WO2025255023A1

WO2025255023A1 - Sustained release prodrug implant

Info

Publication number: WO2025255023A1
Application number: PCT/US2025/031908
Authority: WO
Inventors: Peter Jarrett; Rami EI-HAYEK
Original assignee: Ocular Therapeutix Inc
Current assignee: Ocular Therapeutix Inc
Priority date: 2024-06-03
Filing date: 2025-06-02
Publication date: 2025-12-11
Anticipated expiration: 2026-12-03

Abstract

The invention relates to a sustained release biodegradable drag delivery system such as an implant comprising a hydrogel and a hydrophobic prodrug dispersed within the hydrogel, wherein the hydrophobic prodrug is a hydrophobic ester or amide derivative of a hydrophilic drag so that the prodrug solubility is less than 100 μg/ml, methods of manufacture, a kit: and an injection device comprising it and methods of treatment using the sustained release drug delivery system. The prodrug hydrophobicity is optimized to control the rate of prodrug release from the hydrogel implant.

Description

Sustained Release Prodrug Impiant

TECHNICAL FIELD

[001] The present invention relates to a sustained release biodegradable drug delivery system such as an implant comprising a hydrogel and a hydrophobic prodrug dispersed within the hydrogel, wherein the hydrophobic pradrug is a hydrophobic ester or amide derivative of a hydrophilic drug so that the prodrug solubility is less than 100 pg/mt, methods of manufacture,, a kit and an injection device comprising it and methods of treatment using the sustained retease drug delivery system. In an embodiment of the present invention, pain, such as post-operative pain, can be treated by administering an implant that is biodegradable and provides sustained release of an opioid prodrug. In another exemplary embodiment of this invention,, the slow delivery of art integrin inhibitor or a tyrosine kinase inhibitor to the eye to treat retinal diseases can be accomplished. Another exemplary embodiment of this invention is to slow tine release rate of prostaglandin analog drugs to toe eye to treat glaucoma or ocular hypertension,

BACKGROUND

[002] Sustained drug delivery provides a method for improving the therapeutic administration of drugs, by providing longer term control of local or systemic tissue concentration of toe drug. Tissue concentrations are controlled by the rate of introduction of drug over time and the simultaneous drug clearance rate. Thus, if a drug is administered at B constant rate and cleared at a constant rate, a “steady state" tissue concentration is achieved. While drug infusion and repetitive pulsatile delivery cart achieve a steady state tissue level, these methods are often problematic and lead to poor patient compliance, in cases where prolonged treatment is required, a need exists to define a sustained drug delivery system that combines a terget tissue steady state concentration for prolonged therapy with good btacompatibility and ease of administration,

[002] in many situations, a sustained drug release implant can be toe best solution for the treatment of a patient. These systems can be designed to deliver drug in a programmed, controlled way over relatively long times.

Therefore, perhaps toe most Important property of a sustained drug release implant is the rate of drug release, or drug deli very, into the surrounding tissue of a patient. Many methods have been invented to provide control of drug retease from an implant. Virtually ail these methods involve the encapsulation of the drug within a second material, or matrix, that temporari !y blocks or stews the drug from escape into the surrounding tissue. The encapsulating matrix is often a biodegradable material, such as poiylactide (PLA) or copolymers of lactide and glycolide (PLGA) in the form of microparticles, rods or after geometries. Other methods have included rsnoparticies such as liposomes or poiymersomes. The mechanism of blocking drug escape has varied widely, and each method can be said to have advantages and disadvantages, PtA and PLGA, for example, utilize gradual hydrolysis to form porosity in the matrix over time, releasing the drug gradually. In some cases, however, when PLA and PLGA spheres are used, they take up space in a tiny Insert or imptent which leads to a lower potential total dose and might: impact: duration and efficacy over extended delivery times. Furthermore, FLA or PLGA are not appropriate for the target tissue due to their stiffness or toe acidic degradation products they generate and their potential localized inflammatory response.

Hydrogels have also been an often used matrix material due to their favorable biocompatibility properties. However, hydrogels reiease small molecule drugs via a diffusion control mechanism, that is highly controlled by the drug solubility in the water within the hydrogel. Therefore, the rate of drug delivery is difficult to manipulate in a hydrogel matrix. [004] For ocular treatments, sustained release of active agents over long periods are desirable., as they can greatly improve patient compliance and tolerability of the treatment,. The eye is a unique organ of perfection and complexity and is a microcosm of the body in many ways. It provides a great opportunity for nanomedicine since it is readily accessible allowing for direct drug/gene delivery to maximize the therapeutic effect and minimize side effects. The development of appropriate delivery systems that can sustain and deliver therapeutics to the target tissues is a key challenge that can be addressed by sustained release biodegradable drug delivery' systems. Current delivery systems for anterior ocular segment disorders such as punctum plug, micro- and nano-particte encapsulation,, rtiicroneedte system, iontophoresis, different types of intravitreal implants, etc., represent state-of-the-art tools for sustained and controlled drug release in the eye. Long term release of active agents into the eye is, however, a continued desire.

[005] In the field of pain control, abuse and addiction from opioid use is driving a need for new, less harmful methods of drug delivery' to the patient for relief of post-surgical pain. Furthermore, methods for deterring abuse must include strategies for reducing the possibility of extraction and collection of drug from the product for illicit purposes. Furthermore, sustained release of drugs is desirable for analgesics, particularly in the treatment of postoperative pain, as it reduces the requirement for frequent dosing and increases patient compliance and safety . Sustained-release pharmaceutical preparations focus on the provision of a longer period of pharmacologic effect after the administeation of a drug than is ordinarily experienced after the administration of Immediate release preparations of the same drug. Longer periods of efficacy can provide several inherent therapeutic benefits that are not achieved with corresponding immediate retease preparations, The benefits of prolonged analgesia afforded by sustained release oral or transdermai analgesic preparations have become universally recognized and such opioid analgesic sustained- release preparations are camrtierctally available, Prolonged analgesia is particularly desirable in patients suffering from moderate to severe pain, such as cancer patients, or for treatment of post-operative pain,

[006] However, sustained release formulations for opioid drugs typically include larger amounts of drugs, increasing the abuse potential. Particularly for opioids; the use of prodrugs, derivatives of drugs that: are themselves inactive has been frequently suggested as a potential abuse prevention strategy. However, prodrugs, by themselves, do not offer the abuse-deterrence once hoped for these drugs, see for example Gudin, J. A,; Naiamachu, S. R. An Overview of Prodrug Technology and Its Application for Developing Abuse-Deterrent Opioids. Postgrad. Med, 2016, 128 (1), 97-105; or Mickle, T, C,; Guenther, S, M.; Barrett, A, C.; Roupe, K. A,; Zhou, 1; Dickerson, 0,; Webster, L, R. Pharmacokinetics and Abase Potential of Benzh ydrocodone, a Novel Prodrug of Hydrocodone, After Intranasal Administration in Recreational Drug Users. Pain Med, 2018, 19 (12), 2438-2449, Apadaz^,w (Benzbydrocadone- Acetaminophen) was recentiy developed and serves as an example of a prodrug that is still considered abusable (cf. Mustafa, A, A.; Rajan, R,; Suarez, J. H; Alzghari, S, K, A Review of the Opioid Analgesic genzhydrecodone- Acetaminophen. Cureus 2018), Apadaz did not receive an abuse-deterrent classification.

[007] Sustained release Implants may be used as abuse-deterrent dosage forms, as they are implanted into the human or animal body and are thus no longer accessible for abuse.

[008] Although sustained release implant devices have improved over the years, there are still many deficiencies.

First, not all implants are biodegradable, leaving a permanent foreign object or requiring tedious removal procedures following drug administration. Additional?, most biodegradable implants do not: completely dissolve until iong after their useful lifespan. The user is therefore left with implant residues that may accumulate with repeat treatment and/or interfere with vision, for example in ocular implants. Next, some implants consist of complicated multiple layers requiring extensive manufacturing processes. This leads to increased production costs and time, and raises the likelihood of contamination from additional handling. Aiso, formulations containing hydrophobic drugs with biodegradable matrices can result in very' little or no release of active agent until erosion of the network occurs. This can lead to drug-dumping, which provides little benefit and causes toxicity issues. Finally, in instances where the drug has low solubility' the use of implants have proven less successful because of the delicate balance betweal long term sustained release and the risk of unwanted particle suspension and migration in the middle or back of the eye.

[009] All references disclosed herein are hereby incorporated by reference in their entireties for ail purposes.

OBJECTS ANO SUMMARY OF THE INVENTION

[010] There is a need for sustained release drug delivery platforms or implants having a simple, easy to control release mechanism. Furthermore, there is a need for sustained release drug delivery implants that are biodegradable and dissolve completely 'within a time frame dose to the time of full drug release, are cost effective In production and safe in application.

[011] An object, and an embodiment, Is to provide a sustained release drug delivery system, such as a biodegradable implant comprising a hydrogel and a hydrophobic prodrug dispersed within the hydrogel, wherein the solubility of the prodrug is reduced as compared to the drug: itself. The solubility' of the prodrug can be less than too pg/ml, or less than 50 pg/mL, or less than 10 pg/mL, or less than 1 pg/mL, as measured in phosphate-btefered saline (P8S) at 37 ®C and pH 7.4. In some embodiments, the hydrophobic prodrug is substantially Insoluble in water.

[012] It is another object of the present invention, and an embodiment thereof, to provide a sustained release drug delivery system, such as a biodegradable implant, far administering a hydraphobic pradrug that is an ester or amide derivative of an active principle. Io embodiments thereof, the ester and/or amide derivative of the active principle is formed by reacting hydrophilic groups, such as hydroxyl, thiol, carboxyl or amine groups, on the active principle with at least one of an organic acid, alcohol or amine to font! hydrophobic moleties on the active prlncipie. The ester and/or amide derivative of the active principle can be hydrolyzed in vivo to form the active principle,

[013] in objects and embodiments of the invention., the drug delivery system is formulated for application in a form that in situ forms an implant comprising a hydrogel and a hydrophobic prodrug dispersed: within the hydrogel,

[014] Another object of certain embodiments of the present invention is to provide an implant that can be administered to the body through a needle, thus* providing a minimally' invasive method of administration.

[013] Another object of certain embodiments of the present invention is to provide an implant that is injected In a dry form and hydrates in T?to-(i.e., in the human or animal body) when injected. [ 016] Another object of certain embodiments of the present invention is to provide an insert that can be administered to certain parts of the body using an inserter or applicator without crossing a barrier or a membrane, thus, providing a minimally invasive method of administration.

[017] .Another object of certain embodiments of the present invention is to provide an implant comprising an active agent prodrug that when placed in the eye has low active agent concentration at the implant surface thereby avoiding toxicity of the active agent when the implant gets in contact: with ocular cells or tissues such as the retina.

[018] Another object of certain embodiments of the present invention is to provide an implant comprising a hydrophobic prodrug wherein the implant is stable and has a defined shape and surface area both in a dry state prior to as well as in a hydrated state after the injection (t.e., inside the human or animal body). [019] Another object of certain embodiments of the present invention is to provide an implant that Is easy to handle, in particular that does not spill or fragment easily,

[020] Another object of certain embodiments of toe present invention is to provide a drug delivery system, e>g., a biodegradable implant comprising a hydrophobic prodrug that enables administratior> of an exact dose (within a broad dose range) of the active principle, thereby avoiding the risk of over-dosing and under-dosing. [021] Another object of certain embodiments of the present invention is to provide an implant comprising hydrophobic prodrug that: generally stays in the area of the body to which it was administered,

[022] Another object of certain embodiments of toe present invention is to provide an implant comprising hydrophobic prodrug that is safe and well tolerated, partfcuiarly not inducing severe adverse effects.

[023] Another object of Certain embodiments of the present invention is to provide an implant comprising a hydrophobic prodrug that provides for sustained release of a therapeutically effective amount of the active principle over an extended: period of time, such as over a period of up to 3 months or longer, such as at least 6, at least 9, at least 11 months, or at least 13 months, thereby avoiding the need for frequent Implant administrations.

[024] Another object of certain embodimente of toe present invention is to provide a method of manufacturing an implant comprising a hydrophobic prodrug, [025] Another object of certain embodiments of the present invention is to provide a method of minimizing potential tissue damage during injection of an implant comprising a hydrophobic prodrug.

[028] Another object of certain embodiments of toe present invention is to provide a kit comprising one or more implants comprising a hydrophobic prodrug and optionally comprising a means for injecting the implant,

[027] Additionally, there is a need for novel treatment methods for long-term treatment of pain with reduced potential for abuse. It is thus an object to provide sustained release drug delivery platforms, particularly for analgesics such as opioids, that have a reduced potential for abuse. [028] A further object is to provide treatment methods for long-term treatment of pain, such as moderate to severe pain, for example post-operative pain in a patient in need thereof,

[020 J It is another object of the present invention to provide a sustained release drug delivery system, such as a biodegradable implarit, for administering opioids, that reduces abuse potential. [030] Another object of certain embodiments of the present invention is to provide an implant comprising an opioid analgesic that is easy to handie, in particular that does not spill or fragment easily.

[031] Another object of certain embodiments of the present invention is to provide an implant comprising an opioid analgesic that enables administration of an exact dose (within a broad dose range), thereby avoiding the risk of over- and tinder-dosing, [032] Another object: of certain embodiments of the present invention is to provide an implant comprising an opiotd analgesic that is safe and well tolerated, such as an implant comprising an opioid analgesic that does notinduce severe adverse effects.

[033] Another object of certain embodiments of the present invention is to provide an implant comprising an opioid analgesic that provides for sustained release of a therapeutically effective amount of the opioid analgesic over an extended period of time, such as over a period of up to 3 months or longer, such as at least 6, at least 9, at least

11 months, or at least 13 months, thereby avoiding the need for frequent implant administrations.

[034] Another object of certain embodiments of the present invention is to provide a method of treating pain, such as moderate to severe pain, for example post-operative pain, in a patient in need thereof, by administering a sustained release biodegradable implant comprising art opioid analgesic, [035] Another object of certain embodiments of the present invention is to provide a method of manufacturing an implant comprising an opioid analgesic.

[036] Another object of certain embodiments of the present invention is to provide a method of minimizing potential tissue damage during injection of an implant comprising an opioid analgesic.

[037] Another object of certain embodiments of the present invention is to provide a kit comprising one or more implants comprising an opioid analgesic and optionally comprising a means for injecting the implant.

