When referring to the G precursors, the average molecular weights indicated (i.e., 15,000 or Mn of 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 abbreviations are used herein for other average molecular weights of PEG precursors. 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 after functionalization of the end groups. 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 is an N-hydroxysuccinimidyl (NHS) ester. Such esters include, but are not limited to, "SAZ" (succinimide) and "SAP" (referring to succinimidyl azelate end groups) "SG" (referring to succinimidyl glutarate end groups), and "SS" (referring to succinimidyl glutarate end groups). (referring to a cinimimidyl 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 2") is an end group. A silyl (-SH) end group or other nucleophilic end group is also possible.

[0137] In certain preferred embodiments, the average molecular weight is about 20,000 daltons and and a 4-arm PEG having an electrophilic end group as disclosed in and about 20,000 Daltons. The average molecular weight of the poly(ethylene glycol) copolymer and the 8-arm PEG having a nucleophilic end group as disclosed above are used to prepare the poly(ethylene glycol) copolymer. To form a mer network and thus a hydrogel according to the invention, It is cross-linked.

[0138] Nucleophile-containing PEG units and electrophile-containing PEG units (e.g., amine-terminated PEG units) units and activated ester group-containing PEG units, multiple PEG units of the formula: [ka] wherein m is an integer from 0 to 10; Typically, the number is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In the above formula, for example, when SAZ-terminated PEG is used, m is 6. For the SG end group, m is 3, for the SS end group, m is 2, and for the SS end group, m is 1. All of the crosslinks in 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 persistence in the eye, and in certain embodiments of the present invention Implants comprising hydrogels containing PEG-SAZ units can be administered intraocularly, e.g., in the human eye. in the vitreous humor, and 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 4-arm 20,000 dalton PEG precursor having an amine group (as defined above) is ) is combined with an 8-arm 20,000 dalton PEG precursor. The precursors are referred to herein as 4a20kPEG-SAZ and 8a20kPEG-NH 2 The chemical structure of 4a20kPEG-SAZ is as follows: [ka] In the formula, R represents the pentaerythritol core structure. 2 (Hex The chemical structure of 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 Approximately 1:1, i.e., one amine group is provided per SAZ group. 0kPEG-SAZ and 8a20kPEG-NH2 In the case of Since it contains twice as many terminal groups as the 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, a precursor containing a nucleophilic group, e.g., an amine end group, The body can be used in excess, i.e., 4a20kPEG-SAZ and 8a20kP EG-NH 2 The weight ratio may 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. For example, Any 4-arm or 8-arm PEG-NH The S precursor can be any 4-arm or 8-arm PEG-NH 2 Precursor (or nucleophilic group-containing In addition, electrophilic group-containing precursors can be combined with any other PEG precursor that can be used. The PEG units of the nucleophilic group-containing precursors 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. (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 is not bound to 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, cyano, The visualization agent can be, for example, one of the nucleophilic groups of the crosslinker. The cross-linking agent can be conjugated 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. About 1% to about 20%, or about 5% to about 10%, or about 8% of the nucleophilic groups of the crosslinking agent 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 are comprised of polymers that form a polymer network as disclosed above. In addition to the mer units 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, borate, etc. In one embodiment, the buffer is an acid salt, a bicarbonate, or another buffer such as triethanolamine. In certain embodiments, sodium phosphate buffers (specifically, sodium phosphate monobasic and dibasic sodium phosphate) are used.

[0146] Optionally, a preservative may be used in the implants of the present invention. In certain embodiments, the present invention provides an implant comprising axitinib as an active agent. The implant may contain a preservative, such as an antimicrobial preservative (including but not limited to, benzyl chloride). 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, ) Agents that affect viscosity (e.g., hyaluronic acid, etc.), surfactants, etc.

[0148] In certain embodiments, the insert of the present invention can include a visualization agent. Visualization agents that can be used in this context include those that are conjugated to components of the hydrogel or or hydrogel and may be visible or, for example, may be encapsulated in a particular wave. Any agent that can be visualized when exposed to long-term light or is a contrast agent. 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. The network is formed by conjugating the precursor with either a nucleophilic group or an electrophilic group. Alternatively, the visualization agent may be added during the manufacture of the implant and present within the hydrogel. The drug may be a separate (unconjugated) agent.

[0149] formulation: In certain embodiments, the implant according to the invention comprises a TKI and a hydrogel A polymer prepared from one or more of the polymer precursors disclosed hereinabove, in the form of -Network and optional additional components (e.g. from the production process to the implant In particular, the term "phosphate salts" includes salts that remain in the solution (e.g., phosphate salts used as buffers). In certain preferred embodiments, the TKI is axitinib.

[0150] In one particular embodiment, the implant according to the present invention has a viscosity of about 15 % by weight to about 80% by weight (e.g., about 25% by weight to about 75% by weight) of the TKI and about 15% by weight % to about 80% by weight (e.g., about 20% to about 60% by weight) of the polymer unit, or In one embodiment, about 35% to about 65% by weight of the TKI and about 25% to about 50% by weight of the In a specific embodiment, the inventive polymeric composition may comprise the polymer units of 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), In another specific embodiment, the implant according to the invention is selected from those shown. In its dry state, the composition is about 55% by weight to about 75% by weight of TKI and about 20% by weight to about 40% by weight of glycerin. The TKI and the polymer unit may comprise about 100% by weight of the polymer unit (dry composition) of the present invention. In another specific embodiment, the present invention provides a method for the preparation of a medicament for the treatment of a pulmonary artery disease. The implant according to the invention comprises, in its dry state, about 30% to about 45% by weight of a TKI and about 47% by weight of a glycerol. % 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 axitinib and about 25% to about 50% by weight 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 % to about 44% by weight of PEG units (dry composition). In the present invention, the implant has a dry content of about 55% to about 75% by weight. of 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 the phosphate salt. Thus, the ratio of axitinib:PEG on a dry weight basis in the implant according to the invention is , about 1:1 to about 3:1.

[0153] In certain embodiments, the residual amount 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 in terms of salt content) 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 mer hydrogels 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 amount of 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, 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 is 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) This includes the current situation.

[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% by weight 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), salt, and drug in the solution / suspension. weight) can be utilized. 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 less 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 100% (v / v). The solids content can affect the viscosity, Thus, it may also affect the flexibility of the wet hydrogel composition.

[0159] In certain embodiments, the hydrogel implant (e.g., prior to being loaded into the needle, or loaded into a needle) is its dry (dehydrated / dried) state. The water content may 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 The hydrated implant (e.g., once the implant is administered to the eye) (i) the implant after being exposed to 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 can be obtained without the need for In certain embodiments, the implant is used to refer to both the dry After manufacture, the needles were stored in a glove box under inert nitrogen for at least about 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 Karl Fischer coulometry. 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 mass (also referred to as "mass") of the dried product is about 200 μg (i.e., 0.2 mg) to about The amount of the active ingredient may be about 1.5 mg, or about 400 μg to about 1.2 mg. In one embodiment, the total weight of the implant according to the 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 is In one embodiment, the amount of xanthomonas maxima 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 a state of 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, the implant contains 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 mm of dry implant 3 (per volume) Approx. 200μg to Approx. 100 0 μg of a TKI (e.g., axitinib). In terms of morphology, the implant according to the invention has a thickness of 1 mm in its dry state. 3 About 200 per μg to about 300 μg of axitinib (for example, the implant contains about 160 μg of axitinib In certain other specific embodiments, the amount of the glycerol may be in the range of about 250 μg to about 250 μg. In the present invention, the implant has a thickness of 1 mm in its dry state. 3 Approximately 500μg per serving Approximately 800 μg of axitinib (for example, the implant contains approximately 480 μg to approximately 750 μg may contain axitinib).

[0162] Thus, the implants of the present invention can have different densities. The density of a plant (i.e. in its dry state) depends on 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 may be controlled and determined by The final implant density in certain embodiments will vary at a particular point during the manufacturing process. , can be increased by sonication or degassing (e.g., using a vacuum).

[0163] In certain embodiments, implants according to the invention provide extended release. including a therapeutically effective amount of a TKI (e.g., axitinib) for treating Relatively small length and / or diameter. This is from the standpoint of ease of administration (injection) and This reduces the chance of damaging eye tissue and improves the patient's vision while the implant is in place. The present invention is advantageous in terms of both reducing the possibility of affecting the Runt is a suitable high-dose TKI (i.e., one that is tailored to the needs of the particular patient). This 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 set forth 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 TKIs) The present invention is disclosed in US Pat. No. 6,399,623, 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 a method of manufacture (e.g., by pre-gelling the TKI-containing Various methods are available for producing the gel-containing mixture, depending on the type of gel (e.g., the use of a mold or tube to cast the mixture containing the gel precursor). The implant according to the invention may have any of the following geometric shapes: The term is also referred to herein interchangeably with the term "rod," where: A fiber is generally an object having an elongated shape. An implant (or fiber) is defined herein as The present invention can have different geometric shapes with specific dimensions as disclosed.

[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 that is substantially perpendicular to the length. The width can be about 0.1 mm to about 0.5 mm. A circular diameter fiber (spunbonded) or a cross section of the outer implant shape may be used. Instead of a cylindrical implant, the cross-shaped fibers (i.e., Other cross-sectional geometries, such as ovals or In general, oval, rectangular, triangular, star, etc. shapes may also be used. In some embodiments, the fibers may be twisted. In an embodiment, the dimensions of the implant (i.e., its length and diameter) and its cross-section The geometry of the implant is adapted to attach to a needle, particularly a 25 gauge needle as further disclosed herein. The catheter should 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-1000 is semi-crystalline in the dry state at room temperature or below, and amorphous in the wet state. Even in the expanded form, the dry implant is dimensionally stable at or below room temperature. , which can be advantageous for loading the implant into needles and for quality control.

[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. Generally, the diameter of the implant may increase while the length decreases, or The advantage of this dimensional change is that the implant can A fine diameter needle (e.g., 25 gauge, 27 gauge, or or sometimes even smaller diameter needles such as a 30 gauge needle. However, once placed in the eye, e.g., in the vitreous humor, the implant penetrates the limited area of ​​the eye. It can be made shorter to better fit within a small volume. 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 contact occurs, any ocular tissue damage can be prevented or minimized. In certain embodiments, the dimensional change is due, at least in part, to the manufacture of the implant. The “shape memory” effect introduced by longitudinally stretching the implant during implantation (also disclosed in the "Method of Manufacturing" section below). In the present invention, the stretching is performed either in a dry state or in a wet state, i.e., in the case of 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, the implant will not become inflamed upon hydration. The advantage of this 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 to induce molecular orientation. By fixing the pores, it is possible to impart a certain degree of molecular orientation. In one 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 of 1000° C. and then crystallizing the crystallizable regions. Alternatively, in certain embodiments, a glass of a dried hydrogel may be used. The glass transition temperature is used to determine the molecular orientation of a polymer such as PVA that has a suitable glass transition temperature. Yet another alternative is to stretch the gel before it is completely dried ("wet stretching"). The first step is to stretch the glass (also called "stretching") and then dry the material under tension. 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 swelling that occurs when the diameter of a cylinder increases or is essentially maintained. The longitudinal dimension swells predominantly while the longitudinal dimension swells very little (or even shrinks). This means that the material 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. If stretched with a stretch factor of 1.3 (e.g. by wet stretching), the effect is not significant or water In contrast, for example, the length of about 1.8 When stretched (e.g., by wet stretching) with a stretch factor of For example, if stretched (e.g. by dry stretching) with a stretch factor of 4, 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] Affects the ability to stretch the hydrogel and change the 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 leads to greater hydrogel flexibility 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., In the case of a larger amount of PEG precursor containing a larger number of arms (e.g., 8-arm PEG units), In this case, the hydrogel may become stiffer and less easily stretched without breaking. On the other hand, more flexible building blocks (e.g., PEG precursors containing fewer arms (e.g., For example, hydrogels containing 4-arm PEG units are easier to stretch and are softer. However, it is possible that the implant may swell more when hydrated. Behavior and properties once placed in the eye (i.e., once the hydrogel is (re)hydrated) The implant is formed by altering its structural characteristics and by Adjustments can be made by modifying the plant's processes.

