Organogels for sustained drug delivery, methods of preparation and uses thereof

Abstract

In certain embodiments, the present invention relates to a sustained release biodegradable drug delivery system comprising an organogel comprising a hydrophobic organic liquid and a biodegradable covalently cross-linked polymer network, and an active agent, wherein the hydrophobic organic liquid and the active agent are contained in the biodegradable, covalently cross-linked polymer network. In other embodiments, the present invention relates to a pharmaceutically acceptable biodegradable drug delivery system, such as an implant for controlled release of therapeutic or diagnostic active agents, and methods of making the same. The invention also relates to corresponding therapeutic methods and uses, as well as kits.

Description

Technical Field

[0001] In certain embodiments, the present invention relates to a sustained release biodegradable drug delivery system, which comprises an organogel and an active agent, wherein the organogel comprises a hydrophobic organic liquid and a biodegradable covalently cross-linked polymer network, wherein the hydrophobic organic liquid and the active agent are contained in a biodegradable covalently cross-linked polymer network. Specifically, the present invention relates in certain embodiments to a pharmaceutically acceptable biodegradable drug delivery system, such as an implant for the controlled release of a treatment or diagnosis active agent, and a method for manufacturing the same. The present invention also relates in certain embodiments to corresponding methods of treatment and uses, and a kit. Background Art

[0002] Although organogels (or oleogels) have been known for decades, biomedical interest in organogels has only recently developed. Organogels consist of a continuous liquid phase (usually a solvent or oil) contained in a three-dimensional network. Organogels allow for the embedding of a wide variety of therapeutic compounds, which makes them useful as drug delivery platforms. In order to be considered for pharmaceutical applications, organogels need to be biocompatible.

[0003] Controlled delivery of therapeutic agents has been a major area of ​​research in recent years. Controlled delivery improves therapy, facilitates administration, and leads to better compliance, fewer side effects, and better treatment outcomes.

[0004] Another approach to drug release control is to change the chemical composition of the drug by preparing prodrugs with different solubility that convert back to the parent drug after release from the hydrogel. This approach provides feasible control of release kinetics but requires additional synthesis steps and associated testing requirements. In addition, the slow rate of conversion of the prodrug to the parent drug may cause undesirable effects when released into the tissue.

[0005] The sustained delivery of hydrophilic drug compounds from hydrogel-based implants or inserts is often too fast or too slow for the desired duration of treatment. This is because the rate of drug release from water-based hydrogels increases with increasing water solubility. It is desirable to eliminate solubility limitations. Therefore, there is a need to provide a drug delivery system that allows controlled release of active agents regardless of their solubility in physiological fluids. Summary of the invention

[0006] It is an object and an aspect of certain embodiments of the present invention to provide a pharmaceutically acceptable biodegradable drug delivery system such as an implant for sustained release of an active ingredient into a patient's body.

[0007] Another object and aspect of certain embodiments of the present invention is to provide a method for making such a biodegradable drug delivery system.

[0008] Another object and an aspect of certain embodiments 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.

[0009] Another object and an aspect of certain embodiments of the present invention is to provide methods for treating a disease / medical condition in a patient using a sustained release biodegradable drug delivery system.

[0010] Another object and an aspect of certain embodiments of the present invention is to provide a kit comprising one or more sustained-release biodegradable drug delivery systems.

[0011] Some aspects of the present disclosure relate to a sustained-release biodegradable drug delivery system comprising an organogel and an active agent, the organogel comprising a hydrophobic organic liquid and a biodegradable covalently cross-linked polymer network, wherein the hydrophobic organic liquid and the active agent are contained (e.g., immobilized) in the biodegradable covalently cross-linked polymer network.

[0012] In some aspects of the present disclosure, the active agent is dissolved or dispersed in the hydrophobic organic liquid within the organogel. In other aspects, the active agent is the same as or forms at least a part of the hydrophobic organic liquid, i.e., the hydrophobic organic liquid comprises, consists of, or consists essentially of the active agent and optionally one or more pharmaceutically acceptable excipients.

[0013] In some aspects of the present disclosure, the biodegradable covalently cross-linked polymer network comprises one or more polymer units of polyethylene glycol, polyethylene oxide, polypropylene oxide, polyvinyl alcohol, poly(vinyl pyrrolidone), polylactic acid (PLA), polyglycolic acid (PGA), polylactic-co-glycolic acid (PLGA), p-dioxanone, trimethylene carbonate, caprolactone, random or block copolymers of any of these, and / or combinations or mixtures thereof, or one or more units of polyamino acids, glycosaminoglycans, polysaccharides, or proteins, or combinations or mixtures of any of these.

[0014] In some aspects of the present disclosure, the biodegradable covalently cross-linked polymer network comprises a plurality of hydrophobic polymer units such as polylactic acid (PLA), polypropylene glycol units or polyglycolic acid (PGA) and polylactic acid-co-glycolic acid (PLGA) units, and / or hydrophilic polymer units such as polyethylene glycol units, polyvinyl alcohol, poly(vinyl pyrrolidone), polyethylene imine. In certain embodiments, the hydrophobic polymer units include polyethylene glycol units.

[0015] In some aspects of the disclosure, the polymer network is covalently cross-linked via hydrolyzable bonds between polymer units.

[0016] In some aspects of the present disclosure, the polymer network is formed by at least two multi-arm precursors (e.g., precursors of 2 to 10 arms), the multi-arm precursors include a first multi-arm precursor comprising a first functional group and a second multi-arm precursor comprising a second functional group, the functional group is located at the end of the arm, in certain embodiments, each of the first functional group and the second functional group is selected from the group consisting of an electrophile and a nucleophile, and the reaction between the first functional group and the second functional group is an electrophile-nucleophile reaction forming a covalent bond. In certain embodiments, the cross-linked covalent bonds so formed are hydrolyzable under physiological conditions.

[0017] In some aspects of the present disclosure, the active agent is selected from at least one of a therapeutically active agent or a diagnostically active agent, or a combination thereof.

[0018] In some aspects of the present disclosure, the choice of hydrophobic liquid and / or the hydrophobicity of the polymer network and / or the molar ratio of lactide to glycolide (L / G ratio) are used to modulate the release rate.

[0019] In some aspects of the present disclosure, the release of the active agent of a therapeutically effective amount is provided for a certain period of time after administration, such as 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. In other embodiments, the time period is at least about 25 days, at least one month, at least 3 months, at least 6 months, at least 9 months, or at least 1 year. In other embodiments, the time period is about 25 days, about 1 month, about 3 months, about 6 months, about 9 months, or about 12 months. Any one of about 12 months, about 9 months, about 6 months, about 3 months, about 1 month, or about 25 days. In other aspects of the present disclosure, the release of the active agent of a therapeutically effective amount is provided for a certain period of time after administration, such as up to three weeks, up to 2 weeks, up to 10 days, up to 9 days, 8 days, 7 days, 6 days, 5 days, 4 days, or 3 days, or up to about 1 day.

[0020] In some aspects of the present disclosure, the organogel delays the release of water-soluble active agents, or accelerates the release of hydrophobic active agents.

[0021] In some aspects of the present disclosure, the organogel comprises from about 1 wt % to about 90 wt % of a hydrophobic organic liquid; from about 5 wt % to about 95 wt % of a covalently cross-linked polymer network; from about 1 wt % to about 50 wt % of an active agent; wherein all weight percentages are selected to total 100%, the weight % being based on the total weight of the finished drug delivery system.

[0022] Some aspects of the present disclosure relate to a method of making a sustained-release biodegradable drug delivery system according to any one of the preceding claims, the method comprising the steps of: forming an organogel from at least a covalently cross-linked polymer network, a hydrophobic organic liquid, optionally a solvent, and at least one active agent, wherein the hydrophobic organic liquid and the active agent are contained in the biodegradable covalently cross-linked polymer network; and shaping the organogel as a separate step or as part of the forming step; and optionally removing the solvent from the organogel.

[0023] In some aspects of the present disclosure, the hydrophobic liquid is selected to tailor the hydrophobicity of the polymer network and / or to provide sustained release of the active agent.

[0024] In some aspects of the present disclosure, the step of forming the organogel comprises molding or extruding the reaction mixture before the organogel is completely gelled, gelling the mixture, and optionally removing the solvent.

[0025] Some aspects of the present disclosure relate to a sustained-release biodegradable drug delivery system for coating or use as a medical implant.

[0026] In some aspects of the present disclosure, the drug delivery system is for administration by a variety of different routes, such as orally, parenterally (eg, subcutaneously or intramuscularly), or by surgical insertion or injection.

[0027] Some aspects of the present disclosure relate to a biodegradable drug delivery system for sustained release of a pharmaceutical agent.

[0028] Some aspects of the present disclosure relate to a sustained-release biodegradable drug delivery system for treating a disease / medical condition in a patient, the method comprising forming an organogel comprising a therapeutically active agent dispersed in a hydrophobic organic liquid contained in a covalently cross-linked polymer network, wherein the organogel is formed in situ at a treatment site in a patient, or is preformed and delivered to or implanted at a treatment site in a patient, so as to release the active agent over an extended period of time.

[0029] Some aspects of the present disclosure relate to a method for treating a disease / medical condition in a patient, the method comprising forming an organogel comprising a therapeutically active agent dispersed in a hydrophobic organic liquid contained in a covalently cross-linked polymer network, wherein the organogel is formed in situ at a treatment site in the patient, or is preformed and delivered to or implanted at the treatment site so as to release the active agent over an extended period of time.

[0030] Some aspects of the present disclosure relate to a method for treating a disease / medical condition in a patient, the method comprising administering to the patient an organogel to release a therapeutically active agent over an extended period of time, the organogel comprising the active agent dispersed in a hydrophobic organic liquid contained in a covalently cross-linked polymer network.

[0031] Some aspects of the present disclosure relate to a method for controlling the release of an active agent from a sustained release biodegradable drug delivery system by selecting a combination of a hydrophobic organic liquid (e.g., oil) and the active agent dispersed therein, wherein any one or a combination of the following criteria apply:

[0032] a) the active agent dispersed in the hydrophobic liquid is released from the organogel together with the hydrophobic organic liquid (e.g., oil);

[0033] b) The active agent is eluted from the oil directly into the body.

[0034] Some aspects of the present disclosure relate to a method for controlling the release of an active agent from a sustained-release biodegradable drug delivery system by any one or a combination of the following measures (two or more steps performed in any order or simultaneously):

[0035] a) selecting the L / G ratio of polylactic-co-glycolic acid (PLGA) units to adjust the hydrophobicity of the polymer network;

[0036] b) selecting the L / G ratio of the polylactic-co-glycolic acid (PLGA) units to provide sustained release of the active agent as defined herein;

[0037] c) selecting a molar ratio of the amount of the first crosslinkable precursor to the amount of the second crosslinkable precursor to adjust the hydrophobicity of the polymer network;

[0038] d) selecting a molar ratio of the amount of the first cross-linkable precursor to the amount of the second cross-linkable precursor to provide a sustained release of the active agent as defined herein;

[0039] e) selecting the type of hydrophobic liquid to be contained in the organogel;

[0040] f) adding a third crosslinkable precursor having a lower hydrolyzability than the first and second crosslinkable precursors, optionally varying the molar ratio of the three precursors

[0041] g) Dispersing the active agent with high water solubility in the form of particles into the hydrophobic phase.

[0042] Some aspects of the present disclosure relate to a kit comprising one or more sustained-release biodegradable drug delivery systems or portions thereof as described herein and instructions for using the systems, and / or to a kit wherein portions of the drug delivery system are distributed over more than one separate container to form an organogel in situ at the site of application or treatment.

[0043] definition

[0044] As used herein, the term "biodegradable drug delivery system of sustained release" refers to an object containing an activating agent and, for example, administered to a patient's body as an implant, which retains a certain period of time in the patient's body while releasing the activating agent into the surrounding environment. The drug delivery system can be any predetermined shape (for example, rod-shaped, spherical, oblate, elliptical, disc-shaped, tubular, hemispherical or irregularly shaped) before insertion or application, and when the system enters the desired position, the shape can be maintained to a certain extent, but after application, the size (for example, length and / or diameter) of the system may change due to hydration and / or biodegradation, as further disclosed herein. The drug delivery system can be designed to be biodegradable over time (as disclosed below), therefore it can soften, change its shape and / or reduce size, and can eventually be eliminated by dissolving or disintegrating.

[0045] The term "biodegradable" refers to a material or object (such as a drug delivery system according to the present invention) that degrades in vitro (i.e., when placed in a human or animal body) or when immersed in an aqueous solution under physiological conditions (such as 37°C, pH 7.2-7.4). In the context of the present invention, as disclosed in detail below, a drug delivery system comprising an organogel containing an active agent slowly (bio)degrades over time once applied or deposited in a human or animal body. In certain embodiments, biodegradation occurs at least in part by ester hydrolysis in an aqueous environment in vivo. Biodegradation may occur by hydrolysis or enzymatic cleavage of covalent crosslinks / bonds between precursors and / or within polymer units of the precursors themselves. The drug delivery system slowly softens and disintegrates, thereby being cleared by physiological pathways. In certain embodiments, the organogel of the present invention maintains its shape over an extended period of time (e.g., about 1 month, 3 months, or 6 months or longer). In certain embodiments, the shape is maintained due to covalent crosslinking of the polymer components forming the organogel, for example, until the active agent, or at least a major amount thereof (e.g., at least 50%, at least 75%, or at least 90%), has been released.

[0046] An "organogel" in the present invention is a solid or semisolid system that forms a covalently crosslinked three-dimensional network of one or more hydrophilic or hydrophobic natural or synthetic polymers (as disclosed herein), including a hydrophobic organic liquid disclosed herein. Therefore, in the present invention, "organogel" is limited to so-called chemical organogels, in which the intermolecular interactions between the molecules of the organogelator are chemical bonds (e.g., covalent bonds) formed during gelation by chemical reactions that induce crosslinking. As used herein, "organogel" refers to a three-dimensional polymer network of at least two precursors / gelators that are covalently crosslinked to each other in the presence of a hydrophobic organic liquid and optionally an organic solvent, and contains a hydrophobic organic liquid contained within the covalently crosslinked polymer network.

[0047] The term "polymer network" describes a structure formed by polymer chains (having the same or different molecular structures and the same or different molecular weights) that are covalently cross-linked to each other. 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".

[0048] The term "amorphous" refers to a polymer or polymer network that does not exhibit a melting point or a crystalline structure in X-ray or electron scattering experiments.

[0049] The term "semicrystalline" refers to a polymer or polymer network that has some crystalline characteristics (ie, exhibits a melting point or some crystalline properties in X-ray or electron scattering experiments).

[0050] The term "precursor" or "gelling agent" or "component" refers herein to those molecules or compounds that react with each other and thus connect via covalent crosslinks to form a polymer network and thus form an organogel matrix. Although other materials may be present in the organogel, such as active agents, hydrophobic liquids or solvents, they are not referred to as "precursors".

[0051] The parts of the precursor molecules that are still present in the final polymer network are also referred to herein as "units". Thus, a "unit" is a building block or component of the polymer network that forms the organogel. For example, a polymer network suitable for use in the present invention may comprise the same or different polyethylene glycol units, PLGA units, or other types of polymers as further disclosed herein.

[0052] As used herein, the term "release" (and thus the terms "released", "releasing", etc.) refers to the provision of an active agent from a drug delivery system (such as an implant of the present invention) to a surrounding environment. The surrounding environment can be an in vitro or in vivo environment as described herein. In certain specific embodiments, the surrounding environment is vitreous humor and / or ocular tissue, such as the retina and choroid.

[0053] The term "100% release of the active agent" should be interpreted as 95% to 100%. The way to achieve this controlled release is through a number of parameters that are characteristic of the drug delivery system as disclosed herein. Each such characteristic feature of the drug delivery system can be responsible for controlled release alone or in combination with each other.

[0054] For the purposes of the present invention, the term "sustained release" is intended to characterize a product that is formulated so that the active agent is available over an extended period of time, thereby allowing a reduction in dosing frequency compared to an immediate release dosage form, such as an active agent solution applied topically to the eye (i.e., eye drops). Other terms that may be used interchangeably with "sustained release" herein are "extended release" or "controlled release". Within the meaning of the present invention, the term "sustained release" includes constant active agent release, gradually decreasing active agent release, gradually increasing active agent release, and any combination thereof, such as constant active agent release followed by gradually decreasing active agent release. Within the meaning of the present invention, the term "gradually decreasing" or "gradually decreasing" refers to a decrease in active agent release over time. Specifically, the term "sustained release" refers to the release of an active agent from a drug delivery system in a predetermined manner, and is contrary to immediate release such as a bolus. Controlled release refers to the amount of active agent released within the total number of days required for 100% release of an active agent in an aqueous solution under in vitro physiological conditions, such as at pH 7.2-7.4 and 37°C.

[0055] The term "extended period of time" as used herein refers to any period of time that one of ordinary skill in the art would recognize as prolonged relative to treating a disease, and particularly refers to a period of time such as at least about 1 week or at least about 1 month, or longer, such as up to about 12 months, or any intermediate period of time, 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 as otherwise disclosed herein.

[0056] "Zero order" release or "substantially zero order" release or "near zero order" release is defined as a relatively straight line in a graphical representation of the percentage of active agent released versus time. In certain embodiments of the invention, substantially zero order release is defined as the ratio of the amount of active agent released to the elapsed time being within 20%.

[0057] The terms "API", "active (pharmaceutical) ingredient (ingredient)", "active (pharmaceutical) agent", "active (pharmaceutical) principle (principle)", "(active) therapeutic agent", "active substance" and "drug" are used interchangeably herein and refer to substances used in finished pharmaceutical products (FPP) and substances used in the preparation of such finished pharmaceutical products, which are intended to provide pharmacological activity or otherwise have a direct effect in the diagnosis, cure, mitigation, treatment or prevention of disease, or have a direct effect in restoring, correcting or modifying the physiological function of a patient.

[0058] The activating agent used according to the present invention can be an activating agent for treating and / or preventing a disease or condition, or a diagnostic agent such as a marker. In one embodiment of the invention, the activating agent is a low water-soluble activating agent (i.e., a solubility in water of less than about 1000 μg / mL or less than about 100 μg / mL). In other embodiments of the present invention, the activating agent is a highly water-soluble activating agent (i.e., a solubility in water of greater than about 1000 μg / mL or even greater than 10 mg / mL). This definition does not rely on the agent approved by a government agency.

[0059] For the purposes of the present invention, an active agent in all possible forms thereof may be used, including free acid, free base, polymorph or any pharmaceutically acceptable salt, anhydrous, hydrate, co-crystal, other solvate or derivative, such as prodrug or conjugate. Whenever an active agent is mentioned without further explanation in this specification or in the claims, even if it is not explicitly stated, it also refers to an active agent in the form of any such polymorph, pharmaceutically acceptable salt, anhydrous, solvate (including hydrate) or derivative thereof. With regard to active agents, suitable solid forms include but are not limited to pure substance forms in any physical form known to those of ordinary skill in the art. For example, the active agent may be in the form of particles. The particles may be amorphous or crystalline, or present a mixture of two forms, and may be prepared to have any size, which may be, but is not limited to, classified as coarse particles, fine particles or ultrafine particles, whose size may be particularly visible to the naked eye or visible under a microscope, and have a shape such as a single crystal and / or agglomerate. The particles may also be micronized. As used herein, the term "micronization" refers to small-sized particles, particularly those of microscopic dimensions, which are reduced in particle size without limitation by, for example, jet milling, jaw crushing, hammer milling, wet milling, precipitation in a non-solvent, cryogenic grinding (grinding with liquid nitrogen or dry ice), and ball milling. The active agent may also be present in a dissolved or dispersed state, for example, in a solvent or in an aqueous medium, for example, in the form of particles dispersed in an oil or a compatible aqueous suspension that may optionally include additional excipients such as surfactants.

[0060] As used herein, the term "therapeutically 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, a desired therapeutic outcome would be a reduction in symptoms associated with DED, for example, as measured by in vivo tests known to those of ordinary skill in the art, such as an increase in the Schirmer's tear test score; a decrease in staining values, such as measured by conjunctival lissamine green staining or corneal fluorescein staining; a decrease in dry eye severity and / or dry eye frequency scores on a visual analog scale (VAS); a decrease in the ocular surface disease index and / or standard patient dry eye assessment scores and a decrease in best corrected visual acuity. In one embodiment, "therapeutically effective" refers to the amount of active agent in a sustained release intratubular insert that is capable of achieving a tear concentration comparable in terms of therapeutic effect to a cyclosporine concentration of 0.236 μg / mL (which is believed to be necessary for immunomodulation, Tang-Liu and Acheampong, Clin. Pharmacokinet. 44(3), pp. 247-261)) over an extended period of time (and specifically, once such tear concentration is achieved, for substantially the entire remaining wear period of the insert).

[0061] As used herein, the values ​​"d10", "d50", "d90" and "d100" refer to values ​​that characterize the proportion of particles that meet a certain particle size in a particle size distribution. In a given particle size distribution, 10% of the particles present a particle size of d10 or less, 50% of the particles present a particle size of d50 or less, 90% of the particles present a particle size of d90 or less, and substantially all particles present a particle size of d100 or less. The percentages can be given by different parameters known to those of ordinary skill in the art, for example, the percentages can be based on the volume, weight or number of particles. Thus, d50 can be illustratively a median particle size based on volume, weight or number. For example, a volume-based d90 of 43 μm means that 90% of the particles by volume 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 of ordinary skill in the art, and include sieving methods and laser diffraction methods. In certain embodiments, PSD is measured according to USP <429> Optical diffraction measurement of particle size, measured by laser diffraction. In certain embodiments, PSD is measured by laser diffraction using a Beckman Coulter LS 13 320 based on the optical model "Fraunhofer.rf780z" with an obscuration value in the range of 7% to 9%.

