Ophthalmic sustained release implant

Abstract

The present disclosure relates to the field of ocular implants suitable for sustained release of drugs (e.g., water-soluble drugs), and the use of ocular implants for the treatment of ocular diseases, including glaucoma.

Description

background

[0001] Glaucoma is a group of eye diseases characterized by progressive visual field loss due to damage to the optic nerve. There are four main types of episodic glaucoma in adults, all of which lead to vision loss through the ultimate pathway of retinal ganglion cell (RGC) dysfunction and / or death.

[0002] Interestingly, each form of glaucoma may be associated with multiple, and sometimes different, risk factors, suggesting that multiple triggering mechanisms lead to RGC death. For three of the four subtypes of adult-onset glaucoma, elevated intraocular pressure (IOP) is the most important predictive risk factor for visual field loss after RGC death. Primary open-angle glaucoma (POAG) accounts for 90% of glaucoma cases worldwide and is a leading cause of irreversible blindness. The fourth subtype (normal-tension glaucoma) is not associated with high IOP, and the factors leading to RGC death are largely unknown. Lowering IOP has also been shown to delay visual loss in patients with normal-tension glaucoma.

[0003] A balanced state of intraocular pressure (IOP) is achieved by the equilibrium between aqueous humor (AH) produced by the ciliary body (CB) and its outflow via the conventional trabecular meshwork (TM) pathway and, to a lesser extent, through the non-traditional uveal-scleral pathway. However, in glaucoma, high IOP arises from an imbalance between AH inflow and outflow. Fortunately, IOP can be controlled medically; therefore, reducing IOP is a first-line treatment option for glaucoma.

[0004] Current standard treatment for episodic glaucoma in adults includes topical administration of IOP-lowering medications as eye drops. Unfortunately, this formulation has several drawbacks (e.g., rapid drainage of the drug from the ocular surface to the external eye or into the systemic circulation via the nasolacrimal duct, and very short contact time with the cornea), which may lead to poor absorption and low efficacy. Further administration may result in increased systemic side effects, decreased patient satisfaction, and poor patient adherence. Furthermore, glaucoma primarily affects the elderly, who may find it difficult to self-administer topical eye drops.

[0005] Using the current daily eye drops often leads to a resurgence of IOP before the next dose, resulting in harmful IOP fluctuations. For example, microemulsions containing pregabalin have been found to reduce IOP by more than 40% in Dutch Black Rabbits, but IOP levels returned to baseline approximately 33 hours after administration (Ibrahim MM, Maria DN, Mishra SR, Guragain D, Wang X, Jablonski MM. “Once Daily Pregabalin Eye Drops for Management of Glaucoma.” ACS Nano. 2019 Dec 24;13(12):13728-13744).

[0006] Therefore, there is a need for easily administered, long-acting formulations for the treatment of eye diseases, including glaucoma. summary

[0007] This disclosure relates to providing ocular implants for sustained release of drugs (e.g., water-soluble or water-insoluble drugs) and their use in the treatment of eye diseases. This disclosure also relates to methods for preparing the ocular implants described herein, and methods for treating eye diseases using the ocular implants described herein.

[0008] On the one hand, it provides ocular implants containing various nanofibers, among which: Nanofibers contain a drug (e.g., a water-soluble drug, such as pregabalin) and one or more bioresorbable polymers; Nanofibers provide sustained drug release from the implant; and The implant is suitable for implantation in the eyes of mammals.

[0009] On the other hand, eye implants containing a variety of nanoparticles are provided, wherein: Nanoparticles contain a drug (e.g., a water-soluble drug such as pregabalin) and one or more bioresorbable polymers; Nanoparticles provide sustained drug release from the implant; and The implant is suitable for implantation in the eyes of mammals.

[0010] On one hand, a method for manufacturing an ocular implant comprising multiple nanofibers is provided, the method comprising: A drug (e.g., a water-soluble drug such as pregabalin) and one or more bioresorbable polymers are dissolved in a solvent to provide a solution; Electrospinning the solution provides nanofiber sheets containing multiple nanofibers on the collector surface; Collect nanofiber sheets from the collector surface; and The nanofiber sheet was cut into multiple implants, each containing various nanofibers; among which... Nanofibers provide sustained release of drugs (e.g., water-soluble drugs such as pregabalin) from the implant; and The implant is suitable for implantation in the eyes of mammals.

[0011] On the other hand, a method for manufacturing an ocular implant comprising a variety of nanoparticles is provided, the method comprising: A drug (e.g., a water-soluble drug such as pregabalin) and one or more bioresorbable polymers are dissolved in a solvent to provide a solution; The solution is electrosprayed to provide a variety of nanoparticles (e.g., in the form of dry powder) on the surface of the collector; Collecting various nanoparticles from the collector surface, and Compressing at least a portion of multiple nanoparticles to form an implant; wherein Nanoparticles provide sustained drug release from the implant; and The implant is suitable for implantation in the eyes of mammals.

[0012] On the other hand, methods for treating eye diseases in subjects who require such treatment include placing the implant described herein into the subject's eye. Brief description of the attached figures

[0013] These and other features, aspects, and advantages of this disclosure will be better understood with reference to the following description and accompanying drawings, wherein: Figure 1 (Figures A and B) show scanning electron microscope (SEM) images of pregabalin nanoparticles (Figure A) and pregabalin nanofibers (Figure B).

[0014] Figure 2 The percentage of cumulative pregabalin (PRG) released from the PRG-PLA-PCL (pregabalin: DL-lactide-co-caprolactone) implant (loaded with 1 mg of drug) prepared according to Example 3 over 14 months is shown.

[0015] Figure 3 The percentage of pregabalin penetration within 5 h is shown for PRG-PLA-PCL nanofiber implants (PRG NF, circles) and PRG-Eudragit nanoparticle implants (PRG Np, squares) in an in vitro transscleral permeability study.

[0016] Figure 4 (Figures A and B) show the expansion test of the PRG NF implant (Figure A) and the PRG NP implant (Figure B) over 72 h.

[0017] Figure 5 The moisture absorption rates of PRG NF implants and PRG NP implants are shown. Detailed description 1. Definition

[0018] Those skilled in the art will understand that, in general, the terms used herein, and especially in the appended claims (e.g., the body of the appended claims), are typically used as “open-ended” terms (e.g., the term “comprising” should be interpreted as “including but not limited to,” the term “having” should be interpreted as “at least having,” the term “comprising” should be interpreted as “including but not limited to,” etc.). Those skilled in the art will further understand that if there is an intention to introduce a particular number of claim statements, such intention will be explicitly stated in the claims, and the absence of such a statement indicates that such intention does not exist. For example, to aid understanding, the appended claims may contain the use of introductory phrases such as “at least one” and “one or more” to introduce claim statements. However, the use of such phrases should not be construed as implying that a claim statement introduced by the indefinite article “a (a or an)” limits any particular claim containing such an introduced claim statement to an embodiment containing only one such statement, even if the same claim includes the introductory phrase “one or more” or “at least one”, and indefinite articles such as “a (a or an)” (e.g., “a (a and / or an)” should be interpreted as “at least one” or “one or more”); the same applies to the use of definite articles used to introduce claim statements. Furthermore, even if a specific number in an introduced claim statement is explicitly stated, those skilled in the art will recognize that such a statement should be understood to refer to at least the stated number (e.g., simply stating “two statements” without other modifications implies at least two statements, i.e., two or more statements). Furthermore, in cases similar to the convention of "at least one of A, B, and C," this structure generally assumes that a person skilled in the art would understand the convention (e.g., "a system having at least one of A, B, and C" will include, but is not limited to, systems having a single A, a single B, a single C, A and B together, A and C together, B and C together, and / or A, B, and C together, etc.). In cases similar to the convention of "at least one of A, B, and C," this structure generally assumes that a person skilled in the art would understand the convention (e.g., "a system having at least one of A, B, and C" will include, but is not limited to, systems having a single A, a single B, a single C, A and B together, A and C together, B and C together, and / or A, B, and C together, etc.). A person skilled in the art will further understand that any parallel words or phrases representing two or more different terms, whether in the specification, claims, or drawings, should be understood to presuppose the possibility of including one of the terms, any one of the two terms, or both terms. For example, the phrase “A or B” would be understood to include the possibility of “A” or “B” or “A and B”.

[0019] Furthermore, when the features or aspects of this disclosure are described in accordance with the Markush group, those skilled in the art will recognize that this disclosure is therefore also described in terms of any single member or subgroup of the Markush group.

[0020] As those skilled in the art will understand, for any and all purposes, particularly in providing a written description, all scopes disclosed herein also include any and all possible subscopes and combinations thereof. Any listed scope can be readily identified as sufficiently descriptive and capable of dividing the same scope into at least equal halves, thirds, quarters, fifths, tenths, etc. As a non-limiting example, each scope discussed herein can be readily decomposed into a lower third, a middle third, and an upper third, etc. Those skilled in the art will also understand that all language, such as “up to,” “at least,” “greater than,” “less than,” etc., includes the listed numbers and refers to a scope that can subsequently be decomposed into subscopes as described above. Finally, as those skilled in the art will understand, a scope includes each individual member. Thus, for example, a group having 1-3 items means a group having 1, 2, or 3 items. Similarly, a group having 1-5 items means a group having 1, 2, 3, 4, or 5 items, etc.

[0021] As used herein, "bioresorbable polymers" refers to polymers that are naturally biodegradable under typical eye conditions. In other words, bioresorbable polymers are eventually broken down and / or absorbed by the eye. Bioresorbable polymers and their degradation products are non-toxic and have no significant harmful or adverse effects on the recipient's eyes.

[0022] As used in this article, "eye" refers to all the anatomical tissues and structures that make up the eye, as well as all the anatomical tissues and structures directly surrounding the eye. The eye is a spherical structure with three walls: the outer sclera, the middle choroid, and the inner retina. The sclera consists of a tough fibrous coating that protects the inner layer. It is mostly white except for the transparent area at the front. The inner surface of the sclera and eyelids is covered by a transparent membrane called the conjunctiva. The space between the conjunctiva and sclera is called the subconjunctival space. The cornea is the transparent layer that forms the front of the eye, allowing light to enter. The choroid, located inside the sclera, contains many blood vessels and is transformed into the pigmented iris at the front of the eye.

[0023] The biconvex lens is located directly behind the pupil. The chamber behind the lens is filled with vitreous fluid (a gel-like substance). The anterior and posterior chambers are located between the cornea and iris, respectively, and are filled with aqueous humor.

[0024] At the back of the eye lies the light-sensitive retina. The cornea is an optically transparent tissue that transmits images to the back of the eye. It comprises avascular tissue, nourished and oxygenated by tears and aqueous humor, as well as by blood vessels lining the junction between the cornea and sclera. The cornea also provides a pathway for drugs to penetrate into the eye.

[0025] Other anatomical structures related to the eye include the tear drainage system, which comprises a secretory system, a distribution system, and an excretory system. The secretory system includes secretory organs stimulated by blinking and temperature changes caused by tear evaporation, and reflex secretory organs supplied by efferent parasympathetic nerves and secreting tears in response to physical or emotional stimuli. The distribution system includes the eyelids and the tear film at the eyelid margins of the open eye, which spreads tears evenly across the ocular surface through blinking, thereby reducing the formation of dry areas.

[0026] As used herein, "ocular implant" refers to a device structurally, physically, or otherwise configured for placement in the eye of a mammal. Ocular implants are generally biocompatible with the physiological conditions of the eye and do not cause adverse side effects. Ocular implants can be placed inside the eye without affecting vision.

[0027] As used herein, "subject" refers to an animal, such as a mammal, including but not limited to primates (e.g., humans), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, etc. In some embodiments, the subject is a human.

[0028] As used herein, “suitable for implantation in the eye” means an implant of appropriate size, shape and biocompatibility for insertion into the tissues and structures that constitute and directly surround the eye as defined herein.

[0029] As used herein, "sustained release" refers to the release of a drug from an ocular implant over a period longer than the time required for a bioavailable dose of the drug solution to be produced upon direct administration. Sustained release can be continuous or discontinuous, with a relatively constant or varying release rate. The duration and level of release can be influenced by the type of polymer composition used (e.g., monomer ratios, molecular weight, and different combinations of polymers), the choice of excipients, and the identity and amount of the drug.

[0030] In this art, "sustained release" is also referred to as "improved release," "extended release," "long-acting release ('LAR')," "controlled release," or "delayed release." As used herein, "sustained release" also encompasses "continuous action" or "continuous effect." The terms "continuous action" and "continuous effect," as used herein, refer to a prolonged period of time during which a drug exerts its therapeutic or preventative activity compared to an appropriate control. "Continuous action" is also referred to by those skilled in the art as "extended action" or "delayed effect."

[0031] In some implementations, the sustained release profile of the ocular implant described herein shows an initial burst release of the drug, followed by a slower, sustained release of the drug after administration.

[0032] Without being constrained by any particular theory, drug release is believed to occur through two distinct mechanisms. First, the drug may be released from the polymer matrix of the implant via diffusion. Second, drug release may result from the degradation of the bioresorbable polymer.

[0033] As used herein, “treat,” “treating,” or “treatment” means to reduce, resolve, or prevent an eye disease, eye injury, or eye damage, or to promote the healing of injured or damaged eye tissue. Treatment usually provides effective relief for at least one symptom of an eye disease, eye injury, or eye damage.

[0034] As used in this article, “swelling” refers to the process of absorbing moisture to increase the volume of the polymer network after insertion at the target insertion site, which facilitates drug release from the implant area (e.g., deeper areas of the implant).

[0035] As used in this article, "inflation index" refers to the percentage of inflation calculated according to the following formula: Inflation percentage = [(Weight of the expanded implant - weight of the initial implant) / weight of the initial implant] × 100.

[0036] As used herein, "hygroscopicity" refers to the ability of an implant to absorb moisture from the atmosphere during storage within its shelf life, resulting in the diffusion and adsorption of the polymer matrix, and the gradual passage and filling of the cavity by water. As used in this disclosure, hygroscopicity can be determined using the following formula: Moisture absorption rate (%) = [(Final weight of implant - initial weight of implant) / initial weight of implant] × 100.

[0037] As used herein, “shelf stability” or “shelf-stable” means the ability of an implant to show less than 10% drug degradation (or, if explicitly stated, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, or less than 1%) after being stored under ambient conditions for 4 weeks (or, if explicitly stated, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, or less than 1%).

[0038] As used in this article, "relative humidity" (RH) is the ratio of the partial pressure of water vapor in the air to the saturated vapor pressure of water at the same temperature, expressed as a percentage.

[0039] As used in this article, “protein contamination” refers to the formation of protein aggregates attached to a surface.

[0040] As used in this article, "permeability" refers to the speed at which molecules pass through a membrane and indicates how easily molecules can pass through the membrane in a direction perpendicular to the membrane surface.

[0041] As used in this article, "permeation rate" refers to the rate at which a drug crosses the membrane barrier (the amount of drug per unit time, dM / dt).

[0042] As used herein, the "flux" of the surfactant is the surfactant permeation rate per unit membrane surface area. In some cases, flux can be determined by the following equation: Flux (J) = (dM / dt) / A Where J is the flux, dM / dt is the rate of permeation through the membrane, and A is the membrane surface area.

[0043] As used herein, "permeability coefficient" refers to a measure of permeability as defined in this disclosure. In some cases, the permeability coefficient can be determined by the following equation: P=J / C0 Where P is the permeability coefficient, J is the flux, and C0 is the initial drug concentration of the implant.

[0044] The compounds described herein may contain one or more asymmetric centers and therefore may exist in a variety of isomeric forms, such as enantiomers and / or diastereomers. For example, the compounds described herein may be in the form of an enantiomer, diastereomer, or geometric isomer, or may be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures rich in one or more stereoisomers. Isomers can be separated from mixtures by methods known to those skilled in the art, including chiral high-performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers may be prepared by asymmetric synthesis. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw–Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions p. 268 (EL Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). Additionally, this disclosure also covers the compounds described herein as a single isomer substantially free of other isomers, or as a mixture of various isomers. 2. Eye implants

[0045] In one aspect, this disclosure provides an ocular implant that provides sustained release of a drug formulated within the implant (e.g., a water-soluble drug such as pregabalin). The implants described herein allow for sustained drug release over several months and contain one or more bioresorbable polymers. Therefore, the used implant does not need to be removed surgically or otherwise. 2.1 Nanofiber implants

[0046] In some embodiments, an ocular implant is provided that comprises multiple nanofibers, wherein: Nanofibers contain a drug (e.g., a water-soluble drug, such as pregabalin) and one or more bioresorbable polymers; Nanofibers provide sustained drug release from the implant; and The implant is suitable for implantation in the eyes of mammals.

[0047] In some implementations, the drug is selected from antibacterial agents, antiviral agents, antifungal agents, steroids, sterols, anti-inflammatory agents, angiogenesis inhibitors, growth factors, anticoagulants, antioxidants, pyridine, antihypertensive drugs, antidiabetic drugs, insulin, progenitor cells / stem cells, intraocular pressure-lowering (IOP) drugs, and combinations thereof.

[0048] In some implementations, the drug is an antibacterial agent. Exemplary antibacterial drugs and / or antibiotics include, but are not limited to, amikacin, amoxicillin, clavulanic acid, ampicillin, benzathine penicillin, penicillin G, cephalexin, cefazolin, chloramphenicol, clindamycin, cloxacillin, doxycycline, gentamicin, metronidazole, nitrofurantoin, penicillin V, procaine benzylpenicillin, spectinomycin, sulfamethoxazole, trimethoprim, azithromycin, cefixime, and cefotaxime. Ceftriaxone, cefuroxime, ciprofloxacin, derafloxacin, gemifloxacin, levofloxacin, moxifloxacin, norfloxacin, ofloxacin, clarithromycin, piperacillin, tazobactam, vancomycin, cefdil, ceftazidime, avibactam, tazobactam, colistin, fosfomycin, linezolid, meropenem, faborbactam, prazomicin, polymyxin B, and pharmaceutically acceptable salts of the above drugs and combinations thereof.

[0049] In some implementations, the drug is an antiviral drug. Exemplary antiviral drugs include, but are not limited to, acyclovir, valacyclovir, abacavir, lamivudine, tenofovir, dipyridoxine fumarate, zidovudine, efavirenz, atazanavir, ritonavir, darunavir, lopinavir, dolutegravir, ritegvir, emtricitabine, isoniazid, pyridoxine, sulfamethoxazole, trimethoprim, ribavirin, ganciclovir, valganciclovir, oseltamivir, entecavir, daclatasvir, sofosbuvir, gliclazvir, pirentasvir, ravidasvir, velpatasvir, ledipasvir, pharmaceutically acceptable salts of the above drugs, and combinations thereof.

[0050] In some embodiments, the drug is an antifungal agent. Exemplary antifungal agents include, but are not limited to, clotrimazole, econazole, miconazole, terbinafine, fluconazole, ketoconazole, nifedipine, amphotericin B, and combinations thereof.

[0051] In some embodiments, the drug is a steroid, such as a corticosteroid. Exemplary corticosteroid drugs include, but are not limited to, betamethasone, prednisone, prednisolone, methylprednisolone, dexamethasone, hydrocortisone, cortisone, ethamethasoneb, triamcinolone, fludrocortisone, pharmaceutically acceptable salts of the above drugs, and combinations thereof.

[0052] In some embodiments, the drug is a sterol. Exemplary sterol drugs include, but are not limited to, cholesterol, mycosterols such as ergosterol, phytosterols such as campesterol, sitosterol, stigmasterol, pharmaceutically acceptable salts of the above drugs, and combinations thereof.

[0053] In some implementations, the drug is an anti-inflammatory drug. Exemplary anti-inflammatory drugs include, but are not limited to, aspirin, ibuprofen, naproxen sodium, celecoxib, diclofenac, fenprofen, indomethacin, ketorolac, pharmaceutically acceptable salts of the above drugs, and combinations thereof.

[0054] In some implementations, the drug is an angiogenesis inhibitor, such as an anti-VEGF agent. Exemplary angiogenesis inhibitors include, but are not limited to, pilgatanib, bevacizumab, ranibizumab, sorafenib, dasatinib, sunitinib, nilotinib, pazopanib, aflibercept, pharmaceutically acceptable salts of the above drugs, and combinations thereof.

[0055] In some embodiments, the drug is a growth factor. Exemplary growth factors include, but are not limited to, erythropoiesis stimulants (e.g., acelastine, epoetin afa, afadapoxetine, methoxy-PEG-epoetin afa, and rotexip), granulocyte colony-stimulating factors (e.g., filgrastim, pegfilgrastim, efavirenz, and olprexa), granulocyte-macrophage colony-stimulating factors (e.g., saxaglastine), platelet-stimulating agents (e.g., romimilastine and eltrombopag), pharmaceutically acceptable salts of the above drugs, and combinations thereof.

[0056] In some implementations, the drug is an anticoagulant. Exemplary anticoagulants include, but are not limited to, heparin, rivaroxaban, warfarin, apixaban, argatroban, bivalirudin, pharmaceutically acceptable salts of the above drugs, and combinations thereof.

[0057] In some embodiments, the drug is an antioxidant. Exemplary antioxidants include, but are not limited to, tocopherol, ascorbic acid, rosemary extract, butylated hydroxyanisole, butylated hydroxytoluene, propyl gallate, vitamin C, beta-carotene, selenium, alpha-lipoic acid, lycopene, resveratrol, pharmaceutically acceptable salts of the above drugs, and combinations thereof.