[0173] Exemplary dimensions of the implants used in the following examples are given, inter alia, in the Examples section. Tables 6, 21.1, and 21.2 of the FDA's FDA Approval Guidelines for Acute Myocardial Infarction (AMI) test are shown in Tables 6, 21.1, and 21.2 of the FDA Approval Guidelines for Acute Myocardial Infarction (AMI) test. 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 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 concentration. The diameter of the mold or tube that allows the hydrogel to gel depends on the ratio of the polymer units to the The diameter of the implant can also be controlled by, among other things, the size and shape of the implant. The properties of the hydrogel strands were further determined by stretching (wet or dry) the hydrogel strands formed. The dried strands (after stretching) are cut into segments of the desired length and then impregnated. Thus, the length can be selected as required.

[0174] Below, embodiments of the implant having specific dimensions are disclosed. Whenever the dimensional range or value to be used relates to the length and diameter of the implant, The implant is cylindrical or essentially cylindrical, except that the length and diameter of the cylindrical implant may vary. 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 length of about 17 mm in its dry state. In a specific embodiment, the length of the implant in its dry state may be less than In this state, the size 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 has a diameter of 1 mm or less. 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 The length may be from about 6 mm to about 9 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 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 about 0.2 mm to about 0.4 mm, or about 0. In a specific embodiment, the implant of the present invention may have a diameter of about 3 mm to about 0.4 mm. The thickness of the material is about 0.2 mm to about 0.3 mm, or about 0.3 mm to about 0.4 mm when dry. The diameter of the axial length of the axial groove may be 1.0 mm.

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

[0178] In one particular embodiment, the implant of the present invention has a viscosity of about 6 In certain other embodiments, the implant of the present invention may have a length of 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 the following properties: 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 0.5 to 1.5 μg / kg. .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 1.0 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 invention, the diameter of the implant in the dry state is as disclosed herein. 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 granules 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), the disclosure is based on measurements taken 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 dimensions of the implant decrease over time. (i.e., after 24 hours) may change further (e.g., the length may change slightly again) However, when implant hydration 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 one implant are taken, or if multiple measurements are made during the measurement, When multiple data points are collected, the average, as defined herein, ) (i.e., mean) values ​​are reported. The diameter and diameter of the nucleus can be determined, for example, by microscopy or by (optionally automatically) measuring the diameter of the nucleus as described in Example 6.1. The 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 dry diameter 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 greater than about In certain specific embodiments, the dry impregnation The ratio of the length of the runt to the length of the hydrated implant 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 difficult to use the small diameter injection needles disclosed herein (e.g., This may be advantageous since the implant may fit into a 27-gauge or 5-gauge needle. In addition, the swelling during hydration must be kept at a moderate level to prevent the implant from becoming excessively voided in the vitreous humor. The relatively short length of the implant may be advantageous in order to avoid occupying too much space. , which can be advantageous in reducing the chance of contacting 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 about 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 during in vitro hydration (where in vitro hydration is at 37°C, p H7.2 phosphate buffered saline (measured after 24 hours) ranges in length from about 6.5 mm to about 8 mm. 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, The fiber (cylindrical When dry, it has a size of about 6 mm or about 7 mm to about 12 mm. The inner length and diameter of about 0.25 mm to about 0.50 mm, or about 7 mm to about 10 mm The length may be about 8 mm to about 11 mm and the diameter may be 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, 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 9 mm) and 0.3 mm to 0.4 mm (e.g., about 0.35 mm to about 0.39 mm) The diameter of the axial length ...

[0190] Such implants, upon in vivo hydration within the eye (e.g., in the vitreous humor), , or upon in vitro hydration (wherein in vitro hydration is at 37°C, The diameter of the nuclei was increased by 24 hours in phosphate buffered saline at pH 7.2. The length may be essentially the same, may be reduced, or may be slightly For example, the hydrated state may increase to about 6 mm or about 9 mm to about 12 mm. 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 The length is about 0.5 mm and the diameter 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 in its hydrated form. The fibers (cylindrical) 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.

[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 specimen is 10 mm or less when it is frozen and when it is hydrated (at 37°C and in phosphate buffer at pH 7.2). After 24 hours in saline solution), the or about 9 mm or less, or about 8 mm or less in length.

[0192] In one or more embodiment(s), the above 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 from about 7 to about 3, or at a stretch factor of from 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 may be shorter.

[0193] In certain embodiments, such stretching results in shape memory, i.e. This is because the implant, upon hydration when administered intraocularly, e.g., into the vitreous cavity, retains its original shape. The length shrinks until it (approximately) approaches the equilibrium size determined by the dimensional and compositional variables. Narrowing the drying dimension means that the product can be cut with smaller gauge needles. While this makes administration easier, it also increases the diameter and shortens the length after administration, making it difficult to see behind the eye. In the eye chamber, the implant becomes shorter in relation 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 ocular tissue. Thus, in one embodiment, the present invention provides an active agent (e.g., axitinib) A method of imparting shape memory to a hydrogel fiber comprising: and stretching the hydrogel fibers in the longitudinal direction to impart shape memory. In another aspect, the present invention relates to a method for treating a patient having an active agent (e.g., a TKI, such as axillary activator). The present invention relates to a method for producing an intraocular implant comprising a hydrogel having dispersed therein an anti-inflammatory drug, The implant changes dimensions upon administration to the eye, and the method includes distributing the hydrogel fibers. and stretching the fiber longitudinally.

[0194] In vitro release: The in vitro release of TKI 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, a method to measure the in vitro release of TKIs from implants was developed. The method is a non-sink simulated culture in phosphate-buffered saline (PBS, pH 7.2) at 37°C. Under physiological conditions, PBS was replaced daily at a volume equivalent to the vitreous volume of the human eye. The results of an exemplary implant are shown in FIG. 4A. As described in Example 2, PEG hydride was added to the implant. In the test implants containing axitinib in a Rogel matrix, the higher dose strength , resulting in a higher concentration of axitinib in the release medium.

[0196] Generally, in an embodiment of the invention, the implant according to the invention is maintained at 37° C., pH 7. In vitro, the average daily dose was approximately 0.1 μg to approximately 100 μg / day in 20 mM PBS for a period of 30 days. 3 μg, or about 0.25 μg to about 2.5 μg, or about 0.1 μg to about 2 μg or about 0.25 μg to about 1.5 μg can be released.

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

[0198] In one embodiment, an implant according to the invention containing about 600 μg of axitinib. The in vitro study was performed in phosphate buffered saline (pH 7.2) at 37°C 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, The release of TKIs 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 implants according to the invention containing about 200 μg of axitinib. FIG. 4B shows the ro release data of an infusion according to the present invention containing about 556 μg of axitinib. Accelerated in vitro release data for the plant is presented.

[0200] In one embodiment, an implant according to the invention containing about 200 μg of axitinib. The rats were incubated at 37°C for 3 days in a 25:75 ethanol / water mixture (v / v). Approximately 35% to 45% of nib in 7 days, approximately 65% ​​to 75% 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 containing about 600 μg of axitinib. The rats were incubated at 37°C for 2 days in a 25:75 ethanol / water mixture (v / v). 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 detected in 2 days and approximately 45% to 55% of axitinib in 4 days. Approximately 70% to 80% of axitinib was released in vitro in 1 day and approximately 80% to 90% of axitinib in 6 days. In some cases, they may be released.

[0202] Finally, the release of TKI from the implants of the present invention can be achieved using a 100% TKI concentration, as described in detail in Example 2. In addition, real-time sinks may be quantified under simulated physiological conditions. In the experiment, octadecyl sulfate was added to PBS (pH 7.2) / 0.01% NaF at 37°C. The release of TKI from the implant to the vitreous humor was measured with and without the use of a Nol overlay. Qualitatively simulate the release of TKIs into the ocular tissue and from there their absorption into the ocular tissue. One method for 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 FIG. 14A.

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

[0204] In vitro release tests, particularly the accelerated in vitro release tests described herein, include: For example, for purposes of quality control or other qualitative evaluation, it may be possible to, among other things, 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 invention, the dry implant of the invention is administered to the eye (e.g., the vitreous humor). When administered to the skin, 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 They become smaller, softer, more liquid, and eventually dissolve completely and become invisible. The inventors have recognized from animal studies presented in the Examples section herein below. Thus, the 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, which 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 is directed to a method for the treatment of a human eye disease (e.g., in the vitreous humor). The implant is administered within about 2 to about 15 months, or within about 4 to about 13 months, or is biodegraded within about 9 to about 12 months after administration, specifically within about 9 to about 10.5 months after administration. This was achieved by administering one or two implants (each containing 200 μg of axin). This has been demonstrated in clinical trials using nibs (including nibs). See also FIG.

[0207] In one embodiment, the implant after administration to the vitreous humor is administered to a TKI, such as 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 a TKI (eg, axitinib) for a period of about six months to about nine months.

[0208] In one embodiment of the invention, the implant is administered 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. from about 0.1 μg / day to about 10 μg / day, or from 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 for 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) is The effect is maintained for about 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 amounts 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) may remain at the site of the implant. It remains essentially a cohesive and essentially monolithic structure (see Figs. 7A, 9, and 10). ), which can be delivered intravitreously at levels sufficient to achieve a therapeutic effect. In certain embodiments, however, the release of the TKI into the implant may continue. The entire amount of TKI contained in the implant is released from the implant before the biodegradation of the implant is complete. In this case, the undissolved TKI particles are released after complete biodegradation of the implant. Remain near the implant site or elsewhere in the eye (and / or clump together) It is considered unlikely that

[0211] In one embodiment, the persistence of the hydrogel in an aqueous environment and in the human eye is particularly In particular, it depends on the hydrophobicity of the carbon chain adjacent to the degradable ester group. In the case of the implant, 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 the case of 4a20kPEG-SAZ and 8a20kPEG-NH 2 A precursor different from The implants can be used to biodegrade in the human eye and have similar or different properties to those of the implants illustrated in the examples. It is possible to prepare hydrogel implants that have a sustained release.