[0062] The term "patient" herein includes human and animal patients. Therefore, the biodegradable drug delivery system according to the present invention is suitable for human or veterinary drug applications. Generally speaking, a "subject" is a (human or animal) individual to whom the drug delivery system according to the present invention is applied. A "patient" is a subject who needs treatment due to a specific physiological or pathological condition. A "patient" does not necessarily have a diagnosis of a specific physiological or pathological condition before receiving the drug delivery system.

[0063] The molecular weight of the polymer precursor as disclosed herein and used for the purpose of the present invention can be measured by analytical methods known in the art. The molecular weight of polyethylene glycol can be measured by any method known in the art, such as SDS-PAGE (sodium dodecyl sulfate-polyacrylamide gel electrophoresis), gel permeation chromatography (GPC) (including GPC with static light scattering detector (SLS) or dynamic light scattering (DLS)), liquid chromatography (LC) and mass spectrometry, such as matrix-assisted laser desorption / ionization time of flight (MALDI-TOF) spectrometry or electrospray ionization (ESI) mass spectrometry. The molecular weight of a polymer (including a polyethylene glycol precursor as disclosed herein) is an average molecular weight (based on the molecular weight distribution of a polymer), and therefore can be represented by various average values, including weight average molecular weight (Mw) and number average molecular weight (Mn). In the case of cross-linkable polymer gelling agents (such as polyethylene glycol, PLGA and poloxamer-based precursors) as used in the present invention, the molecular weight indicated herein is the number average molecular weight (Mn) measured by gel permeation chromatography using polystyrene standards according to standard methods known in the art. Typically, the material purchased, especially the multi-arm precursor, has a specific molecular weight defined by the supplier. Suitable PEG precursors, for example, can be obtained from many suppliers such as Jenkem Technology, Sinopeg, Sigma-Aldrich, etc.

[0064] The term "Day 1" as used herein refers to the time point immediately following "Day 0." Therefore, whenever "Day 1" is used, it refers to a period of one day or about 24 hours that has passed after administration of the drug delivery system.

[0065] As used herein, the term "about" with respect to a measurand refers to the normal variation in that measurand that one of ordinary skill in the art would expect when making the measurement and exercising a degree of care commensurate with the purpose of the measurement and the precision of the measuring device.

[0066] The term "at least about" with respect to a measurand refers to the normal variation in the measurand that one of ordinary skill in the art would expect when making the measurement and exercising a degree of care commensurate with the purpose of the measurement and the precision of the measuring equipment, as well as any amount above that normal variation.

[0067] The term "mean" as used herein refers to a central value or typical value in a group of data (points), which is calculated by dividing the sum of the data (points) in the group by their number (ie, the mean of a group of data).

[0068] As used herein, the singular form "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0069] The term "and / or" as used herein in phrases such as "A and / or B" is intended to include both "A and B" and "A or B."

[0070] Open-ended terms such as "include," "including," "contain," "containing," etc. mean "comprising." These open transition phrases are used to introduce an open list of elements, method steps, etc., which do not exclude additional, unrecited elements or method steps.

[0071] When the term "at most" is used herein with a certain value or number, it is intended to include the corresponding value or number.

[0072] The terms "from A to B", "of from A to B" and "of A to B" are used interchangeably herein and all refer to a range from A to B, including upper and lower limits A and B.

[0073] Throughout this disclosure, various aspects of the present invention are presented in the form of ranges. It should be understood that the description in the form of ranges is only for convenience and brevity, and should not be interpreted as an unchangeable limitation to the scope of the present invention. Therefore, the description of the range should be considered to have clearly disclosed all possible sub-ranges and the individual numerical values ​​within the range. For example, a range description such as 1 to 6 should be considered to have clearly disclosed sub-ranges, such as 1 to 3, 1 to 4, 1 to 5, 2 to 4, 2 to 6, 3 to 6, etc., and individual numbers within the range, such as 1, 2, 3, 4, 5 and 6. Regardless of the breadth of the scope, this applies. The numerical range includes the numbers that limit the range and includes each integer within the limited range.

[0074] When the abbreviation "PBS" is used herein, it means phosphate buffered saline.

[0075] When the abbreviation "PEG" is used herein, it means polyethylene glycol.

[0076] When the abbreviation "PLGA" is used herein, it means poly(lactic-co-glycolic acid). If not otherwise indicated, it has a L / G ratio of 1:1 (50:50).

[0077] The term "hydrophobicity" or "lipophilicity" is defined as the property of a polymer or material having a low degree of water attraction or absorption, i.e., the material is repelled by large amounts of water. The term "hydrophilicity" or "lipophobicity" is in turn defined as the property of a material or polymer that attracts or has a strong affinity for water. Hydrophobicity can be measured by determining the contact angle of a droplet, preferably a droplet of water, formed on the surface of a solid polymer and / or gel. Furthermore, a hydrophobic organic liquid as used in the present invention is immiscible or at least not miscible with water.

[0078] The term "immobilized" as used herein refers to long-range immobility, rather than local mobility within a matrix, i.e., the hydrophobic liquid phase exists as a continuous phase within the polymer matrix and may only move slowly in vivo, i.e., it may slowly escape into body fluids over time.

[0079] The term "syneresis" describes the phenomenon whereby liquid (oil) separates out of a (organic) gel during its shrinkage. BRIEF DESCRIPTION OF THE DRAWINGS

[0080] Figure 1 The basic structure of organogels relative to hydrogels is illustrated.

[0081] Figure 2 This is a photograph of the organogel of Example 1.

[0082] Figure 3 is a graph of the in vitro release of the drug delivery systems of Examples 2A-2F.

[0083] Figure 4 is a graph of in vitro release of the drug delivery systems of Examples 3A-3D.

[0084] Figure 5 is a graph of in vitro release of the drug delivery systems of Examples 4A-4H.

[0085] Figure 6 is a graph illustrating the in vitro bupivacaine base release over time for some organogel formulations of Example 5.

[0086] Figure 7 is a graph illustrating the in vitro release of the travoprost organogel formulation of Example 6 over time at different doses and temperatures. DETAILED DESCRIPTION

[0087] In certain embodiments, the present invention provides a sustained release biodegradable drug delivery system comprising an organogel and an active agent, the organogel comprising a hydrophobic organic liquid and a biodegradable covalently cross-linked polymer network, wherein the hydrophobic organic liquid and the active agent are contained in the biodegradable covalently cross-linked polymer network. In certain embodiments, a sustained release biodegradable drug delivery system is provided, comprising an organogel and an active agent, the organogel comprising a hydrophobic organic liquid and a biodegradable covalently cross-linked polymer network, wherein the hydrophobic organic liquid and the active agent are fixed in the biodegradable covalently cross-linked polymer network.

[0088] In certain embodiments, the sustained-release biodegradable drug delivery system comprises at least three components: a biodegradable covalently cross-linked polymer network, a hydrophobic organic liquid, and an active agent.

[0089] In certain embodiments, the organogel is formed by polymerization of nonlinear, multifunctional monomers or polymer precursor components disclosed below, and forms a covalently cross-linked polymer network that includes a hydrophobic organic liquid and fixes it within the polymer network, for example until it is released from the network in vivo. Therefore, the organogel of the present invention is similar to a hydrophobic analog of a hydrogel that contains water instead of a hydrophobic organic phase. The organogel is similar to a hydrogel in that its matrix consists of a polymer component (gel factor) that forms a network and a non-reactive component. In a hydrogel, the non-reactive component is water, while in the organogel of the present invention, it is a hydrophobic organic compound, such as an oil, having a glass transition (Tg) and a melting (Tm) transition temperature below body temperature.

[0090] In certain embodiments, the covalent crosslinking of the precursors forming the polymer network provides limited mobility for the hydrophobic organic liquid (e.g., oil) component. This can provide continuous control of drug release by limiting the diffusion of drug transport through the organogel and / or eliminating the generation of defects that provide a rapid escape path for the drug. In certain embodiments, the drug delivery system of the present invention is a delivery system that is fully or partially diffusion-controlled, that is, the release of oil and / or active agent is mainly controlled by the diffusion process. Degradation of the polymer matrix may occur in the organogel of the present invention in addition, but does not mainly control the release of the active agent. In non-crosslinked gels such as extruded linear polymers, the release of the active agent is mainly controlled by the degradation of the polymer matrix, and the polymer matrix mainly releases the active agent in the degradation control system. The precursors forming the network should be miscible in the hydrophobic organic liquid component so that when crosslinked, it "holds" the component to produce a solid or semi-solid, thereby forming an organogel. In certain embodiments, the compatibility of the hydrophobic organic liquid with the polymer network has an impact on the rate at which the hydrophobic organic liquid escapes into the surrounding tissue fluid in vivo and can be gradually replaced by aqueous fluids, providing an additional method for controlling drug release kinetics to active agent solubility and network degradation.

[0091] In certain embodiments, in the biodegradable drug delivery system of sustained release of the present invention, using organogel therefore allows to change the release of active agent from drug delivery system by customizing or appropriately selecting the precursor components forming the cross-linked polymer network according to its hydrophilic and / or hydrophobic properties. In addition, in certain embodiments, the release of active agent from drug delivery system can be changed or controlled by appropriately selecting hydrophobic organic liquid according to the characteristic of hydrophobic organic liquid (such as hydrophobicity, viscosity, compatibility with active agent, solubility or insolubility of active agent in hydrophobic organic phase, etc.).

[0092] The organogel-based drug delivery systems of certain embodiments of the present invention provide several advantages over hydrogels. For example, certain organogels are anhydrous, so water-degradable (hydrolyzable) components such as water-sensitive active agents can be stable and stored stably over extended periods of time, and do not require hydration when implanted.

[0093] Water-soluble compounds have low solubility or are insoluble in organogels, allowing the drug to be incorporated as a particulate solid embedded in the organogels matrix. The low solubility of the drug in the organogels matrix provides a mechanism to control the rate of drug release. This property greatly increases the range of compounds that can be included in the implant.

[0094] Controlling the lipophilicity / hydrophilicity of organogels can be used to tune the release rate of drugs and influence diffusion rates. Pure hydrogels cannot be tuned in this way because they are water-based, so in these systems the drug itself must be modified to a prodrug form to adjust drug / matrix solubility. In organogels, this can be avoided. Furthermore, varying the lipophilicity / hydrophilicity of organogels can also be used to influence the degradation rate of the polymer matrix, which also has an additional effect on the release rate of the drug.

[0095] Organogels can be designed to slowly release hydrophobic organic liquids (such as oils) from the matrix in vivo, allowing for a slow conversion to a hydrogel followed by degradation. This provides a new mode of controlled drug release and increased biocompatibility.

[0096] The optional addition of solvents to the organogel can be used during the manufacturing process to overcome compatibility issues of the components, and the solvent can be removed to produce an organogel with fixed oil. Removal of the solvent can be accomplished by thermal treatment, which is not possible for materials that undergo melting or glass transitions at high temperatures. Solvent removal can also be accomplished by methods commonly used for non-crosslinked polymers such as water extraction, vacuum drying, freeze drying, evaporation, etc. The lack of the need for careful removal of the solvent greatly simplifies the manufacturing process.

[0097] In certain embodiments, the organogel has the physical qualities of low modulus, dimensional stability, and favorable drug release kinetics. In certain embodiments, the organogel can be dimensionally stable to heat and will not melt. Therefore, implant manufacturing processes such as hot melt extrusion can be used to form certain organogels of the present invention.

[0098] The drug delivery system of the present invention comprising an organogel can be used to deliver a variety of drugs, including steroids, non-steroidal anti-inflammatory drugs (NSAIDS), ocular hypotensive drugs, antibiotics, peptides or other drugs. The organogel can be used to deliver drugs and therapeutic agents, such as anti-inflammatory agents (e.g., diclofenac), analgesics (e.g., bupivacaine), calcium channel blockers (e.g., nifedipine), antibiotics (e.g., ciprofloxacin), cell cycle inhibitors (e.g., simvastatin), proteins or peptides (e.g., insulin), enzymes, anti-tumor agents, local anesthetics, hormones, angiogenic agents, anti-angiogenic agents, growth factors, antibodies, neurotransmitters, psychotropic drugs, anticancer drugs, chemotherapeutic drugs, drugs affecting reproductive organs, genes and oligonucleotides or other configurations, and viruses such as AAV for gene delivery. The rate of release from the organogel may depend on the properties of one or more of the active agent, the hydrophobic organic liquid, and the polymer network, as well as other possible factors including one or more of drug size, relative hydrophobicity, organogel density, organogel solids content, and the like.

[0099] The drug delivery system of the present invention can be in the form of an implant, a medical implant or a pharmaceutically acceptable implant, an implant coating or an oral dosage form.

[0100] Hydrophobic organic liquid / oil

[0101] Hydrophobic organic liquid can be used to change the release of activating agent from drug delivery system. One or more of its characteristics can be appropriately selected, such as hydrophobicity, viscosity, compatibility with activating agent, solubility or insolubility of activating agent in hydrophobic organic phase, etc., to control the release of activating agent from organogel. For example, when the biodegradable drug delivery system of sustained release of the present invention is an implant inserted in human body or an oral dosage form, the hydrophobic organic liquid can diffuse out from the organogel before the activating agent diffuses out from the hydrophobic organic liquid or simultaneously with the activating agent dissolved therein and enter the aqueous environment. For example, the release of hydrophobic drugs can be accelerated by co-diffusion with the oil from the organogel. If the activating agent is a water-soluble solid particle such as dispersed in the hydrophobic organic liquid, the organic liquid can be used to slow down the contact of aqueous environment with the activating agent and delay the leaching of the activating agent from the organogel.

[0102] In certain embodiments, the hydrophobic organic liquid is liquid at human body temperature, such as about 37°C or lower, 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 but non-solid appearance. In addition, for some hydrophobic organic liquids that undergo hydration in aqueous embodiments (such as body fluids), the melting point of the hydrated material at a certain temperature may be different from that of the non-hydrated material. In certain embodiments of the present invention, the hydrated form of such materials is liquid under those conditions as described above.

[0103] In one embodiment, the active agent is dissolved or dispersed in the hydrophobic organic liquid. In another embodiment, the active agent is or forms at least a part of the hydrophobic organic liquid.

[0104] In certain embodiments, the hydrophobic organic liquid is an oil, or comprises an oil or an oil mixture. It can be a biocompatible vegetable oil, synthetic oil or mineral oil, a liquid fatty acid or triglyceride composition, or a hydrophobic biodegradable liquid polymer, or a combination thereof.

[0105] In certain aspects of the present disclosure, the hydrophobic organic liquid is a biocompatible oil, which can be selected from the group consisting of triethyl citrate, acetyl triethyl citrate (ATEC), acetyl tributyl citrate (ATBC), α-tocopherol (vitamin E), α-tocopherol acetate; plant or vegetable 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 and its derivatives (Cremophor®), lipids that are liquid at 37°C or lower, such as saturated or unsaturated fatty acids, monoglycerides, diglycerides, triglycerides (Myglyols®), isopropyl myristate, phospholipids, glycerophospholipids, sphingolipids, sterols, prenols, polyketides, hydrophobic biodegradable liquid polymers (such as low molecular weight PLGA, PGA or PLA, etc.), low melting point waxes such as vegetable waxes, animal waxes or synthetic waxes, lanolin, jojoba oil or combinations thereof.

[0106] In certain aspects, the hydrophobic organic liquid is liquid at human body temperature and can have a glass transition temperature and / or a melting temperature of 45°C or less, or 37°C or less.

[0107] In certain embodiments, the hydrophobic organic liquid is non-volatile, non-toxic and / or biocompatible at 37° C. and ambient pressure, and / or is capable of being cleared from the implantation site, metabolized and / or eliminated from the body unchanged.

[0108] Polymer Network

[0109] In certain embodiments, the organogel of the biodegradable drug delivery system of the present invention comprises a covalently cross-linked polymer network formed by polymerization of multifunctional precursor components. In one embodiment, at least one precursor has a functionality equal to or greater than 3 in order to produce a three-dimensional (3D) polymer network, and is therefore non-linear.

[0110] In the organogel, the biodegradable covalently cross-linked polymer network may comprise one or more polymer units comprising polyalkylene oxides such as polyethylene glycol, polypropylene glycol, poly(ethylene glycol)-block-poly(propylene glycol) copolymers, poloxamers such as Tetronic ®, polyethylene oxide, polypropylene oxide; polyvinyl acetate, polyvinyl alcohol, poly(vinyl pyrrolidone), polylactic acid (PLA), polyglycolic acid (PGA), polylactic-co-glycolic acid (PLGA), p-dioxanone, trimethylene carbonate, caprolactone, random or block copolymers or combinations or mixtures of any of these, or one or more units of polyamino acids, glycosaminoglycans, polysaccharides or proteins, but this list is not intended to be limiting.

[0111] In one embodiment of the present invention, the hydrophobic polymer unit may include at least one poly(ethylene glycol)-block-poly(propylene glycol) copolymer, also known as a poloxamer, such as the commercially available Tetronic ® Poloxamer.

[0112] The biodegradable covalently cross-linked polymer network can be formed from a plurality of hydrophobic polymer units, or from a plurality of hydrophilic polymer units, or from a combination of hydrophobic and hydrophilic units. The polymer units can be selected to tailor the hydrophobicity and hydrophilicity of the organogel so as to adjust it to the properties of the hydrophobic organic phase and / or the active agent. This adjustment enables control of gel formation as well as the degradation behavior of the organogel.

[0113] In one embodiment of the invention, the hydrophobic polymer unit may include at least one of polylactic acid (PLA) and polylactic acid-co-glycolic acid (PLGA) units, preferably a copolymer of PEG and PLGA, and particularly preferably a block copolymer of multi-arm PEG and PLGA copolymers. The copolymer may be end-capped with a desired reactive group, and the molecular weight of PEG in the copolymer and the PEG / PLGA ratio may vary according to the desired hydrophobicity.

[0114] The hydrophilic polymer unit may be selected from at least one of a polyethylene glycol unit, a polypropylene glycol unit or polyglycolic acid (PGA). In one embodiment, the hydrophilic polymer unit comprises a polyethylene glycol unit.

[0115] Each of the polymer units can have 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.

[0116] In one aspect of the invention, the covalently cross-linked polymer network comprises a combination of a plurality of hydrophobic polymer units and a plurality of at least one hydrophilic polymer unit, wherein the hydrophobic polymer unit is selected from at least one of polylactic acid (PLA) and polylactic acid-co-glycolic acid (PLGA), and the hydrophilic polymer unit is selected from at least one of polyethylene glycol (PEG) units, polypropylene glycol (PPG) or polyglycolic acid (PGA) units. In one embodiment, the hydrophilic polymer unit includes a polyethylene glycol (PEG) unit.

[0117] In one embodiment, the polymer network comprises a combination of polylactic acid-co-glycolic acid (PLGA) units and polyethylene glycol (PEG) units. The ratio of polylactic acid-co-glycolic acid (PLGA) units to polyethylene glycol (PEG) units can be selected to be about 2.5:1 to about 1:2.5, or about 2:1 to about 1:2, or about 1:1.

[0118] When PLGA is used, the polylactic-co-glycolic acid (PLGA) units may have an L / G ratio (as % L or G units) ranging from 0:100 to 100:0, or 1:99 to 99:1, or 10:90 to 90:10, or 25:75 to 75:25, or 50:50.

[0119] In certain embodiments, in the organogel of the sustained release drug delivery system, the polymer network is covalently cross-linked by hydrolyzable bonds between polymer units, which facilitates in vivo biodegradation in an aqueous environment such as the human or animal body.

[0120] The hydrolyzable bonds may include bonds selected from the group consisting of amine, amide, carbamate, ester, anhydride, ether, acetal, ketal, nitrile, isonitrile, isothiocyanate or imine bonds and combinations thereof. These bonds are generally formed by polycondensation of appropriately functionalized gelling agents or precursors, respectively.

[0121] Precursor components

[0122] In certain embodiments, the polymer network of the organogel is formed from at least one covalently cross-linkable precursor that is miscible with, preferably soluble or dispersible in, a hydrophobic organic liquid, or optionally a mixture of a hydrophobic liquid and a solvent.

[0123] According to certain embodiments of the present invention, the organogel comprises a polymer network comprising at least two covalently cross-linked multi-armed precursors. In some embodiments, the organogel comprising a polymer network comprises at least two covalently cross-linked multi-armed precursors.

[0124] Thus, a precursor is always a "functional polymer" or "functional material", such as a crosslinking agent (e.g., having a low molecular weight), which is capable of participating in a crosslinking reaction with another precursor 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 a crosslinking reaction with a precursor to form a polymer network.

[0125] The precursor used in the present invention can be any polymer as long as it can react with another precursor in the presence of a hydrophobic organic liquid and is biocompatible. The polymer can be selected from biodegradable natural, semisynthetic, synthetic or biosynthetic polymers.

[0126] Natural polymers may include glycosaminoglycans, polysaccharides (eg dextran), polyamino acids and proteins or mixtures or combinations thereof. Semisynthetic polymers may be selected from carboxymethylcellulose or alkylcelluloses, such as methylcellulose (MC), ethylcellulose (EC).

[0127] In some aspects, synthetic precursors are used. Synthetic refers to molecules not found in nature or not normally found 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, by light and / or heat, and can be mediated by catalysts.

[0128] Generally, for the purposes of the present invention, one or more synthetic polymers from the group comprising polyalkylene glycols, such as polyethylene glycol (PEG), polypropylene glycol, poly(ethylene glycol)-block-poly(propylene glycol) copolymers, or polyethylene oxide, polypropylene oxide, polyvinyl alcohol, poly(vinyl pyrrolidone), polylactic acid (PLA), polylactic-co-glycolic acid (PLGA), para-dioxanone, trimethylene carbonate, caprolactone; one or more units of random or block copolymers or combinations / mixtures of any of these, without this list being intended to be limiting.

[0129] In some aspects of the invention, at least one cross-linkable precursor is hydrophobic or hydrophilic, and when two precursors are used, both can be hydrophobic, or both can be hydrophilic, or one can be hydrophobic and the other can be hydrophilic. For more than two precursors, any mixture of hydrophilic and hydrophobic precursors can be selected, depending on the desired properties of the polymer network. In addition, the precursor can be a copolymer incorporating both hydrophobic and hydrophilic substructures.

