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

Abstract

In certain embodiments, the present invention relates to a sustained-release biodegradable drug delivery system comprising an organogel and an active agent, wherein the organogel comprises a hydrophobic organic liquid and a biodegradable, covalently crosslinked polymer network, and the hydrophobic organic liquid and the active agent are contained in the biodegradable, covalently crosslinked polymer network. In another embodiment, the present invention relates to a pharmaceutically acceptable biodegradable drug delivery system, such as an implant, for the controlled release of a therapeutically or diagnostically active agent and methods of making the same. The present invention also relates to corresponding methods of treatment and use, and kits.

Description

[Technical Field]

[0001] In certain embodiments, the present invention relates to sustained-release biodegradable drug delivery systems comprising an organogel and an active agent, wherein the organogel comprises a hydrophobic organic liquid and a biodegradable, covalently crosslinked polymer network, and the hydrophobic organic liquid and the active agent are contained in the biodegradable, covalently crosslinked polymer network. In particular, the present invention relates, in certain embodiments, to pharmaceutically acceptable biodegradable drug delivery systems, such as implants, for the controlled release of therapeutically or diagnostically active agents and methods of making the same. The present invention also relates, in certain embodiments, to corresponding methods of treatment and use, and kits. [Background technology]

[0002] Although organogels (or oleogels) have been known for several decades, biomedical interest in organogels has only recently developed. Organogels consist of a continuous liquid phase, typically a solvent or oil, contained in a three-dimensional network. Organogels are capable of encapsulating a wide variety of therapeutic compounds, making them useful drug delivery platforms. To be considered for pharmaceutical applications, organogels must be biocompatible.

[0003] Controlled delivery of therapeutic agents has been an area of great research in recent years, as it improves treatment, eases administration, increases compliance, reduces side effects, and improves treatment outcomes.

[0004] Another approach to drug release control is to alter the chemical composition of the drug by creating prodrugs with different solubilities that revert to the parent drug after release from the hydrogel. This method offers viable control over release kinetics, but requires additional synthesis steps and associated testing requirements. Furthermore, slow conversion rates of prodrugs to the parent drug can cause undesirable effects when released into tissues.

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

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

[0007] It is a further object of certain embodiments and aspects of the present invention to provide methods for producing such biodegradable drug delivery systems.

[0008] It is a further object of certain embodiments and aspects of the present invention to provide a method for controlling the release of an active agent from a sustained release biodegradable drug delivery system.

[0009] It is a further object of certain embodiments and aspects of the present invention to provide a method for treating a disease / condition in a patient using a sustained release biodegradable drug delivery system.

[0010] It is a further object of certain embodiments and aspects of the present invention to provide kits that include one or more sustained-release biodegradable drug delivery systems.

[0011] Some aspects of the present disclosure relate to sustained-release biodegradable drug delivery systems comprising an organogel and an active agent, wherein the organogel comprises a hydrophobic organic liquid and a biodegradable, covalently crosslinked polymer network, and wherein the hydrophobic organic liquid and the active agent are contained in, e.g., immobilized in, the biodegradable, covalently crosslinked 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, while 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 consists of, consists essentially of, or comprises the active agent and optionally one or more pharmaceutically acceptable excipients.

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

[0014] In some aspects of the present disclosure, the biodegradable covalently crosslinked polymer network comprises a plurality of hydrophobic polymer units, such as, for example, polylactic acid (PLA), polypropylene glycol units, or polyglycolic acid (PGA) and polylactic-co-glycolic acid (PLGA) units, and / or hydrophilic polymer units, such as polyethylene glycol units, polyvinyl alcohol, poly(vinylpyrrolidone), polyethyleneimine, etc. In certain embodiments, the hydrophobic polymer units comprise polyethylene glycol units.

[0015] In some aspects of the present disclosure, the polymer network is covalently crosslinked by hydrolyzable bonds between the polymer units.

[0016] In some aspects of the present disclosure, the polymer network is formed from at least two multi-arm precursors (e.g., 2- to 10-arm precursors), including a first multi-arm precursor containing a first functional group and a second multi-arm precursor containing a second functional group, the functional groups being located at the ends of the arms. In certain embodiments, each of the first and second functional groups is selected from the group consisting of an electrophile and a nucleophile, and the reaction between the first and second functional groups is an electrophile-nucleophile reaction, forming a covalent bond. In certain embodiments, the cross-linked covalent bond so formed is 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 embodiments of the present disclosure, the selection of the hydrophobic liquid and / or the hydrophobicity of the polymer network and / or the molar ratio of lactide to glycolide (L / G ratio) is used to adjust the release rate.

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

[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 embodiments of the present disclosure, the organogel comprises about 1 to about 90 wt. % hydrophobic organic liquid, about 5 to about 95 wt. % covalently crosslinked polymer network, and about 1 to about 50 wt. % active agent, all weight percentages selected to total 100%, and the weight percentages are based on the total weight of the finished drug delivery system.

[0022] Some aspects of the present disclosure relate to methods of making a sustained release biodegradable drug delivery system according to any of the preceding claims, the method comprising forming an organogel from at least a covalently crosslinked 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 crosslinked polymer network; 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 adjust 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 shaping the organogel includes molding or extruding the reaction mixture before the organogel is completely gelled, allowing the mixture to gel, and optionally removing the solvent.

[0025] Some aspects of the present disclosure relate to sustained release biodegradable drug delivery systems for coating or use as medical implants.

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

[0027] Some aspects of the present disclosure relate to sustained release biodegradable drug delivery systems for use as medicaments.

[0028] Some aspects of the present disclosure relate to sustained release biodegradable drug delivery systems for use in treating a disease / 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 crosslinked polymer network, the organogel being formed in situ at the treatment site in the patient or prefabricated and delivered or implanted at the treatment site in the patient to release the active agent over an extended period of time.

[0029] Some aspects of the present disclosure relate to methods for treating a disease / 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 crosslinked polymer network, the organogel being formed in situ at a treatment site in the patient or prefabricated and delivered to or implanted at the treatment site for release of the active agent over an extended period of time.

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

[0031] Some embodiments of the present disclosure relate to methods 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 an active agent dispersed therein, where any one or combination of the following criteria applies: a) An active agent dispersed in a hydrophobic liquid is released from the organogel along with the hydrophobic organic liquid (e.g., oil). b) The active agent is eluted directly from the oil into the body.

[0032] Some aspects of the present disclosure relate to methods for controlling the release of an active agent from a sustained-release biodegradable drug delivery system by any one or combination of the following measures (in any order, or two or more steps simultaneously): a) Selecting the L / G ratio of poly(lactic-co-glycolic acid) (PLGA) units to adjust the hydrophobicity of the polymer network. b) Selecting the L / G ratio of polylactic-co-glycolic acid (PLGA) units to provide sustained release of the active agent as defined herein. c) Selecting the molar ratio of the amount of the first crosslinkable precursor to the second crosslinkable precursor to adjust the hydrophobicity of the polymer network. d) selecting the molar ratio of the amount of the first crosslinkable precursor to the second crosslinkable precursor to provide sustained release of the active agent as defined herein; e) Select the type of hydrophobic liquid to be included in the organogel. f) adding a third crosslinkable precursor that is less hydrolyzable than the first and second crosslinkable precursors, and optionally varying the molar ratio of the third precursor; g) Dispersing an active agent in particulate form with high water solubility in a hydrophobic phase.

[0033] Some aspects of the present disclosure relate to kits that include one or more sustained-release biodegradable drug delivery systems or portions thereof described herein and instructions for using the systems, and / or kits in which portions of the drug delivery systems are distributed into multiple separate containers for forming organogels in situ at the site of application or treatment.

[0034] definition As used herein, the term "sustained-release biodegradable drug delivery system" refers to a system that contains an active agent and is administered to a patient, e.g., as an implant, where it remains in place for a period of time while releasing the active agent into the surrounding environment. The drug delivery system may be of any predetermined shape (e.g., rod-shaped, spherical, oblate spheroidal, ellipsoidal, disc-shaped, tubular, hemispherical, or irregular) prior to insertion or administration, and this shape may be maintained to some extent upon placement of the system at a desired location, although the dimensions (e.g., length and / or diameter) of the system may change after administration due to hydration and / or biodegradation, as further disclosed herein. Drug delivery systems may be designed to be biodegradable over time (as disclosed below), thereby softening, changing shape, and / or decreasing in size, and ultimately being eliminated by either dissolution or disintegration.

[0035] The term "biodegradable" refers to a material or object (such as a drug delivery system according to the present invention) that degrades in vivo, i.e., when placed in a human or animal body, or in vitro, when immersed in an aqueous solution under physiological conditions, such as pH 7.2-7.4 at 37°C. In the context of the present invention, as disclosed in detail herein below, a drug delivery system comprising an organogel containing an active agent slowly (biodegrades) over time when administered or deposited in the human or animal body. In certain embodiments, biodegradation occurs, at least in part, through ester hydrolysis in the aqueous environment of the body. Biodegradation may also occur through hydrolysis or enzymatic cleavage of covalent crosslinks / bonds between precursors and / or within the polymer units of the precursors themselves. The drug delivery system slowly softens and disintegrates, resulting in elimination via physiological pathways. In certain embodiments, the organogel of the present invention retains its shape for extended periods of time (e.g., about 1 month, 3 months, or 6 months, or longer). In certain embodiments, the shape is maintained by covalent crosslinking of the polymeric 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.

[0036] An "organogel" in the present invention is a solid or semi-solid system that forms a covalently crosslinked three-dimensional network of one or more hydrophilic or hydrophobic natural or synthetic polymers (as disclosed herein) containing a hydrophobic organic liquid as disclosed herein. Therefore, in the present invention, "organogel" is limited to so-called chemical organogels, in which the intermolecular interactions between the organogelating molecules are chemical bonds (e.g., covalent bonds) formed during gelation by a chemical reaction that induces crosslinking. As used herein, "organogel" refers to a three-dimensional polymer network of at least two precursors / gelators, including a hydrophobic organic liquid and, optionally, a hydrophobic organic liquid, covalently crosslinked to each other in the presence of an organic solvent and contained within the covalently crosslinked polymer network.

[0037] The term "polymer network" describes a structure formed from polymer chains (of the same or different molecular structure and of the same or different molecular weight) that are covalently crosslinked to one another. Types of polymers suitable for the purposes of the present invention are disclosed herein below. The term "polymer network" is used interchangeably with the term "matrix."

[0038] The term "amorphous" refers to a polymer or polymer network that does not exhibit a melting point or crystalline structure in X-ray or electron scattering experiments.

[0039] The term "semi-crystalline" refers to a polymer or polymer network that has some crystalline properties, i.e., that exhibits a melting point or some crystalline properties in X-ray or electron scattering experiments.

[0040] As used herein, the terms "precursor" or "gelator" or "component" refer to molecules or compounds that react with each other and thereby bond through covalent crosslinks to form a polymer network and thus an organogel matrix. Other materials, such as active agents, hydrophobic liquids, or solvents, may be present within the organogel, but are not referred to as "precursors."

[0041] Portions of precursor molecules that remain in the final polymer network are also referred to herein as "units." Thus, "units" are building blocks or components of the polymer network that forms the organogel. For example, polymer networks suitable for use in the present invention may contain the same or different polyethylene glycol units, PLGA units, or other types of polymers, as further disclosed herein.

[0042] 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 the surrounding environment. The surrounding environment may be an in vitro environment or an in vivo environment, as described herein. In certain specific embodiments, the surrounding environment is the vitreous humor and / or ocular tissues, such as the retina and choroid.

[0043] The term "100% release of active agent" should be interpreted as 95% to 100%. The manner in which this controlled release is achieved depends on several parameters that are characteristics of the drug delivery system, as disclosed herein. Each such characteristic property of the drug delivery system can contribute, alone or in combination with each other, to the controlled release.

[0044] For purposes of the present invention, the term "sustained release" is intended to characterize a product formulated to make an active agent available over an extended period of time, thereby allowing for reduced dosing frequency compared to immediate-release dosage forms (e.g., solutions of the active agent applied topically to the eye (i.e., eye drops)). Other terms that may be used interchangeably herein with "sustained release" include "extended release" or "controlled release." The term "sustained release" in the context of the present invention includes constant active agent release, tapered active agent release, increasing active agent release, and any combination thereof (e.g., constant active agent release followed by tapered active agent release). The term "tapered" or "tapering" in the context of the present invention refers to the 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, as opposed to immediate release, such as with a bolus injection. Controlled release refers to the release of an amount of active agent over the total number of days required for 100% release of the active agent in an aqueous solution under in vitro physiological conditions, such as pH 7.2-7.4 and 37°C.

[0045] The term "long-term" as used herein refers to any period of time that one of skill in the art would consider to be extended treatment of a disease, particularly at least about 1 week, or at least about 1 month or more, e.g., up to about 12 months, or any intermediate period of time, e.g., 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.

[0046] "Zero order" or "substantially zero order" or "near zero order" release is defined as a linear proportional relationship 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 amount of active agent released proportionally within 20% of the elapsed time.

[0047] The terms "API," "active pharmaceutical ingredient," "active pharmaceutical agent," "active pharmaceutical ingredient," "(active) therapeutic agent," "active drug," and "drug" are used interchangeably herein and refer to substances used in finished pharmaceutical products (FPPs) and in the preparation of such finished pharmaceutical products that provide pharmacological activity or are intended to have a direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to have a direct effect in restoring, correcting, or modifying the physiological function of a patient.

[0048] The active agent used in accordance with the present invention may be an active agent for the treatment and / or prevention of a disease or disorder, or a diagnostic agent such as a marker. In an embodiment of the present invention, the active agent is a low water-solubility active agent (i.e., having a water solubility of less than about 1000 μg / mL or less than about 100 μg / mL). In another embodiment of the present invention, the active agent is a high water-solubility active agent (i.e., having a water solubility of more than about 1000 μg / mL or even more than 10 mg / mL). This definition does not depend on the agent being approved by a government agency.

[0049] For purposes of the present invention, an active agent may be used in any of its possible forms, including free acid, free base, polymorphs, or any pharmaceutically acceptable salt, anhydrate, hydrate, cocrystal, prodrug, or other solvate or derivative, such as a conjugate. In this description or claims, whenever an active agent is referred to without further specification, it also refers to the active agent in any such polymorph, pharmaceutically acceptable salt, anhydrate, solvate (including hydrate), or derivative form, even if not explicitly stated. With respect to an active agent, suitable solid forms include, but are not limited to, pure substance forms in any physical form known to those skilled in the art. For example, the active agent may be in the form of particles. The particles may be amorphous or crystalline, or may represent a mixture of the two forms. They may be produced in any size that can be classified, without limitation, as coarse particles, fine particles, or ultrafine particles, and their dimensions may be visible to the naked eye or under a microscope, and may have shapes such as single grains and / or aggregates. The particles may also be micronized. As used herein, the term "micronization" refers to small-sized particles, particularly microscopic particles, whose particle size is reduced by, but not limited to, for example, jet milling, jaw crushing, hammer milling, wet milling, precipitation in non-solvent, cryo-milling (milling with liquid nitrogen or dry ice) and ball milling.Also, active agent can be present in a dissolved or dispersed state, for example, in a solvent or aqueous medium, for example, in the form of particles dispersed in oil or compatible aqueous suspension (optionally, may contain excipients such as surfactants).

[0050] As used herein, the term "therapeutically effective" refers to the amount of active agent required to produce a desired therapeutic result after administration. For example, in the context of the present invention, one desired therapeutic result would be a reduction in symptoms associated with DED (e.g., as measured by in vivo tests known to those skilled in the art), such as an increase in Schirmer tear test score, a decrease in staining values 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 ocular surface disease index and / or standard patient assessment of dry eye scores, and a decrease in best-corrected visual acuity. In one embodiment, "therapeutically effective" refers to an amount of active agent in a sustained-release intracapillary insert that is capable of achieving a tear fluid concentration equivalent to a cyclosporine concentration of 0.236 μg / mL (believed to be required for immunomodulation (Tang-Liu and Acheampong, Clin. Pharmacokinet. 44(3), pp. 247-261)) in terms of therapeutic efficacy, once this tear fluid concentration is achieved, over an extended period of time, particularly substantially throughout the remainder of the wear period of the insert.

[0051] As used herein, the values "d10," "d50," "d90," and "d100" refer to values that characterize the percentage of particles in a particle size distribution that meet a certain particle size. In a given particle size distribution, 10% of the particles have a particle size of d10 or less, 50% of the particles have a particle size of d50 or less, 90% of the particles have a particle size of d90 or less, and substantially all of the particles have a particle size of d100 or less. The percentage can be expressed by different parameters known to those skilled in the art. For example, the percentage can be based on volume, weight, or number of particles. Thus, d50 can illustratively be the median particle size by volume, weight, or number. For example, a volume-based d90 of 43 μm means that 90% by volume of the particles have a particle size of 43 μm or less. In certain embodiments, d10, d50, and d90 are volume-based values. The particle size distribution (PSD) can generally be measured by methods known to those skilled in the art, including sieving and laser diffraction. In certain embodiments, the PSD is <429> Following optical diffraction measurements of particle size, the PSD is measured by laser diffraction. In a specific embodiment, the PSD is measured by laser diffraction using a Beckman Coulter LS 13 320 with an obscuration value in the range of 7-9% based on the optical model "Fraunhofer.rf780z".

[0052] The term "patient" as used herein includes both human and animal patients. Thus, the biodegradable drug delivery system according to the present invention is suitable for human or veterinary medical use. In general, a "subject" is an individual (human or animal) to whom a drug delivery system according to the present invention is administered. A "patient" is a subject in need of treatment for a particular physiological or pathological condition. A "patient" does not necessarily have to have been diagnosed with a particular physiological or pathological condition prior to receiving the drug delivery system.