[0058] In some embodiments, the drug is pyridine. Exemplary pyridine drugs include, but are not limited to, antimicrobial agents (e.g., isoniazid and ethionamide), antiviral drugs (e.g., nevirapine, telanavir, and doravirine), anticancer drugs (e.g., acalatinib, neratinib, and abexicillin), cardiovascular drugs (e.g., nimodipine and nifedipine), proton pump inhibitors (e.g., esomeprazole and lansoprazole), antiasthmatic drugs (e.g., montelukast), antidiabetic drugs (e.g., pioglitazone), pharmaceutically acceptable salts of the above drugs, and combinations thereof.

[0059] In some implementations, the drug is an antihypertensive medication. Exemplary antihypertensive medications include, but are not limited to, diuretics (e.g., furosemide, bumetanide, torasemide, chlorothiazide, amidochlorothiazide, hydrochlorothiazide, indapamide, metoprolol, and triamterene), beta-blockers (e.g., acebutolol, atenolol, betalolol, carvedilol, carvedilol phosphate, labetalol, metoprolol succinate, metoprolol tartrate, nadolol, nebivolol, indololol, and propranolol), and angiotensin-converting enzyme inhibitors (e.g., captopril, enalapril, fosinopril, lisinopril, perindopril, quinapril, ramipril, trandopril, benazepril, etc.). The following are pharmaceutically acceptable salts and combinations thereof: pril and moxipril), angiotensin II receptor blockers (e.g., candesartan, losartan, and valsartan), calcium channel blockers (e.g., amlodipine, diltiazem, felodipine, isradipine, nicardipine, nifedipine, nisoldipine, and verapamil), alpha blockers (e.g., doxazosin, prazosin, and terazosin hydrochloride), alpha-2 receptor agonists (e.g., methyldopa, clonidine, and guanfaxine), combination alpha and beta blockers (e.g., carvedilol and labetalol hydrochloride), vasodilators (e.g., hydralazine and minoxidil), and pharmaceutically acceptable salts of the above drugs.

[0060] In some embodiments, the drug is an antidiabetic drug. Exemplary antidiabetic drugs include, but are not limited to, sulfonylureas (e.g., glipizide, glibenclamide, gliclazide, and glimepiride), meglitinides (e.g., repaglinide and nateglinide), biguanides (e.g., metformin), thiazolidinediones (e.g., rosiglitazone and pioglitazone), alpha-glucosidase inhibitors (e.g., acarbose, miglitol, and voglibose), DPP-4 inhibitors (e.g., sitagliptin, saxagliptin, vildagliptin, linagliptin, and alogliptin), SGLT2 inhibitors (e.g., dapagliflozin and canagliflozin), cyclosets (e.g., bromocriptine), GLP-1 receptor agonists (e.g., semaglutide, exenatide, liraglutide, and liximab), curcumin, pharmaceutically acceptable salts of the above drugs, and combinations thereof.

[0061] In some implementations, the drug is insulin. Exemplary insulins include, but are not limited to, rapid-acting insulin (e.g., lispro insulin), short-acting insulin (e.g., regular human insulin), intermediate-acting insulin (e.g., NPH insulin), long-acting insulin (e.g., detemir insulin, glargine insulin, glargine insulin-yfgn, and degludec insulin), and insulin mixtures (e.g., NPH / regular insulin, protamine / lispro insulin, or protamine / aspart insulin).

[0062] In some implementations, the drug is a stem cell. Exemplary stem cells include, but are not limited to, embryonic stem cells (pluripotent stem cells), adult stem cells (e.g., hematopoietic stem cells), mesenchymal stem cells (e.g., mesenchymal stem cells derived from umbilical cord tissue), and induced pluripotent stem cells (iPSCs).

[0063] In some implementations, the drug lowers intraocular pressure. Exemplary drugs that lower intraocular pressure include, but are not limited to, CACNA2D1 inhibitors, CACNA2D2 inhibitors, gabapentin derivatives (e.g., pregabalin and gabapentin), calcium channel blockers (e.g., nimodipine, amlodipine, diltiazem, felodipine, isradipine, nicardipine, nifedipine, nisoldipine, and verapamil), cholinergic and adrenergic drugs (e.g., pilocarpine, carbachol, physostigmine, neostigmine, and iodophor), and adrenergic agonists (e.g., renin-angiotensin II). Adrenaline and dipiformin), β-blockers (e.g., timolol, levobunolol, metemolol, cartemolol, and betalolol), carbonic anhydrase inhibitors (e.g., brinzolamide, dzodamine, acetazolamide, and acetazolamide), α-agonist clonidine derivatives (e.g., brimonidine tartrate and aclomid), prostaglandin analogs (e.g., bimatoprost, travoprost, latanoprost, and tafluprost), Rho kinase inhibitors (e.g., nesudil), pharmaceutically acceptable salts of the above drugs, and combinations thereof.

[0064] In some embodiments, the drug is a water-soluble drug. In some embodiments, the water-soluble drug is selected from beta-blockers (e.g., betalol and timolol), prostaglandin analogs (e.g., bimatoprost, latanoprost, and travoprost), alpha-adrenergic agents (e.g., brimonidine tartrate), carbonic anhydrase inhibitors (e.g., brinzolamide, dzodamine, and acetazolamide), calcium channel blockers (e.g., nimodipine and pregabalin), sialic acid, galactose, trianthracycline (NA3) (sialic acid-trianthracycline complex type N-glycan), OT-551 hydrochloride (1-hydroxy-2,2,6,6-tetramethyl-4-piperidinylcyclopropanecarboxylate hydrochloride), brimonidine tartrate, clindamycin, ciprofloxacin, levofloxacin, gatifloxacin, gemifloxacin, ofloxacin, triamcinolone, valacyclovir, pyrimethamine, and valganxi. Lovir, ganciclovir, acyclovir, phosphonoformic acid, prednisolone acetate, difluprednate, triamcinolone, dexamethasone, methotrexate, azathioprine, mycophenolate mofetil, cyclosporine, tacrolimus, cyclophosphamide, ribavirin, bromofenac, ketorolac, naphazoline, ristatin, flurbiprofen, diclofenac, ketotifen, nedolomein, phenformin, azelastine, epinastine, naphazoline / feniramine, olopatadine, betasine, acartadine, pyrimisulfate, tetrahydrozoline with or without zinc sulfate, lodoxamide, naphazoline, phenformin, cromoglycine, emestin, oxymetazoline, xylometazoline, loratadine, desloratadine, phenylglycine, gabapentin, pharmaceutically acceptable salts thereof, and combinations thereof.

[0065] In some implementations, the drug is a water-insoluble drug.

[0066] In some embodiments, the implant comprises 0.1 wt% to 50 wt% of a drug (e.g., a water-soluble or water-insoluble drug), such as 0.1 wt% to 40 wt%, 0.1 wt% to 30 wt%, 0.1 wt% to 20 wt%, 0.1 wt% to 10 wt%, 0.1 wt% to 5 wt%, 1 wt% to 50 wt%, 1 wt% to 40 wt%, 1 wt% to 30 wt%, 1 wt% to 20 wt%, 1 wt% to 10 wt%, 1 wt% to 5 wt%, 5 wt% to 50 wt%, 5 wt% to 40 wt%, 5 wt% to 30 wt%, 5 wt% to 20 wt%, 5 wt% to 10 wt%, 10 wt% to 50 wt%, 10 wt% to 40 wt%, 10 wt% to 30 wt%, 10 wt% to 20 wt%. wt%, 20 wt% to 50 wt%, 20 wt% to 40 wt%, 20 wt% to 30 wt%, 30 wt% to 50 wt%, 30 wt% to 40 wt%, or 40 wt% to 50 wt%. In some embodiments, the implant contains about 20 wt% of the drug (e.g., a water-soluble drug).

[0067] In some embodiments, the implant contains 0.1 mg to 20 mg of a drug (e.g., a water-soluble or water-insoluble drug), such as 0.1 mg to 15 mg, 0.1 mg to 10 mg, 0.1 mg to 5 mg, 0.1 mg to 2.5 mg, 1 mg to 20 mg, 1 mg to 15 mg, 1 mg to 10 mg, 1 mg to 5 mg, 1 mg to 2.5 mg, 2.5 mg to 20 mg, 2.5 mg to 15 mg, 2.5 mg to 10 mg, 2.5 mg to 5 mg, 5 mg to 20 mg, 5 mg to 15 mg, 5 mg to 10 mg, 10 mg to 20 mg, 10 mg to 15 mg, or 15 mg to 20 mg. In some embodiments, the implant contains 0.1 mg to 5 mg of the drug, such as 0.1 mg to 4 mg, 0.1 mg to 3 mg, 0.1 mg to 2 mg, 0.1 mg to 1 mg, 0.5 mg to 5 mg, 0.5 mg to 4 mg, 0.5 mg to 3 mg, 0.5 mg to 2 mg, 0.5 mg to 1 mg, 0.5 mg to 1 mg, 1 mg to 5 mg, 1 mg to 4 mg, 1 mg to 3 mg, 1 mg to 2 mg, 2 mg to 5 mg, 2 mg to 4 mg, 2 mg to 3 mg, 3 mg to 5 mg, 3 mg to 4 mg, and 4 mg to 5 mg. In some embodiments, the implant contains 0.5 mg to 2 mg of the drug (e.g., a water-soluble drug).

[0068] In some embodiments, the drug is a calcium channel blocker. In some embodiments, the drug is pregabalin. In some embodiments, the implant contains 0.1 mg to 5 mg of pregabalin, such as 0.1 mg to 4 mg, 0.1 mg to 3 mg, 0.1 mg to 2 mg, 0.1 mg to 1 mg, 0.5 mg to 5 mg, 0.5 mg to 4 mg, 0.5 mg to 3 mg, 0.5 mg to 2 mg, 0.5 mg to 1 mg, 0.5 mg to 1 mg, 1 mg to 5 mg, 1 mg to 4 mg, 1 mg to 3 mg, 1 mg to 2 mg, 2 mg to 5 mg, 2 mg to 4 mg, 2 mg to 3 mg, 3 mg to 5 mg, 3 mg to 4 mg, and 4 mg to 5 mg. In some embodiments, the implant contains 0.5 mg to 2 mg of pregabalin.

[0069] In some embodiments, one or more bioresorbable polymers include poly(α-hydroxy acid), poly(glycolic acid-co-lactide) (PLG), poly(D,L-lactide-co-caprolactone) (DL-PLCL), polycaprolactone (PCL), poly(L-lactic acid) (PLA), poly(trimethylene carbonate) (PTMC), poly(p-dioxanone) (PDO), poly(4-hydroxybutyrate) (PHB), polyhydroxyalkanoate (PHA), and polyphosphazene. Polyphosphates, polyamino acids, polyphenolic peptides, poly(butylene succinate) (PBS), polyethylene oxide, polypropylene fumarate, polyiminocarbonate, poly(lactide-co-caprolactone) (PLCL), poly(glycolic acid-co-caprolactone) (PGCL) copolymer, poly(D,L-lactic acid), polyglycolic acid, poly(L-lactide-co-D,L-lactide), poly(L-lactide-co-glycolic acid), poly(D,L-lactide-co-glycolic acid) Poly(glycolic acid-trimethylene carbonate), poly(glycolic acid-co-caprolactone) (PGCL), poly(ethyl glutamate-co-glutamic acid), poly(tert-butoxycarbonylmethyl glutamate), polyglycerol sebacate, tyrosine-derived polycarbonates, poly1,3-bis(p-carboxyphenoxy)hexane-co-sebacate, polyphosphazene, ethylglycine polyphosphazene, polycaprolactone-co-butyl acrylate, polyhydroxybutyrate copolymer, maleic anhydride copolymer, poly(trimethylene carbonate) copolymer, polyethylene glycol (PEG), hydroxypropyl methylcellulose and cellulose derivatives, polysaccharides (e.g., hyaluronic acid, chitosan) Polysaccharides and starches), proteins (e.g., gelatin and collagen), polyaspirin, polyphosphazenes, collagen, alginate, albumin, fibrin, vitamin E analogs, D-lactide, D,L-lactide, L-lactide, D,L-lactide-caprolactone (DL-CL), D,L-lactide-glycolic acid-caprolactone (DL-G-CL), dextran, vinylpyrrolidone, polyvinyl alcohol (PVA), PVA-g-PLGA, PEGT-PBT copolymer (multi-active), methacrylates, poly(N-isopropylacrylamide), PEO-PPO-PEO (pluronics), PEO-PPO-PAA copolymer, PLGA-PEO-PLGA, PEG-PLG, PLA-PLGA, poloxamer 407, PEG-PLGA-PEG triblock copolymer, SAIB (sucrose isobutyrate acetate), hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl methylcellulose, carboxymethyl cellulose or its salts, Carbopol®, poly(hydroxyethyl methacrylate), poly(methoxyethyl methacrylate), poly(methoxyethoxyethyl methacrylate), polymethyl methacrylate (PMMA), methyl methacrylate (MMA), gelatin, polyvinyl alcohol, propylene glycol or combinations thereof.

[0070] In some embodiments, one or more bioresorbable polymers include poly(L-lactic acid) (PLA), polycaprolactone (PCL), polyglycolic acid, or copolymers thereof. In some embodiments, one or more bioresorbable polymers include poly(L-lactic acid) (PLA). In some embodiments, one or more bioresorbable polymers include polycaprolactone (PCL). In some embodiments, one or more bioresorbable polymers include poly(L-lactic acid) (PLA). In some embodiments, one or more bioresorbable polymers include copolymers of poly(L-lactic acid) (PLA), polycaprolactone (PCL), and polyglycolic acid.

[0071] In some embodiments, the implant comprises 50 wt% to 99.9 wt% of one or more bioresorbable polymers, such as 60 wt% to 99.9 wt%, 70 wt% to 99.9 wt%, 80 wt% to 99.9 wt%, 80 wt% to 99.9 wt%, or 90 wt% to 99.9 wt%. In some embodiments, the implant comprises 75 wt% to 99.9 wt% of one or more bioresorbable polymers, such as 75 wt% to 95 wt%, 80 wt% to 95 wt%, 85 wt% to 95 wt%, or 90 wt% to 95 wt%. In some embodiments, the implant comprises 80 wt% of one or more bioresorbable polymers.

[0072] In some embodiments, the weight ratio of the drug (e.g., a water-soluble drug) to one or more bioresorbable polymers is 1:1 to 1:20, such as 1:1 to 1:15, 1:1 to 1:10, 1:1 to 1:5, 1:2 to 1:6, 1:2 to 1:5, 1:2 to 1:4, 1:2 to 1:3, 1:3 to 1:6, 1:3 to 1:5, 1:3 to 1:4, 1:4 to 1:6, or 1:4 to 1:5. In some embodiments, the weight ratio of the drug (e.g., a water-soluble drug) to one or more bioresorbable polymers is 1:4.

[0073] In some embodiments, the nanofibers further comprise a permeation enhancer. In some embodiments, the permeation enhancer is selected from D-α-tocopherol polyethylene glycol succinate (TPGS), sodium dioctyl sulfosuccinate, sodium decanoate, sodium N-[8-(2-hydroxybenzoyl)amino]octanoate (SNAC), sodium dodecyl sulfate, sodium salicylate, oleic acid, lecithin, anhydrous ethanol, polysorbate or polyoxyethylene sorbitan fatty acid ester (Tween), sorbitan fatty acid ester (Spans), polyoxyethylene alkyl ether (Brijs), stearic acid... Hydroxyl (40) esters, polyoxyethylene (50) stearates, polyethylene glycol, polyvinyl alcohol, polyvinylpyrrolidone (e.g., polyvinylpyrrolidone K29-32), hydroxypropyl methylcellulose, polyvinylpyrrolidone / vinyl acetate (VP / VA) copolymers, poly(lactic-co-hydroxyacetic acid), disodium ethylenediaminetetraacetate, propylene glycol, glyceryl monooleate, bile salts, octylphenol polyethers, nonionic surfactants, anionic surfactants, cationic surfactants, and combinations thereof.

[0074] In some embodiments, the implant has one of the following shapes: spherical, oblate, ellipsoidal, rod-shaped, disc-shaped, tubular, hemispherical, oval, cylindrical, or irregular. In some embodiments, the implant is rod-shaped.

[0075] In some embodiments, the implant has the following dimensions: length 0.5 mm to 6 mm, width 0.5 mm to 6 mm, and height 0.2 mm to 6 mm. In terms of length, the implant may be 0.5 mm to 5 mm, 0.5 mm to 4 mm, 0.5 mm to 3 mm, 0.5 mm to 2 mm, 0.5 mm to 1 mm, 1 mm to 6 mm, 1 mm to 5 mm, 1 mm to 4 mm, 1 mm to 3 mm, 1 mm to 2 mm, 2 mm to 6 mm, 2 mm to 5 mm, 2 mm to 4 mm, 2 mm to 3 mm, 3 mm to 6 mm, 3 mm to 5 mm, 3 mm to 4 mm, 4 mm to 6 mm, 4 mm to 5 mm, or 5 mm to 6 mm. In terms of width, the implant can be 0.5 mm to 5 mm, 0.5 mm to 4 mm, 0.5 mm to 3 mm, 0.5 mm to 2 mm, 0.5 mm to 1 mm, 1 mm to 6 mm, 1 mm to 5 mm, 1 mm to 4 mm, 1 mm to 3 mm, 1 mm to 2 mm, 2 mm to 6 mm, 2 mm to 5 mm, 2 mm to 4 mm, 2 mm to 3 mm, 3 mm to 6 mm, 3 mm to 5 mm, 3 mm to 4 mm, 4 mm to 6 mm, 4 mm to 5 mm, or 5 mm to 6 mm. In terms of height, the implant can be 0.2 mm to 6 mm, 0.2 mm to 5 mm, 0.2 mm to 4 mm, 0.2 mm to 3 mm, 0.2 mm to 2 mm, 0.2 mm to 1 mm, 0.5 mm to 6 mm, 0.5 mm to 5 mm, 0.5 mm to 4 mm, 0.5 mm to 3 mm, 0.5 mm to 2 mm, 0.5 mm to 1 mm, 1 mm to 6 mm, 1 mm to 5 mm, 1 mm to 4 mm, 1 mm to 3 mm, 1 mm to 2 mm, 2 mm to 6 mm, 2 mm to 5 mm, 2 mm to 4 mm, 2 mm to 3 mm, 3 mm to 6 mm, 3 mm to 5 mm, 3 mm to 4 mm, 4 mm to 6 mm, 4 mm to 5 mm, or 5 mm to 6 mm. In some embodiments, the implant has a length of 2 mm to 6 mm, a width of 1 mm to 3 mm, and a height of 0.2 mm to 1 mm.

[0076] In some embodiments, the nanofibers of the implant have a diameter of 100 nm to 1,000 nm, such as 100 nm to 750 nm, 100 nm to 500 nm, 100 nm to 250 nm, 250 nm to 1,000 nm, 250 nm to 750 nm, 250 nm to 500 nm, 500 nm to 1,000 nm, 500 nm to 750 nm, or 750 nm to 1,000 nm. In some embodiments, the nanofibers of the implant have a diameter of 200 nm to 500 nm, 200 nm to 400 nm, or 300 nm to 350 nm.

[0077] In some embodiments, the implant weighs from 0.5 mg to 10 mg, for example, such as 0.5 mg to 7.5 mg, 0.5 mg to 5 mg, 0.5 mg to 2.5 mg, 2.5 mg to 10 mg, 2.5 mg to 7.5 mg, 2.5 mg to 5 mg, 5 mg to 10 mg, 5 mg to 7.5 mg, or 7.5 mg to 10 mg. In some embodiments, the implant weighs from 3 mg to 8 mg, 3 mg to 6 mg, or 4 mg to 6 mg. In some embodiments, the implant weighs 5 mg.

[0078] In some implementations, when placed in room temperature water for 2 hours, the implant is given water with a pH of 5 to 8, for example, such as 6 to 8, 6 to 7, 7 to 8, or 6.5 to 7.5.

[0079] In some implementations, the ocular implant comprises multiple nanofibers, among which: Nanofibers contain a drug (e.g., a water-soluble drug) and one or more bioresorbable polymers, wherein one or more bioresorbable polymers include poly(L-lactic acid) (PLA), polycaprolactone (PCL), polyglycolic acid, or copolymers thereof. Nanofibers provide sustained drug release from the implant; and The implant is suitable for implantation in the eyes of mammals.

[0080] In some implementations, the ocular implant comprises multiple nanofibers, among which: The nanofibers contain a drug (e.g., a water-soluble drug) and one or more bioresorbable polymers, wherein the drug is pregabalin, and one or more bioresorbable polymers include poly(L-lactic acid) (PLA), polycaprolactone (PCL), polyglycolic acid, or copolymers thereof. Nanofibers provide sustained drug release from the implant; and The implant is suitable for implantation in the eyes of mammals.

[0081] In some implementations, the ocular implant comprises multiple nanofibers, among which: The nanofibers comprise a drug (e.g., a water-soluble drug) and one or more bioresorbable polymers, wherein the one or more bioresorbable polymers include poly(L-lactic acid) (PLA), polycaprolactone (PCL), polyglycolic acid, or copolymers thereof, wherein the weight ratio of the drug to the one or more bioresorbable polymers is 1:1 to 1:20, preferably 1:1 to 1:10, more preferably 1:1 to 1:6, and even more preferably 1:4; Nanofibers enable the sustained release of drugs from the implant; and The implant is suitable for implantation in the eyes of mammals.