[0130] Precursor has functional groups that react with each other, that is, a first functional group that can react with a second functional group. Functional groups react with each other, for example, in electrophilic reagent-nucleophilic reagent reaction, or are configured to participate in other polyreactions. Therefore, the first functional group can be a nucleophilic reagent and the second functional group can be an electrophilic reagent, or vice versa. According to some embodiments of the present invention, every kind of precursor comprises at least two nucleophilic reagents or at least two electrophilic reagents.

[0131] Nucleophiles that may be used in the present invention may include amines (such as primary amines), hydroxyls, thiols, carboxyls, dibenzocyclooctynes, or hydrazides. In certain embodiments, at least one precursor comprises a nucleophile, such as a primary amine.

[0132] Electrophiles that can be used in the present invention may include succinimidyl esters, succinimidyl carbonates, nitrophenyl carbonates, aldehydes, ketones, acrylates, acrylamides, maleimides, vinyl sulfones, iodoacetamides, olefins, alkynes, azides, norbornenes, epoxides, mesylates, tosylates, trifluoroethanesulfonyls (tresyls), cyanurates, orthopyridyl disulfides or halides. These electrophiles include functional groups that participate in electrophile-nucleophile reactions and crosslink precursors, and they preferably include reactive groups in addition, and the reactive groups include hydrolyzable groups or bonds, such as glutarates. For example, in one embodiment of the invention, succinimidyl esters may include reactive groups, such as succinimidyl succinate (SS), succinimidyl glutarate (SG), succinimidyl adipate (SAP), succinimidyl azelate (SAZ) or succinimidyl glutaramide.

[0133] The term "multi-arm" precursor refers to a precursor that is branched, i.e., nonlinear. In the case of a multi-arm polymer, a core refers to a continuous portion of a molecule connected to an arm extending from the core, wherein the arm has a nucleophile or an electrophile, which is typically located at the end of the branch. The precursor may have, for example, 2-100 arms, each arm having an end, and it should be remembered that some precursors may be dendritic polymers or other highly branched materials such as dendritic polymers. The arm on the precursor refers to a linear chain of chemical groups that connect a crosslinkable group to a polymer core. Some embodiments are precursors with arms between 3 and 300; the technician will immediately appreciate that all ranges and values ​​within the clearly defined range are contemplated, for example, 4, 6, 8, 10, 12, 4 to 16, 8 to 100, 6, 8, 10, 12, or at least 4 arms.

[0134] In certain embodiments, a multi-arm precursor of the 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 a polymer unit and having a terminus.

[0135] In some embodiments, when each precursor is multi-arm, it comprises two or more arms, and therefore comprises two or more identical or different electrophiles or nucleophiles, such that each nucleophile can react with another electrophile (in the same precursor or another precursor) in an electrophilic-nucleophilic reaction to form a cross-linked polymer product. Thus, for example, in some aspects, a precursor has 4 arms, each of which terminates with a nucleophile or an electrophile that may be identical or different from its other arms.

[0136] According to one aspect of the present invention, organogel comprises at least two multi-arm precursors, and described multi-arm precursor comprises the first multi-arm precursor comprising nucleophile and / or electrophile and the second multi-arm precursor comprising nucleophile and / or electrophile.In this embodiment, the first multi-arm precursor and the second multi-arm precursor are covalently cross-linked to each other in electrophile-nucleophile reaction.In this context, multi-arm refers to at least 4 arms, at least 8 arms, such as at least 10 arms.

[0137] In one embodiment, if the organogel comprises two kinds of multi-arm precursors, it can comprise the first multi-arm precursor and the second multi-arm precursor, wherein the first multi-arm precursor comprises a nucleophile, such as an amine such as a primary amine, a thiol, a dibenzocyclooctyne or a hydrazide, and the second multi-arm precursor comprises an electrophile, such as a succinimide ester, a succinimide carbonate, a nitrophenyl carbonate, an aldehyde, a ketone, an acrylate, an acrylamide, a maleimide, a vinyl sulfone, an iodoacetamide, an alkene, an alkyne, azide, a norbornene, an epoxide, a mesylate, a toluenesulfonate, a trifluoroethanesulfonyl, a cyanurate, an adjacent pyridyl disulfide or a halide. In an electrophile-nucleophile reaction, a nucleophile and an electrophile are covalently cross-linked to each other. In some embodiments, the first multi-arm precursor is a primary amine, and the second multi-arm precursor is a succinimide ester.

[0138] According to some embodiments of the present invention, the organogel comprises at least two multi-arm precursors, and the multi-arm precursor comprises a first multi-arm precursor comprising a nucleophile and / or an electrophile and a second multi-arm precursor comprising a nucleophile and / or an electrophile. In this embodiment, the first multi-arm precursor and the second multi-arm precursor are covalently cross-linked to each other in an electrophile-nucleophile reaction. In this context, multi-arm refers to at least 4 arms, at least 8 arms, such as at least 10 arms.

[0139] In one embodiment, the organogel comprises at least two multi-arm precursors, and the multi-arm precursor comprises 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 to each other in an electrophile-nucleophile reaction. In this context, multi-arm refers to at least 4 arms, at least 8 arms, such as at least 10 arms. In this embodiment, the nucleophile can be an amine such as a primary amine, a thiol, a dibenzocyclooctyne or a hydrazide, and the electrophile can be a succinimidyl ester, a succinimidyl carbonate, a nitrophenyl carbonate, an aldehyde, a ketone, an acrylate, an acrylamide, a maleimide, a vinyl sulfone, an iodoacetamide, an alkene, an alkyne, azide, a norbornene, an epoxide, a mesylate, a tosylate, a trifluoroethanesulfonyl, a cyanurate, an adjacent pyridyl disulfide or a halide. For example, in one embodiment of the invention, the succinimide ester may comprise a reactive group such as succinimidyl succinate (SS), succinimidyl glutarate (SG), succinimidyl adipate (SAP), succinimidyl azelate (SAZ), or succinimidyl glutarate.

[0140] Some precursors may have a longer hydrolysis half-life than other precursors. This means that the time required for their degradation may be longer. This may be due in part to the reactive groups contained in the precursor. For example, a PEG polymer containing an electrophilic group (such as a succinimidyl ester group) containing a reactive group (such as succinimidyl glutarate (SG)) has a shorter hydrolysis half-life than a PEG polymer containing an electrophilic group (such as a succinimidyl ester group) containing a reactive group (such as succinimidyl glutarate (SG)).

[0141] In one embodiment, the organogel comprises two multi-arm precursors, and it 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 succinimide ester. In another embodiment, the organogel 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 succinimide 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).

[0142] In some embodiments, the precursor is a polyethylene glycol precursor. Thus, in some embodiments, the polymer network of the covalently cross-linked precursor is prepared by or includes at least one polyethylene glycol-containing precursor. Polyethylene glycol (PEG, also known as polyethylene oxide) refers to a polymer having a repeating group (CH2CH2O)n, wherein n is at least 3.

[0143] The polymer precursor with polyethylene glycol has at least three of these repeating groups interconnected in a linear series mode. The PEG polymer that does not participate in the cross-linking reaction between the precursors terminated with a hydroxyl or methoxy group is referred to as " non-functional PEG " as described above, and is therefore not used as one of precursors. Therefore, the PEG polymer terminated with a nucleophilic reagent selected from primary amine, mercaptan, dibenzocyclooctyne or hydrazide is considered to be " functional PEG ", and can be used as one of precursors. In addition, the PEG polymer terminated with an electrophilic reagent selected from succinimidyl ester, succinimidyl carbonate, nitrophenyl carbonate, aldehyde, ketone, acrylate, acrylamide, maleimide, vinyl sulfone, iodoacetamide, olefin, alkynes, azide, norbornene, epoxide, mesylate, toluenesulfonate, trifluoroethanesulfonyl, cyanurate, adjacent pyridyl disulfide or halide is considered to be " functional PEG ", and can be used as one of precursors.

[0144] The polymer network of the organogel drug delivery system of the present invention can comprise one or more multi-arm PEG units having 2 to 10 arms, or 4 to 8 arms, or 4, 5, 6, 7 or 8 arms. The PEG units can have different or the same number of arms. In certain embodiments, the PEG units used in the organogel of the present invention have 4 and / or 8 arms. In certain embodiments, a combination of 4-arm and 8-arm PEG units is utilized.

[0145] In certain embodiments of the present invention, the polyethylene glycol unit used as a precursor has a mean molecular weight in the range of about 1,000 to about 100,000 daltons, or in the range of about 10,000 to about 60,000 daltons, or in the range of about 15,000 to about 50,000 daltons. In certain embodiments, the polyethylene glycol unit has a mean molecular weight in the range of about 10,000 to about 40,000 daltons, or about 20,000 daltons. The PEG precursor of the same mean molecular weight can be used, or the PEG precursors of different mean molecular weights can be combined with each other. The mean molecular weight of the PEG precursor used in the present invention is given as a number-average molecular weight (Mn), and in certain embodiments, it can be measured by gel permeation chromatography relative to polystyrene standards according to a standardized method.

[0146] In a 4-arm PEG, each arm may have an average arm length (or molecular weight) of the total molecular weight of the PEG divided by 4. The 4a20kPEG precursor, which is a precursor that can be used in the present invention, thus has 4 arms, with an average molecular weight of about 5,000 Daltons for each arm. In addition to the 4a20kPEG precursor, the 8a20k PEG precursor that can be used in the present invention thus has 8 arms, with an average molecular weight of 2,500 Daltons for each arm. Thus, the 4a20K PLGA precursor has 4 arms, with an average molecular weight of about 5,000 Daltons for each arm.

[0147] When referring to a PEG precursor with a specific average molecular weight (such as a 15kPEG- or 20kPEG-precursor), the indicated average molecular weight (i.e., an Mn of 15,000 or 20,000, respectively) refers to the PEG portion of the precursor prior to the addition of the end groups ("20k" herein means 20,000 Daltons, and "15k" means 15,000 Daltons - the same abbreviations are used herein for other average molecular weights of PEG or other polymer precursors). In certain embodiments, the Mn of the PEG portion of the precursor is determined by gel permeation chromatography relative to polystyrene standards according to standardized methods. The degree of end group substitution as disclosed herein can be determined by H-NMR after end group functionalization.

[0148] In various embodiments of the invention, the organogel comprises at least two multi-arm precursors, the first precursor being a multi-arm PEG precursor comprising a nucleophile such as an amine (such as a primary amine). In some of these embodiments, the second multi-arm precursor is a multi-arm PEG precursor comprising an electrophile such as a succinimide ester. In other embodiments of these embodiments, the second multi-arm precursor is a multi-arm PLGA precursor comprising an electrophile such as a succinimide ester.

[0149] In some embodiments of the present invention, the organogel comprises three kinds of multi-arm precursors, and the first multi-arm precursor is a multi-arm PEG precursor comprising a nucleophile such as an amine (such as a primary amine). In this embodiment, the second multi-arm precursor is a multi-arm PEG precursor comprising an electrophile (such as a succinimide ester) comprising a first reactive group. In this embodiment, the third multi-arm precursor is a multi-arm PEG precursor comprising an electrophile (such as a succinimide ester) comprising a second reactive group. In this embodiment, the first reactive group and the second reactive group can be selected from succinimidyl succinate (SS), succinimidyl glutarate (SG), succinimidyl adipate (SAP) or succinimidyl azelate (SAZ). SS, SG, SAP and SAZ are all functionalized joints attached to a polymer comprising a reactive group consisting of the N-succinimidyl ester of the corresponding diacid, which has an ester group connection with a polymer that can be degraded by hydrolysis in water at the second acid of the diacid. In some embodiments, the first multi-arm precursor is succinimidyl succinate (SS) and the second multi-arm precursor is succinimidyl glutarate (SG).

[0150] Each and any combination of the PEG precursor containing electrophilic group and nucleophilic group disclosed herein can be used for preparing implant according to the present invention.For example, any 4-arm or 8-arm PEG precursor (for example, with the succinimide ester comprising SS, SG, SAP or SAZ reactive group) can be combined with any 4-arm or 8-arm PEG precursor (for example, with NH2 group or another nucleophilic agent).In addition, the PEG unit of the precursor containing electrophilic agent group and nucleophilic agent group can have the same or can have different mean molecular weights.

[0151] One such combination is a PEG amine precursor and two PEG succinimide ester precursors, one containing a SS reactive group and the other containing a SG reactive group. In certain embodiments, the inventors have found that by maintaining the molar ratio of PEG amine to PEG succinimide ester at about 1:1 and by varying the molar ratio of the reactive groups of the succinimide ester SS and SG, the time it takes for the polymer network to degrade in aqueous solution under physiological conditions can be controlled, but other ratios are also contemplated. The amount of PEG SS and SG to achieve a specific molar ratio of the two reactive groups can be calculated by a skilled artisan and is described below.

[0152] The amount of PEG amine and PEG ester (SS and SG) to be used is calculated by the stoichiometric equation of molar ratio and converting moles to grams. First, determine the reaction end group molar ratio between amine, succinimidyl succinate and succinimidyl glutarate. In the exemplary formulation, 4a20k PEG NH2, 4a20k PEG SS and 4a40k PEG SG are used. The molar ratio between amine and succinimidyl ester group is about 1: 1, and the molar ratio between SS and SG is about 80: 20. The final end group molar ratio between 4a20kNH2: 4a20k SS: 4a40k SG is about 1.0: 0.8: 0.2. Next, the mass amount is determined using the stoichiometric conversion of grams to moles and the stoichiometric conversion of moles to grams. The exemplary 4a20k SS calculation performed with the above molar ratio using 100g 4a20k NH2 is summarized below:

[0153]

[0154] Alternatively, the amount of PEG can be determined by calculating the "molecular weight between cross-links" (MWc) to arm length ratio. The MWc can be calculated by summing the average arm lengths of each multi-arm PEG precursor.

[0155]

[0156]

[0157] The arm length ratio is calculated by dividing the PEG arm length by the MWc. The amount of the multi-arm precursor can be determined by multiplying the arm length ratio of a particular multi-arm precursor by the total PEG batch size. An exemplary calculation of the amount of 4a20k PEG SS is outlined below, with a total batch size of 100 g PEG:

[0158]

[0159] Similar calculations can be performed for other types of polymers as described herein.

[0160] In certain embodiments, 4-arm PEG having an average molecular weight of about 20,000 Daltons and 4-arm PEG having an average molecular weight of about 40,000 Daltons can be used to form the polymer network and thereby form the organogel according to the present invention.

[0161] Thus, the first and / or second precursor may be a 4a20k precursor, where 4 represents an arm and 20k represents Mn. Thus, for example, the first, second and / or third precursor may be a 4a40k precursor. Thus, for example, the first and / or second precursor may be a 4a20k precursor, and the third precursor may be a 4a40k precursor.

[0162] If the polymer unit is PLGA instead of PEG, such a precursor may have the following exemplary structure of a pentaerythritol-derivatized core of 4a20K PLGA-NHS that is fairly hydrophobic and oil soluble:

[0163]

[0164] According to its name, this is a 4-arm PLGA, each PLGA unit has an Mn of about 5,000 Daltons, and the PLGA unit has a L / G ratio of 50:50 (i.e., 1:1), R together with the two carbonyl groups to which it is attached is part of a diacid linker derived from a saturated or unsaturated biocompatible organic diacid such as one of oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, maleic acid, fumaric acid, and NHS represents an N-hydroxysuccinimide electrophile as a functional group on the end of each arm. X is an integer and defines the number of lactic acid units, and y is an integer defining the number of glycolic acid units in the PLGA molecule. For 50:50 PLGA, x and y are equal. N is an integer defining the number of PLGA blocks, and for 50:50 PLGA, n is 1.

[0165] Another example of an electrophile functionalized PLGA precursor is 4a20K PLGA5050-SAP-NHS (x and y are about 15):

[0166]

[0167] In other embodiments, the multi-arm PLGA precursor can also be derived from ethylenediamine as the core instead of pentaerythritol.

[0168] In various embodiments of the present invention, the organogel comprises at least one multi-arm precursor comprising hydrophobic polymer units selected from polylactic acid (PLA) units and polylactic-co-glycolic acid (PLGA) units or combinations or (block) copolymers thereof. In such embodiments, the organogel comprises at least one cross-linking agent, preferably a small molecule amine, such as oil-soluble tris(2-aminoethyl)amine (TAEA) or trilysine.

[0169] In various embodiments of the present invention, the organogel comprises at least one multi-arm precursor comprising hydrophobic polymer units selected from polylactic acid (PLA) units and polylactic-co-glycolic acid (PLGA) units or a combination or (block) copolymer thereof and at least one additional multi-arm precursor comprising hydrophilic polymer units preferably selected from polyethylene glycol (PEG) and polyglycolic acid (PGA).

[0170] As mentioned above, polymer network is formed by at least two kinds of precursors, at least one of the precursors is a multi-arm precursor, and the first multi-arm precursor comprises the first functional group, and the second precursor is selected from a small molecule cross-linking agent or comprises the multi-arm precursor of the second functional group, and the functional group is located at the end of arm or molecule.In various embodiments of the present invention, each in the first functional group and the second functional group is selected from the group consisting of electrophilic reagent and nucleophilic reagent, and the reaction between the first functional group and the second functional group is the electrophilic reagent-nucleophilic reagent reaction that forms a covalent bond in the polymer network.

[0171] The nucleophile and electrophile are selected from the groups as defined herein before. In certain embodiments, the nucleophile is an amine group and the electrophile is an activated ester group.

[0172] Active Agent:

[0173] The active agent according to the invention may be a therapeutically active agent or a diagnostically active agent or a combination thereof. It may be a single active agent or multiple active agents.

[0174] For the purposes of the present invention, active agents include all possible forms thereof, including free acids, free bases, polymorphs, pharmaceutically acceptable salts, anhydrates, hydrates, other solvates, stereoisomers, crystalline forms, co-crystals, prodrugs, conjugates (e.g., pegylated compounds), complexes, and mixtures thereof. For the purposes of the present invention, all forms of active agents are intended to be pharmaceutically acceptable. As used herein, the term "salt" may include, but is not limited to, inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, etc.; organic acid salts such as formates, acetates, trifluoroacetates, maleates, tartrates, glutarates, etc.; sulfonates such as methanesulfonates, benzenesulfonates, p-toluenesulfonates, etc.; and metal salts such as sodium salts, potassium salts, cesium salts, etc.; alkaline earth metals such as calcium salts, magnesium salts, etc.; organic amine salts such as triethylamine salts, pyridinium salts, methylpyridinium salts, ethanolamine salts, triethanolamine salts, dicyclohexylamine salts, N,N'-dibenzylethylenediamine salts, etc. Any salt used herein is a pharmaceutically acceptable salt. As used herein, the term "co-crystal" refers to a combination of an active pharmaceutical ingredient (API) and one or more co-formers such as an acid (such as a carboxylic acid) in the same crystal lattice through non-covalent interactions such as hydrogen bonds, electrostatic interactions, π-π stacking, van der Waals interactions, etc. Therefore, a co-crystal is a multi-component solid. Cocrystals differ from salts in that the former consist only of neutral components, whereas the latter contain ionic components. Cocrystals can modify and, in certain cases and for certain applications, optimize the physicochemical properties of the API, e.g. with respect to stability, solubility, dissolution rate, mechanical properties, etc.

[0175] The therapeutically active agent used herein can be an immunosuppressant, a complement inhibitor (e.g., a CS inhibitor such as eculizumab or avacincaptad pegol), a steroid, an anti-inflammatory agent such as a steroidal and non-steroidal anti-inflammatory agent (e.g., a COXI or COX 2 inhibitor), an antiviral agent, an antibiotic, an anti-glaucoma agent, an anti-VEGF agent, an analgesic, a tyrosine kinase inhibitor, an integrin inhibitor, an IL-6 blocker, a reactive aldehyde species (RASP) inhibitor, a nitric oxide donor PgA, an antihistamine, a mast cell stabilizer, a rho kinase inhibitor, a plasma kallikrein inhibitor, a BCL-2 blocker, a semaphorin antagonist, an HtRA I blocker, an IGF-1 R inhibitor, a VEGF combination agent (multi-specific anti-angiogenic agent), and combinations thereof.

[0176] The therapeutically active agent may be a steroid; a nonsteroidal anti-inflammatory drug (NSAIDS) such as Diclofenac, Ibuprofen, Meclofenamate, Mefenamic A, Salsalate, Sulindac, Tolmetin, Ketoprofen, Diflunisal, Piroxicam, Naproxen, Etodolac, Flurbiprofen, Fenoprofen C, indomethacin, celecoxib, ketorolac, nepafenac; intraocular pressure reducing drugs; antibiotics such as ciprofloxacin; analgesics such as bupivacaine; calcium channel blockers such as nifedipine; cell cycle inhibitors such as simvastatin; proteins such as insulin; small molecule hydrophilic drugs, including carboxylates and amine salts; small molecule hydrophobic drugs, hydrophilic peptides and protein drugs, such as 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, non-steroidal anti-inflammatory drugs (NSAIDs), steroids, antibiotics, analgesics, calcium channel blockers, cell cycle inhibitors, chemotherapeutic agents, antiviral drugs, anesthetics, hormones, anticancer drugs, antitumor agents, etc., or any combination thereof.

