Biodegradable microparticles for sustained drug delivery, their preparation and use.

Abstract

In certain embodiments, the present invention relates to biodegradable microparticles for sustained-release drug delivery comprising an active agent and a covalently and three-dimensionally crosslinked polymer matrix, as well as methods for preparing and using the same. Furthermore, in certain embodiments, the present invention relates to a pharmaceutically acceptable sustained-release, biodegradable drug delivery system comprising biodegradable microparticles for sustained-release drug delivery, particularly for coating medical implants, or for use as medical implants, and methods for producing the same. The present invention also, in certain embodiments, relates to corresponding therapeutic methods, methods for controlling the release of an active agent, and the use of biodegradable microparticles for sustained-release drug delivery.

Description

Technical Field

[0001] In certain embodiments, the present invention relates to biodegradable microparticles for sustained release drug delivery, comprising an active agent and a covalently and three-dimensionally crosslinked polymer matrix, as well as methods for their preparation and use. Further, in certain embodiments, the present invention relates to a pharmaceutically acceptable sustained release, biodegradable drug delivery system comprising biodegradable microparticles for sustained release drug delivery, particularly for coating a medical implant or for use as a medical implant, and a method for manufacturing the same. The present invention also relates, in certain embodiments, to corresponding treatment methods, methods for controlling the release of an active agent, and the use of biodegradable microparticles for sustained release drug delivery.

Background Art

[0002] The controlled release of therapeutic agents has been a broad area of research in recent years. Controlled release can lead to improved treatment, easier administration, improved compliance, reduced side effects, and improved treatment outcomes. [[ID=1�]]

[0003] The sustained delivery of hydrophilic drug compounds from hydrogel-based implants or inserts is often either too fast or too slow for the desired treatment period. This is because the drug release rate from an aqueous hydrogel increases as water solubility increases. It is desirable to eliminate solubility limitations.

[0004] Encapsulating a drug within microparticles of a biodegradable polymer can be used to vary the release rate of the contained drug. For example, since the drug release rate from an aqueous hydrogel increases as water solubility increases, the incorporation of drug-encapsulating microparticles into such a hydrogel allows the drug to be released independent of the degradation characteristics of the hydrogel.

[0005] For delayed administration of active ingredients, drug-carrying microparticles and other sustained-release encapsulation techniques can be used to contain drug compounds and release them gradually. Commonly used encapsulants in forming microparticles are polymers of polylactic acid (PLA), polyglycolic acid (PGA), and polylactic acid-glycolic acid copolymers (PLGA). These materials are biodegradable, established as safe for human use, and have been used in human clinical applications for decades. Numerous methods exist for producing such microparticles, typically involving the precipitation of polymer microparticles from a polymer solution.

[0006] Microparticles for drug delivery are described, for example, in US2018 / 0085307, WO2018 / 169950, WO2021 / 237096, and US2021 / 0251893. For example, US2018 / 0085307 and US2021 / 0251893, incorporated herein by reference, describe the treatment of ocular diseases using a sustained-release intracavitary implant based on a biodegradable hydrogel containing a drug with PLA microparticles. The PLA microparticles are prepared from a solution of a polylactic acid polymer containing the drug by an oil-in-water emulsion method.

[0007] For example, PLA or PLGA microparticles are prepared by rapidly solidifying PLA or PLGA from a solution of a polymer in an organic solvent in the presence of a co-dissolved drug or particulate drug. The microparticles contain the polymer in a physically aggregated form, and the polymer typically has acidic or ester-terminated groups. However, microparticles prepared in this conventional way from biodegradable polymers, copolymers, or polymer blends precipitated from solution, such as PLGA microparticles, are usually glassy materials once the residual solvent is removed. This property can make it difficult to control drug release in vivo.

[0008] The glass transition temperature (Tg) is a characteristic property of polymers that depends on the composition and molecular weight. Furthermore, Tg decreases after implantation as degradation and water content increase. With these materials, it has often been observed that Tg drops below body temperature, plasticizing the microparticles and converting glassy solid microparticles into viscous microdroplets in vivo. This phase change during biodegradation has been found to cause dramatic changes in degradation kinetics and drug release rates in an uncontrolled manner, which is undesirable for the safe and reliable sustained release of active ingredients.

[0009] For sustained release purposes, a zero-order release rate of the drug, i.e., a constant release rate that changes only slightly over time, is often preferred. However, drug release from uncrosslinked polymeric PLA or PLGA microparticles typically follows an S-shaped curve including a delayed phase, a release phase, and a depletion phase, often showing a burst of drug release immediately after implantation. The release rate and phases from PLA or PLGA microparticles depend on the molecular weight, L / G ratio, the polymer's terminal groups (acid or ester), and environmental conditions. Therefore, there is a need to provide microparticles for use in sustained drug delivery systems that allow for better control of the release of the active ingredient, regardless of its solubility in physiological fluids, and produce a reliable degradation rate of the polymer material used to encapsulate the active ingredient. There is also a need to provide microparticles for sustained-release drug delivery that are thermally stable and can be processed at high temperatures.

[0010] All references cited herein are incorporated in their entirety by reference for the purposes of this document. [Overview of the project]

[0011] Therefore, an object of a particular embodiment of the present invention is to provide biodegradable microparticles for sustained-release drug delivery that can provide a substantially constant zero-order release of the active ingredient over time.

[0012] Another object of certain embodiments of the present invention is to provide biodegradable microparticles for sustained-release drug delivery that exhibit little to no burst release of the active ingredient.

[0013] Another object of certain embodiments of the present invention is to provide biodegradable microparticles for sustained-release drug delivery that are thermally stable and can be processed at high temperatures, for example, in a thermal melt extrusion process.

[0014] A particular embodiment and pattern of the present invention aims to provide pharmaceutically acceptable biodegradable microparticles for sustained-release drug delivery of an active agent to a patient's body.

[0015] A further object of certain embodiments and patterns of the present invention is to provide a method for producing such biodegradable microparticles for sustained-release drug delivery of an active agent to a patient's body.

[0016] A further object of specific embodiments and patterns of the present invention is to provide a sustained-release biodegradable drug delivery system comprising biodegradable microparticles for use as a drug-eluting implant or for direct use as a drug, in particular, for sustained-release drug delivery.

[0017] A further object of certain embodiments and patterns of the present invention is to provide a method for controlling the release of an active agent from a sustained-release biodegradable drug delivery system.

[0018] A particular embodiment and further aspect of the present invention is to provide a method for treating a patient's disease / condition using biodegradable microparticles for sustained-release drug delivery of active ingredients to the patient's body.

[0019] A further object of specific embodiments and aspects of the present invention is to provide a method for controlling the release of an active agent from a sustained-release biodegradable drug delivery system comprising biodegradable microparticles for sustained-release drug delivery.

[0020] Some aspects of the present disclosure relate to biodegradable microparticles for sustained-release drug delivery comprising at least one active agent and a covalently and three-dimensionally crosslinked biodegradable polymer, wherein the crosslinked biodegradable polymer comprises at least one of crosslinked polylactic acid (PLA), polyglycolic acid (PGA), polylactic acid-glycolic acid copolymer (PLGA), poly(vinylpyrrolidone), poly-p-dioxanone, poly(trimethylene carbonate), polycaprolactone, and / or polyvinyl alcohol, or copolymers thereof.

[0021] Some aspects of the present disclosure relate to biodegradable microparticles for sustained-release drug delivery comprising at least one active agent and a covalently and three-dimensionally crosslinked biodegradable polymer, wherein the biodegradable microparticles comprise an organogel containing at least one crosslinked polymer and an oil.

[0022] In some aspects of this disclosure, the particles are microspheres having a substantially spherical shape.

[0023] In some embodiments of this disclosure, the active ingredient is dispersed, embedded, or encapsulated in an organogel or a polymer matrix forming an organogel. The organogel is formed by chemically crosslinking at least one polyfunctional precursor in the presence of an oil, optionally, to form a covalently and three-dimensionally crosslinked biodegradable polymer matrix. In some embodiments, the at least one polyfunctional precursor has functional groups for chemical crosslinking greater than 2, greater than 4, greater than 8, or 2-16, 2-10, or 2-8. In some embodiments, the at least one polyfunctional precursor is a dendrimer or multi-arm precursor having a core and 2-10 arms, or 3-10 arms, 4-8 arms, or 4 or 6 arms, each arm containing polymer units and having terminals. Functional groups for chemical crosslinking may be bonded to each terminal.

[0024] In some aspects of this disclosure, the biodegradable covalently crosslinked polymer of the microparticles includes one or more polymer units of polyethylene glycol (PEG), polypropylene glycol (PPG), polyvinyl alcohol, poly(vinylpyrrolidone), polylactic acid (PLA), polyglycolic acid (PGA), polylactic acid-glycolic acid copolymer (PLGA), poly-p-dioxanone, poly(trimethylene carbonate), polycaprolactone, and / or polyvinyl alcohol, or copolymers, random or block copolymers, or combinations or mixtures thereof, or one or more units of polyamino acids, glycosaminoglycans, polysaccharides, or proteins, or combinations or mixtures thereof. The biodegradable covalently and three-dimensionally crosslinked polymer matrix may include a plurality of hydrophobic polymer units and / or hydrophilic polymer units.

[0025] In some aspects of this disclosure, the biodegradable covalently and three-dimensionally crosslinked polymer comprises a plurality of hydrophobic polymer units, such as polylactic acid (PLA) or polylactic acid-glycolic acid copolymer (PLGA) units, and / or hydrophilic polymer units, such as polyethylene glycol units, polypropylene glycol units, or polyglycolic acid (PGA). In certain embodiments, the hydrophobic polymer units include polyethylene glycol units. In certain embodiments, the hydrophobic polymer units include polylactic acid (PLA) units.

[0026] In certain embodiments of the present disclosure, the covalently and three-dimensionally crosslinked biodegradable polymer matrix comprises or consists of poly(lactic-co-glycolic acid) (PLGA) units. The poly(lactic-co-glycolic acid) (PLGA) units can have an L / G ratio (%, of L or G units) in the range of about 0:100 to about 100:0, or about 1:99 to about 99:1, or about 10:90 to about 90:10, or about 25:75 to about 75:25. In certain embodiments, the L / G ratio is 50:50. In an aspect, each polymer unit has an average molecular weight (Mw) in the range of about 1,000 to about 100,000 Daltons, or about 10,000 to about 60,000 Daltons, or about 15,000 to about 50,000 Daltons.

[0027] In some aspects of the present disclosure, the polymer matrix is covalently crosslinked by hydrolyzable bonds, either intramolecularly or intermolecularly, or a combination of both, between polymer units. To form an organogel polymer matrix, at least two functional groups, such as a low molecular weight amine such as tris(2-aminoethyl)amine (TAEA) or trilysin, or at least one crosslinking agent having more than two functional groups can be used to crosslink a multifunctional precursor. Alternatively, or in addition, the organogel can comprise or be formed from at least two crosslinkable dendrimers or multi-arm precursors that are crosslinked intramolecularly to each other. The dendrimer or multi-arm precursor can comprise functional groups at at least three of its arm termini, or at each terminus.

[0028] In some aspects of the present disclosure, the polymer matrix comprises at least two multi-arm precursors (e.g., 2-10 arm precursors) including a first multi-arm precursor containing a first functional group and a second multi-arm precursor containing a second functional group, the functional groups being located at the ends of the arms of the precursors or crosslinking agents, and the first or second functional group may be directly grafted to the precursor end or grafted via a linker molecule. In certain embodiments, each of the first functional group and the second functional group is selected from electrophiles and nucleophiles, functional groups for click chemistry, functional groups for cycloaddition such as 1,3-dipolar cycloaddition, hetero-Diels-Alder cycloaddition, functional groups for nucleophilic ring opening, functional groups for non-aldol carbonyl reactions, functional groups for addition reactions to carbon-carbon multiple bonds, polymerizable vinyl groups, or combinations thereof.

[0029] In one aspect of the present disclosure, each of the first functional group and the second functional group is selected from the group consisting of electrophiles and nucleophiles, and the reaction between the first functional group and the second functional group is an electrophile-nucleophile reaction forming a covalent bond, e.g., a polycondensation reaction. The nucleophile can be selected from one of amines such as primary amines, hydroxyl, alcohol, thiol, azide anion, and carboxyl groups. Electrophiles that can be used in the present invention can be selected from activated ester groups such as succinimidyl ester, succinimidyl carbonate, nitrophenyl carbonate, aldehyde, ketone, acrylate, acrylamide, maleimide, vinyl sulfone, iodoacetamide, alkene, alkyne, azide, norbornene, epoxide, mesylate, tosylate, tresylate, cyanurate, orthopyridyl disulfide, or halogen.

[0030] In one embodiment and one aspect of the present disclosure, the nucleophile is an amine group, e.g., a primary amine, and the electrophile is an activated ester group, e.g., one of the succinimidyl esters selected from succinimidyl succinate, succinimidyl glutarate, succinimidyl adipate, succinimidyl azelate, or succinimidyl glutaramide.

[0031] In some other aspects of the present disclosure, each of the first and second functional groups is selected from functional groups for cyclization, such as [3+2] cyclization, including 1,3-dipolar cyclization, alkene-nitrone cyclization, or alkyne-nitrone cyclization; functional groups for click chemistry, including [4+2] cyclization and hetero-Diels-Alder cyclization; functional groups for thiol-ene reactions; functional groups for nucleophilic ring-opening; functional groups for non-aldol-type carbonyl reactions; functional groups for addition reactions to carbon-carbon multiple bonds; and functional groups for Michael-type addition.

[0032] In such embodiments of the present disclosure, the first functional group is an alkyne compound such as dibenzocyclooctin (DBCO) or bicyclo[6.1.0]-nonine (BCN); or norbornene or trans-cyclooctene (TCO), and the second functional group is an azide, 3,4-dihydroxyphenylacetic acid (DHPA), or tetrazine (Tz). The DBCO, BCN, norbornene, TCO, azide, DHPA, and Tz functional groups may be grafted to the ends of a multi-arm precursor via linkers such as acidic groups, diacidic groups, functionalized aliphatic groups, heteroaliphatic groups, or aromatic or heteroaromatic groups.

[0033] In another aspect of the present disclosure, the first and second functional groups are selected for a [3+2] cycloaddition reaction such as an alkene-nitrone cycloaddition or an alkyne-nitrone cycloaddition.

[0034] In another aspect of the present disclosure, the first and second functional groups are selected for a [4+2] cycloaddition reaction, particularly a hetero-Diels-Alder reaction, where the first functional group is an aldehyde or imine compound and the second functional group is a 1,3-diene compound, an unsaturated carbonyl compound, or a nitrosoalkene compound.

[0035] In further aspects of this disclosure, the first and second functional groups are selected for a thiol-ene reaction, where the first functional group is a thiol compound and the second functional group is an alkene, such as a terminal alkene.

[0036] In other aspects of this disclosure, the first and second functional groups are selected for nucleophilic ring-opening, the first functional group is selected from epoxides, thiiranes, aziridines, or lactams, and the second functional group is a nucleophile.

[0037] In one aspect of the present disclosure, the first and second functional groups are selected for a non-aldol type carbonyl reaction, where the first functional group is an aldehyde or ketone compound, and the second functional group is a primary amine, hydrazide, acylhydrazide, or aminooxy compound, which react to form an imine, amide, isourea, hydrazone, acylhydrazone, or oxime bond.

[0038] In another aspect of the present disclosure, each of the first and second functional groups is selected from polymerizable vinyl groups and acrylates such as (meth)acrylic acid, (meth)acrylic acid esters, acrylamide, fumaric acid, maleic acid, and combinations thereof.

[0039] In certain embodiments of the present disclosure, crosslinking is thermally or photochemically induced using electromagnetic radiation and an initiator such as a free radical photoinitiator (Nourish type I such as 2,2-dimethoxy-1,2-diphenylethane-1-one, 2-hydroxy-2-methyl-1-phenylpropanone, 1-hydroxy-cyclohexylphenyl ketone; or Nourish type II such as benzophenone and its derivatives combined with co-agents such as tertiary amines 2-ethylhexyl-(4-N,N-dimethylamino)benzoate and 2-ethyl-(4-N,N-dimethylamino)benzoate, as well as isopropylthioxanthone); or a cationic photoinitiator.

[0040] In one aspect of the present disclosure, an organogel forming biodegradable microparticles comprises a polymer matrix, the polymer being covalently crosslinked by linkages or bonds between polymer units. The bonds may be selected from amine, amide, urethane, ester, anhydride, ether, acetal, ketal, nitrile, isonitrile, isothiocyanate, isourea, hydrazone, oxime, or imine bonds, and combinations thereof.

[0041] In some aspects of this disclosure, the active agent is selected from at least one of a therapeutically active agent or a diagnostically active agent, or a combination thereof. Therapeutically active agents include steroids; nonsteroidal anti-inflammatory drugs (NSAIDs) such as diclofenac, ibuprofen, meclofenamete, mefanamic A, sarsalate, sulindac, tolmetin, ketoprofen, diflunisal, piroxicam, naproxen, etodolac, flurbiprofen, fenoprofen C, indomethacin, celecoxib, ketorolac, and nepafenac; intraocular pressure lowering agents; antibiotics such as ciprofloxacin; analgesics such as bupivacaine; calcium channel blockers such as nifedipine; cell cycle inhibitors such as simvastatin; proteins such as insulin; carboxylates and amine salts. This includes small molecule hydrophilic drugs; small molecule hydrophobic drugs, hydrophilic peptides and protein drugs (e.g., insulin, single-chain antibody fragments, Fab fragments, IgG antibodies, fusion antibodies, etc.); aptamers; in particular, bupivacaine (BPV-HCl or base), ropivacaine (RPV), dexamethasone, travoprost, axitinib, nonsteroidal anti-inflammatory drugs (NSAIDS), steroids, antibiotics, analgesics, calcium channel blockers, cell cycle inhibitors, chemotherapy drugs, antiviral drugs, anesthetics, hormones, anticancer drugs, antitumor drugs, viruses for gene delivery such as AAV, etc., or any combination thereof.

[0042] In certain aspects of this disclosure, the particles have a particle size (diameter) of about 0.1 μm to about 1000 μm, or about 1 μm to about 150 μm, about 1 μm to about 100 μm, about 20 μm to about 75 μm, about 10 μm to about 106 μm, or about 20 μm to about 55 μm, as determined by sieving, or have an average diameter in the range of about 0.1 μm to about 1000 μm, or about 1 μm to about 150 μm, about 1 μm to about 100 μm, about 20 μm to about 75 μm, about 10 μm to about 106 μm, or about 20 μm to about 55 μm, as determined by laser diffraction and assumed to be substantially spherical in shape. The fine particles may have a particle size distribution of, for example, less than approximately 100 μm, less than approximately 50 μm, or less than approximately 20 μm for D50 particle size, and / or less than approximately 200 μm, or less than approximately 100 μm, or less than 30 μm for D90 particle size, and / or less than approximately 20 μm for D90 particle size. In certain embodiments, the lower limits of D50 and D90 may be 1 μm, 5 μm, or 10 μm, and may be in a range having any of the above values.

[0043] In some aspects of the present disclosure, the biodegradable microparticles comprise or consist of a blend of microparticles having different particle sizes and / or different polymer matrices and / or different active agents.

[0044] In some aspects of this disclosure, the selection of an organogel precursor, and / or the hydrophobicity of the polymer units, and / or the L / G ratio of the PLGA units are used to adjust the release rate. For example, the lipophilicity of the microparticles can be adjusted by using a combination of PEG and a PLA or PLGA precursor in various amounts.

[0045] In one aspect of this disclosure, biodegradable microparticles release an effective amount of active ingredient for a certain period of time, up to approximately 1 year, up to approximately 9 months, up to approximately 6 months, up to approximately 3 months, up to approximately 1 month, or up to approximately 25 days after administration, up to approximately 14 days, or up to approximately 21 days after administration, wherein the release of the active ingredient is optionally substantially constant within a temperature range of approximately 30°C to approximately 45°C, or approximately 36°C to approximately 43°C.

[0046] In some embodiments of this disclosure, the polymer matrix has a glass transition temperature below body temperature, for example, about 37°C or below, or about 36°C or below, about 30°C or below, about 25°C or below, about 20°C or below, or about 10°C or below, and / or the polymer matrix has a melting temperature above about 40°C, about 45°C, about 50°C, about 60°C, or about 70°C. In certain embodiments, the lower limit of the glass transition temperature is about 5°C or about 10°C or about 20°C or about 30°C, and may be in the range having any of the above values. In certain embodiments, the polymer matrix has a melting temperature of about 50°C or about 75°C or about 100°C or about 150°C or below, and may be in the range having any of the above values.

[0047] Some aspects of this disclosure relate to methods for producing biodegradable microparticles for sustained-release drug delivery as disclosed herein, the methods being selected from, for example, one of the following: evaporation-extraction of an emulsion solvent, diffusion of an emulsion solvent, supercritical fluid emulsion, coacervation, spray drying, hydrogel template, microfluidics system, membrane extrusion emulsification, particle replication (PRINT) techniques in a non-wet mold, electrohydrodynamic atomization (EHDA) or electrospraying, or microparticle formation from a gas-saturated solution (PGSS) method, or 3D printing method.

[0048] Some aspects of the present disclosure relate to a method for producing biodegradable microparticles for sustained-release drug delivery as described herein, the method comprising the steps of: (1) forming a gel comprising a covalently crosslinked polymer in the presence of at least one active agent, optionally at least one oil, and optionally a first solvent; (2) producing microparticles in which at least one active agent is dispersed within the covalently crosslinked polymer; and (3) optionally removing the solvent.

[0049] In some aspects of the present disclosure, the above method includes the steps of (a) dissolving at least one of polymer precursors in a first solvent to produce a first mixture; (b) providing a second mixture containing a crosslinking agent in a second solvent; (c) adding at least one active agent and optionally an oil to at least one of the first or second mixtures; (d) combining the first and second mixtures to produce a first phase; (e) providing a second phase containing a third solvent that is miscible with the first and second solvents; (f) introducing the first phase into the second phase under stirring to produce an emulsion of the dispersed first phase in the second phase; and (g) removing the first, second and / or third solvents. These steps may be carried out in any order.

[0050] Step (2) or step (f) of generating fine particles comprises extruding a first phase through a mesh or injecting the first phase into a stirred second phase, wherein the first and / or second solvent and / or third solvent optionally include additives such as emulsifiers, surfactants, dispersion aids, or pologens, and form spherical or nanospherical particles.

[0051] In some aspects of the methods of the present disclosure, the first or second solvent is selected from acetone, acetonitrile, benzyl alcohol, chloroform, dichloromethane (DCM), dioxane, dimethyl carbonate, DMSO, ethanol, ethyl acetate, ethyl formate, ethyl propionate, glycoflore, hexafluoroisopropanol, isosorbide dimethyl ether, isopropanol, methyl chloride, methylene chloride, methyl ethyl ketone, N-methylpyrrolidone, propylene carbonate, or tetrahydrofuran, or any mixture thereof, and the third solvent is water, an alcohol such as methanol, ethanol or propanol, or any mixture thereof.

[0052] In some aspects of the methods of the present disclosure, additives may be used, and these additives are selected from, for example, polyvinyl alcohol (PVA), polyethylene glycol sorbitan monolaurate (Tween®), sorbitan monolaurate (Span®), sodium dodecyl sulfate (SDS); and / or inorganic salts (NaCl, KCl, sodium carbonate or potassium carbonate or bicarbonate, ammonium bicarbonate), such as propyl alcohols, pluronic acid; sodium oleate or potassium oleate; gelatin; mustard oil; mineral oil; cyclodextrin; carbohydrates; bovine serum albumin (BSA); and surfactants or emulsifiers such as photoinitiators, radical polymerization initiators, and combinations thereof.

[0053] In some aspects of the methods of the present disclosure, steps (1) and (2) utilize oil-in-water emulsion technology or water-in-oil emulsion technology, or a combination thereof, such as single or double emulsion technology, microfluidic technology, or a combination thereof.

[0054] In some aspects of the methods of the present disclosure, the removal of the first, and / or second, and / or third solvent is carried out by hot air convection or one of direct drying, indirect drying or contact drying, spray drying, dielectric drying, vacuum drying, freeze-drying, supercritical or superheated vapor drying, or any combination thereof.

[0055] Several aspects of this disclosure relate to sustained-release biodegradable drug delivery systems comprising biodegradable microparticles for sustained-release drug delivery as disclosed herein. In some aspects, the biodegradable microparticles are incorporated into a hydrogel, xerogel, or organogel or a precursor thereof, and optionally for in situ implant formation, by using an extrusion method such as extrusion or injection molding of a reaction mixture containing the biodegradable microparticles of this disclosure dispersed in a hydrogel, xerogel, or organogel. In some aspects, gelation occurs before and / or during the extrusion or injection molding of the gel-forming material containing the biodegradable microparticles.

[0056] In other embodiments, the sustained-release biodegradable drug delivery systems of the Disclosure may be used to coat medical implants or to be used as medical implants. The implants may be selected from those for introduction into intraocular implants, intracavitary implants, intraacular implants, anterior chamber, vitreous humor, episclera, posterior sub-Tenon space (inferior fornix), subconjunctival, intraacular, periocular, posterior, sub-Tenon space, retina, subretinal, intracanaliculi, intravitreous, intrascleral, intrachoroidal, suprachoroidal, retina, subretinal, or the surface of the lens, cornea or conjunctiva, lacrimal puncta (canaliculi, superior / inferior canaliculi), palpebral fornix, superior / inferior palpebral fornix, sub-Tenon space, choroid, suprachoroidal, Tenon, cornea, cancerous tissue, organs, prostate, breast, joint cavity, subdural, tooth, subcutaneous, carpal tunnel, perivascular, surgically formed spaces or injuries, cavities, and latent cavities.

[0057] Some aspects of this disclosure relate to sustained-release biodegradable drug delivery systems comprising biodegradable microparticles, or manufactured by the methods disclosed herein, for use as pharmaceutical agents.

[0058] In some embodiments, the present invention relates to a sustained-release biodegradable drug delivery system comprising biodegradable microparticles disclosed herein or manufactured by the methods disclosed herein for use in the treatment of a patient's disease / condition, wherein such use comprises incorporating the biodegradable microparticles of the present disclosure into a carrier such as a hydrogel, organogel or xerogel, which is formed in situ at the patient's treatment site or pre-formed and delivered or implanted at the patient's treatment site to release the active agent from the microparticles over a long period of time, or the carrier is a solvent or solvent system to produce an injection suspension or dispersion.

[0059] In some embodiments, the present invention relates to a sustained-release biodegradable drug delivery system for use in the treatment of a patient's disease / condition, comprising biodegradable microparticles as disclosed herein or produced by the methods disclosed herein, the methods comprising incorporating the biodegradable microparticles according to the present disclosure into a hydrogel, organogel, or xerogel, wherein the hydrogel, organogel, or xerogel is formed in situ at the patient's treatment site or is pre-formed at the treatment site and delivered or implanted to release the active ingredient over a long period of time.

[0060] In some embodiments, the present invention relates to a method for treating a patient's disease / condition, the method comprising administering to the patient a hydrogel, organogel, or xerogel containing biodegradable microparticles according to the present disclosure in order to release an active agent over a long period of time.