[0082] In some implementations, the ocular implant comprises multiple nanofibers, among which: The nanofibers comprise a drug and one or more bioresorbable polymers, wherein the drug is pregabalin, and the one or more bioresorbable polymers include poly(L-lactic acid) (PLA), polycaprolactone (PCL), polyglycolic acid, or copolymers thereof, wherein the weight ratio of pregabalin to the one or more bioresorbable polymers is 1:1 to 1:20, preferably 1:1 to 1:10, more preferably 1:1 to 1:6, and even more preferably 1:4. Nanofibers provide sustained drug release from the implant; and The implant is suitable for implantation in the eyes of mammals.

[0083] In some implementations, the ocular implant comprises multiple nanofibers, among which: Nanofibers contain a drug (e.g., a water-soluble drug) and one or more bioresorbable polymers, wherein one or more bioresorbable polymers include poly(L-lactic acid) (PLA), polycaprolactone (PCL), polyglycolic acid, or copolymers thereof. Nanofibers provide sustained drug release from the implant; The implant is suitable for implantation in the eyes of mammals; and The implant contains 0.1 mg to 5 mg of medication.

[0084] In some implementations, the ocular implant comprises multiple nanofibers, among which: The nanofibers contain a drug and one or more bioresorbable polymers, wherein the drug is pregabalin and one or more bioresorbable polymers include poly(L-lactic acid) (PLA), polycaprolactone (PCL), polyglycolic acid, or copolymers thereof. Nanofibers provide sustained release of drugs from the implant; The implant is suitable for implantation in the eyes of mammals; and The implant contains 0.1 mg to 5 mg of pregabalin.

[0085] In some implementations, the ocular implant comprises multiple nanofibers, among which: The nanofibers contain 0.1 wt% to 50 wt% of a drug (e.g., a water-soluble drug) and 50 wt% to 99.9 wt% of one or more bioresorbable polymers, wherein one or more bioresorbable polymers include poly(L-lactic acid) (PLA), polycaprolactone (PCL), polyglycolic acid, or copolymers thereof. Nanofibers provide sustained drug release from the implant; and The implant is suitable for implantation in the eyes of mammals.

[0086] In some implementations, the ocular implant comprises multiple nanofibers, among which: The nanofibers contain 0.1 wt% to 50 wt% of a drug and 50 wt% to 99.9 wt% of one or more bioresorbable polymers, wherein the drug is pregabalin and the one or more bioresorbable polymers include poly(L-lactic acid) (PLA), polycaprolactone (PCL), polyglycolic acid or copolymers thereof. Nanofibers provide sustained drug release from the implant; and The implant is suitable for implantation in the eyes of mammals.

[0087] In some implementations, the ocular implant comprises multiple nanofibers, among which: The nanofibers contain 1 wt% to 30 wt% of a drug (e.g., a water-soluble drug) and 75 wt% to 95 wt% of one or more bioresorbable polymers, wherein one or more bioresorbable polymers include poly(L-lactic acid) (PLA), polycaprolactone (PCL), polyglycolic acid, or copolymers thereof. Nanofibers provide sustained drug release from the implant; and The implant is suitable for implantation in the eyes of mammals.

[0088] In some implementations, the ocular implant comprises multiple nanofibers, among which: The nanofibers contain 1 wt% to 30 wt% of a drug and 75 wt% to 95 wt% of one or more bioresorbable polymers, wherein the drug is pregabalin and one or more bioresorbable polymers include poly(L-lactic acid) (PLA), polycaprolactone (PCL), polyglycolic acid or copolymers thereof. Nanofibers provide sustained drug release from the implant; and The implant is suitable for implantation in the eyes of mammals.

[0089] In some implementations, the ocular implant comprises multiple nanofibers, among which: The nanofibers contain 20 wt% of a drug (e.g., a water-soluble drug) and 80 wt% of one or more bioresorbable polymers, wherein one or more bioresorbable polymers include poly(L-lactic acid) (PLA), polycaprolactone (PCL), polyglycolic acid, or copolymers thereof. Nanofibers provide sustained drug release from the implant; and The implant is suitable for implantation in the eyes of mammals.

[0090] In some implementations, the ocular implant comprises multiple nanofibers, among which: The nanofibers contain 20 wt% of a drug and 80 wt% of one or more bioresorbable polymers, wherein the drug is pregabalin and one or more bioresorbable polymers include poly(L-lactic acid) (PLA), polycaprolactone (PCL), polyglycolic acid or copolymers thereof. Nanofibers provide sustained drug release from the implant; and The implant is suitable for implantation in the eyes of mammals. 2.2 Nanoparticle Implants

[0091] In some embodiments, an ocular implant is provided that comprises multiple nanofibers, wherein: Nanoparticles contain a drug (e.g., a water-soluble drug) and one or more bioresorbable polymers; Nanoparticles provide sustained drug release from the implant; and The implant is suitable for implantation in the eyes of mammals.

[0092] In some implementations, the drug is selected from antibacterial agents, antiviral agents, antifungal agents, steroids, sterols, anti-inflammatory agents, angiogenesis inhibitors, growth factors, anticoagulants, antioxidants, pyridine, antihypertensive drugs, antidiabetic drugs, insulin, progenitor cells / stem cells, intraocular pressure (IOP) lowering drugs, and combinations thereof, as described above.

[0093] In some embodiments, an ocular implant is provided that comprises a variety of nanoparticles, wherein: The nanoparticles contain pregabalin and one or more bioresorbable polymers; Nanoparticles provide sustained release of pregabalin from the implant; and The implant is suitable for implantation in the eyes of mammals.

[0094] In some embodiments, the implant contains 0.1 wt% to 50 wt% of a drug (e.g., a water-soluble drug such as pregabalin), for example, such as 0.1 wt% to 40 wt%, 0.1 wt% to 30 wt%, 0.1 wt% to 20 wt%, 0.1 wt% to 10 wt%, 0.1 wt% to 5 wt%, 1 wt% to 50 wt%, 1 wt% to 40 wt%, 1 wt% to 30 wt%, 1 wt% to 20 wt%, 1 wt% to 10 wt%, 1 wt% to 5 wt%, 5 wt% to 50 wt%, 5 wt% to 40 wt%, 5 wt% to 30 wt%, 5 wt% to 20 wt%, 5 wt% to 10 wt%, 10 wt% to 50 wt%, 10 wt% to 40 wt%, 10 wt% to 30 wt%, 10 wt% to 20 wt%, 20 wt% to 50 wt%, 20 wt% to 40 wt%, 20 wt% to 30 wt%, 30 wt% to 50 wt%, 30 wt% to 40 wt%, or 40 wt% to 50 wt%. In some embodiments, the implant contains about 20 wt% of the drug (e.g., a water-soluble drug such as pregabalin).

[0095] In some embodiments, the implant contains 0.1 mg to 20 mg of a drug (e.g., a water-soluble drug such as pregabalin), such as 0.1 mg to 15 mg, 0.1 mg to 10 mg, 0.1 mg to 5 mg, 0.1 mg to 2.5 mg, 1 mg to 20 mg, 1 mg to 15 mg, 1 mg to 10 mg, 1 mg to 5 mg, 1 mg to 2.5 mg, 2.5 mg to 20 mg, 2.5 mg to 15 mg, 2.5 mg to 10 mg, 2.5 mg to 5 mg, 5 mg to 20 mg, 5 mg to 15 mg, 5 mg to 10 mg, 10 mg to 20 mg, 10 mg to 15 mg, or 15 mg to 20 mg. In some embodiments, the implant contains 0.1 mg to 5 mg of a drug (e.g., a water-soluble drug such as pregabalin), for example, such as 0.1 mg to 4 mg, 0.1 mg to 3 mg, 0.1 mg to 2 mg, 0.1 mg to 1 mg, 0.5 mg to 5 mg, 0.5 mg to 4 mg, 0.5 mg to 3 mg, 0.5 mg to 2 mg, 0.5 mg to 1 mg, 0.5 mg to 1 mg, 1 mg to 5 mg, 1 mg to 4 mg, 1 mg to 3 mg, 1 mg to 2 mg, 2 mg to 5 mg, 2 mg to 4 mg, 2 mg to 3 mg, 3 mg to 5 mg, 3 mg to 4 mg, and 4 mg to 5 mg. In some embodiments, the implant contains 0.5 mg to 2 mg of a drug (e.g., a water-soluble drug such as pregabalin).

[0096] In some embodiments, one or more bioresorbable polymers include poly(α-hydroxy acid), poly(glycolic acid-co-lactide) (PLG), poly(D,L-lactide-co-caprolactone) (DL-PLCL), polycaprolactone (PCL), poly(L-lactic acid) (PLA), poly(trimethylene carbonate) (PTMC), poly(p-dioxanone) (PDO), poly(4-hydroxybutyrate) (PHB), polyhydroxyalkanoate (PHA), and polyphosphazene. Polyphosphates, polyamino acids, polyphenolic peptides, poly(butylene succinate) (PBS), polyethylene oxide, polypropylene fumarate, polyiminocarbonate, poly(lactide-co-caprolactone) (PLCL), poly(glycolic acid-co-caprolactone) (PGCL) copolymer, poly(D,L-lactic acid), polyglycolic acid, poly(L-lactide-co-D,L-lactide), poly(L-lactide-co-glycolic acid), poly(D,L-lactide-co-glycolic acid) Poly(glycolic acid-trimethylene carbonate), poly(glycolic acid-co-caprolactone) (PGCL), poly(ethyl glutamate-co-glutamic acid), poly(tert-butoxycarbonylmethyl glutamate), polyglycerol sebacate, tyrosine-derived polycarbonates, poly1,3-bis(p-carboxyphenoxy)hexane-co-sebacate, polyphosphazene, ethylglycine polyphosphazene, polycaprolactone-co-butyl acrylate, polyhydroxybutyrate copolymer, maleic anhydride copolymer, poly(trimethylene carbonate) copolymer, polyethylene glycol (PEG), hydroxypropyl methylcellulose and cellulose derivatives, polysaccharides (e.g., hyaluronic acid, chitosan) Polysaccharides and starches), proteins (e.g., gelatin and collagen), polyaspirin, polyphosphazenes, collagen, alginate, albumin, fibrin, vitamin E analogs, D-lactide, D,L-lactide, L-lactide, D,L-lactide-caprolactone (DL-CL), D,L-lactide-glycolic acid-caprolactone (DL-G-CL), dextran, vinylpyrrolidone, polyvinyl alcohol (PVA), PVA-g-PLGA, PEGT-PBT copolymer (multi-active), methacrylates, poly(N-isopropylacrylamide), PEO-PPO-PEO (pluronics), PEO-PPO-PAA copolymer, PLGA-PEO-PLGA, PEG-PLG, PLA-PLGA, poloxamer 407, PEG-PLGA-PEG triblock copolymer, SAIB (sucrose isobutyrate acetate), hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl methylcellulose, carboxymethyl cellulose or its salts, Carbopol®, poly(hydroxyethyl methacrylate), poly(methoxyethyl methacrylate), poly(methoxyethoxyethyl methacrylate), polymethyl methacrylate (PMMA), methyl methacrylate (MMA), gelatin, polyvinyl alcohol, propylene glycol or combinations thereof.

[0097] In some embodiments, one or more bioresorbable polymers include poly(L-lactic acid) (PLA), polycaprolactone (PCL), polyglycolic acid, or copolymers thereof. In some embodiments, one or more bioresorbable polymers include poly(L-lactic acid) (PLA). In some embodiments, one or more bioresorbable polymers include polycaprolactone (PCL). In some embodiments, one or more bioresorbable polymers include poly(L-lactic acid) (PLA). In some embodiments, one or more bioresorbable polymers include copolymers of poly(L-lactic acid) (PLA), polycaprolactone (PCL), and polyglycolic acid.

[0098] In some embodiments, the implant comprises 50 wt% to 99.9 wt% of one or more bioresorbable polymers, such as 60 wt% to 99.9 wt%, 70 wt% to 99.9 wt%, 80 wt% to 99.9 wt%, 80 wt% to 99.9 wt%, or 90 wt% to 99.9 wt%. In some embodiments, the implant comprises 75 wt% to 99.9 wt% of one or more bioresorbable polymers, such as 75 wt% to 95 wt%, 80 wt% to 95 wt%, 85 wt% to 95 wt%, or 90 wt% to 95 wt%. In some embodiments, the implant comprises 80 wt% of one or more bioresorbable polymers.

[0099] In some embodiments, the weight ratio of the drug (e.g., a water-soluble drug such as pregabalin) to one or more bioresorbable polymers is 1:1 to 1:20, such as 1:1 to 1:15, 1:1 to 1:10, 1:1 to 1:5, 1:2 to 1:6, 1:2 to 1:5, 1:2 to 1:4, 1:2 to 1:3, 1:3 to 1:6, 1:3 to 1:5, 1:3 to 1:4, 1:4 to 1:6, or 1:4 to 1:5. In some embodiments, the weight ratio of the drug (e.g., a water-soluble drug such as pregabalin) to one or more bioresorbable polymers is 1:4.

[0100] In some implementations, the nanoparticles also contain a permeation enhancer. In some embodiments, the penetration enhancer is selected from D-α-tocopherol polyethylene glycol succinate (TPGS), sodium dioctyl sulfosuccinate, sodium decanoate, sodium N-[8-(2-hydroxybenzoyl)amino]octanoate (SNAC), sodium dodecyl sulfate, sodium salicylate, oleic acid, lecithin, anhydrous ethanol, polysorbate or polyoxyethylene sorbitan fatty acid ester (Tween), sorbitan fatty acid ester (Spans), polyoxyethylene alkyl ether (Brijs), poly(40) stearate, polyoxyethylene 50 stearate, polyethylene glycol, polyvinyl alcohol, polyvinylpyrrolidone (e.g., polyvinylpyrrolidone K29-32), hydroxypropyl methylcellulose, polyvinylpyrrolidone / vinyl acetate (VP / VA) copolymer, poly(lactic acid-co-hydroxyacetic acid), disodium ethylenediaminetetraacetate, propylene glycol, glyceryl monooleate, bile salts, octylphenol polyether, nonionic surfactants, anionic surfactants, cationic surfactants, and combinations thereof.

[0101] In some implementations, when placed in water at room temperature for 2 hours, the nanoparticles impart a pH of 5 to 8 to the water, for example, such as 6 to 8, 6 to 7, 7 to 8, or 6.5 to 7.5.

[0102] In some embodiments, the implant has one of the following shapes: spherical, oblate, ellipsoidal, rod-shaped, disc-shaped, tubular, hemispherical, oval, cylindrical, or irregular. In some embodiments, the implant is rod-shaped.

[0103] In some embodiments, the implant has the following dimensions: a length of 2 mm to 10 mm and a diameter of 0.1 mm to 1 mm, such as a length of 3 mm to 8 mm and a diameter of 0.2 mm to 0.8 mm, or a length of 4 mm to 7 mm and a diameter of 0.3 mm to 0.6 mm. In some embodiments, the implant has a length of 6 mm and a diameter of 0.5 mm.

[0104] In some embodiments, the nanoparticles have an average particle size of 300 nm to 1,000 nm, such as 300 nm to 900 nm, 300 nm to 800 nm, 300 nm to 700 nm, 300 nm to 600 nm, 300 nm to 500 nm, 300 nm to 400 nm, 500 nm to 1,000 nm, 500 nm to 900 nm, 500 nm to 800 nm, 500 nm to 700 nm, 500 nm to 600 nm, 750 nm to 1,000 nm, 750 nm to 900 nm, or 750 nm to 800 nm. In some embodiments, the nanoparticle diameter is 300 nm to 400 nm. In some other embodiments, the nanoparticle diameter is 900 nm to 1,000 nm.

[0105] In some embodiments, the polydispersity index (PDI) of the nanoparticles is 0.1 to 1, for example, such as 0.1 to 0.7, 0.1 to 0.5, 0.1 to 0.3, 0.3 to 0.7, 0.3 to 0.5, 0.4 to 0.7, or 0.4 to 0.6.

[0106] In some embodiments, the implant weighs from 0.5 mg to 10 mg, for example, such as 0.5 mg to 7.5 mg, 0.5 mg to 5 mg, 0.5 mg to 2.5 mg, 2.5 mg to 10 mg, 2.5 mg to 7.5 mg, 2.5 mg to 5 mg, 5 mg to 10 mg, 5 mg to 7.5 mg, or 7.5 mg to 10 mg. In some embodiments, the implant weighs from 3 mg to 8 mg, 3 mg to 6 mg, or 4 mg to 6 mg. In some embodiments, the implant weighs 5 mg. 2.3 Polymer Coating

[0107] In some embodiments, the implant further comprises a polymer coating. In some embodiments, the polymer coating comprises polyethylene glycol, a zwitterionic polymer, a hydrophobic bioresorbable polymer, a bioadhesive polymer, or a combination thereof.

[0108] In some embodiments, the polymer coating comprises a zwitterionic polymer. In some embodiments, the zwitterionic polymer is selected from poly(sulfobetaine methacrylate), poly(carboxybetaine methacrylate), and combinations thereof.

[0109] In some embodiments, the polymer coating comprises a bioresorbable polymer. In some embodiments, the polymer coating is the same as the bioresorbable polymer described above. In some embodiments, the bioresorbable polymer coating is different from the bioresorbable polymer described above.

[0110] In some embodiments, the polymer coating comprises a hydrophobic bioresorbable polymer. In some embodiments, the hydrophobic bioresorbable polymer includes polycaprolactone (PCL).

[0111] In some embodiments, the polymer coating comprises a bioadhesive polymer. In some embodiments, the bioadhesive polymer is selected from polyacrylic acid derivatives, cellulose derivatives, natural polymers, polyvinylpyrrolidone (PVP), dextran polymers, polyethylene oxide polymers, thermally reversible polymers, ion-responsive polymers, copolymers of polymethyl vinyl ether and maleic anhydride, and combinations thereof.

[0112] In some embodiments, the polymer coating comprises a bioadhesive natural polymer. In some embodiments, the bioadhesive natural polymer is selected from gum arabic, gum tragali, agar polymers, xanthan gum, copolymers of alginate and sodium alginate, chitosan polymers, pectin, carrageenan, pullulan polymers, modified starch, and combinations thereof.

[0113] In some embodiments, the polymer coating comprises a biocompatible polymer, such as Eudragit. Eudragit is typically an acrylate-methacrylate copolymer that optionally includes quaternary ammonium groups and is available from Rohm Pharma under the trade name Eudragit®. Exemplary Eudragits include those suitable for sustained release, such as Eudragit® RL PO, Eudragit® RL 100, Eudragit® RL 30 D, Eudragit® RL 12.5, Eudragit® RS PO, Eudragit® RS 100, Eudragit® RS 30S, and Eudragit® 12.5. 2.4 Implant Characteristics

[0114] In some implementations, when measured under test conditions, the implant provides sustained release of a drug (e.g., a water-soluble drug) for at least 6 months, such as at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 12 months, at least 13 months, at least 14 months, at least 16 months, at least 18 months, or at least 24 months.

[0115] In some implementations, the implant provides drug release for 9 to 24 months, for example, 9 to 18 months, 9 to 14 months, 9 to 12 months, 12 to 16 months, or 12 to 14 months.

[0116] The test conditions were as follows: the implant was placed in the first chamber of a dual-chamber 1500 μl rapid microbalanced dialyzer (Harvard Apparatus Co., Holliston, MA), which was equipped with a semi-permeable regenerated cellulose membrane (molecular weight cutoff of 1,000 Da) separating the first and second chambers, with the second chamber containing PBS (pH 7.4); the dialyzer was maintained in a thermostatically controlled shaker at 37°C and 50 rpm; and samples were drawn from the second chamber at predetermined time points to assess drug content by HPLC.

[0117] In some embodiments, after six months under test conditions, the implant releases no more than 40 wt%, for example, no more than 50 wt%, no more than 60 wt%, no more than 70 wt%, or no more than 80 wt% of a drug (e.g., a water-soluble drug). In some embodiments, after six months under test conditions, the implant releases no more than 60 wt% of a drug.

[0118] In some implementations, after 11 months under test conditions, the implant releases no more than 80 wt%, for example, no more than 75 wt% or no more than 70 wt% of a drug (e.g., a water-soluble drug).

[0119] In some implementations, after 11 months under test conditions, the implant releases at least 70 wt%, for example, at least 75 wt% or at least 80 wt% of a drug (e.g., a water-soluble drug).

[0120] In some implementations, after 11 months under test conditions, the implant releases at least 70 wt%, for example, at least 75 wt%, at least 80 wt%, at least 85 wt%, at least 90 wt%, or at least 95 wt% of a drug (e.g., a water-soluble drug).

[0121] In some implementations, after fourteen months under test conditions, the implant releases no more than 90 wt%, for example, no more than 85 wt% or no more than 80 wt% of a drug (e.g., a water-soluble drug).

[0122] In some implementations, after 14 months under test conditions, the implant releases at least 80 wt%, for example, at least 85 wt% or at least 90 wt% of a drug (e.g., a water-soluble drug).

[0123] In some implementations, under test conditions, the implant releases no more than 40 wt% of the drug (e.g., water-soluble drug) after six months, no more than 80 wt% of the drug after 11 months, and no more than 90 wt% of the drug after 14 months.

[0124] In some embodiments, the implant releases 0.5 µg / day to 5 µg / day under test conditions, for example, a drug (e.g., a water-soluble drug) such as 0.5 µg / day to 4 µg / day, 0.5 µg / day to 3 µg / day, 0.5 µg / day to 2 µg / day, 0.5 µg / day to 1 µg / day, 1 µg / day to 5 µg / day, 1 µg / day to 4 µg / day, 1 µg / day to 3 µg / day, 1 µg / day to 2 µg, 2 µg / day to 5 µg / day, 2 µg / day to 4 µg / day, 3 µg / day to 5 µg / day, 3 µg / day to 4 µg / day, or 4 µg / day to 5 µg / day. In some embodiments, the implant releases 1 µg / day to 3 µg / day of drug under test conditions.