[0053] The molecular weight of the polymer precursors used for the purposes of the present invention and disclosed herein can be determined by analytical methods known in the art. For example, the molecular weight of polyethylene glycol can be quantified by any method known in the art, including gel electrophoresis, such as SDS-PAGE (sodium dodecyl sulfate-polyacrylamide gel electrophoresis), gel permeation chromatography (GPC) (including GPC with a selective light scattering detector (SLS) or dynamic light scattering (DLS)), liquid chromatography (LC), and mass spectrometry (e.g., matrix-assisted laser desorption / ionization time-of-flight (MALDI-TOF) spectrometry or electrospray ionization (ESI) mass spectrometry). The molecular weight of polymers, including the polyethylene glycol precursors disclosed herein, is an average molecular weight (based on the molecular weight distribution of the polymer) and therefore may be represented by various average values, including weight average molecular weight (Mw) and number average molecular weight (Mn). For crosslinkable polymeric gelling agents used in the present invention, such as polyethylene glycol, PLGA, and poloxamer-based precursors, the molecular weights indicated herein are number-average molecular weights (Mn) determined by gel permeation chromatography using polystyrene standards according to standard methods known in the art. Materials, particularly multi-arm precursors, are typically purchased with specific molecular weights defined by the vendor. Suitable PEG precursors are available from a number of suppliers, including, for example, Jenkem Technology, Sinopeg, and Sigma-Aldrich.

[0054] As used herein, the term "day 1" refers to the time point immediately following "day 0." Thus, whenever "day 1" is used, it refers to the one day or approximately 24-hour period that has already passed after administration of the drug delivery system.

[0055] As used herein, the term "about" in connection with a measured quantity refers to normal variation in that measured quantity that would be expected by one of ordinary skill in the art in making the measurement and exercising a level of care commensurate with the purpose of the measurement and the precision of the measuring device.

[0056] The term "at least about" in relation to a measured amount refers to normal variations in the measured amount and amounts greater than the measured amount that would be expected by one of ordinary skill in the art in making the measurement and exercising a level of care commensurate with the purpose of the measurement and the precision of the measuring device.

[0057] As used herein, the term "mean" refers to the central or representative value within a set of data (points) and is calculated by dividing the sum of the data (points) by the number of data in the set (i.e., the average value of the data set).

[0058] As used herein, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0059] The term "and / or" as used herein in expressions such as "A and / or B" is intended to include both "A and B" as well as "A or B."

[0060] Open terms such as "include," "including," "contain," "containing," and the like mean "comprising." These open-ended transitional phrases are used to introduce an open-ended list of elements, method steps, etc. that does not exclude additional, unlisted elements or method steps.

[0061] When used herein in conjunction with a particular value or number, the term "up to" is meant to include that respective value or number.

[0062] As used herein, the terms "from A to B," "from A to B," and "A to B" are used interchangeably and refer to a range from A to B, with an upper limit A and a lower limit B.

[0063] Throughout this disclosure, various aspects of the invention are presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Thus, the description of a range should be considered to have specifically disclosed not only each individual numerical value within that range, but also all possible subranges. For example, the description of a range such as 1 to 6 should be considered to have specifically disclosed subranges such as 1 to 3, 1 to 4, 1 to 5, 2 to 4, 2 to 6, 3 to 6, etc., as well as each individual number within that range, e.g., 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range. Numerical ranges described are inclusive of the numerical values defining the range and include each integer within the stated range.

[0064] As used herein, the abbreviation "PBS" means phosphate buffered saline.

[0065] As used herein, the abbreviation "PEG" means polyethylene glycol.

[0066] As used herein, the abbreviation "PLGA" means poly(lactic-co-glycolic acid), which has an L / G ratio of 1:1 (50:50), unless otherwise specified.

[0067] The terms "hydrophobic" or "oleophilic" are defined as the property of a polymer or material that has a low degree of water attraction or absorption, i.e., the material is repelled by a body of water. The terms "hydrophilic" or "oleophobic" are defined conversely 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 drop of liquid, preferably a drop of water, formed on a solid polymer and / or gel surface. Furthermore, the hydrophobic organic liquids used in the present invention are immiscible, or at least not easily miscible, with water.

[0068] The term "immobilized" as used herein refers to long-term immobility and not local mobility within the matrix, i.e., the hydrophobic liquid phase exists as a continuous phase within the polymer matrix and can only slowly migrate in vivo, i.e., can slowly migrate into body fluids over time.

[0069] The term "syneresis" describes the phenomenon of separation of liquid (oil) from an (organo)gel during gel shrinkage. [Brief explanation of the drawings]

[0070] [Figure 1] A comparison of the basic structures of organogels and hydrogels is shown. [Figure 2] 1 is a photograph of the organogel of Example 1. [Figure 3] 1 is a graph showing the in vitro release of the drug delivery systems of Examples 2A-2F. [Figure 4] 1 is a graph showing the in vitro release of the drug delivery systems of Examples 3A-3D. [Figure 5] 1 is a graph showing the in vitro release of the drug delivery systems of Examples 4A to 4H. [Figure 6] 1 is a graph showing the in vitro release of bupivacaine base over time for some of the organogel formulations of Example 5. [Figure 7] 1 is a graph showing the in vitro release over time of the travoprost organogel formulation of Example 6 at different doses and temperatures. DETAILED DESCRIPTION OF THE INVENTION

[0071] In certain embodiments, the present invention provides a sustained-release biodegradable drug delivery system comprising an organogel and an active agent, wherein the organogel comprises a hydrophobic organic liquid and a biodegradable, covalently crosslinked polymer network, and wherein the hydrophobic organic liquid and the active agent are contained in the biodegradable, covalently crosslinked polymer network. In certain embodiments, the present invention provides a sustained-release biodegradable drug delivery system comprising an organogel and an active agent, wherein the organogel comprises a hydrophobic organic liquid and a biodegradable, covalently crosslinked polymer network, and wherein the hydrophobic organic liquid and the active agent are immobilized in the biodegradable, covalently crosslinked polymer network.

[0072] In certain embodiments, the sustained release biodegradable drug delivery system comprises at least three components: a biodegradable covalently crosslinked polymer network, a hydrophobic organic liquid, and an active agent.

[0073] In certain embodiments, organogels are formed by polymerization of non-linear, multifunctional monomeric or polymeric precursor components, as described herein below, to form a covalently crosslinked polymer network containing a hydrophobic organic liquid, which remains immobilized within the polymeric network until released from the network, e.g., in vivo. Thus, organogels of the present invention are like hydrophobic analogs of hydrogels, which contain water instead of a hydrophobic organic phase. Organogels are similar to hydrogels in that the matrix is composed of a network-forming polymeric component (gelator) and a non-reactive component. The non-reactive component, whereas in hydrogels it is water, is a hydrophobic organic compound, such as an oil, with a glass transition temperature (Tg) and melting transition temperature (Tm) below body temperature.

[0074] In certain embodiments, covalent crosslinking of the polymer network forming the precursor restricts the mobility of the hydrophobic organic liquid (e.g., oil) component. This can provide continuous control of drug release by limiting drug transport to diffusion through the organogel and / or eliminating the development of defects that provide a rapid escape route for the drug. In certain embodiments, the drug delivery system of the present invention is a fully or partially diffusion-controlled delivery system, i.e., the release of the oil and / or active agent is primarily controlled by diffusion processes. Degradation of the polymer matrix may additionally occur in the organogels of the present invention, but does not primarily control the release of the active agent. In non-crosslinked gels, such as extruded linear polymers, the release of the active agent is primarily controlled by the degradation of the polymer matrix, which releases the active agent in a degradation-controlled system. The network-forming precursor must be miscible with the hydrophobic organic liquid component and, upon crosslinking, "holds" the components together to form a solid or semi-solid, forming the organogel. In certain embodiments, the compatibility of the hydrophobic organic liquid with the polymer network influences the rate at which the hydrophobic organic liquid escapes into the surrounding tissue fluids in vivo and may be gradually replaced by aqueous fluids, providing an additional method of controlling the active agent solubility and drug release kinetics relative to network degradation.

[0075] In certain embodiments, the use of organogels in sustained-release biodegradable drug delivery systems of the present invention thus allows for the modification of the release of active agents from the drug delivery system by adjusting or appropriately selecting the precursor components that form the crosslinked polymer network according to their hydrophilic and / or hydrophobic properties. Furthermore, in certain embodiments, the release of active agents from the drug delivery system can be modified or controlled by appropriately selecting the hydrophobic organic liquid according to its properties, such as hydrophobicity, viscosity, compatibility with the active agent, and solubility or insolubility of the active agent in the hydrophobic organic phase.

[0076] Organogel-based drug delivery systems of certain embodiments of the present invention offer several advantages over hydrogels, including the ability to stabilize water-degradable (hydrolyzable) components, such as water-sensitive active agents, over long periods of storage due to the anhydrous nature of certain organogels, eliminating the need for hydration upon implantation.

[0077] Water-soluble compounds have low solubility or are insoluble in organogel, allowing drugs to be incorporated as particulate solids embedded in the organogel matrix. The low solubility of drugs in the organogel matrix provides a mechanism for controlling the drug release rate. This property significantly increases the range of compounds that can be incorporated into the implant.

[0078] Manipulating the lipophilicity / hydrophilicity of organogels can tune drug release rates and affect diffusion rates. Pure hydrogels are not amenable to this tunability because they are water-based; therefore, in these systems, tailoring drug / matrix solubility requires modifying the drug itself into a prodrug form. Organogel technology circumvents this. Furthermore, altering the lipophilicity / hydrophilicity of organogel can affect the degradation rate of the polymer matrix, further impacting the drug release rate.

[0079] Organogels can be designed to slowly release hydrophobic organic liquids (e.g., oils) from the matrix in vivo, allowing for their slow transformation into degradable hydrogels, thereby offering a new mode of controlled drug release and improving biocompatibility.

[0080] To overcome compatibility issues, solvents can be added to organogel formulations during production, and the resulting organogel can be freed of the oil. While solvent removal can be achieved by thermal treatment, this is not possible for materials that melt or undergo glass transitions at high temperatures. Solvent removal can also be achieved by methods typically used for non-crosslinked polymers, such as water extraction, vacuum drying, freeze-drying, and evaporation. This significantly simplifies the manufacturing process, eliminating the need for careful solvent removal.

[0081] In certain embodiments, organogels have the physical properties of low modulus, dimensional stability, and good drug release kinetics. In certain embodiments, organogels are thermally dimensionally stable and do not melt. Therefore, implant manufacturing processes such as hot-melt extrusion can be used to form certain organogels of the present invention.

[0082] The drug delivery systems of the present invention, including organogels, can be used to deliver a variety of drugs, including steroids, nonsteroidal anti-inflammatory drugs (NSAIDS), ocular hypotensives, antibiotics, peptides, etc. Organogels can be used to deliver drugs and therapeutic agents, such as anti-inflammatory drugs (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, antitumor agents, local anesthetics, hormones, angiogenic agents, antiangiogenic agents, growth factors, antibodies, neurotransmitters, psychotropic drugs, anticancer drugs, chemotherapeutic agents, drugs that affect the reproductive organs, genes, oligonucleotides, or other structures, and viruses such as AAV for gene delivery. The release rate from the organogel may depend on the properties of one or more of the active agent, the hydrophobic organic liquid, and the polymer network, and other possible factors include one or more of the size and relative hydrophobicity of the drug, the density of the organogel, and the solids content of the organogel.

[0083] The drug delivery system of the present invention may be in the form of an implant, a medical implant or a pharmaceutically acceptable implant, an implant coating, or an oral dosage form, or the like.

[0084] Hydrophobic organic liquids / oils The hydrophobic organic liquid can be used to modify the release of the active agent from the drug delivery system. The release of the active agent from the organogel can be controlled by appropriately selecting one or more of its properties, such as hydrophobicity, viscosity, compatibility with the active agent, and the solubility or insolubility of the active agent in the hydrophobic organic phase. For example, when the sustained-release biodegradable drug delivery system of the present invention is an implant inserted into the human body or an oral dosage form, the hydrophobic organic liquid can diffuse into the aqueous environment together with the active agent dissolved therein, before or simultaneously with the diffusion of the active agent from the hydrophobic organic liquid. For example, the release of the hydrophobic drug can be accelerated by co-diffusion with oil from the organogel. When the active agent is, for example, a water-soluble solid microparticle dispersed in the hydrophobic organic liquid, the organic liquid can be used to delay the contact of the active agent with the aqueous environment, thereby delaying the dissolution of the active agent from the organogel.

[0085] In certain embodiments, the hydrophobic organic liquid is liquid at human body temperature, e.g., at temperatures below about 37°C, or in the range of 0°C to 40°C, or 10°C to 38°C, or 15°C to 37°C, or 25°C to 37°C, or liquid at 37°C. The term "liquid" can include viscous fluids that have a creamy or waxy, but not solid, appearance. Also, for some hydrophobic organic liquids that undergo hydration in aqueous embodiments, such as bodily fluids, the melting point at a particular temperature may be different for the hydrated material than for the non-hydrated material. In certain embodiments of the present invention, the hydrated form of such a material is liquid under the above conditions.

[0086] In one embodiment, the active agent is dissolved or dispersed in the hydrophobic organic liquid, hi another embodiment, the active agent is or forms at least part of the hydrophobic organic liquid.

[0087] In certain embodiments, the hydrophobic organic liquid is an oil or comprises an oil or oil mixture, which may be a biocompatible vegetable oil, synthetic oil, or mineral oil, a liquid fatty acid or triglyceride composition, or it may be a hydrophobic biodegradable liquid polymer, or a combination thereof.

[0088] In certain aspects of the present disclosure, the hydrophobic organic liquid phase may be selected from the group consisting of triethyl citrate, acetyl triethyl citrate (ATEC), acetyl tributyl citrate (ATBC), α-tocopherol (vitamin E), α-tocopherol acetate, vegetable oils such as sesame oil, olive oil, soybean oil, sunflower oil, coconut oil, canola oil, rapeseed oil, nut oils such as hazelnut, walnut, pecan, almond, cottonseed oil, corn oil, safflower oil, linseed oil, ethyl oleate, castor oil and its derivatives (Cremophor®), 37 The biocompatible oil may be selected from the group consisting of lipids that are liquid at or below 200°C, such as saturated or unsaturated fatty acids, monoglycerides, diglycerides, triglycerides (Myglyols®), isopropyl myristate, phospholipids, glycerophospholipids, sphingolipids, sterols, prenol, polyketides, hydrophobic biodegradable liquid polymers (such as low molecular weight PLGA, PGA, or PLA), low melting point waxes, such as vegetable, animal, or synthetic waxes, lanolin, jojoba oil, or combinations thereof.

[0089] In certain embodiments, the hydrophobic organic liquid is liquid at human body temperature and may have a glass transition temperature and / or melting temperature of 45°C or less, or 37°C or less.

[0090] In certain embodiments, the hydrophobic organic liquid is non-volatile at 37° C. and ambient pressure, non-toxic, and / or biocompatible, and / or capable of being removed from the implantation site, metabolized from the body, and / or removed unchanged. polymer network

[0091] The organogel of the biodegradable drug delivery system of the present invention, in certain embodiments, comprises a covalently crosslinked polymer network formed by polymerization of multifunctional precursor components, in one embodiment, at least one of the precursors has three or more functional groups to create a three-dimensional (3D) polymer network and is therefore not linear.

[0092] In organogels, the biodegradable, covalently crosslinked polymer network can comprise one or more polymeric units comprising a polyalkylene oxide such as polyethylene glycol, polypropylene glycol, poly(ethylene glycol)-block-poly(propylene glycol) copolymer, a poloxamer such as Tetronic®, polyethylene oxide, polypropylene oxide, polyvinyl acetate, polyvinyl alcohol, poly(vinylpyrrolidinone), polylactic acid (PLA), polyglycolic acid (PGA), polylactic-co-glycolic acid (PLGA), p-dioxanone, trimethylene carbonate, caprolactone, random or block copolymers, or any combination or mixture thereof, or one or more units of a polyamino acid, glycosaminoglycan, polysaccharide, or protein, although this list is not intended to be limiting.

[0093] In embodiments of the present invention, the hydrophobic polymer unit may comprise at least one poly(ethylene glycol)-block-poly(propylene glycol) copolymer, also known as a poloxamer, such as the commercially available Tetronic® poloxamer.

[0094] The biodegradable, covalently crosslinked polymer network can be formed from multiple hydrophobic polymer units, multiple hydrophilic polymer units, or a combination of hydrophobic and hydrophilic units. The polymer units can be selected to tailor the hydrophobicity and hydrophilicity of the organogel to match the properties of the hydrophobic organic phase and / or the active agent. This matching allows for control of the gel formation and degradation behavior of the organogel.

[0095] In embodiments of the present invention, the hydrophobic polymer unit may comprise at least one of a polylactic acid (PLA) unit and a polylactic-co-glycolic acid (PLGA) unit, preferably a copolymer of PEG and PLGA, particularly preferably a block copolymer of multi-arm PEG copolymerized with PLGA. The copolymer may be end-capped with a desired reactive group, and the molecular weight of PEG and the PEG / PLGA ratio in the copolymer may be varied according to the desired hydrophobicity.

[0096] The hydrophilic polymer unit may be selected from at least one of a polyethylene glycol unit, a polypropylene glycol unit, or a polyglycolic acid (PGA). In one embodiment, the hydrophilic polymer unit comprises a polyethylene glycol unit.

[0097] The average molecular weight (Mw) of each of the polymer units may range from about 1,000 to about 100,000 daltons, or from about 10,000 to about 60,000 daltons, or from about 15,000 to about 50,000 daltons.

[0098] In an aspect of the invention, the covalently crosslinked 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) with a plurality of at least one hydrophilic polymer units selected from at least one of polyethylene glycol (PEG) units, polypropylene glycol (PPG), or polyglycolic acid (PGA) units. In one embodiment, the hydrophilic polymer units comprise polyethylene glycol (PEG) units.

[0099] In embodiments, the polymer network comprises a combination of poly(lactic-co-glycolic acid) (PLGA) units and polyethylene glycol (PEG) units. The ratio of poly(lactic-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.

[0100] When PLGA is used, the lactic acid-co-glycolic acid (PLGA) units may have an L / G ratio (L or G unit %) 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.

[0101] In certain embodiments, in organogel sustained release drug delivery systems, the polymer network is covalently crosslinked by hydrolyzable bonds between the polymer units, which facilitates biodegradation in an aqueous environment, such as in vivo in the human or animal body.

[0102] The hydrolyzable bond may include a bond selected from the group consisting of an amine bond, an amide bond, a urethane bond, an ester bond, an anhydride bond, an ether bond, an acetal bond, a ketal bond, a nitrile bond, an isonitrile bond, an isothiocyanate bond, or an imine bond, and combinations thereof, which are typically formed by a condensation polymerization reaction of an appropriately functionalized gellant or precursor, respectively.