[0061] In some aspects of this disclosure, the treatment site may be selected from the anterior chamber, vitreous humor, episclera, posterior subtenon space (inferior fornix), subconjunctival, intraocular, periocular, posterior, subtenon, retina, subretinal, intracanaliculi, intravitreous, intrascleral, intrachoroidal, suprachoroidal, retina, subretinal, or lens, corneal or conjunctival surface, lacrimal puncta (canaliculi, superior / inferior canaliculi), palpebral fornix, superior / inferior palpebral fornix, subtenon space, choroid, suprachoroidal, Tenon, cornea, cancerous tissue, organs, prostate, breast, joints, subdural, teeth, subcutaneous, carpal tunnel, perivascular, surgically formed spaces or injuries, cavities, and latent cavities.

[0062] In some aspects, the disease / condition being treated is an ocular disease, such as any posterior segment ocular disease affecting the vascular system and integrity of the retina, macula, or choroid, causing visual impairment, vision loss, or blindness, particularly age-related macular degeneration (AMD), trauma, surgical intervention, e.g., age-related macular degeneration (AMD), cystoid macular edema (CME), diabetic macular edema (DME), posterior uveitis, and diabetic retinopathy; or posterior segment disease conditions resulting from glaucoma, ocular hypertension, anterior chamber hemorrhage, presbyopia, cataracts, retinal vein occlusion, or inflammation.

[0063] In some embodiments, the Disclosure further relates to methods for controlling the release of an active agent from a sustained-release biodegradable drug delivery system manufactured or produced by the methods disclosed herein, wherein the control of the active agent release includes one or a combination of the following means: selecting an L / G ratio of polylactic acid-glycolic acid copolymer (PLGA) units to adjust the hydrophobicity of the polymer matrix forming the microparticles; selecting an L / G ratio of polylactic acid-glycolic acid copolymer (PLGA) units to result in sustained release of the active agent from the microparticles; selecting a molar ratio of amounts of a first and second crosslinkable precursor to adjust the hydrophobicity of the polymer matrix forming the microparticles; selecting a molar ratio of amounts of a first and second crosslinkable precursor to result in sustained release of the active agent from the microparticles; hydrogels, organogels Selecting the amount and / or particle size of biodegradable microparticles contained in the xerogel; adding a third crosslinkable precursor that is less hydrolyzable than the first and second crosslinkable precursors, and optionally changing the molar ratio of the first, second and / or third precursors when forming biodegradable microparticles; and dispersing a highly water-soluble active agent in particulate form within the organogel of biodegradable microparticles.

[0064] definition The term "biodegradable" refers to a material or object (such as microparticles according to the present invention) that decomposes in vivo, i.e., when placed in the body of a human or animal, or in vitro, when immersed in an aqueous solution under physiological conditions such as pH 7.2-7.4 at 37°C. In the context of the present invention, as disclosed in detail below herein, microparticles containing an active agent are gradually biodegraded over time when administered to or placed in the body of a human or animal. In certain embodiments, biodegradation occurs at least partially by ester hydrolysis in the aqueous environment of the body. Biodegradation may occur by hydrolysis or enzymatic cleavage of covalent crosslinks and / or within polymer units. The microparticles gradually soften and disintegrate, and as a result are cleared via physiological pathways. In certain embodiments, the microparticles of the present invention retain their shape for a long period of time (e.g., about 1 month, 3 months, or 6 months). In certain embodiments, the shape is maintained by covalent crosslinking of the polymer components forming the microparticles until, for example, the active agent or at least a major amount thereof (e.g., at least 50%, at least 75%, or at least 90%) is released from there.

[0065] In embodiments of the present invention, the microparticles comprise an organogel. In the present invention, “organogel” is a solid or semi-solid system that forms a three-dimensional network of one or more hydrophilic or hydrophobic natural or synthetic polymers (as disclosed herein) that are covalently crosslinked, including oil or a hydrophobic organic liquid as generally disclosed herein. Therefore, in the present invention, “organogel” is limited to so-called chemical organogels in which the intermolecular interactions between organogelating agent molecules are chemical bonds (e.g., covalent bonds) formed during gelation by a chemical reaction that induces crosslinking. As used herein, “organogel” refers to a three-dimensional polymer network or matrix of at least two precursors / gelling agents / precursors covalently crosslinked with each other in the presence of oil and optionally an organic solvent, and includes oil contained in the covalently crosslinked polymers forming the microparticles.

[0066] A "hydrogel" is a three-dimensional network of one or more hydrophilic natural or synthetic polymers (as disclosed herein) that swells in water and retains a certain amount of water, while maintaining or substantially maintaining its structure, for example, by chemical or physical crosslinking of individual polymer chains. Due to their high water content, hydrogels are soft and flexible and closely resemble natural tissues. In the present invention, the term "hydrogel" is used to refer to both a hydrated hydrogel (for example, after the hydrogel has been formed in an aqueous solution, or after the hydrogel has been inserted into a body or immersed in an aqueous environment by other means to be hydrated or (re)hydrated) and a dried (dried / dehydrated) hydrogel (for example, after it has been dried to a low water content (e.g., 1% by weight or less), or when a low water content insert can be obtained by preparation without requiring a drying step).

[0067] As used in the context of the microparticles of the present invention, the terms “polymer,” “polymer network,” or “polymer matrix” refer to a structure formed from covalently crosslinked polymer chains (with the same or different molecular structures and the same or different molecular weights). Types of polymers suitable for the purposes of the present invention are disclosed below. The term “polymer network” is used interchangeably with the term “matrix.”

[0068] The term "amorphous" refers to a polymer or polymer network that does not exhibit a melting point or crystalline structure in X-ray or electron scattering experiments.

[0069] The term "semi-crystalline" refers to a polymer or polymer network that possesses some crystalline properties, i.e., exhibits a melting point or some crystalline properties in X-ray or electron scattering experiments.

[0070] In this specification, the terms “precursor,” “gelling agent,” or “component” refer to molecules or compounds that react with each other and are thereby linked via covalent crosslinking to form a polymer network, and optionally, a hydrogel matrix in the presence of oil, thereby forming microparticles.

[0071] The portions of precursor molecules that still exist within the final polymer are also referred to herein as “units.” Thus, “units” are building blocks or constituents of the polymer network that forms the microparticles. For example, a polymer network suitable for use in the present invention may contain the same or different PLGA units, polyethylene glycol units, or other types of polymers, as further disclosed herein.

[0072] As used herein, the terms “release” (and accordingly “released,” “release,” etc.) refer to the delivery of an active agent from a microparticle or drug delivery system, such as an implant containing the microparticles of the present invention, to the surrounding environment. The surrounding environment may be an in vitro or in vivo environment, as described herein. In certain embodiments, the surrounding environment is vitreous fluid and / or ocular tissue such as the retina and choroid.

[0073] The term "100% release of active ingredient" should be interpreted as 95% to 100%. This controlled release method is achieved by several parameters that are characteristics of the drug delivery system, as disclosed herein. Each of these characteristics of the drug delivery system can be involved in controlled release, either individually or in combination with each other.

[0074] In the context of this invention, the term “sustained release” is intended to characterize products such as biodegradable microparticles formulated to make the active ingredient available over a longer period of time, thereby enabling a reduction in the frequency of administration compared to immediate-release formulations (e.g., solutions of the active ingredient applied topically to the eye (i.e., eye drops)). Other terms that may be used interchangeably with “sustained release” herein are “sustained-release” or “controlled release.” In the sense of this invention, the term “sustained release” includes constant release of the active ingredient, decreasing release of the active ingredient, increasing release of the active ingredient, and any combination thereof (e.g., decreasing release of the active ingredient after constant release). In the sense of this invention, the terms “decreased” or “decrease” refer to a decrease in the release of the active ingredient over time. Specifically, the term “sustained release” refers to the release of the active ingredient from microparticles or drug delivery systems containing them in a predetermined manner, in contrast to immediate release such as bolus injection. In certain embodiments, controlled release refers to the amount of active ingredient released over the total number of days required for 100% release of the active ingredient in an aqueous solution under in vitro physiological conditions such as pH 7.2-7.4 and 37°C.

[0075] As used herein, the term “longer period” means any period of time that a person skilled in the art would consider to be an extended treatment of a disease, in particular a period of at least about one week, or at least about one month, for example, up to about 12 months, or any intermediate period such as about 1 to about 6 months, about 2 to about 4 months, about 2 to about 3 months, or about 3 to about 4 months, or any other period otherwise disclosed herein.

[0076] "Zero-order" release, "substantially zero-order" release, or "near zero-order" release is defined as a relatively straight line in a graph of the proportion of released active agent versus time. In certain embodiments of the present invention, substantially zero-order release is defined as an amount of active agent released that is within 20% of the elapsed time.

[0077] The terms “API,” “Active(pharmaceutical) ingredient,” “Active(pharmaceutical) agent,” “Active(pharmaceutical) ingredient,” “(active) therapeutic agent,” “active drug,” and “drug” are used interchangeably herein and refer to substances used in a finished medicine product (FPP) that are intended to impart pharmacological activity or have a direct effect on the diagnosis, cure, alleviation, treatment, or prevention of a disease or on the restoration, correction, or modification of a patient’s physiological function, and substances used in the preparation of such a finished medicine product.

[0078] The active agents used in accordance with the present invention may be active agents for the treatment and / or prevention of disease or disorder, or diagnostic agents such as markers. In embodiments of the present invention, the active agent is a low-water-solubility active agent (i.e., having water solubility of less than about 1000 μg / mL or less than about 100 μg / mL). In another embodiment of the present invention, the active agent is a highly water-soluble active agent (i.e., having water solubility of about 1000 μg / mL or more, or even more than about 10 μg / mL). This definition does not depend on drugs approved by government agencies.

[0079] For the purposes of the present invention, the active agent can be used in all possible forms, including free acids, free bases, polymorphs or any pharmaceutically acceptable salts, anhydrides, hydrates, cocrystals, or other solvates or derivatives (such as prodrugs or conjugates). Wherever the active agent is mentioned in this description or claims without further specification, it also refers to the active agent in any such polymorph, pharmaceutically acceptable salt, anhydride, or solvate (including hydrate) form, even if not explicitly stated (the deletion of this statement shall be considered). With respect to the active agent, preferred solid forms include, without limitation, pure substance forms in any physical form known to those skilled in the art. For example, the active agent may take the form of particles. The particles may be amorphous or crystalline, or may present as a mixture of these two forms, and can be made of any size which can be classified without limitation as coarse particles, fine particles or ultrafine particles, the dimensions which can be seen particularly with the naked eye or under a microscope, and can have shapes such as single grains and / or aggregates. The particles can also be micronized. As used herein, the term “micronization” refers, without limitation, to small-sized particles, particularly microscopic-scale particles, whose particle size has been reduced by, for example, jet milling, jaw crushing, hammer milling, wet milling, precipitation in a non-solvent, cryomilling (milling with liquid nitrogen or dry ice), and ball milling. The active ingredient may also exist in a dissolved or dispersed state, for example, in a solvent or aqueous medium, for example, in an oil, or in a compatible aqueous suspension (which may optionally contain further excipients such as surfactants).

[0080] As used herein, the term “therapeutably effective” refers to the amount of active agent required to produce the desired therapeutic outcome after administration. For example, in the context of the present invention, one desired therapeutic outcome could be a reduction in symptoms associated with DED (measured, for example, by in vivo tests known to those skilled in the art), such as an increase in Schirmer tear test scores, a decrease in staining values ​​measured by conjunctival lysamine green staining or corneal fluorescein staining, a decrease in scores for dry eye severity and / or dry eye frequency on a visual analog scale (VAS), a decrease in the ocular surface disease index and / or standard patient-assessed score for dry eye, and a decrease in best corrected visual acuity. In one embodiment, "therapeutably effective" means an amount of active agent in a sustained-release intratubular implant that, in terms of therapeutic effect, can achieve a tear concentration equivalent to a cyclosporine concentration of 0.236 μg / mL (which is considered necessary for immunomodulation (Tang-Liu and Acheampong, Clin. Pharmacokinet. 44(3), pp. 247-261)), and once this tear concentration is achieved, can be maintained over a long period, particularly substantially throughout the entire remaining period of implantation.

[0081] As used herein, the values ​​"d10", "d50", "d90", and "d100" refer to values ​​that characterize the proportion of particles in a particle size distribution that satisfy a particular particle size. In a given particle size distribution, 10% of the particles have a particle size of d10 or less, 50% of the particles have a particle size of d50 or less, 90% of the particles have a particle size of d90 or less, and substantially all particles have a particle size of d100 or less. The percentages can be expressed by different parameters known to those skilled in the art, for example, the percentages may be based on volume, weight, or the number of particles. Thus, d50 may exemplary be the median particle size on a volume basis, weight basis, or number basis. For example, if d90 on a volume basis is 43 μm, it means that 90% of the volume of particles have a particle size of 43 μm or less. In certain embodiments, d10, d50, and d90 are volume-based values. The particle size distribution (PSD) can generally be measured by methods known to those skilled in the art, including sieving and laser diffraction. In certain embodiments, the PSD is measured by USP <429> Particle size is measured by optical diffraction, specifically by laser diffraction. In certain embodiments, PSD is measured by laser diffraction using a Beckman Coulter LS 13 320, with an obscuration value in the range of 7–9% based on the optical model Fraunhofer rf780z.

[0082] The term “patient” as used herein includes both human and animal patients. Therefore, the biodegradable drug delivery systems according to the present invention are suitable for human or veterinary medical use. Generally, “subject” refers to the individual (human or animal) to whom the drug delivery system according to the present invention is administered. “Patient” refers to a subject requiring treatment due to a specific physiological or pathological condition. A “patient” is not necessarily diagnosed with a specific physiological or pathological condition prior to receiving the drug delivery system.

[0083] The molecular weights of polymer precursors used for the purposes of the present invention and disclosed herein can be determined by analytical methods known in the art. For example, the molecular weight of polyethylene glycol can be determined by any method known in the art, including gel electrophoresis, e.g., SDS-PAGE (sodium dodecyl sulfate-polyacrylamide gel electrophoresis), gel permeation chromatography (GPC) (including GPC with a static light scattering detector (SLS) or dynamic light scattering (DLS)), liquid chromatography (LC), and mass spectrometry (e.g., matrix-assisted laser desorption / ionization time-of-flight (MALDI-TOF) spectroscopy or electrospray ionization (ESI) mass spectrometry). The molecular weights of polymers containing polyethylene glycol precursors disclosed herein are average molecular weights (based on the molecular weight distribution of the polymer) and may therefore be represented by various average values, including weight-average molecular weight (Mw) and number-average molecular weight (Mn). For crosslinkable polymer gelling agents such as polyethylene glycol, PLGA, and poloxamer precursors used in the present invention, the molecular weights shown herein are the number-average molecular weights (Mn) determined by gel permeation chromatography using polystyrene standards, according to standard methods well known to those skilled in the art. Typically, materials, particularly multi-arm precursors, are purchased at specific molecular weights defined by the vendor. Suitable PEG precursors are available from numerous suppliers, such as Jenkem Technology.

[0084] As used herein, the term "Day 1" refers to the point in time immediately following "Day 0." Therefore, whenever "Day 1" is used, it always refers to the period of one day or approximately 24 hours that has already elapsed since the administration of the drug delivery system.

[0085] As used herein, the term “approximately” in relation to a measured quantity refers to the normal variation in that measured quantity that can be expected by a person skilled in the art when performing a measurement and exercising a level of care appropriate to the purpose of the measurement and the precision of the measuring instrument.

[0086] The term "at least about" in relation to a measured quantity refers to the normal variation in the measured quantity and amounts higher than the measured quantity that can be expected by a person skilled in the art when performing a measurement and exercising a level of care appropriate to the purpose of the measurement and the precision of the measuring instrument.

[0087] As used herein, the term “mean” refers to the central or representative value within a set of data (points), calculated by dividing the sum of the data (points) in the set by that number (i.e., the mean of the dataset).

[0088] As used herein, unless otherwise explicitly indicated by the context, the singular forms "a," "an," and "the" refer to multiple objects.

[0089] In this specification, the term "and / or" as used in expressions such as "A and / or B" is intended to include both "A and B" and "A or B".

[0090] Open terms such as "include," "including," "contain," and "containing" all mean "comprising." These unrestricted transition clauses are used to introduce an unrestricted list of elements, method steps, etc., that do not exclude additional unlisted elements or method steps.

[0091] Where used herein in conjunction with a specific value or number, the term “maximum” means including that respective value or number.

[0092] The terms "from A to B," "of A to B," and "to A to B" are used interchangeably in this specification and all refer to the range from A to B, including the upper and lower limits of A and B.

[0093] Throughout this disclosure, various aspects of the invention are presented in range form. It should be understood that the range form is for convenience and brevity only and should not be interpreted as an inflexible limitation on the scope of the invention. Therefore, the range description should be considered to specifically disclose not only the individual numerical values ​​within that range, but also all possible subranges. For example, a range description such as 1 to 6 should be considered to have the specifically disclosed subranges of 1 to 3, 1 to 4, 1 to 5, 2 to 4, 2 to 6, 3 to 6, etc., as well as the individual numbers within that range, e.g., 1, 2, 3, 4, 5, and 6. This applies regardless of the width of the range. A stated range of numerical values ​​includes the numerical value defining the range and each integer within that defined range.

[0094] As used herein, the abbreviation "PBS" means phosphate-buffered saline.

[0095] As used herein, the abbreviation "PEG" means polyethylene glycol.

[0096] As used herein, the abbreviation "PLGA" means poly(lactic acid-glycolic acid). Unless otherwise specified, it has an L / G ratio of 1:1 (50:50).

[0097] The terms "hydrophobic" or "lipophilic" are defined as properties of a polymer or material that have a low degree of water attraction or absorption, i.e., the material is repelled from a mass of water. The terms "hydrophilic" or "lipophilic," conversely, are defined as properties of a material or polymer that attract water or have a strong affinity for water. Hydrophobicity can be measured by determining the contact angle of a liquid, preferably a water droplet, formed on the surface of a solid polymer and / or gel. Furthermore, the hydrophobic organic liquids used in this invention are immiscible with water, or at least not easily miscible.

[0098] The "hydrophilic" molecule, for example, the precursor or precursor moiety, has a solubility of at least 1 g / 100 mL in aqueous solution.

[0099] As used herein, the term “immobilized” refers to long-range immobility and not to local mobility of microparticles within a polymer matrix. For example, oil exists as a continuous phase within a polymer matrix and can only gradually move in vivo; that is, it can gradually leach into bodily fluids over time. [Brief explanation of the drawing]

[0100] [Figure 1] This example demonstrates the optimization of drug release by using a blend of different prior art non-crosslinked polymer microparticles, compared to the release properties of individual prior art non-crosslinked microparticles made from different types of PLA polymers. [Figure 2] This is an image of a used Fibrijet (registered trademark) Y-type mixer. [Figure 3] This is an SEM image of cross-linked PLGA microparticles without an active ingredient after heating at 80°C for 2 hours. [Figure 4] The images show SEM images of fine particles according to an embodiment of the present invention with a diameter of more than 106 μm, before and after heating at 80°C for 2 hours. [Figure 5] The images show SEM images of fine particles according to embodiments of the present invention, with a diameter of 20 to 106 μm, before and after heating at 80°C for 2 hours. [Figure 6] Microscopic images of fine particles according to an embodiment of the present invention (left) and comparative non-crosslinked PLA fine particles (right) after heat treatment at 80°C for 2 hours are shown. [Figure 7] This shows the effects of particle diameter and heat treatment on the in vitro release of travoprost. [Figure 8] This graph shows the in vitro release of travoprost from crosslinked PLGA microparticles compared to non-crosslinked PLA microparticles of prior art. [Figure 9]This graph shows the in vitro release of travoprost from non-crosslinked PLA microparticles at different temperatures for comparison. Detailed description of the invention

[0101] The present invention relates to pharmaceutically acceptable biodegradable microparticles for sustained-release drug delivery of an active agent to a patient's body. In a further embodiment, a method for producing such biodegradable microparticles for sustained-release drug delivery of an active agent to a patient's body is provided. In certain embodiments, the biodegradable microparticles may be incorporated into a sustained-release biodegradable drug delivery system, particularly for use as a drug-eluting implant, or the microparticles may be used directly as a drug, such as in an injectable solution containing biodegradable drug-eluting microparticles in suspension form.

[0102] In one embodiment, biodegradable microparticles for sustained-release drug delivery comprise at least one active agent, such as a drug, and a covalently and three-dimensionally crosslinked biodegradable polymer. The active agent may, for example, be dispersed, embedded, or encapsulated within the covalently crosslinked biodegradable polymer.

[0103] fine particles In certain embodiments, biodegradable microparticles are formed by covalently crosslinking a precursor molecule of a polyfunctional monomer, oligomer, or polymer, as described herein, via the formation of chemical bonds or linkages. A three-dimensional covalently crosslinked polymer network may be formed, containing an active agent (and other optional components) which is immobilized within the polymer network of the microparticles until, for example, released from the microparticles in vivo or in vitro. The microparticles may further contain a solvent or a hydrophobic organic liquid such as an oil, resulting in organogel microparticles.

[0104] In certain embodiments, covalent crosslinking of the polymer-forming precursor results in limited mobility of the active agent dispersed or encapsulated therein. This leads to continuous control of drug release, primarily by restricting drug transport to diffusion through the polymer matrix of the microparticles, which may not be highly dependent on the degradation rate of the polymer itself. Furthermore, the occurrence of defects in the polymer that provide a rapid drug elution pathway, for example, caused by plasticization, is eliminated from such crosslinked polymer microparticles. In certain embodiments, the biodegradable microparticles of the present invention are a fully or at least partially diffusion-controlled delivery system, i.e., the release of the active agent from the microparticles is primarily controlled by a diffusion process. In certain embodiments, in vivo degradation of the polymer also occurs in the microparticles of the present invention, but does not primarily control the release of the active agent. In non-crosslinked microparticles obtained from solvent precipitation of linear polymers, the release of the active agent is primarily controlled by the degradation of the polymer matrix, and the active agent is released in a primarily degradation-controlled system.

[0105] Therefore, in certain embodiments, the use of covalently crosslinked polymers in biodegradable microparticles for drug delivery according to the present invention makes it possible to modify the release of active ingredients from microparticles or drug delivery systems, including the microparticles, by adjusting or appropriately selecting precursor components that form the crosslinked polymers according to their hydrophilic and / or hydrophobic properties.

[0106] Furthermore, in certain embodiments, the release of the active ingredient from the particulate matter or drug delivery system can be modified or controlled by appropriately selecting the type and amount of additives, such as oil (hydrophobic organic liquid), which are selected according to their properties, for example, hydrophobicity, viscosity, compatibility with the active ingredient, and solubility or insolubility of the active ingredient in the oil.

[0107] In embodiments where oil is used within biodegradable microparticles, a crosslinked polymer forms an organogel containing the oil within the crosslinked polymer matrix. The oil may contain an active agent in a soluble or dissolved form and may be used to modify the release of the active agent or to eliminate incompatibility of the active agent with the polymer. In other such embodiments, the active agent may be the oil itself, resulting in an organogel as biodegradable microparticles. A hydrophobic organic liquid may also function as a drug cosolvent during the fabrication of the microparticles.

[0108] The biodegradable microparticles of a particular embodiment of the present invention offer several advantages over the direct incorporation of active ingredients into a hydrogel. For example, the microparticles can be manufactured from a hydrophobic polymer and may be anhydrous, so that components that decompose in water (hydrolyzed), such as water-sensitive active ingredients, can be stabilized by encapsulating them in the biodegradable microparticles, allowing for long-term storage stability and eliminating the need for hydration at the time of planting.

[0109] Water-soluble compounds have low or no solubility in more hydrophobic polymers, allowing drugs to be taken up as particulate solids embedded in microparticles for in vivo dissolution by bodily fluids. The low solubility of drugs in microparticle polymers provides a reliable mechanism for controlling drug release rates. This property significantly increases the range of compounds that can be included in implants.

[0110] Furthermore, by manipulating the lipophilic / hydrophilic properties of the microparticle polymer, the drug release rate can be adjusted and the diffusion rate can be influenced. Simple hydrogels, being water-based, cannot be adjusted in this way; therefore, in these systems, adjusting the solubility of the drug / matrix in this manner requires changing the drug itself into a prodrug form. By using the active ingredient-carrying microparticles described herein, embedded in the hydrogel matrix of the implant, the solubility issues and the use of prodrugs can be avoided. Moreover, changing the lipophilic / hydrophilic properties of the polymer can affect the degradation rate of the polymer matrix itself, which can have an additional effect on the drug release rate from the microparticles.

[0111] During the preparation of microparticles, solvents may be involved, which need to be removed later. Solvent removal can be achieved, for example, by heat treatment, freeze-drying, evaporation, or vacuum drying. Some of these drying treatments may be limited to, or even impossible for, non-crosslinked materials that melt or undergo a glass transition at high temperatures. Other methods, such as freeze-drying, are costly. In certain embodiments of the present invention, covalently crosslinked biodegradable polymers are used to obtain heat-resistant biodegradable microparticles.

[0112] In certain embodiments, the microparticles may be dimensionally stable to heat and will not melt up to temperatures of, for example, about 50°C, 60°C, 70°C, 80°C, 90°C, or about 100°C. Solvent extraction methods requiring heat treatment can be used without affecting the release properties of the microparticles. Furthermore, their thermal stability allows the microparticles to be used in extrusion processes such as thermal melt extrusion, or in 3D printing, for example, while being incorporated into hydrogels or organogels for manufacturing composite implants.

[0113] In certain embodiments, during the production of microparticles, the particles solidify or harden not only through solvent removal in emulsion processes, such as those used with non-crosslinked polymers, but also through crosslinking. This makes the process of producing microspheres faster and simpler.

[0114] In certain embodiments, the microparticles further possess physical properties such as low modulus of elasticity, dimensional stability, and good drug release kinetics. It has also been observed that microparticles in certain embodiments of the present invention exhibit a release profile that is substantially independent of temperature, i.e., unaffected by temperature changes occurring under physiological conditions.

[0115] The microparticles may have a regular or irregular shape. In one general embodiment of the present disclosure, the microparticles are microspheres, which have a substantially spherical shape, typically obtained by the microparticle manufacturing method described herein.

[0116] In one embodiment, the fine particles have a particle size (diameter) of approximately 0.1 μm to approximately 1000 μm, or approximately 1 μm to approximately 150 μm, approximately 1 μm to approximately 100 μm, approximately 20 μm to approximately 75 μm, approximately 10 μm to approximately 106 μm, or approximately 20 μm to approximately 55 μm, as determined by sieving, or have an average diameter in the range of approximately 0.1 μm to approximately 1000 μm, or approximately 1 μm to approximately 150 μm, approximately 1 μm to approximately 100 μm, approximately 20 μm to approximately 75 μm, approximately 10 μm to approximately 106 μm, or approximately 20 μm to approximately 55 μm, as determined by laser diffraction.

[0117] In one embodiment, the biodegradable microparticles have a particle size distribution determined, for example, by laser diffraction, of D50 particle size of less than approximately 100 μm, or less than approximately 50 μm, or less than approximately 20 μm, and / or D90 particle size of less than approximately 200 μm, or less than approximately 100 μm, or less than 30 μm, and / or D90 particle size of less than approximately 20 μm. Can an optional lower limit be added?