[0125] In some implementations, the implant has the following release profile under test conditions: (i) providing sustained release of the drug (e.g., a water-soluble drug) for at least six months, and (ii) releasing no more than 40 wt% of the drug after six months.

[0126] In some implementations, the implant has the following release profiles under test conditions: (i) providing sustained release of the drug (e.g., a water-soluble drug) for at least six months; (ii) releasing no more than 80 wt% of the drug after 11 months; and (iii) releasing no more than 90 wt% of the drug after 14 months.

[0127] In some implementations, the implant has the following release profiles under test conditions: (i) providing sustained release of a drug (e.g., a water-soluble drug) for at least six months, and (ii) releasing 0.5 µg / day to 5 µg / day of drug.

[0128] In some implementations, the implant has the following release profiles under test conditions: (i) providing sustained release of the drug (e.g., a water-soluble drug) for at least six months, (ii) releasing no more than 40 wt% of the drug after six months, (iii) releasing no more than 80 wt% of the drug after 11 months, and (iv) releasing no more than 90 wt% of the drug after 14 months.

[0129] In some implementations, the implant has the following release profiles under test conditions: (i) providing sustained release of the drug (e.g., a water-soluble drug) for at least six months, (ii) releasing no more than 40 wt% of the drug after six months, and (iii) releasing 0.5 µg / day to 5 µg / day of the drug.

[0130] In some implementations, the implant has the following release profiles under test conditions: (i) providing sustained release of the drug (e.g., a water-soluble drug) for at least six months, (ii) releasing no more than 80 wt% of the drug after 11 months, and (iii) releasing 0.5 µg / day to 5 µg / day of the drug.

[0131] In some implementations, the implant has the following release profiles under test conditions: (i) providing sustained release of the drug (e.g., a water-soluble drug) for at least six months, (ii) releasing no more than 40 wt% of the drug after six months, (iii) releasing no more than 80 wt% of the drug after 11 months, and (iv) releasing 0.5 µg / day to 5 µg / day of the drug.

[0132] In some implementations, the implant has the following release profiles under test conditions: (i) providing sustained release of the drug (e.g., a water-soluble drug) for at least six months, (ii) releasing no more than 40 wt% of the drug after six months, (iii) releasing no more than 80 wt% of the drug after 11 months, (iv) releasing no more than 90 wt% of the drug after 14 months, and (v) releasing 0.5 µg / day to 5 µg / day of the drug.

[0133] In some embodiments, the implant provides zero-order release of the drug. In some other embodiments, the implant provides Higuchi release of the drug, i.e., a drug release rate following the Higuchi model. In some embodiments, the implant provides Higuchi-Fickian drug release. In still other embodiments, the implant provides first-order drug release.

[0134] In some embodiments, when placed in water for 2 hours, the implant is given water with a pH of 5 to 8, for example, such as 5 to 7, 5 to 6, 6 to 8, 6 to 7, or 7 to 8. In some embodiments, the pH is selected from 5, 6, 7, or 8.

[0135] In some embodiments, when incubated at 37°C for 1 hour in a plate containing 2% w / v agarose gel, the implant swells by no more than 50% of the initial implant weight, for example, such as no more than 40%, no more than 30%, no more than 20%, no more than 10%, or no more than 5% of the initial implant weight.

[0136] In some embodiments, when incubated at 37°C for 1 hour in a plate containing 2% w / v agarose gel, the implant swells by no more than 15% of the initial implant weight, for example, such as no more than 10% or 5% of the initial implant weight.

[0137] In some embodiments, when incubated at 37°C for 2 hours in a plate containing 2% w / v agarose gel, the implant swelling does not exceed 20% of the initial implant weight, for example, such as not exceeding 15%, 10%, or 5% of the initial implant weight.

[0138] In some embodiments, when incubated at 37°C for 6 hours in a plate containing 2% w / v agarose gel, the implant swelling does not exceed 25% of the initial implant weight, for example, such as not exceeding 20%, 15%, 10%, or 5% of the initial implant weight.

[0139] In some embodiments, when incubated at 37°C for 8 hours in a plate containing 2% w / v agarose gel, the implant swelling does not exceed 35% of the initial implant weight, for example, such as not exceeding 30%, not exceeding 25%, not exceeding 20%, not exceeding 15%, not exceeding 10%, or not exceeding 5% of the initial implant weight.

[0140] In some embodiments, when incubated at 37°C for 48 hours in a plate containing 2% w / v agarose gel, the implant swelling does not exceed 45% of the initial implant weight, for example, such as not exceeding 40%, not exceeding 35%, not exceeding 30%, not exceeding 25%, not exceeding 20%, not exceeding 15%, not exceeding 10%, or not exceeding 5% of the initial implant weight.

[0141] In some embodiments, when incubated at 37°C for 72 hours in a plate containing 2% w / v agarose gel, the implant swelling does not exceed 60% of the initial implant weight, for example, such as not exceeding 55% of the initial implant weight, not exceeding 50% of the initial implant weight, not exceeding 45% of the initial implant weight, not exceeding 40% of the initial implant weight, not exceeding 35% of the initial implant weight, not exceeding 30% of the initial implant weight, not exceeding 25% of the initial implant weight, not exceeding 20% ​​of the initial implant weight, not exceeding 15% of the initial implant weight, not exceeding 10% of the initial implant weight, or not exceeding 5% of the initial implant weight.

[0142] In some implementations, when incubated at 37°C in a plate containing 2% w / v agarose gel, at least two of the following are true: The implant should not expand by more than 15% of its initial weight after 1 hour. The implant should not expand by more than 20% of its initial weight after 2 hours. The implant should not expand by more than 25% of its initial weight after 6 hours. The implant should not expand by more than 35% of its initial weight after 8 hours. The implant should not expand to more than 45% of its initial weight after 48 hours; and The implant will not expand to more than 60% of its initial weight after 72 hours.

[0143] In some implementations, the implant is a nanofiber implant. In some implementations, the implant is a nanoparticle implant.

[0144] In some embodiments, when incubated at 37°C for 1 hour in a plate containing 2% w / v agarose gel, the implant swells by no more than 15% of the initial implant weight, for example, such as no more than 10% or 5% of the initial implant weight.

[0145] In some embodiments, when incubated at 37°C for 2 hours in a plate containing 2% w / v agarose gel, the nanofiber implant expands by no more than 20% of the initial implant weight, for example, such as no more than 15%, no more than 10%, or no more than 5% of the initial implant weight.

[0146] In some embodiments, when incubated at 37°C for 6 hours in a plate containing 2% w / v agarose gel, the nanofiber implant expands by no more than 25% of the initial implant weight, for example, such as no more than 20%, no more than 15%, no more than 10%, or no more than 5% of the initial implant weight.

[0147] In some embodiments, when incubated at 37°C for 8 hours in a plate containing 2% w / v agarose gel, the nanofiber implant expands by no more than 35% of the initial implant weight, for example, such as no more than 30%, no more than 25%, no more than 20%, no more than 15%, no more than 10%, or no more than 5% of the initial implant weight.

[0148] In some embodiments, when incubated at 37°C for 48 hours in a plate containing 2% w / v agarose gel, the implant swelling does not exceed 45% of the initial implant weight, for example, such as not exceeding 40%, not exceeding 35%, not exceeding 30%, not exceeding 25%, not exceeding 20%, not exceeding 15%, not exceeding 10%, or not exceeding 5% of the initial implant weight.

[0149] In some embodiments, when incubated at 37°C for 72 hours in a plate containing 2% w / v agarose gel, the nanofiber implant expands by no more than 60% of the initial implant weight, for example, such as no more than 55% of the initial implant weight, no more than 50% of the initial implant weight, no more than 45% of the initial implant weight, no more than 40% of the initial implant weight, no more than 35% of the initial implant weight, no more than 30% of the initial implant weight, no more than 25% of the initial implant weight, no more than 20% of the initial implant weight, no more than 15% of the initial implant weight, no more than 10% of the initial implant weight, or no more than 5% of the initial implant weight.

[0150] In some implementations, when the nanofiber implant is incubated at 37°C in a plate containing 2% w / v agarose gel, at least two of the following are true: The nanofiber implant expands by no more than 15% of its initial implant weight after 1 hour. The nanofiber implant expanded by no more than 20% of its initial weight after 2 hours. The nanofiber implant expanded by no more than 25% of its initial weight after 6 hours. The nanofiber implant expanded by no more than 35% of its initial weight after 8 hours. The nanofiber implant expanded by no more than 45% of its initial implant weight after 48 hours; and The nanofiber implant expands by no more than 60% of its initial implant weight after 72 hours.

[0151] In some embodiments, when incubated at 37°C for 1 hour in a plate containing 2% w / v agarose gel, the nanoparticle implant expands by no more than 25% of the initial implant weight, for example, such as no more than 20%, no more than 15%, no more than 10%, or no more than 5% of the initial implant weight.

[0152] In some embodiments, when incubated at 37°C for 2 hours in a plate containing 2% w / v agarose gel, the nanoparticle implant expands by no more than 35% of the initial implant weight, for example, such as no more than 30%, no more than 25%, no more than 20%, no more than 15%, no more than 10%, or no more than 5% of the initial implant weight.

[0153] In some embodiments, when incubated at 37°C for 6 hours in a plate containing 2% w / v agarose gel, the nanoparticle implant expands by no more than 40% of the initial implant weight, for example, no more than 35%, 30%, 25%, 20%, 15%, 10%, or 5% of the initial implant weight.

[0154] In some embodiments, when incubated at 37°C for 24 hours in a plate containing 2% w / v agarose gel, the nanoparticle implant expands by no more than 45% of the initial implant weight, for example, such as no more than 40%, no more than 35%, no more than 30%, no more than 25%, no more than 20%, no more than 15%, no more than 10%, or no more than 5% of the initial implant weight.

[0155] In some embodiments, when incubated at 37°C for 48 hours in a plate containing 2% w / v agarose gel, the expansion of the nanoparticle implant does not exceed 50% of the initial implant weight, for example, not exceeding 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, or 5% of the initial implant weight.

[0156] In some embodiments, when incubated at 37°C for 72 hours in a plate containing 2% w / v agarose gel, the nanoparticle implant expands by no more than 60% of the initial implant weight, for example, such as no more than 55% of the initial implant weight, no more than 50% of the initial implant weight, no more than 45% of the initial implant weight, no more than 40% of the initial implant weight, no more than 35% of the initial implant weight, no more than 30% of the initial implant weight, no more than 25% of the initial implant weight, no more than 20% of the initial implant weight, no more than 15% of the initial implant weight, no more than 10% of the initial implant weight, or no more than 5% of the initial implant weight.

[0157] In some implementations, when the nanoparticle implant is incubated at 37°C in a plate containing 2% w / v agarose gel, at least two of the following are true: The nanoparticle implant expands by no more than 25% of its initial implant weight after 1 hour. The nanoparticle implant expanded by no more than 35% of its initial implant weight after 2 hours. The nanoparticle implant expanded by no more than 40% of its initial implant weight after 6 hours. The nanoparticle implant expanded by no more than 45% of its initial implant weight after 8 hours. The nanoparticle implants expanded by no more than 50% of their initial weight after 48 hours; and The nanoparticle implant expands by no more than 60% of its initial implant weight after 72 hours.

[0158] In some embodiments, when incubated for 3 days in a desiccator containing a saturated aqueous solution of ammonium chloride (relative humidity 79.5%), the implant exhibits a moisture absorption rate of 50 wt% or less, such as 40 wt% or less, 30 wt% or less, 20 wt% or less, 10 wt% or less, or 5 wt% or less.

[0159] In some embodiments, when incubated for 3 days in a desiccator containing a saturated aqueous ammonium chloride solution (relative humidity 79.5%), the implant exhibits a moisture absorption rate of 10 wt% or less, such as 9 wt% or less, 8 wt% or less, 7 wt% or less, 6 wt% or less, 5 wt% or less, 4 wt% or less, 3 wt% or less, 2 wt% or less, or 1 wt% or less.

[0160] In some embodiments, when incubated for 3 days in a desiccator containing a saturated aqueous solution of ammonium chloride (relative humidity 79.5%), the implant exhibits a moisture absorption rate of 5 wt% or less, such as 4 wt% or less, 3 wt% or less, 2 wt% or less, or 1 wt% or less.

[0161] In some embodiments, when incubated for 3 days in a desiccator containing a saturated aqueous solution of ammonium chloride (relative humidity 79.5%), the implant exhibits a moisture absorption rate of 3 wt% or less, such as 2 wt% or less or 1 wt% or less.

[0162] In some implementations, the implant exhibited less contamination than the control implant when evaluated under the following conditions: Plastic sheets (polypropylene, PP) were cut into the same shape and size as the implants (rods) and used as controls. The implants and PP rods were placed in 24-well plates and incubated with 1 ml of fibrinogen solution (10 mg / ml) in PBS for 2 h. After 2 h, the implants and PP rods were washed 5 times with PBS, then transferred to new 24-well plates and incubated with 1 ml of horseradish peroxidase-conjugated antifibrinogen (1 μg / ml) in PBS for 1 h, followed by 5 washes with PBS. The implants and PP rods were transferred to new 24-well plates and incubated with 1 ml of o-phenylenediamine citrate phosphate solution containing 0.03% hydrogen peroxide [1 mg / ml; 0.1 M (pH 5)] for 15 min. After 15 min, enzyme activity was terminated by adding 1 ml of 1 M HCl. The absorbance of the plates at 492 nm was measured using a microplate reader spectrophotometer. The absorbance of the wells containing the implants was calculated as a percentage of the absorbance of the wells containing the PP rods.

[0163] In some embodiments, the implant described herein exhibits at least 10% less protein contamination compared to a control implant, such as at least 20% less protein contamination, at least 30% less protein contamination, at least 40% less protein contamination, at least 50% less protein contamination, at least 60% less protein contamination, at least 70% less protein contamination, at least 80% less protein contamination, or at least 90% less protein contamination.

[0164] In certain embodiments, the implant exhibits an ex vivo trans-scleral drug permeation rate of 0.001 to 1 µg / min, for example, such as 0.01 µg / min to 1 µg / min, 0.05 µg / min to 1 µg / min, 0.1 µg / min to 1 µg / min, 0.2 µg / min to 1 µg / min, 0.3 µg / min to 1 µg / min, 0.4 µg / min to 1 µg / min, 0.5 µg / min to 1 µg / min, 0.6 µg / min to 1 µg / min, 0.7 µg / min to 1 µg / min, 0.8 µg / min to 1 µg / min, 0.9 µg / min to 1 µg / min, 0.01 µg / min to 0.9 µg / min, 0.05 µg / min to 0.9 µg / min, 0.1 µg / min to 0.9 µg / min, 0.2 µg / min to 0.9 µg / min, 0.3 µg / min to 0.9 µg / min, 0.4 µg / min to 0.9 µg / min, 0.5 µg / min to 0.9 µg / min, 0.6 µg / min to 0.9 µg / min, 0.7 µg / min to 0.9 µg / min, 0.8 µg / min to 0.9 µg / min, 0.01 µg / min to 0.8 µg / min, 0.05 µg / min to 0.8 µg / min, 0.1 µg / min to 0.8 µg / min, 0.2 µg / min to 0.8 µg / min, 0.3 µg / min to 0.8 µg / min, 0.4 µg / min to 0.8 µg / min, 0.5 µg / min to 0.8 µg / min, 0.6 µg / min to 0.8 µg / min, 0.7 µg / min to 0.8 µg / min, 0.01µg / min to 0.7 µg / min, 0.05 µg / min to 0.7 µg / min, 0.1 µg / min to 0.7 µg / min, 0.2 µg / min to 0.7 µg / min, 0.3 µg / min to 0.7 µg / min, 0.4 µg / min to 0.7 µg / min, 0.5 µg / min to 0.7 µg / min, 0.6 µg / min to 0.7 µg / min, 0.01 µg / min to 0.6 µg / min, 0.05 µg / min to 0.6 µg / min, 0.1 µg / min to 0.6 µg / min, 0.2 µg / min to 0.6 µg / min, 0.3 µg / min to 0.6 µg / min, 0.4 µg / min to 0.6 µg / min, 0.5 µg / min to 0.6 µg / min, 0.01 µg / min to 0.5 µg / min, 0.05 µg / min to 0.5 µg / min, 0.1 µg / min to 0.5 µg / min, 0.2 µg / min to 0.5 µg / min, 0.3 µg / min to 0.5 µg / min, 0.4 µg / min to 0.5 µg / min, 0.01 µg / min to 0.4 µg / min, 0.05 µg / min to 0.4 µg / min, 0.1 µg / min to 0.4 µg / min, 0.2 µg / min to 0.4 µg / min, 0.3 µg / min to 0.4 µg / min, 0.01 µg / min to 0.3 µg / min, 0.05 µg / min to 0.3 µg / min, 0.1 µg / min to 0.3 µg / min, 0.2 µg / min to 0.3 µg / min, 0.01 µg / min to 0.2 µg / min, 0.05 µg / min to 0.2 µg / min, 0.1 µg / min to 0.2 µg / min, 0.01 µg / min to 0.1 µg / min, 0.05 µg / min to 0.1 µg / min or 0.01 µg / min to 0.01 µg / min.

[0165] In certain embodiments, the implant exhibits an ex vivo transscleral drug permeation rate of from 0.1 μg / min to 1.5 μg / min, such as, for example, from 0.2 μg / min to 1.5 μg / min, from 0.3 μg / min to 1.5 μg / min, from 0.4 μg / min to 1.5 μg / min, from 0.5 μg / min to 1.5 μg / min, from 0.6 μg / min to 1.5 μg / min, from 0.7 μg / min to 1.5 μg / min, from 0.8 μg / min to 1.5 μg / min, from 0.9 μg / min to 1.5 μg / min, from 1.0 μg / min to 1.5 μg / min, from 1.1 μg / min to 1.5 μg / min, from 1.2 μg / min to 1.5 μg / min, from 1.3 μg / min to 1.5 μg / min, from 1.4 μg / min to 1.5 μg / min, from 0.1 μg / min to 1.4 μg / min, from 0.2 μg / min to 1.4 μg / min, from 0.3 μg / min to 1.4 μg / min, from 0.4 μg / min to 1.4 μg / min, from 0.5 μg / min to 1.4 μg / min, from 0.6 μg / min to 1.4 μg / min, from 0.7 μg / min to 1.4 μg / min, from 0.8 μg / min to 1.4 μg / min, from 0.9 μg / min to 1.4 μg / min, from 1.0 μg / min to 1.4 μg / min, from 1.1 μg / min to 1.4 μg / min, from 1.2 μg / min to 1.4 μg / min, from 1.3 μg / min to 1.4 μg / min, from 0.1 μg / min to 1.3 μg / min, from 0.2 μg / min to 1.3 μg / min, from 0.3 μg / min to 1.3 μg / min, from 0.4 μg / min to 1.3 μg / min, from 0.5 μg / min to 1.3 μg / min, from 0.6 μg / min to 1.3 μg / min, from 0.7 μg / min to 1.3 μg / min, from 0.8 μg / min to 1.3 μg / min, from 0.9 μg / min to 1.3 μg / min, from 1.0 μg / min to 1.3 μg / min, from 1.1 μg / min to 1.3 μg / min, from 1.2 μg / min to 1.3 μg / min, from 0.1 μg / min to 1.2 μg / min, from 0.2 μg / min to 1.2 μg / min, from 0.3 μg / min to 1.2 μg / min, from 0.4 μg / min to 1.2 μg / min, from 0.5 μg / min to 1.2 μg / min, from 0.6 µg / min to 1.2 µg / min, 0.7 µg / min to 1.2 µg / min, 0.8 µg / min to 1.2 µg / min, 0.9 µg / min to 1.2 µg / min, 1.0 µg / min to 1.2 µg / min, 1.1 µg / min to 1.2 µg / min, 0.1 µg / min to 1.1 µg / min, 0.2 µg / min to 1.1 µg / min, 0.3 to 1.1 µg / min, 0.4 µg / min to 1.1 µg / min, 0.5 µg / min to 1.1 µg / min, 0.6 µg / min to 1.1 µg / min, 0.7 µg / min to 1.1 µg / min, 0.8 µg / min to 1.1 µg / min, 0.9 µg / min to 1.1 µg / min, 1.0 µg / min to 1.1 µg / min, 0.1 µg / min to 1.0 µg / min, 0.2 µg / min to 1.0 µg / min, 0.3 µg / min to 1.0 µg / min, 0.4 µg / min to 1.0 µg / min, 0.5 µg / min to 1.0 µg / min, 0.6 µg / min to 1.0 µg / min, 0.7 µg / min to 1.0 µg / min, 0.8 µg / min to 1.0 µg / min, 0.9 µg / min to 1.0 µg / min, 0.1 µg / min to 0.9 µg / min, 0.2 µg / min to 0.9 µg / min, 0.3 µg / min to 0.9 µg / min, 0.4 µg / min to 0.9 µg / min, 0.5 µg / min to 0.9 µg / min, 0.6 µg / min to 0.9 µg / min, 0.7 µg / min to 0.9 µg / min, 0.8 µg / min to 0.9 µg / min, 0.1 µg / min to 0.8 µg / min, 0.2 µg / min to 0.8 µg / min, 0.3 µg / min to 0.8 µg / min, 0.4 µg / min to 0.8 µg / min, 0.5 µg / min to 0.8 µg / min, 0.6 µg / min to 0.8 µg / min, 0.7 µg / min to 0.8 µg / min, 0.1 µg / min to 0.7 µg / min, 0.2 µg / min to 0.7 µg / min, 0.3 µg / min to 0.7 µg / min, 0.4 µg / min to 0.7 µg / min, 0.5 µg / min to 0.7 µg / min, 0.6 µg / min to 0.7 µg / min, 0.1 µg / min to 0.6 µg / min, 0.2 µg / min to 0.6 µg / min, 0.3 µg / min to 0.6 µg / min, 0.4 µg / min to 0.6 µg / min, 0.5 µg / min to 0.6 µg / min, 0.1 µg / min to 0.5 µg / min, 0.2 µg / min to 0.5 µg / min, 0.3 µg / min to 0.5 µg / min, 0.4 µg / min to 0.5 µg / min, 0.1 µg / min to 0.4 µg / min, 0.2 µg / min to 0.4 µg / min, 0.3 µg / min to 0.4 µg / min, 0.1 µg / min to 0.3 µg / min, 0.2 µg / min to 0.3 µg / min and 0.1 µg / min to 0.2 µg / min.