[0103] Precursor Components In certain embodiments, the polymer network of the organogel is formed from at least one covalently crosslinkable 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.

[0104] According to certain embodiments of the present invention, the organogel comprises a polymer network comprising at least two covalently crosslinked multi-arm precursors. In some embodiments, the organogel comprising the polymer network comprises at least two covalently crosslinked multi-arm precursors.

[0105] Thus, the precursor is always a "functional polymer" or "functional material," such as a (e.g., low molecular weight) crosslinker, that can participate 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 that does not participate in a crosslinking reaction with a precursor to form a polymer network.

[0106] The precursors used in the present invention can be any polymer that can react with another precursor in the presence of a hydrophobic organic liquid and is biocompatible. The polymer can be selected from biodegradable natural polymers, semi-synthetic polymers, synthetic polymers, or biosynthetic polymers.

[0107] Natural polymers may include glycosaminoglycans, polysaccharides (e.g., dextran), polyamino acids, and proteins, or mixtures or combinations thereof. Semi-synthetic polymers may be selected from carboxymethylcellulose or alkylcelluloses such as methylcellulose (MC), ethylcellulose (EC), etc.

[0108] In some embodiments, synthetic precursors are utilized. Synthetic refers to molecules not found in nature or not normally found in the human body. Synthetic polymers can generally be any polymer that is synthetically produced 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 specific initiators, light and / or heat, or can be mediated by a catalyst.

[0109] Generally, for the purposes of the present invention, one or more synthetic polymers of a group comprising one or more units of polyalkylene glycol can be used, such as polyethylene glycol (PEG), polypropylene glycol, poly(ethylene glycol)-block-poly(propylene glycol) copolymers, or polyethylene oxide, polypropylene oxide, polyvinyl alcohol, poly(vinylpyrrolidinone), polylactic acid (PLA), polylactic-co-glycolic acid (PLGA), p-dioxanone, trimethylene carbonate, caprolactone, random or block copolymers, or any combination / mixture thereof, although this list is not intended to be limiting.

[0110] In some embodiments of the present invention, at least one crosslinkable precursor is either hydrophobic or hydrophilic; when two precursors are used, both can be hydrophobic, or both can be hydrophilic, or one can be hydrophobic and the other hydrophilic. With three or more precursors, any mixture of hydrophilic and hydrophobic precursors can be selected depending on the desired properties of the polymer network. Furthermore, the precursors can also be copolymers incorporating both hydrophobic and hydrophilic substructures.

[0111] The precursors have reactive functional groups, i.e., a first functional group that can react with a second functional group. The functional groups are configured to react with each other, for example, in an electrophile-nucleophile reaction, or to participate in other polymerization reactions. Thus, the first functional group can be a nucleophile and the second functional group can be an electrophile, or vice versa. According to certain embodiments of the present invention, each precursor includes at least two nucleophiles or at least two electrophiles.

[0112] Nucleophiles that can be used in the present invention can include amines, such as primary amines, hydroxyls, thiols, carboxyls, dibenzocyclooctynes, or hydrazides. In certain embodiments, at least one precursor includes a nucleophile, such as a primary amine.

[0113] 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, alkenes, alkynes, azides, norbornenes, epoxides, mesylates, tosylates, tresyls, cyanurates, orthopyridyl disulfides, or halides. These electrophiles contain functional groups that participate in electrophile-nucleophile reactions and crosslink precursors, and they preferably further contain reactive groups that include hydrolyzable groups or bonds, such as glutarate. For example, in embodiments of the present invention, succinimidyl esters may contain reactive groups such as succinimidyl succinate (SS), succinimidyl glutarate (SG), succinimidyl adipate (SAP), succinimidyl azelate (SAZ), or succinimidyl glutaramide.

[0114] The term "multi-arm" precursor means that the precursor is branched, i.e., not linear. In a multi-arm polymer, the core refers to a continuous portion of the molecule joined to arms extending from the core, which often have nucleophiles or electrophiles at the ends of the branches. Note that the precursor can have, for example, 2 to 100 arms, each arm having an end, and some precursors may be dendrimers or other highly branched materials such as dendrimers. The arms of the precursor refer to linear chains of chemical groups connecting the crosslinkable groups to the polymer core. Some embodiments are precursors with 3 to 300 arms. One of ordinary skill in the art will readily understand that all ranges and values within the explicitly stated ranges are contemplated, e.g., 4, 6, 8, 10, 12, 4-16, 8-100, 6, 8, 10, 12, or at least 4 arms.

[0115] In certain embodiments, the multi-arm precursors of the present invention have a core and 2 to 10 arms, or 3 to 10 arms, or 4 to 8 arms, or 4 or 8 arms, each arm comprising a polymer unit and having a terminus.

[0116] In some embodiments, when each precursor is multi-armed, it contains two or more arms, and thus two or more of the same or different electrophiles or nucleophiles, such that each nucleophile can react with another electrophile (within the same precursor or in another precursor) in an electrophile-nucleophile reaction to form a crosslinked polymer product. Thus, for example, in some embodiments, a precursor has four arms, each terminating in either a nucleophile or an electrophile, which may be the same or different from the other arms.

[0117] According to an aspect of the present invention, an organogel comprises at least two multi-arm precursors, including 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 crosslinked to each other in an electrophile-nucleophile reaction. In this context, multi-arm refers to at least four arms, at least eight arms, e.g., at least ten arms.

[0118] In one embodiment, when an organogel contains two multi-arm precursors, it can include a first multi-arm precursor containing a nucleophile, such as an amine (e.g., a primary amine), a thiol, a dibenzocyclooctyne, or a hydrazide, and a second multi-arm precursor containing an electrophile, such as a succinimidyl ester, 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 tresyl, a cyanurate, an orthopyridyl disulfide, or a halide. The nucleophile and the electrophile are covalently crosslinked to each other in an electrophile-nucleophile reaction. In some embodiments, the first multi-arm precursor is a primary amine, and the second multi-arm precursor is a succinimidyl ester.

[0119] According to certain embodiments of the present invention, the organogel comprises at least two multi-arm precursors, including 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 and second multi-arm precursors are covalently crosslinked to each other via an electrophile-nucleophile reaction. In this context, multi-arm refers to at least four arms, at least eight arms, for example, at least ten arms.

[0120] In some embodiments, the organogel comprises at least two multi-arm precursors, including a first multi-arm precursor containing a nucleophile and a second multi-arm precursor containing an electrophile. In these embodiments, the first and second multi-arm precursors are covalently crosslinked to each other via an electrophile-nucleophile reaction. In this context, "multi-arm" refers to at least four arms, at least eight arms, or at least ten arms. 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, succinimidyl carbonate, 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 tresyl, a cyanurate, an orthopyridyl disulfide, or a halide. For example, in embodiments of the present invention, the succinimidyl ester may contain a reactive group such as succinimidyl succinate (SS), succinimidyl glutarate (SG), succinimidyl adipate (SAP), succinimidyl azelate (SAZ), or succinimidyl glutaramide.

[0121] Some precursors may have a longer hydrolysis half-life than other precursors, i.e., they may take longer to decompose. 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 succinate (SS), will have 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).

[0122] In some embodiments, the organogel may include two multi-arm precursors: a first multi-arm precursor including a nucleophile, such as an amine, and a second multi-arm precursor including an electrophile, such as a succinimidyl ester. In other embodiments, the organogel may include a first multi-arm precursor including a nucleophile, such as an amine, such as a primary amine, and a second multi-arm precursor including an electrophile, such as a succinimidyl ester, that includes 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).

[0123] In some embodiments, the precursor is a polyethylene glycol precursor. Thus, in some embodiments, the covalently crosslinked precursor polymer network is made from or comprises at least one polyethylene glycol-containing precursor. Polyethylene glycol (PEG, also known as polyethylene oxide) refers to a polymer with repeating groups (CH2CHO)n, where n is at least 3.

[0124] Therefore, polymer precursors containing polyethylene glycol have at least three of these repeating groups linked together in a linear chain. PEG polymers terminated with hydroxyl or methoxy groups that do not participate in the crosslinking reaction between precursors are referred to as "non-functionalized PEGs" as described hereinabove and therefore cannot be used as precursors. Therefore, PEG polymers terminated with a nucleophile selected from primary amines, thiols, dibenzocyclooctynes, or hydrazides are considered "functionalized PEGs" and can be used as precursors. Furthermore, PEG polymers terminated with an electrophile selected from succinimidyl esters, succinimidyl carbonates, nitrophenyl carbonates, aldehydes, ketones, acrylates, acrylamides, maleimides, vinyl sulfones, iodoacetamides, alkenes, alkynes, azides, norbornenes, epoxides, mesylates, tosylates, tresyls, cyanurates, orthopyridyl disulfides, or halides are considered "functionalized PEGs" and can be used as precursors.

[0125] The polymer network of the organogel drug delivery systems of the present invention can include 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 numbers of arms or the same number of arms. In certain embodiments, the PEG units used in the organogels 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.

[0126] In certain embodiments of the present invention, the polyethylene glycol units used as precursors have an average molecular weight in the range of about 1,000 to about 100,000 daltons, or 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 units have an average molecular weight in the range of about 10,000 to about 40,000 daltons, or about 20,000 daltons. PEG precursors of the same average molecular weight may be used, or PEG precursors of different average molecular weights may be combined with each other. The average molecular weight of the PEG precursors used in the present invention is given as the number average molecular weight (Mn), which in certain embodiments may be determined by gel permeation chromatography against polystyrene standards according to standard methods.

[0127] In a 4-arm PEG, each arm can have an average arm length (or molecular weight) equal to the total molecular weight of the PEG divided by 4. Thus, one precursor that can be used in the present invention, the 4a20k PEG precursor, has four arms, each with an average molecular weight of about 5,000 daltons. Thus, the 8a20k PEG precursor, which can be used in the present invention in addition to the 4a20k PEG precursor, has eight arms, each with an average molecular weight of 2,500 daltons. Thus, the 4a20K PLGA precursor has four arms, each with an average molecular weight of about 5,000 daltons.

[0128] When referring to a PEG precursor having a particular average molecular weight, such as a 15k PEG precursor or a 20k PEG precursor, the indicated average molecular weight (i.e., Mn of 15,000 or 20,000, respectively) refers to the PEG portion of the precursor before end groups are added (here, "20k" means 20,000 daltons, and "15k" means 15,000 daltons. The same abbreviations are used herein for other average molecular weights of PEG or other polymer precursors). In certain embodiments, the Mn of the PEG portion of the precursor is determined by gel permeation chromatography against polystyrene standards according to standardized methods. The degree of substitution with the end groups disclosed herein can be determined by H-NMR after end group functionalization.

[0129] In various embodiments of the present invention, the organogel comprises at least two multi-arm precursors, the first of which is a multi-arm PEG precursor containing a nucleophile, such as an amine, e.g., a primary amine. In some of these embodiments, the second multi-arm precursor is a multi-arm PEG precursor containing an electrophile, such as a succinimidyl ester. In other embodiments, the second multi-arm precursor is a multi-arm PLGA precursor containing an electrophile, such as a succinimidyl ester.

[0130] In some embodiments of the present invention, the organogel comprises three multi-arm precursors, the first of which is a multi-arm PEG precursor containing a nucleophile, such as an amine, e.g., a primary amine. In this embodiment, the second of which is a multi-arm PEG precursor containing an electrophile, such as a succinimidyl ester, containing a first reactive group. In this embodiment, the third of which is a multi-arm PEG precursor containing an electrophile, such as a succinimidyl ester, containing a second reactive group. In this embodiment, the first and second reactive groups 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 linkers attached to a polymer containing a reactive group consisting of an N-succinimidyl ester of the corresponding dibasic acid, with an ester group connecting the second acid of the dibasic acid to the polymer, which is hydrolytically degradable in water. In some embodiments, the first multi-arm precursor is succinimidyl succinate (SS) and the second multi-arm precursor is succinimidyl glutarate (SG).

[0131] Each and any combination of the electrophilic-group-containing PEG precursors and nucleophilic-group-containing PEG precursors disclosed herein can be used to prepare implants of the present invention. For example, any 4-arm or 8-arm PEG precursor (e.g., having a succinimidyl ester containing an SS, SG, SAP, or SAZ reactive group) can be combined with any 4-arm or 8-arm PEG precursor (e.g., having an NH group or another nucleophile). Furthermore, the PEG units of the electrophilic-group-containing precursor and the nucleophilic-group-containing precursor can have the same or different average molecular weights.

[0132] One such combination is a PEG amine precursor and two PEG succinimidyl ester precursors, one containing an SS reactive group and another containing an SG reactive group. In certain embodiments, the inventors have found that by maintaining a molar ratio of PEG amine to PEG succinimidyl ester of approximately 1:1 and varying the molar ratio of the succinimidyl ester SS to SG reactive groups, the time it takes for the polymer network to degrade in aqueous solution under physiological conditions can be controlled, although other ratios are also contemplated. The amount of PEG SS and SG to be used to reach a particular molar ratio of the two reactive groups can be calculated by one skilled in the art and can be explained as follows:

[0133] The amounts of PEG amine and PEG ester (SS and SG) to be used are calculated using the stoichiometric formula for the molar ratio and the conversion from moles to grams. First, the molar ratio of reactive end groups between amine, succinimidyl succinate, and succinimidyl glutarate is determined. In one example formulation, 4a20k PEG NH2, 4a20k PEG SS, and 4a40k PEG SG are used. The molar ratio of amine to succinimidyl ester groups is approximately 1:1, and the molar ratio of SS to SG is approximately 80:20. The final end group molar ratio between 4a20k NH2:4a20k SS:4a40k SG is approximately 1.0:0.8:0.2. The mass is then determined using the stoichiometric conversion from grams to moles and vice versa. Below is an example calculation of 4a20k SS at the above molar ratios using 100 g of 4a20k NH2:

number

[0134] Alternatively, the amount of PEG can be determined by calculating the "molecular weight between bridges" (MWc) and arm length ratio. MWc can be calculated through the sum of the average arm lengths of each multi-arm PEG precursor.

number

[0135] The arm length ratio is calculated by dividing the PEG arm length by the MWc. The amount of multi-arm precursor can be determined by multiplying the arm length ratio of a particular multi-arm precursor by the total PEG batch size. Below is an example of how to calculate the amount of 4a20k PEG SS for a total batch size of 100g PEG:

number

[0136] Similar calculations can be performed for the other types of polymers described herein.

[0137] In certain embodiments, 4-arm PEGs having an average molecular weight of about 20,000 daltons and 4-arm PEGs having an average molecular weight of about 40,000 daltons can be used to form polymer networks and, therefore, organogels according to the present invention.

[0138] Thus, the first precursor and / or the second precursor can be a 4a20k precursor, where 4 represents an arm and 20k represents Mn. Thus, for example, the first precursor, the second precursor, and / or the third precursor can be a 4a40k precursor. Thus, for example, the first precursor and / or the second precursor can be a 4a20k precursor and the third precursor can be a 4a40k precursor.

[0139] When the polymer unit is PLGA instead of PEG, such precursors may have the following exemplary structure with a pentaerythritol-derived core of the fairly hydrophobic, oil-soluble 4a20K PLGA-NHS: [ka]

[0140] According to its designation, this is a four-arm PLGA, each PLGA unit has an Mn of approximately 5,000 daltons, the PLGA units have an 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 dibasic acid 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, or fumaric acid, and NHS designates an N-hydroxysuccinimide electrophile as the functional group on the end of each arm. x is an integer defining the number of lactic acid units, and y is an integer defining the number of glycolic acid units in the PLGA molecule. In the case of a 50:50 PLGA, x and y are equal. n is an integer defining the number of PLGA blocks, and in the case of a 50:50 PLGA, n is 1.

[0141] Another example of an electrophile-functionalized PLGA precursor is 4a20K PLGA5050-SAP-NHS (x and y are about 15). [ka]

[0142] In other embodiments, the multi-arm PLGA precursor may be derived from ethylenediamine as the core instead of pentaerythritol.

[0143] In various embodiments of the present invention, the organogel comprises at least one multi-arm precursor comprising hydrophobic polymeric 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 crosslinker, preferably a small molecule amine such as tris(2-aminoethyl)amine (TAEA), which is oil-soluble, or trilysine.

[0144] 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, and at least one further multi-arm precursor comprising hydrophilic polymer units, preferably selected from polyethylene glycol (PEG) and polyglycolic acid (PGA).

[0145] As described above, the polymer network is formed from at least two precursors, at least one of which is a multi-arm precursor, wherein the first multi-arm precursor comprises a first functional group and the second precursor is selected from a small molecule crosslinker or a multi-arm precursor comprising a second functional group, the functional group being located at the end of an arm or molecule. In various embodiments of the present invention, each of the first and second functional groups is selected from the group consisting of an electrophile and a nucleophile, and the reaction between the first and second functional groups is an electrophile-nucleophile reaction that forms a covalent bond in the polymer network.

[0146] The nucleophile and electrophile are selected from the groups defined herein above. In certain embodiments, the nucleophile is an amine group and the electrophile is an activated ester group.

[0147] Active Agent: The active agent according to the present 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.

[0148] For purposes of the present invention, active agents include 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 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, and phosphate; organic acid salts such as formate, acetate, trifluoroacetate, maleate, tartrate, and glutarate; sulfonates such as methanesulfonate, benzenesulfonate, and p-toluenesulfonate; metal salts such as sodium salt, potassium salt, and cesium salt; alkaline earth metal salts such as calcium salt and magnesium salt; and organic amine salts such as triethylamine, pyridine, picolinate, ethanolamine, triethanolamine, dicyclohexylamine, and N,N'-dibenzylethylenediamine. As used herein, any salt is meant to be a pharmaceutically acceptable salt. The term "cocrystal" as used herein refers to the combination of an active pharmaceutical ingredient (API) with one or more conformers, e.g., an acid (e.g., a carboxylic acid), in the same lattice via non-covalent interactions such as hydrogen bonding, electrostatic interactions, π-π stacking, and Wander Waals interactions. Thus, a cocrystal is a multicomponent solid. The difference between a cocrystal and a salt is that the former is composed only of neutral components, whereas the latter contains ionic components. Cocrystallization can alter the physicochemical properties of an API, e.g., stability, solubility, melting rate, and mechanical properties, and in certain cases, can be optimized for specific applications.