[038] One or more of these objects of the present invention and others are solved by one or more embodiments as disclosed and claimed herein,

[039] The individual aspects of the present Invention are disclosed in the specification and claimed in the independent claims, while the dependent claims claim particular embodiments and variations of these aspects of the invention. Details of the various aspects of the present: invention are provided in the detailed description below. [040] Throughout this application various references are cited. The disclosures of these references are hereby incorporated by reference into the present disclosure. in case of conflict, the disclosure in the present application prevails,

BRIEF DESCRIPTION OF THE DRAWINGS [041] Figure 1 Schematic representation of one embodiment of the implant packaging, tn this embodiment, implants are pre-loaded into thin-walled needles separately packaged from the injection device. An all-in-one device with needles already connected to the injection device is also possible.

[042] Figure 2 Schematic representation of traditional prodrag purpose using prpmpiety to affect drug mobility across barriers. [043] Figure 3 Schematic representation of release conW via prodrag solubility.

[044] Figure 4 Schematic representafior> of hydrogel biodegradation over time. As the pradrag is released, a clearance zone is formed (black) as low solubility prodrug particles (white) gradually dissolve, and drug diffuses from hydrogel to the aqueous surrounding (as for instance the vitreous humor), Over time, the gel degrades and is resorbed, while prodrug diffuses out. During the degradation process, die gel gradually swells until degradation is advanced to the point of shrinkage and distortion.

[045] Figures 5A and SB One embodiment of an injector according to the present invention for injecting an implant into the vitreous humor of a patient This depicted embodiment of an injector comprises a Hamilton syringe body and a Nitinoi push wire to deploy the implant. Figure SA shows the Hamilton syringe body inside of an injection molded casing. Figure SB shows a schematic view of the components of this embodiment of the injector. [046] Figure 6A Exploded view diagram of one embodiment: of an injector according to the present invention that is made of an injection molded body. Figure 68 shows a photograph of foe fully assembled injector. Figure 6C shows an exploded view of a first assembly of an injector according to the present invention, Figure 60 shows an exploded view of a second assembly of an injector according to the present invention. Figure 6E shows that foe first and: the second assembly can be aligned. Figure SF shows the cowl of the second assembly being secured to the body of the first assembly. Figure 6G show's the needle shield being removed from the cowl of the second assembly and the plunger clip being removed from the body and plunger of the first assembly. Figure 6H shows the plunger of the first assembly being actuated to deploy the implant from the lumen of the needle of the second assembly,

DEFINITIONS

[047] The term "drug delivery system" as used herein refers to a system for pharmaceutical use for sustained delivery of a hydrophobic prodrug into a human or animal body. Thy drag delivery system may be an implant or insert as further defined below, or it may be a formulation or kit including hydrogel forming components that in situ, for example after injection into an implantation or treatment site within the animat or human body form an implant or insert comprising a hydrogel and a hydrophobic prodrug dispersed within the hydrogel. A "hydrophobic pradrug" as used herein is a derivative of an API having a solubility of less than 100 yg/ml, such as less than SO pg/mL, or less than 10 pg/mL, or less than 1 pg/mL, as measured in phosphate-buffered saline (PBS) at 37 ®C and pH 7.4.

[048] The term “Implant", or synonymously used "insert", as used herein (sometimes also referred to as "depot") refers to an object that contains an active agent prodrug, and that is administered into the human or animal body, where it remains for a certain period of time while It releases the active agent prodrug and or active principle into the surrounding environment. An implant or insert can have any predetermined shape (such as disclosed herein) before being injected, implanted, dr Inserted, which shape is maintained to a certain degree upon placing the. implant into the desired location, although dimensions of the implant (e.g., length and/or diameter) may change after adminisQafion due to hydration as further disclosed herein. In other words, what is injected into the eye is not a solution or suspension, but an already shaped, coherent abject. The implant has thus been completely formed as disclosed herein prior to being administered, and in the embodiments of the present invention is not created in situ at the desired location in the eye (as would generally also be possible with suitable formulations)..,!?* certain alternative embodiments of the invention, the "implant’' can be formed //? sffo, t.e. lipoid precursors forming the implant at a treatmerit site of a patient are administered. Since gelation of hydrogels can occur under mild physiologic conditions, gelation may be done within the patient ' s body. Once administered, over the course of time the implant is biodegraded (as disclosed below) in physiological environment, may thereby change its shape while it decreases in size until it has been completely dissolved, /resorbed, Herein, the term "implant" is used to refer both to an implant in a hydrated (also referred to herein as "wet") state when it contains water, e.g. after the implant has been hydrated or re-hydrated once administered to toe eye or otherwise immersed into an aqueous environment (such as in vitro), as well as to an implant in its/a dry (driM/dehydrated) state, ite,, after the implant has been produced and dried and just prior to being loaded into a needle, or after having been loaded into a needle as disclosed herein, or wherein the implant has been manufactured In a dry state without the need for dehydration. Thus, in certain embodiments, an implant in its dry/dried state in toe context of the present invention may contain no more than about 1% by weight water. The water content of an implant tn its dry/dried state may be measured e,g., by means of a Kart Fischer coulometric method. Whenever dimensions of an implant (i,e„ length, diameter, or volume) are reported herein in the hydrated state, these dimensions ate measured after the implant has Been immersed in phosphate-buffered saline at 37 °C for 24 hours, whenever dimensions of an implant are reported herein in the dry state, these dimensions are measured after the implant has been tolly dried (and thus, in certain embodiments, contain no more than about 1 % by weight water) and the implant is in a state to be loaded into a needle for subsequent administration, in certain embodiments, the implant is kept in an inert atmosphere glove box containing below 20 ppm of Both oxygen and moisture for at least about 7 days.

[049] The term “ocular" as used tn the present invention refers to the eye tn general, or any part or portion of the eye (as an "implant" according to the invention can in principle be administered to any part or portion of the eye) or any disease of toe eye (as in one aspect: the present invention generally refers to treating any diseases of the eye ("ocular diseases"); of various origin and haiyre, The present invention in certain embodiments is directed to intravitreal injection of an implant (in this case the "implant" is thus an "intravitreal implant"), and to the treatment of ocular diseases affecting the posterior segment of the eye, as further disclosed below,

[050] The term "patient" herein includes both human and anima! patients. The Implants according to the present invention are therefore suitable for human or veterinary medicinal applications. Generally, a "subject" is a (human or animai) individual to which an implant according to the present invention is administered, such as during a clinical study. A ”pstFsnft’ⁱ is a subject in need of treatment due to a particular physiological or pathological condition.

[051] The. term "biodegradable" refers to a material cr object (such as the implant according to the present invention) which becomes degraded in vivo, (.e„ when placed in the human or animal body. In die context of the present invention, as disclosed In detail herein below, the implant comprising the hydrogel within which particles of an active agent prodrug are dispersed,, slowly biodegrades over time once deposited within the human or animal body, in certain embodiments biodegradation fates place at least in part via ester hydrolysis in the aqueous environment of the vitreous. The implant slowly dissolves until it is fully resorbed,

[052] A "hydrogel" is a three'dlmensionai network of hydrophilic natural or synthetic polymers (as disclosed herein) that can swell in water and hold an amount of water white maintaining or substantially maintaining Its structure, e.g., due to chemical or physical cross-linking of individual polymer chains. Due to their high water content, hydrogels are soft and flexible, which mates them very similar to natural tissue. In the present invention the term "hydrogel" is used to refer both to a hydrogel in the hydrated state when it contains water (e.g. after the hydragel has seen formed in an aqueous solution, or after the hydragel has been (re-)hydrated ones implanted into the human or animal body or otherwise immersed into an aqueous environment) and to a hydrogel in its dry (dried/dehydrated) state when it has been dried to a low water content of e.g. not more than 1% by weight In the present invention, wherein an active principle is contained (e.g,, dispersed) in a hydrogel, the hydrogel may also be referred to as a "matrix".

[053] The term "polymer network" describes a structure formed of polymer chains (of the same or different molecular structure and of the same or different molecular weight) that are crosslinked with each other. The types of polymers suitable for the purposes of the present ihventioh are disclosed herein. The polymer hetwork may also be formed with the aid of a crosslinking agent as also disclosed herein.

[054] The term "amorphous" refers to a polymer or polymer network or other chemical substance or entity which does not exhibit crystalline structures in x-ray or electron scatering experiments.

[055] The term “semi-crystalline" refers to a polymer or polymer network or other chemical substance or entity which possesses some crystalline character, l.e,, exhibits some crystalline properties in X-ray or electron scattering experiments.

[056] The term "crystalline'' refers to a polymer or polymer network or other chemical substance or entity which has crystalline character as evidenced by X-ray cr electron scattering experiments. [057] The term "precursor" herein refers to those molecules or compounds that are reacted with each other and that are thus connected via crosslinks to form the polymer network and thus the hydrogel matrix. While other materials might be present in the hydrogel, such as active agents or buffers, they are not referred to as "precursors".

[058] The parts of the precursor molecules that are still present In the final polymer network are also called "units" herein. The “units" are thus the building blocks or constituents of the polymer network forming the hydrogel. For example, a polymer network suitable for use in the present Invention may contain Identical or different polyethylene glycol units as further disctosed herein.

[OSS] The molecular weight of a polymer precursor as used for the purposes of the present invention and as disclosed: herein may be determined by analytical methods known in the art. The molecular weight of polyethylene glycol may for example be determined by any method known in the art, including gel electrophoresis such as 5DS- PAGE (Sodium dodecyl sulphate-polyacrylamide gel electrophoresis), get permeation chromatography (GPC), including GPC with dynamic light scattering (DIS), liquid chromatography (LC), as well as mass spectrometry such as matrix-assisted laser desorptlorVionlzabon-rime of flight (MALDl-TOF) spectrometry or electrospray ionization (ESI) mass spectrometry. The molecular weight of a polymer, including a polyethylene glycol precursor as disclosed herein, is an average molecular weight (based on toe polymer's molecular weight distribution), and may therefore be indicated by means of various average values, including the weight average molecular weight (Mw) and the number average molecular weight: (Mn), In toe case of polyethylene glycol precursors as used in the present: invention, the molecular weight indicated herein is the number average molecular weight (Mn).

[060] In certain embodiments of the present invention, the term "fiber" (used: interchangeably herein with the term "rod") characterizes an object (t.e>, in the present case the implant according to the present invention) that in general: has an elongated shape. Specific dimensions of implants of the present invention are disclosed herein. The implant may have a cylindrical or essentially Cylindrical shape, or may have a non-cyllndrlcal shape. The cross* sectional area of toe fiber or the implant may be either round or essentially round, but may in certain embodiments also be oval or oblong, or may in other embodiments have different geometries, such as cross-shaped, star-shaped or other as disclosed: herein.

[061] The term "release" (and accordingly the terms “released", "releasing" etc.) as used herein refers to the movement of agents such as an API from an Implsni: of the present: invention to the surrounding environment The surrounding environment may be an in vitro or in vivo environment as described herein. In certain specific embodiments, the surrounding environment is the human or animal body, e,g., the vitreous humor and/or ocular tissue, such as the retina and the choroid. Thus, whenever it is herein stated that the implant "releases” or "provides for (sustained) release" of an active agent prodrug, this not only refers to the provision of the active agent prodrug directly from the implant while the hydragel has not yet (folly) biodegraded, but also refers to the continued provision of the active agent prodrug to the surrounding environment following full degradation of the hydrogel when remaining active agent prodrug is stili present in this surrounding environment (e.g. in an agglomereted form as further disclosed herein) for an extended period of time and continues to exert its therapeutic effect. Accordingly, the "'treatment period" referred to herein (i.e., the period during which a certain therapeutic effect as described herein is achieved) may extend to a period of time even after the implaut/the hydrogel has fatly biodegraded as further disclosed herein.

[062] The term "sustained release" is defined for the purposes of the present invention to refer to products (in the case of the present invention the products are impiants) which are formulated to make a drug available over an extended period of time, thereby allowing a redtictian in -dosing frequency compared to an immediate release dosage form (such as e.g,, an oral dosage for immediate release., or an injection of the active agent prodrug Itself). Other terms that may be used herein interchangeably with "sustained release" are "extended release" or “controlled release", "Sustained release" thus characterizes the release of an API, that is contained in an implant according to the present invention. The term "sustained retease" per se is not associated with or limited to a p&titv&rf&se of (in vtro or in vivo) release, although in certain embodiments of the invention an implant may be characterized by a certain average rate of (in vitro ar in vivo) release or a certain release profile as disclosed herein. As an implant of the present invention (whether explicitly referred to herem as a "sustained release" implant or simply as an "implant") provides for sustained release of the APf, an implant of the present invention may therefore also be referred to as a ’’depot".

[063] Whenever it is stated herein that a certain administration or injection is performed "concurrently with" or "simultaneously to" or "at the same time as” an administration or injection of an implant according to the present invention, this means that the respective injection of either two or more implants or the injection of one or more implantfs) together with the injection of a suspension or solution e.g. of a different active agent is normally performed immediately one after the other, ire.? without any significant delay. For example, if a total dose of about 40G pg prodrug is to be administered to body and that total dose is comprised in two implants according to the invention, each containing about 200 pg of active agent prodrug, these two impiants are normally injected into thebody immediately one after the other within the same treatment session, of course by respecting all precautions for a safe and precise injection at the desired site, but without any unnecessary delay.

[064] However, under specific circumstances, e.g, in case complications during the administration of the first implant are experienced and/or the physician carrying out the injection concludes that a second injection during the same session on toe same day, ar within toe foilawing days, may not be advisable, the second implant may also be administered e.g,, one or two weeks after the first Implant. Since, as will be disclosed in more detail herein, the implants may persist tn the human or animal body for a duration of an extended period of time, such as for about 9 to about: 12 moriths, the administration of two implants, e.g,, one or two weeks apart is still regarded as "concurrently" in the context of the present invention. Similar considerations apply for the "concurrent" administration of an implant according to the present invention and an additional active agent. Thus, another active agent can be administered concurtently, i.e, at or around the same time as described herein, with the administration of an implant of the present invention.

[06S] In certain other embodiments, however, an additional active agent can also be administered in combination with an implant of the present invention such that toe additional active agent Is administered later, such as 1 month or 2 months Or 3 months after the administration Of toe implant according to the present invention. [066] The term "rescue medication" generally refers to a medication that may be administered to a patient under pre-defined conditions (e.g„ during a study In case a patient does not sufficiently respond to investigational t-ea-ment), or to manage an emergency situation.