[0177] In some embodiments, the steroid can be a corticosteroid, which can include hydrocortisone, loteprednol, cortisol, cortisone, prednisolone, methylprednisolone, dexamethasone, betamethasone, triamcinolone, aldosterone, fludrocortisone, budesonide, fluocinolone, mometasone, fluticasone, rimexolone, fluorometholone, beclomethasone, or flunisolide,

[0178] In some embodiments, NSAIDs may include diclofenac (e.g., diclofenac sodium), flurbiprofen (e.g., flurbiprofen sodium), ketorolac (e.g., ketorolac tromethamine), bromfenac, nepafenac, cyclooxygenase-1 (COX-1), and cyclooxygenase-2 (COX-2), isozymes, salicylates, propionic acid derivatives, acetic acid derivatives, enolic acid derivatives and anthranilic acid derivatives, acetylsalicylic acid, diflunisal, salsalate, ibuprofen, dexibuprofen, naproxen, fenoprofen, ketoprofen, dexketoprofen, oxaprozin, loxoprofen, indomethacin, tolmetin, sulindac, etodolac, aceclofenac, nabumetone, piroxicam, tenoxicam, lornoxicam, phenylbutazone, mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid, celecoxib, pharmaceutically acceptable salts thereof and combinations thereof.

[0179] In some embodiments, the active agent can be an analgesic selected from at least one of the following: acetaminophen, acetaminosalol, aminochlorthenoxazine, acetylsalicylic acid 2-amino-4-picolinic acid, acetylsalicylic acid, anileridine, benoxaprofen, benzylmorprune, 5-bromosalicylic acid acetic acid, bucetin, buprenorphine, butorphanol, utorphanol, capsaicin, cinchophen, ciramadol, clometacin, clonixin, codeine, desomorphine, dezocine, dihydrocodeine, dihydromorprune, dimepheptanol, dipyrocetyl, eptazocine, ethoxazene, ethylmorphine eugenol, floctaferune, fosfosal, glafenine, hydrocodone, hydromorphone, hydroxypethidine, ibufenac, p-lactophenetide, levorphanol, meptazinol, metazocine, metopon, morprune, nalbuphine, nicomorphine (nicomorphine), norlevorphanol, normorphine, oxycodone, oxymorphone, pentazocine, phenazocine, phenocoll, phenoperidine, phenylbutazone, phenyl salicylate, phenylramidol, salicin, salicylamide, tiorphan, tramadol, diacerein, actarit, pharmaceutically acceptable salts thereof, and combinations thereof

[0180] In some embodiments, the IOP lowering agent and / or glaucoma medication can include a prostaglandin analog (e.g., bimatoprost, latanoprost, travoprost, or latanoprostene bunod), a rho kinase inhibitor (e.g., netarsudil), an adrenergic agonist (epinephrine or dipivefrin), a beta-adrenergic antagonist (also known as a beta blocker) (e.g., timolol, levobunolol, metipranolol, carteolol, or betaxolol), an alpha 2-adrenergic agonist (e.g., apraclonidine), or a combination of these agents. nidine, brimonidine or brimonidine tartrate), carbonic anhydrase inhibitors (e.g., brinzolamide, dichlorphenamide, methazolamide, acetazolamide, acetazolamide, or dorzolamide), pilocarpine, echothiophate, demercarium, physostigmine, and / or isofluorophate.

[0181] In some embodiments, anti-infective agents may include antibiotics, including ciprofloxacin, tobramycin, erythromycin, ofloxacin, gentamicin, fluoroquinolone antibiotics, moxifloxacin and / or gatifloxacin, aminoglycosides, penicillins, cephalosporins, fluoroquinolones, macrolides, and combinations thereof. Aminoglycosides may include tobramycin, kanamycin A, amikacin, dibekacin, gentamicin, sisomicin, netilmicin, neomycin B, neomycin C, neomycin E, streptomycin, paromomycin, pharmaceutically acceptable salts thereof, and combinations thereof. Penicillins may include:

[0182] Amoxicillin, ampicillin, bacampicillin, carbenicillin, cloxacillin, dicloxacillin, flucloxacillin, mezlocillin, nafcillin, oxacillin, penicillin G, penicillin V, piperacillin, pivampicillin, pivmecillinam, ticarcillin, pharmaceutically acceptable salts thereof, and combinations thereof. Cephalosporins may include: cefacetrile, cefadroxil, cefalexin, cefaloglycin, cefalonium, cefaloridine, cefalotin, cefapirin, cefatrizine, cefazaflur, cefazedone, cefazolin, cephradine, cefotaxime, cefotaxime, ceftizole, cefaclor, cefmandole, cefrnetazole, cefonicid, cefotetan, cefoxitin, cefprozil, cefuroxime, cefuroxime South, cefcaprine, cefdoxime, cefdinirb, cefditoren, cefditoren, ceftazidime, cefixime, cefmenoxime, cefodizime, cefotaxime, cefimizolin, cefpodoxime, cefditoren, ceftibuten, ceftiofur, ceftiolin, ceftizoxime, ceftriaxone, cefoperazone, ceftazidime, cefixime, cefepime, cefurox ... The invention can include ome, ceftobiprole, ceftaroline, cefuroxime, cefuroxime, cefoperazone, cefoperanil, cefdrol, cefoperazone, ceftriaxone, ceftriaxone, cefuroxime, cefinepidium, cefvectin, cefuroxime, cefuroxime, cefuroxime, cefuroxime, cefuroxime, pharmaceutically acceptable salts thereof and combinations thereof. Fluoroquinolones can include ciprofloxacin, levofloxacin, gatifloxacin, moxifloxacin, ofloxacin, norfloxacin, pharmaceutically acceptable salts thereof and combinations thereof. Macrolides can include azithromycin, erythromycin, clarithromycin, dirithromycin, erythromycin, telithromycin, pharmaceutically acceptable salts thereof and combinations thereof.

[0183] In some embodiments, the active agent can be selected from antiviral agents, including nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, fusion inhibitors, integrase inhibitors, nucleoside analogs, protease inhibitors, and reverse transcriptase inhibitors. Examples of antiviral agents include, but are not limited to, abacavir, aciclovir, acyclovir, adefovir, amantadine, amprenavir, ampligen, arbidol, atazanavir, boceprevir, cidofovir, darunavir, delavir, dine), didanosine, docosanol, edoxudine, efavirenz, emtricitabine, enfovirtide, eutecavir, famciclovir, fomivirsen, fosamprenavir, foscarnet, fosfonet, ganciclovir ciclovir), ibacitabine, imunovir, idoxuridine, imiquimod, iodinavir, inosine, type III interferon, type II interferon, type I interferon, interferon, lamivudine, lopinavir, loviride, maraviroc, moroxydine, methicillin, hisazone, nelfiuavir, nevirapine, nexavir, oseltamivir, peginterferon alfa-2a, penciclovir, peramivir, pleconaril, podophyllotoxin, raltegravir, ribavirin, rimantadine, ritonavir, pyramiding saquinavir, stavudine, tenofovir, tenofovir disoproxil fumarate,In some embodiments, the antiviral agent is one of ganciclovir, iodoxuridine, vidarabine, and / or trifluridine.

[0184] In some embodiments, the active agent can be selected from antifungal agents including amphotericin B, natamycin, voriconazole, fluconazole, miconazole, clotrimazole, ketoconazole, posaconazole, echinocandins, caspofungin and / or micafungin.

[0185] In some embodiments, antimetabolites may include methotrexate, mycophenolate, or azathioprine.

[0186] In some embodiments, the anti-fibrotic agent may include mitomycin C or 5-fluorouracil.

[0187] In some embodiments, angiogenesis inhibitors may include anti-VEGF agents (e.g., aflibercept, ranibizumab, bevacizumab, brolucizumab, conbercept), PDGF-B inhibitors (e.g., Fovista®), complement antagonists (e.g., eculizumab), tyrosine kinase inhibitors (e.g., axitinib, deucretinib, tinib), avapritinib, capmatiuib, pegimatiuib, ripretinib, selpercatinib, selumetinib, tucatinib, entrectinib, erdaftinib, fodratiuib, pexidartiuib, upa Upadacatinib, zanubrutinib, baricitinib, biuimetinib, dacomitinib, fostamatinib, gilteritinib, larotrectinib, lorlatinib, acalabrutinib, brigatinib, midostaurin midostaurin, neratinib, alectinib, cobimetinib, lenvatinib, osimertinib, ceritinib, nintedanib, afatinib, ibrutinib, trametinib, bosutinib, cabozantinibantinib), ponatinib, regorafenib, tofacitinib, crizotinib, ruxolitiuib, vandetanib, pazopanib, lapatinib, nilotinib, dasatinib, sunitinib (vorolanib), sorafenib, erlotinib, gefitinib, imatinib, afatinib, bosutinib, cabozantinib, cediranib, ceritinib, crizotinib, dabrafenib, dasatinib, erlotinib, everolimus, gefitinib, imatinib, lestaurtinib, nilotinib In some embodiments, the present invention may include nilotinib, palbociclib, pazopanib, ponatinib, regorafenib, ruxolitinib, semananib, sirolimus, sorafenib, temsirolimus, tofacitinib, trametinib, vandetanib and vemurafenib) and / or integrin antagonists (e.g., natalizumab and vedolizumab). In another embodiment, the tyrosine kinase inhibitor can be a Src family tyrosine kinase inhibitor, such as but not limited to: A419259, AP23451, AP23464, AP23485, AP23588, AZD0424, AZM475271, BMS354825, CGP77675, CU201, ENMD 2076, KB SRC 4, KX2361, KX2-391, MLR 1023, MNS, PCI-32765, PD166285, PD180970, PKC-412, PKI166, PPl, PP2, SRN004, SU6656, TC-S7003, TG100435, TG100948, TX-1123, VAL 201, WH-4-023, XL 228, fine galactosidase, bosutinib, damnacanthal, dasatinib, herbimycin A, indirubin, neratinib, lavender A, pelitinib, piceatannol, saracatinib, Srcll, foretinib, motesanib, tivozanib, LY2457546, MGCD-265, MGCD-510, tivantinib, AMG458, JNJ-3887, EMD1214063, BMS794833, PHI1665752, SGX-523, lNCB280, pharmaceutically acceptable salts thereof, and combinations thereof.

[0188] In some embodiments, the active agent can be an immunosuppressant selected from at least one of cyclosporine, an mTOR inhibitor (e.g., rapamycin, tacrolimus, temsirolimus, sirolimus, everolimus, KU-0063794, WYE-354, AZD8055 metformin, or Torin-2), cyclophosphamide, etoposide, thiotepa, methotrexate, azathioprine, mercaptopurine, interferon, infliximab, etanercept, mycophenolate mofetil, 15-deoxyspergualin, thalidomide, glatiramer, leflunomide, vincristine, cytarabine, pharmaceutically acceptable salts thereof, and combinations thereof. Active agents may also be selected from anti-inflammatory cytokine targeting agents, such as targeting TNFa, IL-1, IL-4, IL-5, IL-6 or IL-17 or CD20. Such agents may include etanercept, infliximab, adalimumab, daclizumab, rituximab, tocilizumab, certolizumab pegol, golimumab, pharmaceutically acceptable salts thereof, and combinations thereof.

[0189] In some embodiments, for example, for an ophthalmic drug delivery system, the active agent can be selected from anti-glaucoma agents, including beta-blockers such as atenolol, propranolol, metipranolol, betaxolol, carteolol, levobetaxolol, levobunolol, timolol, pharmaceutically acceptable salts thereof, and combinations thereof; adrenergic agonists or sympathomimetics such as epinephrine, dipivefrin, clonidine, apraclonidine, brimonidine, pharmaceutically acceptable salts thereof, and combinations thereof; parasympathomimetic or cholinergic agonists such as pilocarpine, Carbachol, phospholineiodine, physostigmine, pharmaceutically acceptable salts thereof, and combinations thereof; carbonic anhydrase inhibitors, including topical or systemic agents such as acetozolamide, brinzolamide, dorzolamide; methazolamide, ethoxybenzolamide, dichlorphenamide, pharmaceutically acceptable salts thereof, and combinations thereof; mydriatic-cycloplegic agents such as atropine, cyclopentolate, succinylcholine, homatropine, phenylephrine, scopolamine, tropicamide, pharmaceutically acceptable salts thereof, and combinations thereof; prostaglandins such as prostaglandin F2 alpha, antiprostaglandin, prostaglandin precursor or prostaglandin analog agents such as bimatoprost, latanoprost, travoprost, unoprostone, tafluprost, pharmaceutically acceptable salts thereof, and combinations thereof.

[0190] In some embodiments, the cell protectant may include ebselen, sulforaphane, oltipraz, or dimethyl fumarate.

[0191] In some embodiments, neuroprotective agents may include ursodiol, memantine, or acetylcysteine.

[0192] In some embodiments, the anesthetic may include lidocaine, proparacaine, or bupivacaine.

[0193] In some embodiments, the active agent can be dexamethasone, ketorolac, diclofenac, vancomycin, moxifloxacin, gatifloxicin, besifloxacin, travoprost, 5-fluorouracil, methotrexate, mitomycin C, prednisolone, bevacizumab (Avastin®), ranibizumab (Lucentis®), sunitinib, pegaptanib (Macugen®), timolol, latanoprost, brimonidine, nepafenac, bromfenac, triamcinolone, difluprednate, fluocinolone, aflibercept, or a combination thereof. In some embodiments, the agent can be dexamethasone, ketorolac, diclofenac, moxifloxacin, travoprost, 5-fluorouracil, or methotrexate. In some embodiments, the agent is dexamethasone. In some embodiments, the agent is ketorolac. In some embodiments, the agent is travoprost.

[0194] In some embodiments, the active agent can be selected from at least one of the following: cyclosporine, everolimus, tacrolimus, sirolimus, pimecrolimus, ibuprofen, mefenamic acid, diclofenac, nepafenac, flurbiprofen, flurbiprofen sodium, fusidic acid, besifloxacin (base), clarithromycin, azithromycin, ketotifen (base), azelastine (base), azelastine embonate, linoleic acid, alpha-linolenic acid, gamma-linolenic acid, prednisone, prednisolone, prednisolone acetate, methylprednisolone, dexamethasone, dexamethasone acetate, betamethasone sodium phosphate, budesonide, flunisolide, fluticasone propionate, triamcinolone, triamcinolone acetonide (triamcinolone acetonide) acetonide, triamcinolone hexamyl acetonide, triamcinolone diacetate, fluocinolone acetonide, fludrocortisone acetate, loteprednol, loteprednol etabonate, difluprednate, fluorometholone, mometasone furoate, deoxycorticosterone acetate, aldosterone, rimexolone, beclometasone, beclometasone dipropionate, and lifitegrast.

[0195] In some embodiments, the active agent can be selected from at least one of a peptide, a nanobody, an affibody molecule, an ankyrin, and a DARPin. The peptide can be Compstatin, APL-I, Fc-III-4C, Beovu (Brolucizumab), Zimura (Avacincaptad Pegol), Pegcetacoplan, Abicipar Pegol, Larnpalizumab, Fovista, Risuteganib, AXT107, Elamipretide, THR149, ALM201, VGB3, and Largazole. Nanobodies can be selected from GaNOTA anti-HER2-VHH1, GaNOTA-anti-HER2-VHH1, mTc-NM-02, 131I-SGMIB-anti-HER2-VHH1, GaNOTA-anti-MMR-VHH2, mTc-anti-PD-L1, L-DOS47+doxorubicin, L-DOS47+cisplatin / vinorelbine, KN035+trastuzumab / docetaxel, KN035, KN044, TC-210 T cells, CD19 / CD20 bispecific CART cells, BCMA CART cells or TAS266 nanobodies. Affibody molecules can be those described in Stahl et al., Affibody Molecules in Biotechnological and Medical Applications, Trends in biotechnology 2017, 35 (8) pp. 691-712, which is incorporated herein by reference in its entirety. Ankyrins and DARPins are described in, for example, Caputi et al., Current Opinion in Pharmacology 2020, 51: 93-101, which is incorporated herein by reference in its entirety. MP0250, a trispecific DARPin drug candidate that can bind VEGF-A and hepatocyte growth factor (HGF) and one molecule of MP0250 binds to two molecules of human serum albumin (HSA); Abicipar pegol (MPO112 or AGN-150998); Bucizumab, ranibizumab or aflibercept.

[0196] In some embodiments, the therapeutically active agent may be selected from at least one of the complement inhibitors, including those targeting Cl / Cl Q, CJ, CJ convertase, CS, CS convertase, C5a, C5aR, C6, C7, C8, C9, CD59, factor B, factor D, factor H, factor P, or a combination thereof. These may include specific agents such as cinryze, berinert, ruconest, sutimlimab, pegcetacopan (GA), eculizumab, ravuilizumab, avacopan, pozelimab, nomacopan, zilucopan, vilobelimab, crovalimab, avacincapted pegol), cemdisiran, BDB-001, tesidolumab, avdoralimab, MOR210, ALXN1720, danicopan, vemircopan, ACH-5228, ACH-5548, BCX-9330, AMY-101, ANX005, ANX007, narsoplimab, iptacopan, CLG561, GT103, ARGX-117, ALXN1820, NGM621, lampalizumab, NGM621, IONIS-FB-Lrx, GEM I 03, CLG561, pharmaceutically acceptable salts thereof, and combinations thereof

[0197] In some embodiments, the therapeutically active agent can be selected from at least one of the antihistamines, such as loratadine, hydroxyzine, diphenhydramine, chlorpheniramine, brompheniramine, cyproheptadine, terfenadine, clemastine, triprolidine, carbinoxamine, diphenylpyraline, phenibutanone ... and trimipramine, doxylamine, pheniramine, pyrilamine, chiorcyclizine, thonzylamine, pharmaceutically acceptable salts thereof, and combinations thereof.

[0198] In some embodiments, the therapeutically active agent may be selected from at least one of the following: an IL-6 inhibitor, such as sarilumab, tocilizumab, RG6179, a pharmaceutically acceptable salt thereof, and a combination thereof; and / or an HtRA1 inhibitor, such as IC-500, FHTR.2163, RG6147, pharmaceutically acceptable salts thereof and combinations thereof; and / or RASP inhibitors such as reproxalap and pharmaceutically acceptable salts thereof; and / or rho kinase inhibitors such as netardusil, ripasudil, HA-1077, Y-27632, H-1152P, INS-I 15644, Y-39983, SB772077BS, LX7 l D1, AR-12286, AMA-0076, AR-13533, pharmaceutically acceptable salts thereof, and combinations thereof; or plasma kallikrein inhibitors, such as ecallantide, lanadelumab, berotralstat, ATN-249, KVD900, KVD824, THR-149, pharmaceutically acceptable salts thereof, and combinations thereof; and / or nitric oxide donors PgA, such as latanoprost nitrate, NCX470, pharmaceutically acceptable salts thereof, and combinations thereof; or mast cell stabilizers, such as lodoxamide, nedocromil, pemirolast, cromolyn (e.g., sodium cromolyn), pharmaceutically acceptable salts thereof, and combinations thereof; and / or IGF-1 R inhibitors, such as teprotutumab, VRDN-001, VRDN-002, VRDN-003, ganitumab, figitumumab, MEDI-573, cixutumumab, dalotuzumab, robatumumab, AVE!642, BIIB022, xentuzumab, istiratumab, linsitinib, Picropodopbyllin, BMS-754807, BMS-536924, BMS-554417, GSK1838705A, GSK1904529A, NVP-AEW541, NVP-ADW742, GTx-134, AG1024, KW-2450, PL-2258, NVP-AEW541, NSM-18, AZD3463, AZD9362, B1I885578, B1893923, TT-100, XL-228, A-928605, pharmaceutically acceptable salts thereof, and combinations thereof.

[0199] In some embodiments, the therapeutically active agent may be selected from at least one of the TRPV1 antagonists, such as asivatrep, V116517, fused azabicyclic, heterocyclic and amide compounds, such as, for example, U.S. Patent Application No. 2004 / 0157849, U.S. Patent Application No. 2004 / 0209884, U.S. Patent Application No. 2005 / 0113576, International Patent Application No. WO 05 / 016890, U.S. Patent Application No. 2004 / 0254188, U.S. Patent Application No. 2005 / 0043351, International Patent Application No. WO 05 / 040121, U.S. Patent Application No. 2005 / 0085512 and Gomtsyan et al., 2005, J. Med. Chem. 48:744-752; fused pyridine derivatives, such as described in, for example, U.S. Patent Application No. 2004 / 0138454; pyridylpiperazinyl urea, such as described in, for example, Swanson et al., 2005, J. Med. Chem. 48:1857-1872 and U.S. Patent Application No. 2005 / 0049241, as well as AMG8163 (Bannon et al., 2005, 11.sup.th World Congress on Pain) and BCTC (Sun et al., 2003, Chem. Lett. 13:3611-3616); 2-(piperazin-l-yl)-1H-benzimidazole; pyridazinylpiperazine; urea derivatives, such as, for example, U.S. Patent Application No. 2005 / 0107388, U.S. Patent Application No. 2005 / 018729 l and described in U.S. Patent Application No. 2005 / 0154230, as well as A-425619 (ElKouhen et al., 2005, J. Pharmacol. Exp. Tuer. 314:400-409); cinnamamides, including SB-366791 (Gunthorpe et al., 2004, Neuropharmacology 46:133-149) and AMG9810 (Gawa et al., 2005, J. Pharmacol. Exp. Ther. 313:474-484).TRPV-1 antagonists may also include capsaicin, (E)-3-(4-tert-butylphenyl)-N-(2,3-dihydrobenzo[b][l,4)dioxin-6-yl)acrylamide (e.g., commercially available as AMG9810 from Tocris Bioscience, Bristol, United Kingdom), and 4-tert-butylcyclohexane (commercially available as SYMSITIVE 1609 from Symmise GmbH of Holzminden, Germany), as well as TRPVI antagonists disclosed in U.S. Pat. Nos. 8,815,930, 6,933,311, 7,767,705, and U.S. Patent Application Publication Nos. 2010 / 0249203 and 2011 / 0104301, International Application WO / 2008 / 013861; and / or AMG-517 and AMG-628 (Amgen Inc., Thousand Oaks, Calif.). TRPVI antagonists useful in the present invention are also described in, for example, International Patent Application No. WO 2006065484; International Patent Application No. WO 2003070247; US Patent Application No. US2005080095; and International Patent Application No. WO 2005007642.Additional TRPV1 antagonists that can be used in the methods, compositions, and devices disclosed herein include the TRPV1 antagonists ABT-102, AMG8562, AMG9810, BCTC, SB366791, JNJ17203212, I-TIX, JYL-1421, A-425619, N-[4-[6-[4(trifluoromethyl)phenyl)pyrimidin-4-yloxy]benzothiazol-2-yl]acetamide (also known as AL-49975 or AMG-517), (R)-N-(4-(6-(4-(1-(4-fluorophenyl)ethyl)piperazin-1-yl)pyrimidin-4-yloxy)benzo[d]thiazol-2-yl)acetamide (AL-49976, also known as AMG-628), pharmaceutically acceptable salts thereof, and combinations thereof, for example, 1-(2- 1-(2-(4-hydroxy-3,3-dimethylbutyl)-4-(trifluoromethyl)benzyl)-3-(1-methyl-1H-indazol-4-yl)urea; 2,2-dimethyl-4-(2-((3-(1-methyl-1H-indazol-4-yl)urea)methyl)-5-(trifluoromethyl)phenyl)butanoic acid methyl ester; 1-(2-(4-hydroxy-3,3-dimethylbutyl)-4-(trifluoromethyl)benzyl)-3-(1-methyl-1H-indazol-4-yl)urea; 2,2-dimethyl-4-(2-((3-(1-methyl-1H-indazol-4-yl)urea)methyl)-5-(trifluoromethyl)phenyl)butanoic acid; 1-[4-chloro-3-(3,3-dimethylbutyl)benzyl]-3-(1 -methyl-1H-indazol-4-yl) urea; 1-(2-isobutyl-4-(trifluoromethyl)benzyl)-3-(1-methyl-1H-indazol-4-yl) urea; 1-(2-isopropyl-4-(trifluoromethyl)benzyl)-3-(1-methyl-1H-indazol-4-yl) urea; 1-(4-chloro-3-isopropylbenzyl)-3-(1-methyl-1H-indazol-4-yl) urea, pharmaceutically acceptable salts thereof, and combinations thereof.