[0118] In certain embodiments, the biodegradable microparticles consist of, or essentially consist of, at least one active agent and at least one covalently crosslinked biodegradable polymer. In other embodiments, the biodegradable microparticles include at least one active agent and a covalently crosslinked biodegradable polymer, and further additives may be present in the biodegradable polymer.

[0119] Further additives for use in the biodegradable microparticles of the embodiments of the present invention include hydrophobic organic liquids such as oils, solvents, salts, pologens, buffers, non-crosslinked oligomers or polymers, sugars, visualization agents, and markers.

[0120] Microparticles can be formed by crosslinking biodegradable polymer precursors, such as functionalized PLA, PLGA, or other polymers disclosed herein, for example, in the presence of a co-dissolved drug or particulate drug and a solvent. These microparticles may consist solely of the crosslinked polymer precursor or an oil / polymer blend. In certain embodiments, forming an organogel by gelation eliminates the need for rapid solvent removal and yields a rubbery material, i.e., a material above its glass transition temperature. PLGA microparticles are typically glassy at room temperature once the residual solvent is removed. Tg is a characteristic property of PLGA and depends on the composition, i.e., the lactide-to-glycolide ratio and molecular weight. In non-crosslinked PLGA, Tg decreases as degradation and water content increase in the in vivo environment after implantation. In such cases, Tg often drops below body temperature (plasticization), and the glassy solid microparticles of prior art non-crosslinked PLGA are converted in vivo into viscous liquid microdroplets, which can dramatically accelerate degradation kinetics and drug release rates in an uncontrolled environment. In the case of oil-free organogel microparticles, the PLGA matrix is ​​a glassy solid once the solvent is completely removed. Similar to non-crosslinked PLGA, crosslinked PLGA will gradually plasticize under physiological conditions. However, unlike non-crosslinked PLGA, crosslinked PLGA transforms into rubber rather than a viscous liquid above its Tg, which can reveal significant differences in drug release kinetics compared to non-crosslinked PLGA microparticles. In the case of organogel microparticles containing oil in the crosslinked polymer, the oil acts as a plasticizer, lowering Tg and resulting in rubbery microparticles in their initial state. Therefore, Tg may no longer be the primary rate-controlling characteristic for active agent release. In such embodiments, since no transition with Tg occurs, in vivo plasticization is considered to have little or negligible impact on drug release.

[0121] In certain embodiments, biodegradable microparticles may comprise blends of microparticles having different particle sizes and / or different polymers and / or containing different active agents. For example, blends of microparticles of different sizes and / or polymers with different molecular weights can be used to control the release kinetics of active agents and achieve a desired release over time. Blends of microparticles with different active agents can be used to apply multiple agents simultaneously or to co-release therapeutic and diagnostically active agents from the same microparticle mixture.

[0122] According to the present invention, compositions of biodegradable microparticles can be designed as needed for intended and therapeutic uses. In one embodiment, the microparticles contain 5-99% by weight, 5-90% by weight, 10-70% by weight, 10-60% by weight, 15-50% by weight, or 15-35% by weight of a covalently crosslinked polymer, or contain 5-95% by weight, 10-95% by weight, 40-95% by weight, 50-90% by weight, 60-90% by weight, or 60-85% by weight; contain 1-70% by weight of an active agent, or contain 5-65% by weight, 5-50% by weight, 10-45% by weight, or 10-45% by weight; wherein the formula, all weight percent are selected to total 100%, and the weight percent is based on the total mass of the microparticles. In embodiments in which the fine particles further contain an organogel containing oil, the amount of oil may be in the range of 1-70% by weight or 5-65% by weight, 5-60% by weight, 10-50% by weight, 10-40% by weight, 15-40% by weight, or 15-35% by weight, where all weight percentages are selected so as to add up to 100%, and the weight percentage is based on the total mass of the fine particles.

[0123] The microparticles of the embodiments of the present invention can achieve a high drug load. In one embodiment, the biodegradable microparticles have a drug load (active agent content) of at least about 5% by weight, at least about 10% by weight, at least about 20% by weight, at least about 30% by weight, at least about 35% by weight, at least about 40% by weight, at least about 45% by weight, at least about 50% by weight, at least about 55% by weight, at least about 60% by weight, at least about 65% by weight, at least about 70% by weight, or up to about 80% by weight (including any range of any of these values), based on the total mass of the microparticles. In that embodiment, the microparticles contain about 30% by weight to about 60% by weight, for example, about 40% by weight to about 55% by weight, for example, about 45% by weight to about 50% by weight of the active agent, based on the total mass of the microparticles. For example, in the case of oily drugs such as travoprost, the drug load of the microparticles may be up to about 50% by weight, for example, about 10% to about 45% by weight, or about 45% by weight, based on the total mass of the microparticles. For example, in the case of drugs such as dexamethasone, the drug load of the microparticles may be up to about 70% by weight, for example, up to about 65% by weight, or about 40% to about 60% by weight, based on the total mass of the microparticles. Very potent active ingredients may be included with a lower drug load, for example, about 5% to about 20% by weight, based on the total mass of the microparticles, or even lower, for example, about 1% to about 5% by weight.

[0124] In one embodiment, the mass ratio of the active agent to the polymer in the fine particles is about 3:1 to about 1:3, or about 2:1 to about 1:2, or about 1:1.

[0125] In one embodiment, biodegradable microparticles are incorporated into a hydrogel, organogel, or xerogel to form a sustained-release drug delivery system for use as an implant. In this embodiment, the content of biodegradable microparticles relative to the total weight of the implant is about 10% to about 35% by weight, or about 23% to about 27% by weight, or about 12% to about 17% by weight, or about 30% to about 35% by weight, or about 25% by weight, or about 15% by weight, or about 34% by weight.

[0126] When organogels are used to incorporate biodegradable microparticles, the organogel may contain about 1% to about 90% by weight of a hydrophobic organic liquid or oil, or about 5% to about 90% by weight, about 5% to about 60% by weight, about 10% to about 50% by weight, about 10% to about 40% by weight, about 15% to about 40% by weight, or about 15% to about 35% by weight of a covalently crosslinked polymer gel matrix, or about 5% to about 95% by weight, or about 10% to about 95% by weight, or about 40% by weight. It may contain approximately 95% by weight, approximately 50% to approximately 90% by weight, approximately 60% to approximately 90% by weight, or 60% to approximately 85% by weight; and biodegradable particulate matter may contain approximately 1% to approximately 50% by weight, or approximately 5% to approximately 50% by weight, approximately 5% to approximately 40% by weight, 10% to approximately 30% by weight, or approximately 10% to approximately 25% by weight; where all weight percentages are selected to add up to 100%, and each weight percentage is based on the total dry weight of the drug delivery system or implant.

[0127] Biodegradable polymers The biodegradable microparticles of a particular embodiment of the present invention that encapsulate the active ingredient include a covalently and three-dimensionally crosslinked polymer. The polymer units in the biodegradable polymer or its precursor may be selected from, for example, any biodegradable natural, semi-synthetic, synthetic, or biosynthetic polymer, or a combination thereof.

[0128] Examples of natural polymers include glycosaminoglycans, polysaccharides (e.g., dextran), polyamino acids, and proteins, or mixtures or combinations thereof. Semi-synthetic polymers may be selected from carboxymethylcellulose, or alkylcelluloses such as methylcellulose (MC) and ethylcellulose (EC).

[0129] In some embodiments, synthetic precursors are used. Synthesis refers to molecules that do not exist in nature or normally in the human body. Synthetic polymers can generally be any polymer produced synthetically by different types of polymerization (including free radical polymerization, anionic or cationic polymerization, chain growth or addition polymerization, condensation polymerization, ring-opening polymerization, etc.). Polymerization can be initiated by certain initiators, light and / or heat, and can also be mediated by catalysts.

[0130] Generally, the biodegradable microparticles of a particular embodiment of the present invention that encapsulate an active ingredient comprise a covalently and three-dimensionally crosslinked homopolymer or copolymer, which may be selected from polyethylene glycol (PEG), polypropylene glycol (PPG), polyvinyl alcohol, poly(vinylpyrrolidone), polylactic acid (PLA), polyglycolic acid (PGA), polylactic acid-glycolic acid copolymer (PLGA), poly-p-dioxanone, poly(trimethylene carbonate), polycaprolactone, and / or polyvinyl alcohol, a random or block copolymer of any of these, or a combination or mixture of any of these, or one or more polyamino acids, glycosaminoglycans, polysaccharides, or proteins.

[0131] In the first embodiment, the biodegradable microparticles comprise at least one of crosslinked polylactic acid (PLA), polyglycolic acid (PGA), polylactic acid-glycolic acid copolymer (PLGA), poly(vinylpyrrolidone), poly-p-dioxanone, poly(trimethylene carbonate), polycaprolactone, and / or polyvinyl alcohol, or copolymers thereof, and at least one active agent. In that particular embodiment, the covalently crosslinked biodegradable polymer used in the microparticles of the present invention is one of crosslinked polylactic acid (PLA) or crosslinked polylactic acid-glycolic acid copolymer (PLGA).

[0132] In a second embodiment, the biodegradable microparticles comprise an organogel, which comprises at least one crosslinked polymer, random or block copolymer, or any combination or mixture thereof, selected from polyethylene glycol (PEG), polypropylene glycol (PPG), polyvinyl alcohol, poly(vinylpyrrolidone), polylactic acid (PLA), polyglycolic acid (PGA), polylactic acid-glycolic acid copolymer (PLGA), poly-p-dioxanone, poly(trimethylene carbonate), polycaprolactone, and / or polyvinyl alcohol, or one or more polyamino acids, glycosaminoglycans, polysaccharides, or proteins, at least one oil, and at least one active agent. In a particular embodiment, the covalently crosslinked biodegradable polymer used is one of crosslinked polyethylene glycol (PEG) or polypropylene glycol (PPG), or crosslinked polylactic acid-glycolic acid copolymer (PLGA), or a crosslinked copolymer of PEG and PLGA. In some embodiments, the active agent is the oil itself, which together with the crosslinked polymer may form microparticles in the form of an organogel.

[0133] In another embodiment of the second embodiment, the biodegradable microparticles comprise an organogel comprising at least one crosslinked polymer or copolymer thereof selected from polylactic acid (PLA), polyglycolic acid (PGA), polylactic acid-glycolic acid copolymer (PLGA), poly(vinylpyrrolidone), poly-p-dioxanone, poly(trimethylene carbonate), polycaprolactone, and / or polyvinyl alcohol, at least one oil, and at least one active agent. In that particular embodiment, the covalently crosslinked biodegradable polymer used is one of crosslinked polylactic acid (PLA) or crosslinked polylactic acid-glycolic acid copolymer (PLGA). In some aspects thereof, the active agent is the oil itself, which together with the crosslinked polymer may form microparticles in the form of an organogel.

[0134] In another embodiment, copolymers of PEG and PLGA, particularly block copolymers of multi-arm PEG copolymerized with PLGA, may also be used.

[0135] The hydrophilic polymer may be selected from polyglycolic acid (PGA), and at least one of polyethylene glycol or polypropylene glycol may also be used. In one embodiment, the hydrophilic polymer comprises polyglycolic acid (PGA) or polyethylene glycol.

[0136] In further embodiments of the present invention, the covalently crosslinked polymer of the fine particles comprises a combination of multiple hydrophobic polymer units selected from at least one of polylactic acid (PLA) and polylactic acid-glycolic acid copolymer (PLGA), and at least one multiple hydrophilic polymer units selected from at least one polyethylene glycol (PEG) unit, polypropylene glycol (PPG), or polyglycolic acid (PGA) unit. In some embodiments, the hydrophilic polymer units include polyethylene glycol (PEG) units.

[0137] In one embodiment, the crosslinked polymer of the fine particles is formed from a multi-arm precursor comprising a combination of polylactic acid-glycolic acid copolymer (PLGA) units and polyethylene glycol (PEG) units. The ratio of polylactic acid-glycolic acid copolymer (PLGA) units to polyethylene glycol (PEG) units can be selected from about 2.5:1 to about 1:2.5, or about 2:1 to about 1:2, or about 1:1.

[0138] In embodiments in which PLGA is used, the polylactic acid-glycolic acid copolymer (PLGA) units may have an L / G ratio (%) in the range of 0:100 to 100:0, or about 1:99 to about 99:1, or about 10:90 to about 90:10, or about 25:75 to about 75:25, or about 50:50.

[0139] In certain embodiments, in biodegradable microparticles, the polymer is covalently crosslinked by hydrolytic bonds between polymer units, thereby promoting biodegradation in vivo in aquatic environments such as the bodies of humans or animals.

[0140] Hydrolyzable bonds may include bonds or linkages selected from the group consisting of amines, amides, urethanes, esters, anhydrides, ethers, acetals, ketals, nitriles, isonitriles, isothiocyanates, or imine bonds, and combinations thereof. These bonds are typically formed by the condensation polymerization reaction of appropriately functionalized gelling agents or precursors.

[0141] Precursor components In embodiments of the present invention, covalently crosslinked polymers are formed by chemically covalently crosslinking a polyfunctional precursor. In one embodiment, the precursor is a functionalized monomer, oligomer, or polymer molecule having functional groups that can be crosslinked with other precursors or low molecular weight crosslinkers. Low molecular weight precursors generally refer to precursors with a molecular weight of less than about 2000 daltons. Examples of low molecular weight crosslinkers include diamines, triamines, or tetramine compounds, di or triisocyanates, etc. Non-limiting examples include ethylenediamine, tris(2-aminoethyl)amine (TAEA), or trilysine. The precursors, as well as the low molecular weight crosslinkers, may be linear or non-linear, for example, branched, star-shaped, comb-shaped, or dendrimers.

[0142] In one embodiment, at least one precursor or low molecular weight crosslinker has more than two, for example, 3 to 10, or 3 to 9, or 4 to 8, or 4, functional groups relating to chemical crosslinking. In one embodiment, at least one precursor or low molecular weight crosslinker has three or more functionalities to form a three-dimensional (3D) polymer network. Such precursors may be nonlinear, branched, star-shaped, comb-shaped, or dendrimer. Therefore, when a linear bifunctional polymer precursor is used in one embodiment, the low molecular weight crosslinker or second polymer crosslinker is at least trifunctional, and as a result, three-dimensional crosslinking can occur, forming a polymer matrix containing an active agent and optionally oil. When a bifunctional low molecular weight crosslinker is used, at least one multi-arm polymer precursor should have three or more functional groups to achieve three-dimensional crosslinking of the polymer matrix.

[0143] In one embodiment, at least one precursor is a star-shaped, multi-armed, or dendrimer precursor having a core and 2 to 10 arms, or 3 to 10 arms, 4 to 8 arms, or 4 to 6 arms, each arm comprising polymer units and having an end. Polymer units may include, but are not limited to, one or more polyalkylene oxides such as polyethylene glycol, polypropylene glycol, poly(ethylene glycol)-block-poly(propylene glycol) copolymer, commercially available poloxamers such as Tetronic®, or commercially available Jeffamine® polymer, polyethylene oxide, polypropylene oxide; polyvinyl acetate, polyvinyl alcohol, poly(vinylpyrrolidone), polylactic acid (PLA), polyglycolic acid (PGA), polylactic acid-glycolic acid copolymer (PLGA), poly-p-dioxanone, poly(trimethylene carbonate), polycaprolactone, and / or polyvinyl alcohol, or copolymers, random or block copolymers, or any combination or mixture thereof, or one or more units of polyamino acids, glycosaminoglycans, polysaccharides, or proteins.

[0144] Biodegradable microparticles containing covalently crosslinked polymers may be formed from multiple hydrophobic polymer units, multiple hydrophilic polymer units, or a combination of hydrophobic and hydrophilic units. The polymer units may be selected to adjust the hydrophobicity and hydrophilicity of the microparticles to suit the properties of the active ingredient. This adjustment allows for control of specific aspects of the microparticle release dynamics and degradation behavior.

[0145] In one embodiment of the present invention, the multi-arm precursor of hydrophobic biodegradable polymer units may comprise at least one of polylactic acid (PLA) and polylactic acid-glycolic acid copolymer (PLGA) units. The polymer units are suitably functionalized with desired reactive groups at their ends, and the molecular weight of PLA or PLGA, or the L / G ratio in the PLGA copolymer, may vary according to desired polymer properties such as hydrophobicity. Polycaprolactone, polyvinyl alcohol, or poly(vinylpyrrolidone) may also be used.

[0146] In the first embodiment described above, the biodegradable microparticles comprise a covalently crosslinked polymer containing an active agent, and the polymer matrix or network is formed from at least one covalently crosslinkable precursor that is miscible and / or soluble in the solvent. Examples of precursors include polymer units of polylactic acid (PLA), polyglycolic acid (PGA), polylactic acid-glycolic acid copolymer (PLGA), poly(vinylpyrrolidone), polycaprolactone, and / or polyvinyl alcohol. The active agent may be soluble in the same solvent or dispersed therein in the form of microparticles.

[0147] In the second embodiment described above, the biodegradable microparticles are formed from at least one covalently crosslinkable precursor comprising an oil-containing organogel (as an active agent or as an additive in addition to the active agent being oil), wherein the polymer matrix of the organogel is miscible with oil and preferably soluble or dispersible in oil or optionally in a mixture of oil and solvent, as defined herein.

[0148] In some embodiments, the microparticles comprise a polymer network or matrix, optionally in the form of an organogel, comprising or formed from at least one covalently crosslinked multi-arm precursor and a low molecular weight crosslinking agent. In another embodiment of the present invention, the microparticles comprise a polymer network or matrix, optionally in the form of an organogel, comprising or formed from at least two covalently crosslinked multi-arm precursors.

[0149] Therefore, the precursor is always a "functional polymer" or "functional substance," such as a crosslinking agent (e.g., a small molecule with low molecular weight) that can participate in crosslinking reactions with other precursors to form a covalently crosslinked polymer network (or matrix). Thus, the term "non-functional polymer" refers to a polymer that may be present in the organogel of the present invention but does not participate in crosslinking reactions with precursors and does not form a polymer network. The precursor is selected considering the desired properties of the resulting particulate polymer and the structure at the time of formation, for example, compatibility with organic solvents when the crosslinked matrix is ​​formed as an organogel.

[0150] The precursors used in the present invention may include any polymer units described above herein, insofar as they react with other precursors or crosslinking agents in the presence of an active agent and optionally oil to form biocompatible and biodegradable crosslinked polymers in particulate form.

[0151] The crosslinked polymer material for biodegradable microparticles may be formed from any of the biodegradable polymers mentioned in the above section, and the covalently crosslinked precursor comprises units of these polymers having functional groups that can chemically crosslink the precursor by forming covalent bonds for the formation of a crosslinked polymer matrix.

[0152] In some aspects of the present invention, at least one crosslinkable precursor is either hydrophobic or hydrophilic, and when two precursors are used, both may be hydrophobic, both may be hydrophilic, or one may be hydrophobic and the other hydrophilic. In the case of three or more precursors, any mixture of hydrophilic and hydrophobic precursors may be selected depending on the desired properties of the fine particles. Furthermore, the precursors may be copolymers incorporating both hydrophobic and hydrophilic substructures.

[0153] Functional groups for crosslinking The precursor has a pair of functional groups that react with each other, i.e., a first functional group on the first precursor that can react with a second functional group on the second precursor or crosslinking agent. In one embodiment, a first multi-arm precursor containing the first functional group reacts with a second multi-arm precursor or low molecular weight crosslinking agent containing the second functional group, so that the functional group is located at the end of an arm of the precursor or crosslinking agent, where the first or second functional group may be grafted directly onto the precursor end or via a linker molecule. The functional groups are capable of reacting with each other and are configured to form covalent bonds or links, for example in an electrophile-nucleophile reaction, or to participate in other chemical crosslinking reactions as described below.

[0154] In certain embodiments of the present invention, the first and second functional groups are selected from electrophiles and nucleophiles, functional groups for click chemistry, functional groups for cycloaddition, particularly 1,3-dipolar cycloaddition, hetero-Diels-Alder cycloaddition, functional groups for nucleophilic ring-opening, functional groups for non-aldol-type carbonyl reactions, functional groups for addition reactions to carbon-carbon multiple bonds, polymerizable vinyl groups, or combinations thereof. Those skilled in the art will know that a particular pair of functional groups can be classified into several of these groups. For example, in click chemistry, an azide reacting with dibenzocyclooctyne can also be considered an electrophile-nucleophile reaction pair.

[0155] Accordingly, in one embodiment, the first functional group may be an electrophile and the second functional group may be a nucleophile, or vice versa, and the reaction between the first and second functional groups is an electrophile-nucleophile reaction that forms a covalent bond. According to a particular embodiment of the present invention, each precursor or crosslinker comprises at least two or at least three terminal nucleophiles, or at least two or at least three terminal electrophiles.

[0156] The nucleophile may be selected from one of the following: amines such as primary amines, hydroxyl, thiol, carboxyl, dibenzocyclooctin, or hydrazide groups. In certain embodiments, at least one precursor comprises a nucleophile such as a primary amine.

[0157] Electrophiles usable in the present invention may be selected from active ester groups such as succinimidyl esters and succinimidyl carbonates; nitrophenyl carbonates, aldehydes, ketones, acrylates, acrylamides, maleimides, vinyl sulfones, iodoacetamides, alkenes, alkynes, azides, norbornene, epoxides, mesylates, tosylates, tresyl, cyanurates, orthopyridyl disulfide, or halogens. These electrophiles include functional groups that participate in electrophilic-nucleophilic reactions and crosslink precursors, and they preferably further include reactive groups that include hydrolyzable groups or bonds such as glutarates. For example, in one embodiment of the present invention, succinimidyl esters may include reactive groups such as succinimidyl succinate (SS), succinimidyl glutarate (SG), succinimidyl adipate (SAP), succinimidyl azelate (SAZ), or succinimidyl glutaramide. Such electrophilic-nucleophilic crosslinking reactions for multi-armed PEG precursors are described, for example, in US2002 / 0042473A1, which is incorporated by reference.

[0158] Therefore, in some embodiments, the first and second functional groups are selected from a functional group pair for click chemistry and form a covalent bond. For example, in the functionalization of azides and dibenzocyclooctyne, the precursor can be crosslinked via a so-called click chemical reaction. An overview of this type of reaction is given by reference in H. Kolb; M.G. Finn; K.B. Sharpless (2001). “Click Chemistry: Diverse Chemical Function from a Few Good Reactions”, Angewandte Chemie International Edition, 40(11):2004-2021).

[0159] Functional groups for click chemistry are selected from functional groups for cycloaddition, particularly 1,3-dipolar cycloaddition, alkene-nitrone cycloaddition, [3+2] cycloaddition such as alkene-nitrone cycloaddition or alkyne-nitrone cycloaddition, [4+2] cycloaddition, hetero-Diels-Alder cycloaddition; functional groups for thiol-ene reactions; functional groups for nucleophilic ring-opening; functional groups for non-aldol type carbonyl reactions; functional groups for addition reactions to carbon-carbon multiple bonds; and functional groups for Michael type addition.

[0160] For example, the first functional group is an alkyne compound such as dibenzocyclooctin (DBCO) or bicyclo[6.1.0]-nonine (BCN); or norbornene or trans-cyclooctene (TCO); the second functional group is an azide, 3,4-dihydroxyphenylacetic acid (DHPA), or tetrazine (Tz). In these embodiments, the DBCO, BCN, norbornene, TCO, azide, DHPA, and Tz functional groups can be grafted to the ends of the multi-arm precursor via linkers such as acidic groups, diacidic groups, functionalized aliphatic groups, heteroaliphatic groups, or aromatic or heteroaromatic groups.

[0161] In another embodiment, the first and second functional groups are selected for [3+2] cycloaddition reactions such as alkene-nitrone cycloaddition or alkyne-nitrone cycloaddition. In yet another embodiment, the first and second functional groups are selected for [4+2] cycloaddition reactions, particularly hetero-Diels-Alder reactions, where the first functional group is an aldehyde or imine compound and the second functional group is a 1,3-diene compound, an unsaturated carbonyl compound, or a nitrosoalkene compound. In yet another embodiment, the first and second functional groups are selected for thiol-ene reactions, where the first functional group is a thiol compound and the second functional group is an alkene, preferably a terminal alkene. In yet another embodiment, the first and second functional groups are selected for nucleophilic ring-opening, where the first functional group is selected from epoxides, thiirane, aziridine, or lactams and the second functional group is the nucleophile described above. In another embodiment, the first and second functional groups are selected for a non-aldol type carbonyl reaction, where the first functional group is an aldehyde or ketone compound, and the second functional group is a primary amine, hydrazide, acylhydrazide, or aminooxy compound, forming an imine, amide, isourea, hydrazone, acylhydrazone, or oxime bond.

[0162] In yet another embodiment, the first and second functional groups are selected from functional groups that can be radically polymerized / crosslinked.

[0163] In such embodiments, the first and second functional groups are selected, for example, from polymerizable vinyl groups and acrylates such as (meth)acrylic acid, (meth)acrylic acid esters, acrylamide, fumaric acid, maleic acid, and combinations thereof. Crosslinking is optionally induced thermally or photochemically using an initiator such as a free radical photoinitiator (Nourish type I such as 2,2-dimethoxy-1,2-diphenylethane-1-one, 2-hydroxy-2-methyl-1-phenylpropanone, 1-hydroxy-cyclohexylphenyl ketone; or Nourish type II such as benzophenone and its derivatives combined with co-actors such as tertiary amines such as 2-ethylhexyl-(4-N,N-dimethylamino)benzoate and 2-ethyl-(4-N,N-dimethylamino)benzoate, and isopropylthioxanthone); or a cationic photoinitiator.

[0164] Such crosslinking mechanisms with precursors functionalized with terminal vinyl groups are described, for example, in US2021 / 0251893A1, which is incorporated herein by reference.

[0165] Multi-arm precursor The term “multi-armed” precursor means that the precursor is branched, i.e., nonlinear. In the case of multi-armed polymers, the core refers to a continuous portion of molecules bonded to arms of polymer units extending from the core, and the arms often have nucleophilic or electrophilic functional groups at the ends of the branches. Note that precursors may have, for example, 2 to 100 arms, each arm having an end, and some precursors may be dendrimers or other highly branched materials such as dendrimers. The arms of a precursor refer to a linear chain of chemical groups that connect crosslinkable functional groups to the polymer core, i.e., polymer units as defined herein. Some embodiments are precursors having 3 to 300 arms; those skilled in the art will immediately understand that all ranges and values ​​within the explicitly stated ranges, e.g., 4, 6, 8, 10, 12, 4 to 16, 8 to 100, 6, 8, 10, 12, or at least 4 arms are assumed.

[0166] In certain embodiments, the multi-arm precursor of the present invention has a core and 2 to 10 arms, or 3 to 10 arms, 4 to 8 arms, or 4 or 8 arms, each arm comprising polymer units and having a terminal, the terminal having a functional group for crosslinking as defined above. In the multi-arm precursor, since the arms extend from a central core, their polymer terminals are identical, and all arms can be advantageously functionalized in a single reaction using the same functional group.

[0167] Each polymer unit in the multi-arm precursor has an average molecular weight in the range of, for example, about 1,000 to about 100,000 daltons, or about 10,000 to about 60,000 daltons, or about 15,000 to about 50,000 daltons.

[0168] core The core of a multi-arm precursor is a structure suitable for providing a desired number of arms for the precursor. For example, in the case of a 4-arm polymer unit and precursor, the core may be a pentaerythritol or ethylenediamine structure, and in the case of an 8-arm polymer unit and precursor, the core may be a hexaglycerol structure.