[0149] As used herein, a therapeutically active agent can be an immunosuppressant, a complement inhibitor (e.g., a CS inhibitor such as eculizumab or avasincaptad pegol), an anti-inflammatory agent such as steroidal and non-steroidal anti-inflammatory agents (e.g., a COXI or COX2 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 HtRAI blocker, an IGF-1R inhibitor, a VEGF combination agent (a multispecific anti-angiogenic agent), and combinations thereof.

[0150] Therapeutically active agents include steroids; nonsteroidal anti-inflammatory drugs (NSAIDS), such as diclofenac, ibuprofen, meclofenamate, mefanamic A, salsalate, sulindac, tolmetin, ketoprofen, diflunisal, piroxicam, naproxen, etodolac, flurbiprofen, fenoprofen C, indomethacin, celecoxib, ketorolac, and 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; and tandem repeat inhibitors, such as insulin. small molecule hydrophilic drugs including carboxylates and amine salts; small molecule hydrophobic drugs such as insulin, single chain antibody fragments, Fab fragments, IgG antibodies, fusion antibodies, hydrophilic peptide and protein drugs; aptamers; in particular, bupivacaine (BPV-HCl or base), ropivacaine (RPV), dexamethasone, travoprost, axitinib, nonsteroidal anti-inflammatory drugs (NSAIDS), steroids, antibiotics, analgesics, calcium channel blockers, cell cycle inhibitors, chemotherapeutics, antivirals, anesthetics, hormones, anticancer drugs, antitumor drugs, etc., or any combination thereof.

[0151] In some embodiments, the steroid may be a corticosteroid, which may include hydrocortisone, loteprednol, cortisol, cortisone, prednisolone, methylprednisolone, dexamethasone, betamethasone, triamcinolone, aldosterone, fludrocortisone, budesonide, fluocinolone, mometasone, fluticasone, rimexolone, fluorometholone, beclomethasone, or flunisolide.

[0152] In some embodiments, the NSAID is diclofenac (e.g., diclofenac sodium), flurbiprofen (e.g., flurbiprofen sodium), ketorolac (e.g., ketorolac tromethamine), bromfenac, nepafenac, cyclooxygenase-1 (COX-I) and cyclooxygenase-2 (COX-2), isoenzymes, salicylates, propionic acid derivatives, acetic acid derivatives, enolic acid derivatives, and anthranilic acid derivatives, acetylsalicylic acid, diflunisal, salsalate. , ibuprofen, dex-ibuprofen, naproxen, fenoprofen, ketoprofen, dex-ketoprofen, 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.

[0153] In some embodiments, the active agent is acetaminophen, acetaminosalol, aminochlorthenoxazine, acetylsalicyl 2-amino-4-picolinate, acetylsalicylsalicylic acid, anileridine, benoxaprofen, benzylmorprune, 5-bromosalicylacetic acid, bucetin, buprenorphine, butorphanol, capsaicin, cinchophen, ciramadol, clometacin, clonixin, codeine, desomorphine, dezocine, dihydrocodeine, dihydromorprune, dimepheptanol, dipyrocetyl, eptazocine, ethoxazene, ethylmorphine, eugenol, floctafenine The analgesic may be selected from at least one of floctaferune, fosfosal, glafenine, hydrocodone, hydromorphone, hydroxypethidine, ibufenac, p-lactophenetide, levorphanol, meptazinol, metazocine, metopon, morphine, nalbuphine, nicomorphine, norlevorphanol, normorphine, oxycodone, oxymorphone, pentazocine, phenazocine, fenocol, phenoperidine, phenylbutazone, phenylsalicylic acid, phenylramidol, salicin, salicylamide, thiorphan, tramadol, diacerein, actarit, pharmaceutically acceptable salts thereof, and combinations thereof.

[0154] In some embodiments, the IOP-lowering agent and / or glaucoma medication is a prostaglandin analog (e.g., bimatoprost, latanoprost, travoprost, or latanoprost enox), 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, cartebrolol, or betaxol), alpha2-adrenergic agonists (e.g., apraclonidine, brimonidine, or brimonidine tartrate), carbonic anhydrase inhibitors (e.g., brinzolamide, dichlorphenamide, methazolamide acetazolamide, acetazolamide, or dorzolamide), pilocarpine, echothiophate, demercarium, physostigmine, and / or isofluorophate.

[0155] In some embodiments, the anti-infective agent 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.

[0156] Penicillins can include: 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: cefatril, cefadroxil, cephalexin, cephaloglycin, cephalonium, cephaloridine, cephalothin, cephapirin, cefatrizine, cefazaflur, cefazedone, cefazolin, cephradine, cefroxadine, ceftezole, cefaclor, cefamandole, cefmetazole, cefonicid, cefotetan, cefoxitin, cefprozil, cefuroxime, cefuzonam, cefcapene, cefdaloxime, cefdinir, cefditoren, cefetamet, cefixime, cefmenoxime, cefodizime, cefotaxime, cefpimizo ceftazidime, cefteram, ceftibuten, ceftiofur, ceftiolene, ceftizoxime, ceftriaxone, cefoperazone, ceftazidime, cefclidine, cefepime, cefluprenam, cefoselis, cefozopran, cefpirome, cefquinome, ceftobiprole, ceftaroline, cefaclomezine, cephaloram, cefaparol, cefcanel, cefedrol, cefenpidone, cefetrizole, cefibitril, cefmatilen, cefinpidium, cefovecin, cefoxazole, cefrotil, cefsumide, cefrastim, ceftioxide, pharmaceutically acceptable salts thereof, and combinations thereof. Fluoroquinolones may include ciprofloxacin, levofloxacin, gatifloxacin, moxifloxacin, ofloxacin, norfloxacin, pharmaceutically acceptable salts thereof, and combinations thereof. Macrolides may include azithromycin, erythromycin, clarithromycin, dirithromycin, oxithromycin, telithromycin, pharmaceutically acceptable salts thereof, and combinations thereof.

[0157] In some embodiments, the active agent may 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 abacavir, acyclovir, adefovir, amantadine, amprenavir, ampligen, arbidol, atazanavir, boceprevir, cidofovir, darunavir, delavirdine, didanosine, docosanol, edoxudine, efavirenz, emtricitabine, enfovirtide, entecavir, famciclovir, fomivirsen, fosamprenavir, foscarnet, phosphonet, ganciclovir, ibacitabine, immunovir, idoxuridine, imiquimod, iodinavir, inosine, interferon type III, interferon type II, interferon type I, interferon, lamivudine, loxacillus casei, fluticasone ... Antiviral agents include, but are not limited to, pinavir, loviride, maraviroc, moroxydine, methisazone, nelfiuavir, nevirapine, nexavir, oseltamivir, peginterferon alfa-2a, penciclovir, peramivir, pleconaril, podophyllotoxin, raltegravir, ribavirin, rimantadine, ritonavir, pyramiding saquinavir, stavudine, tenofovir, tenofovir disoproxil, tipranavir, trifluridine, trizivir, tromantadine, truvada, valacyclovir, valganciclovir, vicriviroc, vidarabine, viramidine, zalcitabine, zanamivir, zidovudine, pharmaceutically acceptable salts thereof, and combinations thereof. In certain embodiments, the antiviral agent is one of ganciclovir, idoxuridine, vidarabine, and / or trifluridine.

[0158] In some embodiments, the active agent may be selected from antifungal agents including amphotericin B, natamycin, voriconazole, fluconazole, miconazole, clotrimazole, ketoconazole, posaconazole, echinocandins, caspofungin, and / or micafungin.

[0159] In some embodiments, the antimetabolite may include methotrexate, mycophenolate, or azathioprine.

[0160] In some embodiments, the anti-fibrotic agent may include mitomycin C or 5-fluorouracil.

[0161] In some embodiments, the angiogenesis inhibitor is an anti-VEGF agent (e.g., aflibercept, ranibizumab, bevacizumab, brolucizumab, conbercept), a PDGF-B inhibitor (e.g., Favista®), a complement antagonist (e.g., eculizumab), a tyrosine kinase inhibitor (e.g., axitinib, deuclavacitinib, avapritinib, capmatiuib, pegimatiuib, ripretinib, selpercatinib, selumetinib, tucatinib, enantioglobin, entrectinib ... Nutrectinib, erdaftinib, fedratinib, pexidartinib, upadacitinib, zanubrutinib, baricitinib, binimetinib, dacomitinib, fostamatinib, gilteritinib, larotrectinib, lorlatinib, acalabrutinib, brigutinib, midostaurin, neratinib, aretinib, cobimetinib, lenvatinib, osimertinib rtinjb), ceritinib, nintedanib, afatinib, ibrutinib, trametinib, bosutinib, caboantinib, ponatinib, regorafenib, tofacitinib, crizotinib, ruxolitinib, vandetanib, pazopanib, lapatinib, nilotinib, dasatinib, sunitinib (boronib), sorafenib, erlotinib, gefitinib, imatinib, afatinib, bosutinib, cabozan In some embodiments, the therapeutic agent may include integrin antagonists (e.g., cediranib, ceritinib, crizotinib, dabrafenib, dasatinib, erlotinib, everolimus, gefitinib, imatinib, lestauritinib, 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 is selected from the group consisting of, but not limited to, A419259, AP23451, AP23464, AP23485, AP23588, AZD0424, AZM475271, BMS354825, CGP77675, CU201, ENMD2076, KB SRC4, KX2361, KX2-391, MLR1023, MNS, PCI-32765, PD166285, PD180970, PKC-412, PKI166, PP1, PP2, SRN004, SU6656, TC-S7003, TG100435, TG100948, TX-1123, VAL201, WH-4-023, XL228, altenusin, bosutinib, damnacanthal, dasatinib, herbimycin A, indirubin, neratinib, labe The inhibitor may be a Src family tyrosine kinase inhibitor such as Industin A, pelitinib, piceatannol, saracatinib, Srcll, foretinib, motesanib, tivozanib, LY2457546, MGCD-265, MGCD-510, tivantinib, AMG458, JNJ-3887, EMD1214063, BMS794833, PHI1665752, SGX-523, INCB280, pharmaceutically acceptable salts thereof, and combinations thereof.

[0162] In some embodiments, the active agent may 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-deoxyspargalin, thalidomide, glatiramer, leflunomide, vincristine, cytarabine, pharmaceutically acceptable salts thereof, and combinations thereof. The active agent may also be selected from anti-inflammatory cytokine targeting agents, such as TNFα, 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.

[0163] In some embodiments, e.g., for ocular drug delivery systems, the active agent can be a beta-blocker such as atenolol, propranolol, metipranolol, betaxolol, carteolol, levobetaxolol, levobunolol, timolol, pharmaceutically acceptable salts thereof, and combinations thereof; an adrenergic or sympathomimetic agent such as epinephrine, dipivefrin, clonidine, apraclonidine, brimonidine, pharmaceutically acceptable salts thereof, and combinations thereof; a parasympathomimetic or cholinergic agent such as pilocarpine, carbachol, phospholipid, physostigmine, pharmaceutically acceptable salts thereof, and combinations thereof; an acetozolamide, brinzolamide, dorzola antiglaucoma agents including carbonic anhydrase inhibitors, including topical or systemic agents such as methazolamide, etoxolamide, dichlorphenamide, pharmaceutically acceptable salts thereof and combinations thereof, mydriatic cycloplegics, such as atropine, cyclopentolate, succinylcholine, homatropine, phenylephrine, scopolamine, tropicamide, pharmaceutically acceptable salts thereof and combinations thereof, prostaglandins, such as prostaglandin F2 alpha, antiprostaglandins, prostaglandin precursors, or prostaglandin analogue agents, such as bimatoprost, latanoprost, travoprost, unoprostone, tafluprost, pharmaceutically acceptable salts thereof and combinations thereof.

[0164] In some embodiments, the cytoprotective agent may include ebselen, sulforaphane, oltipraz, or dimethyl fumarate.

[0165] In some embodiments, the neuroprotective agent may include ursodiol, memantine, or acetylcysteine.

[0166] In some embodiments, the anesthetic may include lidocaine, proparacaine, or bupivacaine.

[0167] 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, fluocinolide, aflibercept, or a combination thereof. In some embodiments, the drug may be dexamethasone, ketorolac, diclofenac, moxifloxacin, travoprost, 5-fluorouracil, or methotrexate. In some embodiments, the drug is dexamethasone. In some embodiments, the drug is ketorolac. In some embodiments, the drug is travoprost.

[0168] In some embodiments, the active agent is cyclosporine, everolimus, tacrolimus, sirolimus, pimecrolimus, ibuprofen, mefanamic acid, diclofenac, nepafenac, flurbiprofen, flurbiprofen sodium, fusidic acid, besifloxacin (base), clarithromycin, azithromycin, ketotifen (base), azelastine (base), azelastine embonate, linoleic acid, alpha-linoleic acid, gamma-linoleic acid, prednisone, prednisolone, prednisolone acetate, methylprednisolone, dexamethasone, dexamethasone acetate. The anti-inflammatory drug may be selected from at least one of fluticasone, betamethasone sodium phosphate, budesonide, flunisolide, fluticasone propionate, triamcinolone, triamcinolone acetonide, triamcinolone hexacetonide, triamcinolone diacetate, fluocinolone acetonide, fludrocortisone acetate, loteprednol, loteprednol etabonate, difluprednate, fluorometholone, mometasone furoate, deoxycorticosterone acetate, aldosterone, rimexolone, beclomethasone, beclomethasone dipropionate, and lifitegrast.

[0169] In some embodiments, the active agent may be selected from at least one of a peptide, a nanobody, an affibody molecule, ankyrin, and a DARPin. The peptide may be compstatin, APL-I, Fc-III-4C, Beovu (brolucizumab), Zimura (avacincaptad pegol), pegcetacoplan, abicipar pegol, lampalizumab, fovista, risuteganib, AXT107, elamipretide, THR149, ALM201, VGB3, and largazole. The nanobody may 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-210T cells, CD19 / CD20 bispecific CART cells, BCMA CART cells, or TAS266 nanobody. 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, for example, in the review by 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 capable of binding to VEGF-A and hepatocyte growth factor (HGF), and one molecule of MP0250 that binds to two molecules of human serum albumin (HSA); abcipargol (MPO112 or AGN-150998); brolucizumab, ranibizumab, or aflibercept.

[0170] In some embodiments, the therapeutically active agent may be selected from at least one of the subject complement inhibitors, including 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 include Sinrise, Verinert, Ruconest, stimulimab, pegcetacoplan (GA), eculizumab, ravulizumab, avacopan, pozelimab, nomakopan, zircopane, vilobelimab, clovalimab, avasin-capped pegol, semdisiran, BDB-001, tesidolumab, abdullimab, MOR210, ALXN1720, danicopan, bemircopan, ACH-5228, ACH-5548, BCX-9330, AMY-101, ANX005, ANX007, narsoplimab, iptacopan, CLG561, GT103, ARGX-117, ALXN1820, NGM621, lampalizumab, NGM62l, IONIS-FB-Lrx, GEM Specific agents may be included such as I03, CLG561, pharmaceutically acceptable salts thereof, and combinations thereof.

[0171] In some embodiments, the therapeutically active agent may be selected from at least one of antihistamines such as loratadine, hydroxyzine, diphenhydramine, chlorpheniramine, brompheniramine, cyproheptadine, terfenadine, clemastine, triprolidine, carbinoxamine, diphenylpyraline, phenindamine, azatadine, tripelennamine, dexchlorpheniramine, dexbrompheniramine, methdilazine, and trimipramine doxylamine, pheniramine, pyrilamine, chlorcyclizine, thonzylamine, their pharmaceutically acceptable salts, and combinations thereof.

[0172] In some embodiments, the therapeutically active agent is an IL-6 inhibitor such as sarilumab, tocilizumab, RG6179, pharmaceutically acceptable salts thereof and combinations thereof, and / or an HtRA1 inhibitor such as IC-500, FHTR.2163, RG6147, pharmaceutically acceptable salts thereof and combinations thereof, and / or a RASP inhibitor such as reproxalap, and pharmaceutically acceptable salts thereof; and / or netardusil, ripasudil, HA-1077, Y-27632, H-1152P, INS-I15644, Y- 39983, SB772077BS, LX71D1, 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 PgA-donating nitric oxide inhibitors such as latanoprostene bunod and NCX470, pharmaceutically acceptable salts thereof, and combinations thereof. or mast cell stabilizers such as lodoxamide, nedocromil, pemirolast, cromolyn (e.g., cromolyn sodium), pharmaceutically acceptable salts thereof, and combinations thereof; and / or teprotutumab, VRDN-001, VRDN-002, VRDN-003, ganitumab, figitumumab, MEDI-573, cixutumumab, dalotuzumab, lobatumumab, AVE!642, BIIB022, xentuzumab, istiratumab, linsitinib, picropodopyrin, The IGF-1R inhibitor may be selected from at least one of 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, B11885578, B1893923, TT-100, XL-228, A-928605, pharmaceutically acceptable salts thereof, and combinations thereof.