[0200] In some embodiments, the therapeutically active agent can be selected from at least one of the TrkA antagonists, including VM902A, larotrectinib, entrectinib, selitrectinib (LOXO-195, BAY2731954), repotrectinib (TPX-0005), pharmaceutically acceptable salts thereof, and combinations thereof.

[0201] In some embodiments, the therapeutically active agent can be selected from at least one of the lipophilic active agents, such as betamethasone, bevacizumab (avastin), ciprofloxacin hydrochloride, cortisone, cyclosporine, dexamethasone, ketoprofen, ketorolac, salicylic acid, sirolimus, sorafenib, sunitinib maleate, tacrolimus; and / or betaxolol, indomethacin, propranolol, fluconazole, fluorometholone, timolol, ethoxybenzamide, hydrocortisone, cabozantinib, axitinib, tivozanib.

[0202] In certain embodiments, the therapeutically active agent can be a combination of drugs, for example, for combination therapy purposes. The combination of active agents can be co-administered in a drug delivery system (e.g., implant), or can be included as a bispecific molecule. Exemplary combinations that can be used in the drug delivery system of the present invention include a combination of a complement inhibitor and an anti-VEGF agent, which can be used, for example, to treat dry AMD / GA and wet AMD in patients with dry AMD / GA and wet AMD, and to prevent the occurrence of one of the diseases. Such combinations can be used to treat patients with wet AMD who do not suffer from GA, to prevent or delay the development of GA after they receive a combination of anti-VEGF and complement agents. Examples of combinations of complement inhibitors and anti-VEGF agents include Aflibercept + Pegcetacoplan, Aflibercept + Avacincaptad Pegol, Ranibizumab + Pegcetacoplan, Ranibizumab + Pegcetacoplan, Axitinib + Pegcetacoplan, Axitinib + Avacincaptad pegol, Vorolanib + Pegcetacoplan, Vorolanib + Avacincaptad pegol, Lenvatinib + Pegcetacoplan, Lenvatinib + Avacincaptad, Faricimab + Pegcetacoplan, Faricimab + Avacincaptad Pegol, Bevacizumab + Pegcetacoplan, Bevacizumab + Avacincaptad Pegol.

[0203] In other embodiments, the combination of active agents may include anti-VEGF and IL-6 blockers, such as any combination of aflibercept, ranibizumab, bevacizumab, farecimab, axitinib, voronib, lenvatinib (anti-VEGF) with salilumab, tocilizumab, RG6179 (IL-6 blocker).

[0204] In other embodiments, combinations of active agents may include a beta blocker in combination with a PgA analog such as timolol (most commonly used for glaucoma) and any of the PgA analogs such as latanoprost, bimatoprost, travoprost.

[0205] The active agent combinations of the present invention may also include a combination of at least one therapeutic active agent and at least one diagnostic active agent, or a combination of more than two active agents.

[0206] Diagnostic active agent can be, for example, imaging agent, marker or visualization agent. Generally, diagnostic agent can be a material for checking the body to detect whether its normal function is impaired. In some cases, diagnostic agent can be an agent with functional purpose, such as for detecting ocular deformity, illness and pathophysiological aspects. For example, diagnostic agent can be an important and effective diagnostic adjuvant, such as dye (for example, fluorescein dye, indocyanine green, trypan blue, dark quencher such as cyanine dye, azo dye, acridine, fluorene, oxazine, phenanthridine, naphthalimide, rhodamine, benzopyrone, perylene, benzanthrone, p-benzothranolone), to contribute to the visualization of ocular tissue. Diagnostic agent can include paramagnetic molecules, fluorescent compounds, magnetic molecules, radionuclides, x-ray imaging agents and / or contrast media. In some embodiments, diagnostic agent can include radiopharmaceuticals, contrast agents for imaging technology, allergen extracts, activated carbon, different test strips (for example, cholesterol, ethanol and glucose), pregnancy test, 13C urea breath test and various stains / markers. In some embodiments, the labeling moiety is a fluorescent dye or dark quencher selected from the group consisting of: coumarin, cyanine dye, azo dye, acridine, fluorene, oxazine, phenanthridine, naphthalimide, rhodamine, benzopyrone, perylene, benzanthrone and benzanthrone. In specific non-limiting embodiments, the fluorescent dye is a compound selected from the group consisting of or a residue of a compound selected from the group consisting of: coumarin, fluorescein, cyanine 3 (Cy3), cyanine 5 (Cy5), cyanine 7 (Cy7), Alexa dyes, bodipy derivatives, (E)-2-(4-(phenyldiazenyl)phenoxy)acetic acid, 3-(3',3'-dimethyl-6-nitrospiro[chromene-2,2'-indoline]-1'-yl)propionate (spiropyran), 3,5-dihydroxybenzoate and (E)-2-(4-(phenyldiazenyl)phenoxy)acetic acid or a combination thereof.

[0207] In an embodiment of the invention, the active agent is a drug in the form of a liquid oil at temperatures up to 37°C, such as travoprost or the like, which forms at least a part of the hydrophobic organic liquid or can even be used in place of the hydrophobic organic liquid.

[0208] According to certain embodiments of the present invention, the active agent may be oil soluble and dissolved in the hydrophobic organic liquid, or the active agent may be oil insoluble and may be dispersed in the hydrophobic organic liquid in particulate form, or emulsified in liquid form.

[0209] In embodiments where the active agent is used in the form of particles, the active agent particles can be micronized particles, for example, having a D50 particle size of less than about 15 μm, or less than 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, or 5 μm or less, and / or a D98 particle size of about 10 μm or less. In other embodiments, the active agent particles can be nanoscale particles, for example, having 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 measured as disclosed in the "Definitions" subsection herein.

[0210] Composition range

[0211] According to the present invention, the organogel of drug delivery system can be designed according to the needs of intended use and therapeutic application. Generally, the organogel comprises 1% by weight to 90% by weight of hydrophobic organic liquid or 5-90% by weight, 5-60% by weight, 10-50% by weight, 10-40% by weight, 15-40% by weight or 15-35% by weight; 5% by weight to 95% by weight of covalently cross-linked polymer network, or 10-95% by weight, 40-95% by weight, 50-90% by weight, 60-90% by weight or 60-85% by weight; and 1% by weight to 50% by weight of activating agent, or 5-50% by weight, 5-40% by weight, 10-30% by weight or 10-25% by weight; wherein all weight percentages are selected to reach a total of 100%, and weight % is respectively based on the total dry weight of organogel or drug delivery system.

[0212] Manufacturing method

[0213] According to the present invention, a method for manufacturing a biodegradable drug delivery system of sustained release as described herein is provided. In certain embodiments, the method for manufacturing a biodegradable drug delivery system of sustained release includes forming an organogel by at least a covalently crosslinked polymer network, a hydrophobic organic liquid, optionally a solvent and at least one activating agent, wherein the hydrophobic organic liquid and the activating agent are included (for example, fixed) in a biodegradable covalently crosslinked polymer network, the organogel is shaped, and optionally the solvent is removed from the organogel.

[0214] In a particular procedure, the step of forming an organogel (step (1)) comprises providing (a) a hydrophobic organic liquid; (b) at least one active agent; (c) a first covalently crosslinkable precursor comprising a first functional group; (d) a second covalently crosslinkable precursor comprising a second functional group; combining all of these in any suitable order into a reaction mixture; and (e) gelling the reaction mixture by forming a covalently crosslinked polymer network.

[0215] Optionally, at least one organic solvent may be added to any one of (a), (b), (c), (d), and (e) and removed after the organogel is formed.

[0216] In one embodiment, in (c), at least one first multi-arm precursor is provided.Precursor and multi-arm precursor used in the present invention are described in detail in the subsection entitled "precursor component".In some embodiments, at least one multi-arm precursor comprises at least 8 arms or at least 4 arms.At least one multi-arm precursor comprises an electrophile or a nucleophile as the first functional group.

[0217] In another embodiment, at least one first multi-arm precursor comprises at least two multi-arm precursors. In such embodiments, a multi-arm precursor comprises an electrophile, and another multi-arm precursor comprises a nucleophile as the first or second functional group. In another embodiment, at least one multi-arm precursor comprises at least one multi-arm precursor comprising an electrophile or a nucleophile as the first functional group and a small molecule cross-linking agent comprising an electrophile or a nucleophile as the second functional group.

[0218] In these embodiments, the nucleophile can be an amine such as a primary amine, a thiol, a dibenzocyclooctyne, or a hydrazide, and the electrophile can be a succinimidyl ester, a succinimidyl carbonate, a nitrophenyl carbonate, an aldehyde, a ketone, an acrylate, an acrylamide, a maleimide, a vinyl sulfone, an iodoacetamide, an alkene, an alkyne, an azide, a norbornene, an epoxide, a mesylate, a tosylate, a trifluoroethanesulfonyl, a cyanurate, an orthopyridyl disulfide, or a halide. In one embodiment of the invention, if the electrophile is a succinimidyl ester, it can contain a reactive group such as succinimidyl succinate (SS), succinimidyl glutarate (SG), succinimidyl adipate (SAP), succinimidyl azelate (SAZ), or succinimidyl glutarate amide.

[0219] In some embodiments, at least one multi-arm precursor is a first multi-arm PEG precursor comprising a primary amine, or a first multi-arm PLGA precursor comprising a primary amine. Thus, the first covalently cross-linkable precursor comprising a first functional group can be hydrophilic (PEG) or hydrophobic (PLGA).

[0220] In one embodiment, in (d), at least one other second multi-arm precursor is provided.Precursor and multi-arm precursor used in the present invention are described in detail in the subsection entitled "precursor component". In some embodiments, at least one second multi-arm precursor comprises at least 8 arms, or at least 4 arms. At least one second multi-arm precursor may comprise an electrophile or a nucleophile as the second functional group.

[0221] In another embodiment, at least one second multi-arm precursor comprises at least two multi-arm precursors. In such embodiments, a multi-arm precursor comprises an electrophile, and another multi-arm precursor comprises a nucleophile. In another embodiment, at least one second multi-arm precursor comprises at least two multi-arm precursors that each comprises an electrophile.

[0222] In all of these embodiments, the nucleophile can be an amine such as a primary amine, a thiol, a dibenzocyclooctyne, or a hydrazide, and the electrophile can be a succinimidyl ester, a succinimidyl carbonate, a nitrophenyl carbonate, an aldehyde, a ketone, an acrylate, an acrylamide, a maleimide, a vinyl sulfone, an iodoacetamide, an alkene, an alkyne, an azide, a norbornene, an epoxide, a mesylate, a tosylate, a trifluoroethanesulfonyl, a cyanurate, an orthopyridyl disulfide, or a halide. In addition to the classical electrophile-nucleophile condensation reaction, other chemical reaction types based on electrophiles and nucleophiles can also be used in the present invention. For example, in the case of azide and dibenzocyclooctyne functionalization, the precursors can be crosslinked via so-called click chemistry reactions (see HC Kolb; MG Finn; KB Sharpless (2001). "ClickChemistry: Diverse Chemical Function from a Few Good Reactions", AngewandteChemie International Edition, 40 (11): 2004–2021).

[0223] In some embodiments, at least one second multi-arm precursor includes at least two second multi-arm precursors, which include a first multi-arm precursor comprising an electrophilic reagent comprising a first reactive group and a second multi-arm precursor comprising an electrophilic reagent comprising a second reactive group. In one embodiment of the invention, if the electrophilic reagent is a succinimide ester, the first and second reactive groups are selected from succinimidyl succinate (SS), succinimidyl glutarate (SG), succinimidyl adipate (SAP), succinimidyl azelaic acid ester (SAZ) or succinimidyl glutaramide.

[0224] At least one of the first or second crosslinkable precursors has a functionality greater than 2, such as 3 to 10, or 3 to 9, or 4 to 8, or 4, and the first crosslinkable precursor can be a dendrimer or a multi-arm precursor having a core and 2 to 12 arms, or 3 to 10 arms, 4 to 8 arms, or 4 or 8 arms, each arm comprising a polymer unit as defined herein and having an end carrying a first or second functional group. For example, a 4-arm precursor can be derived from pentaerythritol or ethylenediamine, comprising 4 arms of a polymer unit attached thereto. In some embodiments, the arm comprises a hydrophobic polymer unit selected from a polylactic acid (PLA) unit and a polylactic acid-co-glycolic acid (PLGA) unit or a combination thereof. In some embodiments, the arm comprises a hydrophilic polymer unit selected from polyethylene glycol (PEG), polypropylene glycol (PPG) and polyglycolic acid (PGA) or a combination thereof. The second cross-linkable precursor may be a non-polymeric cross-linking agent, preferably a small molecule amine such as tris(2-aminoethyl)amine (TAEA) or trilysine.

[0225] When using PLGA units, the ratio of polylactic acid-co-glycolic acid (PLGA) precursor to polyethylene glycol (PEG) precursor can be set to about 2.5: 1 to about 1: 2.5, or about 2: 1 to 1: 2, or about 1: 1. In addition, polylactic acid-co-glycolic acid (PLGA) precursor can have an L / G ratio (in % L or G blocks) in the range of 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. The L / G ratio of polylactic acid-co-glycolic acid (PLGA) unit can be selected to adjust the hydrophobicity of the polymer network and provide the sustained release of the active agent from the organogel. Additionally or alternatively, the ratio of the amount of the first cross-linkable precursor to the second cross-linkable precursor can be selected to adjust the hydrophobicity of the polymer network and provide the sustained release of the active agent.

[0226] In certain embodiments, each of (a), (b), (c) and (d) above is then processed to obtain (e) and (f). In one embodiment, prior to (e), the first precursor may be premixed with a hydrophobic organic liquid, or the second precursor may be premixed with a hydrophobic organic liquid, and one or more solvents may be optionally added to any of these premixes, and the active agent of (b) may be added to any of these premixes or to the reaction mixture in (e).

[0227] In one embodiment, when all components have been combined in the reaction mixture (e), at least two precursors react in an electrophile-nucleophile reaction to form a covalently crosslinked matrix as an organogel. The reaction can be initiated or promoted by heating, or can occur under ambient conditions.

[0228] The step of shaping the organogel (step (2)) may include molding or extruding or casting the reaction mixture before the organogel is completely gelled, then gelling the mixture, and optionally removing the solvent. Molding can be accomplished by filling the reaction mixture into a mold or tube, gelling the mixture, and optionally removing the solvent before the organogel is completely gelled. In some embodiments, the reaction mixture can be filled into a thin diameter tube or needle to prepare an organogel strand. The reaction mixture can also be applied to a substrate as a coating. As part of the process, the cured organogel can be deformed and hardened to allow injection through the needle cavity, and the rigidity and reshaping are reversible when exposed to the warmth and / or moisture of the tissue. Rigidity can be provided by crystallization, secondary crosslinking mechanisms, or water-soluble temporary structural components (e.g., PEG fibers).

[0229] The composition (e) with the precursor mixed therein can be prepared to have a viscosity suitable for introduction through a small-gauge needle using manual force. The diameter of the small-gauge needle is less than the diameter of a 27-gauge (e.g., 28, 29, 30, 31, 32, or 33-gauge) needle, wherein the specification is specific for the inner diameter and / or outer diameter. In addition, hollow tubing such as used in the intravascular field can be used to deliver materials to the implant site to form a drug delivery device in situ, including those with an inner diameter and / or outer diameter equal to or smaller than the small-gauge needle. Therefore, a viscosity between about 1 to about 100,000 mPa∙s can be used; the technician will immediately understand that all ranges and values ​​within the clearly specified range are contemplated, for example, about 10 to about 10,000 mPa∙s, less than about 5 to about 10,000 mPa∙s, less than about 100 or about 500 mPa∙s, or between about 1 and about 100 mPa∙s. Viscosity can be controlled, for example, by selecting an appropriate precursor, adjusting solid and or solvent concentrations, and reaction kinetics. Generally, lower precursor concentrations, increased hydrophilicity, and lower molecular weight favor lower viscosities.

[0230] Viscosity enhancers can be used in conjunction with precursors. In certain embodiments, the viscosity enhancer does not react with the precursor to form a covalent bond. Although it should be understood that precursors that are generally free of such bonding may sometimes participate in undesirable side reactions, these have little effect on the organogel, so the precursor is "free of" such reactions. For example, if the precursor reacts by an electrophile-nucleophile reaction, the viscosity enhancer may not contain an electrophile or nucleophile that can form a covalent bond with the functional group of the precursor, even if there are some low levels of undesirable side reactions. The viscosity enhancer can be a hydrophilic polymer having a molecular weight of, for example, at least 20,000, or about 10,000 to about 500,000 Daltons; the skilled person will immediately understand that all values ​​and ranges between these clearly specified values ​​are described, for example, at least about 100,000 or 200,000. For example, a concentration of about 1% to about 40%, or about 5% to about 25% w / w can be used. For example, PEG (e.g., MW 100,000 to 250,000) is available. The viscosity enhancer may be free of electrophiles and / or nucleophiles. The viscosity enhancer may be free of one or more functional groups, such as hydroxyl, carboxyl, amine or thiol. The viscosity enhancer may include one or more biodegradable linkages as described herein for the precursor. The viscosity enhancer may be used to prevent the precursor from being lost from the tissue site before the precursor is cross-linked to form a gel.

[0231] Sustained Release Kinetics:

[0232] In certain embodiments, in the biodegradable drug delivery system of sustained release of the present invention, organogel is used to allow the release of activating agent from drug delivery system to be changed by some measures. For example, the precursor component forming the cross-linked polymer network can be customized or suitably selected to form according to its hydrophilic and / or hydrophobic properties and can have an impact on the release of activating agent. In addition, the release of activating agent from drug delivery system can be changed or controlled by suitably selecting hydrophobic organic liquid according to the characteristic of hydrophobic organic liquid (such as hydrophobicity, viscosity, with one or more of the compatibility of activating agent, solubility of activating agent in hydrophobic organic phase or insolubility etc.).

[0233] Therefore, in various embodiments of the present invention, the selection of hydrophobic liquids, and / or the hydrophobicity of the polymer network, and / or the L / G ratio can be used to adjust the release rate. Each of these individual parameters can be selected individually or in combination with each other to provide controlled release of the active agent.

[0234] In certain embodiments, the sustained release drug delivery system of the present invention is formulated so that the active agent is available over an extended period of time, thereby allowing a reduction in dosing frequency compared to an immediate release dosage form (such as an active agent solution (i.e., eye drops) applied topically to the eye). In certain embodiments, the release of the active agent includes a constant release of the active agent, a gradually decreasing release of the active agent, and any combination thereof, such as a constant release of the active agent followed by a gradually decreasing release of the active agent. "Sustained release" can be measured in vitro in an aqueous solution under physiological conditions (such as at pH 7.2-7.4 and 37° C.), and is considered to be the same or substantially the same when the drug delivery system is administered to a subject in vivo.

[0235] In various embodiments of the invention, the active agent release follows zero order release kinetics or substantially zero order release kinetics, preferably without a "burst" of active agent at the beginning of the time period.

[0236] Embodiments of the present invention can provide a therapeutically effective amount of an active agent for a period of time after administration, such as 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. Other embodiments of the present invention can provide a therapeutically effective amount of an active agent for a period of time of up to about 14 days, or up to about 21 days after administration, or a therapeutically effective amount of an active agent for a period of time of about 6 hours or longer after administration, or a period of time of about 12 hours, or 24 hours or longer, or about 48 hours or longer, or about 72 hours or longer, or about 7 days or longer, or about 10 days or longer after administration. All of the above lower and higher time periods in any range combination are contemplated by the present invention.

[0237] In various embodiments of the present invention, the organogel delays the release of water-soluble active agents or accelerates the release of hydrophobic active agents.

[0238] In one aspect of the invention, a sustained release drug delivery system is provided, such as a pharmaceutically acceptable implant, for controlled release of an active agent (e.g., total amount) contained therein. Throughout this subsection, controlled release should be considered as controlled release measured under the time and conditions from the first immersion of the implant in an aqueous solution under physiological conditions such as pH 7.2-7.4 and temperature 37°C. Upon exposure to physiological conditions, the organogel contained in the drug delivery system can slowly release the hydrophobic organic liquid from the organogel and simultaneously form a hydrogel.