[0169] As disclosed above, in certain embodiments, the polymer network of biodegradable microparticles is formed from at least two precursors, at least one of which is a multi-arm precursor, and the second precursor is a low-molecular-weight crosslinker or a multi-arm precursor. The first multi-arm precursor contains a first functional group, and the second precursor is selected from a multi-arm precursor containing a low-molecular-weight crosslinker or a second functional group, the functional group being located at the end of an arm or molecule. In various embodiments of the present invention, each of the first and second functional groups is selected from the group of crosslinkable functional groups defined above. In some embodiments, the functional groups are selected from electrophiles and nucleophiles, and the reaction between the first and second functional groups is an electrophilic-nucleophilic reaction or polycondensation that forms a covalent bond in the polymer of the biodegradable microparticles.

[0170] In some embodiments, if each precursor is multi-armed, it comprises two or more arms and therefore has, for example, two or more identical or different electrophiles or nucleophiles, or any other pair of crosslinkable first and second functional groups as described above, so that each nucleophile reacts with another electrophile (in the same precursor or in another precursor) in an electrophile-nucleophile reaction to form a crosslinked polymer product. Thus, for example, in some embodiments, the precursor has at least four arms, at least eight arms, or at least ten arms, and each arm is terminated with either a nucleophile or electrophile, which may be the same as or different from the other arms.

[0171] In one embodiment, biodegradable microparticles comprising at least two multi-arm precursors include a first multi-arm precursor comprising a nucleophile and a second multi-arm precursor comprising an electrophile. In this embodiment, the first multi-arm precursor and the second multi-arm precursor are covalently cross-linked with each other in an electrophile-nucleophile reaction. In this context, multi-arm refers to at least four arms, at least eight arms, for example, at least ten arms. In this embodiment, the nucleophile may be an amine such as a primary amine, a thiol, dibenzocyclooctin, or a hydrazide, and the electrophile may be succinimidyl ester, succinimidyl carbonate, nitrophenyl carbonate, aldehyde, ketone, acrylate, acrylamide, maleimide, vinyl sulfone, iodoacetamide, alkene, alkyne, azide, norbornene, epoxide, mesylate, tosylate, tresyl, cyanurate, orthopyridyl disulfide, or a halide. For example, in one embodiment of the present invention, the succinimidyl ester may contain a reactive group such as succinimidyl succinate (SS), succinimidyl glutarate (SG), succinimidyl adipate (SAP), succinimidyl azelate (SAZ), or succinimidyl glutaramide.

[0172] Some precursors may have a longer hydrolysis half-life compared to other precursors. In other words, they may require more time to decompose. This can be attributed in part to the reactive groups contained in the precursor. For example, PLPGA polymers containing electrophiles such as succinimidyl ester groups containing reactive groups such as succinimidyl succinate (SS) have a shorter hydrolysis half-life compared to PLGA polymers containing electrophiles such as succinimidyl ester groups containing reactive groups such as succinimidyl glutarate (SG).

[0173] In one embodiment, the biodegradable microparticles may comprise two multi-arm precursors, which may comprise a first multi-arm precursor comprising a nucleophile such as an amine, and a second multi-arm precursor comprising an electrophile such as a succinimidyl ester. In another embodiment, the biodegradable microparticle crosslinked polymer may comprise a first multi-arm precursor comprising a nucleophile such as an amine, such as a primary amine, and a second multi-arm precursor comprising an electrophile such as a succinimidyl ester comprising a first reactive group. In this embodiment, the reactive group is selected from succinimidyl succinate (SS), succinimidyl glutarate (SG), succinimidyl adipate (SAP), or succinimidyl azelate (SAZ).

[0174] As disclosed above, the polymer network of biodegradable microparticles is formed from at least two precursors, at least one of which is a multi-arm precursor, and the second precursor is a low-molecular-weight crosslinker or a multi-arm precursor. The first multi-arm precursor contains a first functional group, and the second precursor is selected from a multi-arm precursor containing a low-molecular-weight crosslinker or a second functional group, the functional group being located at the end of an arm or molecule. In various embodiments of the present invention, each of the first and second functional groups is selected from the group of crosslinkable functional groups defined above. In some embodiments, the functional groups are selected from electrophiles and nucleophiles, and the reaction between the first and second functional groups is an electrophilic-nucleophilic reaction or polycondensation that forms a covalent bond in the polymer of the biodegradable microparticles.

[0175] PLA / PLGA precursor In certain embodiments, the precursor is a polylactic acid-glycolic acid copolymer (PLGA) precursor, i.e., a multi-arm precursor having PLGA polymer units in its core.

[0176] In one embodiment, such a precursor may have the following exemplary structure comprising a fairly hydrophobic and oil-soluble pentaerythritol-derived core from 4a20K PLGA-NHS. [ka]

[0177] According to its name, this is a 4-arm PLGA, where each PLGA unit has approximately 5,000 Daltons of Mn, the PLGA units have a 50:50 (i.e., 1:1) L / G ratio, R is part of a diacid linker derived from one of saturated or unsaturated biocompatible organic diacids, e.g., oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, maleic acid, fumaric acid, along with the two carbonyl groups to which it is bonded, and NHS indicates an N-hydroxysuccinimide electrophile as a functional group at the end of each arm. x is an integer defining the number of lactate units, and y is an integer defining the number of glycolic acid units in the PLGA molecule. For a 50:50 PLGA, x and y are equal. n is an integer defining the number of PLGA blocks in an optional block copolymer unit, where n is 1 for a 50:50 PLGA.

[0178] Another example of an electrophilic functionalized 4-arm PLGA precursor is 4a20K PLGA5050-SAP-NHS (where x and y are approximately 15). [ka]

[0179] In another embodiment, the multi-arm PLGA precursor may be derived from ethylenediamine as the core instead of pentaerythritol. By using different cores, the precursor may have more than four arms, such as 6, 8, 10, or 12 arms, and can extend to dendrimer compounds with up to 100 or more arms.

[0180] In various embodiments of the present invention, the biodegradable microparticle crosslinked polymer comprises or is constructed from a single multi-arm precursor comprising polymer units of polylactic acid-glycolic acid copolymer (PLGA) units, and in other embodiments, comprises or is constructed from polylactic acid (PLA) units, or combinations thereof, or (block) copolymers. In such embodiments, the biodegradable microparticles are formed using at least one crosslinking agent, preferably a low molecular weight amine such as oil-soluble tris(2-aminoethyl)amine (TAEA), or trilysine.

[0181] In certain embodiments, polylactic acid (PLA) units are preferred.

[0182] In some embodiments, these PLGA and / or PLA-based microparticles may contain oils that form an organogel as biodegradable microparticles.

[0183] In some embodiments of the present invention, the biodegradable particulate crosslinked polymer comprises at least one multi-arm precursor comprising hydrophobic polymer units selected from polylactic acid (PLA) units and polylactic acid-glycolic acid copolymer (PLGA) units, or combinations thereof, or (block) copolymers, and at least one further multi-arm precursor comprising hydrophilic polymer units, wherein the hydrophilic polymer units are preferably selected from polyethylene glycol (PEG) and polyglycolic acid (PGA).

[0184] In certain embodiments of the present invention, the PLA and / or PLGA units used as precursors have an average molecular weight in the range of about 1,000 to about 100,000 daltons, or about 10,000 to about 60,000 daltons, or about 15,000 to about 50,000 daltons. In certain embodiments, the PLA and / or PLGA units have an average molecular weight in the range of about 10,000 to about 40,000 daltons, or about 20,000 daltons. PLA and / or PLGA precursors with the same average molecular weight may be used, or PLA and / or PLGA precursors with different average molecular weights may be combined with each other. The average molecular weight of the PLA and / or PLGA precursors used in the present invention is given as the number-average molecular weight (Mn), which in certain embodiments may be determined by gel permeation chromatography against a polystyrene standard according to a standardized method.

[0185] The precursors listed above, such as 4arm PLA SS (20k), 4arm PLGA 50:50 SS (20k, 60k), or 4arm PLGA 75:25 SS (20k, 60k), are commercially available, while others can be obtained from other vendors such as Nanosoft Polymers, Winston-Salem, US, or Creative PEGWorks, Chapel Hill, NC, USA, SinoPEG, CN, or Akina Inc., West Lafayette, Indiana, USA.

[0186] PEG precursor In some embodiments, the precursor is a polyethylene glycol precursor, i.e., having polyethylene glycol polymer units in the core of a multi-arm precursor. Thus, in some embodiments, the covalently crosslinked precursor particulate polymer network is made from or comprises at least one polyethylene glycol-containing precursor. Polyethylene glycol (PEG, also called polyethylene oxide) refers to a polymer having repeating groups (CH2CH2O)n (where n is at least 3).

[0187] Therefore, polymer precursors having polyethylene glycol have at least three of these repeating groups linearly linked to each other. PEG polymers ending with a hydroxyl or methoxy group that does not participate in the crosslinking reaction between precursors are referred to herein as “non-functional PEGs” as described above and are therefore not used as one of the precursors. Thus, PEG polymers ending with a nucleophile selected from primary amines, thiols, dibenzocyclooctin, or hydrazides are considered “functional PEGs” and may be used as one of the precursors. Furthermore, PEG polymers ending with an electrophile selected from succinimidyl esters, succinimidyl carbonates, nitrophenyl carbonates, aldehydes, ketones, acrylates, acrylamides, maleimides, vinyl sulfones, iodoacetamides, alkenes, alkynes, azides, norbornene, epoxides, mesylates, tosylates, tresyl, cyanurates, or orthopyridyl disulfide, or halides are considered “functional PEGs” and may be used as one of the precursors.

[0188] The polymer network of the biodegradable particulate drug delivery system of the present invention may include one or more multi-arm PEG precursors having 2 to 10 arms, or 4 to 8 arms, or 4, 5, 6, 7, or 8 arms. It should be noted that since multi-arm precursors have a core, for example, a 2-arm PEG precursor differs from simple linear PEG due to the presence of a core structure. Two-arm precursors can form a 3D crosslinked network with crosslinking agents having at least 3 functionalities. PEG precursors may have different or the same number of arms. In certain embodiments, the PEG precursors used in the organogel of the present invention have 4 and / or 8 arms. In certain embodiments, combinations of 4-arm and 8-arm PEG units are utilized.

[0189] In certain embodiments of the present invention, the polyethylene glycol units used as precursors have an average molecular weight in the range of about 1,000 to about 100,000 daltons, or about 10,000 to about 60,000 daltons, or about 15,000 to about 50,000 daltons. In some embodiments, the polyethylene glycol units have an average molecular weight in the range of about 10,000 to about 40,000 daltons, or about 20,000 daltons. PEG precursors with the same average molecular weight may be used, or PEG precursors with different average molecular weights may be combined. The average molecular weight of the PEG precursors used in the present invention is given as the number-average molecular weight (Mn), which in certain embodiments may be determined by gel permeation chromatography against a polystyrene standard according to a standardized method.

[0190] In a 4-arm PEG, each arm may have an average arm length (or molecular weight) obtained by dividing the total molecular weight of PEG by 4. Therefore, one precursor usable in this invention, the 4a20kPEG precursor, has four arms, each with an average molecular weight of approximately 5,000 daltons. In this invention, in addition to the 4a20kPEG precursor, the 8a20kPEG precursor can be used, which has eight arms, each with an average molecular weight of 2,500 daltons. Therefore, the 4a20K PLGA precursor has four arms, each with an average molecular weight of approximately 5,000 daltons.

[0191] Generally, when referring to polymer precursors with a specific average molecular weight (e.g., 15kPEG or 20kPEG precursors), the indicated average molecular weight (i.e., Mn of 15,000 or 20,000, respectively) refers to the polymer unit portion of the precursor before the addition of end groups (in this specification, "20k" means 20,000 daltons, and "15k" means 15,000 daltons—the same abbreviations are used herein for PEG or other polymer precursors of other average molecular weights). In certain embodiments, the Mn of the polymer unit portion of the precursor is determined by gel permeation chromatography against a polystyrene standard according to a standardized method. The degree of substitution by end groups disclosed herein may be determined by 1H-NMR after end group functionalization.

[0192] In various embodiments of the present invention, the biodegradable microparticles comprise at least two multi-arm precursors, the first of which is a multi-arm PEG precursor comprising a nucleophile such as an amine, e.g., a primary amine. In some of these embodiments, the second multi-arm precursor is a multi-arm PEG precursor comprising an electrophile such as succinimidyl ester. In other embodiments, the second multi-arm precursor is a multi-arm PLGA precursor comprising an electrophile such as succinimidyl ester.

[0193] In some embodiments of the present invention, the biodegradable microparticle crosslinked polymer comprises three multi-arm precursors, the first being a multi-arm PEG precursor comprising a nucleophile such as an amine, e.g., a primary amine. In this embodiment, the second multi-arm precursor is a multi-arm PEG precursor comprising an electrophile such as a succinimidyl ester comprising the first reactive group. In this embodiment, the third multi-arm precursor is a multi-arm PEG precursor comprising an electrophile such as a succinimidyl ester comprising the second reactive group. In this embodiment, the first and second reactive groups may be selected from succinimidyl succinate (SS), succinimidyl glutarate (SG), succinimidyl adipate (SAP), or succinimidyl azelate (SAZ). SS, SG, SAP, and SAZ are all functionalized linkers bonded to a polymer containing a reactive group consisting of the N-succinimidyl ester of the corresponding diacid, having an ester group bond to the polymer in the second acid of the diacid, and are degradable by hydrolysis in water. In some embodiments, the first multi-arm precursor is succinimidyl succinate (SS), and the second multi-arm precursor is succinimidyl glutarate (SG).

[0194] Each of the electrophile-containing PEG precursors and nucleophile-containing PEG precursors disclosed herein, and any combination thereof, may be used to prepare implants according to the present invention. For example, any 4-arm or 8-arm PEG precursor (e.g., having a succinimidyl ester containing an SS, SG, SAP, or SAZ reactive group) may be combined with any 4-arm or 8-arm PEG precursor (e.g., having an NH2 group or another nucleophile). Furthermore, the PEG units of the electrophile-containing precursor and the nucleophile-containing precursor may have the same average molecular weight or may have different average molecular weights.

[0195] One such combination is a PEG amine precursor and two PEG succinimidyl ester precursors, one containing an SS reactive group and the other containing an SG reactive group. In certain embodiments, the inventors have found that by maintaining a molar ratio of PEG amine to PEG succinimidyl ester at approximately 1:1 and varying the molar ratio of the succinimidyl ester SS and SG reactive groups, the time it takes for the polymer network to decompose in an aqueous solution under physiological conditions can be controlled, although other ratios are also conceivable. The amounts of PEG SS and SG to be used to achieve a specific molar ratio of the two reactive groups can be calculated by those skilled in the art and can be described as follows.

[0196] The amounts of PEGamine and PEG ester (SS and SG) to be used are calculated using stoichiometric formulas for molar ratios and conversion from moles to grams. First, the molar ratios of reactive end groups between the amine, succinimidyl succinate, and succinimidyl glutarate are determined. As an example of a formulation, 4a20k PEG NH2, 4a20k PEG SS, and 4a40k PEG SG are used. The molar ratio of amine to succinimidyl ester group is approximately 1:1, and the molar ratio of SS to SG is approximately 80:20. The molar ratio of end-terminal groups between 4a20k NH2, 4a20k SS, and 4a40k SG is approximately 1.0:0.8:0.2. Next, the mass is determined using stoichiometric conversion from grams to moles and vice versa. Below is an example of calculating 4a20k SS using the above molar ratio with 100g of 4a20k NH2.

number

[0197] Alternatively, the amount of PEG can be determined by calculating the "molecular weight between crosslinks" (MWc) and the arm length ratio. MWc can be calculated by summing the average arm lengths of each multi-arm PEG precursor.

number

[0198] The arm length ratio is calculated by dividing the PEG arm length by the MWc. The amount of a multi-arm precursor can be determined by multiplying the arm length ratio of a specific multi-arm precursor by the total PEG batch size. Below is an example of calculating the amount of 4a20k PEG SS when the total batch size is 100g PEG:

number

[0199] Similar calculations can be performed for other types of polymers described herein.

[0200] In certain embodiments, 4-arm PEG with an average molecular weight of approximately 20,000 daltons and 4-arm PEG with an average molecular weight of approximately 40,000 daltons can be used to form covalently crosslinked polymers of fine particles according to the present invention.

[0201] Therefore, the first precursor and / or the second precursor may be a 4a20k precursor, where 4 represents the arm and 20k represents Mn. Thus, for example, the first, second and / or third precursor may be a 4a40k precursor.

[0202] Active ingredient: The active agent in the biodegradable microparticles of the embodiments of the present invention may be a therapeutically active agent, a diagnostically active agent, or a combination thereof. It may be a single active agent or a plurality of active agents.

[0203] Therapeutically active drugs include steroids; non-steroidal anti-inflammatory drugs (NSAIDs) such as diclofenac, ibuprofen, meclofename, mefanamic A, sarsalate, sulindac, tolmetin, ketoprofen, diflunisal, piroxicam, naproxen, etodolac, flurbiprofen, fenoprofen C, indomethacin, celecoxib, ketorolac, and nepafenac; intraocular pressure lowerers; antibiotics such as ciprofloxacin; analgesics such as bupivacaine; calcium channel blockers such as nifedipine; cell cycle inhibitors such as simvastatin; proteins such as insulin; carboxylates and amino acids. Small molecule hydrophilic drugs containing ammonium salts; small molecule hydrophobic drugs, hydrophilic peptides and protein drugs (e.g., insulin, single-chain antibody fragments, Fab fragments, IgG antibodies, fusion antibodies, etc.); aptamers; in particular, bupivacaine (BPV-HCl or base), ropivacaine (RPV), dexamethasone, travoprost, axitinib, nonsteroidal anti-inflammatory drugs (NSAIDS), steroids, antibiotics, analgesics, calcium channel blockers, cell cycle inhibitors, chemotherapy drugs, antiviral drugs, anesthetics, hormones, anticancer drugs, antitumor drugs, viruses for gene delivery such as AAV, etc., or any combination thereof.

[0204] In some embodiments, the steroid may be a corticosteroid, which may include hydrocortisone, loteprednol, cortisol, cortisone, prednisolone, methylprednisolone, dexamethasone, betamethasone, triamcinolone, aldosterone, or fludrocortisone.

[0205] In some embodiments, the NSAID may include diclofenac (e.g., diclofenac sodium), fluviprofen (e.g., fluviprofen sodium), ketrolac (e.g., ketrolactromethamine), bromfenac, or nepafenac.

[0206] In some embodiments, the IOP-lowering agent and / or glaucoma treatment agent is a prostaglandin analog (e.g., bimatoprost, latanoprost, travoprost, or latanoprostenbunod), a Rho kinase inhibitor (e.g., netaludil), an adrenergic agonist (epinephrine or dipivefrin), or a beta-adrenergic antagonist also known as a beta-blocker (e.g., timolol, levobunolol, metipranolol, carteo This may include alpha-2 adrenergic agonists (e.g., apraclonidine, brimonidine, or brimonidine tartrate), carbonic anhydrase inhibitors (e.g., brinzolamide, dichlorfenamide, metazolamide, acetazolamide, or dorzolamide), pilocarpine, ecothiophate, demercarium, physostigmine, and / or isofluorophate.

[0207] In some embodiments, antiinfective agents may include antibiotics comprising ciprofloxacin, tobramycin, erythromycin, ofloxacin, gentamicin, fluoroquinolone antibiotics, moxifloxacin, and / or gatifloxacin; antiviral agents comprising ganciclovir, idoxuridine, vidarabine, and / or trifluridine; and / or antifungal agents comprising amphotericin B, natamycin, voriconazole, fluconazole, miconazole, clotrimazole, ketoconazole, posaconazole, echinocandin, caspofungin, and / or micafungin.

[0208] In some embodiments, the antimetabolite may include methotrexate, mycophenolic acid, or azathioprine.

[0209] In some embodiments, the antifibrotic agent may include mitomycin C or 5-fluorouracil.

[0210] In some embodiments, the angiogenesis inhibitor may include anti-VEGF agents (e.g., aflibercept, ranibizumab, bevacizumab), PDGF-B inhibitors (e.g., Fovista®), complement antagonists or inhibitors (e.g., eculizumab, abasincaptadopegol), tyrosine kinase inhibitors (e.g., sunitinib, axitinib), and / or integrin antagonists (e.g., natalizumab and vedolizumab).

[0211] In some embodiments, the cytoprotective agent may include ebselen, sulforaphane, ortiplasm, or dimethyl fumarate.

[0212] In some embodiments, the neuroprotective agent may include ursodiol, memantine, or acetylcysteine.

[0213] In some embodiments, the anesthetic may include lidocaine, propalacaine, or bupivacaine.

[0214] In some embodiments, the active agent may be dexamethasone, ketorolac, diclofenac, vancomycin, moxifloxacin, gatifloxin, becifloxacin, travoprost, 5-fluorouracil, methotrexate, mitomycin C, prednisolone, bevacizumab (Avastin®), ranibizumab (Lucentis®), sunitinib, pegaptanib (Macugen®), timolol, latanoprost, brimonidine, nepafenac, bromfenac, triamcinolone, difluprednate, fluocinolide, aflibercept, or a combination thereof. In some embodiments, the drug may be dexamethasone, ketorolac, diclofenac, moxifloxacin, travoprost, 5-fluorouracil, or methotrexate. In some embodiments, the drug is dexamethasone. In some embodiments, the drug is ketorolak. In some embodiments, the drug is travoprost.

[0215] Diagnostically active agents may be, for example, contrast agents, markers, or visualization agents. Generally, diagnostic agents may be substances used to examine the body to detect impairments in the normal functioning of the body. In some cases, diagnostic agents may be agents with a functional purpose, such as being used to detect deformities, diseases, and pathophysiological aspects of the eye. For example, diagnostic agents may be important and effective diagnostic aids such as dyes to aid in the visualization of ocular tissue (e.g., dark quenchers such as fluorescein dye, indocyanine green, trypan blue, cyanine dyes, azo dyes, acridine, fluoron, oxazine, phenanthridine, naphthalimide, rhodamine, benzopyrone, perylene, benzantrone, and prabenzoxanthrone). Diagnostic agents may include paramagnetic molecules, fluorescent compounds, magnetic molecules, radionuclides, X-ray imaging agents, and / or contrast agents. In some embodiments, the diagnostic agent may include radiopharmaceuticals, contrast agents used in imaging techniques, allergen extracts, activated carbon, various test strips (e.g., cholesterol, ethanol, and glucose), pregnancy tests, breath tests with urea 13C, and various stains / markers. In some embodiments, the labeling portion is a fluorescent dye or dark quencher selected from the group consisting of coumarin, cyanine dyes, azo dyes, acridine, fluorone, oxazine, phenanthridine, naphthalimide, rhodamine, benzopyrone, perylene, benzantrone, and benzoxanthrone. In certain non-limiting embodiments, the fluorescent dye is a compound selected from the group consisting of coumarin, fluorescein, cyanine 3 (Cy3), cyanine 5 (Cy5), cyanine 7 (Cy7), Alexa dye, bodipy derivatives, (E)-2-(4-(phenyldiazenyl)phenoxy)acetic acid, 3-(3',3'-dimethyl-6-nitrospiro[chromen-2,2'-indoline]-1'-yl)propanoate (spiropyran), 3,5-dihydroxybenzoate, and (E)-2-(4-(phenyldiazenyl)phenoxy)acetic acid, or a combination thereof, or a residue thereof.

[0216] In certain embodiments of the present invention, the active ingredient is dispersed, embedded, or encapsulated in, for example, a covalently crosslinked biodegradable polymer. In certain embodiments, the active ingredient may be in particulate form.

[0217] In certain embodiments of the present invention, the active agent is a drug in the form of a liquid oil at temperatures up to 37°C, such as travoprost, which forms an organogel with a crosslinked biodegradable polymer of microparticles in vivo, and which contains the active agent as a liquid within the crosslinked polymer in vivo. According to another embodiment of the present invention, the active agent may be oil-soluble and dissolved in a hydrophobic organic liquid or oil, respectively, which forms an organogel with a crosslinked biodegradable polymer of microparticles. Alternatively, the active agent may be oil-insoluble and dispersed in particulate form in a hydrophobic organic liquid or oil, or emulsified in liquid form, and also form an organogel with a crosslinked biodegradable polymer of microparticles. In these embodiments, the biodegradable microparticles are formed as a liquid phase immobilized within the crosslinked particles, or from an organogel containing the active agent in a liquid phase.

[0218] In embodiments in which the active ingredient is used in particulate form, the active ingredient particles may be finely milled particles having, for example, a D50 particle size of less than about 15 μm or less than about 10 μm, and / or a D99 particle size of less than about 100 μm or less than about 50 μm, or a D90 particle size of about 50 μm or less, and / or a D98 particle size of about 10 μm or less. In another embodiment, the active ingredient particles may be nano-sized particles having, for example, a D50 particle size of less than about 100 nm or less than about 50 nm, and / or a D99 particle size of less than about 50 nm, or a D90 particle size of about 5 nm or less, and / or a D98 particle size of about 10 nm or less. The particle size is determined as disclosed in the “Definitions” section of this specification.

[0219] Oil / Additives In certain embodiments of the present invention, an oil is incorporated into a crosslinked polymer to form an organogel constituting the microparticles of these embodiments. These organogel microparticles have a mostly rubbery appearance. This oil (generally a hydrophobic organic liquid) can be used to modify the release of the active agent from the drug delivery system of the microparticles. One or more of its properties, such as hydrophobicity, viscosity, compatibility with the active agent, and solubility or insolubility of the active agent in the oil, can be appropriately selected to control the release of the active agent from the organogel particles of these embodiments. For example, when the biodegradable microparticles for sustained-release drug delivery of embodiments of the present invention are used in a hydrogel or other matrix as implants inserted into the human body, or when used directly as an oral dosage form, the oil can diffuse from the organogel microparticles into the aqueous environment along with the active agent dissolved in it, before or simultaneously with the diffusion of the active agent from the oil. If the active agent is, for example, water-soluble solid particles dispersed in a hydrophobic organic liquid, the oil can be used to delay contact between the aqueous environment and the active agent, thereby delaying the elution of the active agent from the organogel microparticles.

[0220] In certain embodiments, the oil or hydrophobic organic liquid is liquid at body temperature, for example, below about 37°C, or in the range of 0°C to 40°C, or 10°C to 38°C, or 15°C to 37°C, or 25°C to 37°C, or at 37°C. The term “liquid” may include viscous fluids having a creamy or waxy appearance but not a solid. Also, in the case of some hydrophobic organic liquids that undergo hydration in aqueous embodiments such as body fluids, the melting point at a certain temperature may differ in the hydrated material from that of the unhydrated material. In certain embodiments of the present invention, the hydrated form of such material is liquid under the above conditions.

[0221] In one embodiment, the active agent is dissolved or dispersed in an oil before being incorporated into the crosslinked polymer of the fine particles. In another embodiment, the active agent is itself an oil or an oily hydrophobic organic liquid, or forms at least a part of it. An example is travoprost as the active agent.

[0222] In certain embodiments, the oil may include an oil mixture. The oil may be a biocompatible vegetable oil, synthetic oil or mineral oil, a liquid fatty acid or triglyceride composition, or it may be a hydrophobic biodegradable liquid polymer, or a combination thereof.