[067] As used herein, the term "about" in connection with a measured quantity, refers to the normal variations in that measured quantity', as expected by one of ordinary skill in the art in making the measurement and exercising a level of care commensurate with the objective of measurement and the precision of the measuring equipment.

[068] The term "at least about' tn connection with a measured: quantity refers to the normal variations in the measured quantity, as expected by one of ordinary skill in the art in making the measurement and exercising a level of care commensurate with the objective of measurement and precisions of the measuring equipment and any quantities higher than that

[069] The term "average" as used herein refers to a central or typical value in a set of date(points), which is calculated by dividing the sum of the dataf points) in the set by their number (i.e., the mean value of a set of data).

[070] As used herein., the singular forms "a,” ’’an", arid "the'* include plural references unless the context clearly indicates otherwise,

[071] The term "and/or¹’ as used in a phrase such as ”A and/or B" herein is intended to include both "A and B" and “A or 8".

[072] Open terms such as "include," "including," “contain," "containing" and the like as used herein mean ‘’comprising" and are intended to refer to open-ended lists or enumerations of elements, method steps, or the like and are thus not intended to be limited to the recited elements, method steps or the like but are intended to also include additional, unrecited elements, method steps or the like.

[073] The term "up to" when used herein together with a certain value or number is meant to include the respective value or number,

[074] The terms "from A to 8" "of from A to B", and "of A to B" are used interchangeably herein and all refer to a range from A to 8, including the upper and tower limits A and B>

[075] The terms "API", "active (pharmaceutical) ingredient", "active (pharmaceutical) agent", "active (pharmaceutical) principle", "(active) therapeutic agent", "active", and "drug" are used interchangeably herein arid refer to toe substance intended to furnish pharmacological activity or to otherwise have direct effect in the diagnosis, cure, mitigation, treatment or prevention of a disease, or to have direct: effect: in restoring, correcting or modifying physiological functions in a patient.

[078] The "active principle" utilized herein is the pharmaceutical active form of the drug without chemical bond modification. The term "parent drug" is used interchangeably with the term active principle. [077] The terms "active agent prodrug", or "prodrug", utilized herein is a chemically modified form of any hydrophilic drug to render ft hydrophobic, or a hydrophobic derivative of an active principle, such as esters or amides as described herein, phatmaceutically acceptable salts thereof, or combinations thereof. The purpose of the chemical modification is to reduce the water solubility of the drug; thus, providing a slower drug release rate of the active agent prod rag from a hydrogel i mplant than the unmodified active principle. The hydrophobic "pradrug" as the term is used herein can be Itself pharmaceutically active, like the unmodified active agent, or may in certain embodiments be less pharmaceutically active or even pharmaceutically inactive, but is generally required to be less soluble than the unmodified active agent.

[078] A "hydrophilic drug" in the present invention is any drug having a solubility in water at 25*C of at least O.inig/'ml, such as Q.5mg,''mL or more, or 1.0 rng/ml or more.

[079] For the purposes of the present Invention, active agents or prodrugs thereof in all their possible forms, including any polymorphs or any ^armaceuScatty acceptable sate, anhydrates, hydrates, other solvates or derivatives of active agents or prodrogs thereof, can be used. Whenever in this description or in the claims an active agent or prodrug is referred to by name, e.g., "morphine'', even if not explicitly stated, it also refers to any such polymorphs, pharmaceutically acceptable sate, anhydrates, solvates (including hydrates) or derivatives of the active agent or active agent prodrug.

[080] T he term "polymorph” as used herein refers to any crystalline form of an active agent or active agent prodrug. Frequently, active agents or active agent prodrugs that are solid at room temperature exist in a variety of different crystalline forms, i.e. , polymorphs, with one polymorph being the thermodynamically most stable at a given temperature and pressure. In situations where the active agent or prodrug can exist in multiple polymorphic forms, the polymorph with optimal solubility may be chosen to achieve the desired drug release kinetics.

[081] As used herein, the tenm "therapeutically effective" refers to the amount of drug or active agent pradrug needed to produce a certain desired therapeutic result after administration. For example, in the context of an embodiment of the present invention, one desired therapeutic result would be the reduction of the central subfield thickness (C5FT) as measured by optical coherence tomography in a patient suffering from neoyascuiar AMD as patients suffering from neovascular AMD have elevated CSFT. A "toerapeuticaliy effective" amount of an active agent or active agent prodrug in the context of the present invention may also te a multiple of the ICsa this active agent or active agent prodrug provides against; a particular substrate, such as 50 or more times the ICsa,

[082] The abbreviation "PSS" when used herein means phosphate-buffered saline.

[083] The abbreviation "PEG” when used herein means polyethylene glycol.

DETAILED DESCRIPTION [084] The inventors of the present invention have found that the use of implants for drug delivery may offer many advantages over traditional dosage forms or injections. Hydrogels release small molecule drugs mainly via two different mechanisms, the degradation rate of the hydrogel matrix in vivo, and, a diffusion control mechanism, that is highly controlled by the drug solubility' in the water within the hydrogel. Therefore, the rate of drug delivery is difficult to manipulate in a hydrogel matrix:, sjrecffically from hydrophilic drugs. Th® current invention uses a hydrogel matrix, but controls drug solubility itself so the dreg can be released from the hydrogel maw at a desired rate. This is achieved by chemical modification of the active agent to farm a prodrug. This is s fundamentally different purpose than prodrugs have been designed for until now.

[085] The present invention describes implants for sustained delivery of prodrugs of hydrophilic drugs from a hydrophilic matrix to human or animal tissue. Derivatizing hydrophilic drugs to form hydrophobic prodrugs provides a method for controlling drug release rate from a hydrogel matrix. Temporarily appending hydrophobic groups (promoieties) to the parent dreg molecule to block hydrophilic moieties thereof can be used to reduce the rate of prodrug release from a hydrogel matrix. This method can also be used to convert drugs considered hydrophobic to more hydrophobic farms for the purpose of further slowing release from a hydrogel matrix. Once released from the hydrogel, the hydrophobic prod rug can be transfarmed back into the active form of the drug by removal of the hydrophobic groups, Removal can be accomplished by local enzymes, such as carboxyesterases, or by simple hydrolysis,

[086] The use of hydraphobic hydrolyzable prodrugs as described herein offers two mechanisms of release control: via reduced aqueous solubility of the prodrug versus the active principle itself, allowing to control diffusion rates from the hydrogel matrix to the surrounding tissue, and controlling hydrolysis rates of tee prodreg itself as s second factor influencing tee release kinetics of the active principle,

[087] One case where such solubility control is desirable is opioid prodregs for the treatment of pain, such as moderate to severe pain, tor example post-operative pain, in an embodiment of the present invention, pain, such as post-operative pate, can be treated by administering an implant teat is biodegradable and provides sustained release of an opioid prodrug, in another exemplary embodiment of this invention, the slow delivery of an integrin inhibitor or a tyrosine kinase inhibitor to the eye to treat retinal diseases cart be accomplished, Another exemplary' embodiment of this invention is to slow the retajse rate of prostaglandin analog dregs to the eye to treat glaucoma or ocular hypertension.

[088] Sustained release implants may be placed in or adjacent to the body tissues to be treated and offer better drug release and treatment duration potential, Placement is done by a physician, for example post surgically, so that the implant may not be easily accessible to any person,

[089] A controlled dreg delivery platform:, Elutyx™ based on an inert hydrogel containing embedded microparticles of drug, is known from Ocular Therapeutix. The dried hydrogel (known as a xerogel) can be sterilized by irradiation (gamma or electron beam irradiation) and stored at room temperature in a "ready to use" format, such as a fiber or rod in a pre-fifed injector The hydrogel contains a covalently crosslinked network of a gelator molecule, usually polyethylene glycol (PEG). The network contains linkages that slowly hydrolyze in aqueous tissue fluid,, eventually resulting in disintegration and dissoKstion of the hydrogel matrix. Controlled drug delivery platforms based on inert hydrogels containing embedded drugs to be eluted in vivo have proven to be an ideal vessel for sustained drug delivery also of low solubility compounds, such as dexamethasone (Dextenza®, a sustained dexamethasone delivery product for the eye). The hydrogel vehicle’s atributes include high water content (approximately 90%), biocompatibility, biodegradability, and a minimally invasive, easy-to-use format.

[a9O| Hydrophobic drugs can be formulated into the hydrogel as embedded insoluble microparticies that contrtjiiabiy erode to gradually release the drug into the hydrogel and then release dissolved drug across the hydrogel-tissue interface into the local tissue. The rate of drug release is dependent primarily on the drug solubility in the local tissue fluid that permeates the hydrogel and an the size dimensions (surface area) of the swollen hydrogel.

[091] For example, morphine, and other opioids, are too soluble to adequately sustain drug release into tissue fluid: over prolonged periods. However, most opioids are readily formed into fully revereabie prodrugs. These prodrugs can be designed with eontrollably reduced solubility by esterification of hydroxyl groups on the starting molecule. The concept of morphine prodrug has a long history, heroin (aka. diacetylmorphine) being the first example. The traditional purpose of prodrugs is as depicted in Fig. 2, where the prodrug is modified to provide improved transport across B limiting membrane in the body, such as the blood- brain-barrier (BS8).

[092] Tn embodiments of the present invention, the prodrug modification of hydrophilic active principles such as opioids utilizes the enhanced hydrophobicity of the prodrug to slow the rate of release from the hydrogel matrix. The purpose of a prodrug in embodiments of the present invention is to control the release rate by controlling prodrug solubility in the hydrogel via promoiety hydrophobicity. The low, saturated drug concentration at the interface of hydrogel and tissue fluid determines the concentration gradient, which drives prodrug release. Hydrogel surface area is directly proportional to release rate. Thus, a sustained drug delivery can be achieved when the rate of drug elution and the duration of drug release, is controlled primarily by the solubility' of the prodrug. [093] Enzymatic hydrolysis of the prodrug yields the active drug form as the prodrug is slowly released. The rate of ertzyme hydrolysis of the prodrug relative to the rate of prodrug release from the hydrogel will determine how much of the prodrug will be found in tissues distant from the implant site, such as the cerebrospinal fluid. The hydrolysis rate may far exceed the release rate; therefore, conversion to the active drug form may occur in close proximity' to the implant site. Conversion to the active form may also occur via a non-enzymatic route. For example, the promoieties are susceptible to hydrolysis once the prodrug dissolves, i.e., is released from the solid or crystalline structure, in this case the release kinetics will be more complex but will still provide prolonged release.

[094] Release of hydrophobic drugs from hydrogel matrices has been studied extensively, with Dextenza being an example of a commercial product using this mechanism. Upon impiantotion, the xerogel is quickly swollen in aqueous tissue fluid to form a hydrogel, with an equilibrium water content based on hydrogel properties, typically about 90% water plus any dissolved molecules. The drug quickly saturates the hydragel and transfer of (pro)drug to the surrounding tissue fluid begins. The rate of transfer to the tissue is governed by the concentration gradient at the hydrogel-tissue interface. At advanced degrees of (pro)drug toss, usuaHy greater than 50%, a ’zone clearance" effect can be seen that extends into the implant as release progresses. Release is close to zero-order over approximately the first 60% of (pro)dmg loss, followed by a gradual reduction in rate until cessation.

[095] Opioids activate g-opiotd receptors (pORs) in the central nervous system (O4S), and also on the peripheral nerve endings of nociceptor neurons. The implant of an embodiments of the present invention provides the ability to deli ver and maintain a high focal concentration of opioid at the wound site by direct i nstillation or Injection of the implant into or near the wound bed, The Implant, being a solid article, will remain at or near the. implant site throughout its drug delivery life, followed by disihtegratton and absorption of the hydrogel. Local implantation, such as in the subcutaneous space at the wound site, can therefore provide opioid delivery both locally anti systemically.

[096] The Implant of an opioid embodiment of the present invention further provides abuse-deterrence, since the hydrogel or xerogel matrix format offers a number of advantageous attributes than can deter the potential for abuse. For example, the implant is administered/impianted by a physician, so the drug is administered one-time by the physician e.g,, post-surgically. There Is no opportunity for access to the drug by the patient Physician administration ensures the drug is locked and controlled per DEA procedures. Furthermore, the implant can be fashioned so that is not retrievable as its form or particles disperse at the subcutaneous implantation site and cannot be readily removed. Also, the hydrogel implant cannot be ground or melted, so the drug cannot be separated from the xerogel matrix mechanically or thermally, because it is a crosslinked composite material.

[097] in emisodiments of the invention, the formulation will be in contained a prefilied device for subcutaneous or other types of injection, so there is only limited accessibility. The device inventory- tan be rigorously controlled in a hospital setting. This device component also offers design potential to reduce accessibility- to the formulatian through measures such as two-part: devices with matched pairs, i.e., ’''lock and key’'. Furthermore, implants of embodiments of the present invention have a limited oral abuse potential. Swallowing the formulation could provide some drug extraction and absorption. However, low gastric pH (1.5-3, 5) will slow the hydrolysis of the hydrogel crosslinks; The presence of the hydrogel, and tow solubility of the prodrug, may slow foe rate of absorption, reduce reduce bioavallability.

[098] Also, with the hydrogel implants of embodiments of the present invention, there is limited drug extractability. To extract the dreg, a suitable organic solvent for both the hydrophobic prodrug and the hydrophilic polymer matrix must be used. In addition, the solvent must be readily separable from the drug prior to injection to avoid solvent toxicity. Such solvents and extraction techniques are not typically available to untrained people.

1. The drag delivery system or implant

[099] in embodiments of the invention, a sustained release drug delivery system, such as an implant, is provided that comprises or essentially consists of a hydrogel and a hydrophobic prodrug dispersed within the hydrogel. The solubility of the prodrug is less than WO pg/ml, such as less than 50 pg/mL, or less than W pg/mL, or less than 1 pg/mL, as measured in phosphate-buffered saline (PBS) at 37 °C and pH 7.4. [100] In embodiments of the invention, the hydrophobic prodrug can be selected from an ester or amide derivative of an active principle, or from any other derivative of an active principle having at least ope hydrolyzable bond. The ester and/or amide derivative or other hydrolyzable derivative of the active principle is formed by reacting hydrophilic groups on the active principle, Such as hydroxyl, thiol, carboxyl or amine groups, with at least one of an organic add, alcohol, thiol, or amine to fcf rn hydrophobic moieties on the active principle, The ester, thioester and/or amide derivative of the active principle Is more hydrophobic and thus less soluble in aqueous media such as P85 buffer than the non-cterivatized active Ingredient itself. Ip embodiments of the present invent Ion, the ester, thioester and/or amide derivative of the active principle can be hydrolyzed, with or without enzymatic action, in vivo to form or release the active principle or active metabolite. This allows to control, e.g. stow down, the release and/or bioavaiiablllty over time of the hydrophobic prodrug or active agent from the hydrogel matrix. Release is governed not only by diffusion processes, but also by pradrug: solubility as described herein. Furthermore, different types of hydrophobic derivatizatron of the active agent, for example, by forming esters with long or short chain aliphatic hydrocarbons can be used to further control the active agent release after the prodrug has diffused out of the hydrogel, due to different hydrolysis rates of different ester or amide derivatives. As an example, longer aikyi chain esters may have lower hydrolysis rates than shorter chain alkyl esters or amides, and aromatic carboxylic acid ester derivatives often have fess solubility in water than alkyl ester derivatives.