[0166] In certain embodiments, the implant exhibits an in vitro transscleral drug permeation rate of 0.001 µg / min to 1 µg / min, for example, such as 0.01 µg / min to 1 µg / min, 0.05 µg / min to 1 µg / min, 0.1 µg / min to 1 µg / min, 0.2 µg / min to 1 µg / min, 0.3 µg / min to 1 µg / min, 0.4 µg / min to 1 µg / min, 0.5 µg / min to 1 µg / min, 0.6 µg / min to 1 µg / min, 0.7 µg / min to 1 µg / min, 0.8 µg / min to 1 µg / min, 0.9 µg / min to 1 µg / min, 0.01 µg / min to 0.9 µg / min, 0.05 µg / min to 0.9 µg / min, 0.1 µg / min to 0.9 µg / min, 0.2 µg / min to 0.9 µg / min, 0.3 µg / min to 0.9 µg / min, 0.4 µg / min to 0.9 µg / min, 0.5 µg / min to 0.9 µg / min, 0.6 µg / min to 0.9 µg / min, 0.7 µg / min to 0.9 µg / min, 0.8 µg / min to 0.9 µg / min, 0.01 µg / min to 0.8 µg / min, 0.05 µg / min to 0.8 µg / min, 0.1 µg / min to 0.8 µg / min, 0.2 µg / min to 0.8 µg / min, 0.3 µg / min to 0.8 µg / min, 0.4 µg / min to 0.8 µg / min, 0.5 µg / min to 0.8 µg / min, 0.6 µg / min to 0.8 µg / min, 0.7 µg / min to 0.8 µg / min, 0.01 µg / min to 0.7 µg / min, 0.05 µg / min to 0.7 µg / min, 0.1 µg / min to 0.7 µg / min, 0.2 µg / min to 0.7 µg / min, 0.3 µg / min to 0.7 µg / min, 0.4 µg / min to 0.7 µg / min, 0.5 µg / min to 0.7 µg / min, 0.6 µg / min to 0.7 µg / min, 0.01 µg / min to 0.6 µg / min, 0.05 µg / min to 0.6 µg / min, 0.1 µg / min to 0.6 µg / min, 0.2 µg / min to 0.6 µg / min, 0.3 µg / min to 0.6 µg / min, 0.4 µg / min to 0.6 µg / min, 0.5 µg / min to 0.6 µg / min, 0.01 µg / min to 0.5 µg / min, 0.05 µg / min to 0.5 µg / min, 0.1 µg / min to 0.5 µg / min, 0.2 µg / min to 0.5 µg / min, 0.3 µg / min to 0.5 µg / min, 0.4 µg / min to 0.5 µg / min, 0.01 µg / min to 0.4 µg / min, 0.05 µg / min to 0.4 µg / min, 0.1 µg / min to 0.4 µg / min, 0.2 µg / min to 0.4 µg / min, 0.3 µg / min to 0.4 µg / min, 0.01 µg / min to 0.3 µg / min, 0.05 µg / min to 0.3 µg / min, 0.1 µg / min to 0.3 µg / min, 0.2 µg / min to 0.3 µg / min, 0.01 µg / min to 0.2 µg / min, 0.05 µg / min to 0.2 µg / min, 0.1 µg / min to 0.2 µg / min, 0.01 µg / min to 0.1 µg / min, 0.05 µg / min to 0.1 µg / min or 0.01 µg / min to 0.01 µg / min. .

[0167] In some implementations, the implant showed an average transscleral drug flux of 0.0005 μg / cm³. 2 •hr to 5 μg / cm 2 •hr. In some implementations, the implant delivers an ex vivo transscleral average drug flux of 0.0005 μg / cm³. 2 •hr to 1 μg / cm 2 •hr. In some implementations, the implant delivers an ex vivo transscleral average drug flux of 0.0005 μg / cm³. 2 •hr to 0.1 μg / cm 2 •hr. In some implementations, the implant delivers an ex vivo transscleral average drug flux of 0.0005 μg / cm³. 2 •hr to 0.05 μg / cm 2 •hr, for example, such as 0.0006 μg / cm 2 •hr to 0.05 μg / cm 2 •hr, 0.0007 μg / cm 2 •hr to 0.05 μg / cm 2 •hr, 0.0008 μg / cm 2•hr to 0.05 μg / cm 2 •hr, 0.0009 μg / cm 2 •hr to 0.05 μg / cm 2 •hr, 0.001 μg / cm 2 •hr to 0.05 μg / cm 2 ·hr, 0.002μg / cm 2 •hr to 0.05 μg / cm 2 •hr, 0.003 μg / cm 2 •hr to 0.05 μg / cm 2 •hr, 0.004 μg / cm 2 •hr to 0.05 μg / cm 2 •hr, 0.005 μg / cm 2 •hr to 0.05 μg / cm 2 •hr, 0.006 μg / cm 2 •hr to 0.05 μg / cm 2 •hr, 0.007 μg / cm 2 •hr to 0.05 μg / cm 2 •hr, 0.008 μg / cm 2 •hr to 0.05 μg / cm 2 •hr, 0.009 μg / cm 2 •hr to 0.05 μg / cm 2 •hr, 0.01 μg / cm 2 •hr to 0.05 μg / cm 2 •hr, 0.02 μg / cm 2 •hr to 0.05 μg / cm 2 •hr, 0.03 μg / cm 2 •hr to 0.05 μg / cm 2 •hr, 0.04 μg / cm 2 •hr to 0.05μg / cm 2 •hr, 0.0005 μg / cm 2 •hr to 0.04 μg / cm 2 •hr, 0.0006 μg / cm 2 •hr to 0.04 μg / cm 2 •hr, 0.0007 μg / cm 2 •hr to 0.04 μg / cm 2 •hr, 0.0008 μg / cm 2•hr to 0.04 μg / cm 2 •hr, 0.0009 μg / cm 2 •hr to 0.04 μg / cm 2 •hr, 0.001 μg / cm 2 •hr to 0.04 μg / cm 2 •hr, 0.002 μg / cm 2 •hr to 0.04 μg / cm 2 •hr, 0.003 μg / cm 2 •hr to 0.04 μg / cm 2 •hr, 0.004 μg / cm 2 •hr to 0.04 μg / cm 2 •hr, 0.005 μg / cm 2 •hr to 0.04 μg / cm 2 •hr, 0.006 μg / cm 2 •hr to 0.04 μg / cm 2 •hr, 0.007 μg / cm 2 •hr to 0.04 μg / cm 2 •hr, 0.008 μg / cm 2 •hr to 0.04 μg / cm 2 •hr, 0.009 μg / cm 2 •hr to 0.04 μg / cm 2 •hr, 0.01 μg / cm 2 •hr to 0.04 μg / cm 2 •hr, 0.02 μg / cm 2 •hr to 0.04 μg / cm 2 •hr, 0.03 μg / cm 2 •hr to 0.04 μg / cm 2 •hr, 0.0005 μg / cm 2 •hr to 0.03 μg / cm 2 •hr, 0.0006 μg / cm 2 •hr to 0.03 μg / cm 2 •hr, 0.0007 μg / cm 2 •hr to 0.03 μg / cm 2 •hr, 0.0008 μg / cm 2 •hr to 0.03 μg / cm 2 •hr, 0.0009 μg / cm 2•hr to 0.03 μg / cm 2 •hr, 0.001 μg / cm 2 •hr to 0.03 μg / cm 2 •hr, 0.002 μg / cm 2 •hr to 0.03 μg / cm 2 •hr, 0.003 μg / cm 2 •hr to 0.03 μg / cm 2 •hr, 0.004 μg / cm 2 •hr to 0.03 μg / cm 2 •hr, 0.005 μg / cm 2 •hr to 0.03 μg / cm 2 •hr, 0.006 μg / cm 2 •hr to 0.03 μg / cm 2 •hr, 0.007 μg / cm 2 •hr to 0.03 μg / cm 2 •hr, 0.008 μg / cm 2 •hr to 0.03 μg / cm 2 •hr, 0.009 μg / cm 2 •hr to 0.03 μg / cm 2 •hr, 0.01 μg / cm 2 •hr to 0.03 μg / cm 2 •hr, 0.02 μg / cm 2 •hr to 0.03 μg / cm 2 •hr, 0.0005 μg / cm 2 •hr to 0.02 μg / cm 2 •hr, 0.0006 μg / cm 2 •hr to 0.02 μg / cm 2 •hr, 0.0007 μg / cm 2 •hr to 0.02 μg / cm 2 •hr, 0.0008 μg / cm 2 •hr to 0.02 μg / cm 2 •hr, 0.0009 μg / cm 2 •hr to 0.02 μg / cm 2 •hr, 0.001 μg / cm 2 •hr to 0.02 μg / cm 2 •hr, 0.0005 μg / cm 2•hr to 0.01 μg / cm 2 •hr, 0.0006 μg / cm 2 •hr to 0.01 μg / cm 2 •hr, 0.0007 μg / cm 2 •hr to 0.01 μg / cm 2 •hr, 0.0008 μg / cm 2 •hr to 0.01 μg / cm 2 •hr, 0.0009 μg / cm 2 •hr to 0.01 μg / cm 2 •hr, 0.01 μg / cm 2 •hr to 0.02 μg / cm 2 •hr, 0.005 μg / cm 2 •hr to 0.009 μg / cm 2 •hr, 0.006 μg / cm 2 •hr to 0.009 μg / cm 2 •hr, 0.007 μg / cm 2 •hr to 0.009 μg / cm 2 •hr, 0.008 μg / cm 2 •hr to 0.009 μg / cm 2 •hr, 0.005 μg / cm 2 •hr to 0.008 μg / cm 2 •hr, 0.006 μg / cm 2 •hr to 0.008 μg / cm 2 •hr, 0.007 μg / cm 2 •hr to 0.008 μg / cm 2 •hr, 0.005 μg / cm 2 •hr to 0.007 μg / cm 2 •hr, 0.006 μg / cm 2 •hr to 0.007 μg / cm 2 •hr, or 0.005 μg / cm 2 •hr to 0.006 μg / cm 2 •hr, 0.0005 μg / cm 2 •hr to 0.0009 μg / cm 2 •hr, 0.0006 μg / cm 2 •hr to 0.0009 μg / cm 2 •hr, 0.0007 μg / cm2 •hr to 0.0009 μg / cm 2 •hr, 0.0008 μg / cm 2 •hr to 0.0009 μg / cm 2 •hr, 0.0005 μg / cm 2 •hr to 0.0008 μg / cm 2 •hr, 0.0006 μg / cm 2 •hr to 0.0008 μg / cm 2 •hr, 0.0007 μg / cm 2 •hr to 0.0008 μg / cm 2 •hr, 0.0005 μg / cm 2 •hr to 0.0007 μg / cm 2 •hr, 0.0006 μg / cm 2 •hr to 0.00007 μg / cm 2 •hr or 0.0005 μg / cm 2 •hr to 0.006 μg / cm 2 ·hr.

[0168] In some implementations, the implant exhibits a permeability coefficient of 0.01·10⁻⁶. -4 cm / min to 1.10 -4 cm / min, preferably 0.01·10 -4 cm / min to 0.5·10 -4 cm / min, more preferably 0.01·10 -4 cm / min to 0.1 · 10 -4 cm / min, for example, such as 0.02·10 -4 cm / min to 0.1·10 -4 cm / min, 0.03·10 -4 cm / min to 0.1·10 -4 cm / min, 0.04·10 -4 cm / min to 0.1·10 -4 cm / min, 0.05·10 -4 cm / min to 0.1·10 -4 cm / min, 0.06·10 -4 cm / min to 0.1·10 -4 cm / min, 0.07·10 -4 cm / min to 0.1·10 -4 cm / min, 0.08·10-4 cm / min to 0.1·10 -4 cm / min, 0.09·10 -4 cm / min to 0.1·10 -4 cm / min, 0.01·10 -4 cm / min to 0.09·10 -4 cm / min, 0.02·10 -4 cm / min to 0.09·10 -4 cm / min, 0.03·10 -4 cm / min to 0.09·10 -4 cm / min, 0.04·10 -4 cm / min to 0.09·10 -4 cm / min, 0.05·10 -4 cm / min to 0.09·10 -4 cm / min, 0.06·10 -4 cm / min to 0.09·10 -4 cm / min, 0.07·10 -4 cm / min to 0.09 · 10 -4 cm / min, 0.08·10 -4 cm / min to 0.09·10 -4 cm / min, 0.01·10 -4 cm / min to 0.08·10 -4 cm / min, 0.02·10 -4 cm / min to 0.08·10 -4 cm / min, 0.03·10 -4 cm / min to 0.08·10 -4 cm / min, 0.04·10 -4 cm / min to 0.08·10 -4 cm / min, 0.05·10 -4 cm / min to 0.08·10 -4 cm / min, 0.06·10 -4 cm / min to 0.08·10 -4 cm / min, 0.07·10 -4 cm / min to 0.08·10 -4 cm / min, 0.01·10 -4 cm / min to 0.07 · 10 -4 cm / min, 0.02·10-4 cm / min to 0.07·10 -4 cm / min, 0.03·10 -4 cm / min to 0.07·10 -4 cm / min, 0.04·10 -4 cm / min to 0.07·10 -4 cm / min, 0.05·10 -4 cm / min to 0.07·10 -4 cm / min, 0.06·10 -4 cm / min to 0.07·10 -4 cm / min, 0.01·10 -4 cm / min to 0.06·10 -4 cm / min, 0.02·10 -4 cm / min to 0.06·10 -4 cm / min, 0.03·10 -4 cm / min to 0.06·10 -4 cm / min, 0.04·10 -4 cm / min to 0.06·10 -4 cm / min, 0.05·10 -4 cm / min to 0.06·10 -4 cm / min, 0.01·10 -4 cm / min to 0.05·10 -4 cm / min, 0.02·10 -4 cm / min to 0.05·10 -4 cm / min, 0.03·10 -4 cm / min to 0.05·10 -4 cm / min, 0.04·10 -4 cm / min to 0.05·10 -4 cm / min, 0.01·10 -4 cm / min to 0.04·10 -4 cm / min, 0.02·10 -4 cm / min to 0.04·10 -4 cm / min, 0.03·10 -4 cm / min to 0.04·10 -4 cm / min, 0.01·10 -4 cm / min to 0.03·10 -4 cm / min, 0.02·10-4 cm / min to 0.03·10 -4 cm / min, 0.01·10 -4 cm / min to 0.02·10 -4 cm / min, 0.01·10 -4 cm / min to 0.001 cm / min, 0.02·10 -4 cm / min to 0.001 cm / min, 0.03·10 -4 cm / min to 0.001 cm / min, 0.04·10 -4 cm / min to 0.001 cm / min, 0.05·10 -4 cm / min to 0.001 cm / min, 0.06·10 -4 cm / min to 0.001 cm / min, 0.07·10 -4 cm / min to 0.001 cm / min, 0.08·10 -4 cm / min to 0.001 cm / min, 0.09·10 -4 cm / min to 0.001 cm / min, 0.01·10 -4 cm / min to 0.09·10 -4 cm / min, 0.01·10 -4 cm / min to 0.05·10 -4 cm / min or 0.01·10 -4 cm / min to 0.02·10 -4 cm / min.

[0169] In some embodiments, the implant is stable for at least six months, for example, such as at least seven months, at least eight months, at least nine months, at least ten months, at least eleven months, or at least twelve months, when evaluated under one or more of the following conditions: 25°C and 60% relative humidity; 30°C and 65% relative humidity; and 40°C and 75% relative humidity, for example, such as... As used herein, "stable" means minimal or no change in physical appearance (e.g., size, shape, and color), maintaining a pH within ocularly tolerable limits (3.5–8.5), and having 90%–110% of the initial drug content when measured by HPLC. 3. Methods for preparing ocular implants

[0170] In one aspect, this disclosure provides a method for preparing the ocular implant described herein.

[0171] In some embodiments, methods for manufacturing ocular implants comprising multiple nanofibers include: A solution is prepared by dissolving a drug (e.g., a water-soluble or water-insoluble drug) and one or more bioresorbable polymers in a solvent. Electrospinning this solution provides nanofiber sheets containing multiple nanofibers on the collector surface. Collect nanofiber sheets from the collector surface, and Nanofiber sheets are cut into multiple implants, each containing various nanofibers; among them Nanofibers provide sustained drug release from the implant; and The implant is suitable for implantation in the eyes of mammals.

[0172] In embodiments of the methods described herein, the drug is as described above. In some embodiments, the drug is pregabalin.

[0173] The bioresorbable polymers described above can be used in the provided methods. In some embodiments, one or more bioresorbable polymers include poly(L-lactic acid) (PLA), polycaprolactone (PCL), polyglycolic acid, or copolymers thereof. In some embodiments, one or more bioresorbable polymers include poly(L-lactic acid) (PLA). In some embodiments, one or more bioresorbable polymers include polycaprolactone (PCL). In some embodiments, one or more bioresorbable polymers include poly(L-lactic acid) (PLA). In some embodiments, one or more bioresorbable polymers include copolymers of poly(L-lactic acid) (PLA), polycaprolactone (PCL), and polyglycolic acid.

[0174] The drug and one or more bioresorbable polymers are dissolved in any solvent in which both components are soluble. Exemplary solvents include organic solvents, organic acid solvents, inorganic acid solvents, and water.

[0175] In some embodiments, the solvent includes an organic solvent. In some embodiments, the organic solvent includes chloroform, acetone, dichloromethane, dimethylformamide, ethyl acetate, tetrahydrofuran, dimethyl sulfoxide, alcohols (e.g., methanol, ethanol, propanol, isopropanol, trifluoroethanol, hexafluoroisopropanol) or combinations thereof.

[0176] In some embodiments, the solvent includes an organic acid solvent. In some embodiments, the organic acid solvent includes acetic acid, trifluoroacetic acid, propionic acid, or combinations thereof. In some embodiments, the organic acid solvent includes acetic acid. In some embodiments, the organic acid solvent includes glacial acetic acid. In some embodiments, the organic acid solvent is composed of glacial acetic acid.

[0177] In some embodiments, the solvent contains less than 5 wt% water, for example, such as 0 wt% to 5 wt%, 0 wt% to 3 wt%, 0 wt% to 1 wt%, 0.1 wt% to 5 wt%, 0.1 wt% to 3 wt%, 0.1 wt% to 1 wt%, 0.5 wt% to 5 wt%, 0.5 wt% to 3 wt%, or 0.5 wt% to 1 wt%.

[0178] In some embodiments, the drug (e.g., a water-soluble drug) and the bioresorbable polymer are combined in solution at a weight ratio of 1:1 to 1:20, such as 1:1 to 1:15, 1:1 to 1:10, 1:1 to 1:5, 1:2 to 1:6, 1:2 to 1:5, 1:2 to 1:4, 1:2 to 1:3, 1:3 to 1:6, 1:3 to 1:5, 1:3 to 1:4, 1:4 to 1:6, or 1:4 to 1:5. In some embodiments, the weight ratio of the drug to one or more bioresorbable polymers is 1:4.

[0179] In some embodiments, the drug (e.g., a water-soluble drug) and one or more bioresorbable polymers are dissolved in a solvent to provide a solution by heating the mixture of the drug and the bioresorbable polymer to facilitate dissolution. In some embodiments, the mixture is heated to 30°C to 100°C, for example, such as 30°C to 75°C, 30°C to 50°C, 50°C to 100°C, 50°C to 75°C, or 75°C to 100°C.

[0180] In some embodiments, the drug (e.g., a water-soluble drug) and the bioresorbable polymer are mixed (e.g., shaken or stirred) to promote dissolution.

[0181] Once a solution of the drug and one or more bioresorbable polymers is prepared, the solution is electrospun using an electrospinning machine (e.g., a Spinbox from NanoScience Instruments (Phoenix, AZ)) to provide a nanofiber sheet containing multiple nanofibers deposited on a collector surface (e.g., the collector surface of the electrospinning machine). Those skilled in the art will understand that the parameters of the electrospinning machine will vary depending on the components being electrospun and their relative amounts.

[0182] In some embodiments, the electrospinning machine has one spray needle. In other embodiments, the electrospinning machine has multiple spray needles, such as two or more, three or more, or four or more spray needles.

[0183] In some implementations, coaxial electrospinning technology is employed. The main improvement in coaxial electrospinning technology lies in the spinning head, which consists of two capillaries, with the smaller (inner) one concentrically inserted into the larger (outer) capillaries to form a coaxial structure.