[0223] In certain aspects of this disclosure, oil is a biocompatible oil, and may include triethyl citrate, acetyl triethyl citrate (ATEC), acetyl tributyl citrate (ATBC), α-tocopherol (vitamin E), α-tocopherol acetate; plant oils or vegetable oils such as sesame oil, olive oil, soybean oil, sunflower oil, coconut oil, canola oil, and rapeseed oil; nut oils such as hazelnut oil, walnut oil, pecan oil, and almond oil; cottonseed oil, corn oil, safflower oil, and other oils. The following can be selected from the group including linseed oil, ethyl oleate, castor oil and its derivatives (Cremophor®), lipids that become liquid at 37°C or below, such as saturated or unsaturated fatty acids, monoglycerides, diglycerides, triglycerides (Myglyols®), phospholipids, glycerophospholipids, sphingolipids, sterols, prenols, polyketides, hydrophobic biodegradable liquid polymers, low-melting-point waxes such as plant, animal, or synthetic waxes, lanolin, jojoba oil, or combinations thereof.

[0224] In certain embodiments, the oil may be liquid at body temperature and have a glass transition temperature and / or melting temperature of 45°C or below, or 37°C or below.

[0225] In certain embodiments, the oil is non-volatile, non-toxic, and / or biocompatible at 37°C and ambient pressure, and / or can be discharged from the implantation site, metabolized, and / or eliminated from the body without change.

[0226] Manufacturing method Methods for producing polymer microparticles are known to those skilled in the art, and these methods are mainly applied to embodiments of the present invention and can be suitably adapted.

[0227] Some aspects of this disclosure include methods for producing biodegradable microparticles for sustained-release drug delivery, selected from one of the following methods: evaporation-extraction of an emulsion solvent, diffusion of an emulsion solvent, supercritical fluid emulsion, coacervation, spray drying, use of a hydrogel template, a microfluidic system, membrane extrusion emulsification, particle replication (PRINT) techniques in a non-wet mold, electrohydrodynamic atomization (EHDA) or electrospraying, or the microparticles may be obtained by a gas-saturated solution (PGSS) method or 3D printing.

[0228] Lagreca et al., Progress in Biomaterials, 2020, volume 9, pages 153-174, incorporated herein by reference, provides an overview of these preparation methods for microparticles made of PLA or PLGA polymers. These methods can also be used primarily with other biodegradable polymers and the multi-arm precursors described herein.

[0229] Exemplary preparation methods that may be preferably used in embodiments of the present invention are single emulsion techniques and double emulsion techniques.

[0230] A functionalization precursor of hydrophobic polymer units such as polylactic acid (PLA), polylactic acid-glycolic acid copolymer (PLGA), poly(vinylpyrrolidone), or polycaprolactone, and a lipophilic drug are dissolved in an organic nonpolar solvent, combined with a crosslinking agent and optionally a second solution, and the resulting mixture is added to an aqueous phase containing a surfactant or emulsifier under agitation, stirring, sonication, or homogenization to form an oil-in-water emulsion. Fine particles are formed and cured, for example, during the removal of the organic solvent by evaporation and crosslinking. Evaporation can be facilitated by continuous stirring or by using a solvent extraction system under negative pressure.

[0231] A variation of this technique, in which the active ingredient / drug is solid and / or insoluble in organic solvents, involves dispersing or suspending the active ingredient / drug in an organic solvent or crosslinking agent solution containing a dissolved polymer precursor. Oil may be optionally added, resulting in organogel microparticles.

[0232] By applying the double emulsion technique, at least one appropriately functionalized polymer precursor is dissolved in an organic solvent, and an aqueous solution containing a water-soluble drug and optionally a hydrophilic crosslinking agent or a second functionalization precursor is added to this organic solution. This mixture is then emulsified into a water-in-oil emulsion, for example, by a sonicator. The resulting emulsion is then added to a large continuous aqueous phase containing an emulsifier, thereby forming a double emulsion (oil-in-water). Solidification and crosslinking of the fine particles occur during emulsion formation and subsequent solvent removal.

[0233] More complex techniques, such as microfluidic technology, rely on the same fundamental principles as single-emulsion or double-emulsion technology by using corresponding microfluidic devices and are suitable for the production of microparticles of the present invention. For example, the preparation of non-crosslinked monodisperse biodegradable polymer microparticles using a microfluidic flow-focusing device is described in Xu, Q., et al., “Preparation of Monodispersed Biodegradable Polymer Microparticles Using a Microfluidic Flow-Focusing Device for Controlled Drug Delivery”, Small, Vol 5(13):1575-1581, 2009. The use of microfluidic devices for generating microspheres is further described in Duncanson, W.J et al., “Microfluidic Synthesis of Monodisperse Porous Microspheres with Size-tunable Pores”, Soft Matter, Vol 8, 10636-10640, 2012, and US8, 916, 196 B1 describes apparatus and methods for the production of emulsion-based microparticles that can be used in connection with the present invention.

[0234] In a generally applicable embodiment, a method for producing biodegradable microparticles for sustained-release drug delivery comprises the steps of: (1) forming a gel comprising a covalently crosslinked polymer in the presence of at least one active agent, optionally at least one oil, and optionally a first solvent; (2) generating microparticles in which at least one active agent is dispersed within the covalently crosslinked polymer; and (3) optionally removing the solvent.

[0235] If oil is present in step (1), an organogel containing oil is formed in the crosslinked polymer in which the fine particles are formed. The active ingredient can be dissolved or dispersed in the oil.

[0236] In one embodiment, the method comprises the following steps: (a) dissolving at least one of polymer precursors in a first solvent to produce a first mixture; (b) providing a second mixture containing a crosslinking agent in a second solvent; (c) adding at least one active agent and optionally an oil to at least one of the first or second mixtures; (d) combining the first and second mixtures to produce a first phase; (e) providing a second phase containing a third solvent immiscible with the first and second solvents; (f) introducing the first phase into the second phase under stirring to produce a dispersed emulsion of the first phase in the second phase; and (g) removing the first, second and / or third solvents. Stirring includes using stirring, sonication, vortexing, or a homogenizer known in the art.

[0237] In certain embodiments, the step of generating fine particles (step (2)) or step (f) includes extruding a first phase through a mesh or injecting the first phase into a stirred second phase, wherein the first and / or second solvent and / or third solvent optionally include additives such as emulsifiers, surfactants, dispersion aids, or pologens, and form spherical or nanospherical particles.

[0238] In certain embodiments of this method, the first solvent and / or the second solvent is an organic solvent in which the precursor and the crosslinking agent are soluble, and the second solvent may be the same as the first solvent. The third solvent is a solvent in which the precursor, the crosslinking agent, and / or the formed organogel are insoluble.

[0239] The first and / or second solvent is selected from acetone, acetonitrile, benzyl alcohol, chloroform, dichloromethane (DCM), dioxane, dimethyl carbonate, DMSO, ethanol, ethyl acetate, ethyl formate, ethyl propionate, glycoflore, hexafluoroisopropanol, isosorbide dimethyl ether, isopropanol, methyl chloride, methylene chloride, methyl ethyl ketone, N-methylpyrrolidone, propylene carbonate, or tetrahydrofuran, or any mixture thereof; the third solvent is water, an alcohol such as methanol, ethanol or propanol, or any mixture thereof.

[0240] The additives may be surfactants or emulsifiers such as polyvinyl alcohol (PVA), polyethylene glycol sorbitan monolaurate (Tween®), sorbitan monolaurate (Span®), sodium dodecyl sulfate (SDS), which may be used in the second aqueous phase; and / or inorganic salts (NaCl, KCl, sodium carbonate or potassium carbonate or bicarbonate, ammonium bicarbonate), pluronic acid; sodium oleate or potassium oleate; gelatin; mustard oil; mineral oil; cyclodextrin; carbohydrates; bovine serum albumin (BSA); photoinitiators, radical polymerization initiators, and combinations thereof.

[0241] According to some embodiments, method steps (1) and (2) utilize oil-in-water emulsion or water-in-oil single or double emulsion technology, or a combination thereof, in particular single or double emulsion technology, or microfluidic technology, or a combination thereof.

[0242] The removal of the first and / or second and / or third solvent is carried out by one of the following methods: hot air convection or direct drying, indirect drying or contact drying, spray drying, dielectric drying, vacuum drying, freeze-drying, supercritical or superheated vapor drying, or any combination thereof.

[0243] In exemplary embodiments, the active agent containing biodegradable microparticles for drug delivery is prepared by an evaporation / extraction technique of an oil-in-water emulsifying solvent. A suitably functionalized multi-arm precursor described herein, e.g., 4a20kPLGA-NHS, and at least one active agent, e.g., travoprost, are dissolved in a first solvent, e.g., dichloromethane (DCM), to prepare a single-phase solution, or, if the drug is in particulate form and insoluble in the solvent, a suspension is prepared, which is the first solution (or suspension). A second solution is prepared, containing a low molecular weight crosslinking agent or a second functionalized multi-arm precursor in the same or a similar miscible solvent. Both solutions are combined and added as the dispersed phase (DP) to a stirred third solution containing an immiscible solvent designated as the continuous phase (CP).

[0244] In the case of hydrophobic polymer precursors such as PLA or PLGA, the solvents in the first and second solutions are nonpolar, while the solvent in the third solution is polar and immiscible with the first solvent; the opposite is true for hydrophilic polymer precursors. Adding the dispersed phase, a combination of the first and second solutions, to the stirred third solution can be done, for example, by injection via a syringe or syringe pump. When a hydrophobic precursor and a nonpolar solvent are used for the combined dispersed phase, the third solution may be, for example, an aqueous solution of polyvinyl alcohol (PVA) that forms the continuous phase (CP). The solution may have a concentration of about 1% (w / w), or any other suitable concentration. PVA primarily acts as an emulsifier or surfactant by stabilizing the microdroplets of DP, and then crosslinks the droplets to harden into microspheres, but also increases the viscosity of the continuous phase, which promotes sphere formation.

[0245] In certain embodiments, the injection is performed immediately before passing the DP through an inline homogenizer to disperse it among the nascent microparticles. This introduction step of adding the dispersed phase to the continuous phase allows time for the droplets to disperse before crosslinking and curing to create a primary emulsion. These nascent microparticles in the CP flow can then flow into a stirred CP (quench medium) in a jacketed reactor maintained at a controlled temperature. This emulsion is stirred in a quenching medium for a sufficient amount of time to extract and evaporate the DCM and cure the microparticles.

[0246] In certain embodiments, the obtained fine particles are filtered, washed, and sieved into appropriate size fractions, for example, using a vibrating sieve. Optionally, the fine particles are dried or freeze-dried to remove residual solvent, ultimately yielding dried biodegradable fine particles containing a covalently crosslinked polymer. Since the crosslinked polymer fine particles of embodiments of the present invention are relatively thermally stable, solvent removal can be advantageously carried out by one of the following methods: hot air convection or direct drying, indirect or contact drying, spray drying, dielectric drying, vacuum drying, supercritical or superheated steam drying, or any combination thereof, which can use high temperatures and thus avoid complex and costly freeze-drying steps or freeze-drying.

[0247] In one embodiment, when all components are combined in the reaction mixture of step (f), at least one precursor and one low molecular weight crosslinking agent or at least two precursors react in an electrophile-nucleophile reaction to form a covalently crosslinked matrix. If oil is present, organogel microparticles are formed. The reaction can be initiated or accelerated by heating, or it can occur under ambient conditions.

[0248] In another embodiment, when all components are combined in the reaction mixture of step (f), at least one precursor and one low molecular weight crosslinking agent, or at least two precursors functionalized with polymerizable acrylic groups, react in a radical polymerization reaction to optionally photo-induced, covalently crosslinked polymer matrix in particulate form. The reaction may be initiated or accelerated by heating, or it may occur under ambient conditions. Functionalization by click chemistry as described above may also be used.

[0249] Emulsions such as those formed in step (f) having the mixed precursor can be prepared using manual force to a viscosity suitable for introduction via a small gauge needle. The small gauge needle has a diameter smaller than that of a 27 gauge needle, e.g., 28, 29, 30, 31, 32, or 33 gauge needle, and the gauge is specific to the inner and / or outer diameter. Thus, viscosities of about 1 to about 100,000 mPa·s can be used; those skilled in the art will immediately understand that all ranges and values ​​within the explicitly stated ranges, e.g., about 10 to about 10,000 mPa·s, about 5 to less than about 10,000 mPa·s, less than about 100 or about 500 mPa·s, or between about 1 and about 100 mPa·s, are intended. Viscosity can be controlled, for example, by selecting a suitable precursor, adjusting the solid and / or solvent concentrations, and the reaction rate. Generally, the lower the concentration of the precursor, the higher the hydrophilicity, and the lower the molecular weight, the lower the viscosity.

[0250] Release kinetics In embodiments of the present invention, biodegradable microparticles enable drug delivery and allow for modification or adaptation of the release of the active agent from the microparticles by several means. For example, adapting or appropriately selecting precursor components that form the crosslinked polymer of the microparticles according to their hydrophilic and / or hydrophobic properties affects the release of the active agent. Furthermore, when an oil containing an organogel-type polymer matrix is ​​used, the diffusion rate and release of the active agent from the microparticles or the drug delivery system containing them can be modified or controlled by appropriately selecting the oil components according to one or more of their properties, such as hydrophobicity, viscosity, compatibility with the active agent, and solubility or insolubility of the active agent in the oil.

[0251] Accordingly, in various embodiments of the present invention, the type, composition and properties of the oil, and / or the hydrophobicity of the polymer network, as well as the L / G ratio in the PLCA, may be used to adjust the release rate. Each of these individual parameters may be selected individually or in combination with each other to enable controlled release of the active ingredient.

[0252] In certain embodiments, biodegradable microparticles and / or drug delivery systems containing them are formulated to make the active ingredient available over a longer period, thereby enabling a reduction in the frequency of administration compared to immediate-release formulations (e.g., solutions of the active ingredient applied topically to the eye (i.e., eye drops)). In certain embodiments, the release of the active ingredient includes a constant release, a tapered release, and any combination thereof (e.g., a constant release of the active ingredient followed by a tapered release). "Sustained release" can be measured in vitro in an aqueous solution under physiological conditions such as pH 7.2–7.4 and 37°C, and is considered to be the same as, or substantially the same as, when the drug delivery system is administered to a subject in vivo.

[0253] In various embodiments of the present invention, the release of the active agent follows zero-order release dynamics or substantially zero-order release dynamics, preferably without a "burst" of the active agent at the start of the period. A burst is a rapid initial release of the active agent from microparticles at relatively short intervals, immediately after implant insertion, for example, on the first day after insertion. According to the present invention, bursts are minimized.

[0254] Certain embodiments of the present invention may provide the release of a therapeutically effective amount of active ingredient over a period of up to 1 year, up to 9 months, up to 6 months, up to 3 months, up to 1 month, or up to about 25 days after administration. Another embodiment of the present invention may provide the release of a therapeutically effective amount of active ingredient over a period of up to about 14 days, or up to about 21 days, or over a period of about 6 hours or more, or over a period of about 12 hours, or 24 hours or more, or over a period of about 48 hours or more, or over a period of about 72 hours or more, or over a period of about 7 days or more, or over a period of about 10 days or more after administration. The present invention intends to achieve all of the above shorter and longer periods in any combination of ranges.

[0255] In some embodiments of the present invention, biodegradable microparticles of a crosslinked polymer delay the release of a water-soluble active agent or promote the release of a hydrophobic active agent. In another embodiment, biodegradable microparticles of a crosslinked polymer delay the release of a hydrophobic active agent or promote the release of a water-soluble active agent.

[0256] In one aspect of the present invention, a sustained-release drug delivery system comprising biodegradable microparticles for sustained drug delivery, or biodegradable microparticles such as a pharmaceutically acceptable implant, is provided for controlled release of the active ingredient contained therein (e.g., total amount). Throughout this disclosure, controlled release should be considered as controlled release measured under physiological conditions, starting from the time the implant is first immersed in an aqueous solution under physiological conditions such as pH 7.2–7.4 and temperature 37°C. After exposure to physiological conditions, the crosslinked polymer or organogel of the microparticles, or those contained in the drug delivery system, gradually release a hydrophobic organic liquid from the organogel while simultaneously forming a hydrogel.

[0257] In certain embodiments, controlled release may be characterized by the amount of active ingredient released on day 1 being 0-50% of the total amount of active ingredient, the amount of active ingredient released per day from day 2 to the final day of release being 0-50% of the total amount of active ingredient, and / or the number of days required for 100% release of the total amount of active ingredient being at least 2 days.

[0258] In certain embodiments, controlled release may be characterized in that the amount of active ingredient released on day 1 is 0 to about 50% of the total amount of active ingredient, the amount of active ingredient released per day from day 2 to the final day of release is 0 to about 50% of the total amount of active ingredient, and / or the number of days required for 100% release of the total amount of active ingredient is at least 3 days.

[0259] In certain embodiments, controlled release may be characterized in that the amount of active ingredient released on day 1 is 0 to about 50% of the total amount of active ingredient, the amount of active ingredient released per day from day 2 to the final day of release is 0 to about 50% of the total amount of active ingredient, and / or the number of days required for 100% release of the total amount of active ingredient is at least 4 to 7 days.

[0260] In certain embodiments, controlled release may be characterized in that the amount of active ingredient released on day 1 is 0 to about 50% of the total amount of active ingredient, the amount of active ingredient released per day from day 2 to the final day of release is 0 to about 50% of the total amount of active ingredient, and / or the number of days required for 100% release of the total amount of active ingredient is at least 10 to 15 days.

[0261] In certain embodiments, controlled release may be characterized in that the amount of active ingredient released on day 1 is 0 to about 50% of the total amount of active ingredient, the amount of active ingredient released per day from day 2 to the final day of release is 0 to about 50% of the total amount of active ingredient, and / or the number of days required for 100% release of the total amount of active ingredient is at least 10 to 30 days.

[0262] In certain embodiments, controlled release may be characterized in that the amount of active ingredient released on day 1 is 0 to about 50% of the total amount of active ingredient, the amount of active ingredient released per day from day 2 to the final day of release is 0 to about 50% of the total amount of active ingredient, and / or the number of days required for 100% release of the total amount of active ingredient exceeds 30 days.

[0263] According to certain embodiments of the present invention, controlled release is characterized by: the amount of active ingredient released on day 1 being 0 to about 25%, 0 to about 20%, 0 to about 10%, 0 to about 5%, or about 0% of the total amount of active ingredient; and the amount of active ingredient released per day from day 2 to the final day of release being 0 to about 50%, 0 to about 40%, 0 to about 30%, 0 to about 20%, 0 to about 10%, or 0 to about 5% of the total amount of active ingredient. In certain embodiments, the number of days required for 100% release of the total amount of active ingredient is at least 3 days, but 30 days or less, 25 days or less, or 16 days or less. In other embodiments, the time is as disclosed above.

[0264] In one embodiment, the controlled release characterized above includes zero-order release, such as near-zero-order release, or substantially zero-order release. In one embodiment, zero-order release, near-zero-order release, or substantially zero-order release is initiated at least one day after the pharmaceutically acceptable implant is immersed under physiological conditions such as pH 7.2-7.4 and 37°C.

[0265] A dosage form or implant exhibiting a zero-order release rate will show a relatively straight line in a graph of the relationship between the percentage of active ingredient released versus time. In certain embodiments of the present invention, zero-order release is achieved over the entire release period. In certain embodiments of the present invention, zero-order release is achieved over a portion of the release period. In certain such embodiments, zero-order release is achieved from the end of day 1, i.e., from 24 hours after the start of release until the end of release. If less or no release is achieved before the end of day 1, such release is considered to have a 1-day or 24-hour delay. Such a delay may also be longer. If a high release is achieved before the end of day 1, such release is considered to have a burst within the first 1 day or 24 hours. The duration of such a burst may also be longer. Zero-order release can also be achieved during the entire release period. The entire release period is defined in this context as until 95% of the release is achieved.

[0266] Within the scope of the present invention, zero-order emission is defined as being achieved when the emission during each time period is proportional to the elapsed time. Proportional to elapsed time means that the proportional emission is calculated based on the total time of the zero-order emission that defines the range of the straight line (the % cumulative emission during the entire period over which the zero-order is achieved divided by the total time that defines the range of the straight line), and that at any point in time thereafter, i.e., between the start and end of the zero-order emission, the emission is within 20 percent points of the % cumulative emission of the proportional emission defined by the straight line.

[0267] Sustained-release drug delivery systems: In certain embodiments, a sustained-release biodegradable drug delivery system is provided, comprising biodegradable microparticles for sustained-release drug delivery as described herein. To provide the drug delivery system, the biodegradable microparticles are incorporated into a hydrogel, xerogel, or organogel, optionally using extrusion or 3D printing. In embodiments of the present invention, such a system is used to coat medical implants. In another embodiment, the drug delivery system is used to generate or form medical implants, and the biodegradable microparticles are embedded or dispersed in a hydrogel, xerogel, or organogel matrix.

[0268] Unlike conventional non-crosslinked polymer particles, biodegradable microparticles are rubber-like materials with thermal stability above their glass transition temperature. Therefore, they do not melt, and can be used in heat-intensive processing steps, such as extrusion, for molding medical implants or applying implant coatings. Methods involving heat-intensive processing steps may include, for example, thermal melt extrusion of reaction mixtures containing biodegradable microparticles dispersed in hydrogels, xerogels, or organogels, or their precursors; or extrusion methods such as injection molding; or 3D printing. In such methods, gelation occurs before and / or during the extrusion or injection molding of the gel-forming material containing the biodegradable microparticles. The use of extrusion methods available for the manufacture of these implants enables high-volume production using heat-stable biodegradable microspheres.

[0269] In certain embodiments of the present invention, the biodegradable microparticles as defined herein are incorporated, i.e., dispersed or distributed, into a biodegradable hydrogel, organogel, or xerogel. In certain embodiments, the biodegradable microparticles are uniformly dispersed in the biodegradable polymer. Preparations of hydrogel matrices suitable for incorporating the biodegradable microparticles of the present invention are described in the following sections “PEG Hydrogel” and “Method for Preparing a Drug Delivery System or Implant Containing Biodegradable Microparticles,” and the principles described apply to the incorporation of biodegradable microparticles into hydrogels made of polymers other than PEG, for example, hydrogels made of polymers described herein as useful for the preparation of the microparticles themselves, and also apply to incorporation into organogel matrices (including oils) instead of hydrogels, as shown in

[0266] . Unlike conventional non-crosslinked polymer particles, the biodegradable microparticles are heat-resistant and rubbery materials with thermal stability above the glass transition temperature, and therefore do not melt, and can be used in heating-intensive processing steps, such as extrusion, for molding such medical implants or for applying implant coatings. Methods involving processing steps that require the application of heat may include, for example, extrusion methods such as thermal melt extrusion, injection molding of reaction mixtures containing biodegradable microparticles dispersed in hydrogels, xerogels, or organogels, or their precursors, or 3D printing methods incorporating the biodegradable microparticles of the present invention.

[0270] PEG Hydrogel In certain embodiments, the hydrogel comprises a polymer network comprising one or more units of polyethylene glycol. In certain embodiments of the present invention, the polymer network forming the hydrogel comprises polyethylene glycol (PEG) units. PEG is known in the art to form hydrogels when crosslinked, and these PEG hydrogels are suitable for pharmaceutical applications, for example, as a matrix for drugs intended to be administered to any part of the human or animal body.

[0271] The polymer network of the hydrogel implant of the present invention may include PEG units with 2 to 10 arms, or 4 to 8 arms, or one or more multi-armed units having 4, 5, 6, 7, or 8 arms. In a particular embodiment, the PEG unit used in the hydrogel of the present invention has 8 arms. In a particular embodiment, an 8-armed PEG is utilized.

[0272] In certain embodiments, the polyethylene glycol unit is a polyethylene glycol unit with 4 to 10 arms, or a polyethylene glycol unit with 8 arms.

[0273] The molecular weight of polyethylene glycol refers to the number-average molecular weight (Mn) by weight. As used herein, a multi-arm PEG unit having a specified molecular weight may be abbreviated in the form of, for example, 8a15kPEG, which, as described above herein, refers to an 8-arm PEG with a molecular weight of 15,000 daltons.

[0274] In 4-arm PEG, each arm can have an average arm length (or molecular weight) obtained by dividing the total molecular weight of PEG by 4. Therefore, the 4a20k PEG precursor, which is particularly suitable for use in the present invention, has four arms, each with an average molecular weight of approximately 5,000 daltons. The 8a20k PEG precursor, which can be used in combination with or as an alternative to the 4a20k PEG precursor, therefore has eight arms, each with an average molecular weight of 2,500 daltons. Longer arms may be more flexible than shorter arms. PEGs with longer arms may swell more than PEGs with shorter arms. Also, PEGs with fewer arms may swell more and be more flexible than PEGs with more arms. In certain embodiments, only 4-arm PEG precursors are used in the present invention. In certain embodiments, two different 4-arm PEG precursors are used in the present invention. In certain other embodiments, a combination of 4-arm PEG precursors and 8-arm precursors is used in the present invention. Furthermore, longer PEG arms have a higher melting point when dry, which can provide greater dimensional stability during storage.

[0275] In certain embodiments, the polymer network of a hydrogel embedding biodegradable microparticles is formed by reacting an electrophile-containing multi-arm polymer precursor with a nucleophile-containing crosslinking agent. In particular, in certain embodiments, the multi-arm polymer precursor is a 4-10 arm polyethylene glycol precursor or an 8 arm polyethylene glycol precursor.

[0276] In certain embodiments, the electrophilic end group used with the PEG precursor to prepare the hydrogel of the present invention is an N-hydroxysuccinimidyl (NHS) ester, which refers to, for example, NHS dicarboxylic acid esters such as succinimidyl malonate group, succinimidyl maleate group, succinimidyl fumarate group, "SAZ" referring to succinimidyl azelate end group, "SAP" referring to succinimidyl adipate end group, "SG" referring to succinimidyl glutarate end group, and "SS" referring to succinimidyl succinate end group, but is not limited thereto.

[0277] In certain embodiments, the multi-arm polymer precursor is selected from the group consisting of 8-arm-15K-SG polyethylene glycol or 8-arm-15K-SAZ polyethylene glycol.

[0278] In certain embodiments, the electrophilic group is selected from the group consisting of succinimidyl glutarate (SG) group and succinimidyl azelate (SAZ) group.

[0279] In certain embodiments of the present invention, the polymer network is formed by reacting an electrophilic group-containing multi-arm polymer precursor with a nucleophilic group-containing crosslinking agent. The electrophilic group is selected from the group consisting of succinimidyl glutarate (SG) group and succinimidyl azelate (SAZ) group. The multi-arm polymer precursor is selected from the group consisting of 8-arm-15K-SG polyethylene glycol or 8-arm-15K-SAZ polyethylene glycol; the nucleophilic group-containing crosslinking agent is trilysin or 8-arm-15K-SAZ polyethylene glycol; the polymer network is a polymer network containing trilysin or 8-arm-ethylene glycol crosslinked with a group represented by the following formula

Chemical formula

[0280] Therefore, in certain embodiments, the PEG precursor is an NHS dicarboxylic acid ester-terminated multi-arm PEG precursor that can be represented by the following formula: [ka] In the formula, n is determined by the molecular weight of each PEG arm, m is an integer from 0 to 10, specifically 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, and x is the number of arms (thus, for example, 2, 4, 8, etc.; see above). When m is 1, each arm is terminated with a succinimidyl succinate (SS) end group; when m is 2, each arm is terminated with a succinimidyl glutarate (SG) group; when m is 3, each arm is terminated with a succinimidyl adipate (SAP) group; and when m is 6, each arm is terminated with a succinimidyl azelaic acid (SAZ) group. Using these specific electrophilic end groups, a multi-arm PEG unit can be abbreviated in the form, for example, 4a20kPEG-SAP, which refers to a 4-arm PEG with succinimidyl adipate end groups and a molecular weight of 20,000. In the above formula, R is a suitable core structure for providing the desired number of arms. For a 4-arm PEG unit and precursor, R may be a pentaerythritol structure, while for an 8-arm PEG unit and precursor, R may be a hexaglycerol structure.