[101] With the use of a hydrophobic active agent prodrug in a hydrogel it is possible to control: the reiease rate by controlling prodrug solubiiity in the hydrogel via promoiety hydrophobicity.: In the embodiments c<f the invention, the low, saturated drug concentration at the interface of hydrogel and tissue fluid determines the concentration gradient, which drives prodrug release. Consequently, hydrogel surface area Is directly proportional to reiease rate.

[102] In embodiments of the invention, the hydrophobic prodrug, or ester, thiol, and/or amide derivative can be selected from at least one of an aliphatic carboxylic acid ester, an aliphatic carboxylic acid thio ester, an aliphatic carboxylic acid amide, an aromatic carboxylic add ester, an aromatic carboxylic acid thioester, an aromatic carboxylic acid amide, an heteroaromatic carboxylic acid ester or throester, and an heteroaromatic carboxylic acid amide, of the active principle, or any combinations thereof. The hydrophobic prodrug can be selected from the group of a monoester, a diester, a multi-ester, a monoamide, a diamide, and a multi-amide of the active principle, depending on the number of reactive hydroxyl, carboxyl and/or amine groups in the active principle, pharmaceutically acceptable salts thereof, or any combinations thereof.

[103] If the active principle includes more than one hydrophilic group that can be reacted to form a hydrophobic prodrug, one or more hydrophobic promoieties may be bonded to the active principle. Multiple promoieties, optionally the same or different from each other may be used to further delay active principle reiease. Multiple promoieties on the prddrog may have different hydrolysis rates, depending on the number and type of promoieties attached to the active principle, and/or may require more than one enzyme for being cleaved. As an example, prostaglandin analogs such as travoprost, tafluprast or latarroprost. are Itself prodrugs including an isopropyl: ester that is enzymatically hydrolyzed by carboxylesterase 1 (CES1) to produce the travoprost free acid active metabolite. In an embodiment of the present invention, travoprost may be additionaiiy esterified at: its three remaining hydroxy! groups, for example by acetate groups (see Examples 2, 5 and 6 below) to produce mono, di or triacetate ester, preferably travoprost triacetate, having a significantly reduced solubility. The travoprpst acetates then require two enzymes, CES1 and CES2 for hydrolyzing the isopropyl and the acetate esters tn order to end up with the active metabolite, since CESi does not hydrolyze the acerate esters, whereas CES2 does not hydrolyze the isopropyl ester. As another example, dexamethasone acetate or dipropionate may be produced by acetylation of dexamethasone with acetic anhydride or reaction with propionic anhydride, and dexamethasone isanicotinate may be produced, far example, by reaction of dexamethasone with isonicotinoyl chloride.

[104] The aliphatic carboxylic add ester, thioester, or -amide can be the reaction product of one or more hydroxyl, carboxyl and/or amine groups in the active principle,, or any group subject to esterification or amidation or others in the active principle to create a degradable functional group, with one or more linear or branched, optionally substituted Cj to Gar, such as C? to CJS, aikanoic acids, optionally substituted Cj to G>&, such as Cs to Cw, cycloaikanoic acids, linear er branched, optionally substituted Ci to Cas, such as Ct to Ci®, alkyl alcohols or thiols, optionally substituted Cz to Cm, such as G to Csw cycloalkyl alcohols or thiols, optionally substituted G to Go, such as Ci to Go, aikyl amines, and optionally substituted Cs to Qt>, such as G to Cw cycloaikyl amines. Examples for suitable aliphatic mono- or di-esters are ethanoyl (acetate), propanoyl (propionyl)., butanoyl, iso- butanoyl, tert- butanoyl (tebutate), pentenoyl, hexanoyi, heptanoyl, octanoyl, nonanoyl, or decanoyi mono- or di-esters, and isomers thereof,

[105] The aromatic carboxylic acid ester, thioester, or amide can be the reaction product of one or more hydroxyl., thiol, carboxyl and/or amine groups in toe active principle with one or more optionally substituted C; to G®, such as Cx to CM, mono- or polycyclic aromatic or heteroaromatlc carboxylic adds, pharmaceutically acceptable salts thereof, or combinations thereof. Examples for suitable aromatic or heteroaromstic mono- or di-estens are benzoyl, phenyipropanoyl, naphthaienoyl, salicyl, nicotinoyl or isonicotinoyl mono- or di-esters, and Corners thereof.

[109] In some embodiments, the hydrophobic prodrug is present in the hydrogel in particle form, for example the hydrophobic ptodrug particles are dispersed within the hydrogel. The hydrophobic prodrug particles may be mlcronized particles, and, optionally, the hydrophobic prodrug particles may be encapsulated in a hydrogel or polymer shell. The hydrogel encapsulation material may be the same or different from toe hydrogel implant matrix. Furthermore, the encapsulated hydrophobic prodrug particles are dispersed within the hydrogel.

[107] In certain embodiments, the implant is for administration to a route selected from subcutaneous, intraocular, intracaveal, intracameral, punctal, intravitreal, subconjunctival, intrascteral, subretinal, episcleral, subconjunctival, choroidal, suprachoroidal, periocular, peribulbar, retrobulbar, intracorneal, retinal, subretlnai, intracanalicular, posterior sub-Tenon's delivery, anterior sub-Tenon's delivery, cul-de-sac delivery, fornix delivery, or an implant for introduction into the anterior chamber, the vitreous, in the posterior subtenon's space (inferior fornix), sub-tenon, or a lens, a surface of the cornea or the conjunctiva, puncta (Canaliculus, upper/lower canaliculus), ocular fornix, upper/tower ocular fornix, subtenon space, cancer tissue, organ, prostate, breast, joint space, subdural, dental, subcutaneous, carpal tunnel, perivascular, surgically created space or injUEy, void space, and potential space. [108] In the embodiments of the invention, the implant after administration to the human or animal body releases a therapeutically effective amount of hydrophobic prodrug over a period of at least about 5 days, such as 6 days, or 7 days, or 5 days to 2 months, or 5 days to 1 month, or 5 days to 3 weeks, such as 5 or 6 days to 2 weeks, or for at least about 1 month, at least about 2 months, at least about 3 months, at least about 6 months, at least about 9 months, at least about 10 months, at least about 11 months, or at least about 12 months after administration, for example, the implant after administration to the human or animal body releases a therapeutically effective amount of hydrophobic prodr ug over a period of at least 1 week, or 2. weeks, or 3 weeks, or 1 month, or 6 months, or the implant after administration to the human or animal body releases a therapeutically effective amount of hydrophobic prodrug over a period of at least 1 week to 9 months. [109] In some embodiments, the implants disclosed hereto ate suitable for subcutaneous delivery, or delivery in surgically created space or injury, or ocular delivery' to a route selected from, e.g., pupctai, intra vitreal, suixonjunctival, iptrascleral, subrednal, suprachdroidal, periocular, peribulbar, retrobulbar, intracorneal, posterior sub-tenon's delivery, anterior sub-tenon's delivery, cul-de-sac delivery, or fornix delivery. The administration can be, e.g<, by injection with a needle or insertion with a delivery device into the selected ocular delivery route. [110] The needle can be a gauge selected from, e.g,. 18 gauge, 19 gauge, 20 gauge, 21 gauge, 22 gauge, 23 gauge, 24 gauge, 25 gauge, 26 gauge, 27 gauge, 28 gauge, 29 gauge, 30 gauge, 31 gauge, 32 gauge or 33 gauge.

[111] In certain embodiments, the administration can be with a modified device as described in U.S. Patent No. 8,808,225; U.S, Patent No, 10,722,396; U.S. Patent No. 10,390,901; U.S, Patent no, 10,188,550; U.S. Patent No.

9,956,114; U.S. Patent No. 9,931,330; U.S. Patent Application Publication No. 2019/0290485; U.S. Patent Application Publication No, 2019/0000669; and U.S, Patent Application Publication No. 2018/0042767,

[112] In alternative embodiments, the administration can optionally be performed without a needle, e.g,, manually or with the aid of forceps, applicator or other delivery aid.

[113] The disclosed amounts of active agent prodrug, such as the opioid or opioid prodrug, including the mentioned variances, refer to both the final content of the active principle in the implant, as well as to the amount of active principle used as a starting component per implant when manufacturing the implant. The doses disclosed herein can also be applicable to other active agent prodrugs in certain embodiments.

[114] As will be disclosed in more detail herein below, in certain embodiments of the invention the total dose of the active agent prodrug to be administered to a patient, may be contained in two, three or more implants administered concurrently. [115] The implant may have a suitable form for being injectable or instiiiabte as a subcutaneous Implant, by minimal!/ invasive administration, such as by needles. In certain embodiments, the hydrophobic prodrug may be combined with a loading dose of the parent active principle. The implant of embodiments of the present invention is, since It is used under controlled conditions, an abuse-deterrent configuration that enhances safety' and/or tolerability, and minimal local tissue response can be expected. Active principles and prodrugs thereof

[116] The hydrophobic prodrag included in the hydrogel can be an aliphatic, aromatic, or heteroaromatic (thio)ester or amide derivative of an active principle selected from at least one of a therapeutically active agent or a diagnostically active agent, or combinations thereof. The active principle may be hydrophilic, or hydrophobic to a certain extent, and will be mere hydrophobic once amidated or esterified to form a hydrophilic prodrug,

[117] in embodiments of the invention, the active principle is a drug having at least one hydrophilic group, such as hydroxyl, thiol, carboxyl or amine that can be reacted with at least one of an organic acid, aicohgi or amine to form hydrophobic promoietfes on the active principle, thus forming the hydrophobic prodrug.

[118] in certain embodiments, the active principle in the hydrophobic prodrug can be an opioid analgesic such as a hydrophobic opioid or opioid prodrug dispensed within the hydrogel. The hydrophobic opioid or opioid prodrug can be at least one of hydrocodone, buprenorphine, or a hydrophobic ester or ether derivative of an opioid agonist or antagonist selected from the group consisting of morphine, dihydromorphine, desmorphine, normorphine, oxycodone, hydromorphone, buprenorphine, codeine, dihydrocodeine, nalbuphine, nalorphine, naloxone, naltrexone, etorphine, dihydroetorphine, pharmaceutically acceptable salts thereof, or combinations thereof. [119] In some embodiments, the active principle in the hydrophobic prodrug can be an intraocular pressure (tOP) towering drug. IOP towering agents and/or glaucoma medications can comprise prostaglandin analogs (e,g., bimaioprost; latanoprdst, travoprast, tafluprost, or latancprostene bunod), Rho kinase inhibitor (e.g., netarsudil), adrenergic agonists (epinephrine or diptvefrin), beta-adrenergic antagonists also Known as beta blockers (e>g., timolol., (evobunolol, metipranoloi, carteoiol, or betaxaiol), a:lpha2-adrenergic agonists (e,g,, apractonidtne., brimonidine, or brimonidine tartrate), carbonic anhydrase inhibitors (e.g., brinzolamide, dichiorphenamide, methazolamtoe acetazolamide, acetazdiamide, or ddrzoiamide), pilocarpine, echothiophate, demercariom, physostigmine, and/or isoftaorophate. In some embodiments for ocular implants, the active pdnciple tn the hydrophobic prodrug a prostaglandin analog such as bimatoprost, latanoprost, travoprost, tafiuprast, or iatanoprostene bused. [120] In some embodiments, tntegrin inhibitors that may be utilized as the active principle in the hydrophobic prodreg . Integrin inhibitors include lifitegrast, vedolizumab, nataiizumab, efalizumah, tirofiban, eptifibatide, abeiximab,. IDL-2965, PLf4-748<39, UN-1474, PN-943, 7HP349, MORF057, OS2966, QTT166, AXT-I07, JSM-6427, Risiiteganib.. THR-687 (D/ced), pharmaceutically acceptable salts thereof and combinations thereof.

[121] In some embodiments, the active principle in the hydrophobic prodrug can be a steroid. Steroids may be selected from corticosteroids that can comprise hydrocortisone, loteprednol, cortisol, cortisone, prednisoione, methylprednisolone, dexamethasone, betamethasone, triamcinolone, aldosterone, or fludrocortisone.

[122] In other embodiments, the active principle in the hydrophobic prodrug ran be a tyrosine kinase Inhibitor. Tyrosine kinase inhibitors that may be utilized in the implants and methods of the present invention include deucravacitinib, axitinib, avapritinib, capmatinib, pegimatinib, ripretinib, selpercatinlb, selumetinib, tucatinib, entrectinib, erdaftinib, fedratinib, pexidartinib, upadacatinib, zanubrutinib, baricitinib, binimetinib, dacomitinib, fostamatinib, gilteritinib, larotrectinib, lorlatinib, acalabrutinib, brigatinib, midostaurin, neratinib, alectinib, cobimetinib, lenvatinib, osimertinib, ceritinib, nintedanib, afatinib, ibrutinib, trametinib, bosutinib, cabozantinib, ponatinib, regorafenib, tofacitinib, crizotinib, ruxoiitinib, vandetanib, pazopanib, lapatinib, nilotinib, dasatinib, sunitinib (vorolanib), sorafenib, erlotinib, gefitinib, imatinib, afistinib, bosutinib, rabozantinib, cediraoib, ceritinib, crizofinlb, dabrafentb, dasatinib, erlotinib, everolimus, get'itiriib, fmatinib, lestaurtmib, nilotinib, paltociciib, pazopanib, ponatinib, regorafenib, ruxoiitinib, semanarilb, Sirallmus, sorafenib, temsiroiimus, tofacitinib, trametinib,. vandetanib, and vemurafenib. In another embodiment, the tyrosine kinase inhibitor is a Src family tyrosine kinase inhibitor, such as bat not limited to, A419259, AP234S1, AP23464, AP2348S, AP33588, AZD0424, AZIWS271, BMS35482S, CGP77675, QJ201, ENMD 2076, K8 SRC 4, KX2361, KX2-391, MLR 1023, MNS, PCI-32765, PD166285, PD18Q970,

PKC-412, PKI166, PPI, PP2, SRN 004, SU6656, TC-S70Q3, TG10043S, TG1Q0948, TX-1123, VAL 201, WH-4-023, XL 228, altenusirt, teutirtib, damnacanthaL dasatinib, herbimycin A, indirubin, neratinib, iavendustin A, peiitinlb, piceatannoi, saracatinib, Srcll, foretinib, motesanib, tivoranib, LY2457546, MGCD-265, MGCD-510, tivantinib, AMG4S8, JNJ-3887, EMD1214063, BMS794S33, PHI166S752, SGX-523, INC828Q, pharmaceutically acceptable salts thereof and combinations thereof.