[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. As used in the examples of this application, 4a20kPEG-SAZ and 8a20kPEG- NH 2 Implants formed from 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 high solubility in physiological media. It has been determined that the activity 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 a specific geometric shape and surface. 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 in the hydrogel. The drug gradually dissolves. This is because the hydrogel 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 innermost regions dissolve and diffuse last, while the outermost regions dissolve and diffuse first). In this embodiment, the outer region of the hydrogel is devoid of drug particles. Also called the "clearance zone," this is restricted to dissolved drug only and is beyond the drug's solubility. In certain embodiments, this low surface concentration is achieved when the implant Physically separating drug particles from tissue (retina or other cells) when they come into contact with the tissue This can protect such tissues from potential drug toxicity. In the present specification, the "clearance zone" refers to the active site within the inner region of the hydrated hydrogel upon hydration. The outer region has a lower concentration of 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 out of the zone, cavities form, making the drug softer and more brittle. Concurrently with diffusion out of the gel, the hydrogel may, for example, release esters into the aqueous environment of the eye. They can also degrade slowly by hydrolysis. This degradation occurs uniformly throughout the bulk of the hydrogel. In the advanced stages of degradation, distortion and erosion of the hydrogel begins to occur. As this occurs, the hydrogel becomes softer and more liquid (and therefore distorts its shape). Eventually, the hydrogel dissolves and is completely absorbed. This process is shown diagrammatically in Figure 3. This has been demonstrated by infrared reflectance (IR) imaging, for example in Figure 10. It has been done.

[0216] Since axitinib is a relatively poorly soluble drug, in certain embodiments, After the implant has already completely degraded, the undissolved axitinib particles remain in the implant. These residual undissolved axitinib particles may remain at the site of injection. Since they are not fixed or separated by a hydrogel, they aggregate and become essentially 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 quickly. The axitinib particles form a monolithic structure from which axitinib slowly dissolves. Therefore, axitinib is completely released before the hydrogel completely degrades. 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, for example up to 15 months. The present inventors believe that this is because the neovascular age-related macular degeneration can be advantageously maintained. This has proven to be a great 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 according to the invention 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 of an agonist containing about 160 μg to about 250 μg (e.g., about 200 μg) of axitinib is Plant: In one particular embodiment, the present invention provides a method for the preparation of a medicament for the treatment of atopic dermatitis comprising administering to a subject a therapeutically effective amount .... About 250 μg, or about 180 μg to about 220 μg, particularly about 200 μg. Regarding the sustained release biodegradable intraocular implant containing xitinib, the hydrogel is polyethylene. The implant contains a polymer network of ethylene glycol units in a dry state. In this embodiment, the polymer network is a multi-arm polyethylene glycol. Recall unit (for example, an average value within the range of about 10,000 Daltons to about 60,000 Daltons) Polyethylene glycol units having 4-arm and / or 8-arm molecular weights In this embodiment, the polymer of the implant comprises polyethylene glycol units. The network is 4a20kPEG-SAZ to 8a20kPEG-NH 2 and weight ratio of about 2:1 In this embodiment, when formed, The hydrogel (i.e., the wet composition) before drying is about 6.5% to about 7.5% poly(ethylene glycol). Contains ethylene glycol (weight of polyethylene glycol ÷ weight of fluid × 100) In this embodiment, the implant contains about 45% to about 55% by weight of the cellulose in a dry state. % by weight of axitinib and about 37% to about 47% by weight of polyethylene glycol units, or about 47% to about 52% by weight axitinib and about 40% to about 45% by weight poly Ethylene glycol units (e.g., about 49% by weight 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 about 1% or less water by weight, or about 0.25% or less water by weight in its dry state. do.

[0220] In this embodiment, axitinib is administered at a dose of about 160 μg to about 250 μg, or at a dose of about 180 μg to about 250 μg. Implants containing an amount in the range of 200 μg to about 220 μg, specifically about 200 μg, are phosphate buffered saline at an average of approximately 0.0 mg / day in vitro over a 30-day period. In this embodiment, the injectable composition releases 1 μg to about 0.15 μg of axitinib. The implants were incubated at 37°C for 3 days in a 25:75 ethanol / water (v / v) mixture. 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 terms of morphology, the implants were buffered in 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 57%, 5 months to 70% to 80%, and 7 months to 70%. 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 have a diameter of less than about 20 mm or less than about 17 mm in its dry state. 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 or upon hydration in vitro ( In vitro hydration was performed after 24 hours in phosphate buffered saline at 37°C and pH 7.2. The length decreases and the diameter increases, reaching a length of about 6.5 mm to about 8 mm in the hydrated state (measured at 100°C). The diameter of the hydrated particles can range from 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 imparting memory. The tube may be non-cylindrical.

[0222] In this embodiment, the hydrated state of the implant contains 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 lengths of the two phases may 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 about 10 μg to about 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 include about 2 Implants of the invention containing a dose of 0.100 μg (used in the clinical trial presented in Example 6) The individual characteristics of the implants (including those implanted in the It has been shown, and we will reproduce it here. [Table 1-1] [Table 1-2]

[0226] The implant is an intravitreal implant, and contains about 180 μg to about 220 μg of axin. It has a cylindrical shape, including a nib, and has a length of 17 mm or less and a length of about 0.2 mm to about 0. 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 h, 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 comprises crosslinked 4a20k and 8a20k PEG units, and The crosslinking of [ka] 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 of an agonist containing about 480 μg to about 750 μg (e.g., about 600 μg) of axitinib is Plant: In another specific embodiment, the present invention provides axitinib dispersed in a hydrogel. A sustained release biodegradable intraocular implant comprising in an amount ranging from about 480 μg to about 750 μg. wherein the hydrogel is a polymer comprising cross-linked polyethylene glycol units. The amount of axitinib in the implant is about 540 μg to 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 glycols. Recall unit (for example, an 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 comprises 4a20kPEG and 8a20kPEG units, and 4a20kPEG-SAZ was converted to 8a20kPEG-N H 2 in a weight ratio of about 2:1.

[0230] In this embodiment, the implant comprises, on a dry basis, about 45% to about 55% a 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% by weight of poly 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 one particular embodiment, the implant is about 68% sodium phosphate. ~About 69% axitinib and about 26% polyethylene glycol units (dry composition) The remainder is sodium phosphate. The implant may contain up to about 1% by weight water. %, or up to about 0.25% by weight water.

[0231] In this embodiment, axitinib is administered at a dose of about 480 μg to about 750 μg, or at a dose of about 540 μg to about 750 μg. This implant contains in an amount ranging from about 600 μg to about 660 μg. was observed in vitro at approximately 100 mg / day in phosphate buffered saline at 37°C for a period of 30 days. The implant releases 0.3 μg to approximately 0.5 μg of axitinib. Approximately 10% of axitinib was detected in 25:75 (v / v) ethanol / water at 7°C for 2 days. 40% to 60% of axitinib in 4 days, 65% to 85% of axitinib in 6 days In this embodiment, the implant releases 75% to about 90% of the active ingredient in the composition in vitro. The cells were incubated at 37°C for 2 days in a 25:75 ethanol / water (v / v) mixture to induce axillary hyperplasia. 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 In its dry state, it may have a shape of less than about 20 mm or less than about 17 mm. Less than 1 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 about 8 mm to about 11 mm and a diameter of about 0.3 mm to about 0.4 mm, and may be absorbed in the vitreous humor. may increase in diameter upon hydration in vivo or in vitro (where In vitro hydration was performed after 24 hours in phosphate-buffered saline, pH 7.2, at 37°C. In a specific embodiment, an implant containing about 600 μg of axitinib is The granules are approximately 10 mm or less, or approximately 8.5 mm or less, or approximately 7 mm to approximately 9 mm, or about 7 mm to about 8.5 mm in length and about 0.3 mm to about 0.4 mm (for example 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, 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 about 0.80 mm in diameter. In a specific embodiment, about 600 Implants containing μg of axitinib in their hydrated state (here, in vitro Hydration at 37°C in phosphate buffered saline, pH 7.2, is measured after 24 hours, approximately Lengths 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 vitreous humor of the eye may have a diameter of about 0.8 mm to about 0.9 mm. A length of about 10 mm or less (e.g., about 9 mm or less) when inserted into the eye 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 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. In a dry state, the amount is about 0.8 mg to about 1.1 mg, for example, about 0.9 mg to about 1.0 mg. In the dry state, such implants can have a mass of approximately 70 μg per mm of final length. ~ about 85 μg of axitinib, mm3 Approximately 500μg to 800μ 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. 25 gauge) for injection into the eye, e.g. vitreous humor 7 gauge needle.

[0238] In summary, about 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. The above 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 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. The PEG comprises 4a20k and 8a20k PEG units, and the linkage between the PEG units is of the formula [ka] where 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 a sustained release biodegradable intraocular The present invention also relates to a method for producing an implant. Generally, the method includes 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; The method includes the steps of forming a hydrogel and drying the hydrogel, more specifically The polymer network is formed by integrating electrophilic multi-arm PEG precursors with nucleophilic multi-arm PEG precursors. A multi-arm PEG precursor or another nucleophilic group-containing crosslinker (referred to herein as the "polymer network"). The precursors and crosslinkers disclosed in the "PEG hydrogel" and "PEG hydrogel" sections and the TKI particles are It is formed by mixing and reacting the mixture in a buffer solution in the presence of an ion, causing the mixture to gel. In an embodiment of the invention, the hydrogel is formed by Prior to complete gelation, the mixture was cast into a tube to obtain the hyaluronic acid hydrochloride disclosed herein. In certain embodiments, the hydrogel strands are formed into hydrogel strands. is stretched longitudinally 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 any of its In one embodiment, the TKI (e.g., axitinib) is tinib) is used in micronized form to prepare the implant as disclosed herein. and may have a particle size as disclosed in the "Active Ingredients" section of this specification. In certain specific embodiments, axitinib has a diameter of less than about 30 μm, Or may have a d90 of less than about 10 μm. Micronized TKIs, specifically micronized axitinib By using a microtube, during casting of the hydrogel strands, as shown in FIG. This is believed to 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. PEGs crosslinked using PEG precursors are disclosed in detail in the section on When preparing the network, in certain embodiments, a method for manufacturing an implant The electrophilic group-containing polymer precursor (e.g., electrophilic group-containing multi-arm polyethylene glycol) Cole, e.g., 4a20kPEG-SAZ) is reacted with 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 reacted. 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., and other nucleophilic group-containing precursors or crosslinkers) may be used. .