[0184] In some embodiments, the solution is electrospun at a flow rate of 1 μl / min to 20 μl / min, for example, such as 1 μl / min to 15 μl / min, 1 μl / min to 10 μl / min, 5 μl / min to 20 μl / min, 5 μl / min to 15 μl / min, 5 μl / min to 10 μl / min, 10 μl / min to 20 μl / min, 10 μl / min to 15 μl / min, or 15 μl / min to 20 μl / min. In some embodiments, the solution is electrospun at a flow rate of 8 μl / min.

[0185] In some embodiments, the distance between the nozzle and the collector surface of the electrospinning machine is 5 cm to 20 cm, for example, such as 5 cm to 15 cm, 5 cm to 10 cm, 10 cm to 20 cm, 10 cm to 15 cm, 15 cm to 20 cm, or 13 cm to 19 cm.

[0186] In some embodiments, the potential difference applied between the nozzle and the current collector surface of the electrospinning machine is 10 kV to 22 kV, such as 10 kV to 20 kV, 10 kV to 15 kV, 15 kV to 22 kV, or 15 kV to 20 kV. In some embodiments, the applied potential difference is 17 kV.

[0187] In some embodiments, the thickness of the nanofiber sheet is greater than 2 mm, for example, such as 2 mm to 10 mm, 2 mm to 8 mm or 2 mm to 5 mm.

[0188] In some embodiments, nanofiber sheets are collected from the collector surface as a single sheet. In some embodiments, nanofiber sheets are collected from the surface as multiple sheets.

[0189] In some embodiments, a cutting punch is used to cut the nanofiber sheet into multiple implants. In some embodiments, an oval-shaped punch is used to cut the nanofiber sheet into multiple implants.

[0190] In some embodiments, the nanofiber sheet is diced to provide an implant having one or more of the following shapes: spherical, oblate, ellipsoidal, rod-shaped, disc-shaped, tubular, hemispherical, oval, cylindrical, or irregular. In some embodiments, the nanofiber sheet is diced to provide a rod-shaped implant.

[0191] In some embodiments, methods for manufacturing ocular implants comprising multiple nanoparticles include: A drug (e.g., a water-soluble drug such as pregabalin) and one or more bioresorbable polymers are dissolved in a solvent to provide a solution; The solution is electrosprayed to provide a variety of nanoparticles on the collector surface. Collecting various nanoparticles from the collector surface, and Compressing at least a portion of multiple nanoparticles to form an implant; wherein Nanoparticles provide sustained drug release from the implant; and The implant is suitable for implantation in the eyes of mammals.

[0192] The bioresorbable polymers described above can be used in the provided methods. In some embodiments, one or more bioresorbable polymers include poly(L-lactic acid) (PLA), polycaprolactone (PCL), polyglycolic acid, or copolymers thereof. In some embodiments, one or more bioresorbable polymers include poly(L-lactic acid) (PLA). In some embodiments, one or more bioresorbable polymers include polycaprolactone (PCL). In some embodiments, one or more bioresorbable polymers include poly(L-lactic acid) (PLA). In some embodiments, one or more bioresorbable polymers include copolymers of poly(L-lactic acid) (PLA), polycaprolactone (PCL), and polyglycolic acid.

[0193] The drug (e.g., a water-soluble drug) and one or more bioresorbable polymers are dissolved in any solvent in which both components are soluble. Exemplary solvents include organic solvents, organic acid solvents, inorganic acid solvents, and water.

[0194] In some embodiments, the solvent includes an organic solvent. In some embodiments, the organic solvent includes chloroform, acetone, dichloromethane, dimethylformamide, ethyl acetate, tetrahydrofuran, dimethyl sulfoxide, alcohols (e.g., methanol, ethanol, propanol, isopropanol, trifluoroethanol, hexafluoroisopropanol) or combinations thereof.

[0195] In some embodiments, the solvent includes an organic acid solvent. In some embodiments, the organic acid solvent includes acetic acid, trifluoroacetic acid, propionic acid, or combinations thereof. In some embodiments, the organic acid solvent includes acetic acid. In some embodiments, the organic acid solvent includes glacial acetic acid. In some embodiments, the organic acid solvent is composed of glacial acetic acid.

[0196] In some embodiments, the solvent includes an organic solvent. In some embodiments, the organic solvent includes chloroform, acetone, dichloromethane, dimethylformamide, ethyl acetate, methanol, ethanol, or combinations thereof. In some embodiments, the organic solvent includes methanol.

[0197] In some embodiments, the solvent contains less than 5 wt% water, for example, such as 0 wt% to 5 wt%, 0 wt% to 3 wt%, 0 wt% to 1 wt%, 0.1 wt% to 5 wt%, 0.1 wt% to 3 wt%, 0.1 wt% to 1 wt%, 0.5 wt% to 5 wt%, 0.5 wt% to 3 wt%, or 0.5 wt% to 1 wt%.

[0198] In some embodiments, the drug (e.g., a water-soluble or water-insoluble drug) and the bioresorbable polymer are combined in solution at a weight ratio of 1:1 to 1:20, such as 1:1 to 1:15, 1:1 to 1:10, 1:1 to 1:5, 1:2 to 1:6, 1:2 to 1:5, 1:2 to 1:4, 1:2 to 1:3, 1:3 to 1:6, 1:3 to 1:5, 1:3 to 1:4, 1:4 to 1:6, or 1:4 to 1:5. In some embodiments, the drug is combined with one or more bioresorbable polymers at a weight ratio of 1:4.

[0199] In some embodiments, a drug (e.g., a water-soluble drug such as pregabalin) and one or more bioresorbable polymers are dissolved in a solvent to provide a solution by heating the mixture of the drug and the bioresorbable polymer to facilitate dissolution. In some embodiments, the mixture is heated to 30°C to 100°C, for example, such as 30°C to 75°C, 30°C to 50°C, 50°C to 100°C, 50°C to 75°C, or 75°C to 100°C.

[0200] In some implementations, the drug and the bioresorbable polymer are mixed, for example by shaking or stirring, to promote dissolution.

[0201] Once a solution of the drug and one or more bioresorbable polymers is prepared, the solution is electrosprayed using an electrosprayer (e.g., a Spinbox from NanoScience Instruments (Phoenix, AZ)) to deliver multiple nanoparticles deposited on a collector surface (e.g., the collector surface of the electrosprayer). Those skilled in the art will understand that the parameters of the electrosprayer will vary depending on the components being electrosprayed and their relative amounts.

[0202] In some implementations, the solution is in the form of 1 l / min to 20 Electrospraying is performed at a flow rate of l / min, for example, such as 1 l / min to 15 l / min, 1 l / min to 10 l / min, 5 l / min to 20 l / min, 5 l / min to 15 l / min, 5 l / min to 10 l / min, 10 l / min to 20 l / min, 10 l / min to 15 l / min or 15 l / min to 20 l / min. In some embodiments, the solution is at 8 l / min. Electrospraying is performed at a flow rate of l / min.

[0203] In some embodiments, the distance between the nozzle of the electro-sprayer and the surface of the collector is 5 cm to 20 cm, for example, such as 5 cm to 15 cm, 5 cm to 10 cm, 10 cm to 20 cm, 10 cm to 15 cm, 15 cm to 20 cm, or 13 cm to 19 cm.

[0204] In some embodiments, the applied potential difference between the nozzle and the collector surface is 10 kV to 22 kV, such as 10 kV to 20 kV, 10 kV to 15 kV, 15 kV to 22 kV, or 15 kV to 20 kV. In some embodiments, the applied potential difference is 17 kV.

[0205] Electrospraying provides a dry powder comprising a variety of nanoparticles. In some embodiments, some or all of the various nanoparticles deposited on the surface of the electrosprayer collector are collected and compressed to form an implant. Compression can be performed using any suitable device, such as a tablet press or a mold. As those skilled in the art will understand, the specific device and its setup vary depending on the desired implant shape. In some embodiments, compression provides one of the following implant shapes: spherical, oblate, ellipsoidal, rod-shaped, disc-shaped, tubular, hemispherical, or irregular. In some embodiments, compression provides a rod-shaped implant.

[0206] In some implementations, the method also includes filing the implant to remove rough edges. Filing can be done with any suitable device, such as a file or sandpaper.

[0207] In some embodiments, the methods for preparing nanoparticle implants or nanofiber implants described herein further include applying a polymer coating to the implant. The polymer coating can be applied using any suitable device, such as a coating dryer or a microcoating dryer. In some embodiments, the polymer coating includes polyethylene glycol, a zwitterionic polymer, a hydrophobic bioresorbable polymer, a bioadhesive polymer, or a combination thereof.

[0208] In some embodiments, the polymer coating comprises a zwitterionic polymer. In some embodiments, the zwitterionic polymer is selected from poly(sulfobetaine methacrylate), poly(carboxybetaine methacrylate), and combinations thereof.

[0209] In some embodiments, the polymer coating comprises a bioresorbable polymer. In some embodiments, the polymer coating is the same as the bioresorbable polymer described above. In some embodiments, the bioresorbable polymer coating is different from the bioresorbable polymer described above.

[0210] In some embodiments, the polymer coating comprises a hydrophobic bioresorbable polymer. In some embodiments, the hydrophobic bioresorbable polymer comprises polycaprolactone (PCL).

[0211] In some embodiments, the polymer coating comprises a bioadhesive polymer. In some embodiments, the bioadhesive polymer is selected from polyacrylic acid derivatives, cellulose derivatives, natural polymers, polyvinylpyrrolidone (PVP), dextran polymers, polyethylene oxide polymers, thermally reversible polymers, ion-responsive polymers, copolymers of polymethyl vinyl ether and maleic anhydride, and combinations thereof.

[0212] In some embodiments, the polymer coating comprises a bioadhesive natural polymer. In some embodiments, the bioadhesive natural polymer is selected from gum arabic, gum tragali, agar polymers, xanthan gum, copolymers of alginate and sodium alginate, chitosan polymers, pectin, carrageenan, pullulan polymers, modified starch, and combinations thereof.

[0213] In some embodiments, the polymer coating comprises a biocompatible polymer, such as Eudragit. Eudragit is typically an acrylate-methacrylate copolymer that optionally contains quaternary ammonium groups and is available from Rohm Pharma under the trade name Eudragit®. Exemplary Eudragits include those suitable for sustained release, such as Eudragit® RLPO, Eudragit® RL 100, Eudragit® RL 30 D, Eudragit® RL 12.5, Eudragit® RS PO, Eudragit® RS 100, Eudragit® RS 30S, and Eudragit® 12.5.

[0214] In some embodiments, the methods for preparing nanoparticle implants or nanofiber implants described herein further include sterilizing the implant. Any suitable sterilization method can be used, such as ethylene oxide, gamma radiation, or electron beam radiation. 4. Treatment methods

[0215] In one aspect of this disclosure, a method for treating an eye disease in a subject is provided, the method comprising placing the implant described herein in the subject's eye.

[0216] Implants can be placed in any functional (e.g., for vision) or structural tissue found in the eye, or partially or completely arranged in layers of tissue or cells inside or outside the eye. Specific examples of ocular regions include the anterior chamber, posterior chamber, vitreous cavity, choroid, suprachoroidal space, conjunctiva, subconjunctival space, suprascleral space, intracorneal space, supracorneal space, sclera, ciliary plane, surgically induced avascular area, macula, and retina.

[0217] In some embodiments, the implant is placed in one of the following locations: the subconjunctival space, anterior chamber, posterior chamber, vitreous cavity, subtendon sheath space, lower eyelid sulcus, upper eyelid sulcus, suprachoroidal space, or anterior chamber. In some embodiments, the implant is placed in the subconjunctival space of the eye. In some embodiments, the implant is placed in the anterior chamber of the eye.

[0218] In other implementations, the implant is placed in other parts of the subject's body besides the eyes, such as under the skin or intradermally, to provide long-term control of systemic diseases.

[0219] For subconjunctival placement of implants, in some cases, a pouch is created by incising the lower fornix of the eye. The implant is then placed into the pouch. The implant is placed by injection, for example, using a syringe with a needle. The needle gauge (G) should be appropriate for the desired injection site in the eye. In some embodiments, a syringe with a 19 G to 25 G needle is used. In some embodiments, a syringe with a 21 G needle is used to inject the implant into the subconjunctival space. In some embodiments, a syringe with a 30 G needle is used to inject into the vitreous cavity. Once the implant is placed in the subconjunctival space, the incision is closed, for example, by sutures.

[0220] In some implementations, for subconjunctival placement, the implant is injected using a syringe. In such implementations, no incision or suture steps are required.

[0221] In some implementations, a topical antibiotic is administered to the subject after implantation to prevent infection.

[0222] In some implementations, the implant is placed in one of the subject's eyes. In some implementations, one implant is placed in each of the subject's eyes.

[0223] In some embodiments, the implant provides sustained release as described above for the treatment of eye diseases. In some embodiments, the eye disease is selected from elevated IOP, glaucoma, intraocular inflammation, keratitis, dry eye, macular edema, diabetic macular edema (DME), infection, macular degeneration, age-related macular degeneration (AMD), blurred vision, herpetic conjunctivitis, blepharitis, retinal or choroidal neovascularization, uveitis, diabetic retinopathy, ischemic retinopathy, optic neuropathy, ocular cancer, chronic ocular allergic diseases, and cataracts.

[0224] In some implementations, the eye disease is elevated IOP. In some implementations, the eye disease is glaucoma-related elevated IOP. In some implementations, the eye disease is glaucoma.

[0225] In some implementations, this method reduces the subject's IOP from baseline by at least 10%, for example, such as at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 100% of baseline.

[0226] In some embodiments, the method reduces the IOP from the baseline by at least 2 mm Hg, at least 3 mm Hg, at least 4 mm Hg, at least 5 mm Hg, at least 6 mm Hg, at least 7 mm Hg, at least 8 mm Hg, at least 9 mm Hg, at least 10 mm Hg, at least 11 mm Hg, at least 12 mm Hg, at least 13 mm Hg, at least 14 mm Hg, or at least 15 mm Hg.

[0227] In some implementations, this method reduces IOP from a baseline greater than 21 mm Hg to 21 mm Hg or lower during treatment, for example, such as 21 mm Hg to 10 mm Hg, 20 mm Hg to 10 mm Hg, 19 mm Hg to 10 mm Hg, 18 mm Hg to 10 mm Hg, 17 mm Hg to 10 mm Hg, 16 mm Hg to 10 mm Hg, 15 mm Hg to 10 mm Hg, 14 mm Hg to 10 mm Hg, or 13 mm Hg to 10 mm Hg.

[0228] In some implementations, the reduction in IOP is maintained for at least 6 consecutive months from the time of implantation, such as at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 12 months, at least 13 months, at least 14 months, at least 15 months, at least 18 months, or at least 24 months. In some implementations, the reduction in IOP is maintained for at least 12 months from the time of implantation.

[0229] In some implementations, the change in IOP during treatment is less than 5 mm Hg, for example, such as less than 4 mm Hg, less than 3 mm Hg, less than 2 mm Hg, or less than 1 mm Hg.

[0230] In some implementations, these methods also include placing one or more follow-up implants after the initial implant has been exhausted. In some implementations, an implant is placed in the subject's eye every 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 18, or 24 months. In some implementations, an implant is placed in each of the subject's eyes every 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 18, or 24 months. Example Example 1: Preparation of the implant

[0231] For nanoparticle and nanofiber implants, pregabalin and the polymer are dissolved in a solvent or solvent system in the amounts provided in Table 1. The solution is loaded into a 20 ml syringe and then connected to the Spinbox infusion pump. Using the Spinbox electric sprayer / spinner at 8... The solution was electrosprayed (for nanoparticles) or electrospun (for nanofibers) at a flow rate of l / min. The distance between the nozzle and the collector was maintained between 13 cm and 19 cm. The applied potential difference between the nozzle and the collector was maintained at 17 kV. After spraying all the solution (approximately 40 hours), the product was collected from the collector surface. For nanoparticles, the product was collected in powder form using a scraper and stored in sealed glass vials until further analysis. Nanofibers were collected as a sheet (in the form of a thin film) and stored in an airtight glass container until further analysis. Note that Eudragit is not a bioresorbable polymer, but it was used as a biocompatible polymer for proof of concept in Table 1 to demonstrate the formation of nanoparticles.

[0232] Table 1. Composition of electrospraying and electrospinning solutions

[0233] Some of the pregabalin / polymer / solvent compositions in Table 1 have proven unsuitable for electrospinning or electrospraying (the “form” marked with “--”), or have not produced usable nanostructures when electrospinning or electrospraying.

[0234] The external structure of the obtained nanofibers and nanoparticles was examined using a scanning electron microscope (SEM) on a Carl Zeiss EVO HD LS15 (LaB6) equipped with a VPSE, STEM detector, and Oxford EDS detector. Figure 1 ).

[0235] For nanofibers, the obtained tablets were cut into rod-shaped implants with dimensions (4.0 x 2.0 x 0.5 mm, L x W x H) weighing 5 mg using a cutting punch. For nanoparticles, the powder was compressed into rod-shaped tablets with dimensions (6 mm in length and 0.5 mm in diameter) using a Vice handheld tablet press. Example 2: Physical properties of the implant composition

[0236] The physical properties of pregabalin nanofibers and nanoparticle implants were characterized by measuring pH using a pH meter and assessing particle size, polydispersity index (PDI), and zeta potential using a zeta sizer. The uniformity of drug content was determined by HPLC to evaluate the pregabalin nanofibers and nanoparticle implants in vitro.

[0237] Table 2 details the characteristics of the implant prepared according to Example 1.

[0238] Table 2. Properties of the implant composition

[0239] Regarding Table 2, "particle size" refers to the particle size of the nanoparticle implant formulation. "Particle size" refers to the diameter of the nanofibers in the nanofiber formulation.

[0240] The pH of nanoparticles or nanofibers was measured using a pH meter (Corning pH meter 440; Corning Inc., Corning, New York) by placing the nanoparticles or nanofibers in water and measuring the pH of the water. Half a gram of nanoparticles or nanofibers was dispersed in 10 mL of Milli-Q water at room temperature for 2 h, and then the pH was measured. The experiment was repeated three times, and the results are expressed as mean ± SEM.

[0241] After appropriate dilution, the particle size, polydispersity index (PDI), and zeta potential of the nanoparticles were determined using a Zetasizer (Nano series, nano-ZS, Malvern Instruments Limited, UK). All measurements were performed at 25 °C. Results from three independent trials are expressed as mean ± SEM.

[0242] The uniformity of drug content was measured by randomly selecting 10 implants. Each implant was dissolved separately in 10 ml of a common solvent containing both the drug and the polymer used to manufacture the implant. After complete dissolution, the solution was filtered through a 0.22 mm membrane filter, and the drug content was determined using UV-HPLC and calculated based on a standard curve. The drug content of each implant was calculated as a percentage of the labeled amount.

[0243] Characterization of the physical properties of the pregabalin nanofiber and nanoparticle implants showed that both implants had pH values ​​within the ocularly tolerable range. The relatively large particle size of both implants is expected to reduce surface area and support sustained, slow PRG release after subconjunctival application. Both implants exhibited high zeta potential values, indicating excellent shelf stability. Furthermore, the drug content of both the pregabalin nanofiber and nanoparticle implants was appropriate, within the acceptable pharmacopoeia range (90%–110%), indicating minimal drug loss during implant preparation. Example 3: In vitro release

[0244] The drug release behavior from the rod was evaluated as described in the following references:

[0245] In summary, the sustained release behavior of pregabalin from different implants was investigated using a 1500 μl rapid microequilibration dialyzer (Harvard Apparatus Co., Holliston, MA) in PBS (pH 7.4). This dialyzer featured a semi-permeable regenerated cellulose membrane (molecular weight cutoff of 1,000 Da) separating the two chambers. The implant was placed in the first chamber, and the second chamber contained PBS (pH 7.4). The dialyzer was maintained in a thermostatically controlled shaker at 37 °C and 50 rpm. Samples were drawn at predetermined time intervals over 24 h, and the pregabalin content was analyzed by HPLC.

[0246] Figure 2 Release profiles of pregabalin from the PRG-PLA-PCL (DL-lactide-co-caprolactone) nanofiber implant over 14 months are presented. Following an initial burst release of 8.0 ± 1.6% within the first hour, the implant exhibits an average release of 1.38 ± 0.25 g / day, which corresponds to 84.7 ± 13.0% (mean ± SEM; n = 3) of its cargo released over a period exceeding 14 months. Extrapolation of these data indicates Higuchi Fickian release kinetics over multiple months, assuming that drug release reaches 100% at a constant rate as the implant degrades. These data suggest that the PRG-PLA-PCL nanofiber implant can maintain and control PRG release in vitro for over a year. Furthermore, these promising in vitro release data for the PRG-PLA-PCL nanofiber implant support its annual application. Without being bound by theory, it is assumed that one or two nanofiber network structures and the avoidance of nanostructure compression during implant fabrication may contribute to the prolonged release time observed in the nanofiber implant disclosed herein. Example 4: Scleral / choroidal permeability

[0247] The permeability, steady-state flux, and permeability of pregabalin across the sclera / choroid can be measured using published methods, such as those described in PCT / US2018 / 066235. The modified Franz diffusion cell consists of two vertically connected chambers (donor chamber and recipient chamber) interconnected by a spherical connector suitable for spherical tissue (i.e., the sclera). The donor chamber has a volume of 0.5 ml, and the recipient chamber has a volume of 5 ml. The recipient chamber is stirred at 50 rpm using a magnetic stir bar to allow continuous mixing of the contents. An orifice with a diameter of 9 mm is located at the junction between the two chambers, where the sclera / conjunctival tissue is fixed, the implant is sandwiched between the sclera and conjunctiva, and the drug diffuses through the sclera into the recipient chamber. One implant is placed in the donor chamber. The recipient chamber is filled with 5 ml of BSS-Plus (balanced salt solution+), and the entire cell is surrounded by a warm water jacket to maintain the temperature at 37°C. 0.5 ml of sample was removed from the receptor chamber every 1 h for 5 h, and replaced with fresh BSS-Plus maintained at 37°C. The collected samples were analyzed for drug content using standard HPLC. The experiment was repeated six times, and the results were calculated as mean ± SEM. Data were plotted against time with cumulative permeation (μg). Permeability, steady-state flux, and permeability coefficient were calculated based on the slope of the plot.