[0281] In certain embodiments, the multi-arm polymer precursor has a mass-average molecular weight in the range of about 10,000 to about 20,000 daltons. In more specific embodiments, the multi-arm polymer precursor has a mass-average molecular weight of 15,000 ± 10% daltons.

[0282] In certain embodiments, for example, as a result of a reaction between a nucleophile-containing crosslinking agent and electrophile-containing PEG units (for example, a reaction between an amine-containing crosslinking agent and activated ester-containing PEG units), multiple PEG units are crosslinked via amide groups by the crosslinking agent.

[0283] In the case of PEG having an NHS-ester terminal group (e.g., succinimidylazelaic acid (SAZ)-, succinimidyladipic acid (SAP)-, or succinimidylglutaric acid (SG)-terminal PEG unit (see above)), as a result of reaction with an amine-containing crosslinking agent, multiple PEG units are crosslinked by the crosslinking agent via a hydrolyzable linker having the following formula: [ka] In the formula, m is an integer between 0 and 10, specifically 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. For a SAZ-terminated group, m is 6. For an SAP-terminated group, m is 3; for an SG-terminated group, In is 2; and for an SS-terminated group, m is 1.

[0284] In certain embodiments, the nucleophile-containing crosslinking agent is an amine. In other embodiments, the nucleophile-containing crosslinking agent is a low molecular weight amine with a molecular weight of 1,000 Da or less containing two or more primary aliphatic amine groups. In certain embodiments, the nucleophile-containing crosslinking agent is a low molecular weight amine selected from the group consisting of dyridine, trilysine, tetralysine, ethylenediamine, 1,3-diaminopropane, 1,3-di-aminopropane, diethylenetriamine, and trimethylhexamethylenediamine. In one embodiment, the nucleophile-containing crosslinking agent is trilysine. In a particular embodiment, the nucleophile-containing crosslinking agent is trilysine acetate.

[0285] In another embodiment, trilysine is labeled with a visualization agent selected from the group consisting of fluorophores such as fluorescein, rhodamine, coumarin, and cyanine. Specifically, the nucleophilic crosslinking agent is fluorescein-bonded trilysine. More specifically, fluorescein-bonded trilysine is obtained by reacting trilysine acetate with N-hydroxysuccinimide (NHS)-fluorescein. Even more specifically, trilysine is labeled by partial conjugation with a visualization agent.

[0286] Method for preparing a drug delivery system or implant containing biodegradable microparticles In a further embodiment, the present invention relates to a method for manufacturing a sustained-release drug delivery system, such as an implant, comprising biodegradable microparticles for sustained drug delivery as described herein. The method comprises the following steps: a) To prepare biodegradable microparticles for sustained drug delivery as described herein, b) Prepare a precursor mixture containing a hydrogel, organogel, or xerogel precursor and biodegradable microparticles. c) Crosslinking a precursor mixture using a crosslinking agent to form a polymer network, and obtaining a mixture of hydrogel or organogel containing the polymer network, and d) To provide a drug delivery system or implant by drying a mixture of hydrogels or organogels.

[0287] The types of components, component content, and mass ratios described in the preceding sections relating to the production of fine particles and hydrogels are also applied according to the manufacturing method of the present invention.

[0288] In another aspect, the present invention relates to a sustained-release, biodegradable drug delivery system or implant obtained by the above method.

[0289] Steps b) and c) of the above method can be carried out by any suitable mixing and crosslinking method, which is further described herein and known, for example, from US2021 / 0251893A1 or US2018 / / 085307A1. The components can be mixed in a syringe, the implant chain or pellet can be extruded, and even directly inserted into the body of a human or animal as known in the prior art. Furthermore, because the biodegradable microparticles are thermally stable, thermal processing steps, such as extrusion, can be used to form such medical implants or to apply implant coatings.

[0290] A method involving a processing step that requires heating can be, for example, an extrusion method such as the hot melt extrusion or injection molding of a reaction mixture containing biodegradable microparticles dispersed in a hydrogel, xerogel, or organogel, or their precursors.

[0291] For example, in the case of acrylate-modified hydrogel or organogel precursors, especially when a more complex implant structure is required, a 3D printing method using radiation curing such as UV curing may be employed.

[0292] Administration A sustained-release biodegradable drug delivery system containing biodegradable microparticles can be provided in the form of the above-mentioned implants such as medical implants or pharmaceutically acceptable implants, but can also be provided as an implant coating or an oral dosage form.

[0293] When a sustained-release biodegradable drug delivery system containing biodegradable microparticles is an implant, the implant can be one of the implants for introduction into the intraocular implant, intraperitoneal implant, intraocular chamber implant, anterior chamber, vitreous body, suprachoroid, sub-Tenon's space (lower lid), subconjunctival, intraocular, peribulbar, retrobulbar, sub-Tenon's, retina, subretinal, intratubular, vitreous, intrascleral, intrachoroidal, suprachoroidal, retina, subretinal, or on the surface of the lens, cornea or conjunctiva, lacrimal punctum (duct, upper / lower duct), eyelid lid, upper / lower eyelid lid, sub-Tenon's space, choroid, suprachoroidal, Tenon's, cornea, cancer tissue, organ, prostate, breast, joint cavity, subdural, tooth, subcutaneous, hand canal, perivascular, surgically formed space or injury, void, and potential void.

[0294] In certain embodiments of the present invention, biodegradable microparticles or drug delivery systems containing biodegradable microparticles can be formulated for direct or indirect administration via a variety of routes, such as oral, parenteral, or surgical insertion or injection. Oral dosage forms may consist of the biodegradable microparticles of the present invention, which may optionally be enterically coated or filled into capsules. Injectable formulations may consist of the biodegradable microparticles of the present invention suspended in an injectable liquid or the like.

[0295] Treatment method According to the present invention, sustained-release biodegradable microparticles, or a biodegradable drug delivery system containing biodegradable microparticles, are configured for use as pharmaceuticals, for example, in the treatment of a patient's disease or medical condition.

[0296] In one embodiment, a method for treating a patient's disease / condition includes administering to the patient biodegradable microparticles containing a therapeutically active agent, or administering a hydrogel, organogel, or xerogel containing biodegradable microparticles, thereby releasing the active agent over a long period of time.

[0297] One embodiment of the present invention involves incorporating biodegradable microparticles into a hydrogel, organogel, or xerogel, and the formation of the hydrogel, organogel, or xerogel is performed in situ at the treatment site of the patient to release the active ingredient over a long period of time.

[0298] In another embodiment, the treatment method involves incorporating biodegradable microparticles into a hydrogel, organogel, or xerogel, which is pre-fabricated and delivered to or implanted at the patient's treatment site to release the active ingredient over a long period of time.

[0299] The treatment site may be one of the following: anterior chamber, vitreous humor, episclera, posterior subtenon space (inferior fornix), subconjunctiva, intraocular chamber, periocular, posterior, subtenon, retina, subretinal, intracanaliculi, intravitreous, intrascleral, intrachoroidal, suprachoroidal, retina, subretinal, or lens, corneal or conjunctival surface, lacrimal puncta (canaliculi, superior / inferior canaliculi), palpebral fornix, superior / inferior palpebral fornix, subtenon space, choroid, suprachoroidal, Tenon, cornea, cancerous tissue, organs, prostate, breast, joint cavity, subdural, teeth, subcutaneous, carpal tunnel, perivascular, surgically formed spaces or injuries, cavities, and latent cavities.

[0300] In embodiments of the present invention, the disease or condition to be treated is an ocular disease, such as any posterior segment ocular disease affecting the vascular system and integrity of the retina, macula, or choroid and causing visual impairment, vision loss, or blindness, particularly age-related macular degeneration (AMD), trauma, surgical intervention, etc., such as age-related macular degeneration (AMD), cystoid macular edema (CME), diabetic macular edema (DME), posterior uveitis, and diabetic retinopathy; or posterior segment disease conditions resulting from glaucoma, ocular hypertension, anterior chamber hemorrhage, presbyopia, cataracts, retinal vein occlusion, inflammation. Eye diseases include retinal neovascularization, choroidal neovascularization, exudative AMD, dry AMD, retinal vein occlusion, diabetic macular edema, retinal degeneration, corneal transplant rejection, retinoblastoma, melanoma, glaucoma, autoimmune uveitis, uveitis, proliferative vitreoretinopathy, and corneal degeneration, acute and chronic macular neuroretinopathy, central serous chorioretinopathy, macular edema, acute multiple plaque epithelial disease, Behçet's disease, and birdshot nettle. Choroidopathy, posterior uveitis, posterior scleritis, creeping choroiditis, subretinal fibrosis, uveitis syndrome, Vogt-Koyanagi-Harada syndrome, retinal artery occlusion, central retinal vein occlusion, disseminated intravascular coagulation, branch retinal vein occlusion, hypertensive fundus changes, ocular ischemic syndrome, retinal artery microaneurysms, Cort's disease, parafoveal telangiectasia, hemiretinal vein occlusion, papillary vasculitis, carotid artery disease (CAD), dendritic vasculitis, sickle vein Syringomyeloid retinopathy, retinal pigment streaks, familial exudative vitreoretinopathy, Eels' disease, proliferative vitreoretinopathy, diabetic retinopathy, retinal diseases with tumors, congenital retinal pigment epithelial hypertrophy (RPE), posterior uveal melanoma, choroidal hemangioma, choroidal osteoma, choroidal metastasis, complex hamartoma of the retina and retinal pigment epithelium, retinoblastoma, vascular proliferative neoplasm of the fundus, retinal astrocytoma, intraocular lymphoma, myopic retinal degeneration, acute retinal color The following conditions may be selected: porphyria, glaucoma, endophthalmitis, cytomegalovirus retinitis, retinal cancer, retinitis pigmentosa, Leber congenital amaurosis, congenital choroidal agenesis, X-linked retinitis pigmentosa, Best vitiligo macular dystrophy, X-linked retinoschisis, CNGA3 color blindness, CNGB3 color blindness, LHON, Stargardt disease, Usher syndrome, Norrie disease, Walde-Wiedl syndrome, and red-green color blindness.

[0301] The methods described in this section may include the administration of biodegradable microparticles and, optionally, in combination with other drugs, also known as “combination therapy,” within a pharmaceutically acceptable drug delivery system such as an implant.

[0302] In one embodiment, the combination therapy comprises administering biodegradable microparticles, optionally in combination with one or more additional agents on the same day or on different days, within a drug delivery system such as a pharmaceutically acceptable implant. In one embodiment, the additional agents to be administered in the combination therapy may be in liquid form or in oral dosage form. Thus, the additional agents may be any of the small molecules, large molecules, proteins, nanoparticles, or any other active agents described herein.

[0303] Treatment methods involving the administration of biodegradable microparticles may be included in a drug delivery system such as an optional, pharmaceutically acceptable implant, and may include one of the following: intravitreous injection, anterior chamber injection, subconjunctival injection, retrobulbar injection, sub-Tenon's capsule injection, subretinal injection, and suprachoroidal injection. The method of administration may be local or oral.

[0304] The active or additional medication to be administered in combination therapy may be a diagnostic agent. A diagnostic agent may be a substance used to examine the body to detect impairments in normal bodily functions, as described above. In some cases, a diagnostic agent may be a drug with a functional purpose, such as being used to detect eye deformities, diseases, and pathophysiological aspects.

[0305] Release control method In one embodiment, the present invention relates to a method for controlling the release of an active agent from a sustained-release biodegradable drug delivery system, such as those described herein, which includes biodegradable microparticles. The control of the release may be carried out by one or a combination of the following means: - Selecting the L / G ratio of polylactic acid-glycolic acid copolymer (PLGA) units to adjust the hydrophobicity of the polymer matrix forming the microparticles; - Select the L / G ratio of the polylactic acid-glycolic acid copolymer (PLGA) units to ensure sustained release of the active ingredient from the microparticles; - Selecting the molar ratio of the amounts of the first crosslinkable precursor and the second crosslinkable precursor to adjust the hydrophobicity of the polymer matrix forming the microparticles, thereby changing the crosslink density and structure of the polymer matrix; - Select the molar ratio of the first crosslinkable precursor to the second crosslinkable precursor to ensure sustained release of the active ingredient from the microparticles; - Select the amount and / or particle size of biodegradable microparticles contained in hydrogels, organogels, and xerogels; - Adding a third crosslinkable precursor that is less hydrolyzable than the first and second crosslinkable precursors, and optionally changing the molar ratio of the first, second and / or third precursors when forming biodegradable microparticles; - Dispersing an active ingredient having high water solubility in particulate form in oil using an organogel for forming biodegradable microparticles.

[0306] In certain embodiments of the present invention, the release of the active ingredient is primarily controlled by the diffusion of the active ingredient from the crosslinked polymer or from a hydrophobic liquid (e.g., oil) in the organogel forming the polymer matrix. The rate of degradation of the polymer network provides another independent additional release control mechanism. In certain embodiments, the oil can delay or accelerate degradation, which can be used as another way to control the release of the active ingredient. When the active ingredient dispersed in oil is released together with the oil from the organogel microparticles, the rate of drug release is essentially influenced or determined by the rate at which the oil diffuses into the surrounding tissue or body environment. In another embodiment, the active ingredient may diffuse more readily from the oil than from the polymer network.

[0307] The biodegradable microparticles of the present invention swell upon contact with aqueous bodily fluids by absorbing water. The degree of swelling is primarily determined by the gel-forming components used and their hydrophobic / hydrophilic properties. The swelling may result in an increase of up to about 2000%, up to about 1000%, up to about 100%, up to about 95%, up to about 90%, up to about 80%, up to about 75%, up to about 70%, up to about 60%, up to about 50%, up to about 40%, up to about 30%, up to about 20%, or up to about 10% in the length and / or diameter dimensions of the organogel according to the present invention. In certain embodiments, the swelling may result in an increase of at least 1.05, 1.1, 1.2, 1.5, or 2 in the length and / or diameter dimensions of the organogel, and may be in the range having any of the above values.

[0308] However, in certain embodiments, even after swelling, the biodegradable microparticles comprising the drug delivery system of the present invention retain their shape or substantial shape for a long period of time due to the crosslinking of polymer components. In certain embodiments, the polymer network and / or microparticles of the drug delivery system substantially decompose only after all of the active agent has been released, or after at least the majority of the active agent has been released, for example, at least about 50% by weight, at least about 60% by weight, at least about 70% by weight, at least about 80% by weight, at least about 90% by weight, or at least about 99% by weight, or at least about 100% by weight of the active agent.

[0309] For example, water replacing the oil in organogel microparticles over time can ensure that a hydrophilic active ingredient dispersed in the oil but not dissolved is dissolved, and this can be used to further control the release of the active ingredient. In this embodiment, the release of the active ingredient is, primarily or entirely, a controlled diffusion of the active ingredient into the surrounding tissue via the oil and polymer. In certain embodiments, when the release rate of the active ingredient is largely independent of the diffusion rate of the hydrophobic liquid, for example, when the hydrophilic ingredient is dispersed as solid particles in oil, another factor that affects or determines the release of the active ingredient dispersed in oil is the rate at which water diffuses into the organogel particles and / or oil, thereby subsequently dissolving and eluting the active ingredient from the organogel into the surrounding aqueous environment.

[0310] Furthermore, in certain embodiments, organogel microparticles are gradually converted to hydrogel microparticles by the gradual replacement of oil by water, however, they remain crosslinked and maintain their shape, and can then be more readily degraded (in vivo) by hydrolysis and / or enzymatic reactions after the active ingredients and / or oil in the microparticles or drug delivery system have been depleted.

[0311] The overall release of the active ingredient is controlled by at least one of these release mechanisms, or by a combination thereof.

[0312] In embodiments of the present invention comprising PLGA units in a crosslinked polymer or organogel matrix, yet another mechanism can be utilized to influence or control the release of the active ingredient. The hydrophobicity of the covalently crosslinked polymer network in the patient's body can be altered by adjusting the ratio of lactic acid to glycolic acid units. The hydrophobicity of the polymer network can be altered by changing or selecting the L / G ratio of polylactic acid-glycolic acid copolymer (PLGA) units. More hydrophobic lactic acid (L) units increase the hydrophobicity of the polymer and decrease swelling and water uptake; increasing the content of relatively hydrophilic glycolic acid (G) units decreases the hydrophobicity of the polymer and increases swelling and water uptake.

[0313] Another possibility for adjusting the hydrophobicity of the polymer network is provided in embodiments of the present invention by changing and / or selecting the molar ratio of a first crosslinkable precursor to a second crosslinkable precursor. By using a larger amount of the hydrophobic precursor in combination with a more hydrophilic precursor such as PEG units, and vice versa, it becomes possible to adjust the swelling and release of the hydrophobic liquid and / or active agent.

[0314] By adding a third crosslinkable precursor that differs from the first and second precursors in terms of hydrophobicity, and by further utilizing the change in the molar ratio of the constituent components, it is possible to influence swelling and release of hydrophobic liquids and / or active ingredients, as well as the diffusion rates of the active ingredients, hydrophobic liquids and / or water. [Examples]

[0315] The following examples are included to illustrate specific aspects and embodiments of the invention as described in the claims. However, those skilled in the art should understand that the following description is illustrative and should not be construed as limiting the invention in any way.

[0316] Materials and abbreviations used in the examples: 4a20kPLGA-NHS is a 4-arm 20k Dalton electrophile-functionalized polymer precursor obtained by functionalizing commercially available 4a20kPLGA (with a 50:50 L / G ratio) with N-hydroxysuccinimide (NHS). TAEA is tris(2-aminoethyl)amine, which is commercially available from Sigma-Aldrich / Merck. DMC stands for dimethyl carbonate. DCM is dichloromethane. PBS is a phosphate-buffered saline solution with a physiological salt concentration and a pH of 7.4. A 1% PVA aqueous solution was obtained by diluting a commercially available 4% PVA aqueous solution from Sigma-Aldrich.

[0317] Example 1 Thermal stability of cross-linked PLGA microspheres Biodegradable microparticles containing a crosslinked PLGA polymer matrix but without active ingredients were produced using 4a20k-PLGA-NHS as an electrophile-functionalized polymer precursor, TAEA as a low molecular weight nucleophilic crosslinking agent, and DCM as a solvent (sample number RH-558-1).

[0318] 4a20k-PLGA-NHS (1000 mg) was dissolved in DCM (2 mL), and a portion of the solution was filled into a first syringe. Separately, TAEA (10 mg) was mixed into DCM (2 mL), and the solution was filled into a second syringe. Using a Fibrijet® Y-type mixer (Figure 2), the two solutions were merged sequentially, and the mixed precursor solution was injected through a 21 G needle into a stirred 1% PVA aqueous solution (300 mL) (with a 700 rpm inclined impeller). The resulting emulsion was stirred overnight to extract the DCM, evaporate it, and harden the microparticles. The formed microparticles were then removed from the solution and washed with water. The washed microparticles were then sieved to separate them into two fractions: particles with a particle size greater than 10⁶ μm and particles with a particle size of 20–10⁶ μm. The remaining water was removed from the microparticles by freeze-drying to obtain dried cross-linked PLGA microparticles.

[0319] [Table 1]

[0320] Fine particles with a particle size greater than 106 μm, obtained according to Example 1, were heated on a glass slide at 80°C for 2 hours. The SEM image in Figure 3 shows that the fine particles retained their shape, indicating that no melting occurred and that the fine particles were thermally stable.

[0321] Example 2 Biodegradable microparticles containing an organogel and an active agent were produced using 4a20k-PLGA-NHS as an electrophile-functionalized polymer precursor, travoprost as the active agent, TAEA as a low molecular weight nucleophile / crosslinking agent, and DCM as the solvent (sample number RH-558-7).

[0322] 4a20k-PLGA-NHS (500 mg) and travoprost (500 mg) were dissolved in DCM (2.5 mL), and the solution was filled into the first syringe. Separately, TAEA (5 mg) was dissolved in DCM (2.5 mL), and the solution was filled into the second syringe. As in Example 1, the two solutions were successively merged using a Fibrijet® Y-type mixer (Figure 2), and the mixed solution was injected through a 21 G needle into a stirred (700 rpm inclined impeller) 1% PVA aqueous solution (300 mL). The resulting emulsion was stirred overnight to extract it, evaporate the DCM, and harden the microparticles. The formed microparticles were then removed from the solution and washed with water. The washed microparticles were then sieved, and the microparticles were separated into two fractions: particles with a particle size greater than 10⁶ μm and particles with a particle size of 20–10⁶ μm. The remaining water was removed from the microparticles by freeze-drying to obtain dried travoprost-containing cross-linked PLGA microparticles. The travoprost content was determined by the following method: Travoprost in the microparticles was extracted with acetonitrile and diluted with PBS. The extract was analyzed by ULC using an Acquity BEH C18, 2.1 mm × 50 mm, 1.7 μm particle column in a Water Acquity system (Waters Corporation, US). The mobile phase was isopropanol and 50:50 0.1% TFA:acetonitrile, using a gradient flow. The run time was 5 minutes, the travoprost peak was at 1.4 minutes, and UV detection was at 220 nm. The results are summarized in Table 2 below.

[0323] [Table 2]

[0324] [Table 3]

[0325] Fine particles obtained according to Example 1 and comparative fine particles prepared from non-crosslinked PLGA according to the prior art method were each heated on a glass slide at 80°C for 2 hours. The SEM images in Figures 4 and 5 show that fine particles with a particle size of 20-106 μm (Figure 4) and fine particles with a particle size of over 106 μm (Figure 5) mainly retained their shape, indicating that no melting of the fine particles occurred and that the fine particles were thermally stable. In Figures 4 and 5, the left image was taken at room temperature before heating, and the right image was taken after heat treatment at 80°C for 2 hours.

[0326] Figure 6 shows images of the microparticles from Example 2 (left, colored with purple dye (D&C Violet #2) for better visualization) and non-crosslinked PLA microparticles for comparison (right) prepared by the method described in Example 1 of US2018 / 0085307A1, after heat treatment at 80°C for 2 hours. The heat-stable microparticles of Example 2 retain their shape, while the comparison PLGA microparticles show a disintegrated shape due to melting.

[0327] Example 3 The effect of heat treatment and particle size on the release of active ingredients in vitro. The cross-linked microparticles prepared in Example 2, having the two particle size fractions described therein (20-106 μm and greater than 106 μm), were subjected to accelerated in vitro travoprost release kinetics measurements in 50 mL of modified 1x PBS buffer (containing 0.5% PEG40 castor oil and 0.01% NaF) at 40°C, both without heat treatment and after heat treatment at 80°C for 2 hours, such that 100% release was less than 5-10 times that of sink conditions. The in vitro release data is shown in Figure 7.

[0328] As shown in Figure 7, the active ingredient (travoprost) is released in a constant, gradual, and sustained manner over a long period, following substantially zero-order dynamics, with no initial bursts observed. The release dynamics of the active ingredient are diffusion-controlled, as the polymer particles are expected to degrade substantially only after 6 months. No effects from particle degradation are observed.

[0329] Furthermore, smaller particles with a diameter size of 20–10⁶ μm release travoprost faster than particles with a diameter larger than 10⁶ μm. This can be explained by the larger ratio of surface area to volume for particles with a diameter of 20–10⁶ μm compared to particles with a diameter size larger than 10⁶ μm, resulting in a higher diffusion rate as diffusion occurs at the surface of the particles.

[0330] Figure 7 also shows that the release of active ingredients from cross-linked PLGA microparticles is essentially unaffected by heat treatment at 80°C for 2 hours, which is because the release is similar to that of the corresponding unheated microparticles.

[0331] Example 4 Comparison with conventional fine particles The release of the active ingredient from crosslinked microparticles derived from particle size fractions greater than 106 μm, prepared in Example 2, was compared with non-crosslinked PLA microparticles designated as 4.5A PLA, 8A PLA, and 10.5A PLA, prepared in the same manner as described in paragraph

[0149] of US2018 / 0085307A1 or paragraph

[0501] of US2021 / 0251893A1 (where A indicates acid-terminated linear PLA, and the polymer molecular weights differ: 4.5A has an intrinsic viscosity of 0.3-0.4 dL / g, 8A has an intrinsic viscosity of 0.7-0.9 dL / g, and 10.5A has an intrinsic viscosity of 1.0-1.1 dL / g, all in chloroform, 0.5% w / v, at a temperature of 30°C, using an Ubbelohde viscometer size 0 B, with an approximate viscometer constant (C) of 0.005 mm². 2 / s 2 (Measured by capillary working length (L) 40 mm, valve volume (V) 3.0 mL, capillary inner diameter (d) 0.46 mm, and approximate flow time of solvent (CHCl3) (78 seconds).

[0332] For all microparticles, as in Example 3, accelerated in vitro travoprost release kinetics were measured at 40°C in 50 mL of modified 1x PBS buffer, such that 100% release was less than 5 to 10 times that of the sink conditions. The in vitro release data is shown in Figure 8.

[0333] As can be seen in Figure 8, the travoprost emission from non-crosslinked PLA microparticles is significantly faster, less linear, and has a larger burst for 4.5A PLA particles compared to the substantially zero-order emission from PLGA microparticles in Example 2, which does not show an initial burst.