[0244] In certain embodiments, a combination of an electrophilic group-containing precursor and a nucleophilic group-containing precursor or other crosslinking precursor is used. A bridge agent, a TKI, and optionally a buffer (and optionally, This can be done in a variety of orders, and the order is In the first step, an electrophilic group-containing precursor and a nucleophilic group-containing precursor are first reacted with each other. 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 is then mixed with another buffer / precursor mixture (in this case, buffer / electrophile-containing A mixture of all the components is then combined with 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 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 This may depend on the concentration and solids content of the gel composition, but may also depend on external conditions such as temperature. The properties of the wet hydrogel composition are particularly favorable when the composition is cast into fine diameter tubes. Flexibility can be improved by reducing the viscosity of the wetting composition. This can include 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 (including, but 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), then the elongated circle To obtain a cylindrical shape, the reactive mixture is inserted into a fine diameter tube such as a PU or silicone tube. The hydrophilic material can be cast into a tube (e.g., 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 reduced by stretching), may be reduced) and 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. The geometry may be a cross (or other) geometric shape. The shape of the implant can increase the surface area of ​​the implant. In the morphology, the amount of TKI incorporated into the implant is determined by the cross-shaped geometric shape. The overall effect is increased by using a cross-shaped geometry. and, in certain embodiments, increasing the release of the API from the implant. 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 change of the implant upon hydration). As disclosed in detail in the section on chemical reactions, In a particular embodiment, the stretch factor can be g factor) (also referred to herein as "stretch factor" (also referred to as "pair") 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 in the range of 0.01 to 0.05 after stretching of a particular hydrogel strand. The ratio of the length of the hydrogel strand to the length of the hydrogel strand before stretching. For example, the stretch factor of dry stretching The number 2 indicates that the length of the dry hydrogel strand after (dry) stretching is longer than 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, the stretching and / or drying may be performed while the hydrogel is still in the tube. Alternatively, the hydrogel may be stretched while in the tube. In certain embodiments, the implant may be placed at or below room temperature. As long as it is stored dry, it will maintain its dimensions even after stretching.

[0249] After stretching and drying, the hydrogel strands are removed from the tube (if still in 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 removed from the tube immediately after the injection.) 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 final prepared implant is then immersed in 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 a smaller gauge needle (eg, a 30 gauge needle).

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

[0252] In certain embodiments, an injection device (e.g., a syringe or another injection device) The device (s) can be packaged separately and are referred to below as a kit (another embodiment of the present invention, As disclosed herein (see the "Injection Devices and Kits" section), e.g., gamma It can be sterilized 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 melted. 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 is soluble at room temperature. It is a solid. Molten PEG is applied to the tip of the needle by dipping or dripping, and the needle is then cooled. and a droplet or segment of hardened PEG at and within the tip of the needle (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 0.1% 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 injected into the eye with a needle. It melts at body temperature when exposed to heat.

[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 hard at body temperature 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 can also be used (including: (non-limiting): poloxamers or poloxamers that melt / liquid at body temperature -blend, crystallized sugar or salt (e.g., trehalose or sodium chloride), a Gallose, cellulose, polyvinyl alcohol, poly(lactic-co-glycolic acid), U A combination of V cured polymer, chitosan, or a mixture thereof.

[0257] The plug or tip maintains 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 needle and syringe during the administration procedure, i.e. when the physician is administering the implant. While preparing the injector and when the needle is inserted into the eye to inject the implant (implant Immediately prior to the actual injection of the implant, positive pressure within the eye may be required to induce at least some early hydration of the implant. To prevent premature hydration of the implant in the needle due to the ingress of moisture, which may cause The tip or plug can also be heated by body heat and exposed to moisture. and lubrication, thereby allowing the implant to be successfully placed. In addition, by blocking the needle lumen, needle tip processing can prevent tissue damage, i.e. tissue coreing. the possibility of suctioning (the process in which pieces of tissue are removed by the needle as it passes through the tissue) Minimize sexuality.

[0258] One procedure is used to apply a PEG (or other material) tip / plug to the lumen of the needle. In the form, the needle containing the implant is filled with molten PEG (or other material). The needle can be dipped into the molten material by hand or by an automatic device. Hold the needle submerged for 2 seconds to allow the molten material to flow upward into the needle by capillary action. Depending on the residence time, depth of immersion, 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 can 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 about 15 mg to about 0.55 mg. In vivo 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] In addition, 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 or other medicine or vaccine, the protective effect of the implant (or the 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 caused by stretching has already been described in detail above with regard to the characteristics of the implant. 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 the steps of: 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 accomplished by stretching the hydrogel strands longitudinally.

[0262] Similarly, therefore, in certain embodiments, the present invention provides a method for dissolving an active agent in a hydrogel. 1. A method for producing an intraocular implant comprising a hydrogel having a drug dispersed therein, the method comprising the steps of: The present invention also relates to a method for administering a hydrogel to an eye, the method comprising administering to the eye a hydrogel. It involves preparing a strand of gel and stretching it longitudinally.

[0263] The stretch factor for use in these methods of the present invention may be utilized as already disclosed above. The described manufacturing method (including the extension method) can be used to Implants containing xitinib are not limited to hydrogels containing other active pharmaceutical agents. The present invention also provides a method for preparing a hydrogel-forming PEG-based polymerizable composition that is capable of forming a gel or hydrogel rather than being formed from PEG units. 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 the hydrogel, the stretching is performed for about 2 to about 5 minutes after drying the hydrogel. The stretching can be carried out with 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 In certain embodiments comprising an amount of 0 μg, the stretching is performed after wetting the hydrogel prior to 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 factor (wet stretching).

[0266] III. Injection Devices and Kits In certain embodiments, the present invention further provides a method for the preparation of ... medicament for use in a pharmaceutical composition comprising the steps of: 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, In specific embodiments, the gauge is 24, 25, 26, 27, 28, 29, or 30. In the present case, the needle may be a 25 gauge or 27 gauge needle(s), or a 30 The diameter of the needle may be smaller than the gauge of the dried needle. Based on the final diameter of the implant in its stretched (and optionally expanded) state, The active agent contained in the implant is generally a TKI (eg, 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 the amount of 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 loaded with an implant containing a range of doses, 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 needle.

[0269] If two or more implants are included in a kit, the implants 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 a This is described in detail in the section on “Manufacturing of the Needle” and in particular in the subsection on “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 cell may be occluded by a PEG material.

[0271] The kit further includes a device for administering the implant(s) into 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 the one or more needle(s) into which the implant is loaded. In such an embodiment, the injection device is packaged in Before the implant can be inserted, it must be connected to one or more loaded needles. stomach.

[0272] In certain embodiments, the number of injection devices provided separately in the kit may vary. The number of implants provided in the dispenser 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 includes a device for administering an implant into the patient's eye (e.g., into the patient's vitreous). one or more injection devices for injecting into a liquid, The chair may be pre-connected to a needle loaded with an implant or may be unconnected. Thus, in one embodiment, 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 already connected to the injection device, the impingement The physician administering the implant must remove both the needle and the injection device containing the implant from the packaging. The implant must then be removed from the eye and the needle must be connected 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. Push wire can be stainless steel or stainless steel / Teflon push wire. The wire allows the implant to be deployed more easily from the needle.

[0275] In other embodiments, the injection device and / or needle may include a stop that controls 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 A glass syringe or a push wire (e.g., a Nitinol wire) The ear is inserted into the syringe and is engaged with the syringe plunger during implant placement. To facilitate entry of the Nitinol push wire into the needle, A hub insert may be added to the vitreous humor of a patient. 1 shows an 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. FIG. 25A shows the Hammer inside the injection molded casing. FIG. 25B shows the ilton syringe body. FIG. 1 is a schematic diagram of a Hamilton syringe body and a syringe according to a specific embodiment. The syringe, including the syringe housing, is preassembled in the kit according to the invention. The injector is ready to use (no needle containing implant or needle attachment). In an embodiment, the syringe is assembled by the physician prior to attachment of the needle containing the implant. It must be erected.

[0277] In another embodiment, the injection device is an injection molded syringe. A schematic exploded view of one embodiment of an extruded syringe is shown in FIG. This reduces the number of assembly steps that the physician must perform immediately prior to administering the agent.

[0278] The kit further includes 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 an embodiment, the anti-VEGF agent is bevacizumab. The anti-VEGF agent is aflibercept. The anti-VEGF agent is 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 can be aspirated into another injection device.

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

[0280] In addition to the kit, the present invention in one embodiment includes a sustained release biodegradable intraocular The invention also relates to an injection device suitable for injecting an 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 include a needle-insertion device for injecting a drug 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, the push wire being 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 a plunger connecting the wire to two The plunger is secured in place with a clip by inserting it between the snap-fit ​​syringe body. Injection devices and implants according to certain embodiments of the present invention are obtainable. A needle preloaded with the drug is shown in FIG.

[0281] As shown in FIG. 1, in some embodiments, an injection device (e.g., an impinger) is The first injection device is packaged separately (e.g., in separate housings). FIG. 26C shows a first assembly and a second assembly. FIG. 26C 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 and a first 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 a distal end of the plunger clip. The plunger clip is connected to the plunger and the body to prevent the plunger from operating. The body includes a first body half and a second body half configured to interconnect with each other. The body may include a body half adapted to move the plunger in response to actuation of the plunger. The living hinge may include a living hinge that is connected to the protrusion and that is adapted to withstand application of a threshold force. The plunger can be actuated in response to the pressure.

[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 cap secured 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) in the user's body and provides the 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 plant is conditioned (e.g., nitrogen conditioned). In an embodiment, the implant is not included in the housing with the first assembly, so that the first The assembly is made from materials with a higher moisture content and / or is sealed in an enclosure. Do not undergo conditioning prior to 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 assembly and the second assembly may be aligned. The recess may be aligned with one or more inner projections 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 assembly. Referring to FIG. 26F, the second assembly may include a The cowl of the assembly may be in a state where the protrusion on the inside of the cowl is inserted into the recess on the outside of the body. The needle sleeve is secured to the body of the first assembly (by fastening the needle sleeve to the body of the first assembly). The bolt is removed from the cowl of the second assembly and the plunger clip is inserted into the cowl of the first assembly. Referring to FIG. 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 from the lumen of the needle of the second assembly. wherein the body is capable of actuating the plunger in response to a threshold force being applied to the plunger. In some embodiments, the lumen of the needle has a living hinge that allows the lumen to be 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 its end. By inserting it into the user, the coring of the user's tissue (e.g., tissue fragments that later become The lumen can be placed in the body to 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 liquefies, the implant can be inserted into the It can be deployed from the lumen by actuation of the lunger.

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

[0287] In a specific embodiment, the present invention provides a method for treating an ocular disorder in a patient in need thereof. The method includes administering to a patient a hydrogel and at least about 150 μg Patients will receive a sustained-release biodegradable intraocular implant containing a tyrosine kinase inhibitor (TKI). wherein the TKI particles are dispersed within the hydrogel.