[123] in some embodiments, the active principle in the hydrophobic prodrug can be an anti-infective drug. Anti- infecdves can comprise antibiotics such as ciprofloxacin, tobramycin, erythromycin, ofloxacin, gentamicin, fluoi'oquinoldne antibiotics, moxtfloxacin, and/or gattfloxacin; antivirals comprising ganciclovir., idoxuridine, vidarabine, and/or trifiuridine; and/or antifungals comprising amphotericin B, natamycin, voriconazole, fluconazole, miconazoie, clotrimazole, ketoconazole, posaconazole, echinocandin, caspofungiri, and/or micafangim

[124] in some embodiments, the active principle in the hydrophobic prodrug ran be an antimetabolite such as methotrexate, mycophenolate, or azathioprine. in some embodiments, antifibrotfc agents can comprise mitomycin C or 5-fluorouracil.

[125] In some embodiments, the active principle in the hydrophobic prodrug can be an angiogenesis inhibitor. Angiogenesis inhibitors can comprise anti-VEGF agents (e.g., afllbercept, ranibtzumab, bevacizumab), PDGF-B inhibitors (e,g,, Fovistatih), complement antagonists (e.g., eailizumab), tyrosine kinase inhibitors (e.g., sunitlnib, axitipib), and/or integrih antagonists (e.g., oataliziimab and vedo&umab). In certain entteffiments, the active agent can be selected from peptides selected from the group consisting of Compstatin, APL-I, Fc-in -dC.. Beovu {Bfoiucfzdmab),. Zlmura (Avaciricaptad Pegoi), Pegcetacoplsil,, Abicipar Pegol, Lampaiizumab, Fovista, Rlsuteganlb, AXT107, Bamipretide, THR149, ALM201, VG83, and largazole.

[126] In seme embodiments, prodtugs of nanobodies can be included in the iiydrageis. Nanobedies are described, for example, in Yang et al, (2020), Nanobodies: Next Generation of Cancer Diagnostics and Therapeutics, Front. Oncol, 10:1182, which is incorporated herein by reference in its entirety. Nanobodies may be selected from 68GaNOTA-Anti-HER2-VHHl, 68GaNOTA-Anti-HER2-VHHl, 99mTc-NM-<32, 131I-SGMlB-Anti-HER2-VHHl, 68GaNOTA-Ant!-MMR~VHH2, 99mTc-Anti-PD-U, L-DO547 + Doxorubicin, L-DOS47 + Cisplatin/Vinorelbine, RN035 + Trastuzumab/Docetaxel, KN035, KN044, TC-210 T Cells, CD19/CD20 bispecific CAR T cells, BCMA CAR T cells, or TAS266 nanobodies.

[127] In some embodiments, the active principle in the hydrophobic prodrug can be an affibody. Nonimmunoglobulin affinity proteins such as affibodies can be included in the hydrogel delivery systems. Affibody molecules are described, for example, in StShl et al., Affibody Molecules in Biotechnological and Medical Applications, Trends in Biotechnology 2017, 35 (8) p.691-712, which is incorporated herein by reference in its entirety.

[128] In some embodiments, binding proteins such as ankyrins and DARPins can be included in the hydrogel. Ankyrins and DARPins are described, for example, in a review by Caputi et al., Current Opinion in Pharmacology 2020, 51:93-101, which is incorporated herein by reference in its entirety. Ankyrins and DARPins may be selected from MP0250, a tri-specific DARPin drug candidate that can bind VEGF-A and hepatocyte growth factor (HGF) as well as one molecule of MP0250 binding two molecules of human serum albumin (HSA); Abicipar pegol (MP0112 or AGN- 150998); Brolucizumab, Ranibizumab, or Aflibercept.

[129] In some embodiments, the active principle in the hydrophobic prodrug can be a cytoprotective or neuroprotective agent, or an anesthetic. In some embodiments, neuroprotective agents can comprise ursodiol, memantine or acetylcysteine. In some embodiments, anesthetic agents can comprise lidocaine, proparacaine or bupivacaine. :

[130] In some embodiments, the active agent in the hydrophobic prodrug can be dexamethasone, ketorolac, diclofenac, vancomycin, moxifloxacin, gatifloxicm, besifloxacin, travoprost, 5-fluorouracil, methotrexate, mitomycin C, prednisolone, bevacizumab (Avastin®), ranibizumab (Lucentis® ), sunitinib, pegaptanib (Macugen®), timolol, latanoprost, brimonidine, nepafenac, bromfenac, triamcinolone, diflu prednate, fluocinolide, aflibercept, or combinations thereof. In some embodiments, the agent may be dexamethasone, ketorolac, diclofenac, moxifloxacin, travoprost, 5-fluorouracil, or methotrexate. :

[131] In alternative embodiments, the active principle in the hydrophobic prodrug can include immunosuppressants, complement inhibitors (e.g., C5 inhibitors such as eculizumab or Avacincaptad pegol), steroids, anti-inflammatories such as steroidal and non-steroidal anti-inflammatories (e.g COXI or COX 2 inhibitors), antivirals, antibiotics, anti-glaucoma agents, anti-VEGF agents, analgesics, tyrosine kinase inhibitors, integrin inhibitors, IL-6 blockers, reactive aldehyde species (RASP) inhibitors, nitric oxide donating PgAs, antihistamines, mast cell stabilizers, rho kinase inhibitors, plasma kallikrein inhibitors, BCL-2 blockers, semaphore antagonists, HtRAl blockers, IGF-1R inhibitors, VEGF combination agents (multi-specific antiangiogenic agents) and combinations thereof.

[132] Immunosuppressants include but are not limited to cyclosporine, mTOR inhibitors (e.g., rapamycin, tacrolimus, temsirolimus, sirolimus, everolimus, KU-0063794, WYE-354, AZD8055, metformin, or Torin-2), cyclophosphamide, atoposide, thiotepa, methotrexate, azathioprine, mercaptopurine, interferons, infliximab, etanercept, mycophenolate mofetil, 15-deoxyspergualin, thalidomide, glatiramer, leflunomide, vincristine, cytarabine, pharmaceutically acceptable salts thereof and combinations thereof. [133] In some embodiments, the active principle in the hydrophobic prodrug can be a non-steroidal antiinflammatory drug (NSAID). NSAIDs can comprise diclofenac (e.g., diclofenac sodium), flurbiprofen (e.g., flurbiprofen sodium), ketorolac (e.g., ketorolac tromethamine), bromfenac, or nepafenac.

[134] Non-steroidal anti-inflammatory compounds can further include inhibitors of the cyclooxygenase (COX) enzyme such as cyclooxygenase- 1 (COX-1) and cyclooxygenase-2 (COX-2) isozymes. General classes of non-steroidal anti-inflammatory compounds include salicylates, propionic acid derivatives, acetic acid derivatives, enolic acid derivatives, and anthranilic acid derivatives. Examples of non-steroidal anti-inflammatory compounds include acetylsalicylic acid, diflunisal, salsalate, ibuprofen, dex-ibuprofen, naproxen, fenoprofen, ketoprofen, dex-ketoprofen, flurbiprofen, oxaprozin, loxoprofen, indomethacin, tolmedn, sulindac, etodolac, ketorolac, diclofenac, aceclofenac, nabumetone, piroxicam, tenoxicam, tenoxicam, loroxicam, phenylbutazone, mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid, celecoxib, pharmaceutically acceptable salts thereof and combinations thereof.

[135] Anti-inflammatory agents that may be utilized in the implants and methods of the present invention may include agents that target inflammatory cytokines such as TNFa, IL-1, IL-4, IL-5, 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.

[136] Analgesics that may be utilized in the implants and methods of the present invention include acetaminophen, acetaminosalol, aminochlorthenoxazin, acetylsalicylic 2-amino-4-picoline acid, acetylsalicylsalicylic acid, anileridine, benoxaprofen, benzylmorphine, 5-bromosalicylic acetate acid, bucetin, buprenorphine, butorphanol, capsaicin, cinchophen, ciramadol, clometacin, clonixin, codeine, desomorphine, dezocme, dihydrocodeine, dihydromorphine, dimepheptanol, dipyrocetyl, eptazocine, ethoxazene, ethylmorphine, eugenol, floctafenine, fosfosal, glafenine, hydrocodone, hydromorphone, hydroxypethidine, ibufenac, p-lactophenetide, levorphanol, meptazinol, metazocine, metopon, morphine, nalbuphine, nicomorphine, norlevorphanol, normorphine, oxycodone, oxymorphone, pentazocine, phenazocine, phenocoll, phenoperidine, phenylbutazone, phenylsalicylate, phenylramidol, salicin, salicylamide, tiorphan, tramadol, diacerein, actarit, pharmaceutically acceptable salts thereof and combinations thereof.

[137] Antibiotic that may be utilized in the implants and methods of the present invention include aminoglycosides, penicillins, cephalosporins, fluoroquinolones, macrolides, and combinations thereof. Aminoglycosides may include tobramycin, kanamycin A, amikacin, dibekacin, gentamicin, sisomicin, netilmicin, neomycin 8, neomycin C, neomycin E, streptomycin, paramomycin, pharmaceutically acceptable salts thereof and combinations thereof. Penicillins may include amoxicillin, ampicillin, bacampicillin, carbenicillin, cloxacillin, dicloxacillin, flucloxadllin, mezlocillin, nafcillin, oxacillin, penicillin G, penicillin V, piperacillin, pivampicillin, pivmecillinam, ticarcillin, pharmaceutically acceptable salts thereof and combinations thereof. Cephalosporins may include cefacetrile, cefadroxil, cefalexin, cefaloglycin, cefalonium, cefaloridine, cefalotin, cefapirin, cefatrizine, cefazaflur, cefazedone, cefazolin, cefradine, cefroxadine, ceftezole, cefaclor, cefamandole, cefmetazole, cefonicid, cefotetan, cefoxitin, cefprozil, cefuroxime, cefuzonam, cefcapene, cefdaloxime, cefdinir, cefditoren, cefetamet, cefixime, cefmenoxime, cefodizime, cefotaxime, cefpimizole, cefpodoxime, cefteram, ceftibuten, ceftiofur, ceftiolene, ceftizoxime, ceftriaxone, cefoperazone, ceftazidime, cefclidine, cefepime, cefluprenam, cefoselis, cefozopran, cefpirome, cefquinome, ceftobiprole, ceftaroline, cefaclomezine, cefaloram, cefaparole, cefcanel, cefedrolor, cefempidone, cefetrizole, cefivitril, cefmatilen, cefmepidium, cefovecin, cefoxazole, cefrotil, cefsumide, cefuracetime, ceftioxide, pharmaceutically acceptable salts thereof and combinations thereof. Fluoroquinolones may include ciprofloxacin, levofloxadn, 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.

[138] Antivirals that may be utilized in the implants and methods of the present invention include nucleoside reverse transcriptase inhibitors, non-nudeoside reverse transcriptase inhibitors, fusion inhibitors, integrase inhibitors, nucleoside analogs, protease inhibitors, and reverse transcriptase inhibitors. Examples of antiviral agents include, but are not limited to, abacavir, aciclovir, acyclovir, adefovir, amantadine, amprenavir, ampligen, arbidol, atazanavir, boceprevir, cidofovir, dat unavir, delavirdine, didanosine, docosanol, edoxudine, efavirenz, emtricitabine, enfuvirtide, entecavir, famciclovir, fomivirsen, fosamprenavir, foscarnet, fosfonet, ganciclovir, ibacitabine, imunovir, idoxuridine, imiquimod, indinavir, inosine, interferon type in, interferon type II, interferon type I, interferon, lamivudine, lopinavir, loviride, maraviroc, moroxydine, methisazone, nelfinavir, 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, valaciclovir, valganciclovir, vicriviroc, vidarabine, viramidine, zalcitabine, zanamivir, zidovudine, pharmaceutically acceptable salts thereof and combinations thereof. [139] Steroidal anti-inflammatory agents that may be utilized in the implants or inserts and methods of the present invention include dexamethasone, budensonide, triamcinolone, hydrocortisone, fluocmolone, loteprednol, prednisolone, mometasone, fluticasone, rimexolone, fluoromethotone, beclomethasone, flunisolide, pharmaceutically acceptable salts thereof and combinations thereof. In some embodiments, the drug delivery system or insert includes a derivative of dexamethasone such as one of dexamethasone valerate, dexamethasone acetate (flumeprednisolone), dexamethasone cipecilate, dexamethasone diethylaminoacetate, dexamethasone dipropionate, dexamethasone tebutate (dexamethasone te/t-butylacetate), dexamethasone succinate, dexamethasone isonicotinate, dexamethasone linoleate, dexamethasone metasulphobenzoate, dexamethasone acefurate, dexamethasone palmitate, dexamethasone phosphate, dexamethasone sulfate, dexamethasone pivalate, and dexamethasone troxundate. [140] Anti-glaucoma agents that may be utilized in the implants and methods of the present invention include beta-blockers such as atenolol propranolol, metipranolol, betaxolol, carteolol, tevobetaxolol, levobunolol timolol, pharmaceutically acceptable salts thereof and combinations thereof; adrenergic agonists or sympathomimetic agents such as epinephrine, dipivefrin, clomdine, apardonidine, brimonidine, pharmaceutically acceptable salts thereof and combinations thereof; parasympathomimetics or cholinergic agonists such as pilocarpine, carbachol, phospholine iodine, physostigmine, pharmaceutically acceptable salts thereof and combinations thereof; carbonic anhydrase inhibitor agents, including topical or systemic agents such as acetozolamide, brinzolamide, dorzolamide; methazolamide, ethoxzolamide, dichlorphenamide, pharmaceutically acceptable salts thereof and combinations thereof; mydriatic-cycloplegic agents such as atropine, cyclopentolate, succinylcholine, homatropine, phenylephrine, scopolamine, tropicamide, pharmaceutically acceptable salts thereof and combinations thereof; prostaglandins such as prostaglandin F2 alpha, antiprostaglandins, prostaglandin precursors, or prostaglandin analog agents such as bimatoprost, latanoprost, travoprost, unoprostone, tafluprost, pharmaceutically acceptable salts thereof and combinations thereof.