[0239] According to some aspects of the present invention, a sustained release drug delivery system is provided, such as a pharmaceutically acceptable implant, for the controlled release of the total amount of an active agent contained therein. In certain embodiments, the controlled release may be characterized as an amount of the active agent released on the 1st day being 0 to 50% of the total amount of the active agent, an amount of the active agent released every day from the 2nd day to the last day of release being 0 to 50% of the total amount of the active agent, and / or the number of days required for 100% release of the total amount of the active agent being at least 2 days.

[0240] In certain embodiments, controlled release can be characterized by the amount of active agent released on day 1 being between 0 and 50% of the total amount of active agent, the amount of active agent released each day from day 2 to the last day of release being between 0 and 50% of the total amount of active agent, and / or the number of days required for 100% release of the total amount of active agent being at least 3 days.

[0241] In certain embodiments, controlled release can be characterized by the amount of active agent released on day 1 being between 0 and 50% of the total amount of active agent, the amount of active agent released each day from day 2 to the last day of release being between 0 and 50% of the total amount of active agent, and / or the number of days required for 100% release of the total amount of active agent being at least 4-7 days.

[0242] In certain embodiments, controlled release can be characterized by the amount of active agent released on day 1 being between 0 and 50% of the total amount of active agent, the amount of active agent released each day from day 2 to the last day of release being between 0 and 50% of the total amount of active agent, and / or the number of days required for 100% release of the total amount of active agent being at least 10-15 days.

[0243] In certain embodiments, controlled release can be characterized by the amount of active agent released on day 1 being between 0 and 50% of the total amount of active agent, the amount of active agent released each day from day 2 to the last day of release being between 0 and 50% of the total amount of active agent, and / or the number of days required for 100% release of the total amount of active agent being at least 10-30 days.

[0244] In certain embodiments, controlled release can be characterized by the amount of active agent released on day 1 being between 0 and 50% of the total amount of active agent, the amount of active agent released each day from day 2 to the last day of release being between 0 and 50% of the total amount of active agent, and / or the number of days required for 100% release of the total amount of active agent being greater than 30 days.

[0245] According to certain embodiments of the invention, the controlled release is characterized in that the amount of active agent released on the first day is 0 to 25%, 0 to 20%, 0 to 10%, 0 to 5%, or about 0% of the total amount of active agent, and the amount of active agent released each day from the second day until the last day of release is 0 to 50% or 0 to 40% or 0 to 30% or 0 to 20% or 0 to 10% or 0 to 5% of the total amount of active agent. In certain embodiments, the number of days required for 100% release of the total amount of active agent is at least 3 days but not more than 30 days, 25 days or not more than 16 days. In other embodiments, the time is as disclosed above.

[0246] 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 or near zero-order release or substantially zero-order release begins at least 1 day after the pharmaceutically acceptable implant is immersed under physiological conditions (such as pH 7.2-7.4 and 37°C).

[0247] A dosage form or implant showing a zero-order release rate will present a relatively straight line in a graphical representation of the percentage of the active agent released versus time. In certain embodiments of the invention, zero-order release is completed in a complete release period. In certain embodiments of the invention, zero-order release is completed in a portion of the release period. In certain such embodiments, zero-order release is completed from the end of the 1st day (i.e., 24 hours after the release begins) to the end of the release. If less release or incomplete release is completed before the end of the 1st day, this release will be considered to have a lag time of one day or 24 hours. This lag time can also be longer. If a high release is completed before the end of the 1st day, this release will be considered to break out during the first day or 24 hours. This burst time can also be longer. Zero-order release can also be completed in a complete release period. In this context, a complete release period is defined as until 95% of the release is completed.

[0248] Within the meaning of the present invention, a zero-order release is defined as being achieved if the release is proportional to the time elapsed during the corresponding time. Proportional to the time elapsed means that the proportional release is calculated over the entire time of the zero-order release defining the straight line (release in % cumulative release during the complete time period, where the zero-order release separated by said complete time period defining a straight line is completed) and the release at any time point in between, i.e. the start of the zero-order release and the end of the zero-order release are within 20% of the % cumulative release of said proportional release defined by said straight line.

[0249] Application

[0250] The drug delivery system of the invention may be in the form of an implant, such as a medical implant or a pharmaceutically acceptable implant, an implant coating or an oral dosage form, etc. The drug delivery system may also be provided in the form of a kit as further defined below, for example for forming an implant in situ.

[0251] If the sustained-release biodegradable drug delivery system is an implant, the implant can be one of the following: an intraocular implant; an intracavetal implant; an intracameral implant; an implant for introduction into the anterior chamber, vitreous, extrascleral, posterior subtenon's space (inferior fornix), subconjunctival, intracameral, periorbital, retrobulbar, subfascial, retinal, subretinal, intracanalicular, intravitreal, intrascleral, choroidal, suprachoroidal space, retina, subretinal or lens, surface of cornea or conjunctiva, lacrimal puncta (canaliculus, superior / inferior canaliculus), fornix, superior / inferior fornix, subfascial space, choroid, suprachoroidal, fascia, cornea, cancer tissue, organ, prostate, breast, joint space, subdural, tooth, subcutaneous, carpal tunnel, perivascular, surgically created space or injury, void space and potential space.

[0252] In certain embodiments of the present invention, the sustained release biodegradable drug delivery system can be formulated for administration by a variety of different routes, such as oral, parenteral, or by surgical insertion or injection. The oral dosage form can be composed of the organogel of the present invention, which can be optionally enteric coated, or in the form of small particles filled into capsules, etc.

[0253] Treatment

[0254] According to the present invention, a sustained-release biodegradable drug delivery system is configured for use as a medicament, such as for treating a disease or medical condition in a patient, the method comprising forming an organogel comprising a therapeutically active agent dispersed in a hydrophobic organic liquid contained in a covalently cross-linked polymer network, wherein the organogel is formed in situ at a treatment site in a patient, or is preformed and delivered to or implanted at a treatment site in a patient, so as to release the active agent over an extended period of time.

[0255] Methods for treating a disease or medical condition in a patient are provided, the methods comprising forming an organogel comprising a therapeutically active agent dispersed in a hydrophobic organic liquid contained in a covalently cross-linked polymer network, wherein the organogel is formed in situ at a treatment site in the patient, or is preformed and delivered to or implanted at the treatment site so as to release the active agent over an extended period of time. Methods for treating a disease or medical condition in a patient may comprise administering an organogel comprising an active agent dispersed in a hydrophobic organic liquid contained in a covalently cross-linked polymer network to the patient so as to release the therapeutically active agent over an extended period of time.

[0256] The treatment site can be one of the following: anterior chamber, vitreous, episcleral, posterior subfascial space (inferior fornix), subconjunctival, intracameral, periorbital, retrobulbar, subfascial, retinal, subretinal, intracanalicular, intravitreal, intrascleral, choroidal, suprachoroidal space, retina, subretinal or lens, surface of cornea or conjunctiva, lacrimal puncta (canaliculus, superior / inferior canaliculus), fornix, superior / inferior fornix, subfascial space, choroid, suprachoroidal, fascia, cornea, cancer tissue, organ, prostate, breast, joint space, subdural, tooth, subcutaneous, carpal tunnel, perivascular, surgically created space or injury, void space and potential space.

[0257] In an embodiment of the invention, the disease or medical condition to be treated is an eye disease, particularly a posterior eye disease, such as any posterior segment eye disease affecting the vasculature and integrity of the retina, macula or choroid, leading to visual acuity impairment, vision loss or blindness, particularly posterior segment disease states caused by 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 glaucoma, ocular hypertension, hyphema, presbyopia, cataract, retinal vein occlusion, inflammation.The ocular disease may be selected from retinal neovascularization, choroidal neovascularization, wet 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 multifocal squamous pigment epitheliopathy, Behcet's disease, shotgun choroidopathy, posterior uveitis, posterior scleritis, creeping choroiditis, subretinal fibrosis, uveitis syndrome, Vogt-Koyanagi-Harada syndrome, retinal artery occlusive disease, central retinal vein occlusion, disseminated intravascular coagulation, branch retinal vein occlusion, fundus hypertensive changes, ocular ischemic syndrome, retinal artery microaneurysms, Coat's disease, disease), juxtafoveal telangiectasia, hemiretinal vein occlusion, papillary phlebitis, carotid artery disease (CAD), frosted branch angiitis, sickle cell retinopathy, angioid streaks, familial exudative vitreoretinopathy, Eales disease, proliferative vitreoretinopathy, diabetic retinopathy, tumor-related retinal diseases, congenital hypertrophy of the retinal pigment epithelium (RPE), posterior uveal melanoma, choroidal hemangioma, choroidal osteoma, choroidal metastatic carcinoma, combined hamartoma of the retina and retinal pigment epithelium, retinoblastoma, fundus vascular proliferative tumors, retinal astrocytoma, intraocular lymphoid tumors, myopic retinal degeneration, acute retinal pigment epitheliitis, glaucoma, endophthalmitis, cytomegalovirus retinitis, retinal carcinoma, retinitis pigmentosa, Leber's congenital amaurosis, choroideremia, X-linked retinitis pigmentosa, Best's vitelliform macular dystrophy, vitelliform maculardystrophy), X-linked retinoschisis, achromatopsia CNGA3, achromatopsia CNGB3, LHON, Stargardt disease, Usher syndrome, Norrie disease, Bardet-Biedl syndrome, and red-green color blindness.

[0258] In the therapeutic method of the present invention, a biodegradable drug delivery system of sustained release as discussed in a separate subsection herein is applied to a subject or patient. The drug delivery system is used for the controlled release of any active agent discussed in a separate subsection herein. Controlled release is also defined in a separate subsection herein.

[0259] The methods described in this subsection may also include administering the drug delivery system in combination with another agent, such as a pharmaceutically acceptable implant, also referred to as combination therapy.

[0260] In one embodiment, the combination therapy includes administering a pharmaceutically acceptable implant of the present invention in combination with one or more additional agents on the same day or on a different day. In one embodiment, the additional agent to be administered in the combination therapy can be a liquid formulation of the agent, or it can be included in an oral dosage form. Therefore, the additional agent can be any small molecule, macromolecule, protein, nanoparticle, or any other active agent described herein.

[0261] In some combination therapy embodiments, the therapeutically active agent can be a combination of drugs. The combination of active agents can be co-administered by including all active agents in a drug delivery system (e.g., implant), or can be included as a bispecific molecule. Exemplary combinations that can be used in the drug delivery system of the present invention include a combination of a complement inhibitor and an anti-VEGF agent, which can be used, for example, to treat dry AMD / GA and wet AMD in patients with dry AMD / GA and wet AMD, and prevent the occurrence of one of the diseases. Such combinations can be used to treat patients with wet AMD who do not suffer from GA, to prevent or delay the development of GA after they receive a combination of anti-VEGF and complement agents. Examples of combinations of complement inhibitors and anti-VEGF agents include Aflibercept + Pegcetacoplan, Aflibercept + Avacincaptad Pegol, Ranibizumab + Pegcetacoplan, Ranibizumab + Pegcetacoplan, Axitinib + Pegcetacoplan, Axitinib + Avacincaptad pegol, Voronib + Pegcetacoplan, Voronib + Avacincaptad pegol, Lenvatinib + Pegcetacoplan, Lenvatinib + Avacincaptad, Farecimab + Pegcetacoplan, Farecimab + Avacincaptad Pegol, Bevacizumab + Pegcetacoplan, Bevacizumab + Avacincaptad Pegol.

[0262] In other embodiments, the combination of active agents may include anti-VEGF and IL-6 blockers, such as any combination of aflibercept, ranibizumab, bevacizumab, farecimab, axitinib, voronib, lenvatinib (anti-VEGF) with salilumab, tocilizumab, RG6179 (IL-6 blocker).

[0263] In other embodiments, combinations of active agents may include a beta blocker in combination with a PgA analog such as timolol (most commonly used for glaucoma) and any of the PgA analogs such as latanoprost, bimatoprost, travoprost.

[0264] The active agent combinations of the present invention may also include a combination of at least one therapeutic active agent and at least one diagnostic active agent, or a combination of more than two active agents.

[0265] Therapeutic methods including administration of a drug delivery system as described in this subsection (such as a pharmaceutically acceptable implant) may include intravitreal, intracameral, subconjunctival, retrobulbar, subfascial, subretinal, and suprachoroidal injections. Administration may also be topical or oral.

[0266] The activating agent or other agent to be used in the combination therapy can also be a diagnostic agent. Diagnostic agent can be a material for checking the body to detect whether its normal function is impaired. In some cases, diagnostic agent can be an agent with functional purpose, such as for detecting eye deformity, illness and pathophysiological aspects. For example, diagnostic agent can be an important and effective diagnostic adjuvant, such as dye (for example, fluorescein dye, indocyanine green, trypan blue, dark quencher such as cyanine dye, azo dye, acridine, fluorene, oxazine, phenanthridine, naphthalimide, rhodamine, benzopyrone, perylene, benzanthrone, p-benzothranolone), to contribute to the visualization of eye tissue. Diagnostic agent can include paramagnetic molecules, fluorescent compounds, magnetic molecules, radionuclides, x-ray imaging agents and / or contrast media. In some embodiments, diagnostic agents may include radiopharmaceuticals, contrast agents for imaging techniques, allergen extracts, activated charcoal, different test strips (e.g., cholesterol, ethanol, and glucose), pregnancy tests, 13C urea breath tests, and various stains / markers. In some embodiments, the labeling moiety is a fluorescent dye or dark quencher selected from the group consisting of coumarins, cyanine dyes, azo dyes, acridines, fluorenes, oxazines, phenanthridines, naphthalimides, rhodamines, benzopyranones, perylenes, benzanthrones, and benzanthrones. In a specific non-limiting embodiment, the fluorescent dye is a compound selected from the group consisting of coumarin, fluorescein, cyanine 3 (Cy3), cyanine 5 (Cy5), cyanine 7 (Cy7), Alexa dyes, bodipy derivatives, (E)-2-(4-(phenyldiazenyl)phenoxy)acetic acid, 3-(3',3'-dimethyl-6-nitrospiro[chromene-2,2'-indolino]-1'-yl)propionate (spiropyran), 3,5-dihydroxybenzoate and (E)-2-(4-(phenyldiazenyl)phenoxy)acetic acid, or a combination thereof.

[0267] Release control method

[0268] In one aspect, the present invention relates to a method for controlling the release of an active agent from a sustained release biodegradable drug delivery system as previously described herein, by selecting a combination of a hydrophobic organic liquid and an active agent dispersed therein, wherein any one or a combination of the following criteria applies:

[0269] a) The active agent dispersed in a hydrophobic liquid (e.g., oil) is released from the organogel along with the hydrophobic liquid (the diffusion / absorption rate of the oil determines the agent release rate);

[0270] b) Direct elution of the active agent from a hydrophobic liquid (e.g., oil) into the body, where the agent release rate is controlled by at least one of the drug solubility and / or diffusivity in the hydrophobic liquid (e.g., oil) and / or the surface area on the implant (the agent release rate is largely independent of the diffusion / absorption rate of the hydrophobic liquid).

[0271] In certain embodiments of the present invention, the release of activating agent is mainly controlled by the diffusion of activating agent and / or hydrophobic liquid (for example, oil).The degradation rate of polymer network provides another independent other mechanism for release control.In certain embodiments, hydrophobic liquid delays or accelerates degradation, which can be used as another method for controlling the release of activating agent.When the activating agent dispersed in the hydrophobic liquid is released from the organogel together with the hydrophobic liquid, the release rate of the agent will be substantially affected by the influence of the speed in the surrounding tissue or the body environment or determined by it.In other embodiments, activating agent can diffuse out from the polymer network more easily than oil diffuses out from the hydrophobic liquid.

[0272] When in contact with aqueous body fluids, the organogels of the invention swell by absorbing water. The degree of swelling depends largely on the gel-forming components used and their hydrophobicity / hydrophilicity. Swelling may result in an increase in the length and / or diameter size of the organogels according to the invention by up to 2000%, 1000%, 100%, 95%, 90%, 80%, 75%, 70%, 60%, 50%, 40%, 30%, 20% or 10%.

[0273] However, even after swelling, in certain embodiments, the drug delivery system of the present invention maintains its shape or substantial shape over an extended period of time due to crosslinking of the polymer components. In certain embodiments, the polymer network of the organogel will only substantially degrade after all active agent has been released, or at least after a majority of the active agent, e.g., at least 50%, 60%, 70%, 80%, 90%, 99%, or 100% by weight of the active agent has been released.

[0274] In certain embodiments, it is believed that while swelling primarily results in, for example, an increase in the size of an organogel implant, it also has an effect on the release of the active agent and / or the biodegradation of the gel matrix. Through the swelling of the organogel, as the amount of water intruding into the organogel increases, the hydrophobic organic liquid can be expelled from the gel matrix together with the active agent dissolved therein, or if the active agent is not dissolved in the hydrophobic liquid phase, not together with the active agent, or its outward diffusion is accelerated and the hydrophobic liquid is subsequently replaced by water,

[0275] For example, over time, the replacement of the organic hydrophobic liquid in the gel by water can stably dissolve the hydrophilic active agent that is dispersed but not dissolved in the organic hydrophobic liquid, which can be used to control the release of the active agent. In this embodiment, the active agent release is mainly or entirely a controlled diffusion of the active agent through the oil and polymer into the surrounding tissue. In certain embodiments, when the active agent release rate is largely independent of the diffusion rate of the hydrophobic liquid, such as when it is a hydrophilic agent dispersed in the hydrophobic liquid as solid particles, another factor that affects or determines the release of the active agent dispersed in the hydrophobic liquid is the rate at which water diffuses into the gel and / or the hydrophobic liquid, thereby subsequently dissolving the active agent and eluting it from the organic gel into the surrounding aqueous environment.

[0276] Furthermore, in certain embodiments, the slow replacement of the hydrophobic organic liquid by water slowly transforms the organogel into a hydrogel, which remains cross-linked and therefore maintains its shape, but can then more easily be (bio)degraded by hydrolysis and / or enzymatic reactions after the active agent and / or the hydrophobic liquid of the drug delivery system are exhausted.

[0277] The overall release of the active agent is controlled by at least one or a combination of all of these release mechanisms.

[0278] Additionally, in certain embodiments, while maintaining or substantially maintaining its structure due to chemical cross-linking of individual polymer chains, the organogel becomes softer and more flexible during swelling through absorption to mimic natural tissue.

[0279] In another aspect, the present invention relates to a method for controlling the release of an active agent from a sustained release biodegradable drug delivery system as previously described herein, by any one or a combination of the following measures:

[0280] a) selecting the L / G ratio of polylactic-co-glycolic acid (PLGA) units to adjust the hydrophobicity of the polymer network;

[0281] b) selecting the L / G ratio of the polylactic-co-glycolic acid (PLGA) unit to provide sustained release of the active agent;

[0282] c) selecting the molar ratio of the amount of the first crosslinkable precursor to the second crosslinkable precursor in order to adjust the hydrophobicity of the polymer network; (= combining hydrophobic and hydrophilic precursors in different ratios)

[0283] d) selecting a molar ratio of the amount of the first cross-linkable precursor to the amount of the second cross-linkable precursor to provide sustained release of the active agent;

[0284] e) selecting the type of hydrophobic liquid to be included (e.g., immobilized) in the organogel;

[0285] f) adding a third crosslinkable precursor having a lower hydrolyzability than the first and second crosslinkable precursors, thereby changing the molar ratio of the components;

[0286] g) dispersing an active agent having high water solubility in the form of particles into the hydrophobic phase;

[0287] h) Incorporation of degradable end groups into the PLGA precursor to accelerate the hydrolysis of crosslinks relative to the internal ester linkages of PLGA.

[0288] In embodiments of the present invention involving PLGA units in a gel matrix, another mechanism can also be utilized to influence or control the release of an active agent. The hydrophobic properties of a covalently cross-linked polymer network in a patient's body can be altered by adjusting the ratio of lactic acid to glycolic acid units. By changing or selecting the L / G ratio of polylactic-co-glycolic acid (PLGA) units, the hydrophobicity of the polymer network can be altered. More hydrophobic lactic acid (L) units will increase the hydrophobicity of the gel matrix and reduce swelling and water absorption; increasing the content of relatively more hydrophilic glycolic acid (G) units will reduce the hydrophobicity of the gel matrix and will increase swelling and water absorption of the organogel.

[0289] In an embodiment of the invention, by varying and / or selecting the molar ratio of the first crosslinkable precursor to the second crosslinkable precursor, another possibility of adjusting the hydrophobicity of the polymer network is provided. The use of a higher amount of a hydrophobic precursor in combination with a more hydrophilic precursor such as a PEG unit, and vice versa, allows adjustment of swelling and hydrophobic liquid and / or active agent release.

[0290] Adding a third cross-linkable precursor having a different hydrophobicity than the first and second precursors and varying the molar ratios of the components can further be used to affect swelling and hydrophobic liquid and / or active agent release, as well as diffusion rates of active agent, hydrophobic liquid and / or water.

[0291] Reagent test kit

[0292] In one aspect, the present invention also relates to a kit comprising one or more sustained release biodegradable drug delivery systems as described herein. The kit may also include instructions for using the system. In some embodiments, the kit includes portions of the drug delivery system distributed on more than one separate container for forming an organogel and / or implant in situ at the application site or treatment site.

[0293] The kit for preparing the drug delivery system of the present invention may include premixed precursors and other components required to form an organogel in a separate compartment, and an applicator for merging the premix and forming the organogel when needed, so that the precursor of the organogel is stored in the kit and is prepared into an organogel / drug delivery system when needed for the patient. And the kit can be prepared for applying the organogel itself, that is, already in the form of an organogel. The applicator can be used in combination with the organogel. The kit is manufactured using medically acceptable conditions and contains components with pharmaceutically acceptable sterility, purity and preparation. The kit may include an applicator when appropriate, as well as instructions for use. The organogel component can be provided as: one or more containers with separate components or precursors, which are optionally premixed with a hydrophobic organic liquid and / or an active agent. The solvent / solution may be provided in the kit or provided separately, or the component may be premixed with a solvent. The kit may include a syringe and / or needle for mixing and / or delivery. The kit or system may include components described herein.