[0288] In this treatment, the dosage per eye is to be 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 a treatment period (i.e., during a treatment period). The dose of TKI (specifically axitinib) per eye is about 200 μg to about 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 another embodiment, the amount of the saturation agent is in the range of about 400 μg to about 440 μg. The dose is within the range of about 480 μg to about 750 μg, or about 540 μg to about 660 μg, or about 600 μg. In 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 about 100 μg to about 1100 μg. In this case, the dose is about 960 μg to about 1500 μg, or about 1080 μg to about 132 In certain embodiments, the dose is within the range of about 100 μg or about 1200 μg during the treatment period. The dose administered 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 eye according to the invention. The duration of treatment for the treatment of the disease is 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 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 disease including acute multifocal macular edema, -Chett's disease, birdshot retinochoroidopathy, infectious diseases (syphilis, Lyme disease, tuberculosis, toxoplasmosis) uveitis), intermediate uveitis (pars planitis), multifocal choroiditis, multiple disappearing white dots syndrome Group (MEWDS), ocular sarcoidosis, posterior scleritis, serpiginous choroiditis, subretinal fibrosis, Uveitis syndrome or Vogt-Koyanagi-Harada syndrome, eye disease is vascular Disease or exudative diseases (Coat's disease, parafoveal telangiectasia, papillary vasculitis, frosted branch vessels) retinopathy, sickle cell retinopathy and other hemoglobinopathies, angioid streaks, and familial edema. vitreoretinopathy) or the eye disease is due to trauma or surgery (concomitant Infectious ophthalmia, uveitis, retinal disease, retinal detachment, trauma, photodynamic laser therapy, photocoagulation, surgery hypoperfusion, radiation retinopathy, or bone marrow transplant retinopathy).

[0294] In an alternative embodiment, a method for the preparation of a therapeutically effective amount of a hydrogel comprising the hydrogel of the present invention and a tyrosine kinase inhibitor is provided. 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 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] In general, 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 mellitus, Selected from the list consisting of: pathologic 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 in a patient with elevated central retinal thickness. and is effective in reducing central space retinal thickness (CSFT) as measured by optical coherence tomography. Elevated in this context is when compared to other individuals who do not suffer from a particular eye disease. This means that the patient has a higher CSFT. The reduction in CSFT in patients with retinal edema may be due to the presence of intraretinal fluid. A baseline measured in the patient prior to initiation, i.e., prior to administration of the implant of the present invention. The implant of the present invention can be used to evaluate the efficacy and safety of a cohort of patients. In the present study, the CSFT was reduced and the reduced CSFT was maintained for a long period of time, or The ability to maintain quality is demonstrated in Examples 6.3 and 6.4. In accordance with the present invention, a treatment comprising 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 edema, the CSFT is considered to be at a certain given level. Qualitatively maintain or prevent a clinically significant increase in CSFT in patients, On the other hand, the subretinal or intraretinal fluid does not increase significantly (i.e., it is essentially maintained). This is also what is meant.

[0298] In certain embodiments, CSFT is present in a patient following administration of an implant of the present invention. 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 months The reduced level is maintained for a period of months or more. In some embodiments, CSFT is measured by measuring the patient's baseline CSFT prior to administration of the implant. The criteria were at least 6 months, at least 9 months, or at least In certain other embodiments, the reduction in retinal fluid volume and / or Reduction in CSFT or CSFT may reduce the need to administer rescue medication (e.g., injection of an anti-VEGF agent). or infrequent administration of rescue medication during treatment (e.g., 1, 2, or 3 times) The present invention provides a method for treating a patient with an implant of the present invention comprising administering the implant to a patient having a pulmonary circulation that is at least 4.5 times as long as the patient has a pulmonary circulation that is at least 3 times as long as the patient has a pulmonary circulation that is at least 4.5 ... 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, Thus, in this embodiment, the implant according to the invention During treatment with rituximab, patients may not require 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., Afliberce The drug is administered intravitreally in the form of a suspension or solution. In certain specific embodiments, the rescue medication is afliberce. The dose of 2 mg of acetaminophen is administered by intravitreal injection. Therefore, according to another embodiment of the invention disclosed herein, an anti-VEG Concurrent (i.e., scheduled) administration of F medication does not qualify as a “rescue medication.” In further particular embodiments, the administration of an implant according to the present invention reduces Fluid and / or CSFT levels are increased without (or at low frequency of) rescue medication. The duration of treatment that is maintained or essentially maintained (with only rescue medication) is In certain embodiments, the present invention provides a method for treating a patient with a pulmonary syndrome. Patients treated with dental implants should be advised to use steroids (e.g., dexamethasone) during the treatment period. Concomitant administration of bronchodilators (or prednisolone drops) is not required.

[0300] In another embodiment, a treatment according to the invention comprising administration of an implant according to the 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, vision as represented by best corrected visual acuity (also referred to herein as "BCVA"). In certain embodiments, the force of the present invention is not reduced or is not significantly reduced. Treatment according to the invention, including administration of an implant according to the invention, can result in improved vascularity (e.g., as indicated by BCVA). (If the patient's vision 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 relates to a method for treating conditions in which vision is impaired (e.g., associated with neovascularization). The study provides a method to improve vision in patients with impaired vision due to retinal fluid produced by ocular disease. The method includes administering to a patient, for example by intravitreal injection, an implant according to the invention. 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 or at least 20 characters. can be.

[0302] In certain embodiments, a TKI (e.g., axinib) is administered once during the treatment period. The total dose per eye of 100 mg / kg (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 100 mg / kg / day administered per eye during the treatment period is The dose is, for example, contained in two implants, where each implant contains, for example, about 200 The dose of axitinib is 1 μg (total dose of about 400 μg). In embodiments, the dose administered per eye during the treatment period is, for example, 3 in. plant, where each implant contains, for example, a dose of about 200 μg of axitinib. (which would result in a total dose of about 600 μg). In this study, the dose of axitinib administered to one eye was approximately 600 μg. Included in implants.

[0303] Implants according to the invention can be used to treat ocular disorders, such as retinal disorders (including AMD). In the course of the procedure, it is generally desirable to inject the drug into the patient's eye (e.g., into the vitreous humor). The injection method is easy to administer and reduces the risk 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. The therapeutically effective dose (i.e., for a particular patient type and condition) of the TKI is delivered into the small implant. The present invention provides an implant having a dosage 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 particular patient). It advantageously combines the advantages of a consistent therapeutically effective dose with the advantages of a relatively small implant size. 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 in which the drug is connected to a pre-loaded needle. or connected to a needle preloaded with an implant as disclosed herein. The drug may be administered by a separate injection device (e.g., a (modified) Hamilton syringe) suitable for administering the drug. In another embodiment, the compound according to US 8,808,225 (hereby incorporated by reference) may be administered. As disclosed in the above, 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 disclosed hereinabove. 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 study 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 may 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. A needle with a gauge of 22-23, e.g., a 25-gauge or 27-gauge needle, or a smaller gauge 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 an embodiment, 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 invention as described above. Implants containing 200 μg and 600 μg are shown in Tables 21.1 and 21.2, respectively. To show explicitly.

[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 portion of the vitreous humor. In an embodiment, the implant is delivered by hollow microneedles, e.g., US8, 808,225, which is incorporated herein by reference. It is administered intrasclera into the eye at the site of entry 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. In accordance with one embodiment of the present invention, a "treatment period" refers to a period 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" means that the material is substantially or partially maintained. Therapeutic strategies to reduce or essentially maintain CSFT over an extended period of time, referred to as the "treatment period," are In certain embodiments, to maintain a therapeutic effect that prevents a clinically significant increase in Only a single injection (of the implant of the present invention) is required. This is advantageous over more frequent dosing. This represents a major 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 and / or frequency of administering rescue medication during the treatment period is very low. In certain embodiments, the treatment period (e.g., from about 6 months to about 9 months after administration of the implant) In certain other embodiments, no rescue medication is required during the treatment period. Rescue medications will only be needed infrequently (e.g., 1, 2, or 3 times) during this period The patient's visual acuity may be, for example, increased by BCVA (e.g., For example, the ETDRS character count is at least 10 characters, at least 15 characters, or at least 2 0 character increase).

[0309] In one particular embodiment, the present invention provides a method for treating neovascular age-related macular degeneration, comprising: The present invention relates to a method for administering to a patient in need thereof a polymer network. A hydrogel containing the workpiece and a sustained release biosensor containing about 200 μg of a tyrosine kinase inhibitor. This involves administering a degradable intraocular implant, with one implant per eye Both were administered once over a 9-month treatment period, and patients had a history of anti-VEGF therapy. In embodiments, the treatment includes reducing the central area as measured by optical coherence tomography during the treatment period. This results in a reduction in focal retinal thickness (CSFT) or at least a preservation of CSFT. In certain embodiments, the TKI can further be axitinib, wherein axitinib is kPEG-SAZ to 8a20kPEG-NH 2 A poly(ethylene glycol) compound was formed by reacting The implant is dispersed within a hydrogel comprising a mer network, where the implant is dried prior to administration. In this embodiment, the hydrogel is in a state in which it is formed and dried. Add approximately 7.5% polyethylene glycol (weight of polyethylene glycol divided by weight of fluid) before Alternatively, the patient may be treated with 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 present invention relates to a method for administering to a patient in need thereof a polymer network. and a sustained release biodegradable composition comprising about 200 μg of a tyrosine kinase inhibitor. 2 per eye forming a total dose of about 400 μg, including administering an intraocular implant One implant at least once during a treatment period of at least 3 months or at least 9 months and 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 was a reduction (or less) in central space retinal thickness (CSFT) as measured by optical coherence tomography. In this embodiment, the TKI is further axitinib. Axitinib can be synthesized by converting 4a20kPEG-SAZ to 8a20kPEG-NH 2 and The polymer network formed by reacting the polymers is dispersed in a hydrogel. In this embodiment, the implant is in a dried state prior to administration. The rogel, when formed and before drying, was dissolved in about 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 patient a The present invention is directed to a method for administering to a patient in need thereof a polymer network. A hydrogel containing a tyrosine kinase inhibitor and a sustained release biosynthetic composition containing about 200 μg of a tyrosine kinase inhibitor. The method includes administering a dissolving intraocular implant to each eye forming a total dose of about 600 μg. Three implants were placed within a treatment period of at least three months or at least nine months. The patient has a history of anti-VEGF therapy or has a history of anti-VEGF therapy. In this embodiment, the treatment is a treatment phase. During the study, 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 converting 4a20kPEG-SAZ to 8a20kPEG-NH Dispersed within the hydrogel containing the polymer network formed by reacting 2 wherein the implant is in a dry state prior to administration. The hydrogel, when formed and before drying, contained approximately 7.5% polyethylene glycol. (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 comprising administering to the patient a polymer network; Axitinib dispersed in a hydrogel containing the compound is within the range of about 480 μg to about 750 μg. and administering to the patient a sustained release biodegradable intraocular implant comprising: and administered once during a treatment period of at least three 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 within the range of about 480 μg to about 750 μg, or in an amount of about 560 μg to about 660 μg, or about 600 μg. The implants are made, for example, by means of 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 was at least 6 months, or at least 9 months, or at least 12 months, Or about 6 months to about 9 months.

[0313] In some embodiments, a sustained release biodegradable intraocular implant (including or a sustained release biodegradable intraocular infusion comprising 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 brodalumab. In certain embodiments, the anti-VEGF inhibitor may be selected from the group consisting of anti-VEGF inhibitors, ... and anti-VEGF inhibitors. In certain embodiments, the anti-VEGF agent is aflibercept. In certain embodiments, the anti-VEGF agent is administered intravitreously in a sustained release manner. Concurrently (as defined above) with 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 reasons related to the patient. For this reason, if the same session is not possible, consecutive administration in two or more different sessions ( For example, two implants administered 7 days apart can be applied alternatively. can still be considered "concurrent" administration in the context of the present invention.