[141] Anti-VEGF agents that may be utilized in the implants and methods of the present invention include bevacizumab, pegaptanib, ranibizumab, brolucizumab, conbercept, aflibercept, pharmaceutically acceptable salts thereof and combinations thereof.

[142] Complement pathway modulators that may be utilized l n the systems, implants and methods of the present invention include those that target, e.g., C1/C1Q, C3, C3 Convertase, C5, C5 convertase, C5a, C5aR, C6, C7, C8, C9,

CD59, Factor B, Factor D, Factor H, Factor P, or a combination thereof. Particular agents may include cinryze, berinert, ruconest, sutimhmab, pegcetacoplan (GA), ecuhziumab, ravuilizumab, avacopan, pozelimab, nomacopan, zilucopan, vilobelimab, crovalimab, avacincapted pegol), cemdisiran, BDB-001, tesidolumab, avdoralimab, MOR210,

ALXN1720, danicopan, vemircopan, ACH-5228, ACH-5548, BCX-9330, AMY-101, ANXOOS, ANX007, narsoplimab, iptacopan, O.G561, GT103, ARGX-117, ALXN1820, NGM621, lampalizumab, NGM621, lONIS-FB-Lrx, GEM103, CLG561, pharmaceutically acceptable salts thereof and combinations thereof.

[143] Antihistamines that may be utilized in the implants and methods of the present invention include loratadine, hydroxyzine, diphenhydramine, chlorpheniramine, brompheniramine, cyproheptadine, terfenadine, clemastine, triprolidine, carbinoxamine, diphenylpyraline, phenindamine, azatadine, tripelennamine, dexchlorpheniramine, dexbrompheniramine, methdilazine, and trimprazine doxylamine, pheniramine, pyrilamine, chiorcydizine, thonzylamine, pharmaceutically acceptable salts thereof and combinations thereof.

[144] IL-6 inhibitors that may be utilized in the implants and methods of the present invention include sarilumab, tocilizumab, RG6179, pharmaceutically acceptable salts thereof and combinations thereof.

[145] HtrAl inhibitors that may be utilized in the implants and methods of the present invention include IC-500, FHTR2163, RG6147, pharmaceutically acceptable salts thereof and combinations thereof.

[146] RASP inhibitors that may be utilized in the implants and methods of the present invention include reproxalap and pharmaceutically acceptable salts thereof.

[147] Rho kinase inhibitors that may be utilized in the implants and methods of the present invention include netardusil, ripasudil, HA-1077, Y-27632, H-1152P, INS-115644, Y-39983, SB772077BS, LX71D1, AR-12286, AMA- 0076, AR- 13533, pharmaceutically acceptable salts thereof and combinations thereof

[148] Plasma kallikrein inhibitors that may be utilized in the implants and methods of the present invention include ecallantide, lanadelumab, berotralstat, ATN-249, KVD900, KVD824, THR-149, pharmaceutically acceptable salts thereof and combinations thereof. [149] Nitric Oxide Donating PgAs that may be utilized in the implants and methods of the present invention include Latanoprostene Bunod, NCX470, NCX125, pharmaceutically acceptable sate thereof and combinations thereof

[150] Mast Cell Stabilizers that may be utilized in the implants and methods of the present invention include lodoxamide, nedocromil, pemirolast, cromolyn (e.g., chromolyn sodium), pharmaceutically acceptable salts thereof and combinations thereof.

[151] IGF-1R Inhibitors that may be utilized in the implants and methods of the present invention include teprotutumab, VRDN-001, VRDN-002, VRDN-003, ganitumab, figitumumab, MEDI-573, cixutumumab, dalotuzumab, robatumumab, AVE1642, BIIB022, xentuzumab, istiratumab, linsitinib, picropodophyllin, BMS-754807, BMS-536924, BMS-554417, GSK1838705A, GSK1904529A, NVP-AEW541, NVP-ADW742, GTx-134, AG1024, KW-2450, PL-2258, NVP-AEW541, NSM-18, AZD3463, AZD9362, B1I885578, B1893923, TT-100, XL-228, A-928605, pharmaceutically acceptable salts thereof and combinations thereof.

[152] TRPV1 antagonists that may be utilized in the implants and methods of the present invention include asivatrep, VI 16517, fused azabicyclic, heterocyclic, and amide compounds as described, for example, in U.S. Patent Application No. 2004/0157849, U.S. Patent Application No. 2004/0209884, U.S. Patent Application No. 2005/0113576, International Patent Application No. WO 05/016890, U.S. Patent Application No. 2004/0254188, U.S.

Patent Application No. 2005/0043351, International Patent Application No. WO 05/040121, U.S. Patent Application No. 2005/0085512, and Gomtsyan et al., 2005, J. Med. Chem. 48:744-752; fused pyridine derivatives as described, for example, in U.S. Patent Application No. 2004/0138454; pyridyl piperazinyl ureas as described, for example, 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, ll.sup.th World Congress on Pain) and BCTC (Sun et al., 2003, Chem. Lett. 13:3611-

3616); 2-(piperazine-l-yl)-lH-Benzimidazole; pyridazinylpiperazines; urea derivatives as describe, for example, in U.S. Patent Application No. 2005/0107388, U.S. Patent Aoplication No. 2005/0187291, and U.S. Patent Application No. 2005/0154230, as well as A-425619 (El Kouhen et al., 2005, J. Pharmacol. Exp. Ther. 314:400-409); cinnamides, including SB-366791 (Gunthorpe et al., 2004, Neuropharmacology 46:133-149) and AMG 9810 (Gawa et al., 2005, J. Pharmacol. Exp. Ther. 313:474-484).

[153] In some embodiments, TRPV1 antagonists useful in the methods and compositions as disclosed herein include, for example, TRPV-1 antagonists include capsazepine, (E)-3-(4-t-butylphenyl)-N-(2,3- dihydrobenzo[b][l,4]dioxin-6-yl)acrylamide (commercially available for example as AMG9810 from Tocris Bioscience, Bristol, United Kingdom), and 4-tertiary butyl cyclohexane (commercially available as SYMSITIVE 1609 from Symrise GmbH of Holzminden, Germany, as well as TRPV1 antagonists as disclosed in U.S. Pat. Nos. 8,815,930, 6,933,311, 7,767,705 and U.S. Pat. App. Pub, Nos. 2010/0249203 and 2011/0104301, International Application WO/2008/013861.

[154] In some embodiments, TRPV1 antagonists useful in the methods and compositions and devices as disclosed herein include AMG-517 and AMG-628 (Amgen Inc., Thousand Oaks, Calif.). TRPV1 antagonists useful in the present application are also described, for example, in International Patent Application No. WO 2006065484; International Patent Application No. WO 2003070247; U.S. Patent Application No. US 2005080095; and International Patent Application No. WO 2005007642. Additional TRPV1 antagonists useful in the methods and compositions and devices as disclosed herein include TRPV1 antagonists: ABT-102, AMG8562, AMG9810, BCTC, SB366791, JN JI 7203212, 1- TTX, JYL-1421, A-425619, N-[4-[6-[4(Trifluoromethyl)phenyl)pyrimidin-4-yloxy]benzothiazol-2-yrjacetamide (also known as AL-49975 or AMG-517), (R)— N-(4-(6-(4-(l-(4-fluorophenyl)ethyl)piperazin-l-yl)pyrimidin-4- yloxy)benzo[d]thiazol-2-yl)acetamide (AL-49976, also known as AMG-628), pharmaceutically acceptable salts thereof and combinations thereof.

[ 155] Other TRPV1 antagonists useful in the methods and compositions and devices as disclosed herein are those that have a low inhibitory activity against CYP3A4, such as, e.g., l-(2-(3,3-dimethylbutyl)-4-(trifluoromethyl)benzyl)- 3-(l-methyl-lH-in-dazol-4-yl)urea; methyl 2,2-dimethyl-4-(2-((3-(l-methyl-lH-indazol-4-yl)ureido)methyl)-5-(trifluo- romethyl)phenyl)butanoate; l-(2-(4-hydroxy-3,3-dimethylbutyl)-4-(trifluoromethyl)benzyl)-3-(l-methyl- -IH-indazol- 4-yl)urea; 2,2-dimethyl-4-(2-((3-(l-methyl-lH-indazol-4-yl)ureido)methyl)-5-trifluor-omethyl)phenyl)butanoic acid; 1- [4-Chloro-3-(3,3-dimethylbutyl)benzyl]-3-(l-methyl-lH-irdazol-4-yl)urea-; l-(2-isobutyl-4-(trifluoromethyl)benzyl)-3- (l-methyl-lH-indazol-4-yl)urea; l-(2-isopropyl-4-(trifluoromethyl)benzyl)-3-(l-methyl-lH-indazol-4-yl)urea; l-(4- Chloro-3-isopropylbenzyl)-3-(l-methyl-lH-indazol-4-yl)urea, pharmaceutically acceptable salts thereof and combinations thereof.

[156] TrkA antagonists that may be utilized in the implants and methods of the present invention include VM902A, Larotrectinib, Entrectinib, Selitrectinib (LOXO-195, BAY 2731954), repotrectinib (TPX-0005), pharmaceutically acceptable salts thereof and combinations thereof. [157] For the purposes of the present invention, an active agent includes all its possible forms, including free add, free base, polymorphs, pharmaceutically acceptable salts, anhydrates, hydrates, other solvates, stereoisomers, crystalline forms, cocrystals, conjugates (e.g., pegylated compounds), complexes and mixtures thereof that can be reacted as described herein to form hydrophilic prodrugs.

[158] The hydrophobic prodrug administered by the drug delivery systems of the present invention can, e.g., have an aqueous solubility of less than about less than about 100 pg/mL, less than about 75 pg/mL, less than about 50 pg/mL, less than about 25 pg/mL, less than about 10 pg/mL, less than about 5 pg/mL, less than about 1 pg/mL, less than about 0.5 pg/mL, less than about 0.4 pg/mL, less than about 0.3 pg/mL, less than about 0.2 pg/mL or less than about 0.1 pg/mL, measured in PBS at pH 7.4 and 37°C. In some embodiments, the active agent prodrug is substantially insoluble in water. As an example, the solubility of dexamethasone (free alcohol) in PBS at pH 7.4 and 37°C is about 75 pg/mL, for dexamethasone valerate it is about 10,7 pg/mL, for dexamethasone acetate it is about 9 pg/mL, for dexamethasone dipropionate it is about 1.2 pg/mL, and for dexamethasone isonicotinate it is about 0.5 pg/mL.

[159] In other embodiments, the active agent prodrugs administered by the devices of the present invention can have an aqueous solubility classified as very slightly soluble (1,000-10,000 parts solvent needed for 1 part solute) or practically insoluble or insoluble (>10,000 parts solvent needed for 1 part solute) as described in Remington, The Science and Practice of Pharmacy 22nd Edition 2012,

[160] In addition to the hydrophobic prodrugs, In certain embodiments the implant may in combination include a further active agent prodrug or a combination of two or more of the prodrugs selected from those as described above.

[161] The active agent prodrug is contained in the implant of the invention and is dispersed or distributed in the hydrogel that is comprised of a polymer network, for example as dispersed particles. In certain embodiments, the particles are homogeneously or essentially homogeneously dispersed in the hydrogel. The hydrogel may prevent the particles from agglomerating and may provide a matrix for the particles which holds them in the desired location in the eye white slowly releasing drug.

[162] In certain embodiments of the invention, the hydrophobic prodrug particles may be microencapsulated. The term "microcapsule" (also referred to as "microparticle") is sometimes defined as a roughly spherical particle with a size varying between e.g„ about 50 nm to about 2 mm. Microcapsules have at least one discrete domain (or core) of active agent prodrug encapsulated in a surrounding material, sometimes also referred to as a shell. One suitable agent (without limiting the present disclosure to this) for microencapsulating the active agent prodrug, for the purposes of the present invention, is poly (lactic-co-glycolic acid). Suitable microencapsulation methods are described, for example, in US 2018/0085307, WO 2018/169950, WO 2021/237096, US 2021/0251893, and in International Patent Application No. PCT/US2024/15968, which are incorporated herein by reference,

[163] In other embodiments, the opioid prodrug particles are not microencapsulated and are thus dispersed in the hydrogel and thus in the implant of the invention as they are, i.e., without being admixed to or adjoined with or microencapsulated by another material such as (but not limited to) poly (lactic-co-glycolic acid).

[164] In one embodiment, the active agent prodrug particles may be micronized particles. Micronization refers to the process of reducing the average diameter of particles of a solid material. Particles with reduced diameters may have inter alia higher dissolution and erosion rates, which increases the bioavailability of active pharmaceutical ingredients and may have in certain embodiments a positive impact on release kinetics. Furthermore, micronized particles may have a reduced tendency to agglomerate during manufacturing operations. In the composite materials field, particle size is known to affect the mechanical properties when combined with a matrix, with smaller particles providing superior reinforcement for a given mass fraction. Thus, a hydrogel matrix filled with micronized hydrophobic prodrug particles may have improved mechanical properties (e.g„ britleness, strain to failure, etc.) compared to a similar mass fraction of larger active agent prodrug particles. Such properties are important in manufacturing, during implantation, and during degradation of the implant. Micronization may also promote a more homogeneous distribution of the active ingredient in the chosen dosage form or matrix.