[0173] In some embodiments, the therapeutically active agent is a compound described in, 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. WO05 / 016890, U.S. Patent Application No. 2004 / 0254188, U.S. Patent Application No. 2005 / 0043351, International Patent Application No. WO05 / 040121, U.S. Patent Application No. 2005 / 0085512, and Gomtsyan et al. TRPV1 antagonists such as ashibatrep, V116517, fused azabicyclic, heterocyclic, and amide compounds, as described in Swanson et al., 2005, J. Med. Chem. 48:744-752; fused pyridine derivatives, as described in U.S. Patent Application No. 2004 / 0138454; pyridylpiperazinyl ureas, as described in 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, 11th World Congress on Pain) and BCTC (Sun et al. al., 2003, Chem. Lett. 13:3611-3616; 2-(piperazin-1-yl)-1H-benzimidazole; pyridazinylpiperazine; urea derivatives such as those described in U.S. Patent Application Nos. 2005 / 0107388, 2005 / 0187291, and 2005 / 0154230, as well as A-425619 (El Kouhen et al., 2005, J. Pharmacol. Exp. Tuer. 314:400-409); SB-366791 (Gunthorpe et al., 2004, Neuropharmacology 46:133-149) and AMG 9810 (Gawa et al., 2004, Neuropharmacology 46:133-149). al., 2005, J. Pharmacol. Exp. Ther. 313:474-484).TRPV-1 antagonists also include capsazepine, (E)-3-(4-t-butylphenyl)-N-(2,3-dihydrobenzo[b][1,4)dioxin-6-yl)acrylamide (commercially available, for example, as AMG 981O from Tocris Bioscience, Bristol, United Kingdom), and 4-tertiary butylcyclohexane (SYMSITIVE 1609 from Symise GmbH of Holzminden, Germany, as well as the TRPVI antagonists described 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 No. WO / 2008 / 013861, and / or AMG-517 and AMG-628 (Amgen Inc., Thousands of OAks, Calif.) TRPVI antagonists useful in the present invention are described, for example, in International Patent Application No. WO2006065484, International Patent Application No. WO2003070247, U.S. Patent Application No. US2005080095, and International Patent Application No. WO2005007642.Additional TRPV1 antagonists useful in the methods, compositions, and devices disclosed herein include the following TRPV1 antagonists: ABT-102, AMG8562, AMG9810, BCTC, SB366791, JNJ1 7203212, 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, such as l-(2-(3,3-dimethylbutyl)-4-(trifluoromethyl)benzyl)-3-(l-methyl-lH-indazol-4-yl)urea; 2,2-dimethyl-4-(2-((3-(1-methyl-1H-indazol-4-yl)ureido)methyl)-5-(trifluoromethyl)phenyl)methyl butanoate; 1-(2- (4-Hydroxy-3,3-dimethylbutyl)-4-(trifluoromethyl)benzyl)-3-(I-methyl-1H-indazol-4-yl)urea;2,2-Dimethyl-4-(2-((3-(1-methyl-1H-indazol-4-yl)ureido)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-(l-methyl-1H-indazol-4-yl)urea; 1-(2-isopropyl-4-(trifluoromethyl)benzyl)-3-(l-methyl-1H-indazol-4-yl)urea; 1-(4-chloro-3-isopropylbenzyl)-3-(l-methyl-1H-indazol-4-yl)urea, pharmaceutically acceptable salts thereof and combinations thereof.

[0174] In some embodiments, the therapeutically active agent may be selected from at least one of TrkA antagonists including VM902A, larotrectinib, entrectinib, ceritrectinib (LOXO-195, BAY2731954), repotrectinib (TPX-0005), pharmaceutically acceptable salts thereof, and combinations thereof.

[0175] In some embodiments, the therapeutically active agent may be selected from at least one of betamethasone, bevacizumab (Avastin), ciprofloxacin HCl, cortisone, cyclosporine, dexamethasone, ketoprofen, ketorolac, salicylic acid, sirolimus, sorafenib, sunitinib maleate, tacrolimus; and / or lipophilic active agents such as betaxolol, indomethacin, propranolol, fluconazole, fluorometholone, timolol, ethoxzolamide, hydrocortisone, cabozantinib, axitinib, tivozanib, etc.

[0176] In certain embodiments, the therapeutically active agent may be a combination of drugs, for example, for combination therapy.The combination of active agents may be co-administered in a drug delivery system, for example, an implant, or may be included as a bispecific molecule.An exemplary combination useful in the drug delivery system of the present invention includes a complement inhibitor combined with an anti-VEGF agent, which may be used, for example, to treat patients with both dry AMD / GA and wet AMD, and to prevent the onset of one of these diseases.Such a combination can be used to treat patients with wet AMD without GA, and prevent or delay the onset of GA after the patient is administered a combination of anti-VEGF and a complement agent. Examples of combinations of complement inhibitors and anti-VEGF agents include aflibercept and pegcetacoplan, aflibercept and avacincaptad pegol, ranibizumab and pegcetacoplan, ranibizumab and pegcetacoplan, axitinib and pegcetacoplan, axitinib and avacincaptad pegol, borolanib and pegcetacoplan, borolanib and avacincaptad pegol, lenvatinib and pegcetacoplan, lenvatinib and avacincaptad, faricimab and pegcetacoplan, faricimab and avacincaptad pegol, bevacizumab and pegcetacoplan, and bevacizumab and avacincaptad pegol.

[0177] In other embodiments, the combination of active agents may include an anti-VEGF and an IL-6 blocker, such as aflibercept, ranibizumab, bevacizumab, faricimab, axitinib, borolanib, lenvatinib (anti-VEGF) in any combination with sarilumab, tocilizumab, RG6179 (IL-6 blocker).

[0178] In other embodiments, the combination of active agents may include a beta-blocker in combination with a PgA analog, such as timolol (most commonly used for glaucoma), and a PgA analog, such as any one of latanoprost, bimatoprost, or travoprost.

[0179] Combinations of active agents in the present invention can also include combinations of at least one therapeutically active agent with at least one diagnostically active agent, or combinations of three or more active agents.

[0180] A diagnostically active agent may be, for example, a contrast agent, a marker, or a visualization agent. Generally, a diagnostic agent may be a substance used to examine the body to detect disorders in the body's normal functions. In some cases, a diagnostic agent may be an agent with a functional purpose, such as for use in detecting ocular deformities, diseases, and pathophysiological aspects. For example, a diagnostic agent may be an important and effective diagnostic aid, such as dyes to aid in the visualization of ocular tissues (e.g., dark quenchers such as fluorescein dyes, indocyanine green, trypan blue, cyanine dyes, azo dyes, acridines, fluorenes, oxazines, phenanthridines, naphthalimides, rhodamines, benzopyrones, perylenes, benzanthrones, and prabenzoxanthrones). Diagnostic agents may include paramagnetic molecules, fluorescent compounds, magnetic molecules, radionuclides, X-ray imaging agents, and / or contrast agents. In some embodiments, diagnostic agents may include radiopharmaceuticals, contrast agents used in imaging techniques, allergen extracts, activated charcoal, various test strips (e.g., cholesterol, ethanol, and glucose), pregnancy tests, urea C 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 coumarin, cyanine dyes, azo dyes, acridine, fluorene, oxazine, phenanthridine, naphthalimide, rhodamine, benzopyrone, perylene, benzanthrone, and benzoxanthrone. In certain non-limiting embodiments, the fluorescent dye is a compound, or a residue thereof, 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)propanoate (spiropyran), 3,5-dihydroxybenzoate, and (E)-2-(4-(phenyldiazenyl)phenoxy)acetic acid, or a combination thereof.

[0181] 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, which forms at least a part of the hydrophobic organic liquid or may be used in place of the hydrophobic organic liquid.

[0182] According to certain embodiments of the present invention, the active agent is oil soluble and can be dissolved in a hydrophobic organic liquid, or the active agent is oil insoluble and can be dispersed in a hydrophobic organic liquid in particulate form or emulsified in liquid form.

[0183] In embodiments, the active agent is used in particulate form, and the particles of the active agent can be microparticles, e.g., 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 than 5 μm and / or a D98 particle size of about 10 μm or less. In other embodiments, the particles of the active agent can be nanoparticles, e.g., 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. Particle size is determined as disclosed in the "Definitions" section of this specification.

[0184] Composition Range According to the present invention, organogel drug delivery systems can be designed as needed for their intended use and therapeutic application. Typically, organogel comprises 1-90 wt%, 5-90 wt%, 5-60 wt%, 10-50 wt%, 10-40 wt%, 15-40 wt%, or 15-35 wt% hydrophobic organic liquid, 5-95 wt%, 10-95 wt%, 40-95 wt%, 50-90 wt%, 60-90 wt%, or 60-85 wt% covalently crosslinked polymer network, and 1-50 wt%, 5-50 wt%, 5-40 wt%, 10-30 wt%, or 10-25 wt% active agent, all weight percentages selected to total 100%, and weight percentages are based on the total dry weight of the organogel or drug delivery system, respectively.

[0185] Manufacturing method The present invention provides a method for producing the sustained-release biodegradable drug delivery system described herein. In certain embodiments, the method for producing the sustained-release biodegradable drug delivery system includes forming an organogel from at least a covalently crosslinked polymer network, a hydrophobic organic liquid, optionally a catalyst, and at least one active agent, where the hydrophobic organic liquid and the active agent are contained, e.g., immobilized, in the biodegradable covalently crosslinked polymer network; shaping the organogel; and optionally removing the solvent from the organogel.

[0186] In certain procedures, the step of forming the organogel (step (1)) includes providing (a) a hydrophobic organic liquid, (b) at least one active agent, (c) a first covalently crosslinkable precursor comprising a first functional group, and (d) a second covalently crosslinkable precursor comprising a second functional group, all combined in any suitable order into a reaction mixture, and (e) gelling the reaction mixture by forming a covalently crosslinked polymer network.

[0187] Optionally, at least one organic solvent can be added to any of (a), (b), (c), (d) and (e) and removed after the organogel is formed.

[0188] In one embodiment, in (c), at least one first multi-arm precursor is provided. Precursors and multi-arm precursors used in the present invention are described in detail in the section entitled "Precursor Components." In some embodiments, the at least one multi-arm precursor comprises at least eight arms, or at least four arms. The at least one multi-arm precursor comprises an electrophile or a nucleophile as a first functional group.

[0189] In another embodiment, the at least one first multi-arm precursor comprises at least two multi-arm precursors. In such an embodiment, one multi-arm precursor comprises an electrophile and another multi-arm precursor comprises a nucleophile as a first or second functional group. In another embodiment, the at least one multi-arm precursor comprises at least one multi-arm precursor comprising an electrophile or nucleophile as a first functional group and a small molecule crosslinker comprising an electrophile or nucleophile as a second functional group.

[0190] In these embodiments, the nucleophile may be an amine, such as a primary amine, a thiol, a dibenzocyclooctyne, or a hydrazide, and the electrophile may be a succinimidyl ester, succinimidyl carbonate, 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 tresyl, a cyanurate, an orthopyridyl disulfide, or a halide. In embodiments of the present invention, if the electrophile is a succinimidyl ester, it may contain a reactive group such as succinimidyl succinate (SS), succinimidyl glutarate (SG), succinimidyl adipate (SAP), succinimidyl azelate (SAZ), or succinimidyl glutaramide.

[0191] In some embodiments, at least one multi-arm precursor is a first multi-arm PEG precursor containing a primary amine or a first multi-arm PLGA precursor containing a primary amine. Thus, the first covalently cross-linkable precursor containing a first functional group can be hydrophilic (PEG) or hydrophobic (PLGA).

[0192] In one embodiment, in (d), at least one additional second multi-arm precursor is provided. The precursors and multi-arm precursors used in the present invention are described in detail in the section entitled "Precursor Components." In some embodiments, the at least one second multi-arm precursor comprises at least eight arms, or at least four arms. The at least one second multi-arm precursor may comprise an electrophile or a nucleophile as the second functional group.

[0193] In another embodiment, the at least one second multi-arm precursor comprises at least two multi-arm precursors. In such an embodiment, one multi-arm precursor comprises an electrophile and another multi-arm precursor comprises a nucleophile. In another embodiment, the at least one second multi-arm precursor comprises at least two multi-arm precursors, each comprising an electrophile.

[0194] 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 tresyl, a cyanurate, an orthopyridyl disulfide, or a halide. In addition to the classical electrophile-nucleophile condensation reaction, other types of chemistry based on electrophiles and nucleophiles can also be used in the present invention. For example, by functionalization with azides and dibenzocyclooctynes, precursors can be crosslinked via the so-called click chemistry reaction (see H.C. Kolb; M.G. Finn; K.B. Sharpless (2001). “Click Chemistry: Diverse Chemical Function from a Few Good Reactions”, Angewandte Chemie International Edition, 40(11):2004-2021).

[0195] In some embodiments, the at least one second multi-arm precursor comprises at least two second multi-arm precursors, including a first multi-arm precursor comprising an electrophile comprising a first reactive group and a second multi-arm precursor comprising an electrophile comprising a second reactive group. In embodiments of the present invention, when the electrophile is a succinimidyl ester, the first reactive group and the second reactive group are selected from succinimidyl succinate (SS), succinimidyl glutarate (SG), succinimidyl adipate (SAP), succinimidyl azelate (SAZ), or succinimidyl glutaramide.

[0196] At least one of the first or second crosslinkable precursors has a functionality of 3 or more, e.g., 3 to 10, 3 to 9, 4 to 8, or 4. The first crosslinkable precursor may be a dendrimer or multi-arm precursor having a core and 2 to 12 arms, or 3 to 10 arms, 4 to 8 arms, or 4 to 8 arms, each arm comprising a polymeric unit as defined herein and having a terminus bearing a first or second functional group. For example, a four-arm precursor may be derived from pentaerythritol or ethylenediamine, comprising four arms of polymeric units attached thereto. In some embodiments, the arms comprise hydrophobic polymeric units selected from polylactic acid (PLA) units and polylactic-co-glycolic acid (PLGA) units, or a combination thereof. In some embodiments, the arms comprise hydrophilic polymeric units selected from polyethylene glycol (PEG), polypropylene glycol (PPG), and polyglycolic acid (PGA), or a combination thereof. The second crosslinkable precursor may be a non-polymeric crosslinker, preferably a small molecule amine such as tris(2-aminoethyl)amine (TAEA) or trilysine.

[0197] When PLGA units are used, the ratio of lactic 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. Furthermore, the lactic acid-co-glycolic acid (PLGA) precursor can have an L / G ratio (% of L or G blocks) ranging from 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 the lactic acid-co-glycolic acid (PLGA) units can be selected to adjust the hydrophobicity of the polymer network and provide sustained release of the active agent from the organogel. Additionally, or alternatively, the ratio of the amount of the first crosslinkable precursor to the second crosslinkable precursor can be selected to adjust the hydrophobicity of the polymer network and provide sustained release of the active agent.

[0198] In certain embodiments, (a), (b), (c), and (d) above are then processed to obtain (e) and (f), respectively. In embodiments, 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 optionally be added to either of these premixes, and the active agent of (b) may be added to either of these premixes or to the reaction mixture of (e).

[0199] In one embodiment, once all components of reaction mixture (e) are combined, at least two precursors react in an electrophile-nucleophile reaction to form a covalently crosslinked matrix, i.e., an organogel. The reaction can be initiated or accelerated by heating or can occur at ambient conditions.

[0200] The step of shaping the organogel (step (2)) can include molding, extruding, or casting the reaction mixture before fully gelling the organogel, then allowing the mixture to gel and optionally removing the solvent. Shaping can be accomplished by filling the reaction mixture into a mold or tube, allowing the mixture to gel, and optionally removing the solvent before fully gelling the organogel. In some embodiments, the reaction mixture can be filled into a thin-diameter tube or needle to prepare organogel chains. The reaction mixture can also be applied as a coating onto a substrate. As part of the process, the cured organogel can be deformed and rigidified to allow injection through the needle lumen, with the rigidity and reformation being reversible upon contact with the warmth and / or moisture of tissue. Rigidity can be provided by crystallization, a secondary crosslinking mechanism, or a water-soluble, temporary structural component, such as PEG fibers.

[0201] Composition (e), including the precursors mixed therein, can be prepared using manual force with a viscosity suitable for introduction through a small-gauge needle. Small-gauge needles have diameters smaller than those of 27-gauge needles, e.g., 28, 29, 30, 31, 32, or 33-gauge needles, where the gauge is specific to the inner and / or outer diameter. Furthermore, hollow tubing wires, such as those used in intravascular techniques, may be used to deliver materials to implantation sites to form in situ drug delivery devices, including those with inner and / or outer diameters comparable to or smaller than those of small-gauge needles. Thus, viscosities of about 1 to about 100,000 mPa·s can be used. Those skilled in the art will readily understand that all ranges and values within the explicitly stated ranges are contemplated, e.g., about 10 to about 10,000 mPa·s, about 5 to less than about 10,000 mPa·s, about 100 or less than about 500 mPa·s, or about 1 to about 100 mPa·s. Viscosity can be controlled, for example, by selecting appropriate precursors, adjusting solids and / or solvent concentrations, and reaction rate. Generally, lower precursor concentrations, more hydrophilic properties, and lower molecular weights result in lower viscosities.

[0202] Viscosity improvers may be used in combination with the precursors. In certain embodiments, the viscosity improver does not react with the precursor to form a covalent bond. While it is understood that precursors that do not generally contain such bonds may participate in undesirable side reactions, the precursors are "free" of such reactions because they have little effect on the organogel. For example, if the precursor reacts via an electrophile-nucleophile reaction, the viscosity improver may be free of electrophiles or nucleophiles that can form covalent bonds with functional groups of the precursor, even if there are some low levels of undesirable side reactions. The viscosity improver may be a hydrophilic polymer with a molecular weight of, for example, at least 20,000, or from about 10,000 to about 500,000 daltons. Those skilled in the art will readily understand that all values and ranges between these explicitly stated values, e.g., at least about 100,000 or 200,000, are referred to. For example, concentrations of about 1% to about 40%, or from about 5% to about 25% w / w may be used. For example, PEG (e.g., MW 100,000-250,000) is useful. The viscosity enhancing agent may be free of electrophiles and / or nucleophiles. The viscosity enhancing agent may be free of one or more functional groups, such as hydroxyl, carboxyl, amine, or thiol. The viscosity enhancing agent may include one or more biodegradable linkages as described herein for the precursor. The viscosity enhancing agent may be useful in preventing the precursor from flowing out of the tissue site before it crosslinks to form a gel.

[0203] Sustained release kinetics: In certain embodiments, the use of organogels in the sustained-release biodegradable drug delivery systems of the present invention allows for the modification of the release of active agents from the drug delivery systems by several means. For example, tailoring or appropriately selecting the precursor components that form the crosslinked polymer network according to their hydrophilicity and / or hydrophobicity can affect the release of the active agent. Furthermore, the release of the active agent from the drug delivery system can be modified or controlled by appropriately selecting the hydrophobic organic liquid according to one or more of the following properties: hydrophobicity, viscosity, compatibility with the active agent, solubility or insolubility of the active agent in the hydrophobic organic phase, etc.

[0204] Thus, in various embodiments of the present invention, the release rate can be tuned using the selection of the hydrophobic liquid, and / or the hydrophobicity of the polymer network, and / or the L / G ratio. Each of these individual parameters may be selected alone or in combination with one another to provide a controlled release of the active agent.

[0205] In certain embodiments, the sustained release drug delivery systems of the present invention are formulated to make the active agent available over an extended period of time, thereby allowing for reduced dosing frequency compared to immediate release dosage forms (e.g., solutions of the active agent applied topically to the eye (i.e., eye drops)). In certain embodiments, the release of the active agent includes constant active agent release, tapered active agent release, and any combination thereof (e.g., constant active agent release followed by tapered active agent release). "Sustained release" may be measured in vitro under physiological conditions, such as in aqueous solution 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 in vivo to a subject.