[0314] In another embodiment, an anti-VEGF agent is used in combination with an implant of the present invention. However, not simultaneously (i.e., not simultaneously), during the treatment period of the implant of the present invention. In certain embodiments, the anti-V The EGF agent should be administered within about 1 month, 2 months, or 3 months after the administration of the implant. or more months, i.e., before or after implant. The combined (and planned) co-administration of anti-VEGF agents can be is distinct from a rescue drug as defined herein.

[0315] In certain embodiments of the invention, the patient has primary subfoveal glaucoma secondary to AMD (e.g., 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. Have a previously treated diagnosis of subfoveal neovascularization (SFNV) secondary to type 2 AMD. In these patients, prior treatment was with an anti-VEGF agent.

[0317] In some embodiments, the patient is at least 50 years old 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 liquid.

[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-associated leukemia and 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 a treatment period as defined above) to prevent or reduce prior anti-VEGF therapy. 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 systemic concentration of TKIs is minimal. This also 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 in addition. This is particularly effective for

[0320] Once injected, the (hydrogel and drug) of certain embodiments of the present invention The implant, as disclosed above, may be used for an extended period of time, for example, within about 9 to 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 degrades. This allows the patient to maintain a TKI delivery rate sufficient for therapeutic effect (i.e., inhibition of vascular leakage). Figure 15 shows the absorption and infusion of the hydrogel in one patient up to 11 months after administration. The figure shows an example of axitinib particles remaining at the site 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, no 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 comparison of the results of the clinical trials whose results are presented (to the extent available) 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 focuses on ocular diseases involving 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 The present invention provides a method for treating a subject with a sustained release biodegradable ophthalmic solution comprising the tyrosine kinase inhibitor of the present invention disclosed herein. In certain embodiments, the method comprises administering an intraocular implant to a patient 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 period of reduced central retinal thickness for at least 15 months or more (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 one embodiment, the present invention relates to a method for treating a patient suffering from reduced vision (e.g., caused by an ocular disease involving neovascularization). The present invention is also directed to a method of improving vision in a patient with retinal fluid in the eyes, the method comprising administering to the patient an injection of the retina in accordance with 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 implants. 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. A sustained release biodegradable intraocular implant as described in 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 claim 7. 9. The sustained release formulation of claim 8, comprising the tyrosine kinase inhibitor in an amount of about 400 μg. Biodegradable intraocular implants. 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 as described in claim 0. 12. The sustained release formulation according to item 11, comprising the tyrosine kinase inhibitor in an amount of about 600 μg. A rapidly evolving 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. 2. A sustained release biodegradable intraocular implant as described in claim 1. 15. The sustained release formulation according to item 14, comprising the tyrosine kinase inhibitor in an amount of about 800 μg. A rapidly evolving biodegradable intraocular implant. 16. The method according to any one of the preceding claims, 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 interface 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. A rapidly evolving biodegradable intraocular implant. 20. The implant is in a dry state prior to administration and once administered into the eye 4. The sustained release biodegradable intraocular implant of any of the preceding claims, wherein the sustained release biodegradable intraocular implant is hydrated with 21. The hydrogel is made of polyethylene glycol, polyethylene oxide, polypropylene Polyvinyl oxide, polyvinyl alcohol, poly(vinylpyrrolidinone), polylactic acid, polymilk Glycolic acid-co-glycolic acid, random or block copolymers of any of these, or may be one or more units of a combination or mixture of polyamino acids, glycosaminoglycans, , polysaccharide, or protein units. Item 14. A sustained release biodegradable intraocular implant according to any one of items 1 to 3. 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 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, comprising a polyethylene glycol unit 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 drug unit. 30. The multi-arm polymer unit is one or more 4-8 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 4-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 reacting an electrophilic group-containing multi-arm polymer precursor with a nucleophilic group. 21 to 32, which are formed by reacting a multi-arm polymer precursor containing 2. The sustained release biodegradable intraocular implant according to claim 1 . 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 implants. 36. The method according to claim 35, wherein the electrophilic group is an N-hydroxysuccinimidyl (NHS) group. A sustained release biodegradable intraocular implant as described. 37. The method according to claim 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 . 39. The polymer network is 4a20kPEG-SAZ and 8a20kPEG- NH 2 Item 38. The support according to item 38, which is obtained by reacting Sustained release biodegradable intraocular implant. 40. The implant, when dried, contains about 25% to about 75% by weight of tyrosine. 39. The composition according to any one of claims 1 to 39, comprising a kinase inhibitor and about 20% by weight to about 60% by weight of a polymer unit. 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: Sustained release biodegradable intraocular implant. 43. The implant comprises one or more phosphates, borates, or carbonates. 4. The sustained release biodegradable intraocular implant of any of the preceding claims. 44. The implant is produced 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 (polyethylene glycol). weight of polyethylene glycol ÷ fluid weight × 100) The sustained release biodegradable intraocular implant described above. 46. ​​The hydrogel is made of about 7.5% to about 15% polyethylene glycol (polyethylene The sustained release bioavailable composition according to item 45, which contains the product (weight of glycol ÷ weight of fluid × 100) Dissolvable intraocular implants. 47. The method of the preceding paragraph, 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 method of claim 1, wherein the implant is administered to the eye by a needle. Releasable biodegradable intraocular implant. 51. The sustained release biocide according to item 50, wherein the needle is a 25 gauge or 27 gauge needle. Degradable intraocular implants. 52. When hydrated in vivo or in vitro in the eye, the implant or the diameter of the implant increases and the length of the implant increases. 4. The sustained release biodegradable intraocular implant of any of the preceding items, 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 intraocular pressure is measured at 1000 psi. 54. The implant is biodegraded 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 is biodegraded 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 is biodegraded 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 The sustained release method according to any one of items 2 to 56, wherein the sustained release method is carried out 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. Inner 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. Inner implant. 60. Axitinib is administered from about 0.1 μg / day to about 10 μg / day from the implant after administration. 60. The sustained release biodegradable intraocular composition 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 rate of 100 mg / kg. 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 a tyrosine kinase inhibitor particle contained in the implant. 63. The method according to any one of items 17 to 62, which is biodegradable 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 The composition according to any one of items 17 to 63, wherein the composition is released before the composition is completely decomposed in the vitreous humor. The sustained release biodegradable intraocular implant described above. 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. 4. The sustained release biodegradable intraocular implant of any of the preceding items, which 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. The fiber is 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 about 250 μg of axitinib dispersed in a hydrogel, or A sustained-release biodegradable intraocular implant containing about 180 μg to about 220 μg, or about 200 μg. The hydrogel is a polymeric nanoparticle comprising polyethylene glycol units. said sustained release network, said implant being in a dry state prior to administration. Biodegradable intraocular implants. 69. The polymer network is 4a20kPEG-SAZ to 8a20kPEG-N H 2 69. The sustained release biodegradable intraocular implant according to claim 68, which is formed by reacting Plant. 70. The hydrogel, when formed and before drying, is mixed with 7.5% polyethylene. Glycol (equivalent to polyethylene glycol weight ÷ fluid weight × 100), item 69 2. A sustained release biodegradable intraocular implant as described in claim 1. 71. The implant, in a dried state, has about 45% to about 55% by weight of axillin. Item 68 - nib and about 37% by weight to about 47% by weight of polyethylene glycol units 71. A sustained release biodegradable intraocular implant according to any one of claims 70 to 70. 72. The implant according to any one of claims 68 to 70, wherein the implant contains about 1% by weight or less of water in a dried state. 72. A sustained release biodegradable intraocular implant according to any one of 71. 73. The polymer network is 4a20kPEG-SAZ to 8a20kPEG-N H2 in a weight ratio of about 2:1 or less. 2. The sustained release biodegradable intraocular implant according to claim 1 . 74. The implant is in vitro immunized 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. 68 to 73. A sustained release biodegradable intraocular implant according to any one of claims 68 to 73. 75. The implant is placed in a 25:75 ethanol / water mixture (v / v) at 37°C. In the third day, the amount of axitinib was about 35% to about 45% and in the seventh day, the amount of axitinib was about 65% to about 50%. % to about 75%, 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 in a phosphate buffered diet with an octanol overlay at 37°C, pH 7.2. In saline, about 25% to about 35% of the axitinib at 2 months and about 25% to about 35% of the axitinib 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 Items 68-75 release approximately 90%-100% of axitinib in vitro. 2. The sustained release biodegradable intraocular implant according to claim 1 . 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. 8. The sustained release biodegradable intraocular implant according to any one of claims 8 to 76. 78. When hydrated in vivo or in vitro in the eye, the length decreases and the diameter The in vitro hydration was increased by 24 h in phosphate buffered saline at 37°C and pH 7.2. 78. The sustained release biodegradable intraocular implant according to item 77, measured after 24 hours. 79. The implant has an average length of about 6.5 to about 8 mm in its hydrated state 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. Releasable biodegradable intraocular implant. 82. The method according to item 81, wherein the fiber is dry stretched by a factor of about 3 to about 4.5 after drying. Sustained release biodegradable intraocular implants. 83. The implant is dried and fitted with a 25 gauge tube for injection into the vitreous humor. 83. The method 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. Releasable biodegradable intraocular implant. 84. Axitinib dispersed in a hydrogel is administered 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 average molecular weights in the range of 1000 tonnes 88. The sustained release biodegradable intraocular implant according to any one of items 84 to 87, comprising a glycerol unit. to. 89. The polyethylene glycol unit according to item 88, wherein the polyethylene glycol unit comprises a 4a20kPEG unit. Sustained release biodegradable intraocular implant. 90. The polymer network is 4a20kPEG-SAZ to 8a20kPEG-N H 2 89. The sustained release biodegradable intraocular implant according to claim 89, which is formed by reacting Plant. 91.4a20kPEG-SAZ vs. 8a20kPEG-NH 2 The weight ratio is about 2:1 or less. Item 91. The sustained release biodegradable intraocular implant according to Item 90. 92. The implant, when dried, has about 45% to about 55% by weight of axillin. Item 84 - nib and about 37% by weight 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 any one of claims 84 to 9, 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 claims 92 to 92. 94. The implant has an average length of about 7 mm to about 12 mm in its dried state. and 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 claims 3 to 4. 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 implants. 96. The method according to any one of items 84 to 95, wherein the implant is for administration to the vitreous humor. Sustained release biodegradable intraocular implant. 97. Hydration in vivo or in vitro in the eye increases the diameter, 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 of about 9 mm to about 12 mm in its hydrated state 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 to about 0.8 mm in its hydrated state. 99. The sustained release biodegradable composition according to claim 98, having an average length of about 9 mm or less or about 9 mm or less. Sexual intraocular implants. 100. The implant comprises 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 patch 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 the experiment, 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 about 85%, and in 6 days, about 75% to about 90% of the axitinib 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 the experiment, the amount of axitinib was about 45% to about 55% in 2 days and about 7% in 4 days. In vitro release of 0% to about 80% of the axitinib in 6 days and about 80% to about 90% of the axitinib 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 a fiber. 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 described above. 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 implants. 106. The fiber is wet stretched by a factor of about 1.5 to about 3.5 before drying. 2. A sustained release biodegradable intraocular implant as described in 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 described above. 108. The implant is loaded in a dry 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, 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 claims 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 prior to The implant is dimensionally stable when in a dry state at or below room temperature, 11. The sustained release biodegradable intraocular implant according to any one of claims 10 to 11. 112. A method for treating an ocular disease in a patient in need thereof, comprising administering to said patient a hydrogen peroxide solution. A sustained release biodegradable ophthalmic solution comprising a tyrosine kinase inhibitor according to any one of the preceding claims. administering to said patient an intravenous implant, The dose per eye administered once is about 150 μg to about 1200 μg of the tyrosine kinase. The method according to any one of claims 1 to 4, wherein the compound is an enzyme inhibitor. 113. The method of claim 112, wherein the tyrosine kinase inhibitor is axitinib. 114. The dose per eye administered once during the treatment period is about 200 μg to about 114. The method according to claim 112 or 113, wherein the amount of the active ingredient 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 claim 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 claim 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 claim 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 according to claim 112 or 113, wherein the range of 122. The method of claim 121, wherein the dose is about 800 μg. 123. The method according to any of items 112 to 122, wherein the ocular disease is accompanied by neovascularization. 124. The ocular disease is characterized by the expression of one or more receptor tyrosine kinases (RTKs), specifically 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 acute multifocal spotted pigment epitheliopathy, Behcet's disease, Bard's disease, Shott's retinochoroidopathy, infectious (syphilis, Lyme disease, tuberculosis, toxoplasmosis), intermediate bud Uveitis (pars planitis), multifocal choroiditis, multiple evanescent 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, pigmented streaks, and familial exudative vitreoretinopathy or the eye disease is due to trauma or surgery (sympathetic ophthalmia, Uveitic retinal disease, retinal detachment, trauma, photodynamic laser therapy, photocoagulation, intraoperative hypoperfusion, radiation retinopathy, or bone marrow transplant retinopathy), or the above-mentioned eye 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 The method according to any one of items 112 to 124, wherein the obstruction is a chronic obstructive disease. 