[0248] The ex vivo transscleral permeability of PRG-PLA-PCL nanofiber implants (PRG-NF) and PRG-Eudragit nanoparticle implants (PRL-NP) was measured as described below.

[0249] General steps: In this study, freshly isolated conjunctiva and sclera from the eyes of New Zealand white rabbits were used. A PRG implant was sandwiched between the conjunctiva and sclera, which were mounted on a modified circular connector Franz diffusion cell. The cell temperature was maintained at 37 ± 0.5 °C with the aid of a circulating water bath. The recipient chamber was continuously stirred and filled with 5 mL of a balanced salt solution rich in bicarbonate, glucose, glutathione, and BSS-PLUS. At predetermined time intervals (1 h, 2 h, 3 h, 4 h, and 5 h), 500 μL was removed from the recipient chamber and replaced with an equal volume of fresh, warm BSS-PLUS. The permeated PRG concentration in the extracted samples was then immediately determined using UV-HPLC. Both implants delivered PRG through the sclera of the New Zealand white rabbits at a controlled rate.

[0250] The ex vivo transscleral permeability parameters of PRG-loaded nanofibers and nanoparticle implants are listed in Table 3.

[0251] Table 3. Ex vivo transscleral permeability parameters of PRG-loaded nanofibers and nanoparticle implants.

[0252] The results are as follows Figure 3 As shown, PRG-NF and PRG-NP implants controlled the high permeability of PRG (BCS Class I drugs) and demonstrated the implants' ability to deliver the drug at a constant rate for 12 months. Example 5: In vivo efficacy, safety and biocompatibility

[0253] When PRG implants are placed in anesthetized Dutch-Belted (DB) rabbits, a fully characterized preclinical model with spontaneously elevated IOP is achieved (Hays, C., Okafor, K., High, R., Singh, D. & Toris, C. Consequences of Publicity on Efficacy of Intraocular Pressure-Lowering Drugs in Male Dutch-Belted Rabbits). J Ocul Pharmacol Ther In subconjunctival incisions (34, 76-84 (2018)), the efficacy, safety, and biocompatibility of latanoprost in reducing intraconjunctival obstruction (IOP) were measured. This study was a non-GLP, prospective, randomized, parallel-group, masked design, employing two PRG doses (0.5 mg / implant and 2 mg / implant to compare response to dose levels) and four controls: 1) sham surgery; 2) placebo implant; 3) PRG microemulsion (0.6%) (e.g., PCT / US2018 / 066235); and 4) a control comparing the active agent of latanoprost. Two male and two female rabbits were evaluated under each experimental condition. Efficacy, safety, and biocompatibility were determined as described below. Primary outcome measures included changes in IOP, anterior / posterior segment parameters, and tissue compatibility. The number and severity of adverse events were recorded.

[0254] Implant insertion: Using an eyelid speculum, conjunctival forceps, and a sterile area, one implant (4 mm x 2 mm x 0.5 mm, inserted longitudinally; the same implant was placed in both eyes of each rabbit) was placed in a surgical bag formed by a 2.5 mm incision in the lower fornix of the eye. After implant placement, the incision was sutured with 10-0 nylon sutures, and topical antibiotics were applied to the eye.

[0255] Therapeutic effects: To determine the efficacy, the Tono-pen Avia tonometer and the published method (Ibrahim, M) were used. et al.Once Daily Pregabalin Eye Drops for Management of Glaucoma. ACS Nano 13, 13728-13744 (2019)) Measure IOP. Readings were taken daily before enrollment and for 2 weeks after implantation. IOP was then assessed weekly. With each IOP reading, the eyes were visually examined for inflammation, swelling, irritation, etc. If any adverse reactions were observed, rabbits were evaluated using the following safety protocol. IOP was measured one month after PRG release from the implant to identify any persistent physiological effects following drug release.

[0256] Safety and biocompatibility: The safety and biocompatibility of the PRG implant and the four controls described above were determined using the following method: SPOTS system (Eaton, J., Miller, P., Bentley, E., Thomasy, S. & CJ, M. The SPOTS System: An Ocular Scoring System Optimized for Use in Modern Preclinical Drug Development and Toxicology). J. Ocular Pharmacol Ther 33,718-734 (2017); in vivo slit-lamp biomicroscopy; and histopathology. Each rabbit underwent clinical examination prior to study enrollment, except for the following timeframes after implantation (1 day; 1 week; and monthly until the end of the study).

[0257] Anterior segment examination was performed using a slit-lamp biomicroscope: pupillary light reflex; conjunctival hyperemia, swelling, and congestion; corneal opacity and vascularization; anterior chamber cells and flares, iris involvement, and anterior vitreous cell infiltration; severity and area of ​​corneal fluorescein staining; and lens opacity. Although not part of the SPOTS system, each eye was examined to determine if the implant had moved and for any signs of inflammation, rejection, etc., at and away from the implant insertion site.

[0258] Posterior segment examination using a slit-lamp biological microscope and a 78 diopter lens revealed: vitreous opacities; fundus visual field deterioration; and paravascular sheath formation in the retina.

[0259] Histopathology: After euthanizing each group of rabbits, the following ocular tissues were processed for histopathological examination: the full-thickness eyeball at the implant site, including a 2 mm margin; the iridocorneal angle, including the ciliary body and outflow structures; and the central and peripheral retina. Sections obtained from the area surrounding the implant were stained with Masson's trichrome and CD45 to determine foreign body reaction, the presence of collagen capsule formation, and the presence of infiltrating T cells, respectively. The perimeter of the implant was measured to estimate the amount of remaining implant. To determine whether the endothelium was negatively affected, the cornea was hemisectioned, and one half was stained with Alizarin S to calculate the density of the corneal endothelium.

[0260] Biodistribution of PRG: These studies determined the distribution of the drug in the eye one month after implantation and at the conclusion of the study. The following tissues were analyzed: conjunctiva, sclera, and choroid (at the insertion site and 180º); aqueous humor; cornea; lens; ciliary body; trabecular meshwork; vitreous body; and a small portion of the retina was taken for histopathological examination. The amount of PRG in the following tissues was compared between different treatments: PRG-loaded implants; placebo implants; sham surgery; and PRG ME.

[0261] Rigor, statistical analysis, and gender as variables: Assuming a power of 80% and a significant difference in IOP of 25%, this study was estimated to require testing 8 eyes for each experimental condition. An equal number of male and female rabbits were included, and responses for each sex were initially assessed separately; if no significant difference was found, they were pooled. To ensure the rigor of the clinical evaluation, 3–5 measurements were collected from each eye per test per rabbit, averaged, and considered as one biological sample. To reduce bias, the experimenter was unaware of the formulation ingredients used to administer the drug to each eye. Quantitative and semi-quantitative values ​​are expressed as mean ± SEM. Statistical differences between groups were analyzed by one-way ANOVA, followed by Tukey post-hoc tests using GraphPad Prism software (if the F-test was significant). p < 0.05 was defined as significant. Example 6: Expansion behavior of pregabalin nanofiber and pregabalin nanoparticle implants

[0262] The expansion behavior of PRG-PLA-PCL nanofibers (PRG-NF) and PRG-Eudragit nanoparticles (PRL-NP) implants was examined as described below.

[0263] General steps: The swelling index of the prepared pregabalin nanofiber (PRG-NF) and pregabalin nanoparticle (PRG-NP) long-acting implants was determined using the agarose gel plate method. Plates containing 15 mL of 2% w / v agar solution were prepared and allowed to cure at room temperature. The PRG implants were initially weighed using an analytical balance and maintained at 37°C. Agarose gel plates at 1°C. The PRG implants were reweighed using an analytical balance after several time intervals (1 h, 2 h, 6 h, 24 h, 48 h, and 72 h). The agarose gel plates were covered with glass lids throughout the experiment.

[0264] The inflation index is calculated using the following formula: Expansion percentage = [(Weight of expanded implant - Weight of initial implant) / Weight of initial implant] x 100 Figure 4 (Figures A and B) show the results. PRG-NF and PRG-NP implants exhibited significant swelling in the first few hours. The swelling reached equilibrium after day 1 (mean ± SEM; n=6).

[0265] This expansion line is expected to support the release of the drug at a constant rate after administration. Example 7: Moisture absorption rate of pregabalin nanofiber and nanoparticle implants

[0266] The hygroscopic behavior of PRG-PLA-PCL nanofiber implants (PRG-NF) and PRG-Eudragit nanoparticle implants (PRL-NP) was investigated to evaluate the shelf stability of the implants at room temperature.

[0267] General steps: PRG-NF and PRG-NP implants were stored in a desiccator at a relative humidity (RH) of 79.5%. RH was generated using a saturated ammonium chloride aqueous solution to determine the moisture absorption capacity of the PRG-NF and PRG-NP implants, thus testing their stability during shelf storage at room temperature (24 ± 1 °C). The weights of the PRG-NF and PRG-NP implants were weighed using an analytical balance initially and after three days of storage. The moisture absorption rate was determined using the following formula: Moisture absorption rate (%) = [(Final weight of implant - Initial weight of implant) / Initial weight of implant] x 100 Figure 5 The results of the moisture absorption test over three days are shown. Both PRG-NF and PRG-NP implants were stable with minimal moisture absorption (mean ± SEM; n=6). These results indicate that the PRG-NF and PRG-NP implants have suitable shelf stability. 6. Equivalents and incorporation by reference

[0268] Although the disclosed contents have been specifically shown and described with reference to preferred embodiments and various alternative embodiments, those skilled in the art should understand that various changes in form and detail may be made without departing from the spirit and scope of the disclosed contents.

[0269] For all purposes, all references, granted patents and patent applications cited in the text of this specification are incorporated herein by reference in their entirety. In particular, PCT patent application number PCT / US2018 / 066235 (filed December 18, 2018), PCT patent application number PCT / US2021 / 047109 (filed August 23, 2021), and U.S. Provisional Patent Application No. 63 / 579,826 (filed August 31, 2023) are incorporated herein by reference in their entirety.

Claims

1. An ocular implant comprising multiple nanofibers, wherein: The nanofibers contain a drug (e.g., a water-soluble drug or a water-insoluble drug) and one or more bioresorbable polymers. The nanofibers provide sustained release of the drug from the implant; and The implant is suitable for implantation in the eye of a mammal, for example, in the subconjunctival space of the eye of the mammal.

2. The implant according to claim 1, wherein the drug is selected from antibacterial agents, antiviral agents, antifungal agents, steroids, sterols, anti-inflammatory drugs, angiogenesis inhibitors, growth factors, anticoagulants, antioxidants, pyridine, antihypertensive drugs, antidiabetic drugs, insulin, progenitor cells / stem cells, intraocular pressure (IOP) lowering drugs, and combinations thereof.

3. The implant according to claim 1, wherein the drug is selected from the following water-soluble drugs: β-blockers (preferably betalol and timolol), prostaglandin analogs (preferably bimatoprost, latanoprost, and travoprost), α-adrenergic agents (preferably brimonidine tartrate), carbonic anhydrase inhibitors (preferably brinzolamide, dazolamide, and acetazolamide), calcium channel blockers (preferably nimodipine and pregabalin), sialic acid, galactose, trianthracycline (NA3) (sialic acid-trianthracycline complex type N-glycan), OT-551 hydrochloride (1-hydroxy-2,2,6,6-tetramethyl-4-piperidinylcyclopropionic acid hydrochloride), brimonidine tartrate, clindamycin, ciprofloxacin, levofloxacin, gatifloxacin, gemimifloxacin, ofloxacin Triamcinolone, valacyclovir, pyrimethamine, valganciclovir, ganciclovir, acyclovir, phosphonoformic acid, prednisolone acetate, difluoroprednisolone, triamcinolone, dexamethasone, methotrexate, azathioprine, mycophenolate mofetil, cyclosporine, tacrolimus, cyclophosphamide, ribavirin, bromofenac, ketorolac, naproxen, ristatin, flurbiprofen, diclofenac, ketotifen, nadolol Romi, phenoxybenzamine, azelastine, epinastine, naphazoline / feniramine, olopatadine, betasine, acartadine, pyrimisulfate, tetrahydrozoline with or without zinc sulfate, lodusamide, naphazoline, phenoxybenzamine, cromoglycine, emestin, oxymetazoline, xylometazoline, loratadine, desloratadine, phenylglycine, gabapentin, pharmaceutically acceptable salts of the above drugs, and combinations thereof.

4. The implant according to claim 3, wherein the water-soluble drug is pregabalin.

5. The implant according to any one of claims 1-4, wherein the implant comprises 0.1 wt% to 50 wt%, preferably 1 wt% to 30 wt%, or 10 wt% to 30 wt%, more preferably 20 wt% of the drug.

6. The implant according to any one of claims 1-5, wherein the one or more bioresorbable polymers comprise poly(α-hydroxy acid), poly(glycolic acid-co-lactide) (PLG), poly(D,L-lactide-co-caprolactone) (DL-PLCL), polycaprolactone (PCL), poly(L-lactic acid) (PLA), poly(trimethylene carbonate) (PTMC), poly(p-dioxanone) (PDO), poly(4-hydroxybutyrate) (PHB), and polyhydroxyalkanoates. (PHA), polyphosphazene, polyphosphate ester, polyamino acid, polyphenolic peptide, poly(butylene succinate) (PBS), polyethylene oxide, polypropylene fumarate, polyiminocarbonate, poly(lactide-co-caprolactone) (PLCL), poly(glycolic acid-co-caprolactone) (PGCL) copolymer, poly(D,L-lactic acid), polyglycolic acid, poly(L-lactide-co-D,L-lactide), poly(L-lactide-co-glycolic acid), poly(D,L-lactide-co-glycolic acid) Poly(glycolic acid-trimethylene carbonate), poly(glycolic acid-co-caprolactone) (PGCL), poly(ethyl glutamate-co-glutamic acid), poly(tert-butoxycarbonylmethyl glutamate), polyglycerol sebacate, tyrosine-derived polycarbonates, poly1,3-bis(p-carboxyphenoxy)hexane-co-sebacate, polyphosphazene, ethylglycine polyphosphazene, polycaprolactone-co-butyl acrylate, polyhydroxybutyrate copolymer, maleic anhydride copolymer, poly(trimethylene carbonate) copolymer, polyethylene glycol (PEG), hydroxypropyl methylcellulose and cellulose derivatives, polysaccharides (e.g., hyaluronic acid, chitosan) Polysaccharides and starches), proteins (e.g., gelatin and collagen), polyaspirin, polyphosphazenes, collagen, alginate, albumin, fibrin, vitamin E analogs, D-lactide, D,L-lactide, L-lactide, D,L-lactide-caprolactone (DL-CL), D,L-lactide-glycolic acid-caprolactone (DL-G-CL), dextran, vinylpyrrolidone, polyvinyl alcohol (PVA), PVA-g-PLGA, PEGT-PBT copolymer (multi-active), methacrylates, poly(N-isopropylacrylamide), PEO-PPO-PEO (pluronics), PEO-PPO-PAA copolymer, PLGA-PEO-PLGA, PEG-PLG, PLA-PLGA, poloxamer 407, PEG-PLGA-PEG triblock copolymer, SAIB (sucrose isobutyrate acetate), hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl methylcellulose, carboxymethyl cellulose or its salts, Carbopol®, poly(hydroxyethyl methacrylate), poly(methoxyethyl methacrylate), poly(methoxyethoxyethyl methacrylate), polymethyl methacrylate (PMMA), methyl methacrylate (MMA), gelatin, polyvinyl alcohol, propylene glycol or combinations thereof.

7. The implant of claim 6, wherein the one or more bioresorbable polymers comprise or consist of poly(L-lactic acid) (PLA), polycaprolactone (PCL), polyhydroxyacetic acid, or combinations thereof.

8. The implant according to claim 7, wherein the one or more bioresorbable polymers are copolymers of poly(L-lactic acid) (PLA), polycaprolactone (PCL), and polyhydroxyacetic acid.

9. The implant according to any one of claims 1-8, wherein the implant comprises 50 wt% to 99.9 wt%, preferably 75 wt% to 95 wt%, more preferably 80 wt% of one or more of the bioresorbable polymers.

10. The implant according to any one of claims 1-9, wherein the weight ratio of the drug to one or more bioresorbable polymers is 1:1 to 1:20, preferably 1:1 to 1:10, more preferably 1:2 to 1:6, and even more preferably 1:

4.

11. The implant according to any one of claims 1-10, wherein the nanofibers further comprise a permeability enhancer.

12. The implant according to claim 11, wherein the permeability enhancer is selected from D-α-tocopherol polyethylene glycol succinate (TPGS), sodium dioctyl sulfosuccinate, sodium decanoate, sodium N-[8-(2-hydroxybenzoyl)amino]octanoate (SNAC), sodium dodecyl sulfate, sodium salicylate, oleic acid, lecithin, anhydrous ethanol, polysorbate or polyoxyethylene sorbitan fatty acid ester (Tween), sorbitan fatty acid ester (Spans), polyoxyethylene alkyl ether (Brij) s), poly(40) stearate, poly(50) stearate, polyethylene glycol, polyvinyl alcohol, polyvinylpyrrolidone (e.g., polyvinylpyrrolidone K29-32), hydroxypropyl methylcellulose, polyvinylpyrrolidone / vinyl acetate (VP / VA) copolymer, poly(lactic-co-hydroxyacetic acid), disodium ethylenediaminetetraacetate, propylene glycol, glyceryl monooleate, bile salts, octylphenol polyether, nonionic surfactants, anionic surfactants, cationic surfactants, and combinations thereof.

13. The implant according to any one of claims 1-12, wherein the implant has one of the following shapes: spherical, flattened, ellipsoidal, rod-shaped, disc-shaped, tubular, hemispherical, oval, cylindrical, or irregular.

14. The implant of claim 13, wherein the implant is rod-shaped.

15. The implant according to any one of claims 1-14, wherein the implant has the following dimensions: a length of 0.5 mm to 6 mm, a width of 0.5 mm to 6 mm, and a height of 0.2 mm to 6 mm.

16. The implant according to any one of claims 1-15, wherein the nanofiber has a diameter of 100 nm to 1,000 nm, preferably 100 nm to 500 nm, more preferably 200 nm to 400 nm.

17. The implant according to any one of claims 1-14, wherein the implant comprises 0.1 mg to 5 mg of the drug, preferably 0.5 mg to 2 mg of the drug.

18. The implant according to any one of claims 1-17, wherein the implant weighs from 0.5 mg to 10 mg, preferably from 3 mg to 8 mg, more preferably from 3 mg to 6 mg or 5 mg.

19. An ocular implant comprising multiple nanoparticles, wherein: The nanoparticles comprise a drug (e.g., a water-soluble drug such as pregabalin) and one or more bioresorbable polymers. The nanoparticles provide sustained release of the drug from the implant; and The implant is suitable for implantation in the eye of a mammal, for example, in the subconjunctival space of the eye of the mammal.

20. The implant of claim 19, wherein the drug is selected from antibacterial agents, antiviral agents, antifungal agents, steroids, sterols, anti-inflammatory drugs, angiogenesis inhibitors, growth factors, anticoagulants, antioxidants, pyridine, antihypertensive drugs, antidiabetic drugs, insulin, progenitor cells / stem cells, intraocular pressure (IOP) lowering drugs, and combinations thereof.

21. The implant according to claim 19, wherein the drug is selected from the group consisting of water-soluble drugs: β-blockers (preferably betalol and timolol), prostaglandin analogs (preferably bimatoprost, latanoprost, and travoprost), α-adrenergic agents (preferably brimonidine tartrate), carbonic anhydrase inhibitors (preferably brinzolamide, dazolamide, and acetazolamide), calcium channel blockers (preferably nimodipine and pregabalin), sialic acid, galactose, trianthracycline (NA3) (sialic acid-trianthracycline complex type N-glycan), OT-551 hydrochloride (1-hydroxy-2,2,6,6-tetramethyl-4-piperidinylcyclopropionic acid hydrochloride), brimonidine tartrate, clindamycin, ciprofloxacin, levofloxacin, gatifloxacin, gemimifloxacin, ofloxacin Star, Triamcinolone, Valacyclovir, Pyrimethamine, Valganciclovir, Ganciclovir, Acyclovir, Foscarboxylic Acid, Prednisolone Acetate, Difluoropregnane Butylesteride, Triamcinolone, Dexamethasone, Methotrexate, Azathioprine, Mycophenolate Mofetil, Cyclosporine, Tacrolimus, Cyclophosphamide, Ribavirin, Bromfenac, Ketoprofen, Naphazoline, Rittal, Flurbiprofen, Diclofenac, Ketotifen, Nadol Romi, phenoxybenzamine, azelastine, epinastine, naphazoline / feniramine, olopatadine, betasine, acartadine, pyrimisulfate, tetrahydrozoline with or without zinc sulfate, lodusamide, naphazoline, phenoxybenzamine, cromoglycine, emestin, oxymetazoline, xylometazoline, loratadine, desloratadine, phenylglycine, gabapentin, pharmaceutically acceptable salts of the above drugs, and combinations thereof.