[0334] For further comparison, Figure 9 shows the in vitro release of travoprost from different blends of uncrosslinked PLA microparticles at 37°C and 40°C in modified 1x PBS buffer, as described in Example 3. A clear initial burst of microparticles releasing more than 10% of travoprost is observed at both temperatures. Furthermore, while the release of travoprost from polymer blend microparticles at 37°C (similar to the blend curve in Figure 1) is nearly constant, this release from blended uncrosslinked PLA microparticles is not temperature-stable, and a nonlinear release is observed at 40°C. Compared to the linear zero-order release of crosslinked PLGA microparticles of the present invention at the same temperature (see Figure 8), this demonstrates better control of release kinetics by using the crosslinked microparticle drug delivery system of the embodiments of the present invention. The present invention will be further explained by the following list of items. First item list 1. Biodegradable microparticles for sustained-release drug delivery comprising an active agent and a covalently and three-dimensionally crosslinked biodegradable polymer matrix, wherein the crosslinked biodegradable polymer comprises at least one polymer unit from crosslinked polylactic acid (PLA), polyglycolic acid (PGA), polylactic acid-glycolic acid copolymer (PLGA), poly(vinylpyrrolidone), poly-p-dioxanone, poly(trimethylene carbonate), polycaprolactone, and / or polyvinyl alcohol, or a mixture or copolymer thereof. 2. Biodegradable microparticles as described in item 1, wherein the microparticles are microspheres having a substantially spherical shape. 3. Biodegradable microparticles as described in item 1 or 2, wherein the active ingredient is dispersed, embedded, or encapsulated in a crosslinked polymer. 4. The biodegradable microparticles according to any one of the preceding items, wherein the crosslinked polymer further comprises at least one oil, and the microparticles consist of an organogel containing at least one active agent and at least one oil in the crosslinked polymer. 5. Biodegradable microparticles of any one of the preceding items, wherein the polymer units further comprise units selected from at least one of polyethylene glycol (PEG), polypropylene glycol (PPG), and / or polyamino acids, glycosaminoglycans, polysaccharides, or proteins, and optionally a copolymer or mixture thereof with any of the polymer units described in item 1. 6. Biodegradable microparticles according to any one of item 5, wherein the biodegradable covalently and three-dimensionally crosslinked polymer comprises a plurality of hydrophobic polymer units and / or hydrophilic polymer units. 7. The biodegradable microparticles according to item 6, wherein the hydrophobic polymer units are selected from at least one of polylactic acid (PLA) and polylactic acid-glycolic acid copolymer (PLGA) units, and the hydrophilic polymer units are selected from at least one of polyethylene glycol units, polypropylene glycol units, or polyglycolic acid (PGA), preferably polyethylene glycol units. 8. Biodegradable microparticles according to any one of the preceding items, wherein the covalently and three-dimensionally crosslinked biodegradable polymer contains or consists of crosslinked polylactic acid-glycolic acid copolymer (PLGA) units. 9. The biodegradable fine particles according to item 8, wherein the polylactic acid-glycolic acid copolymer (PLGA) units have an L / G ratio (%) in the range of 0:100 to 100:0, or 1:99 to 99:1, or 10:90 to 90:10, or 25:75 to 75:25, preferably 50:50. 10. Biodegradable microparticles as described in any one of the preceding items, wherein each polymer unit has an average molecular weight (Mw) in the range of approximately 1,000 to approximately 100,000 daltons, or approximately 10,000 to approximately 60,000 daltons, or approximately 15,000 to approximately 50,000 daltons. 11. Biodegradable microparticles according to any one of the preceding items, wherein the polymer is covalently crosslinked by bonds between polymer units. 12. Biodegradable microparticles as described in item 11, wherein the bonds are optionally selected from the group consisting of amine, amide, urethane, ester, anhydride, ether, acetal, ketal, nitrile, isonitrile, isothiocyanate, isourea, hydrazone, oxime, or imine bonds, and are produced by polycondensation, radical polymerization, or click chemistry reactions, or combinations thereof. 13. Biodegradable microparticles as described in any one of the preceding items, wherein the active agent is selected from at least one of the following: a therapeutically active drug, a diagnostically active drug, or a combination thereof. 14. Therapeutically active drugs include: steroids; non-steroidal anti-inflammatory drugs (NSAIDs) such as diclofenac, ibuprofen, meclofename, mefanamic A, sarsalate, sulindac, tolmetin, ketoprofen, diflunisal, piroxicam, naproxen, etodolac, flurbiprofen, fenoprofen C, indomethacin, celecoxib, ketorolac, and nepafenac; intraocular pressure lowering agents; antibiotics such as ciprofloxacin; analgesics such as bupivacaine; calcium channel blockers such as nifedipine; cell cycle inhibitors such as simvastatin; proteins such as insulin; and small molecule hydrophilic drugs including carboxylates and amine salts. ; Small molecule hydrophobic drugs, hydrophilic peptides and protein drugs (e.g., insulin, single-chain antibody fragments, Fab fragments, IgG antibodies, fusion antibodies, etc.); Aptamers; In particular, biodegradable microparticles as described in any one of the preceding items, selected from bupivacaine (BPV-HCl or base), ropivacaine (RPV), dexamethasone, travoprost, axitinib, nonsteroidal anti-inflammatory drugs (NSAIDS), steroids, antibiotics, analgesics, calcium channel blockers, cell cycle inhibitors, chemotherapy, antiviral drugs, anesthetics, hormones, anticancer drugs, antitumor drugs, viruses, viruses for gene delivery such as AAV, etc., or any combination thereof. 15. Biodegradable microparticles as described in any one of the preceding items, wherein the microparticles have a particle size (diameter) of 0.1 to 1000 μm, or 1 to 150 μm, 1 to 100 μm, 20 to 75 μm, 10 to 106 μm, or 20 to 55 μm as determined by sieving, or have an average diameter in the range of 0.1 to 1000 μm, or 1 to 150 μm, 1 to 100 μm, 20 to 75 μm, 10 to 106 μm, or 20 to 55 μm as determined by laser diffraction. 16. Biodegradable microparticles as described in any one of the preceding items, wherein the microparticles may have a particle size distribution of, for example, less than approximately 100 μm, less than approximately 50 μm, or less than approximately 20 μm for D50 particle size, and / or less than approximately 200 μm, or less than approximately 50 μm for D90 particle size, or less than approximately 100 μm, or less than 30 μm for D90 particle size, and / or less than approximately 20 μm for D90 particle size. 17. Biodegradable microparticles according to any one of the preceding items, comprising a blend of microparticles having different particle sizes and / or different polymer matrices and / or different active agents. 18. A biodegradable microparticle according to any one of the preceding items, wherein the crosslinked biodegradable polymer has a glass transition temperature lower than human body temperature, for example, below 37°C, or below 36°C, below 30°C, below 25°C, below 20°C, or below 10°C, and / or the polymer has a melting temperature greater than 40°C, 45°C, 50°C, 60°C, or 70°C. 19. A biodegradable microparticle according to any one of the preceding items, which provides releasing a therapeutically or diagnostically effective amount of active agent for a period of up to 1 year, up to 9 months, up to 6 months, up to 3 months, up to 1 month, or up to about 25 days after administration, preferably up to 14 days, or up to 21 days after administration, and optionally the release of the active agent is substantially constant within a temperature range of 30°C to 45°C or 36°C to 43°C. Second item list 1. Biodegradable microparticles for sustained-release drug delivery comprising an organogel containing at least one active agent, at least one oil, and a covalently and three-dimensionally crosslinked biodegradable polymer matrix, wherein the crosslinked biodegradable polymer comprises at least one polymer unit, random or block copolymer, or any combination or mixture thereof from among polyethylene glycol (PEG), polypropylene glycol (PPG), polyvinyl alcohol, poly(vinylpyrrolidone), polylactic acid (PLA), polyglycolic acid (PGA), polylactic acid-glycolic acid copolymer (PLGA), poly-p-dioxanone, poly(trimethylene carbonate), polycaprolactone, and / or polyvinyl alcohol, or one or more from among polyamino acids, glycosaminoglycans, polysaccharides, or proteins. 2. Biodegradable microparticles as described in item 1, wherein the microparticles are microspheres having a substantially spherical shape. 3. Biodegradable microparticles as described in item 1 or 2, wherein the active ingredient is dispersed, embedded, or encapsulated in a crosslinked polymer. 4. Biodegradable particulate matter according to any one of the preceding items, wherein at least one oil is liquid at a temperature below the body temperature, for example, about 37°C, or in the range of 0°C to 40°C, or 10°C to 38°C, or 15°C to 37°C, or 25°C to 37°C, or liquid at 37°C. 5. At least one oil is triethyl citrate, acetyl triethyl citrate (ATEC), acetyl tributyl citrate (ATBC), α-tocopherol (vitamin E), α-tocopherol acetate; plant oils such as sesame oil, olive oil, soybean oil, sunflower oil, coconut oil, canola oil, rapeseed oil; nut oils such as hazelnut oil, walnut oil, pecan oil, almond oil; cottonseed oil, corn oil, safflower oil, linseed oil, etc.; ethyl oleate; castor oil Biodegradable microparticles as described in any one of the preceding items, selected from the group including and derivatives thereof (Cremophor®), lipids that become liquid at 37°C or below, such as saturated or unsaturated fatty acids, monoglycerides, diglycerides, triglycerides (Myglyols®), phospholipids, glycerophospholipids, sphingolipids, sterols, prenols, polyketides, hydrophobic biodegradable liquid polymers, low-melting-point waxes such as plant, animal, or synthetic waxes, lanolin, jojoba oil, or combinations thereof. 6. Biodegradable microparticles according to any one of the preceding items, wherein the biodegradable covalently and three-dimensionally crosslinked polymer comprises a plurality of hydrophobic polymer units and / or hydrophilic polymer units. 7. The biodegradable microparticles according to item 6, wherein the hydrophobic polymer units are selected from at least one of polylactic acid (PLA) and polylactic acid-glycolic acid copolymer (PLGA) units, and the hydrophilic polymer units are selected from at least one of polyethylene glycol units, polypropylene glycol units, or polyglycolic acid (PGA), preferably polyethylene glycol units. 8. Biodegradable microparticles according to any one of the preceding items, wherein the covalently and three-dimensionally crosslinked biodegradable polymer contains or consists of crosslinked polylactic acid-glycolic acid copolymer (PLGA) units. 9. The biodegradable fine particles according to item 8, wherein the polylactic acid-glycolic acid copolymer (PLGA) units have an L / G ratio (%) in the range of 0:100 to 100:0, or 1:99 to 99:1, or 10:90 to 90:10, or 25:75 to 75:25, preferably 50:50. 10. Biodegradable microparticles as described in any one of the preceding items, wherein each polymer unit has an average molecular weight (Mw) in the range of approximately 1,000 to approximately 100,000 daltons, or approximately 10,000 to approximately 60,000 daltons, or approximately 15,000 to approximately 50,000 daltons. 11. Biodegradable microparticles according to any one of the preceding items, wherein the polymer is covalently crosslinked by bonds between polymer units. 12. Biodegradable microparticles as described in item 11, wherein the bonds are optionally selected from the group consisting of amine, amide, urethane, ester, anhydride, ether, acetal, ketal, nitrile, isonitrile, isothiocyanate, isourea, hydrazone, oxime, or imine bonds, and are produced by polycondensation, radical polymerization, or click chemistry reactions, or combinations thereof. 13. Biodegradable microparticles as described in any one of the preceding items, wherein the active agent is selected from at least one of the following: a therapeutically active drug, a diagnostically active drug, or a combination thereof. 14. Therapeutically active drugs include: steroids; non-steroidal anti-inflammatory drugs (NSAIDs) such as diclofenac, ibuprofen, meclofename, mefanamic A, sarsalate, sulindac, tolmetin, ketoprofen, diflunisal, piroxicam, naproxen, etodolac, flurbiprofen, fenoprofen C, indomethacin, celecoxib, ketorolac, and nepafenac; intraocular pressure lowering agents; antibiotics such as ciprofloxacin; analgesics such as bupivacaine; calcium channel blockers such as nifedipine; cell cycle inhibitors such as simvastatin; proteins such as insulin; and small molecule hydrophilic drugs including carboxylates and amine salts. ; Small molecule hydrophobic drugs, hydrophilic peptides and protein drugs (e.g., insulin, single-chain antibody fragments, Fab fragments, IgG antibodies, fusion antibodies, etc.); Aptamers; In particular, biodegradable microparticles as described in any one of the preceding items, selected from bupivacaine (BPV-HCl or base), ropivacaine (RPV), dexamethasone, travoprost, axitinib, nonsteroidal anti-inflammatory drugs (NSAIDS), steroids, antibiotics, analgesics, calcium channel blockers, cell cycle inhibitors, chemotherapy, antiviral drugs, anesthetics, hormones, anticancer drugs, antitumor drugs, viruses, viruses for gene delivery such as AAV, etc., or any combination thereof. 15. Biodegradable microparticles as described in any one of the preceding items, wherein the microparticles have a particle size (diameter) of 0.1 to 1000 μm, or 1 to 150 μm, 1 to 100 μm, 20 to 75 μm, 10 to 106 μm, or 20 to 55 μm as determined by sieving, or have an average diameter in the range of 0.1 to 1000 μm, or 1 to 150 μm, 1 to 100 μm, 20 to 75 μm, 10 to 106 μm, or 20 to 55 μm as determined by laser diffraction. 16. Biodegradable microparticles as described in any one of the preceding items, wherein the microparticles may have a particle size distribution of, for example, less than approximately 100 μm, less than approximately 50 μm, or less than approximately 20 μm for D50 particle size, and / or less than approximately 200 μm, or less than approximately 50 μm for D90 particle size, or less than approximately 100 μm, or less than 30 μm for D90 particle size, and / or less than approximately 20 μm for D90 particle size. 17. Biodegradable microparticles according to any one of the preceding items, comprising a blend of microparticles having different particle sizes and / or different polymer matrices and / or different active agents. 18. A biodegradable microparticle according to any one of the preceding items, wherein the crosslinked biodegradable polymer or organogel has a glass transition temperature lower than human body temperature, for example, below 37°C, or below 36°C, below 30°C, below 25°C, below 20°C, or below 10°C, and / or the polymer has a melting temperature greater than 40°C, 45°C, 50°C, 60°C, or 70°C. 19. A biodegradable microparticle according to any one of the preceding items, which provides releasing a therapeutically or diagnostically effective amount of active agent for a period of up to 1 year, up to 9 months, up to 6 months, up to 3 months, up to 1 month, or up to about 25 days after administration, preferably up to 14 days, or up to 21 days after administration, and optionally the release of the active agent is substantially constant within a temperature range of 30°C to 45°C or 36°C to 43°C. Third item list 1. Biodegradable microparticles for sustained-release drug delivery comprising an active agent and a covalently and three-dimensionally crosslinked biodegradable polymer matrix, satisfying at least one of the following conditions: - The crosslinked biodegradable polymer comprises at least one of the following: crosslinked polylactic acid (PLA), polyglycolic acid (PGA), polylactic acid-glycolic acid copolymer (PLGA), poly(vinylpyrrolidone), poly-p-dioxanone, poly(trimethylene carbonate), polycaprolactone, and / or polyvinyl alcohol, or copolymers thereof; - The biodegradable microparticles comprise an organogel containing a covalently crosslinked biodegradable polymer and oil. 2. Biodegradable microparticles as described in item 1, wherein the microparticles are microspheres having a substantially spherical shape. 3. Biodegradable microparticles as described in item 1 or 2, in which the active ingredient is dispersed, embedded, or encapsulated in an organogel. 4. Biodegradable microparticles according to any one of the preceding items, wherein the organogel is formed by chemically crosslinking at least one polyfunctional precursor in the presence of an oil, to form a covalently and three-dimensionally crosslinked polymer matrix. 5. The biodegradable microparticles according to item 4, wherein at least one precursor has a functional group relating to chemical crosslinking that is greater than 2, for example, 3 to 10, or 3 to 9, or 4 to 8, or 4. 6. A biodegradable microparticle according to any one of item 4 or 5, wherein at least one precursor is a dendrimer or multi-arm precursor having a core and 2 to 10 arms, or 3 to 10 arms, 4 to 8 arms, or 4 to 6 arms, each arm comprising polymer units and having an end. 7. Biodegradable microparticles as described in any one of items 4 to 6, wherein the polymer units are selected from polyethylene glycol (PEG), polypropylene glycol (PPG), polyvinyl alcohol, poly(vinylpyrrolidone), polylactic acid (PLA), polyglycolic acid (PGA), polylactic acid-glycolic acid copolymer (PLGA), poly-p-dioxanone, poly(trimethylene carbonate), polycaprolactone, random or block copolymers, or any combination or mixture thereof, or one or more units of polyamino acids, glycosaminoglycans, polysaccharides, or proteins. 8. Biodegradable microparticles as described in any one of items 4-7, wherein the polymer units within the arms of the multi-arm precursor are of the same or different types of polymer units. 9. Biodegradable microparticles according to any one of items 4 to 8, further comprising at least two functional groups, or at least one crosslinking agent having two or more functional groups, preferably a low molecular weight amine such as tris(2-aminoethyl)amine (TAEA), or trilysine. 10. A biodegradable microparticle according to any one of items 4 to 8, wherein the organogel comprises at least two crosslinkable dendrimers or multi-arm precursors that are crosslinked with respect to each other. 11. A biodegradable microparticle according to any one of items 4 to 10, wherein the dendrimer or multi-arm precursor(s) has a functional group at at least three of its arm ends, or at each end. 12. A biodegradable microparticle according to any one of items 4 to 11, wherein the polymer matrix is ​​formed from a first multi-arm precursor containing a first functional group, a second multi-arm precursor or crosslinker containing a second functional group, and a functional group located at the end of the arms of the precursor or crosslinker, wherein the first or second functional group may be grafted directly onto the precursor end or grafted via a linker molecule. 13. Biodegradable microparticles as described in item 12, wherein each of the first and second functional groups is selected from electrophiles and nucleophiles, functional groups for click chemistry, in particular functional groups for cycloaddition such as 1,3-dipolar cycloaddition and hetero-Diels-Alder cycloaddition, functional groups for nucleophilic ring-opening, functional groups for non-aldol type carbonyl reactions, functional groups for addition reactions to carbon-carbon multiple bonds, polymerizable vinyl groups, or a combination thereof. 14. The biodegradable microparticles described in item 13, wherein each of the first and second functional groups is selected from an electrophile and a nucleophile, and the reaction between the first and second functional groups is an electrophilic-nucleophilic reaction that forms a covalent bond. 15. Biodegradable microparticles as described in item 14, wherein the nucleophile is selected from one of the following: amines such as primary amines, hydroxyl groups, alcohols, thiols, azido anions, and carboxyl groups. 16. Biodegradable microparticles as described in item 14 or 15, wherein the electrophile is selected from activated ester groups such as succinimidyl esters, succinimidyl carbonates, nitrophenyl carbonates, aldehydes, ketones, acrylates, acrylamides, maleimides, vinyl sulfones, iodoacetamides, alkenes, alkynes, azides, norbornene, epoxides, mesylates, tosylates, tresyl, cyanurates, orthopyridyl disulfide, or halogens. 17. A biodegradable microparticle according to any one of items 14-16, wherein the nucleophile is an amine group, in particular a primary amine, and the electrophile is an activated ester group, in particular a succinimidyl ester selected from succinimidyl succinate, succinimidyl glutarate, succinimidyl adipate, succinimidyl azelate, or succinimidyl glutaramide. 18. Biodegradable microparticles as described in item 13, wherein each of the first and second functional groups is selected from functional groups for click chemistry, in particular functional groups for cycloaddition, in particular [3+2] cycloaddition such as 1,3-dipolar cycloaddition, alkene-nitrone cycloaddition or alkyne-nitrone cycloaddition, [4+2] cycloaddition, hetero-Diels-Alder cycloaddition; functional groups for thiol-ene reactions; functional groups for nucleophilic ring-opening; functional groups for non-aldol type carbonyl reactions; functional groups for addition reactions to carbon-carbon multiple bonds; and functional groups for Michael type addition. 19. Biodegradable microparticles as described in item 18, wherein the first functional group is an alkyne compound such as dibenzocyclooctin (DBCO) or bicyclo[6.1.0]-nonine (BCN); or norbornene or trans-cyclooctene (TCO), and the second functional group is an azide, 3,4-dihydroxyphenylacetic acid (DHPA), or tetrazine (Tz). 20. Biodegradable microparticles as described in item 19, wherein DBCO, BCN, norbornene, TCO, azide, DHPA, and Tz functional groups are grafted to the ends of a multi-arm precursor via linkers such as acidic groups, diacidic groups, functionalized aliphatic groups, heteroaliphatic groups, or aromatic or heteroaromatic groups. 21. Biodegradable microparticles as described in item 13, wherein the first and second functional groups are selected for a [3+2] cycloaddition reaction such as an alkene-nitrone cycloaddition or an alkyne-nitrone cycloaddition, or the first and second functional groups are selected for a [4+2] cycloaddition reaction, particularly a hetero-Diels-Alder reaction, wherein the first functional group is an aldehyde or imine compound and the second functional group is a 1,3-diene compound, an unsaturated carbonyl compound, or a nitrosoalkene compound. 22. Biodegradable microparticles as described in item 13, wherein the first and second functional groups are selected for a thiol-ene reaction, the first functional group being a thiol compound and the second functional group being an alkene, preferably a terminal alkene, or the first and second functional groups are selected for nucleophilic ring-opening, the first functional group being selected from epoxides, tilanes, aziridines, or lactams and the second functional group being a nucleophile. 23. Biodegradable microparticles as described in item 13, wherein the first and second functional groups are selected for a non-aldol type carbonyl reaction, the first functional group is an aldehyde or ketone compound, and the second functional group is a primary amine, hydrazide, acylhydrazide, or aminooxy compound, forming an imine, amide, isourea, hydrazone, acylhydrazone, or oxime bond. 24. Biodegradable microparticles as described in item 13, wherein each of the first and second functional groups is selected from polymerizable vinyl and acrylic groups such as (meth)acrylic acid, (meth)acrylic acid esters, acrylamide, fumaric acid, maleic acid, and combinations thereof, and the crosslinking is optionally induced thermally or photochemically using a free radical photoinitiator (Nourish type I such as 2,2-dimethoxy-1,2-diphenylethane-1-one, 2-hydroxy-2-methyl-1-phenylpropanone, 1-hydroxy-cyclohexylphenyl ketone; or Norish type II such as benzophenone and its derivatives combined with co-actors such as tertiary amines such as 2-ethylhexyl-(4-N,N-dimethylamino)benzoate and 2-ethyl-(4-N,N-dimethylamino)benzoate, and isopropylthioxanthone); or a cationic photoinitiator. List of items number 4 1. A method for producing biodegradable microparticles for sustained-release drug delivery as described in any one of the items in Lists 1 to 3, wherein the method is selected from one of the following techniques: evaporation-extraction of emulsion solvent, diffusion of emulsion solvent, supercritical fluid emulsion, coacervation, spray drying, hydrogel template, microfluidics system, membrane extrusion emulsification, particle replication (PRINT) techniques in non-wet molds, electrohydrodynamic atomization (EHDA) or electrospraying, or microparticle formation from gas-saturated solution (PGSS) method, or 3D printing. 2. The method described in item 1, wherein the method includes the following steps: (1) Forming a gel comprising a covalently crosslinked polymer in the presence of at least one active agent, optionally at least one oil, and optionally a first solvent. (2) To generate fine particles, wherein at least one active agent is dispersed within a covalently crosslinked polymer. (3) Remove the solvent at your discretion. 3. The method described in item 2, comprising the following steps: (a) Dissolving at least one polymer precursor in a first solvent to produce a first mixture; (b) To provide a second mixture containing a crosslinking agent in a second solvent; (c) Adding at least one active ingredient and optionally an oil to at least one of the first mixture or the second mixture; (d) Combining the first mixture and the second mixture to produce the first phase; (e) To provide a second phase comprising a third solvent that is miscible with the first and second solvents; (f) Introducing the first phase into the second phase under stirring, thereby generating an emulsion of the first phase dispersed in the second phase; and (g) Remove the first, second and / or third solvent. 4. The method according to item 2 or 3, wherein the step of generating fine particles (step (2)) or step (f) comprises extruding a first phase through a mesh or injecting the first phase into a stirred second phase, and the first and / or second solvent and / or third solvent optionally include additives such as emulsifiers, surfactants, dispersion aids, or pologens, and forming spherical or nanospherical particles. 5. The method according to any one of items 2 to 4, wherein the first solvent and / or the second solvent is an organic solvent in which the precursor is soluble, and the third solvent is a solvent in which the first phase and / or the organogel formed thereon is insoluble. 6. The method according to item 5, wherein the first and / or second solvent is selected from acetone, acetonitrile, benzyl alcohol, chloroform, dichloromethane (DCM), dioxane, dimethyl carbonate, DMSO, ethanol, ethyl acetate, ethyl formate, ethyl propionate, glycoflore, hexafluoroisopropanol, isosorbide dimethyl ether, isopropanol, methyl chloride, methylene chloride, methyl ethyl ketone, N-methylpyrrolidone, propylene carbonate, or tetrahydrofuran, or any mixture thereof, and the third solvent is water, an alcohol such as methanol, ethanol or propanol, or any mixture thereof. 7. The method according to any one of items 4 to 6, wherein the additive is selected from surfactants or emulsifiers such as polyvinyl alcohol (PVA), polyethylene glycol sorbitan monolaurate (Tween®), sorbitan monolaurate (Span®), sodium dodecyl sulfate (SDS); and / or inorganic salts (NaCl, KCl, sodium carbonate or potassium carbonate or bicarbonate, ammonium bicarbonate), pluronic acid; sodium oleate or potassium oleate; gelatin; mustard oil; mineral oil; cyclodextrin; carbohydrates; bovine serum albumin (BSA); photoinitiators, radical polymerization initiators, and combinations thereof. 8. A method according to any one of items 2-7, wherein steps 1 and 2 utilize oil-in-water emulsion technology or water-in-oil emulsion technology, or a combination thereof, in particular single or double emulsion technology, or microfluidic technology, or a combination thereof. 9. The method according to any one of items 2 to 8, wherein the removal of the first and / or second and / or third solvent is carried out by hot air convection or one of the following: direct drying, indirect drying or contact drying, spray drying, dielectric drying, vacuum drying, freeze drying, supercritical or superheated steam drying, or any combination thereof. 10. Biodegradable microparticles for sustained drug delivery, obtained by a method described in any one of the preceding items. List of items 5 1. A sustained-release biodegradable drug delivery system comprising biodegradable microparticles for sustained-release drug delivery as described in any one of the items listed in the first to third items above. 2. A drug delivery system as described in item 1, wherein biodegradable microparticles are incorporated into a hydrogel, xerogel, or organogel. 3. A drug delivery system as described in item 1 or 2, for coating medical implants or for use as a medical implant. 4. A medical implant for sustained drug delivery, comprising incorporating biodegradable microparticles for sustained-release drug delivery described in any one of the items listed in items 1 to 3 above into a hydrogel, xerogel, or organogel. 5. A drug delivery system or implant described in any one of items 1 to 4, selected from the group consisting of intraocular implants, intracavitary implants, intraacular implants, anterior chamber, vitreous humor, episclera, posterior sub-Tenon's space (inferior fornix), subconjunctival, intraacular, periocular, posterior, sub-Tenon's space, retina, subretinal, intracanaliculi, intravitreous, intrascleral, intrachoroidal, suprachoroidal, retina, subretinal, or the surface of the lens, cornea or conjunctiva, lacrimal puncta (canaliculi, superior / inferior canaliculi), palpebral fornix, superior / inferior palpebral fornix, sub-Tenon's space, choroid, suprachoroidal, Tenon, cornea, cancerous tissue, organs, prostate, breast, joint cavity, subdural, tooth, subcutaneous, carpal tunnel, perivascular, surgically formed spaces or injuries, cavities, and latent cavities. 6. A drug delivery system or implant according to any one of items 1 to 4, wherein the system or implant is obtained by extrusion or injection molding of a reaction mixture comprising a hydrogel, xerogel, or organogel, or a precursor thereof, in which biodegradable microparticles are dispersed. 7. A drug delivery system or implant as described in item 6, wherein gelation occurs before and / or during the extrusion or injection molding of a gel-forming material containing biodegradable microparticles. 8. A drug delivery system or implant according to any one of items 2 to 7, wherein the content of biodegradable microparticles embedded in a hydrogel, organogel, or xerogel relative to the total weight of the drug delivery system or implant is about 10% to about 35% by weight, or about 23% to about 27% by weight, or about 12% to about 17% by weight, or about 30% to about 35% by weight, or about 25% by weight, or about 15% by weight, or about 34% by weight. 9. A drug delivery system or implant according to any one of the preceding items, which provides releasing a therapeutically or diagnostically effective amount of active agent over a period of up to 1 year, up to 9 months, up to 6 months, up to 3 months, up to 1 month, or up to about 25 days after administration, preferably up to 14 days, or up to 21 days after administration, and optionally the release of the active agent is substantially constant within a temperature range of 30°C to 45°C or 36°C to 43°C. 10. A sustained-release, biodegradable drug delivery system or implant described in any one of items 1-8, for use as a pharmaceutical agent. 11. A sustained-release biodegradable drug delivery system or implant for use in the treatment of a patient's disease / condition, comprising incorporating biodegradable microparticles described in any one of the above item lists 1 to 3 into a carrier such as a hydrogel, organogel, or xerogel, the hydrogel, organogel, or xerogel being formed in situ at the patient's treatment site or pre-fabricated and delivered or implanted at the patient's treatment site to release the active agent from the microparticles over a long period of time, or the carrier being a solvent or solvent system to produce an injection suspension or dispersion. 12. A method for treating a patient's disease / condition, comprising incorporating a biodegradable microparticle described in any one of the items listed in items 1 to 3 above into a hydrogel, organogel, or xerogel, wherein the hydrogel, organogel, or xerogel is formed in situ at the patient's treatment site or pre-formed and delivered or implanted at the treatment site to release an active agent over a long period of time. 13. A method for treating a patient's disease / condition, comprising administering to the patient a hydrogel, organogel, or xerogel containing biodegradable microparticles described in any one of the above-mentioned list items 1 to 3, for the purpose of releasing an active agent over a long period of time. 14. A system or treatment method for use as described in any one of items 9-12, where the treatment site is selected from the anterior chamber, vitreous humor, episclera, posterior sub-Tenon's space (inferior fornix), subconjunctival, intraocular, periocular, posterior, sub-Tenon's space, retina, subretinal, intracanaliculi, intravitreous, intrascleral, intrachoroidal, suprachoroidal, retina, subretinal, or lens, corneal or conjunctival surface, lacrimal puncta (canaliculi, superior / inferior canaliculi), palpebral fornix, superior / inferior palpebral fornix, sub-Tenon's space, choroid, suprachoroidal, Tenon, cornea, cancerous tissue, organs, prostate, breast, joints, subdural, teeth, subcutaneous, carpal tunnel, perivascular, surgically formed spaces or injuries, cavities, and latent cavities. 15. A system or method of treatment for use as described in any one of items 9-13, where the disease / condition being treated is an eye disease, such as any posterior segment eye disease affecting the vascular system and integrity of the retina, macula, or choroid and causing impaired vision, vision loss, or blindness, in particular due to age, trauma, surgical intervention, etc., such as age-related macular degeneration (AMD), cystoid macular edema (CME), diabetic macular edema (DME), posterior uveitis, and diabetic retinopathy; or a posterior segment disease condition resulting from glaucoma, ocular hypertension, anterior chamber hemorrhage, presbyopia, cataract, retinal vein occlusion, inflammation. List of items number 6 1. A method for controlling the release of an active agent from biodegradable microparticles for sustained drug delivery as described in the first to third item lists above, the method comprising one or a combination of the following means: - Select / adjust the L / G ratio of polylactic acid-glycolic acid copolymer (PLGA) units to adjust the hydrophobicity of the polymer matrix forming the microparticles; - Select / adjust the L / G ratio of the polylactic acid-glycolic acid copolymer (PLGA) units to ensure sustained release of the active ingredient from the microparticles; - Select / adjust the molar ratio of the amounts of the first crosslinkable precursor to the second crosslinkable precursor in order to adjust the hydrophobicity of the polymer matrix that forms the particles; - Select / adjust the molar ratio of the first crosslinkable precursor to the second crosslinkable precursor to ensure sustained release of the active ingredient from the microparticles; - Adding a third crosslinkable precursor that is less hydrolyzable than the first and second crosslinkable precursors, and optionally changing the molar ratio of the first, second and / or third precursors when forming biodegradable microparticles; - Dispersing an active agent with high water solubility in particulate form within a biodegradable microparticle organogel; - Selecting / adjusting the amount and type of oil in organogel microparticles; - Select / adjust the amount and / or particle size of biodegradable microparticles contained in hydrogels, organogels, and xerogels.