127. The method according to item 126, wherein the disease is neovascular age-related macular degeneration. 128. The effect of the treatment on patients with high 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 items 112 to 127, which is effective. 129. The dose per eye administered 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 according to any one of claims 112 to 112, wherein the implant is administered by injection into the vitreous humor. 29. A method according to any one of claims 29 to 30. 131. The treatment period is at least about 3 months, at least about 4.5 months, at least about 6 months, at least about 9 months, at least about 11 months, at least about 12 months, at least 13 months or at least 14 months, Method of posting. 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 said treatment with said sustained release intraocular implant, an anti-VEGF agent or an anti-VEGF agent is administered to said patient within about 1 hour from said administration of said implant. 133. The method according to any one of items 112 to 132, wherein the method is administered within about 2, or about 3 months. . 134. The anti-VEGF agent is aflibercept, bevacizumab, pegaptanib, ranibizumab, 134. The method of claim 133, wherein the anti-inflammatory agent 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. Any of the methods described above. 137. Item 1, wherein the patient receiving the implant has a history of anti-VEGF treatment. A method according to any one of 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 mouse is 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 comprising a synthase kinase inhibitor; One implant per eye is administered once over a treatment period of at least nine 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 comprising a synthase kinase inhibitor; Two implants per eye forming a total dose of approximately 400 μg were administered for at least 3 months of therapy. The therapeutic agent is administered once during a treatment period, and the patient may or may not have a history of anti-VEGF treatment. , the method. 141. The treatment comprises: a central area retinal defect measured by optical coherence tomography during the treatment period; 141. The method according to item 139 or 140, which results in a reduction in thickness (CSFT). 142. The tyrosine kinase inhibitor is axitinib, The agent is 4a20kPEG-SAZ and 8a20kPEG-NH 2 By reacting with Dispersed within the hydrogel containing 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 prior to administration. 143. The hydrogel, when formed and before drying, is dissolved in about 7.5% polyethylene. Items including polyethylene glycol (equivalent to polyethylene glycol weight ÷ fluid weight × 100) 142. The method according to claim 142. 144. The method according to any one of items 140 to 143, wherein the treatment period is at least 9 months. How to. 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 that includes a polymer network. A sustained release biodegradable intraocular implant containing nibs in an amount ranging from about 480 μg to about 750 μg. wherein the implant is administered for at least 3 months of treatment. 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 146. The method according to item 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 according to any one of 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 at least 149. The method according to any 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. 152. The patient receiving the implant has a history of anti-VEGF treatment, and have no history of anti-VEGF treatment (are anti-VEGF naive), items 145 to 151 2. The method according to claim 1 , 153. The anti-VEGF agent is administered to the patient contemporaneously with the implant. The method according to any one of items 145 to 152. 154. The anti-VEGF agent is aflibercept, bevacizumab, pegaptanib, ranibizumab, 154. The method of claim 153, wherein the anti-inflammatory agent 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. Any of the methods described above. 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 according to item 157, wherein the number of cases is small. 159. The 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 polymeric polymer dispersed within the hydrogel. forming said hydrogel comprising tyrosine kinase inhibitor particles having a hydrogel structure; 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 granules are dispersed throughout the matrix. 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 copolymer is formed by crosslinking aryl units. . 163. The hydrogel is electrophilically reacted in a buffer solution in the presence of the tyrosine kinase inhibitor. Multi-arm polyethylene glycol containing nucleophilic groups and multi-arm polyethylene glycol containing nucleophilic groups A polymer formed by mixing and reacting with lycohol and gelling the mixture. The method according to any one of items 159 to 162, comprising a network. 164.4a20kPEG-SAZ to 8a20kPEG-NH 2 and about 2:1 by weight. Item 164. The method according to item 163, comprising reacting 165. The method further comprises: mixing the mixture to provide a desired final shape of the hydrogel. filling a mold or tube with the mixture before it is completely gelled; and and drying the hydrogel. 4. The method according to claim 4. 166. The mixture is filled into a fine diameter tube to prepare a hydrogel fiber. 166. 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 inside of the tube has a geometric shape other than a circle. Law. 169. The method according to item 168, wherein the interior of the tube has a cross-shaped geometric shape. . 170. The method further comprises 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 stretched with a stretch 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 172. The method according to 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 172. The method according to item 171, wherein 175. The method further comprises 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 claim 175, wherein the needle is a 25 gauge or 27 gauge needle. 177. A method for imparting shape memory to a hydrogel fiber, comprising: The hydrogel fiber includes an active agent dispersed within the hydrogel, and the hydrogel fiber is stretched in the longitudinal direction. The method according to claim 1, wherein the shape memory is imparted by 178. A device that contains a hydrogel with an active agent dispersed therein and that changes dimensions upon administration to the eye. 13. 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 drying the hydrogel, and the fiber is dried. 177 or 178, which are stretched in the longitudinal direction (wet or dry stretching) before or after The method described above. 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 3 177 to 179, which are stretched by a factor of about 4.5 or by a factor of about 1 to about 2. Any method as described above. 181. 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. The method according to any one of items 177 to 181, comprising a network. 183. The fiber, upon hydration, retains approximately its original length it had before stretching and / or 183. The method according to any of items 177 to 182, wherein the diameter is fully or partially restored to its original diameter. 184. The dimensional change is an increase in diameter or an increase in diameter accompanied by a decrease in length. The method according to any one of Items 177 to 183. 185. A kit comprising the composition 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. A method for producing a plant comprising the steps of: (a) growing a plant; and (b) growing one or more needles, the method comprising the steps of: Each of the 1000-mL ocular implants was preloaded in a dry state with one sustained release biodegradable intraocular implant. The kit. 186. Item 1, wherein the needle(s) is / are a 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 is implanted with an amount of axitinib in the range of 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, containing one 25-gauge or 27-gauge needle loaded with an implant 186. 190. The method according to item 189, wherein the implant contains axitinib in an amount of about 600 μg. Kit included. 191. The method of claim 1, further comprising an injection device for injecting the implant into the patient's eye. 185 to 190. The 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. The injection device is pre-connected to a needle loaded with an implant. 191. The kit according to claim 191. 194. The injection device includes a pusher for placing the implant in the eye from an injection needle. 193. The kit according to item 191 or 192, comprising Schweyer. 195. The method according to any one of items 185 to 194, further comprising administering a ready-to-inject one-dose 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 is administered intraocularly. 2. An injection device suitable for injecting into 197. The injection device according to item 196, comprising a 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 injector is injected from the needle into the eye. Includes a push wire for positioning the plant, and is described in any of items 196 to 198. The injection device. 200. The push wire is made of Nitinol or stainless steel / Teflon. 200. The injection device according to item 199, 201. Affix the wire to the plunger and attach it to two snap-fit ​​syringes. and fastening said plunger with a clip between said body parts. An injection device according to item 199 or 200. 202. A pharmaceutical product, comprising a sustained release drug according to any one of items 1 to 111, which is 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 who needs treatment for an ocular disease described in any one of items 112 to 138, The treatment of an eye disease, or any one of items 139 to 158, 210, or 211. The method for treating neovascular age-related macular degeneration in a patient in need of the treatment according to the present invention 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 comprising an enzyme inhibitor. 204. A method for treating an ophthalmic disease according to any one of items 112 to 138, comprising administering to a patient in need thereof or any of items 139 to 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 medicine comprising administering to said patient a tyrosine kinase inhibitor according to any one of items 1 to 111. Use of sustained release biodegradable intraocular implants. 205. In patients with increased central retinal thickness due to neovascular ocular disease, Reduces clinically significant increases in central retinal thickness as measured by optical coherence tomography, essentially A method for maintaining or preventing the occurrence of a pulmonary embolism, comprising administering to the patient a chemotherapy drug according to any one of items 1 to 111. and administering a sustained release biodegradable intraocular implant containing a rosine 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 prior to administration of the implant. a patient's baseline central retinal thickness for 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 for at least about 2 months, at least about 13 months, or at least about 14 months Item 20. The method of claim 20, wherein the central area retinal thickness is maintained at or a clinically significant increase in the central area retinal thickness is prevented. 5 or 206. 208. A method according to any one of items 205 to 207, 210, or 211, in which angiogenesis is involved. In patients with ocular disease-related elevated central retinal thickness, measured by optical coherence tomography Reduce, essentially maintain, or prevent a clinically significant increase 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 method according to any one of items 205 to 207, 210, or 211, in which angiogenesis is involved. In patients with ocular disease-related elevated central retinal thickness, measured by optical coherence tomography To reduce, essentially maintain, or prevent a clinically significant increase in central retinal thickness in A tyrosine kinase inhibitor according to any one of items 1 to 111, in the preparation of a pharmaceutical for 23. Use of a sustained release biodegradable intraocular implant comprising: 210. The patient's visual acuity, as measured by best corrected visual acuity, is not decreased or is 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 only need to be administered 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 Method of posting. 212. The duration of the treatment period is Item 212. The method according to item 211, wherein the period is from 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 The method of claim 213, wherein the obstruction is 215. The patient's vision is reduced by the presence of retinal fluid, item 213 or item 21 4. The method according to claim 4. 216. The improvement in visual acuity is manifested by an increase in best corrected visual acuity, 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, comprising the method 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 A sustained release biodegradable intraocular implant comprising the tyrosine kinase inhibitor according to any one of claims 1 to 5. to. 219. A method for treating an ocular disease associated with neovascularization, comprising the 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 A sustained release biodegradable intraocular implant comprising the tyrosine kinase inhibitor according to any one of claims 1 to 5. Use of. Second List of Items 1. A compound that contains a tyrosine kinase inhibitor, a polymer network, and a clearance zone. A sustained release biodegradable intraocular hydrogel implant, the clearance zone being The sustained release biodegradable intraocular hydrogel implant is free of the TKI prior to release of the KI. Runt. 2. When the TKI is contained within the hydrogel implant, the TKI 2. The intraocular hydrogel of item 1, which is not in contact with membrane cells. 3. The TKI is present within the hydrogel implant at or near its saturation level. 3. The intraocular hydrogel according to item 1 or 2. 4. The size of the clearance zone increases as a function of the amount of TKI released, items 1 to 3 13. An intraocular hydrogel implant according to any one of claims 1 to 12. 5. The intraocular hydrogel implant is administered after the TKI has been released or after the TKI has been administered. is 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 after about 3 months. Ruimplant. 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. 13. An intraocular hydrogel implant according to any one of claims 1 to 12. 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] (In the formula, n represents a repeating unit of ethylene oxide, and the wavy lines represent the repeating units of the polymer network. PEG units having a PEG-2 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, k-PEG-NH 2 , 8a20k PEG-NH 2 and trilysine, or a salt thereof By reacting with 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 mixture of 4a20k PEG-SAZ and 8a20k PEG -NH 2 13. The eye according to any one of items 1 to 12, which is formed by reacting Intracellular hydrogel implant. 14. Any of items 1 to 13, wherein the polymer network is amorphous (under aqueous conditions). 13. An intraocular hydrogel implant according to any one of claims 1 to 12. 15. Any of items 1 to 14, wherein the polymer network is semi-crystalline in the absence of water. 10. An intraocular hydrogel implant according to any one of claims 1 to 9. 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. The 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. 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. 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. 13. An intraocular hydrogel implant according to any one of claims 1 to 12. 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 polymerized microparticles. nt. 25. The tyrosine kinase inhibitor is abemaciclib, acalabrutinib, afatinib alectinib, axitinib, balictinib, binimetinib, brigatinib, cabozantinib ceritinib, cobratinib, crizotinib, dabrafenib, dacomitinib , dasatinib, encalafenib, erlotinib, everolimus, fostamatinib, gefitinib Fitinib, Gilteritinib, Gilteritinib, Ibrutinib, Imatinib, Larotrek tinib, lenvatinib, lorlatinib, axitinib, idelalisib, lenvatinib, mitomycin 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 10. An intraocular hydrogel implant according to any one of claims 1 to 9. 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 lacrimal punctum of the eye, An intraocular hydrogel implant as described. 28. A method of treating an ocular condition in a subject in need thereof, comprising: The subject is 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, Behcet's disease, Birdshot chorioretinopathy, Intermediate uveitis, Multifocal venous ulcers Ocular ocular inflammation, Multiple evanescent white dot syndrome (MEWDS), Ocular sarcoidosis, Posterior meningitis, Serpentine Choroiditis, Subretinal fibrosis and uveitis syndrome, Vogt-Koyanagi-Harada syndrome, Tuberosity, parafoveal telangiectasia, papillary vasculitis, frosty branch vasculitis, sickle cell retinopathy, retina 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 break, solid tumor, posterior uveal melanoma, choroidal hemangioma, choroidal bone retinoblastoma, choroidal metastasis, retinoblastoma, fundus angioproliferative tumor, retinal astrocytoma, and intraocular lymphoma 30. The method according to item 28 or 29, wherein the tumor is selected from the group consisting of hepatic and peripheral tumours. 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. EXAMPLES