[0206] In various embodiments of the present invention, release of the active agent follows zero order or substantially zero order release kinetics, preferably without a "burst" of active agent at the beginning of the period.

[0207] Embodiments of the invention provide for release of a therapeutically effective amount of an active agent for a period of time, 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 25 days after administration. Other embodiments of the invention may provide for release of a therapeutically effective amount of an active agent for up to about 14 days or up to about 21 days after administration, or for a period of about 6 hours or more after administration, or about 12 hours or more, or about 24 hours or more, or about 48 hours or more, or about 72 hours or more, or about 7 days or more, or about 10 days or more after administration. The invention contemplates all of the above shorter and longer periods, in any combination of ranges.

[0208] In various embodiments of the present invention, the organogel slows the release of water-soluble active agents or accelerates the release of hydrophobic active agents.

[0209] In one aspect of the present invention, a sustained-release drug delivery system, such as a pharmaceutically acceptable implant, is provided for controlled release of an active agent (e.g., total amount) contained therein. Throughout this section, controlled release shall be considered as controlled release measured under physiological conditions, such as a pH of 7.2-7.4 and a temperature of 37°C, from the time the implant is initially immersed in an aqueous solution under those conditions. After exposure to physiological conditions, the organogel contained in the drug delivery system can slowly release a hydrophobic organic liquid from the organogel and simultaneously form a hydrogel.

[0210] According to certain aspects of the present invention, sustained-release drug delivery systems, such as pharmaceutically acceptable implants, are provided for controlled release of the total amount of active agent contained therein. In certain embodiments, the controlled release may be characterized by the amount of active agent released on the first day being 0-50% of the total amount of active agent, the amount of active agent released per day from the second to the final day of release being 0-50% of the total amount of active agent, and / or the number of days required to release 100% of the total amount of active agent being at least 2 days.

[0211] In certain embodiments, the controlled release may be characterized by the amount of active agent released on day 1 being 0-50% of the total amount of active agent, the amount of active agent released per day from the second to the last day of release being 0-50% of the total amount of active agent, and / or the number of days required to release 100% of the total amount of active agent is at least 3 days.

[0212] In certain embodiments, the controlled release may be characterized by the amount of active agent released on day 1 being 0-50% of the total amount of active agent, the amount of active agent released per day from the second to the last day of release being 0-50% of the total amount of active agent, and / or the number of days required to release 100% of the total amount of active agent being at least 4-7 days.

[0213] In certain embodiments, the controlled release may be characterized by the amount of active agent released on day 1 being 0-50% of the total amount of active agent, the amount of active agent released per day from the second to the last day of release being 0-50% of the total amount of active agent, and / or the number of days required to release 100% of the total amount of active agent being at least 10-15 days.

[0214] In certain embodiments, the controlled release may be characterized by the amount of active agent released on day 1 being 0-50% of the total amount of active agent, the amount of active agent released per day from the second to the last day of release being 0-50% of the total amount of active agent, and / or the number of days required to release 100% of the total amount of active agent being at least 10-30 days.

[0215] In certain embodiments, the controlled release may be characterized by the amount of active agent released on day 1 being 0-50% of the total amount of active agent, the amount of active agent released per day from the second to the last day of release being 0-50% of the total amount of active agent, and / or the number of days required to release 100% of the total amount of active agent being greater than 30 days.

[0216] According to certain embodiments of the present invention, the controlled release is characterized by the amount of active agent released on day 1 being 0-25%, 0-20%, 0-10%, 0-5%, or about 0% of the total amount of active agent, and the amount of active agent released per day from the second to the last day of release being 0-50%, 0-40%, 0-30%, 0-20%, 0-10%, or 0-5% 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 16 days. In other embodiments, the time period is as disclosed above.

[0217] In one embodiment, the controlled release as characterized above comprises a zero-order release, e.g., a near-zero-order release, or a substantially zero-order release. In one embodiment, the zero-order, near-zero-order, 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.

[0218] A dosage form exhibiting a zero-order release rate will exhibit a linearly proportional relationship in a graphical representation of the percentage of active agent released versus time. In certain embodiments of the present invention, zero-order release is achieved throughout the entire release period. In certain embodiments of the present invention, zero-order release is achieved over a portion of the release period. In certain such embodiments, zero-order release is achieved from the end of the first day, i.e., from 24 hours after the start of release to the end of release. If little or no release occurs by the end of the first day, such release is considered to have had a lag time of 1 day or 24 hours. Such lag times can also be longer. If a significant release is achieved by the end of the first day, such release is considered to have had a burst within the first day or within 24 hours. Such bursts can also be longer. Zero-order release can also be achieved throughout the entire release period. In this context, the entire release period is defined as until 95% of release is achieved.

[0219] Within the meaning of the present invention, zero-order release is defined as being achieved when the release during each time period is proportional to the elapsed time. Proportional to the elapsed time means that the proportional release is calculated based on the total time of zero-order release that defines the line (the % cumulative release during the entire period in which zero-order is achieved divided by the total time that defines the line), and the release at any point in time, i.e., between the start of zero-order release and the end of zero-order release, is within 20% points of the % cumulative release of the proportional release defined by the line.

[0220] Administration The drug delivery system of the present 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 herein below, for example to form an in situ implant.

[0221] When the sustained-release biodegradable drug delivery system is an implant, the implant can be one of an intraocular implant, an intravenous implant, an intracameral implant, an anterior chamber implant, anterior chamber, vitreous, episcleral, intraposterior sub-Tenon's (inferior fornix), subconjunctival, intracameral, peribulbar, retrobulbar, sub-Tenon's, retinal, subretinal, intracanalicular, intravitreal, intrascleral, choroid, suprachoroidal, retinal, subretinal, or lens, corneal or conjunctival surface, punctum (major canal, superior / inferior canaliculus), fornix, superior / inferior fornix, sub-Tenon's, choroid, suprachoroid, Tenon's, cornea, cancerous tissue, organ, prostate, breast, joint cavity, subdural, dental, subcutaneous, carpal tunnel, perivascular, surgically created space or lesion, void space, and implant for introduction into a potential space.

[0222] In certain embodiments of the present invention, the sustained-release biodegradable drug delivery system can be formulated for administration via a variety of routes, such as orally, parenterally, or by surgical insertion or injection. Oral dosage forms can consist of the organogel of the present invention, which can optionally be enteric coated, or can be in the form of small particulates filled into capsules or the like.

[0223] Treatment method In accordance with the present invention, a sustained-release biodegradable drug delivery system is configured for use as a pharmaceutical, such as for use in treating a disease or 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 crosslinked polymer network, the organogel being formed in situ at a treatment site in a patient or prefabricated and delivered to or implanted at a treatment site in a patient to release the active agent over an extended period of time.

[0224] Methods of treating a disease or 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 crosslinked polymer network, the organogel being formed in situ at a treatment site in the patient or prefabricated and delivered to or implanted at the treatment site for release of the active agent over an extended period of time. The methods of treating a disease or condition in a patient can comprise administering to the patient an organogel comprising a therapeutically active agent dispersed in a hydrophobic organic liquid contained in a covalently crosslinked polymer network for release of the active agent over an extended period of time.

[0225] The treatment site can be one of the anterior chamber, vitreous, episclera, in the posterior lower Tenon's capsule (lower fornix), subconjunctival, intracameral, peribulbar, retrobulbar, sub-Tenon's capsule, retinal, subretinal, intracanalicular, intravitreal, intrascleral, choroid, suprachoroidal, retinal, subretinal, or lens, corneal or conjunctival surface, punctum (major canaliculus, superior / inferior canaliculus), fornix, superior / inferior fornix, lower Tenon's capsule, choroid, suprachoroidal, Tenon's capsule, cornea, cancerous tissue, organ, prostate, breast, joint cavity, subdural, dental, subcutaneous, carpal tunnel, perivascular, surgically created space or lesion, void space, and potential space.

[0226] In embodiments of the present invention, the disease or condition to be treated is an ocular disease, particularly a disease of the back of the eye, such as any ocular disease of the posterior segment that affects the vasculature and integrity of the retina, macula, or choroid leading to vision impairment, vision loss, or blindness, particularly disease states of the posterior segment resulting from aging, 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, lacrimation, presbyopia, cataract, retinal vein occlusion, inflammation. Eye diseases include 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 platelet pigment epitheliopathy, Behcet's disease, Birdseye syndrome, and others. retinal choroidopathy, posterior uveitis, posterior scleritis, creeping choroiditis, subretinal fibrosis, uveitis syndrome, Vogt-Koyanagi-Harada syndrome, retinal artery occlusion, central retinal vein occlusion, disseminated intravascular coagulation, branch retinal vein occlusion, hypertensive fundus changes, ocular ischemic syndrome, retinal artery microaneurysms, Coats disease, parafoveal telangiectasia, hemiretinal vein occlusion, papillary vasculitis, carotid artery disease (CAD), frost-like vasculitis, Sickle cell retinopathy, angioid streaks, familial exudative vitreoretinopathy, Eales' disease, proliferative vitreoretinopathy, diabetic retinopathy, retinal diseases associated with tumors, congenital hypertrophy of the retinal pigment epithelium (RPE), posterior uveal melanoma, choroidal hemangioma, choroidal osteoma, choroidal metastasis, combined hamartoma of the retina and retinal pigment epithelium, retinoblastoma, angioproliferative tumor of the fundus, retinal astrocytoma, intraocular lymphoma, myopic retinal degeneration, acute retinal pigment ulcer The condition may be selected from epithelitis, glaucoma, endophthalmitis, cytomegalovirus retinitis, retinal cancer, retinitis pigmentosa, Leber's congenital amaurosis, congenital choroideremia, X-linked retinitis pigmentosa, Best vitelliform macular dystrophy, X-linked retinoschisis, CNGA3 color vision deficiency, CNGB3 color vision deficiency, LHON, Stargardt disease, Usher syndrome, Norrie disease, Bardet-Biedl syndrome, and red-green color blindness.

[0227] In the treatment methods of the present invention, a sustained release biodegradable drug delivery system, as discussed elsewhere herein, is administered to a subject or patient. The drug delivery system is for the controlled release of any of the active agents discussed elsewhere herein. Controlled release is also defined elsewhere herein.

[0228] The methods described in this section may also involve administering a drug delivery system, such as a pharmaceutically acceptable implant, in combination with another agent, also referred to as combination therapy.

[0229] In one embodiment, the combination therapy comprises administering the pharmaceutically acceptable implant of the present invention in combination with one or more additional drugs on the same or different days.In one embodiment, the additional drug to be administered in the combination therapy can be a liquid drug or can be contained in an oral dosage form.Therefore, the additional drug can be any small molecule, large molecule, protein, nanoparticle, etc. of the active agent described herein.

[0230] In certain combination therapy embodiments, the therapeutic active agent may be a combination of drugs.The combination of active agents may be administered simultaneously, including all active agents in a drug delivery system, such as an implant, or may be included as a bispecific molecule.An exemplary combination useful in the drug delivery system of the present invention includes a complement inhibitor combined with an anti-VEGF agent, which may be used, for example, to treat patients with both dry AMD / GA and wet AMD, and to prevent the onset of one of these diseases.Such a combination can be used to treat patients with wet AMD without GA, and prevent or delay the onset of GA after the patient is administered a combination of anti-VEGF and a complement agent. Examples of combinations of complement inhibitors and anti-VEGF agents include aflibercept and pegcetacoplan, aflibercept and avacincaptad pegol, ranibizumab and pegcetacoplan, ranibizumab and pegcetacoplan, axitinib and pegcetacoplan, axitinib and avacincaptad pegol, borolanib and pegcetacoplan, borolanib and avacincaptad pegol, lenvatinib and pegcetacoplan, lenvatinib and avacincaptad, faricimab and pegcetacoplan, faricimab and avacincaptad pegol, bevacizumab and pegcetacoplan, and bevacizumab and avacincaptad pegol.

[0231] In other embodiments, the combination of active agents may include an anti-VEGF and an IL-6 blocker, such as aflibercept, ranibizumab, bevacizumab, faricimab, axitinib, borolanib, lenvatinib (anti-VEGF) in any combination with sarilumab, tocilizumab, RG6179 (IL-6 blocker).

[0232] In other embodiments, the combination of active agents may include a beta-blocker in combination with a PgA analog, such as timolol (most commonly used for glaucoma), and a PgA analog, such as any one of latanoprost, bimatoprost, or travoprost.

[0233] Combinations of active agents in the present invention can also include combinations of at least one therapeutically active agent with at least one diagnostically active agent, or combinations of three or more active agents.

[0234] The therapeutic methods described in this section that involve administering a drug delivery system, such as a pharmaceutically acceptable implant, can include any one of intravitreal, intracameral, subconjunctival, retrobulbar, subtenon, subretinal, and suprachoroidal injections. The administration method can be topical or oral.

[0235] The active or additional agent to be administered in combination therapy may be a diagnostic agent. A diagnostic agent may be a substance used to examine the body to detect impairments in its normal functions. In some cases, a diagnostic agent may have a functional purpose, such as use in detecting ocular deformities, diseases, and pathophysiological aspects. For example, a diagnostic agent may be an important and effective diagnostic aid, such as dyes to aid in visualization of ocular tissues (e.g., dark quenchers such as fluorescein dyes, indocyanine green, trypan blue, cyanine dyes, azo dyes, acridines, fluorenes, oxazines, phenanthridines, naphthalimides, rhodamines, benzopyrones, perylenes, benzanthrones, and prabenzoxanthrones). Diagnostic agents may include paramagnetic molecules, fluorescent compounds, magnetic molecules, radionuclides, X-ray imaging agents, and / or contrast agents. In some embodiments, diagnostic agents may include radiopharmaceuticals, contrast agents used in imaging techniques, allergen extracts, activated charcoal, various test strips (e.g., cholesterol, ethanol, and glucose), pregnancy tests, urea C 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 coumarin, cyanine dyes, azo dyes, acridine, fluorene, oxazine, phenanthridine, naphthalimide, rhodamine, benzopyrone, perylene, benzanthrone, and benzoxanthrone. In certain non-limiting embodiments, the fluorescent dye is a compound, or a residue thereof, 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)propanoate (spiropyran), 3,5-dihydroxybenzoate, and (E)-2-(4-(phenyldiazenyl)phenoxy)acetic acid, or a combination thereof.

[0236] Controlled Release Method In one aspect, the present invention relates to a method for controlling the release of an active agent from the sustained release biodegradable drug delivery system described herein above by selecting a combination of a hydrophobic organic liquid and an active agent dispersed therein, wherein any one or combination of the following criteria applies: a) An active agent dispersed in a hydrophobic liquid (e.g., oil) is released from the organogel along with the hydrophobic organic liquid (the diffusion / absorption rate of the oil determines the release rate of the agent). b) The active drug is dissolved directly into the body from a hydrophobic liquid (e.g., oil), and the drug release rate is controlled by at least one of drug solubility and / or diffusivity in the hydrophobic liquid (e.g., oil) and / or in the surface region of the implant (the drug release rate is largely independent of the diffusion / absorption rate of the hydrophobic liquid).

[0237] In certain embodiments of the present invention, the release of the active agent is controlled primarily by the diffusion of the active agent and / or the hydrophobic liquid (e.g., oil). The degradation rate of the polymer network provides another independent and additional release control mechanism. In certain embodiments, the hydrophobic liquid slows or accelerates degradation, which can be used as another method of controlling the release of the active agent. When an active agent dispersed in a hydrophobic liquid is released from the organogel along with the hydrophobic liquid, the release rate of the agent is essentially influenced or determined by the diffusion rate of the oil into the surrounding tissue or body environment. In other embodiments, the active agent may diffuse more easily from the hydrophobic liquid than the oil diffuses from the polymer network.

[0238] The organogels of the present invention swell by taking up water when in contact with aqueous body fluids. The degree of swelling is determined primarily by the gel-forming components used and their hydrophobicity / hydrophilicity. Swelling can result in an increase in the length and / or diameter dimensions of the organogels of the present invention of up to 2000%, 1000%, 100%, 95%, 90%, 80%, 75%, 70%, 60%, 50%, 40%, 30%, 20%, or 10%.

[0239] However, even after swelling in certain embodiments, the drug delivery systems of the present invention retain their shape or substantial shape for extended periods of time due to cross-linking of the polymeric components. In certain embodiments, the polymer network of the organogel substantially degrades only after all of the active agent has been released, or at least a majority of the active agent, e.g., at least 50%, 60%, 70%, 80%, 90%, or 99% by weight, or 100% by weight, has been released.

[0240] In certain embodiments, the swelling primarily leads to, for example, an increase in the size of the organogel implant, but may also affect the release of the active agent and / or the biodegradation of the gel matrix. As the amount of water entering the organogel increases, the swelling of the organogel may cause the hydrophobic organic liquid to be extruded from the gel matrix or accelerate outward diffusion, either with the active agent dissolved therein or without the active agent if the active agent is not dissolved in the hydrophobic liquid phase, after which the hydrophobic liquid is replaced by water.

[0241] For example, the displacement of water over time by the organic hydrophobic liquid in the gel can ensure that any hydrophilic active agent dispersed but not dissolved in the organic hydrophobic liquid dissolves, which can be used to control the release of the active agent. In this embodiment, the release of the active agent is primarily or completely controlled by diffusion of the active agent through the oil and polymer into the surrounding tissue. In certain embodiments, where the release rate of the active agent is largely independent of the diffusion rate of the hydrophobic liquid, e.g., a hydrophilic agent dispersed as solid particles in a hydrophobic liquid, another factor that influences or determines the release of an active agent dispersed in a hydrophobic liquid is the diffusion rate of water into the gel and / or hydrophobic liquid, which subsequently dissolves and elutes the active agent from the organogel into the surrounding aqueous environment.

[0242] Furthermore, in certain embodiments, water slowly displacing the hydrophobic organic liquid slowly converts the organogel into a hydrogel, which is still crosslinked and therefore maintains its shape, but can then be more easily (bio)degraded by hydrolysis and / or enzymatic reactions after the active agent and / or hydrophobic liquid of the drug delivery system are depleted.

[0243] The overall release of the active agent is controlled by at least one or a combination of all these release mechanisms.

[0244] Furthermore, in certain embodiments, the organogel becomes more flexible and pliable, resembling natural tissue, during swelling due to incorporation, while maintaining or substantially maintaining its structure due to chemical cross-linking of individual polymer chains.