Claims

1. Biodegradable microparticles for sustained-release drug delivery comprising an active agent and a covalently and three-dimensionally crosslinked biodegradable polymer matrix, wherein the biodegradable microparticles satisfy at least one of the following conditions: - The crosslinked biodegradable polymer comprises at least one of the following: crosslinked polylactic acid (PLA), polyglycolic acid (PGA), polylactic acid-glycolic acid copolymer (PLGA), poly(vinylpyrrolidone), poly-p-dioxanone, poly(trimethylene carbonate), polycaprolactone, and / or polyvinyl alcohol, or copolymers thereof; - The biodegradable microparticles include an organogel containing the crosslinked biodegradable polymer and oil.

2. The biodegradable fine particles according to claim 1, wherein the fine particles are substantially spherical microspheres.

3. The biodegradable microparticles according to claim 1 or 2, wherein the active agent is dispersed, embedded, or encapsulated in the polymer or organogel.

4. The biodegradable microparticles according to any one of the prior claims, wherein the organogel or crosslinked polymer is formed by chemically crosslinking at least one polyfunctional precursor in the presence of oil, optionally, to form the covalently and three-dimensionally crosslinked polymer matrix.

5. The biodegradable fine particles according to claim 4, wherein the at least one precursor has a functional group relating to chemical crosslinking that is greater than 2, for example, 3 to 10, 3 to 9, 4 to 8, or 4.

6. The biodegradable microparticles according to any one of claims 4 or 5, wherein the at least one precursor is a dendrimer or multi-arm precursor having a core and 2 to 10 arms, or 3 to 10 arms, 4 to 8 arms, or 4 to 6 arms, each arm comprising polymer units and having an end.

7. The biodegradable microparticles according to any one of claims 4 to 6, wherein the polymer unit is selected from polyethylene glycol (PEG), polypropylene glycol (PPG), polyvinyl alcohol, poly(vinylpyrrolidone), polylactic acid (PLA), polyglycolic acid (PGA), polylactic acid-glycolic acid copolymer (PLGA), poly-p-dioxanone, poly(trimethylene carbonate), polycaprolactone, random or block copolymer, or any combination or mixture thereof, or one or more units of polyamino acids, glycosaminoglycans, polysaccharides, or proteins.

8. The biodegradable microparticles according to any one of claims 4 to 7, wherein the polymer units in the arms of the multi-arm precursor are the same or different types of polymer units.

9. The biodegradable fine particles according to any one of claims 4 to 8, wherein the biodegradable covalently and three-dimensionally crosslinked polymer matrix comprises a plurality of hydrophobic polymer units and / or hydrophilic polymer units.

10. The biodegradable fine particles according to claim 9, wherein the hydrophobic polymer unit is selected from at least one of polylactic acid (PLA) and polylactic acid-glycolic acid copolymer (PLGA) units, preferably from polylactic acid (PLA).

11. The biodegradable fine particles according to claim 9, wherein the hydrophobic polymer unit is selected from at least one of polyethylene glycol units, polypropylene glycol units, or polyglycolic acid (PGA), preferably polyethylene glycol units.

12. The biodegradable fine particles according to any one of claims 1 to 8, wherein the covalently and three-dimensionally crosslinked polymer contains or consists of polylactic acid-glycolic acid copolymer (PLGA) units or polylactic acid (PLA).

13. The biodegradable fine particles according to any one of claims 4 to 12, wherein each of the polymer units has an average molecular weight (Mw) in the range of about 1,000 to about 100,000 daltons, or about 10,000 to about 60,000 daltons, or about 15,000 to about 50,000 daltons.

14. The biodegradable fine particles according to claim 11 or 12, wherein the polylactic acid-glycolic acid copolymer (PLGA) units have an L / G ratio (percentage of L or G units) in the range of 0:100 to 100:0, or 1:99 to 99:1, or 10:90 to 90:10, or 25:75 to 75:25, preferably 50:

50.

15. The biodegradable fine particles according to any one of claims 4 to 14, further comprising at least two functional groups, or at least one crosslinking agent having more than two functional groups, preferably a low molecular weight amine such as tris(2-aminoethyl)amine (TAEA), or trilysine.

16. The biodegradable microparticles according to any one of claims 4 to 14, wherein the organogel comprises at least two crosslinkable dendrimers or multi-arm precursors that are crosslinked with respect to each other.

17. The biodegradable microparticles according to any one of claims 4 to 16, wherein the dendrimer or multi-arm precursor comprises a functional group at at least three of its arm ends, or at each end.

18. The biodegradable microparticles according to any one of claims 15 to 17, wherein the polymer matrix is ​​formed from a first multi-arm precursor containing a first functional group and a second multi-arm precursor or crosslinking agent containing a second functional group, the functional group being located at the end of the arm of the precursor or crosslinking agent, and the first or second functional group may be grafted directly onto the end of the precursor or grafted via a linker molecule.

19. The biodegradable fine particles according to claim 18, wherein each of the first and second functional groups is selected from electrophiles and nucleophiles, functional groups for click chemistry, in particular functional groups for cycloaddition such as 1,3-dipolar cycloaddition and hetero-Diels-Alder cycloaddition, functional groups for nucleophilic ring opening, functional groups for non-aldol type carbonyl reactions, functional groups for addition reactions to carbon-carbon multiple bonds, polymerizable vinyl groups, or a combination thereof.

20. The biodegradable fine particles according to claim 19, wherein each of the first functional group and the second functional group is selected from an electrophile and a nucleophile, and the reaction between the first functional group and the second functional group is an electrophile-nucleophile reaction that forms a covalent bond.

21. The biodegradable fine particles according to claim 20, wherein the nucleophile is selected from one of amines such as primary amines, hydroxyl groups, alcohols, thiols, azido anions, and carboxyl groups.

22. The electrophile is selected from activated ester groups such as succinimidyl ester, succinimidyl carbonate, nitrophenyl carbonate, aldehyde, ketone, acrylate, acrylamide, maleimide, vinyl sulfone, iodoacetamide, alkene, alkyne, azide, norbornene, epoxide, mesylate, tosylate, tresyl, cyanurate, orthopyridyl disulfide, or halogen, as described in claim 20 or claim 21.

23. The biodegradable fine particles according to any one of claims 20 to 22, wherein the nucleophile is an amine group, in particular a primary amine, and the electrophile is an activated ester group, in particular a succinimidyl ester selected from succinimidyl succinate, succinimidyl glutarate, succinimidyl adipate, succinimidyl azelate, or succinimidyl glutaramide.

24. The biodegradable microparticles according to claim 18, wherein each of the first and second functional groups is selected from functional groups for click chemistry, in particular functional groups for cycloaddition, in particular [3+2] cycloaddition such as 1,3 dipolar cycloaddition, alkene-nitrone cycloaddition or alkyne-nitrone cycloaddition, [4+2] cycloaddition, hetero-Diels-Alder cycloaddition; functional groups for thiol-ene reactions; functional groups for nucleophilic ring-opening; functional groups for non-aldol type carbonyl reactions; functional groups for addition reactions to carbon-carbon multiple bonds; and functional groups for Michael type addition.

25. The biodegradable microparticles according to claim 24, wherein the first functional group is an alkyne compound such as dibenzocyclooctin (DBCO) or bicyclo[6.1.0]-nonine (BCN); or norbornene or trans-cyclooctene (TCO), and the second functional group is an azide, 3,4-dihydroxyphenylacetic acid (DHPA), or tetrazine (Tz).

26. The biodegradable microparticles according to claim 25, wherein the DBCO, BCN, norbornene, TCO, azide, DHPA, and Tz functional groups are grafted to the ends of the multi-arm precursor via linkers such as acidic groups, diacidic groups, functionalized aliphatic groups, heteroaliphatic groups, aromatic groups, or heteroaromatic groups.

27. The biodegradable microparticles according to claim 18, wherein the first and second functional groups are selected for a [3+2] cycloaddition reaction such as an alkene-nitrone cycloaddition or an alkyne-nitrone cycloaddition.

28. The biodegradable fine particles according to claim 18, wherein the first and second functional groups are selected for a [4+2] cycloaddition reaction, particularly a hetero-Diels-Alder reaction, and the first functional group is an aldehyde or imine compound, and the second functional group is a 1,3-diene compound, an unsaturated carbonyl compound, or a nitrosoalkene compound.

29. The biodegradable fine particles according to claim 18, wherein the first and second functional groups are selected for a thiol-ene reaction, the first functional group is a thiol compound, and the second functional group is an alkene, preferably a terminal alkene.

30. The biodegradable microparticles according to claim 18, wherein the first and second functional groups are selected for nucleophilic ring-opening, the first functional group is selected from epoxide, thiirane, aziridine, or lactam, and the second functional group is a nucleophile.

31. The biodegradable microparticles according to claim 18, wherein the first and second functional groups are selected for a non-aldol type carbonyl reaction, the first functional group is an aldehyde or ketone compound, and the second functional group is a primary amine, hydrazide, acylhydrazide, or aminooxy compound, and forms an imine, amide, isourea, hydrazone, acylhydrazone, or oxime bond.

32. The biodegradable fine particles according to claim 18, wherein each of the first and second functional groups is selected from polymerizable vinyl groups and acrylates such as (meth)acrylic acid, (meth)acrylic acid esters, acrylamide, fumaric acid, maleic acid, and combinations thereof.

33. Biodegradable microparticles according to claim 32, wherein crosslinking is optionally induced thermally or photochemically using an initiator such as a free radical photoinitiator (Nourish type I such as 2,2-dimethoxy-1,2-diphenylethane-1-one, 2-hydroxy-2-methyl-1-phenylpropanone, 1-hydroxycyclohexylphenyl ketone; or Norish type II such as benzophenone and its derivatives combined with a co-agent such as a tertiary amine 2-ethylhexyl-(4-N,N-dimethylamino)benzoate and 2-ethyl-(4-N,N-dimethylamino)benzoate, and isopropylthioxanthone); or a cationic photoinitiator.

34. The biodegradable fine particles according to any one of the prior claims, wherein the polymer is covalently crosslinked by bonds between polymer units.

35. The biodegradable fine particles according to claim 34, wherein the bond is selected from the group consisting of amine, amide, urethane, ester, anhydride, ether, acetal, ketal, nitrile, isonitrile, isothiocyanate, isourea, hydrazone, oxime, or imine bond, and combinations thereof.

36. The active agent is selected from at least one of a therapeutically active agent, a diagnostically active agent, or a combination thereof, as described in any one of the prior claims, for the biodegradable microparticles described in any one of the prior claims.

37. The aforementioned therapeutically active drugs include steroids; nonsteroidal anti-inflammatory drugs (NSAIDs) such as diclofenac, ibuprofen, meclofename, mefanamic A, sarsalate, sulindac, tolmetin, ketoprofen, diflunisal, piroxicam, naproxen, etodolac, flurbiprofen, fenoprofen C, indomethacin, celecoxib, ketorolac, and nepafenac; intraocular pressure lowering agents; antibiotics such as ciprofloxacin; analgesics such as bupivacaine; calcium channel blockers such as nifedipine; complement inhibitors such as abasincaptadopegol; cell cycle inhibitors such as simvastatin; proteins such as insulin; carboxylates and amine salts Biodegradable microparticles according to any one of the prior claims, selected from small molecule hydrophilic drugs; small molecule hydrophobic drugs, hydrophilic peptides and protein drugs (e.g., insulin, single-chain antibody fragments, Fab fragments, IgG antibodies, fusion antibodies, etc.); aptamers; in particular, bupivacaine (BPV-HCl or base), ropivacaine (RPV), dexamethasone, travoprost, axitinib, nonsteroidal anti-inflammatory drugs (NSAIDs), steroids, antibiotics, analgesics, calcium channel blockers, cell cycle inhibitors, chemotherapy, antiviral drugs, anesthetics, hormones, anticancer drugs, antitumor drugs, viruses, viruses for gene delivery such as AAV, etc., or any combination thereof.

38. The biodegradable fine particles according to any one of the prior claims, wherein the fine particles have a particle size (diameter) of 0.1 to 1000 μm, or 1 to 150 μm, 1 to 100 μm, 20 to 75 μm, 10 to 106 μm, or 20 to 55 μm as determined by sieving, or have an average diameter in the range of 0.1 to 1000 μm, or 1 to 150 μm, 1 to 100 μm, 20 to 75 μm, 10 to 106 μm, or 20 to 55 μm as determined by laser diffraction.

39. The biodegradable fine particles according to any one of the prior claims, wherein the fine particles have a particle size distribution of, for example, less than 100 μm, less than 50 μm, or less than 20 μm D50 particle size, and / or less than 200 μm, or less than 50 μm D90 particle size, or less than 100 μm, or less than 30 μm D90 particle size, and / or less than 20 μm D90 particle size.

40. Biodegradable microparticles according to any one of the preceding claims, comprising a blend of microparticles having different particle sizes and / or different polymer matrices and / or different active agents.

41. The biodegradable microparticles according to any one of the prior claims, wherein the selection of the organogel precursor and / or the hydrophobicity of the polymer units and / or the L / G ratio of the PLGA units are used to adjust the release rate.

42. The biodegradable microparticles according to any one of the prior claims, which provide to release a therapeutically or diagnostically effective amount of the active agent for a period of up to 1 year, up to 9 months, up to 6 months, up to 3 months, up to 1 month, or up to about 25 days after administration, preferably up to 14 days, or up to 21 days after administration, and optionally the release of the active agent is substantially constant within a temperature range of 30°C to 45°C, or 36°C to 43°C.

43. The polymer matrix has a glass transition temperature below the body temperature, for example, about 37°C or below, or about 36°C or below, 30°C or below, 25°C or below, 20°C or below, or 10°C or below, and / or the polymer matrix has a melting temperature above 40°C, 45°C, 50°C, 60°C, or 70°C, according to any one of the prior claims.

44. A method for producing biodegradable microparticles for sustained-release drug delivery according to any one of the prior claims, wherein the method is selected from one of the following techniques: evaporation-extraction of an emulsion solvent, diffusion of an emulsion solvent, supercritical fluid emulsion, coacervation, spray drying, hydrogel template, microfluidics system, membrane extrusion emulsification, particle replication (PRINT) technique in a non-wet mold, electrohydrodynamic atomization (EHDA) or electrospraying, or microparticles obtained from a gas-saturated solution (PGSS) method, or 3D printing.

45. A method for manufacturing according to claim 44, wherein the method comprises the following steps: (1) Forming a gel comprising a covalently crosslinked polymer in the presence of at least one active agent, optionally at least one oil, and optionally a first solvent. (2) To generate fine particles, wherein at least one active agent is dispersed within the covalently crosslinked polymer. (3) The method described above, wherein the solvent is optionally removed.

46. The method according to claim 45, comprising the following steps: (h) Dissolving at least one of the polymer precursors in a first solvent to produce a first mixture; (i) To provide a second mixture containing a crosslinking agent in a second solvent; (j) Adding at least one activeing ​​agent and optionally an oil to at least one of the first mixture or the second mixture; (k) Combining the first mixture and the second mixture to produce a first phase; (l) To provide a second phase comprising a third solvent that is immiscible with the first and second solvents; (m) Introducing the first phase into the second phase under stirring, thereby generating an emulsion of the first phase dispersed in the second phase; and (n) Removing the first, second and / or third solvent.

47. The method according to claim 45 or 46, wherein the step of generating fine particles (step (2) or step f) includes extruding the first phase through a mesh or injecting the first phase into the stirred second phase, and the first and / or second solvent and / or third solvent optionally include additives such as emulsifiers, surfactants, dispersion aids, or pologens, which form spherical or nanospherical particles.

48. The method according to any one of claims 45 to 47, wherein the first solvent and / or the second solvent is an organic solvent in which the precursor is soluble, and the third solvent is a solvent in which the first phase and / or the formed organogel is insoluble.

49. The method according to claim 48, wherein the first or second solvent is selected from acetone, acetonitrile, benzyl alcohol, chloroform, dichloromethane (DCM), dioxane, dimethyl carbonate, DMSO, ethanol, ethyl acetate, ethyl formate, ethyl propionate, glycoflore, hexafluoroisopropanol, isosorbide dimethyl ether, isopropanol, methyl chloride, methylene chloride, methyl ethyl ketone, N-methylpyrrolidone, propylene carbonate, or tetrahydrofuran, or any mixture thereof, and the third solvent is water, an alcohol such as methanol, ethanol or propanol, or any mixture thereof.

50. The method according to any one of claims 46 to 49, wherein the additive is selected from surfactants or emulsifiers such as polyvinyl alcohol (PVA), polyethylene glycol sorbitan monolaurate (Tween®), sorbitan monolaurate (Span®), and sodium dodecyl sulfate (SDS); and / or inorganic salts (NaCl, KCl, sodium carbonate or potassium carbonate or bicarbonate, ammonium bicarbonate), pluronic acid; sodium oleate or potassium oleate; gelatin; mustard oil; mineral oil; cyclodextrin; carbohydrates; bovine serum albumin (BSA); and pologens such as photoinitiators, radical polymerization initiators, and combinations thereof.

51. The method according to any one of claims 45 to 50, wherein steps 1 and 2 utilize oil-in-water emulsion technology or water-in-oil emulsion technology, or a combination thereof, in particular single or double emulsion technology, or microfluidic technology, or a combination thereof.

52. The method according to any one of claims 45 to 51, wherein the removal of the first and / or second and / or third solvent is carried out by hot air convection or one of direct drying, indirect drying or contact drying, spray drying, dielectric drying, vacuum drying, freeze drying, supercritical or superheated steam drying, or any combination thereof.

53. A sustained-release biodegradable drug delivery system comprising biodegradable microparticles for sustained-release drug delivery according to any one of claims 1 to 43.

54. The sustained-release biodegradable drug delivery system according to claim 52, wherein the biodegradable microparticles are incorporated into a hydrogel, xerogel, or organogel by optionally using extrusion or 3D printing.

55. A sustained-release biodegradable drug delivery system according to claim 53 or 54, for coating medical implants or for use as medical implants.

56. The sustained-release biodegradable drug delivery system according to claim 55, wherein the implant is selected from the group consisting of intraocular implants, intracavitary implants, intraacular implants, anterior chamber, vitreous humor, episclera, posterior sub-Tenon space (inferior fornix), subconjunctival, intraacular, periocular, posterior, sub-Tenon space, retina, subretinal, intracanaliculi, intravitreous, intrascleral, intrachoroidal, suprachoroidal, retina, subretinal, or lens, corneal or conjunctival surface, lacrimal puncta (canaliculi, superior / inferior canaliculi), palpebral fornix, superior / inferior palpebral fornix, sub-Tenon space, choroid, suprachoroidal, Tenon, cornea, cancerous tissue, organs, prostate, breast, joint cavity, subdural, tooth, subcutaneous, carpal tunnel, perivascular, surgically formed spaces or injuries, cavities, and latent cavities.

57. The sustained-release biodegradable drug delivery system according to any one of claims 53 to 58, wherein the system is obtained by extrusion or injection molding of a reaction mixture containing biodegradable fine particles according to any one of claims 1 to 43, dispersed in a hydrogel, xerogel, or organogel, or a precursor thereof.

58. The sustained-release biodegradable drug delivery system according to claim 57, wherein the gelation occurs before and / or during the extrusion or injection molding of the gel-forming material containing biodegradable microparticles.

59. A sustained-release biodegradable drug delivery system according to any one of claims 53 to 57, for use as a pharmaceutical agent, or a sustained-release biodegradable drug delivery system manufactured according to any one of claims 44 to 52.

60. A sustained-release biodegradable drug delivery system for use in the treatment of a patient's disease / condition, as described in any one of claims 53 to 57, or a sustained-release biodegradable drug delivery system manufactured according to any one of claims 44 to 52, wherein the use comprises the incorporation of biodegradable microparticles as described in any one of claims 1 to 43 into a carrier such as a hydrogel, organogel or xerogel, wherein the hydrogel, organogel or xerogel is formed in situ at the patient's treatment site or pre-formed and delivered or implanted at the patient's treatment site to release the active agent from the microparticles over a long period of time, or the carrier is a solvent or solvent system to produce an injectable suspension or dispersion.

61. A method for treating a patient's disease / condition, the method comprising incorporating the biodegradable microparticles described in any one of claims 1 to 43 into a hydrogel, organogel or xerogel, wherein the hydrogel, organogel or xerogel is formed in situ at the treatment site of the patient or pre-formed and delivered or implanted at the treatment site to release the active agent over a long period of time.

62. A method for treating a patient's disease / condition, the method comprising administering to the patient a hydrogel, organogel, or xerogel containing biodegradable microparticles according to any one of claims 1 to 43, in order to release the drug over a long period of time.

63. A system or method for use according to any one of claims 53 to 62, wherein the treatment site is selected from the anterior chamber, vitreous humor, episclera, posterior sub-Tenon's space (inferior fornix), subconjunctiva, intraocular, periocular, posterior, sub-Tenon's space, retina, subretinal, intracanaliculi, intravitreous, intrascleral, intrachoroidal, suprachoroidal, retina, subretinal, or lens, corneal or conjunctival surface, lacrimal punctum (canaliculi, superior / inferior canaliculi), palpebral fornix, superior / inferior palpebral fornix, sub-Tenon's space, choroid, suprachoroidal, Tenon, cornea, cancerous tissue, organs, prostate, breast, joints, subdural, teeth, subcutaneous, carpal tunnel, perivascular, surgically formed spaces or injuries, cavities, and latent cavities.

64. The disease / condition to be treated is an eye disease, such as any posterior segment eye disease affecting the vascular system and integrity of the retina, macula, or choroid and causing visual impairment, vision loss, or blindness, in particular age, trauma, surgical intervention, such as age-related macular degeneration (AMD), cystoid macular edema (CME), diabetic macular edema (DME), posterior uveitis, and diabetic retinopathy; or a posterior segment disease condition resulting from glaucoma, ocular hypertension, anterior chamber hemorrhage, presbyopia, cataract, retinal vein occlusion, inflammation, etc., according to any one of claims 53 to 62.

65. A method for controlling the release of an active agent from a sustained-release biodegradable drug delivery system according to any one of claims 53 to 60, by any one of the following means or combination thereof, or a method manufactured according to the method according to any one of claims 44 to 52: - Selecting the L / G ratio of the polylactic acid-glycolic acid copolymer (PLGA) units to adjust the hydrophobicity of the polymer matrix forming the fine particles; - Selecting the L / G ratio of the polylactic acid-glycolic acid copolymer (PLGA) unit to result in the sustained release of the active agent from the fine particles; - Selecting the molar ratio of the amounts of the first crosslinkable precursor and the second crosslinkable precursor in order to adjust the hydrophobicity of the polymer matrix forming the fine particles; - Selecting the molar ratio of the first crosslinkable precursor to the second crosslinkable precursor so that the active agent is continuously released from the fine particles; - Selecting the amount and / or particle size of the biodegradable microparticles contained in the hydrogel, organogel, or xerogel; - Adding a third crosslinkable precursor having lower hydrolysis properties than the first and second crosslinkable precursors, and optionally changing the molar ratio of the first, second and / or third precursors when forming the biodegradable fine particles; - Dispersing an active agent having high water solubility in particulate form within the biodegradable microparticle organogel.

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