[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 illustrative only and that It should be understood that these and other terms should not be construed as limiting the invention in any manner whatsoever.

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

[0326] 4a20K PEG-SAZ (with N-hydroxysuccinimidyl reactive end groups) 20 kDa PEG with 4 arms (sometimes referred to as "NHS" end groups) , 8a20K PEG NH2 (20 kDa P with 8 arms having amine end groups) The polymer network of the implant was formed by reacting with 1 part of EG. Therefore, the polyurethane tube was cut into small pieces of appropriate length. PEG-NH2 dibasic sodium phosphate solution was prepared and sterile filtered to obtain the endotoxin. Toxins and particles larger than 0.2 μm (pore size of the filter) were removed. 100 ml of PEG amine solution was weighed into a syringe. The desired amount of PEG amine solution was then added to the implant. Weigh out the corresponding amount of solid axitinib into a separate syringe according to the final axitinib dose. The syringe of powdered axitinib and the syringe of PEG amine were carefully mixed to disperse 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. The desired PEG-amine solution was then added and sterile filtered as described for the PEG-amine solution. A quantity of PEG SAZ solution was weighed into a separate syringe. The components of the rinse (4a20K PEG SAZ monobasic sodium phosphate solution and axyti 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 h to allow for early drying before gelation of the hydrogel. In the chamber, the hydrogel axitinib suspension in the tube was crosslinked. This completes the creation of a highly reacted homogenous 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 mm. After drying for 96 hours, the dried strand segments were removed from the tubes and The strand was then placed in the clamps of a stamstretcher. The material 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 create a small The desired diameter was achieved to fit a needle of suitable gauge (stretch factor of about 1 to about 3, or about 1.3 to about 2.5). After stretching, the strands are stretched under conditions as described for the dry stretching process. , and dried under tension.

[0328] This stretching creates a shape memory, meaning that the implant stays in the vitreous cavity of the eye. Upon hydration when administered into the bloodstream, the length rapidly shrinks until it approaches its 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 increases the diameter and shortens the length after administration. In the posterior chamber of the eye, the implant shortens (or in certain embodiments, lengthens) relative to the diameter of the eye. (thickness not much more than approximately 10 mm) to minimize the possibility of contact with surrounding ocular tissue. Generally, the amount of shrinkage 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, for example, when stretched with a stretch factor of about 1.8 (wet stretching), This can lead to a significant shortening of the length during hydration. For example, Dry stretching) results in a much shorter length upon hydration (e.g., from a length of about 15 mm to about 8 mm).

[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 vacuum the 25 gauge or 27 gauge Gauge needle (e.g., FDA approved 25G UTW 1 / 2 inch with inner diameter of approximately 0.4 mm, or or 25G UTW 1 inch, or 27G TW 1.25 inch needles) and 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, a small droplet of hardened PEG (which provides lubrication) was formed on the needle tip. This retains the implant in place within the needle, allowing for successful placement and during administration. In addition, the PEG tip prevents premature rehydration of the implant within the needle. tissue damage, i.e. tissue coring (fragments of tissue being pulled by the needle as it passes through the tissue) The PEG-tipped needle is then reinserted into the needle, minimizing the process of removal. The needles were inspected and those that did not meet the quality requirements were discarded. The needles that passed were inspected and the needles were discarded. The needles were then individually placed in pouches and recapped to ensure that they were not contaminated. The injection device, e.g., a modified H Amilton glass syringes have a push function that makes implant placement from the needle easier The injection needle had a wire (e.g., a nitinol push wire) to control the depth of the injection. The injection device may include a stop function that controls the injection of the needle. can be individually packaged and sealed under nitrogen in foil pouches so that Alternatively, the implant may be preassembled with a loaded needle or in a preloaded syringe. It is contemplate...

Claims

1. 1. A sustained release biodegradable intraocular implant comprising a hydrogel and 160-750 μg of axitinib, The hydrogel comprises cross-linked polyethylene glycol (PEG) units, the cross-links between the PEG units being represented by the formula: 【Chemistry 1】 wherein m is 6; Axitinib particles are dispersed within the hydrogel; the implant is cylindrical and has a length of less than 17 mm and a diameter of 0.1 mm to 0.5 mm in its dry state; For treating diabetic retinopathy in a patient in need thereof, The sustained release biodegradable intraocular implant.

2. 10. The sustained release biodegradable intraocular implant of claim 1, comprising 375 μg to 600 μg of axitinib.

3. 3. The sustained release biodegradable intraocular implant of claim 1 or 2, wherein the implant is administered by intravitreal injection.

4. 4. The sustained release biodegradable intraocular implant of claim 1, wherein the implant has a length of 6 mm to 10 mm and a diameter of 0.2 mm to 0.5 mm in its dry state.

5. 5. The sustained release biodegradable intraocular implant according to any one of claims 1 to 4, wherein the implant is cylindrical and has a length of 6 to 10 mm and a diameter of 0.5 to 0.8 mm in its hydrated state (after 24 hours in phosphate buffered saline at 37°C, pH 7.2).

6. The sustained release biodegradable intraocular implant of any one of claims 1 to 5, wherein the implant comprises, in its dry state, 25% to 75% by weight of axitinib and 20% to 60% by weight of PEG units (dry composition).

7. The sustained release biodegradable intraocular implant according to any one of claims 1 to 6, wherein the hydrogel comprises multi-arm PEG units having the same or different number average molecular weights of 10,000 to 40,000 Daltons.

8. The sustained release biodegradable intraocular implant of any of claims 1 to 7, wherein the axitinib particles have a d90 particle size of less than 10 μm and / or a d50 particle size of less than 5 μm and / or a d10 particle size of less than 3 μm as determined by laser diffraction.

9. The sustained release biodegradable intraocular implant according to any one of claims 3 to 8, wherein the hydrogel biodegrades in the vitreous humor within 4 to 15 months after administration.

10. 10. The sustained release biodegradable intraocular implant according to any one of claims 3 to 9, wherein the treatment period with the implant is at least 3 months, or at least 6 months, or at least 9 months, or at least 12 months.

11. The sustained release biodegradable intraocular implant according to any one of claims 3 to 10, wherein the treatment period is 6 to 12 months.

12. 12. The sustained release biodegradable intraocular implant of any of claims 3-11, wherein axitinib is released from the implant into the vitreous humor at an average rate of 0.5 μg / day to 2 μg / day over the treatment period.

13. The sustained release biodegradable intraocular implant of any of claims 1 to 12, wherein the treatment is effective to prevent, inhibit, or inhibit vascular leakage.

14. The sustained release biodegradable intraocular implant of any of claims 1 to 13, wherein the treatment is effective to improve the patient's visual acuity as represented by best corrected visual acuity (BCVA).

15. 15. The sustained release biodegradable intraocular implant of claim 14, wherein the BCVA increases by at least 10 ETDRS letters during the treatment period.

16. The sustained release biodegradable intraocular implant of any of claims 3 to 15, wherein the implant is injected through a needle with a gauge size of 22 to 30.

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