22. The implant of claim 21, wherein the drug is pregabalin.

23. The implant of claim 19, wherein the one or more bioresorbable polymers comprise poly(α-hydroxy acid), poly(glycolic acid-co-lactide) (PLG), poly(D,L-lactide-co-caprolactone) (DL-PLCL), polycaprolactone (PCL), poly(L-lactic acid) (PLA), poly(trimethylene carbonate) (PTMC), poly(p-dioxanone) (PDO), poly(4-hydroxybutyrate) (PHB), and polyhydroxyalkanoates (P... HA), polyphosphazene, polyphosphate, polyamino acids, polyphenolic peptides, poly(butylene succinate) (PBS), polyethylene oxide, polypropylene fumarate, polyiminocarbonate, poly(lactide-co-caprolactone) (PLCL), poly(glycolic acid-co-caprolactone) (PGCL) copolymer, poly(D,L-lactic acid), polyglycolic acid, poly(L-lactide-co-D,L-lactide), poly(L-lactide-co-glycolic acid), poly(D,L-lactide-co-glycolic acid) Poly(glycolic acid-trimethylene carbonate), poly(glycolic acid-co-caprolactone) (PGCL), poly(ethyl glutamate-co-glutamic acid), poly(tert-butoxycarbonylmethyl glutamate), polyglycerol sebacate, tyrosine-derived polycarbonates, poly1,3-bis(p-carboxyphenoxy)hexane-co-sebacate, polyphosphazene, ethylglycine polyphosphazene, polycaprolactone-co-butyl acrylate, polyhydroxybutyrate copolymer, maleic anhydride copolymer, poly(trimethylene carbonate) copolymer, polyethylene glycol (PEG), hydroxypropyl methylcellulose and cellulose derivatives, polysaccharides (e.g., hyaluronic acid, chitosan) Polysaccharides and starches), proteins (e.g., gelatin and collagen), polyaspirin, polyphosphazenes, collagen, alginate, albumin, fibrin, vitamin E analogs, D-lactide, D,L-lactide, L-lactide, D,L-lactide-caprolactone (DL-CL), D,L-lactide-glycolic acid-caprolactone (DL-G-CL), dextran, vinylpyrrolidone, polyvinyl alcohol (PVA), PVA-g-PLGA, PEGT-PBT copolymer (multi-active), methacrylates, poly(N-isopropylacrylamide), PEO-PPO-PEO (pluronics), PEO-PPO-PAA copolymer, PLGA-PEO-PLGA, PEG-PLG, PLA-PLGA, poloxamer 407, PEG-PLGA-PEG triblock copolymer, SAIB (sucrose isobutyrate acetate), hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl methylcellulose, carboxymethyl cellulose or its salts, Carbopol®, poly(hydroxyethyl methacrylate), poly(methoxyethyl methacrylate), poly(methoxyethoxyethyl methacrylate), polymethyl methacrylate (PMMA), methyl methacrylate (MMA), gelatin, polyvinyl alcohol, propylene glycol or combinations thereof.

24. The implant of claim 20, wherein the one or more bioresorbable polymers comprise or consist of poly(L-lactic acid) (PLA), polycaprolactone (PCL), polyhydroxyacetic acid, or combinations thereof.

25. The implant of claim 24, wherein the one or more bioresorbable polymers are copolymers of poly(L-lactic acid) (PLA), polycaprolactone (PCL), and polyhydroxyacetic acid.

26. The implant according to any one of claims 19-25, wherein the implant comprises 50 wt% to 99.9 wt%, preferably 75 wt% to 95 wt%, more preferably 80 wt% of one or more of the bioresorbable polymers.

27. The implant according to any one of claims 19-26, wherein the implant comprises 0.1 wt% to 50 wt%, preferably 1 wt% to 30 wt%, or 10 wt% to 30 wt%, more preferably 20 wt% of the drug.

28. The implant according to any one of claims 19-27, wherein the weight ratio of the drug to one or more bioresorbable polymers is 1:1 to 1:20, preferably 1:1 to 1:10, more preferably 1:2 to 1:6, and even more preferably 1:

4.

29. The implant according to any one of claims 19-28, wherein the nanoparticles further comprise a permeability enhancer.

30. The implant of claim 29, wherein the permeability enhancer is selected from D-α-tocopherol polyethylene glycol succinate (TPGS), sodium dioctyl sulfosuccinate, sodium decanoate, sodium N-[8-(2-hydroxybenzoyl)amino]octanoate (SNAC), sodium dodecyl sulfate, sodium salicylate, oleic acid, lecithin, anhydrous ethanol, polysorbate or polyoxyethylene sorbitan fatty acid ester (Tween), sorbitan fatty acid ester (Spans), polyoxyethylene alkyl ether (Brij) s), poly(40) stearate, poly(50) stearate, polyethylene glycol, polyvinyl alcohol, polyvinylpyrrolidone (e.g., polyvinylpyrrolidone K29-32), hydroxypropyl methylcellulose, polyvinylpyrrolidone / vinyl acetate (VP / VA) copolymer, poly(lactic-co-hydroxyacetic acid), disodium ethylenediaminetetraacetate, propylene glycol, glyceryl monooleate, bile salts, octylphenol polyether, nonionic surfactants, anionic surfactants, cationic surfactants, and combinations thereof.

31. The implant according to any one of claims 19-30, wherein the average particle size of the nanoparticles is 300 nm to 1000 nm in diameter, preferably 300 nm to 400 nm or 900 nm to 1000 nm.

32. The implant according to any one of claims 19-31, wherein the polydispersity index (PDI) of the nanoparticles is 0.1 to 1, preferably 0.4 to 0.

7.

33. The implant according to any one of claims 19-32, wherein the implant has one of the following shapes: spherical, flattened, ellipsoidal, rod-shaped, disc-shaped, tubular, hemispherical, oval, cylindrical, or irregular.

34. The implant of claim 33, wherein the implant is rod-shaped.

35. The implant according to any one of claims 19-34, wherein the implant has the following dimensions: a length of 2 mm to 10 mm and a diameter of 0.1 mm to 1 mm, preferably a length of 4 mm to 7 mm and a diameter of 0.3 mm to 0.6 mm, more preferably a length of 6 mm and a diameter of 0.5 mm.

36. The implant according to any one of claims 19-35, wherein the implant comprises 0.1 mg to 5 mg, preferably 0.5 mg to 2 mg, of pregabalin.

37. The implant according to any one of claims 19-36, wherein the implant weighs from 0.5 mg to 10 mg, preferably from 3 mg to 8 mg, more preferably from 3 mg to 6 mg or 5 mg.

38. The implant according to any one of claims 1-37, further comprising a polymer coating on the implant.

39. The implant of claim 38, wherein the polymer coating comprises polyethylene glycol, a zwitterionic polymer, a hydrophobic bioresorbable polymer, a bioadhesive polymer, or a combination thereof.

40. The implant of claim 38, wherein the polymer coating comprises a hydrophobic bioresorbable polymer, preferably polycaprolactone (PCL).

41. The implant of claim 38, wherein the polymer coating comprises a bioadhesive polymer selected from the group consisting of polyacrylic acid derivatives, cellulose derivatives, natural polymers, polyvinylpyrrolidone (PVP), dextran polymers, polyethylene oxide polymers, thermally reversible polymers, ion-responsive polymers, copolymers of polymethyl vinyl ether and maleic anhydride, and combinations thereof.

42. The implant of claim 41, wherein the polymer coating comprises a natural polymer.

43. The implant according to claim 42, wherein the natural polymer is selected from gum arabic, gum tragali, agar polymer, xanthan gum, copolymers of alginate and sodium alginate, chitosan polymer, pectin, carrageenan, pullulan polymer, modified starch, and combinations thereof.

44. The implant according to any one of claims 1-43, wherein the implant provides sustained release of the drug for at least six months under test conditions comprising: placing the implant in the first chamber of a dual-chamber 1500 μl rapid microbalanced dialyzer (Harvard Apparatus Co., Holliston, MA), the dialyzer being equipped with a semi-permeable regenerated cellulose membrane (molecular weight cutoff 1,000 Da) separating the first and second chambers, wherein the second chamber contains PBS (pH 7.4); maintaining the dialyzer in a thermostatically controlled shaker at 37°C and 50 rpm; and extracting samples from the second chamber at predetermined time points to assess drug content by HPLC.

45. The implant of claim 44, wherein the sustained release of the drug is a Higuchi Fickian release over a period of six months under test conditions for at least two months, preferably at least three months, more preferably at least four months.

46. ​​The implant according to claim 44 or 45, wherein the implant releases no more than 40 wt%, preferably no more than 50 wt%, more preferably no more than 60 wt% of the drug after 6 months under test conditions.

47. The implant according to any one of claims 44-46, wherein the implant releases no more than 80 wt% of the drug after 11 months under test conditions.

48. The implant according to any one of claims 44-47, wherein the implant releases no more than 90 wt% of the drug after 14 months under test conditions.

49. The implant according to any one of claims 44-48, wherein the implant releases an average of 0.5g under test conditions. g / day to 5 g / day, preferred 1 g / day to 3 The drug is described in g / day.

50. The implant according to any one of claims 1-49, wherein the implant, when incubated in a plate containing 2% w / v agarose gel at 37°C for 1 hour, expands by no more than 15% of the initial implant weight, preferably no more than 25% of the initial implant weight.

51. The implant according to any one of claims 1-50, wherein the implant exhibits a moisture absorption rate of 10% or less when incubated for 3 days in a desiccator containing a saturated aqueous solution of ammonium chloride (relative humidity 79.5%).

52. The implant according to any one of claims 1-51, wherein the implant, when incubated in fibrinogen solution (10 mg / ml) for up to 24 h and the amount of adhered protein is determined by ELISA, shows at least 10% less protein contamination than a polypropylene control implant of the same shape and size.

53. The implant according to any one of claims 1-52, wherein the implant is stable for at least six months when evaluated under one or more of the following conditions: 25°C and 60% relative humidity, 30°C and 65% relative humidity, and 40°C and 75% relative humidity.

54. The implant according to any one of claims 1-53, wherein when the implant is incubated at 37°C in a plate containing 2% w / v agarose gel, at least two of the following are true: The implant does not expand by more than 15% after 1 hour; The implant does not expand by more than 20% after 2 hours. The implant expands by no more than 25% of its initial weight after 6 hours. The implant expands by no more than 35% of its initial weight after 24 hours. The implant expands by no more than 45% of its initial weight after 48 hours; and The implant expands to no more than 60% of its initial weight after 72 hours.

55. The implant according to any one of claims 1-53, wherein when the implant is incubated at 37°C in a plate containing 2% w / v agarose gel, at least two of the following are true: The implant does not expand by more than 25% after 1 hour; The implant does not expand by more than 35% after 2 hours. The implant expands by no more than 40% of its initial weight after 6 hours. The implant expands by no more than 45% of its initial weight after 24 hours. The implant expands by no more than 50% of its initial weight after 48 hours; and The implant expands to no more than 60% of its initial weight after 72 hours.

56. The implant according to any one of claims 1-55, wherein the implant exhibits an ex vivo transscleral drug permeation rate of 0.001 µg / min to 1.5 µg / min.

57. The implant according to any one of claims 1-56, wherein the implant provides 0.0005 μg / cm 2 •hr to 0.1 μg / cm 2 • hr average drug throughput.

58. The implant according to any one of claims 1-57, wherein the implant exhibits a permeability coefficient of 0.01·10⁻⁶. -4 cm / min to 0.1 cm / min.

59. A method of manufacturing an ocular implant, said ocular implant comprising a plurality of nanofibers as described in any one of claims 1-18, said method comprising: A solution is prepared by dissolving a drug (e.g., a water-soluble drug or a water-insoluble drug) and one or more bioresorbable polymers in a solvent. Electrospinning the solution provides nanofiber sheets containing multiple nanofibers on the surface of a collector; The nanofiber sheets are collected from the surface of the collector; and The nanofiber sheet is cut into multiple implants, each containing multiple nanofibers.

60. The method of claim 59, wherein the solvent comprises an organic acid.

61. The method according to claim 60, wherein the organic acid is selected from acetic acid, trifluoroacetic acid, propionic acid, and combinations thereof.

62. The method of claim 61, wherein the solvent comprises acetic acid.

63. The method according to any one of claims 59-62, wherein the solvent comprises less than 5 wt% water, preferably 0 wt% to 3 wt% water.

64. The method according to any one of claims 59-63, wherein the weight ratio of the drug to one or more bioresorbable polymers in the solution is 1:1 to 1:20, preferably 1:1 to 1:10, more preferably 1:2 to 1:6, and even more preferably 1:

4.

65. The method according to any one of claims 59-64, wherein the solution is in a concentration of 1... l / min to 20 l / min, preferred 8 Electrospinning was performed at a flow rate of l / min.

66. The method according to any one of claims 59-65, wherein the distance between the nozzle of the electrospinning machine and the surface of the collector is 5 cm to 20 cm, preferably 13 cm to 19 cm.

67. The method according to any one of claims 59-66, wherein the potential difference applied between the nozzle of the electrospinning machine and the surface of the collector is 10 kV to 22 kV, preferably 17 kV.

68. The method according to any one of claims 59-67, wherein the thickness of the nanofiber sheet is greater than 2 mm.

69. The method according to any one of claims 59-68, wherein the nanofiber sheet is cut into a plurality of implants using a cutting punch, preferably an oval-shaped holding punch.

70. The method of claim 69, wherein the implant has one of the following shapes: spherical, oblate, ellipsoidal, rod-shaped, disc-shaped, tubular, hemispherical, oval, cylindrical, or irregular.

71. The method of claim 70, wherein the implant is rod-shaped.

72. The method according to any one of claims 59-71, wherein the implant has the following dimensions: length from 0.5 mm to 6 mm, width from 0.5 mm to 6 mm, and height from 0.2 mm to 6 mm.

73. The method according to any one of claims 59-72, wherein the nanofibers have a diameter of 100 nm to 1,000 nm, preferably 100 nm to 500 nm, more preferably 200 nm to 400 nm.

74. The method according to any one of claims 59-73, wherein the implant comprises 0.1 mg to 5 mg of the drug, preferably 0.5 mg to 2 mg of the drug.

75. The method according to any one of claims 59-74, wherein the implant weighs 0.5 mg to 10 mg, preferably 3 mg to 8 mg, more preferably 3 mg to 6 mg or 5 mg.

76. A method of manufacturing an ocular implant, said ocular implant comprising a plurality of nanofibers as described in any one of claims 19-37, said method comprising: A drug (e.g., a water-soluble drug such as pregabalin) and one or more bioresorbable polymers are dissolved in a solvent to provide a solution; Solution electrospraying is used to deliver a variety of nanoparticles to the collector surface. The various nanoparticles are collected from the surface of the collector, and At least a portion of the various nanoparticles are compressed to form the implant.

77. The method of claim 76, wherein the solvent comprises an organic solvent.

78. The method according to claim 77, wherein the organic solvent is selected from chloroform, acetone, dichloromethane, dimethylformamide, ethyl acetate, methanol, ethanol, and combinations thereof.

79. The method of claim 78, wherein the solvent comprises methanol.

80. The method according to any one of claims 76-79, wherein the solvent comprises less than 5 wt% water, preferably 0 wt% to 3 wt% water.

81. The method according to any one of claims 76-80, wherein the weight ratio of the drug to one or more bioresorbable polymers in the solution is 1:1 to 1:20, preferably 1:1 to 1:10, more preferably 1:2 to 1:6, and even more preferably 1:

4.

82. The method according to any one of claims 76-81, wherein the solution is in a concentration of 1... l / min to 20 l / min, preferred 8 Electrospraying is performed at a flow rate of l / min.

83. The method according to any one of claims 76-82, wherein the distance between the nozzle of the electro-sprayer and the surface of the collector is 5 cm to 20 cm, preferably 13 cm to 19 cm.

84. The method according to any one of claims 76-83, wherein the potential difference applied between the nozzle of the electro-sprayer and the surface of the collector is 10 kV to 22 kV, preferably 17 kV.

85. The method according to any one of claims 76-84, wherein the compression is performed using a tablet press.

86. The method according to any one of claims 76-85, wherein the implant has one of the following shapes: spherical, oblate, ellipsoidal, rod-shaped, disc-shaped, tubular, hemispherical, or irregular.

87. The method of claim 86, wherein the implant is rod-shaped.

88. The method according to any one of claims 76-87, further comprising filing the implant.

89. The method according to any one of claims 76-88, wherein the implant has the following dimensions: a length of 2 mm to 10 mm and a diameter of 0.1 mm to 1 mm, preferably a length of 4 mm to 7 mm and a diameter of 0.3 mm to 0.6 mm, more preferably a length of 6 mm and a diameter of 0.5 mm.

90. The method according to any one of claims 76-89, wherein the implant comprises 0.1 mg to 5 mg, preferably 0.5 mg to 2 mg of the drug.

91. The method according to any one of claims 76-90, wherein the implant weighs 0.5 mg to 10 mg, preferably 3 mg to 8 mg, more preferably 3 mg to 6 mg or 5 mg.

92. The method according to any one of claims 76-91, wherein the average particle size of the nanoparticles is 300 nm to 1,000 nm in diameter, preferably 300 nm to 400 nm or 900 nm to 1,000 nm.

93. The method according to any one of claims 76-92, wherein the polydispersity index (PDI) of the nanoparticles is 0.1 to 1, preferably 0.4 to 0.

7.

94. The method according to any one of claims 59-93, further comprising applying a polymer coating to the implant.

95. The method of claim 94, wherein the polymer coating comprises polyethylene glycol, a zwitterionic polymer, a hydrophobic bioresorbable polymer, a bioadhesive polymer, or a combination thereof.

96. The method of claim 95, wherein the polymer coating comprises a hydrophobic bioresorbable polymer, preferably polycaprolactone (PCL).

97. The method of claim 95, wherein the polymer coating comprises a bioadhesive polymer selected from the group consisting of polyacrylic acid derivatives, cellulose derivatives, natural polymers, polyvinylpyrrolidone (PVP), dextran polymers, polyethylene oxide polymers, thermally reversible polymers, ion-responsive polymers, copolymers of polymethyl vinyl ether and maleic anhydride, and combinations thereof.

98. The method of claim 97, wherein the polymer coating comprises a natural polymer.

99. The method according to claim 98, wherein the natural polymer is selected from gum arabic, gum tragacanth, agar polymer, xanthan gum, copolymers of alginate and sodium alginate, chitosan polymer, pectin, carrageenan, pullulan polymer, modified starch, and combinations thereof.

100. The method according to any one of claims 59-99, further comprising sterilizing the implant.

101. A method for treating an eye disease in a subject who requires it, the method comprising placing an implant according to any one of claims 1-58 into the eye of the subject.

102. The method of claim 101, wherein the implant is placed in one of the following locations: subconjunctival space, anterior chamber, posterior chamber, vitreous cavity, subtendon sheath space, lower eyelid sulcus, upper eyelid sulcus, suprachoroidal space or anterior chamber, preferably subconjunctival space.

103. The method according to claim 101 or 102, wherein the method comprises: A surgical bag is created in the lower fornix of the eye through an incision. The implant is injected into the surgical bag, and Close the surgical bag, for example, with sutures.

104. The method according to any one of claims 101-103, wherein the implant is placed in the eyes of the subject.

105. The method according to any one of claims 101-104, wherein the implant provides sustained drug delivery to the subject's eye for at least six months, preferably at least nine months, and more preferably at least twelve months from the date of implantation.

106. The method of claim 105, wherein the sustained release of the drug is Higuchi Fickian for at least two months, preferably at least three months, and more preferably at least four months within a six-month period.

107. The method according to any one of claims 101-106, wherein the implant releases no more than 40 wt%, preferably no more than 50 wt%, more preferably no more than 60 wt% of the drug into the eye of the subject six months after implantation.

108. The method according to any one of claims 101-107, wherein the implant releases no more than 90 wt% of the drug into the eye of the subject 14 months after implantation.

109. The method according to any one of claims 101-108, wherein the implant is at an average of 0.5 g / day to 5 g / day, preferred 1 g / day to 3 The drug is released into the subject's eyes at a dose of g / day.

110. The method according to any one of claims 101-109, wherein the ocular disease is selected from elevated intraocular pressure (IOP), glaucoma, intraocular inflammation, keratitis, dry eye, macular edema, diabetic macular edema (DME), infection, macular degeneration, age-related macular degeneration (AMD), blurred vision, herpetic conjunctivitis, blepharitis, retinal or choroidal neovascularization, uveitis, diabetic retinopathy, ischemic retinopathy, optic neuropathy, ocular cancer, chronic ocular allergic diseases, and cataracts.

111. The method of claim 110, wherein the eye disease is selected from elevated IOP, glaucoma-related elevated IOP, and glaucoma.

112. The method according to claim 110 or 111, wherein the drug is pregabalin.

113. The method of claim 111 or 112, wherein the subject's IOP decreases by at least 10% from baseline after placement of the implant.

114. The method according to any one of claims 111-113, wherein the subject's IOP decreases from baseline by at least 2 mm Hg after placement of the implant.

115. The method according to any one of claims 111-114, wherein after placement of the implant, the subject's IOP decreases from greater than 21 mm Hg at baseline to 21 mm Hg or lower.

116. The method according to any one of claims 113-115, wherein the reduction in IOP is maintained for a continuous period of at least six months.

117. The method according to any one of claims 111-116, wherein the IOP change during the treatment process is less than 5 mm Hg.

118. The method according to any one of claims 101-117, further comprising placing one or more subsequent implants in the eye of the subject at least six months, preferably 12 months, after the placement of the initial implant.

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