[165] The particle size distribution can be measured by methods known in the art, including sieving, laser diffraction or dynamic light scattering. In certain embodiments of the invention the active agent prodrug particles used in preparing the implants of the present invention may have a d90 of less than about 100 pm and/or a d50 of less than about 50 pm, or a d90 of less than about 75 pm and/or a d50 or less than about 20 pm as determined by laser diffraction. In specific embodiments, the d90 of the prodrug may be less than about 30 pm, less than about 20 pm as determined by laser diffraction, in embodiments thereof, the d90 of the active agent prodrug is less than about 10 pm as determined by laser diffraction. In these or other embodiments, the d50 of the active agent prodrug particles used in preparing the implants of the present invention may be less than about 5 pm as determined by laser diffraction. In these or other embodiments, the dlO of the active agent prodrug particles used in the present invention may be less than about 3 pm as determined by laser diffraction. In certain embodiments, the dlOO of the active agent prodrug particles used in the preparation of the implants of the present invention may be less than about 20 pm as determined by laser diffraction. The "d90" (also referred to as "D90" herein) value means that 90 volume-% of all particles within the measured bulk material (which has a certain particle size distribution) have a particle size below the indicated value. For example, a d90 particle size of less than about 10 pm means that 90 volume-% of the particles in the measured bulk material have a particle size below about 10 pm. Corresponding definitions apply to other ”d" values, such as the "dlO", "d50" or the "dlOO" values (also referred to herein as the "DIO", "D50" and "D100" values, respectively). In certain other embodiments also prodrug particles with diameters above this specification may be used.

[166] Micronized prodrug particles may be purchased per specification from the supplier, or may be prepared e.g., according to the following exemplary procedure (similar to the method disclosed in WO 2016/183296 Al, Example 13): 1800 ml of sterile Water For Injection (WFI) is measured into a 2 L beaker and placed on a stir plate stirring at 600 RPM with a stir bar, creating a large WFI vortex in the center of the beaker. One 60 ml BD syringe containing prodrug dissolved in a suitable solvent that is miscible with water, e.g., ethanol, is placed on a syringe pump which is clamped above the WFI beaker. A hypodermic needle (21G, BD) is connected to the syringe and aimed directly into the center of the vortex for dispensation of the prodrug solution. The syringe pump is then run at 7.5 mL/min in order to add the opioid prodrug solution dropwise to the WFI to precipitate micronized prodrug. After micronization, the opioid prodrug is filtered, e.g., through a 0.2 pm vacuum filter and rinsed with WFI. After filtration, the prodrug powder is collected from the filter e.g., by using a spatula and vacuum dried for an extended period of time, such as for about 12 or about 24 hours, in order to remove excess water and solvent. Another exemplary method of micronizing prodrug is disclosed in Example 9 of WO 2017/091749. The described method of micronization is not limiting, and other methods of micronizing the active agent prodrug may equally be used. The disclosed micronization method (or other methods) may also be used for other actives or ingredients than prodrugs. [167] Another aspect of the present invention is a sustained release biodegradable implant comprising a hydrogel and a hydrophobic prodrug, wherein hydrophobic prodrug particles are dispersed within the hydrogel, and wherein the implant in its dry state has a total weight of about 0.2 mg to about 1.5 mg.

[168] In certain embodiments, the total weight (also referred to herein as "total mass") of an implant according to the present invention in its dry state may be from about 400 pg to about 1.2 mg. In certain specific embodiments, the total weight of an implant according to the invention in its dry state may be from about 0.3 mg to about 0.6 mg, such as from about 0.4 mg to about 0.5 mg, or may be from about 0.8 mg to about 1.1 mg, such as from about 0.9 mg to about 1.0 mg. [169] All features (individually or any combinations of features) disclosed herein with respect to an implant according to the present invention may be used to characterize the sustained release biodegradable implant comprising a hydrogel a hydrophobic active agent prodrug, wherein active agent prodrug particles are dispersed within the hydrogel, and wherein the implant in its dry state has a total weight of about 0,2 mg to about 1.5 mg.

The polymer network:

[170] In certain embodiments, the sustained release biodegradable implant comprises a hydrogel, and the hydrogel comprises a polymer network comprising one or more units of polyethylene glycol, polyethylene oxide, polypropylene oxide, polyvinyl alcohol, poly (vinylpyrrolidinone), polylactic acid, polylactic-co-glycolic acid, random or block copolymers or combinations or mixtures of any of these, or one or more units of polyaminoadds, glycosaminoglycans, polysaccharides, or proteins. In certain embodiments, the implant is in a dried state prior to administration and becomes hydrated once administered or implanted into the human or animal body. The hydrogel may be formed from precursors having functional groups that form crosslinks to create a polymer network. These crosslinks between polymer strands or arms may be chemical (i.e., may be covalent bonds) and/or physical (such as ionic bonds, hydrophobic association, hydrogen bridges etc.) in nature.

[171] In embodiments of the present invention, the polymer network may be prepared from precursors, either from one type of precursor or from two or more types of precursors that are allowed to react. Precursors are chosen in consideration of the properties that are desired for the resultant hydrogel. There are various suitable precursors for use in making the hydrogels. Generally, any pharmaceutically acceptable and crosslinkable polymers forming a hydrogel may be used for the purposes of the present invention. The hydrogel and thus the components incorporated into it, including the polymers used for mak ng the polymer network, should be physiologically safe such that they do not elicit e.g., an immune response or other adverse effects. Hydrogels may be formed from natural, synthetic, or biosynthetic polymers.

[172] Natural polymers may include glycosaminoglycans, polysaccharides (e.g., dextran), polyaminoacids and proteins or mixtures or combinations thereof.

[173] Synthetic polymers may generally be any polymers that are synthetically produced from a variety of feedstocks by different types of polymerization, including free radical polymerization, anionic or cationic polymerization, chain-growth or addition polymerization, condensation polymerization, ring-opening polymerization etc. The polymerization may be initiated by certain initiators, by light and/or heat, and may be mediated by catalysts.

[174] Generally, for the purposes of the present invention one or more synthetic polymers of the group comprising one or more units of polyalkylene glycol, such as polyethylene glycol (PEG), polypropylene glycol, polyethylene glycol)-block-poly(propylene glycol) copolymers, or polyethylene oxide, polypropylene oxide, polyvinyl alcohol, poly (vinylpyrrolidinone), polylactic acid, polylact c-co-glycolic acid, random or block copolymers or combinations/mixtures of any of these can be used, while this list is not intended to be limiting. [175] To form covalently crosslinked polymer networks, the precursors may be covalently crosslinked with each other. In certain embodiments, precursors with at least two reactive centers (for example, in free radical polymerization) can serve as crosslinkers since each reactive group can participate in the formation of a different growing polymer chain. [176] The precursors may have biologically inert and hydrophilic portions, e.g., a core. In the case of a branched polymer, a core refers to a contiguous portion of a molecule joined to arms that extend from the core, where the arms carry a functional group, which is often at the terminus of the arm or branch. Multi-armed PEG precursors are examples of such precursors and are further disclosed herein below.

[177] Thus, a hydrogel for use in the present invention can be made e.g. from one multi-armed precursor with a first (set of) functional group(s) and another multi-armed precursor having a second (set of) functional group(s). By way of example, a multi-armed precursor may have hydrophilic arms, e.g., polyethylene glycol units, terminated with primary amines (nucleophile), or may have activated ester end groups (electrophile). The polymer network according to the present invention may contain identical or different polymer units crosslinked with each other.

[178] Certain functional groups can be made more reactive by using an activating group. Such activating groups include (but are not limited to) carbonyldiimidazole, sulfonyl chloride, aryl halides, sulfosuccinimidyl esters, N- hydroxysuccinimidyl ester, succinimidyl ester, epoxide, aldehyde, maleimides, imidoesters, acrylates and the like. The N-hydroxysuccinimide esters (NHS) are useful groups for crosslinking of nucleophilic polymers, e.g., primary amine- terminated or thiol-terminated polyethylene glycols. An NHS-amine crosslinking reaction may be carried out in aqueous solution and in the presence of buffers, e.g., phosphate buffer (pH S.0-7.5), triethanolamine buffer (pH 7.5- 9.0), borate buffer (pH 9.0-12), or sodium bicarbonate buffer (pH 9.0-10.0).

[179] In certain embodiments, each precursor may comprise only nucleophilic or only electrophilic functional groups, so tong as both nucleophilic and electrophilic precursors are used in the crosslinking reaction. Thus, for example, if a crosslinker has only nucleophilic functional groups such as amines, the precursor polymer may have electrophilic functional groups such as N-hydroxysuccinimides. On the other hand, if a crosslinker has electrophilic functional groups such as sulfosuccinimides, then the functional polymer may have nucleophilic functional groups such as amines or thiols. Thus, functional polymers such as proteins, poly (allyl amine), or amine-terminated di-or multifunctional polyethylene glycol) can be also used to prepare the polymer network of the present invention.

[180] In one embodiment a first reactive precursor has about 2 to about 16 nucleophilic functional groups each (termed functionality), and a second reactive precursor allowed to react with the first reactive precursor to form the polymer network has about 2 to about 16 electrophilic functional groups each. Reactive precursors having a number of reactive (nucleophilic or electrophilic) groups as a multiple of 4, thus, for example, 4, 8 and 16 reactive groups, are particularly suitable for the present invention. Any number of functional groups, such as including any of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, IS, or 16 groups, is possible for precursors to be used in accordance with the present invention, while ensuring that the functionality is sufficient to form an adequately crosslinked network. PEG hydrogels:

[181] In a certain embodiments of the present invention, the polymer network forming the hydrogel contains polyethylene glycol (PEG) units, PEGs are known in the art to form hydrogels when crosslinked, and these PEG hydrogels are suitable for pharmaceutical applications e.g., as matrix for drugs intended to be administered to all parts of the human or animal body.

[182] The polymer network of the hydrogel implants of the present invention may comprise one or more multiarm PEG units having from 2 to 10 arms, or 4 to 8 arms, or 4, 5, 6, 7 or 8 arms. The PEG units may have a different or the same number of arms. In certain embodiments, the PEG units used in the hydrogel of the present invention have 4 and/or 8 arms. In certain particular embodiments, a combination of 4- and 8-arm PEG units is utilized. [183] The number of arms of the PEG used contributes to controlling the flexibility or softness of the resulting hydrogel. For example, hydrogels formed by crosslinking 4-arm PEGs are generally softer and more flexible than _; those formed from 8-arm PEGs of the same molecular weight, In particular, if stretching the hydrogel prior to or after drying as disclosed herein below in the section relating to the manufacture of the implant is desired, a more flexible hydrogel may be used, such as a 4-arm PEG, optionally in combination with another multi-arm PEG, such as an 8- arm PEG as disclosed above.

[184] In certain embodiments of the present invention, polyethylene glycol units used as precursors have an average molecular weight in the range from about 2,000 to about 100,000 Daltons, or in a range from about 10,000 to about 60,000 Daltons, or in a range from about 15,000 to about 50,000 Daltons. In certain particular embodiments the polyethylene glycol units have an average molecular weight in a range from about 10,000 to about 40,000 Daltons, or of about 20,000 Daltons. PEG precursors of the same average molecular weight may be used, or

PEG precursors of different average molecular weight 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 MALDI.

[185] In a 4-arm PEG, each of the arms may have an average arm length (or molecular weight) of the total molecular weight of the PEG divided by 4. A 4a20kPEG precursor, which is one precursor that can be utilized in the present invention thus has 4 arms with an average molecular weight of about 5,000 Daltons each. An 8a20k PEG precursor, which may be used in addition to the 4a20kPEG precursor in the present invention, thus has 8 arms each having an average molecular weight of 2,500 Daltons, longer arms may provide increased flexibility as compared to shorter arms. PEGs with longer arms may swell more as compared to PEGs with shorter arms. A PEG with a lower number of arms also may swell more and may be more f exible than a PEG with a higher number of arms. In certain particular embodiments, combinations of PEG precursors with different numbers of arms, such as a combination of a 4-arm PEG precursor and an 8-arm precursor, may be utilized in the present invention. In addition, longer PEG arms have higher melting temperatures when dry, which may provide more dimensional stability during storage. For example, an 8-arm PEG with a molecular weight of 15,000 Dalton crosslinked with trilysine may not be able to maintain a stretched configuration at room temperature, whereas a 4-arm 20,000 Dalton PEG crosslinked with an 8- arm 20,000 Dalton PEG may be dimensionally stable in a stretched configuration at room temperature.

[186] When referring to a PEG precursor having a certain average molecular weight, such as a 15kPEG- or a 20kPEG-precursor, the indicated average molecular weight (i.e., a Mn of 15,000 or 20,000, respectively) refers to the PEG part of the precursor, before end groups are added ("20k" here means 20,000 Daltons, and "15k" means 15,000 Daltons - the same abbreviation is used herein for other average molecular weights of PEG precursors), In certain embodiments, the Mn of the PEG part of the precursor is determined by MALDI. The degree of substitution with end groups as disclosed herein may be determined by means of ^-NMR after end group functionalization.

[187] In certain embodiments, electrophilic end groups for use with PEG precursors for preparing the hydrogels of the present invention are N-hydroxysuccinimidyl (NHS) esters, including but not limited to: "SAZ" referring to a succinimidylazelate end group, "SAP" referring to a succinimidyladipate end group, "SG" referring to a succinimidylglutarate end group, and "SS" referring to a succinimidylsuccinate end group.

[188] In certain embodiments, nucleophilic end groups for use with PEG precursors for preparing the hydrogels of the present invention are amine (denoted as "NHr") end groups. Thiol (-SH) end groups or other nucleophilic end groups are also possible.

[189] In certain preferred embodiments, 4-arm PEGs with an average molecular weight of about 20,000 Daltons and an electrophilic end group as disclosed above and 8-arm PEGs also with an average molecular weight of about 20,000 Daltons and with a nucleophilic end group as disclosed above are crosslinked for forming the polymer network and thus the hydrogel according to the present invention. [190] Reaction of nucleophilic group-containing PEG units and electrophilic group-containing PEG units, such as amine end-group containing PEG units and activated ester-group containing PEG units, results in a plurality of PEG integer from 0 to 10, and specifically is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In one particular embodiment, m is 6, e.g. in the case a SAZ-end group-containing PEG is used. For an SAP-end group, m would be 3, for a SG-end group, m would be 2 and for an SS-end group m would be 1. All crosslinks within the polymer network may be the same, or may be different.

[191] In certain preferred embodiments, the SAZ end group is utilized in the present invention. This end group may provide for increased duration in the eye, and the implant of certain embodiments of the present invention comprising a hydrogel comprising PEG-SAZ units is biodegraded in the eye, such as in the vitreous humor of a human eye, only after an extended period of time, e.g., 9 to 12 months as further disclosed below, and may in certain circumstance persist even longer. The SAZ group is more hydrophobic than e.g. the SAP-, SG- or SS-end groups because of a higher number of carbon atoms in the chain (m being 6, and the total of carbon atoms between the amide group and the ester group being 7).