[0245] In a further aspect, the present invention relates to a method for controlling the release of an active agent from the sustained release biodegradable drug delivery system described herein above by any one or combination of the following means: a) Selecting the L / G ratio of poly(lactic-co-glycolic acid) (PLGA) units to adjust the hydrophobicity of the polymer network. b) Selecting the L / G ratio of polylactic-co-glycolic acid (PLGA) units to provide sustained release of the active agent. c) Selecting the molar ratio of the amount of the first crosslinkable precursor to the second crosslinkable precursor to adjust the hydrophobicity of the polymer network (equivalent to mixing hydrophobic and hydrophilic precursors in various ratios). d) Selecting the molar ratio of the amount of the first crosslinkable precursor to the second crosslinkable precursor to provide sustained release of the active agent. e) Selecting the type of hydrophobic liquid to be included, e.g. immobilized, in the organogel. f) Adding a third crosslinkable precursor that is less hydrolyzable than the first and second crosslinkable precursors and varying the molar ratio of the components. g) Dispersing an active agent in particulate form with high water solubility in a hydrophobic phase. h) Incorporation of degradable end groups onto PLGA precursors to accelerate hydrolysis of crosslinks compared to the internal ester bonds of PLGA.

[0246] In embodiments of the present invention that include PLGA units in the gel matrix, yet another mechanism can be utilized to influence or control the release of the active agent. The hydrophobicity of the covalently crosslinked 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 the lactic acid-co-glycolic acid (PLGA) units, the hydrophobicity of the polymer network can be varied. More hydrophobic lactic acid (L) units increase the hydrophobicity of the gel matrix and reduce swelling and water uptake. Increasing the content of relatively more hydrophilic glycolic acid (G) units decreases the hydrophobicity of the gel matrix, resulting in increased swelling and water uptake of the organogel.

[0247] Another possibility to tailor the hydrophobicity of the polymer network is provided in embodiments of the present invention by varying and / or selecting the molar ratio of the first crosslinkable precursor to the second crosslinkable precursor: Using higher amounts of hydrophobic precursors in combination with more hydrophilic precursors, such as PEG units, and vice versa, allows tailoring the swelling and release of hydrophobic liquids and / or active agents.

[0248] The addition of a third crosslinkable precursor having a different hydrophobicity than the first and second precursors and varying the molar ratio of the components can further be used to affect the swelling and release of the hydrophobic liquid and / or active agent, and the diffusion rate of the active agent, hydrophobic liquid and / or water.

[0249] kit In one aspect, the present invention further relates to a kit comprising one or more sustained-release biodegradable drug delivery systems described herein. The kit may further comprise instructions for using the system. In some embodiments, the kit comprises portions of the drug delivery system dispersed in multiple separate containers for forming organogel and / or implant in situ at the site of application or treatment.

[0250] Kits for preparing the drug delivery systems of the present invention may include premixed precursors and other components necessary to form an organogel in separate compartments, and, if necessary, an applicator for combining the premix to form the organogel, thereby storing the organogel precursors in the kit and converting them into an organogel / drug delivery system when needed for patient use. Kits may also be prepared for applying the organogel as is, i.e., already in organogel form. The applicator may be used in combination with the organogel. The kits are manufactured using medically acceptable conditions and contain components with sterility, purity, and pharmaceutically acceptable formulations. The kits may optionally include an applicator and instructions for use. The organogel components may be provided as one or more containers of individual components or precursors, optionally premixed with a hydrophobic organic liquid and / or active agent. The solvent / solution may be provided within the kit or separately, or the components may be premixed with the solvent. The kits may include a syringe and / or needle for mixing and / or delivery. The kit or system may include the components described herein.

[0251] Packaging of the precursor and / or the entire kit may be carried out under dry, oxygen-free conditions. The precursor and / or kit components may be placed in a hermetically sealed container that is impermeable to moisture or oxygen, such as a glass or metal (foil) container.

[0252] The organogels or premixes for making them may be gamma sterilized at the end of the implantable material manufacturing process. Alternatively, or in addition, there may be a sterilization process either before and / or after assembly and sealing of the kit. This technique may use low moisture conditions.

[0253] Preferred Specific Embodiments 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 (a 20,000 Da PEG with four arms terminating in succinimidyl azelate groups) and 4a18k T1307 NH2 (an 18,000 Da Tetronic® 1307 with four arms terminating in amine groups) in the presence of 30 wt % (based on the total dry weight of the system) acetyltriethyl citrate (ATEC) as a hydrophobic oil, 14 wt % (based on the total dry weight of the system) bupivacaine base and dimethyl carbonate (DMC) as a solvent, followed by removal of the solvent under reduced pressure.

[0254] According to another specific embodiment, the sustained-release biodegradable drug delivery system of the present invention is formed by gelling equal amounts of 4a18k-Tet1307-SAP-NHS as an electrophile-functionalized precursor (Tet1307 or T1307 is a four-arm ethylenediaminetetrakis(ethoxylate-block-propoxylate) tetrol copolymer) 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 wt% based on the dry gel, and 16 wt% micronized ropivacaine base (RPV) is used as the active agent, with the solvent subsequently removed.

[0255] According to another specific embodiment, the sustained-release biodegradable drug delivery system of the present invention is formed by gelling 4a20k-PLGA-NHS as an electrophile-functionalized polymer precursor crosslinked with a small molecular crosslinker TAEA in an amount of about 2.5 wt% (relative to the dry gel) using acetyltriethyl citrate (ATEC) oil in an amount of 40 wt% relative to the dry gel as a hydrophobic organic liquid in the presence of DMC:acetone (80:20 w / w), followed by removal of the solvent.

[0256] According to another specific embodiment, the sustained-release biodegradable drug delivery system of the present invention is formed by gelling equal amounts of 4a20k-PLGA-NHS as an electrophile-functionalized polymer precursor crosslinked with 4a18k Tet1307-NH2 as a nucleophile-functionalized ethoxylate-block-propoxylen polymer precursor and micronized ropivacaine base (RPV) as an active agent in an amount of 14% by weight of the dry gel using acetyltriethyl citrate (ATEC) oil as a hydrophobic organic liquid in the presence of DMC:acetone (80:20 w / w) in an amount of 29% by weight of the dry gel, followed by removal of the solvent.

[0257] According to another specific embodiment, the sustained-release biodegradable drug delivery system of the present invention is formed by gelling equal amounts of 4a20k-Tet1307-SAP-NHS as an electrophile-functionalized ethoxylate-block-propoxylene polymer precursor crosslinked with 4a3.6kTet701-NH2 as a nucleophile-functionalized polymer precursor and micronized ropivacaine base (RPV) as an active agent in an amount of 20% by weight of the dry gel, using acetyltriethyl citrate (ATEC) oil as a hydrophobic organic liquid in an amount of 37% by weight of the dry gel, in the presence of DMC:acetone (80:20 w / w), followed by removal of the solvent.

[0258] According to another specific embodiment, the sustained-release biodegradable drug delivery system of the present invention is formed by gelling 4a20k-PLGA-NHS as an electrophile-functionalized polymer precursor in an amount of about 40 wt% (relative to the dry gel) crosslinked with a small molecular weight crosslinker TAEA in an amount of about 0.4 wt% (relative to the dry gel) using acetyltriethyl citrate (ATEC) oil in an amount of 40 wt% (relative to the dry gel) as a hydrophobic organic liquid in the presence of DMC:acetone (80:20 w / w), followed by removing the solvent.

[0259] According to another specific embodiment, the sustained-release biodegradable drug delivery system of the present invention is formed by gelling equal amounts of 4a20k-PLGA-NHS as an electrophile-functionalized polymer precursor crosslinked with 4a18k Tet1307-NH2 as a nucleophile-functionalized ethoxylate-block-propoxylate polymer precursor and bupivacaine-HCl (BPV-HCl) as an active agent in an amount of 14% by weight of the dry gel, in the presence of DMC:acetone (80:20 w / w) using acetyltriethyl citrate (ATEC) oil as a hydrophobic organic liquid in an amount of 29% by weight of the dry gel, followed by removal of the solvent. [Example]

[0260] The following examples are included to demonstrate certain aspects and embodiments of the claimed invention. However, those of skill in the art should understand that the following description is illustrative only and should not be construed as limiting the invention in any way.

[0261] Materials and abbreviations used in the examples: 4a18k Tet1307-SAP or 4a18k Tet1307-SAP-NHS is a four-arm, 18 kDalton electrophile-functionalized ethoxylate-block-propoxylate polymer precursor (ethylenediaminetetrakis(ethoxylate-block-propoxylate) tetrol 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 kDaltons. 4a18k Tet1307-NH2 is a four-armed, 18 kDalton, nucleophile-functionalized ethoxylate-block-propoxylate polymer precursor obtained by functionalizing commercially available Tetronic 1307 with hydroxylamine. 4a3.6k Tet701-NH2 or 4a3.6kT701-NH2 is a four-armed, 3.6 kDalton, nucleophile-functionalized ethoxylate-block-propoxylate polymer precursor obtained by functionalizing commercially available Tetronic 701 with hydroxylamine. 4a20kSAZ or 4a20kPEG-SAZ or 4a20kPEG-SAZ-NHS is a four-arm, 20 kDalton electrophile-functionalized polyethylene glycol precursor obtained by functionalizing commercially available 4a20kPEG with succinimidyl azelate (i.e., azelaic acid and N-hydroxysuccinimide (NHS)). 4a20kNH2 or 4a20kPEG-NH2 is a nucleophile (amine) functionalized polyethylene glycol precursor with a molecular weight of 20 kDaltons. 4a20kPLGA-NHS is a four-arm 20 kDalton electrophile-functionalized polymer precursor obtained by functionalizing commercially available 4a20kPLGA (with a L / G ratio of 50:50) with N-hydroxysuccinimide (NHS). ATEC is acetyltriethyl citrate (triethyl 2-acetylcitrate), which is commercially available from Sigma-Aldrich / Merck. ATBC is acetyl tributyl citrate (tributyl O-acetyl citrate), which is commercially available from Sigma-Aldrich / Merck. TAEA is tris(2-aminoethyl)amine, which is commercially available from Sigma-Aldrich / Merck. DMC is dimethyl carbonate. PBS is phosphate buffered saline with a physiological salt concentration, pH 7.4.

[0262] Example 1 In Example 1A, an organogel drug delivery system was fabricated using tocopherol (vitamin E acetate) as the hydrophobic organic liquid, micronized ropivacaine base (RPV) as the active agent, and two polymer precursors: 4a18k-Tet1307-SAP-NHS (Tet1307 or T1307 is a four-arm ethylenediaminetetrakis(ethoxylate-block-propoxylate) tetrol copolymer) as the electrophile-functionalized precursor and 4a20k PEG-NH2 as the nucleophile-functionalized polyethylene glycol precursor. In Comparative Example 1B, no hydrophobic organic liquid was used. The composition details are shown in Table 1 below.

[0263] The precursor, active agent, and, if used, a hydrophobic organic liquid were combined in a reaction mixture with a mixture of DMC:acetone (90:10 w / w), tube-cast to form a gel, and dried overnight to remove the solvent.

[0264] [Table 1]

[0265] Both compositions formed solid gels with a gelation time of approximately 2 minutes. The comparative gel without oil was clear, while the inventive gel of Example 1A was white and opaque (see Figure 2). No syneresis was observed in either gel.

[0266] Example 2 In Example 2A, an organogel drug delivery system was fabricated using acetyltriethyl citrate (ATEC) oil as the hydrophobic organic liquid, micronized ropivacaine base (RPV) as the active agent, and 4a20k-PLGA-NHS as the electrophile-functionalized polymer precursor, crosslinked with the small molecule crosslinker TAEA (Table 2). In Comparative Example 2B, no hydrophobic organic liquid was used.

[0267] The precursor, active agent, and, if used, a hydrophobic organic liquid were combined in a reaction mixture with a mixture of DMC:acetone (80:20 w / w), tube-cast to form a gel, and dried overnight to remove the solvent.

[0268] [Table 2]

[0269] Both examples formed solid gels with gelation times of less than 3 minutes. The comparative gel without the oil component was opaque and firm, while the inventive gel of Example 2A was opaque and flexible and showed some syneresis immediately after preparation, but no syneresis after drying and a translucent appearance.

[0270] In Example 2C, an organogel drug delivery system was fabricated using acetyltriethyl citrate (ATEC) oil as the hydrophobic organic liquid, micronized ropivacaine base (RPV) as the active agent, and 4a20k-PLGA-NHS as the electrophile-functionalized polymer precursor, crosslinked with 4a18k Tet1307-NH2 as the nucleophile-functionalized ethoxylate-block-propoxylate polymer precursor (Table 3). In Comparative Example 2D, no hydrophobic organic liquid was used.

[0271] [Table 3]

[0272] Both examples formed solid gels with gelation times of less than 3 minutes. Both gels had an opaque appearance and were rubbery and stretchy. No syneresis was observed in either gel.

[0273] In Example 2E, a further organogel drug delivery system was prepared using acetyltriethyl citrate (ATEC) oil as the hydrophobic organic liquid, micronized ropivacaine base (RPV) as the active agent, and 4a20k-Tet1307-SAP-NHS as the electrophile-functionalized ethoxylate-block-propoxylate polymer precursor, crosslinked with 4a3.6kTet701-NH2 as the nucleophile-functionalized polymer precursor (Table 4). In Comparative Example 2F, no hydrophobic organic liquid was used.

[0274] [Table 4]

[0275] Both examples formed solid gels with gelation times of over 2 hours. Both gels had an opaque appearance and were brittle and sticky. No syneresis was observed in either gel.

[0276] The release data for Inventive Example 2A (PLGA / TAEA gel) shows delayed release of ropivacaine when compared to Comparative Example 2B, which does not contain an organic hydrophobic liquid. The release data for Inventive Examples 2C and 2E (PLGA / Tet1307 or Tet1307 / Tet701 gels), which have more hydrophobic gelling agent, show increased release of ropivacaine when compared to Comparative Examples 2D and 2F, respectively, which do not contain an organic hydrophobic liquid. The presence of an oil component in the organogel can be used to vary the release of active agents that are more water-soluble than oil-soluble, depending on the properties of the gel polymer used (see Figure 3).

[0277] Example 3 In Example 3A, an organogel drug delivery system was fabricated using acetyltriethyl citrate (ATEC) oil as the hydrophobic organic liquid, non-micronized bapivacaine-HCl (BPV-HCl) as the active agent, and 4a20k-PLGA-NHS as the electrophile-functionalized polymer precursor, crosslinked with the small molecule crosslinker TAEA (Table 5). In Comparative Example 3B, no hydrophobic organic liquid was used.

[0278] The precursor, active agent, and, if used, a hydrophobic organic liquid were combined in a reaction mixture with a mixture of DMC:acetone (80:20 w / w), tube-cast to form a gel, and dried overnight to remove the solvent.

[0279] [Table 5]

[0280] Both examples formed solid gels with gelation times of less than 3 minutes. The gels were opaque, flexible, and showed no syneresis.

[0281] In Example 3C, an organogel drug delivery system was prepared using acetyltriethyl citrate (ATEC) oil as the hydrophobic organic liquid, non-micronized bupivacaine-HCl (BPV-HCl) as the active agent, and 4a20k-PLGA-NHS as the electrophile-functionalized polymer precursor, crosslinked with 4a18k Tet1307-NH2 as the nucleophile-functionalized ethoxylate-block-propoxylate polymer precursor (Table 6). In Comparative Example 3D, no hydrophobic organic liquid was used.

[0282] [Table 6]

[0283] Both examples formed solid gels with gelation times of less than 3 minutes, which had excellent gel properties. No syneresis was observed in either gel.

[0284] The in vitro release kinetics (37°C, 1xPBS pH 7.4) of Examples 3A-3D are shown in Figure 4. As shown there, even though BPV is a more oil-soluble drug than ropivacaine, the release of the active agent is slowed by the presence of an organic hydrophobic liquid.

[0285] Example 4 A series of organogel drug delivery systems were prepared as previously described herein using different oils as the hydrophobic organic liquid, non-micronized bupivacaine-HCl (BPV-HCl) as the active agent, and 4a18k Tet1307-SAP-NHS (Table 8) or 4a20k-PLGA-NHS (Table 9) as the electrophile-functionalized polymer precursor, crosslinked with 4a18k Tet1307-NH2 as the nucleophile-functionalized ethoxylate-block-propoxylate polymer precursor. For comparison, each gel was also prepared without the hydrophobic organic liquid.

[0286] The hydrophobic organic liquids used were acetyl triethyl citrate (ATEC), acetyl tributyl citrate (ATBC), and α-tocopherol acetate (vitamin E acetate). To prepare the organogel, two premixes were prepared. The first contained a mixture of electrophile and, if used, hydrophobic organic liquid, and 300 mg of DMC:acetone (80:20 w / w). The second contained nucleophile, active agent, and 200 mg of DMC:acetone (80:20 w / w). Both 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 Tables 7A, 7B, 8A, and 8B below.

[0287] [Table 7] [Table 8]

[0288] [Table 9] [Table 10]

[0289] The in vitro release kinetics (37°C, 1x PBS pH 7.4) of Examples 4A-4H are shown in Figure 5. As shown therein, the release of the active agent BPV-HCl from Tetronic gels 4A-4D is slowed by the presence of ATEC and ATBC and accelerated by vitamin E acetate, respectively, compared to the gels without oil. For PLGA gels 4E-4H, the release of the active agent BPV-HCl is accelerated by ATEC and slowed by the presence of ATBC and vitamin E acetate.

[0290] Example 5 A series of organogel drug delivery systems have been prepared as previously described herein using bupivacaine base (BPV base) as the active agent and three different polymer precursor formulations A, B, and C shown in Table 9. For each of the formulations, the hydrophobic organic liquid used was acetyltriethyl citrate (ATEC) or acetyltributyl citrate (ATBC) in an amount of 0% (comparative), 20%, or 40% by weight of the formulation.

[0291] Formulation A contained a hydrophilic polymer network (PEG-based) and was assigned a hydrophobicity value of 0% HB. Formulation B contained a more hydrophobic polymer network (PEG-poloxamer-based) and was assigned a hydrophobicity value of 15% HB. Formulation C contained the most hydrophobic polymer network (PLGA-poloxamer-based) and was assigned a hydrophobicity value of 65% HB.