[0294] The packaging of the precursor and / or the entire kit can be carried out under dry conditions without oxygen. The precursor and / or kit components can be placed in an airtight container that is impermeable to moisture or oxygen, such as a glass or metal (foil) container.

[0295] The organogels or premixes used to prepare them can be gamma sterilized at the end of the implantable material manufacturing process. Alternatively or in addition, there can be a sterilization process before and / or after the assembly and sealing of the kit. Low humidity conditions can be used in this technique.

[0296] Preferred specific embodiments

[0297] According to a specific embodiment, the sustained-release biodegradable drug delivery system of the present invention is formed by gelling equimolar amounts of 4a20k PEG SAZ (20,000 Da PEG having 4 arms terminated with succinimidyl azelate groups) and 4a18k T1307 NH2 (18,000 Da Tetronic® 1307 having 4 arms terminated with amine groups) in the presence of 30 wt % (based on the total dry weight of the system) of acetyl triethyl citrate (ATEC) as a hydrophobic oil, 14 wt % of bupivacaine base (based on the total dry weight of the system) and dimethyl carbonate (DMC) as a solvent, and then removing the solvent under reduced pressure.

[0298] According to another specific embodiment, the sustained release biodegradable drug delivery system of the present invention is formed by gelling the same amount of 4a18k-Tet1307-SAP-NHS (Tet1307 or T1307 is a 4-arm ethylenediamine tetra (ethoxylate-block-propoxylate) tetraol copolymer as an electrophile functionalized precursor and 4a20k PEG-NH2 as a nucleophile functionalized polyethylene glycol precursor in the presence of DMC: acetone (90: 10 w / w). Tocopherol (vitamin E acetate) is used as a hydrophobic organic liquid in an amount of 42% by weight based on the dry gel, 16% by weight of micronized ropivacaine base (RPV) is used as an active agent, and the solvent is then removed.

[0299] According to another specific embodiment, the sustained-release biodegradable drug delivery system of the present invention is formed by using 40 wt % of acetyl triethyl citrate (ATEC) oil based on the dry gel as the hydrophobic organic liquid and 20 wt % of micronized ropivacaine base (RPV) based on the dry gel as the active agent, and cross-linking 4a20k-PLGA-NHS as an electrophile-functionalized polymer precursor with a small molecule cross-linker TAEA in an amount of about 2.5 wt % (based on the dry gel) in the presence of DMC: acetone (80:20 w / w) and then removing the solvent.

[0300] According to another specific embodiment, the sustained-release biodegradable drug delivery system of the present invention is formed by using acetyl triethyl citrate (ATEC) oil in an amount of 29 wt % based on the dry gel as the hydrophobic organic liquid and using 14 wt % of micronized ropivacaine base (RPV) based on the dry gel as the active agent, and making the same amount of 4a20k-PLGA-NHS as an electrophile-functionalized polymer precursor cross-linked with 4a18k Tet1307-NH2 as a nucleophile-functionalized ethoxylate-block-propoxylate polymer precursor in the presence of DMC: acetone (80:20 w / w) and then removing the solvent.

[0301] According to another specific embodiment, the sustained-release biodegradable drug delivery system of the present invention is formed by using acetyl triethyl citrate (ATEC) oil in an amount of 37 wt % based on the dry gel as the hydrophobic organic liquid and using 19 wt % of micronized ropivacaine base (RPV) based on the dry gel as the active agent, and making the same amount of 4a20k-Tet1307-SAP-NHS as an electrophile-functionalized ethoxylate-block-propoxylate polymer precursor cross-linked with 4a3.6kTet701-NH2 as a nucleophile-functionalized polymer precursor gel in the presence of DMC:acetone (80:20 w / w) and then removing the solvent.

[0302] According to another specific embodiment, the sustained-release biodegradable drug delivery system of the present invention is formed by using 40 wt % of acetyl triethyl citrate (ATEC) oil based on the dry gel as the hydrophobic organic liquid and 20 wt % of bupivacaine-HCl (BPV-HCl) based on the dry gel as the active agent, and cross-linking the small molecule cross-linking agent TAEA in an amount of about 0.4 wt % (based on the dry gel) with about 40 wt % (based on the dry gel) of 4a20k-PLGA-NHS as an electrophile-functionalized polymer precursor in the presence of DMC: acetone (80:20 w / w) and then removing the solvent.

[0303] According to another specific embodiment, the sustained-release biodegradable drug delivery system of the present invention is formed by using acetyl triethyl citrate (ATEC) oil in an amount of 29 wt % based on the dry gel as the hydrophobic organic liquid and using bupivacaine-HCl (BPV-HCl) in an amount of 14 wt % based on the dry gel as the active agent, and making the same amount of 4a20k-PLGA-NHS as an electrophile-functionalized polymer precursor cross-linked with 4a18k Tet1307-NH2 as a nucleophile-functionalized ethoxylate-block-propoxylate polymer precursor in the presence of DMC: acetone (80:20 w / w) and then removing the solvent.

[0304] Example

[0305] The following examples are included to demonstrate certain aspects and embodiments of the present invention as described in the claims. However, it should be understood by those skilled in the art that the following description is illustrative only and should not be considered in any way as limiting the present invention.

[0306] Materials and abbreviations used in the examples:

[0307] 4a18kTet1307-SAP or 4a18kTet1307-SAP-NHS is a four-arm 18 kilodalton electrophile functionalized ethoxylate-block-propoxylate polymer precursor (ethylenediaminetetra(ethoxylate-block-propoxylate)tetraol copolymer) obtained by functionalizing commercially available Tetronic 1307 with succinimidyl adipate (i.e., adipic acid and N-hydroxysuccinimide (NHS)). 4a20k-Tet1307-SAP-NHS is the same precursor with a molecular weight of 20 kilodaltons.

[0308] 4a18kTet1307-NH2 is a four-arm 18 kilodalton nucleophile functionalized ethoxylate-block-propoxylate polymer precursor obtained by functionalizing the commercially available Tetronic 1307 with hydroxylamine. 4a3.6kTet701-NH2 or 4a3.6kT701-NH2 is a four-arm 3.6 kilodalton nucleophile functionalized ethoxylate-block-propoxylate polymer precursor obtained by functionalizing the commercially available Tetronic 701 with hydroxylamine.

[0309] 4a20kSAZ or 4a20kPEG-SAZ or 4a20kPEG-SAZ-NHS is a four-arm 20 kilodalton electrophile functionalized polyethylene glycol precursor obtained by functionalizing commercially available 4a20kPEG with succinimidyl azelate (ie, azelaic acid and N-hydroxysuccinimide (NHS)).

[0310] 4a20kNH2 or 4a20kPEG-NH2 is a nucleophile (amine) functionalized polyethylene glycol precursor having a molecular weight of 20 kilodaltons.

[0311] 4a20kPLGA-NHS is a four-arm 20 kilodalton electrophile functionalized polymer precursor obtained by functionalizing commercially available 4a20kPLGA (with a 50:50 L / G ratio) with N-hydroxysuccinimide (NHS).

[0312] ATEC is acetyl triethyl citrate (2-acetyl triethyl citrate), which is commercially available from Sigma-Aldrich / Merck

[0313] ATBC is acetyl tributyl citrate (O-acetyl tributyl citrate), which is commercially available from Sigma-Aldrich / Merck.

[0314] TAEA is tris(2-aminoethyl)amine, which is commercially available from Sigma-Aldrich / Merck.

[0315] DMC is dimethyl carbonate.

[0316] PBS is phosphate buffered saline at physiological salt concentration, pH 7.4.

[0317] Example 1

[0318] In Example 1A, an organogel drug delivery system was prepared using tocopherol (vitamin E acetate) as a hydrophobic organic liquid, micronized ropivacaine base (RPV) as an active agent, and two polymer precursors 4a18k-Tet1307-SAP-NHS as electrophile functionalized precursors (Tet1307 or T1307 is a 4-arm ethylenediamine tetra (ethoxylate-block-propoxylate) tetraol copolymer) and 4a20k PEG-NH2 as a nucleophile functionalized polyethylene glycol precursor. Comparative Example 1B does not contain a hydrophobic organic liquid. The composition details are shown in Table 1 below.

[0319] Precursors, active agents and hydrophobic organic liquid (if used) were combined into a reaction mixture with a mixture of DMC:acetone (90:10 w / w) and tube cast to form a gel, which was dried overnight to remove the solvent.

[0320] Table 1:

[0321]

[0322] Both compositions formed solid gels within a gel time of about 2 minutes. While the comparative gel without the oil component was transparent, the inventive gel of Example 1A was white and opaque (see Figure 2 ). No syneresis was observed in either gel.

[0323] Example 2

[0324] In Example 2A, an organogel drug delivery system was prepared using acetyl triethyl citrate (ATEC) oil as the hydrophobic organic liquid, micronized ropivacaine base (RPV) as the active agent, and 4a20k-PLGA-NHS cross-linked with a small molecule cross-linker TAEA as the electrophile functionalized polymer precursor (Table 2). Comparative Example 2B did not contain a hydrophobic organic liquid.

[0325] Precursors, active agents and hydrophobic organic liquid (if used) were combined into a reaction mixture with a mixture of DMC:acetone (80:20 w / w) and tube cast to form a gel, which was dried overnight to remove the solvent.

[0326] Table 2

[0327]

[0328] Both examples formed solid gels in a gel time of less than 3 minutes. While the comparative gel without the oil component was opaque and rigid, the inventive gel of Example 2A was opaque and soft and exhibited some syneresis immediately after preparation, but no syneresis and a translucent appearance after drying.

[0329] In Example 2C, an organogel drug delivery system was prepared using acetyl triethyl citrate (ATEC) oil as the hydrophobic organic liquid, micronized ropivacaine base (RPV) as the active agent, and 4a20k-PLGA-NHS cross-linked with 4a18k Tet1307-NH2 as the nucleophile functionalized ethoxylate-block-propoxylate polymer precursor as the electrophile functionalized polymer precursor (Table 3). Comparative Example 2D did not contain a hydrophobic organic liquid.

[0330] Table 3

[0331]

[0332] Both examples formed solid gels in a gel time of less than 3 minutes. Both gels had an opaque appearance and were rubbery and stretchable. No syneresis was observed in either gel.

[0333] In Example 2E, another organogel drug delivery system was prepared using acetyl triethyl citrate (ATEC) oil as the hydrophobic organic liquid, micronized ropivacaine base (RPV) as the active agent, and 4a20k-Tet1307-SAP-NHS cross-linked with 4a3.6kTet701-NH2 as the nucleophile functionalized polymer precursor in the example as the electrophile functionalized ethoxylate-block-propoxylate polymer precursor (Table 4). Comparative Example 2F did not contain a hydrophobic organic liquid.

[0334] Table 4

[0335]

[0336] Both examples formed solid gels within a gel time of no more than 2 hours. Both gels had an opaque appearance and were brittle and sticky. No syneresis was observed in either gel.

[0337] The release data for Example 2A (PLGA / TAEA gel) of the present invention shows a delay in the release of ropivacaine compared to Comparative Example 2B, which does not contain an organic hydrophobic liquid. The release data for Examples 2C and 2E (PLGA / Tet1307 or Tet1307 / Tet701 gels) of the present invention, which have a more hydrophobic gelling agent, each show an increase in the release of ropivacaine compared to Comparative Examples 2D and 2F, which do not contain an organic hydrophobic liquid. Depending on the nature of the gel polymer used, the presence of an oil component in the organogel can be used to modify the release of an active agent that is more water soluble than oil soluble (see Figure 3 ).

[0338] Example 3

[0339] In Example 3A, an organogel drug delivery system was prepared using acetyl triethyl citrate (ATEC) oil as the hydrophobic organic liquid, non-micronized bupivacaine-HCl (BPV-HCl) as the active agent, and 4a20k-PLGA-NHS cross-linked with a small molecule cross-linker TAEA as the electrophile functionalized polymer precursor (Table 5). Comparative Example 3B did not contain a hydrophobic organic liquid.

[0340] Precursors, active agents and hydrophobic organic liquid (if used) were combined into a reaction mixture with a mixture of DMC:acetone (80:20 w / w) and tube cast to form a gel, which was dried overnight to remove the solvent.

[0341] Table 5

[0342]

[0343] Both examples formed solid gels in a gel time of less than 3 minutes. The gels were opaque and flexible and showed no syneresis.

[0344] In Example 3C, an organogel drug delivery system was prepared using acetyl triethyl citrate (ATEC) oil as the hydrophobic organic liquid, non-micronized ropivacaine-HCl (BPV-HCl) as the active agent, and 4a20k-PLGA-NHS cross-linked with 4a18k Tet1307-NH2 as the nucleophile functionalized ethoxylate-block-propoxylate polymer precursor as the electrophile functionalized polymer precursor (Table 6). Comparative Example 3D did not contain a hydrophobic organic liquid.

[0345] Table 6

[0346]

[0347] Both examples formed solid gels with excellent gel properties within a gel time of less than 3 minutes. No syneresis was observed in either gel.

[0348] The in vitro release kinetics (37°C, 1xPBS pH 7.4) of Examples 3A to 3D are shown in Figure 4 As can be seen, even though BPV is a more oil-soluble drug than ropivacaine, the release of the active agent is delayed by the presence of the organic hydrophobic liquid.

[0349] Example 4

[0350] A series of organogel drug delivery systems were prepared as described previously herein using different oils as hydrophobic organic liquids, non-micronized bupivacaine-HCl (BPV-HCl) as the active agent, and 4a18k Tet1307-SAP-NHS (Table 8) or 4a20k-PLGA-NHS (Table 9) cross-linked with 4a18k Tet1307-NH2 as nucleophile functionalized ethoxylate-block-propoxylate polymer precursors as electrophile functionalized polymer precursors. For comparison, each gel was also prepared without the use of a hydrophobic organic liquid.

[0351] The hydrophobic organic liquids used were acetyl triethyl citrate (ATEC), acetyl tributyl citrate (ATBC), α-tocopheryl acetate (vitamin E acetate).

[0352] To prepare the organogels, two premixes were prepared, the first premix comprising a mixture of electrophile and hydrophobic organic liquid (if used) and 300 mg DMC: acetone (80: 20 w / w), and the second premix comprising a mixture of nucleophile, activator and 200 mg DMC: acetone (80: 20 w / w). The two premixes were combined into a reaction mixture and tube cast to form a gel, which was dried overnight to remove the solvent. The compositions are detailed in Table 7A, Table 7B, Table 8A and Table 8B below.

[0353] Table 7A

[0354]

[0355] Table 7B

[0356]

[0357] Table 8A

[0358]

[0359] Table 8B

[0360]

[0361] The in vitro release kinetics (37°C, 1xPBS pH 7.4) of Examples 4A to 4H are shown in Figure 5 As can be seen, the release of the active agent BPV-HCl from Tetronic gels 4A to 4D was delayed by the presence of ATEC and ATBC and accelerated by vitamin E acetate, respectively, compared to the oil-free gel. For PLGA gels 4E to 4H, the release of the active agent BPV-HCl was accelerated by ATEC and delayed by the presence of ATBC and vitamin E acetate.

[0362] Example 5

[0363] A series of organogel drug delivery systems were prepared as previously described herein using bupivacaine base (BPV base) as the active agent and three different polymer precursor formulations A, B and C as shown in Table 9. For each formulation, the hydrophobic organic liquid used was either acetyl triethyl citrate (ATEC) or acetyl tributyl citrate (ATBC) in an amount of 0% (comparative), 20% or 40% by weight of the formulation.

[0364] Formulation A includes a hydrophilic polymer network (PEG-based) and is assigned a hydrophobicity value of 0% HB. Formulation B includes a more hydrophobic polymer network (PEG-poloxamer-based) and is assigned a hydrophobicity value of 15% HB. Formulation C includes the most hydrophobic polymer network (PLGA-poloxamer-based) and is assigned a hydrophobicity value of 65% HB.

[0365] Table 9:

[0366]

[0367] All formulations were prepared as organogel strands with an average diameter of 2.9 mm, which were cut into 5 mm long blocks with an average surface area of ​​59 mm² per block and an average drug load (dose) of 1600 μg.

[0368] The in vitro release kinetic data (37°C, 1xPBS pH 7.4) of the formulation of Example 5 are shown in Table 10 below. It can be seen that the release of the active agent BPV base from the PLGA gel of formulation C does not last for 3 days, but shows a very small initial burst (2h release value). Compared with ATEC, the release is delayed by the more hydrophobic oil ATBC, and the release can be further delayed by improving the cross-linking properties of the gel. For the less hydrophobic gel formulation B, the burst data is similar to the PLGA gel of formulation C, but the gel delays the release of BPV base for a longer time, lasting up to about 5 days. Similar effects of oil hydrophobicity are observed. Higher oil loads initially increase the burst and daily release. For the least hydrophobic gel formulation A, a higher amount of oil increases the burst, but the daily release does not seem to be affected by the amount of oil. Overall, formulation B provides a good balance of properties for delaying the release of BPV base. The samples with 20% (w / w) oil generally give the most reliable results, largely avoiding the initial burst.

[0369] Table 10

[0370]

[0371] Nomenclature: A-20E = Formulation A with 20% ATEC oil (4a20kPEG-SAZ / 4a20kPEG-NH2). A-20B = Formulation A with 20% ATBC oil (4a20kPEG-SAZ / 4a20kPEG-NH2).

[0372] Figure 6 The in vitro bupivacaine base release over time of several Formulations A and B of Example 5 is illustrated.

[0373] Example 6

[0374] An organogel drug delivery system was prepared using travoprost as the active agent, which simultaneously served as the hydrophobic organic liquid and substituted for the hydrophobic organic liquid. Travoprost is a transparent hydrophobic oil that is almost insoluble in water. For the gel-forming component, the hydrophobic 4a18K-Tet1307-SAP-NHS was used as an electrophile-functionalized polymer precursor, which was cross-linked with 4a20K-NH2, a more hydrophilic amine (nucleophile) functionalized PEG. (Table 11).

[0375] The precursor, hydrophobic liquid active agent (travoprost) and a mixture of DMC:acetone (80:20 w / w) were combined into a reaction mixture and tube cast to form a gel, which was dried overnight to remove the solvent.

[0376] Table 11

[0377]

[0378] A solid gel is formed in a gel time of less than 3 minutes. The gel is opaque and flexible and does not show syneresis, and is cast into fibers. Fiber sheets corresponding to drug doses of 3400 μg, 734 μg, and 730 μg were cut, and accelerated in vitro release kinetics were measured at 40°C, 1xPBS pH 7.4 for the 3400 μg and 734 μg doses, and accelerated in vitro release kinetics were measured at 37°C, 1xPBS pH 7.4 for the 730 μg dose sample, each in 60 ml buffer, so 100% release corresponds to 4 times less than the sink condition. Release experiments at 37°C showed the expected slower release and stopped after 6 weeks, and the extrapolation of the curve showed that continuous sustained release would be expected in about half a year. The in vitro release data are summarized in Table 12 below and are shown in Figure 7 middle.

[0379] Table 12

[0380]

[0381] from Figure 7 As can be seen in the Figure 1, the active agent is released in a constant slow sustained manner following zero-order kinetics over an extended period of time, with little initial burst. Since the gel is expected to be substantially degraded after only 6 months, the release kinetics of the active agent are diffusion controlled. No effect of gel degradation was observed. In addition, comparison of the two different doses shows that the analytical methods are compatible and that the slow sustained release kinetics observed with the high dose sample are not due to drug saturation in the release buffer.

Claims

1. A sustained-release biodegradable drug delivery system comprising an organogel and an active agent, wherein the organogel comprises: a hydrophobic organic liquid, and Biodegradable covalently cross-linked polymer network, wherein the hydrophobic organic liquid and the active agent are contained in the biodegradable covalently cross-linked polymer network.

2. A system as described in claim 1, wherein the hydrophobic organic liquid is liquid at human body temperature, preferably liquid at a temperature of about 37°C or lower, or in the range of 0°C to 45°C, or 10°C to 38°C, or 15°C to 37°C, or 25°C to 37°C, or at 37°C.

3. The system of claim 1 or 2, wherein the active agent is dissolved or dispersed in the hydrophobic organic liquid.

4. A system as claimed in any preceding claim, wherein the active agent is or forms at least a part of the hydrophobic organic liquid.

5. The system of any one of the preceding claims, wherein the hydrophobic organic liquid is, or comprises, an oil or an oil mixture.

6. The system of any of the preceding claims, wherein the hydrophobic organic liquid is a biocompatible oil selected from the group consisting of triethyl citrate, acetyl triethyl citrate (ATEC), acetyl tributyl citrate (ATBC), alpha-tocopherol (vitamin E), alpha-tocopheryl acetate; plant or vegetable 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, flaxseed oil Oil, ethyl oleate, castor oil and its derivatives (Cremophor®), lipids that are liquid at 37° C. or lower, such as saturated or unsaturated fatty acids, monoglycerides, diglycerides, triglycerides (Myglyols®), isopropyl myristate, phospholipids, glycerophospholipids, sphingolipids, sterols, prenol, polyketide; hydrophobic biodegradable liquid polymers (such as low molecular weight PLGA, PGA or PLA), low melting point waxes such as vegetable waxes, animal waxes or synthetic waxes, lanolin, jojoba oil or combinations thereof.

7. The system of any of the preceding claims, wherein the hydrophobic organic liquid has a glass transition temperature and / or a melting temperature equal to or lower than 37°C.

8. A system as claimed in any one of the preceding claims, wherein the hydrophobic organic liquid is non-volatile at 37°C, and / or biocompatible, and / or capable of being cleared from the implantation site, metabolized and / or eliminated from the body unchanged.