[0292] [Table 11]

[0293] All formulations were manufactured as organogel strands with an average diameter of 2.9 mm, cut into 5 mm long pieces, each with an average surface area of 59 mm 2 and the average drug loading (dose) is 1600 μg.

[0294] The in vitro release kinetics data (37°C, 1x PBS pH 7.4) for the formulations of Example 5 are shown in Table 10 below. As can be seen, the release of the active agent BPV base from the PLGA gel of Formulation C does not last for 3 days and shows a very small initial burst (2-hour release value). The release is slowed by the more hydrophobic oil ATBC compared to ATEC and can be further slowed by improving the crosslinking properties of the gel. For the less hydrophobic gel formulation B, the burst data is similar to that of the PLGA gel of Formulation C, but the gel delays the release of BPV base for a longer period, up to approximately 5 days. A similar effect of oil hydrophobicity is observed. Higher oil loading increases the burst and initial daily release. For the least hydrophobic gel formulation A, increasing the amount of oil increases the burst, but the daily release does not appear to be significantly affected by the amount of oil. Overall, formulation B offers a good balance of properties for delaying the release of BPV base. The sample with an overall oil content of 20% (w / w) gave the most reliable results, largely avoiding the initial burst.

[0295] [Table 12]

[0296] FIG. 6 shows the in vitro release of bupivacaine base over time for several of Formulations A and B of Example 5.

[0297] Example 6 Organogel drug delivery systems were fabricated using travoprost as the active agent, which simultaneously serves as a hydrophobic organic liquid. Travoprost is a clear, hydrophobic oil that is virtually insoluble in water. For the gel-forming component, the hydrophobic 4a18K-Tet1307-SAP-NHS was used as the electrophile-functionalized polymer precursor and crosslinked with the more hydrophilic amine (nucleophile)-functionalized PEG, 4a20K-NH2 (Table 11).

[0298] The precursor, a hydrophobic liquid active agent (travoprost), was mixed with a mixture of DMC:acetone (80:20 w / w) in a reaction mixture, tube-cast to form a gel, and dried overnight to remove the solvent.

[0299] [Table 13]

[0300] A solid gel formed in less than 3 minutes. The gel was opaque, flexible, and showed no syneresis when cast into fibers. Fiber pieces corresponding to drug doses of 3400 μg, 734 μg, and 730 μg were cut and subjected to accelerated in vitro release kinetics measurements in 60 ml of buffer at normal body temperature conditions: 40°C, 1x PBS pH 7.4 for the 3400 μg and 734 μg dose samples, and 37°C, 1x PBS pH 7.4 for the 730 μg dose sample. The release experiment at 37°C showed slower release as expected and was discontinued after 6 weeks, but extrapolation of the curves indicates that continuous sustained release over approximately six months is expected. The in vitro release data are summarized in Table 12 below and shown in Figure 7.

[0301] [Table 14]

[0302] As shown in Figure 7, the active agent is released in a consistent, slow, sustained manner over an extended period of time, following zero-order kinetics, with little initial burst observed. The release kinetics of the active agent are diffusion-controlled, as the gel is expected to degrade substantially only after six months. No effect of gel degradation is observed. Furthermore, comparison of the two different doses indicates that the analytical method was compatible and that the slower release kinetics observed in the high-dose sample was not due to drug saturation in the release buffer.

Claims

1. 1. A sustained release biodegradable drug delivery system comprising an organogel and an active agent, wherein the organogel comprises: a hydrophobic organic liquid; a biodegradable covalently crosslinked polymer network; The system wherein the hydrophobic organic liquid and the active agent are contained within the biodegradable covalently crosslinked polymer network.

2. 2. The system of claim 1, wherein the hydrophobic organic liquid is liquid at human body temperature, preferably at a temperature of about 37°C or less, 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 37°C.

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

4. 10. A system according to any one of the preceding claims, wherein the active agent is, or forms at least part of, the hydrophobic organic liquid.

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

6. The hydrophobic organic liquid may be selected from the group consisting of triethyl citrate, acetyltriethyl citrate (ATEC), acetyltributyl citrate (ATBC), α-tocopherol (vitamin E), α-tocopherol acetate; vegetable oils such as sesame oil, olive oil, soybean oil, sunflower oil, coconut oil, canola oil, and rapeseed oil; nut oils such as hazelnut, walnut, pecan, almond, cottonseed oil, corn oil, safflower oil, and linseed oil; ethyl oleate; castor oil and its derivatives (Cremophor®); lipids that are liquid at 37°C or less, such as 10. The system of claim 1, wherein the biocompatible oil is selected from the group consisting of saturated or unsaturated fatty acids, monoglycerides, diglycerides, triglycerides (Myglyols®), isopropyl myristate, phospholipids, glycerophospholipids, sphingolipids, sterols, prenol, polyketides, hydrophobic biodegradable liquid polymers (such as low molecular weight PLGA, PGA, or PLA), low melting point waxes such as vegetable, animal, or synthetic waxes, lanolin, jojoba oil, or combinations thereof.

7. 10. A system according to any one of the preceding claims, wherein the hydrophobic organic liquid has a glass transition temperature and / or melting temperature of 37°C or less.

8. 10. A system according to 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 removed from the implantation site, metabolized from the body and / or removed unchanged.

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

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

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

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

13. 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 crosslinked 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 - a plurality of at least one of hydrophilic polyethylene glycol (PEG), polypropylene glycol (PPG), or polyglycolic acid (PGA) units.

15. 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, particularly preferably a block copolymer of multi-arm PEG copolymerized with PLGA.

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

1.

17. 17. The system of any one of claims 11 to 16, wherein the poly(lactic-co-glycolic acid) (PLGA) units have an L / G ratio (% 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. 10. The system of any one of the preceding claims, wherein the polymer network is covalently crosslinked by hydrolyzable bonds between polymer units.

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

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

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

22. 22. The system of claim 20 or 21, wherein the at least one crosslinkable precursor has 3 or more functional groups, such as 3 to 10, or 3 to 9, or 4 to 8, or 4.

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

24. 24. The system of any one of claims 20 to 23, wherein the at least one crosslinkable precursor comprises hydrophobic polymer units selected from polylactic acid (PLA) units and polylactic-co-glycolic acid (PLGA) units, copolymers, 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 crosslinkable precursor that is hydrophilic.

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

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

29. The system of any one of claims 20 to 28, wherein the at least one covalently crosslinkable precursor comprises three or more functional groups.

30. 29. 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. 31. The system of claim 30, wherein the polymer network is formed from at least two multi-arm precursors, including 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. 38. The system of claim 37, wherein each of the first functional group and the second functional group is selected from an electrophile and a nucleophile, and the reaction between the first functional group and the second functional group is an electrophile-nucleophile reaction that forms a covalent bond.

33. 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. 34. The system of claim 32 or 33, wherein the electrophile is selected from succinimidyl ester, succinimidyl carbonate, nitrophenyl carbonate, aldehyde, ketone, acrylate, acrylamide, maleimide, vinyl sulfone, iodoacetamide, alkene, alkyne, azide, norbornene, epoxide, mesylate, tosylate, tresyl, cyanurate, orthopyridyl disulfide, or preferably a halide, and the succinimidyl ester comprises a reactive group selected from succinimidyl succinate, succinimidyl glutarate, succinimidyl adipate, succinimidyl azelate, or succinimidyl glutaramide.

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. 10. The system of any one 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 therapeutically active agent is selected from the group consisting of nonsteroidal anti-inflammatory drugs (NSAIDS), steroids, antibiotics, pain relievers, and the like.

10. The system of any one of the preceding claims, wherein the compound is selected from the group consisting of: anti-inflammatory cytokines, anti-inflammatory drugs, anti-VEGF agents, tyrosine kinase inhibitors, complement inhibitors, antihistamines, IL-6 inhibitors, HtRA1 inhibitors, RASP inhibitors, rho-kinase inhibitors, plasma kallikrein inhibitors, nitric oxide donors PgA, mast cell stabilizers, IGF-1R inhibitors, TRPV1 antagonists, TrkA antagonists, pharmaceutically acceptable salts, anhydrates, hydrates, solvates, polymorphs, stereoisomers, crystalline forms, co-crystals, prodrugs, conjugates, complexes, and mixtures thereof.

38. 10. A system according to any one of the preceding claims, wherein the active agent is a drug, such as travoprost, that is in the form of a liquid oil at temperatures up to 37°C and forms at least a part of or replaces the hydrophobic organic liquid.

39. 10. A system according to any one of the preceding claims, wherein the active agent is oil soluble and is dissolved in the hydrophobic organic liquid.

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

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

42. 41. The system of claim 40, wherein the particles of the active agent are nano-sized particles having a D50 particle size of less than about 10 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. 10. The system according to any one of the preceding claims, wherein the selection of the hydrophobic liquid and / or the hydrophobicity of the polymer network and / or the L / G ratio are used to adjust the release rate.

44. 10. The system of any one of the preceding claims, providing release of a therapeutically effective amount of the active agent for a period 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 after administration.

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

46. 10. The system of any one of the preceding claims, providing release of a therapeutically effective amount of the active agent for a period of about 6 hours or more after administration, or for a period of about 12 hours or more after administration.

47. 10. The system of any one 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 organogel is 1 to 90% by weight (based on total dry weight) of the hydrophobic organic liquid, or 5 to 90%, 5 to 60%, 10 to 50%, 10 to 40%, or 15 to 40% by weight; 5 to 95 wt % of the covalently crosslinked polymer network (based on total dry weight), or 10 to 95 wt %, 40 to 95 wt %, 50 to 90 wt %, 60 to 90 wt %, or 60 to 85 wt %; 1-50% by weight (based on total dry weight) of the active agent, or 5-50% by weight, 5-40% by weight, 10-30% by weight, or 10-25% by weight; 10. The system of claim 1, wherein all weight percentages are selected to add up to 100%, said weight percentages being based on the total dry weight of the drug delivery system.

49. 10. A method for producing a sustained release biodegradable drug delivery system according to any of the preceding claims, comprising: (a) The organogel is prepared by dissolving at least (b) a covalently crosslinked polymer network; (c) a hydrophobic organic liquid; (d) optionally a solvent, and (e) at least one active agent, (f) forming, wherein the hydrophobic organic liquid and the active agent are contained within the biodegradable covalently crosslinked polymer network; (g) shaping the organogel; (h) optionally removing the solvent from the organogel.

50. The step of forming the organogel (step (1)) a) providing said hydrophobic organic liquid; b) providing said at least one active agent; c) providing a first covalently cross-linkable precursor comprising a first functional group; d) providing a second crosslinkable 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; 50. The method of claim 49, comprising:

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

52. 52. The method of claim 50 or 51, wherein the first covalently crosslinkable precursor comprising the first functional group is hydrophobic or hydrophilic.

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

54. 54. The method of any of claims 50 to 53, wherein at least one of the first crosslinkable precursor or the second crosslinkable precursor has a functionality of 3 or more, for example, from 3 to 10, or from 3 to 10, or from 4 to 8, or 4.

55. 55. The method of any one of claims 50 to 54, wherein the first crosslinkable precursor is a dendrimer or a multi-arm precursor having a core and 2 to 12 arms, or 3 to 10 arms, or 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. 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. 56. The method of claim 55, wherein the arms comprise hydrophilic polymer units selected from polyethylene glycol (PEG), polyethyleneimine, polyvinyl chloride, poloxamer, or combinations thereof.

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

59. 58. The method of any one of claims 50 to 57, wherein the second crosslinkable precursor is a dendrimer or a multi-arm precursor having a core and 2 to 12 arms, or 3 to 10 arms, or 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. 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. 60. The method of claim 59, wherein the arms comprise hydrophilic polymer units selected from polyethylene glycol (PEG), polypropylene glycol (PPG), and polyglycolic acid (PGA), or combinations thereof.

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

63. 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. 64. The system of claim 62 or 63, wherein the electrophile is selected from succinimidyl ester, succinimidyl carbonate, nitrophenyl carbonate, aldehyde, ketone, acrylate, acrylamide, maleimide, vinyl sulfone, iodoacetamide, alkene, alkyne, azide, norbornene, epoxide, mesylate, tosylate, tresyl, cyanurate, orthopyridyl disulfide, or preferably a halide, and the succinimidyl ester comprises a reactive group selected from succinimidyl succinate, succinimidyl glutarate, succinimidyl adipate, succinimidyl azelate, or succinimidyl glutaramide.

65. 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. 66. The method of claim 65, wherein the activated ester group is a succinimidyl ester containing a reactive group selected from succinimidyl succinate, succinimidyl glutarate, succinimidyl adipate, succinimidyl azelaate, and succinimidyl glutamate.

67. 67. The method of any one of claims 50 to 66, wherein the first multi-arm precursor and / or the second multi-arm precursor have an average molecular weight (Mw) in the range of about 1,000 to about 100,000 daltons, about 7,000 to about 80,000 daltons, about 10,000 to about 60,000 daltons, or about 15,000 to about 50,000 daltons.

68. 68. The method of any one of claims 50-67, wherein the arms of the first multi-arm precursor and / or the second multi-arm precursor have an average molecular weight (Mw) in the range of from about 500 to about 20,000 daltons, from about 1,000 to about 18,000 daltons, from about 2,000 to about 15,000 daltons, from about 3,000 to about 10,000 daltons, or from about 4,000 to about 8,000 daltons.

69. 66. The method of any one of claims 54-65, wherein the ratio of poly(lactic-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. 70. The method of any one of claims 60 to 69, wherein the poly(lactic-co-glycolic acid) (PLGA) precursor has an L / G ratio (mol % of 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. 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. 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 sustained release of the active agent as defined in claims 43 to 47.

73. 73. The method of any one of claims 50 to 72, wherein the ratio of the amount of the first crosslinkable precursor to the amount of the second crosslinkable 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. 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 sustained release of the active agent as defined in claims 43 to 47.

75. 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 before the organogel is completely gelled, allowing the mixture to gel, and optionally removing the solvent.

76. 76. The method of claim 75, wherein said shaping comprises filling the reaction mixture into a mold or tube before the organogel is completely gelled, allowing the mixture to gel, and optionally removing the solvent.

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

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

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

80. 49. The sustained-release biodegradable drug delivery system of any one of claims 1 to 48, wherein the implant is selected from the group consisting of an intraocular implant, an intravenous implant, an intracameral implant, an anterior chamber implant, an intraocular implant, an intravitreal implant, an anterior chamber implant, an intravitreal implant, an intravitreal implant, an intracameral implant, an intravitreal implant, an intracameral implant, an intravitreal implant, an intravitreal implant, an intrachoroidal implant, an intraretinal implant, an intraretinal implant, an intravitreal implant, an intravitreal implant, an intrascleral implant, an intrachoroidal implant, an intraretinal implant, an intraretinal implant, an intraretinal implant, an intravitreal implant, an intrascleral implant, an intrachoroidal implant, an intraretinal implant, an intraretinal implant, an intralenticular ...

81. 49. The sustained release biodegradable drug delivery system of any one of claims 1 to 48 for administration via a variety of routes, such as orally, parenterally, or by surgical insertion or injection.

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

83. 100. A sustained release biodegradable drug delivery system for use in treating a disease / condition in a patient, the system comprising forming an organogel comprising a therapeutically active agent dispersed in a hydrophobic organic liquid contained in a covalently crosslinked polymer network, the organogel being formed in situ at a treatment site in the patient or prefabricated and delivered to or implanted at a treatment site in the patient for release of the active agent over an extended period of time.

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

85. A method for treating a disease / condition in a patient, comprising administering to the patient an organogel comprising a therapeutically active agent dispersed in a hydrophobic organic liquid contained in a covalently crosslinked polymer network for release of the active agent over an extended period of time.

86. 86. The system for use or method of treatment of any one of claims 82 to 85, wherein the treatment site is selected from the anterior chamber, vitreous, episclera, in the posterior lower Tenon's capsule (lower fornix), subconjunctival, intrachamber, peribulbar, retrobulbar, sub-Tenon's capsule, retinal, subretinal, intracanalicular, intravitreal, intrascleral, choroid, suprachoroidal, retinal, subretinal, or lens, corneal or conjunctival surface, lacrimal punctum (major canaliculus, superior / inferior canaliculus), fornix, superior / inferior fornix, lower Tenon's capsule, choroid, suprachoroidal, Tenon's capsule, cornea, cancerous tissue, organ, prostate, breast, joint, subdural, dental, subcutaneous, carpal tunnel, perivascular, surgically created space or lesion, void space, and potential space.

87. 87. The system for use or method of treatment of any one of claims 82 to 86, wherein the disease / condition to be treated is an ocular disease such as a disease of the back of the eye such as any ocular disease of the posterior segment affecting the vasculature and integrity of the retina, macula or choroid leading to vision impairment, vision loss or blindness, in particular disease states of the posterior segment caused by aging, 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.

88. A method for controlling the release of an active agent from a sustained release biodegradable drug delivery system according to any one of claims 1 to 48 or produced 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 one or any combination of the following criteria apply: - the active agent dispersed in the hydrophobic liquid is released from the organogel together with the hydrophobic liquid; The active agent is dissolved directly into the body from the oil.

89. A method for controlling the release of an active agent from a sustained release biodegradable drug delivery system according to any one of claims 1 to 48 or produced according to the method of any one of claims 49 to 78 by any one or a combination of the following procedures: - selecting the L / G ratio of the poly(lactic-co-glycolic acid) (PLGA) units to adjust the hydrophobicity of the polymer network; - selecting the L / G ratio of the polylactic-co-glycolic acid (PLGA) units to provide sustained release of the active agent as provided in claims 43 to 48; - selecting the molar ratio of the amount of the first crosslinkable precursor to the second crosslinkable precursor to adjust the hydrophobicity of the polymer network; - selecting said molar ratio of the amount of said first crosslinkable precursor to said second crosslinkable precursor to provide sustained release of said active agent as defined in claims 43 to 48; - selecting the type of hydrophobic liquid contained in the organogel; adding a third crosslinkable precursor that is less hydrolyzable than the first and second crosslinkable precursors, and optionally varying the molar ratio of the first, second, and / or third precursors; - Dispersing the active agent in particulate form with high water solubility in a hydrophobic phase.

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

91. 91. The kit of claim 90, wherein the portions of the drug delivery system are dispersed into multiple separate containers for forming an organogel in situ at the site of application or treatment.

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