9. The system of any of the preceding claims, wherein the biodegradable, covalently cross-linked polymer network comprises one or more polymer units of polyethylene glycol, polyethylene oxide, polypropylene oxide, polyvinyl alcohol, poly(vinyl pyrrolidone), polylactic acid (PLA), polyglycolic acid (PGA), polylactic-co-glycolic acid (PLGA), p-dioxanone, trimethylene carbonate, caprolactone, random or block copolymers of any of these, or combinations or mixtures thereof, or one or more units of polyamino acids, glycosaminoglycans, polysaccharides, or proteins.

10. The system of any one of the preceding claims, wherein the biodegradable covalently cross-linked polymer network comprises a plurality of hydrophobic polymer units and / or hydrophilic polymer units.

11. The system of claim 10, wherein the hydrophobic polymer unit is selected from at least one of polylactic acid (PLA) and polylactic-co-glycolic acid (PLGA) units.

12. The system according to any one of claims 9 or 11, wherein the hydrophilic polymer unit is selected from at least one of polyethylene glycol units, polypropylene glycol units or polyglycolic acid (PGA), preferably polyethylene glycol units.

13. The system of any one of claims 9 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 system of any one of claims 9 to 13, wherein the covalently cross-linked polymer network comprises a combination of: - a plurality of hydrophobic polymer units selected from at least one of polylactic acid (PLA) and polylactic-co-glycolic acid (PLGA), and - at least one of a plurality of hydrophilic polyethylene glycol (PEG) units, polypropylene glycol (PPG) or polyglycolic acid (PGA) units.

15. The system of claim 14, wherein the polymer network comprises a combination of polylactic-co-glycolic acid (PLGA) units and polyethylene glycol (PEG) units, preferably a copolymer of PEG and PLGA, and particularly preferably a block copolymer of multi-arm PEG and PLGA.

16. The system of claim 15, wherein the ratio of polylactic-co-glycolic acid (PLGA) units to polyethylene glycol (PEG) units is about 2.5:1 to 1:2.5, or 2:1 to 1:2, or 1:

1.

17. The system of any one of claims 11 to 16, wherein the polylactic-co-glycolic acid (PLGA) units have an L / G ratio (as % 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, or 50:

50.

18. The system of any of the preceding claims, wherein the polymer network is covalently cross-linked via hydrolyzable bonds between polymer units.

19. The system of claim 19, wherein the hydrolyzable bond is selected from the group consisting of an amine, amide, carbamate, ester, anhydride, ether, acetal, ketal, nitrile, isonitrile, isothiocyanate, or imine bond, and combinations thereof.

20. The system of any one of the preceding claims, wherein the polymer network is formed from at least one covalently cross-linkable precursor that is miscible with, soluble or dispersible in the hydrophobic organic liquid.

21. The system of claim 20, wherein the at least one cross-linkable precursor is hydrophobic.

22. The system of any one of claims 20 or 21, wherein at least one cross-linkable precursor has a functionality greater than 2, such as 3 to 10, or 3 to 9, or 4 to 8, or 4.

23. The system of any one of claims 20 to 22, wherein the at least one cross-linkable precursor is a dendrimer or a multi-arm precursor having a core and 2 to 10 arms, or 3 to 10 arms, 4 to 8 arms, or 4 or 8 arms, each arm comprising a polymer unit and having a terminus.

24. The system of any one of claims 20 to 23, wherein the at least one cross-linkable precursor comprises hydrophobic polymer units selected from polylactic acid (PLA) units and polylactic-co-glycolic acid (PLGA) units, copolymers thereof, or combinations thereof.

25. The system of any one of claims 20 to 24, further comprising at least one cross-linking agent, preferably a small molecule amine such as tris(2-aminoethyl)amine (TAEA) or trilysine.

26. The system of any one of claims 20 to 24, further comprising at least one hydrophilic cross-linkable precursor.

27. The system of claim 26, wherein the polymer network comprises a covalently cross-linked combination of: - one or more multi-arm precursors selected from polyethylene glycol (PEG) and polyglycolic acid (PGA), and - One or more multi-arm precursors selected from polylactic acid (PLA) and polylactic-co-glycolic acid (PLGA).

28. The system of claim 27, wherein the multi-arm precursor has a core and 2 to 10 arms, or 3 to 10 arms, 4 to 8 arms, or 4 or 8 arms, each arm having a terminal end.

29. The system of any one of claims 20 to 28, wherein the at least one covalently cross-linkable precursor comprises more than 2 functional groups.

30. The system of any one of claims 23 to 28, wherein the multi-arm precursor comprises a functional group on at least three of its arm ends or on each end.

31. The system of claim 30, wherein the polymer network is formed by at least two multi-arm precursors, the multi-arm precursors comprising a first multi-arm precursor comprising a first functional group and a second multi-arm precursor comprising a second functional group, the functional groups being located at the ends of the arms.

32. The system of claim 31, 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 to form a covalent bond.

33. The system of claim 32, wherein the nucleophile is selected from one of an amine such as a primary amine, a hydroxyl, a thiol, a carboxyl, a dibenzocyclooctyne, or a hydrazide.

34. The system of claim 32 or 33, wherein the electrophile is selected from succinimidyl esters, succinimidyl carbonates, nitrophenyl carbonates, aldehydes, ketones, acrylates, acrylamides, maleimides, vinyl sulfones, iodoacetamides, olefins, alkynes, azides, norbornenes, epoxides, mesylates, tosylates, trifluoroethanesulfonyls, cyanurates, orthopyridyl disulfides or halides, preferably wherein the succinimidyl ester comprises a reactive group selected from succinimidyl succinate, succinimidyl glutarate, succinimidyl adipate, succinimidyl azelate or succinimidyl glutarate.

35. The system of any one of claims 32 to 34, wherein the nucleophile is an amine group and the electrophile is an activated ester group.

36. The system of any of the preceding claims, wherein the active agent is selected from at least one of a therapeutically active agent or a diagnostically active agent or a combination thereof.

37. The system of any of the preceding claims, wherein the therapeutically active agent is selected from nonsteroidal anti-inflammatory drugs (NSAIDS), steroids, antibiotics, analgesics, analgesics, calcium channel blockers, cell cycle inhibitors, chemotherapeutic agents, antivirals, anesthetics, hormones, anticancer drugs, antitumor agents, viruses, viruses for gene delivery such as AAV, peptides, nanobodies, affibody molecules, ankyrins, DARPins, immunosuppressants, anti-inflammatory cytokine targeting agents, anti-glaucoma agents, anti-VEGF agents, tyrosine kinase inhibitors, complement inhibitors, antihistamines, IL-6 inhibitors, HtRA1 inhibitors, RASP inhibitors, rho kinase inhibitors, plasma kallikrein inhibitors, nitric oxide donor PgA, mast cell stabilizers, IGF-1 R inhibitors, TRPV1 antagonists, TrkA antagonists, pharmaceutically acceptable salts, anhydrates, hydrates, solvates, polymorphs, stereoisomers, crystalline forms, co-crystals, prodrugs, conjugates, complexes and mixtures thereof.

38. A system as claimed in any preceding claim, wherein the active agent is a drug in the form of a liquid oil at a temperature of up to 37°C, such as travoprost or the like, which forms at least a part of or replaces the hydrophobic organic liquid.

39. The system of any of the preceding claims, wherein the active agent is oil-soluble and is dissolved in the hydrophobic organic liquid.

40. The system of any of the preceding claims, wherein the active agent is oil-insoluble and is dispersed in the hydrophobic organic liquid in particulate form.

41. The system of claim 40, wherein the active agent particles are micronized particles having 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, or 5 μm or less and / or a D98 particle size of about 10 μm or less.

42. The system of claim 40, wherein the active agent particles are nanoscale particles having 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.

43. The system of any of the preceding claims, wherein the choice of the hydrophobic liquid, and / or the hydrophobicity of the polymer network, and / or the L / G ratio are used to modulate the release rate.

44. A system as described in any of the preceding claims, which provides release of a therapeutically effective amount of the active agent for a certain period of time after administration, such as 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.

45. The system of any of the preceding claims, which provides for release of a therapeutically effective amount of the active agent up to about 14 days or up to about 21 days after administration.

46. ​​The system of any of the preceding claims, which provides release of a therapeutically effective amount of the active agent for a period of about 6 hours or longer after administration, or for a period of about 12 hours or longer after administration.

47. The system of any of the preceding claims, wherein the organogel delays the release of a water-soluble active agent or accelerates the release of a hydrophobic active agent.

48. The system of any of the preceding claims, wherein the organogel comprises: 1 wt % to 90 wt % (based on total dry weight) of the hydrophobic organic liquid, or 5-90 wt %, 5-60 wt %, 10-50 wt %, 10-40 wt % or 15-40 wt %; 5 wt % to 95 wt % (based on total dry weight) of the covalently cross-linked polymer network, or 10-95 wt %, 40-95 wt %, 50-90 wt %, 60-90 wt % or 60-85 wt %; 1% to 50% by weight (based on total dry weight) of the active agent, or 5-50%, 5-40%, 10-30% or 10-25% by weight; Wherein all weight percentages are selected to total 100%, the weight % are based on the total dry weight of the drug delivery system.

49. A method of manufacturing a sustained release biodegradable drug delivery system according to any one of the preceding claims, the method comprising the steps of: (a) forming an organogel from at least the following: (b) Covalently cross-linked polymer networks, (c) hydrophobic organic liquids, (d) optionally a solvent, and (e) at least one active agent, (f) wherein said hydrophobic organic liquid and said active agent are contained within said biodegradable covalently cross-linked polymer network, (g) shaping the organogel, and (h) optionally removing the solvent from the organogel.

50. The method of claim 49, wherein the step of forming the organogel (step (1)) comprises: a) providing the hydrophobic organic liquid; b) providing the at least one active agent; c) providing a first covalently cross-linkable precursor comprising a first functional group; d) providing a second cross-linkable precursor comprising a second functional group; e) combining a), b), c) and d) in any order to form a reaction mixture; f) allowing the reaction mixture to gel.

51. The method of claim 50, wherein at least one organic solvent is optionally added to any one of a), b), c), d) and e).

52. The method of any one of claims 50 or 51, wherein the first covalently cross-linkable precursor comprising a first functional group is hydrophobic or hydrophilic.

53. The method of any one of claims 50 to 52, wherein the second cross-linkable precursor comprising a second functional group is hydrophobic or hydrophilic.

54. The method of any one of claims 50 to 53, wherein at least one of the first or second crosslinkable precursors has a functionality greater than 2, such as 3 to 10, or 3 to 10, or 4 to 8, or 4.

55. The method of any one of claims 50 to 54, wherein the first cross-linkable precursor is a dendritic polymer or a multi-arm precursor having a core and 2 to 12 arms, or 3 to 10 arms, 4 to 8 arms, or 4 or 8 arms, each arm comprising a polymer unit and having a terminus carrying the first functional group.

56. The method of claim 55, wherein the arms comprise hydrophobic polymer units selected from polylactic acid (PLA) units and polylactic-co-glycolic acid (PLGA) units, polypropylene glycol (PPG) and polyglycolic acid (PGA), or combinations thereof.

57. The method of claim 55, wherein the arm comprises a hydrophilic polymer unit selected from polyethylene glycol (PEG), polyethyleneimine, polyvinyl chloride, poloxamer, or a combination thereof.

58. The method of any one of claims 50 to 57, wherein the second cross-linkable precursor is a non-polymeric cross-linking agent, preferably a small molecule amine such as tris(2-aminoethyl)amine (TAEA) or trilysine.

59. The method of any one of claims 50 to 57, wherein the second cross-linkable precursor is a dendritic polymer or a multi-arm precursor having a core and 2 to 12 arms, or 3 to 10 arms, 4 to 8 arms, or 4 or 8 arms, each arm comprising a polymer unit and having a terminus carrying the second functional group.

60. The method of claim 59, wherein the arms comprise hydrophobic polymer units selected from polylactic acid (PLA) units and polylactic-co-glycolic acid (PLGA) units, or combinations thereof.

61. The method of claim 59, wherein the arm comprises a hydrophilic polymer unit selected from polyethylene glycol (PEG), polypropylene glycol (PPG), and polyglycolic acid (PGA), or a combination thereof.

62. The method of any one of claims 50 to 61, wherein the first functional group and the second functional group are selected from electrophiles and nucleophiles, and the reaction between the first functional group and the second functional group is an electrophile-nucleophile reaction that forms covalent bonds in the polymer network upon gelation.

63. The method of claim 62, wherein the nucleophile is selected from one of an amine such as a primary amine, a hydroxyl, a thiol, a carboxyl, a dibenzocyclooctyne, or a hydrazide.

64. The method of claim 62 or 63, wherein the electrophile is selected from succinimidyl esters, succinimidyl carbonates, nitrophenyl carbonates, aldehydes, ketones, acrylates, acrylamides, maleimides, vinyl sulfones, iodoacetamides, olefins, alkynes, azides, norbornenes, epoxides, mesylates, tosylates, trifluoroethanesulfonyl, cyanurates, orthopyridyl disulfides or halides, preferably wherein the succinimidyl ester comprises a reactive group selected from succinimidyl succinate, succinimidyl glutarate, succinimidyl adipate, succinimidyl azelate or succinimidyl glutaramide.

65. The method of any one of claims 62 to 64, wherein the nucleophile is an amine group and the electrophile is an activated ester group.

66. The method of claim 65, wherein the activated ester group is a succinimide ester comprising a reactive group selected from the group consisting of succinimidyl succinate, succinimidyl glutarate, succinimidyl adipate, succinimidyl azelate, and succinimidyl glutaramide.

67. as described in any one of the methods in claim 50 to 66, wherein said first and / or second multi-armed precursor has about 1,000 to about 100,000 dalton, about 7,000 to about 80,000 dalton, about 10,000 to about 60,000 dalton or about 15,000 to about 50,000 dalton scope average molecular weight (Mw).

68. methods as described in any one in claim 50 to 67, the described arm of wherein said multi-arm first and / or second multi-arm precursor has about 500 to about 20,000 dalton, about 1,000 to about 18,000 dalton, about 2,000 to about 15,000 dalton, about 3,000 to about 10,000 dalton or about 4,000 to about 8, the average molecular weight (Mw) in the range of 000 dalton.

69. The method of any one of claims 54 to 65, wherein the ratio of polylactic-co-glycolic acid (PLGA) precursor to polyethylene glycol (PEG) precursor is about 2.5:1 to 1:2.5, or 2:1 to 1:2, or 1:

1.

70. The method of any one of claims 60 to 69, wherein the polylactic-co-glycolic acid (PLGA) precursor has an L / G ratio (in terms of mole % L or G units) in the range of 1:99 to 99:1, or 10:90 to 90:10, or 25:75 to 75:25, or 50:

50.

71. The method of claim 70, wherein the L / G ratio of the polylactic-co-glycolic acid (PLGA) units is selected to adjust the hydrophobicity of the polymer network.

72. The method of claim 70 or 71, wherein the L / G ratio of the polylactic-co-glycolic acid (PLGA) units is selected to provide a sustained release of the active agent as defined in claims 43 to 47.

73. The method of any one of claims 50 to 72, wherein the ratio of the amounts of the first cross-linkable precursor to the second cross-linkable precursor is selected to adjust the hydrophobicity of the polymer network and / or to provide sustained release of the active agent as defined in claims 43 to 47.

74. The method of any one of claims 49 to 73, wherein the hydrophobic liquid is selected to adjust the hydrophobicity of the polymer network and / or to provide a sustained release of the active agent as defined in claims 43 to 47.

75. The method of any one of claims 49 to 74, wherein the step of shaping the organogel (step (2)) comprises molding or extruding the reaction mixture, gelling the mixture, and optionally removing the solvent before the organogel is completely gelled.

76. The method of claim 75, wherein molding comprises the steps of: The reaction mixture is filled into a mold or tube, the mixture is allowed to gel, and the solvent is optionally removed before the organogel is completely gelled.

77. The method of claim 76, wherein the reaction mixture is filled into a thin diameter tube to prepare an organogel strand.

78. The method of any one of claims 49 to 77, wherein the cross-linked polymer network comprises a polymer network comprising one or more cross-linked polymer units of polyethylene glycol, polypropylene glycol, polypropylene oxide, polyethylene oxide, polyvinyl alcohol, poly(vinyl pyrrolidone), polyimide, polylactic acid (PLA), polylactic-co-glycolic acid (PLGA), p-dioxanone, trimethylene carbonate, caprolactone, a random or block copolymer of any of these, or a combination or mixture, or one or more units of a polyamino acid, glycosaminoglycan, polysaccharide, or protein.

79. The sustained release biodegradable drug delivery system of any one of claims 1 to 48 for coating a medical implant or for use as a medical implant.

80. The biodegradable drug delivery system of sustained release as described in any one of claims 1 to 48, wherein the implant is selected from the group consisting of: an intraocular implant; an intracavitary implant; an intracameral implant; an implant for introduction into the anterior chamber, vitreous, extrascleral, posterior subfascial space (lower fornix), subconjunctival, intracameral, periorbital, posterior to the eyeball, subfascial, retina, subretinal, intratubular, intravitreal, intrascleral, choroid, suprachoroidal space, retina, subretinal or lens, cornea or conjunctival surface, lacrimal puncta (tubules, upper / lower tubules), fornix, upper / lower fornix, subfascial space, choroid, suprachoroidal, fascial, cornea, cancer tissue, organ, prostate, breast, joint space, subdural, tooth, subcutaneous, carpal tunnel, perivascular, surgically generated space or injury, void space and potential space.

81. A sustained release biodegradable drug delivery system as described in any one of claims 1 to 48 for administration by various different routes, such as orally, parenterally or by surgical insertion or injection.

82. A sustained-release biodegradable drug delivery system as described in any one of claims 1 to 48 or manufactured according to the method as described in any one of claims 49 to 78 for use as a medicament.

83. A sustained release biodegradable drug delivery system as described in any one of claims 1 to 48 or manufactured according to the method of any one of claims 49 to 78, for treating a disease / medical condition in a patient, the method comprising forming an organogel comprising a therapeutically active agent dispersed in a hydrophobic organic liquid contained in a covalently cross-linked polymer network, wherein the organogel is formed in situ at a treatment site in the patient, or is preformed and delivered to or implanted into a treatment site in the patient, so as to release the active agent over an extended period of time.

84. A method for treating a disease / medical condition in a patient, the method comprising forming an organogel comprising a therapeutically active agent dispersed in a hydrophobic organic liquid contained in a covalently cross-linked polymer network, wherein the organogel is formed in situ at a treatment site in the patient, or is preformed and delivered to or implanted at a treatment site so as to release the active agent over an extended period of time.

85. A method for treating a disease / medical condition in a patient, said method comprising administering to said patient an organogel so as to release a therapeutically active agent over an extended period of time, said organogel comprising said active agent dispersed in a hydrophobic organic liquid contained in a covalently cross-linked polymer network.

86. A system for use or a method of treatment according to any one of claims 82 to 85, wherein the treatment site is selected from the group consisting of anterior chamber, vitreous, episcleral, posterior subfascial space (inferior fornix), subconjunctival, intracameral, periorbital, retrobulbar, subfascial, retinal, subretinal, intracanalicular, intravitreal, intrascleral, choroidal, suprachoroidal space, retina, subretinal or lens, surface of cornea or conjunctiva, lacrimal puncta (canaliculi, superior / inferior canaliculi), fornix, superior / inferior fornix, subfascial space, choroid, suprachoroidal, fascia, cornea, cancer tissue, organ, prostate, breast, joint, subdural, tooth, subcutaneous, carpal tunnel, perivascular, surgically created space or lesion, void space, and potential space.

87. A system for use or a method of treatment according to any one of claims 82 to 86, wherein the disease / medical condition to be treated is an eye disease, such as a posterior ocular disease, such as any posterior segment eye disease affecting the vasculature and integrity of the retina, macula or choroid, resulting in visual acuity impairment, vision loss or blindness, particularly posterior segment disease states caused by 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 glaucoma, intraocular hypertension, hyphema, presbyopia, cataract, retinal vein occlusion, inflammation.

88. A method for controlling the release of an active agent from a sustained release biodegradable drug delivery system as described in any one of claims 1 to 48 or manufactured according to the method of any one of claims 49 to 78, by selecting a combination of a hydrophobic organic liquid and an active agent dispersed therein, wherein any one or a combination of the following criteria applies: - the active agent dispersed in the hydrophobic liquid is released from the organogel together with the hydrophobic liquid; - The active agent is eluted from the oil directly into the body.

89. A method for controlling the release of an active agent from a sustained release biodegradable drug delivery system as described in any one of claims 1 to 48 or manufactured according to the method as described in any one of claims 49 to 78, by any one or a combination of the following measures: - selecting the L / G ratio of the polylactic-co-glycolic acid (PLGA) units to adjust the hydrophobicity of the polymer network; - said L / G ratio of said polylactic-co-glycolic acid (PLGA) units is selected so as to provide a sustained release of said active agent as defined in claims 43 to 48; - selecting the molar ratio of the amount of the first crosslinkable precursor to the amount of the second crosslinkable precursor to adjust the hydrophobicity of the polymer network; - the molar ratio of the amount of the first cross-linkable precursor to the second cross-linkable precursor is selected to provide a sustained release of the active agent as defined in claims 43 to 48; - selecting the type of hydrophobic liquid to be contained in the organogel; - adding a third crosslinkable precursor having a lower hydrolyzability than said first and second crosslinkable precursors, optionally modifying the molar ratio of said first, second and / or third precursors; - An active agent with high water solubility in the form of particles is dispersed in the hydrophobic phase.

90. A kit comprising one or more sustained release biodegradable drug delivery systems or portions thereof as described in any one of claims 1 to 48 or manufactured according to the method of any one of claims 49 to 78, and instructions for use of the systems.

91. The kit of claim 90, wherein the parts of the drug delivery system are distributed over more than one separate container for forming an organogel in situ at an application site or treatment site.

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