[192] In certain preferred embodiments, a 4-arm 20,000 Dalton PEG precursor is combined with an 8-arm 20,000 Dalton PEG precursor, such as a 4-arm 20,000 Dalton PEG precursor having a SAZ group (as defined above) combined with an 8-arm 20,000 Dalton PEG precursor having an amine group (as defined above). These precursors are also abbreviated herein as 4a20kPEG-SAZ and SaZOk’EG-NHj, respectively. The chemical structure of 4a20kPEG- SAZ1S: ^: wherein R represents a pentaerythritol core structure. The chemical structure of 8a20kPEG-NH2 (with a hexaglycerol core) is:

In the above formulae, n is determined by the molecular weight of the respective PEG-arm.

[193] In certain embodiments, the molar ratio of the nucleophilic and the electrophilic end groups reacting with each other is about 1:1, i.e., one amine group is provided per one SAZ group. In the case of 4a20kPEG-SAZ and : 8a20kPEG-NH? this results in a weight ratio of about 2:1, as the 8-arm PEG contains double the amount of end groups as the 4-arm PEG. However, an excess of either the electrophilic (e.g. the NHS end groups, such as the SAZ) end groups or of the nucleophilic (e.g. the amine) end groups may be used. In particular, an excess of the nucleophilic, such as the amine-end group containing precursor may be used, i.e., the weight ratio of 4a20kPEG-SAZ and 8a20kPEG-NH₂ may also be less than 2:1. [194] Each and any combination of electrophilic- and nucleophilic-group containing PEG precursors disclosed ^: herein may be used for preparing the implant according to the present invention, For example, any 4-arm or 8-arm PEG-NHS precursor (e.g. having a SAZ, SAP, SG or SS end group) may be combined with any 4-arm or 8-arm PEG- NHj precursor (or any other PEG precursor having a nucleophilic group). Furthermore, the PEG units of the electrophilic- and the nucleophilic group-containing precursors may have the same, or may have a different average molecular weight. [195] Another nucleophilic group-containing crosslinking agent may be used instead of a PEG-based crosslinking agent. For example, a low-molecular weight amine linker can be used, such as trilysine (or a trilysine salt or derivative, such as trilysine acetate) or other low-molecular weight multi-arm amines.

[196] In certain embodiments, the nucleophilic group-containing crosslinking agent may be bound to or conjugated with a visualization agent. A visualization agent is an agent that contains a fluorophoric or other visualization-enabling group. Fluorophores such as fluorescein, rhodamine, coumarin, and cyanine may for example be used as visualization agents. The visualization agent may be conjugated with the crosslinking agent e.g. through some of the nucleophilic groups of the crosslinking agent Since a sufficient amount of the nucleophilic groups are necessary for crosslinking, "conjugated" or "conjugation" in general includes partial conjugation, meaning that only a part of the nucleophilic groups are used for conjugation with the visualization agent, such as about 1% to about 20%, or about 5% to about 10%, or about 8% of the nucleophilic groups of the crosslinking agent may be conjugated with a visualization agent. In other embodiments, a visualization agent may also be conjugated with the polymer precursor, e.g. through certain reactive (such as electrophilic) groups of the polymer precursors.

Additional ingredients: _:

[197] The drug-delivery systems and implants of the present invention may contain, in addition to the polymer units forming the polymer network as disclosed above and the active principle, other additional ingredients. Such additional ingredients are for example salts originating from buffers used during the preparation of the hydrogel, such as phosphates, borates, bicarbonates, or other buffer agents such as triethanolamine. In certain embodiments of the present invention sodium phosphate buffers (specifically, mono- and dibasic sodium phosphate) are used.

[198] Optionally, preservatives may be used for the implants of the present invention. However, in certain embodiments, the implants of the present invention are free of preservatives, such as anti-microbial preservatives (including, but not limited to benzalkonium chloride (BAK), chlorobutanol, sodium perborate, and stabilized oxychloro complex (SOC)), or are substantially free of such preservatives.

[199] If an in situ gelation is preferred in an embodiment of the invention, possible additional ingredient may be other agents used during manufacture of the hydrogel, such as (without being limited to) viscosity-influencing agents (such as hyaluronic acid etc.), surfactants etc.

[200] In certain embodiments, the inserts of the present invention may contain a visualization agent. Visualization agents that may be used in the context of the invention are all agents that can be conjugated with the components of the hydrogel or can be entrapped within the hydrogel, and that are visible, or may be made visible when exposed e.g., to light of a certain wavelength, or that are contrast agents. Suitable visualization agents for use in the present invention are (but are not limited to) e.g. fluoresceins, rhodamines, coumarins, cyanines, europium chelate complexes, boron dipyromethenes, benzofrazans, dansyls, bimanes, acridines, triazapentalenes, pyrenes and derivatives thereof. A visualization agent may be conjugated with either the nucleophilic- or the electrophilic group- containing precursor of which the polymer network is formed, as disclosed above, or the visualization agent may be a separate (non-conjugated) agent that is added during the manufacture of the implant and that is present in the hydrogel;

Formulation:

[201] In certain embodiments, implants according to the present invention comprise an active agent prodrug, such as a hydrophobic prodrug, a polymer network made from one or more polymer precursors as disclosed herein above in the form of a hydrogel, and optional additional components such as salts etc. remaining in the implant from the production process (such as phosphate salts used as buffers etc.).

[202] In certain embodiments, the implants according to the present invention in their dry state may contain from about 15% to about 80%, such as from about 25% to about 75% by weight active agent prodrug and from about 15% to about 80%, such as from about 20% to about 60% by weight polymer units, or in particular embodiments from about 35% to about 65% by weight active agent prodrug and from about 25% to about 50% by weight polymer units (dry composition). In specific embodiments, the implants according to the present invention may contain from about 45% to about 55% by weight active agent prodrug and from about 37% to about 47% by weight polymer units (dry composition), with the active agent prodrug and the polymer units being selected from those disclosed herein above. In other specific embodiments, the implants according to the present invention in their dry state may contain from about 55% to about 75% by weight active agent prodrug and from about 20% to about 40% by weight polymer units (dry composition), with the active agent prodrug and the polymer units being selected from those disclosed herein above. In other specific embodiments, the implants according to the present invention in their dry state may contain from about 30% to about 45% by weight active agent prodrug and from about 47% to about 70% by weight polymer units (dry composition), with the active agent prodrug and the polymer units being selected from those disclosed herein above.

[203] In one particular embodiment, the implants according to the present invention in their dry state may contain from about 25% to about 75% by weight active agent prodrug and from about 20% to about 60% by weight PEG units, or from about 35% to about 65% by weight active agent prodrug and from about 25% to about 50% by weight PEG units, or from about 4S% to about 55% by weight active agent prodrug and from about 37% to about 47% by weight PEG units, or from about 48% to about 52% by weight active agent prodrug and from about 40% to about 44% by weight PEG units (dry composition), In other particular embodiments, the implants according to the present invention in their dry state may contain from about 55% to about 75% by weight active agent prodrug and from about 20% to about 40% by weight PEG units, or from about 60% to about 75% by weight prodrug and from about 21% to about 31% by weight PEG units (dry composition).

[204] In one further particular embodiment, on a dry weight basis the active agent prodrug to PEG ratio in an implant according to the invention may be approximately 50% by weight or more active agent prodrug to approximately 40% by weight or less PEG, the balance being phosphate salt. Alternatively, on a dry weight basis the active agent prodrug to PEG ratio in an implant according to the invention may be from about 1:1 to about 3:1. [205] In certain embodiments, the balance of the implant in its dried state (i.e., the remainder of the formulation when active agent prodrug, and polymer hydrogel, such as PEG hydrogel, have already been taken account of) may be salts remaining from buffer solutions as disclosed above. In certain embodiments, such salts are phosphate, borate or (bi) carbonate salts. In one embodiment the buffer salt is sodium phosphate (mono- and/or dibasic). [206] The amounts of the active agent prodrug and the polymer/ s) may be varied, and other amounts of the active agent prodrug and the polymer hydrogel may be used to prepare implants according to the invention.

[207] In certain embodiments, the maximum amount of drug within the formulation is about two times the amount of the polymer (e.g., PEG) units, but may be higher in certain cases, but it is desired that the mixture comprising, e.g., the precursors, buffers and drug (in the state before the hydrogel has gelled completely) can be uniformly cast into a mold or tubing. > /

[208] In one embodiment of the invention, the hydrogel after being formed and prior to being dried, i.e., in a wet state, may comprise about 3% to about 20% polyethylene glycol representing the polyethylene glycol weight divided by the fluid weight x 100. In one embodiment, the hydrogel in a wet state comprises about 5% to about 15%, such as about 7.5% to about 15%, or about 5% to about 10% polyethylene glycol representing the polyethylene glycol weight divided by the fluid weight x 100.

[209] In one embodiment of the invention, the wet hydrogel composition (i.e,, after the hydrogel composition has been formed, i.e., all components forming the hydrogel have been admixed) comprises from about 5% to about 50% by weight active agent prodrug, and from about 5% to about 50% or from about 5% to about 30% by weight PEG units. [210] In certain embodiments, a solids content of about 10% to about 50%, or of about 25% to about 50% (w/v)

(wherein "solids" means the combined weight of polymer precursor(s), salts and the drug in solution/suspension) may be utilized in the wet composition when forming the hydrogel for the implants according to the present invention. Thus, in certain embodiments, the total solids content of the wet hydrogel composition to be cast into a mold or tubing in order to shape the hydrogel may be no more than about 60%, or no more than about 50%, or no more than about 40%, such as equal to or lower than about 35% (w/v). The content of active agent prodrug may be no more than about 40%, or no more than about 30%, such as equal to or lower than about 25% (w/v) of the wet composition. The solids content may influence the viscosity and thus may also influence the castability of the wet hydrogel composition.

[211] In certain embodiments, the water content of the hydrogel implant in its dry (dehydrated/dned) state, e.g. prior to being loaded into a needle, or when loaded in a needle, may be very low, such as not more than 1% by weight of water. The water content may in certain embodiments also be lower than that, possibly not more than 0.25% by weight or even not more than 0.1% by weight. In the present invention the term "implant" is used to refer both to an implant in a hydrated state when it contains water (e.g. after the implant has been (re-)hydrated once administered to the eye or otherwise immersed into an aqueous environment) as well as to an implant in its dry (dried/dehydrated) state, e.g., when it has been dried to a low water content of e.g. not more than about 1% by weight or when the preparation results in such a low water content implant without the necessity of a drying step. In certain embodiments, an implant in its dry state is an implant that after production is kept under inert nitrogen atmosphere (containing less than 20 ppm of both oxygen and moisture) in a glove box for at least about 7 days prior to being loaded into a needle. The water content of an implant may be e.g. measured using a Karl Fischer coulometric method.

[212] In certain embodiments, the total weight (also referred to herein as "total mass") of an implant according to the present invention in its dry state may be from about 200 pg (i.e., 0.2 mg) to about 5000 mg (i.e., 5g), or from about 400 pg to about 2000 mg. In certain specific embodiments, the total weight of an implant according to the invention in its dry state may be from about 0.3 mg to about 600 mg, such as from about 0.4 mg to about 500 mg. In certain other specific embodiments, the total mass of an implant according to the invention in its dry state may be from about 0.75 mg to about 2000 mg, or from about 0.8 mg to about 1000 mg, or from about 0.9 mg to about 900 mg.

[213] In certain embodiments, an implant according to the present invention in its dry state may contain from about 200 pg to about 1000 pg active agent prodrug, per mm³ (i.e., per 1 mm³ volume of the dry implant). In certain specific embodiments, an implant according to the present invention in its dry state may contain from about 200 pg to about 300 pg active agent prodrug per mm³, e.g. in case the implant contains active agent prodrug in an amount of from about 160 pg to about 250 pg. In certain other specific embodiments, an implant according to the present invention in its dry state may contain from about 500 pg to about 800 pg active agent prodrug per mm³, e.g., in case the implant contains active agent prodrug in an amount of from about 480 pg to about 750 pg. [214] In certain embodiments, an implant according to the present invention in its dry state may contain from about 200 mg to about 1000 mg active agent prodrug, per mm³ (i.e., per 1 mm³ volume of the dry implant). In certain specific embodiments, an implant according to the present invention in its dry state may contain from about 200 mg to about 300 mg active agent prodrug per mm³, e.g., in case the implant contains active agent prodrug in an amount of from about 160 mg to about 250 mg. In certain other specific embodiments, an implant according to the present invention m its dry state may contain from about 500 mg to about 800 mg active agent prodrug per mm³, e.g., in case the implant contains active agent prodrug in an amount of from about 480 mg to about 750 mg.

[215] The disclosed amounts of active agent prodrug, such as the opioid or opioid prodrug, including the mentioned variances, refer to both the final content of the active principle in the implant, as well as to the amount of active principle used as a starting component per implant when manufacturing the implant. [216] In some embodiments, the total dose of the act ve agent prodrug to be administered to a patient, may be contained in two, three or more implants administered concurrently. For example, a dose of about 400 pg of prodrug may be administered in one implant containing about 400 pg prodrug, or in two implants e.g., each containing about 200 pg prodrug and so on. Of course, one may not only combine two or more identical implants (or implants containing the identical dose), but also two or more different implants (or implants containing different doses) in order to arrive at a desired total dose. In a particular embodiment, a total opioid prodrug of from about 480 pg to about 750 pg, or from about 540 pg to about 660 pg, or of about 600 pg, is contained in one implant and only one such implant is administered to a patient in need of such treatment in accordance with the invention. In another embodiment, a total dose of higher than about 600 pg, such as from about 800 pg to about 1250 pg, or from about 900 pg to about 1100 pg, or of about 1000 pg, or a total dose from about 960 pg to about 1500 pg, or from about 1080 pg to about 1320 pg, or of about 1200 pg, or a total dose from about 1440 pg to about 2250 pg, or from about

1620 pg to about 1980 pg, or of about 1800 pg is contained in one implant and only one such implant is administered to a patient in need of such treatment in accordance with the invention. In other embodiments, the total dose administered to a patient in accordance with the present invention may be contained in two or more implants (containing the same or different amounts of API) administered concurrently. [217] Amounts of active agent prodrug in the implant may be adapted by the skilled person as required for the specific drug or prodrug used, the maximum implant size suitable for a specific treatment location, and the type of treatment envisaged.

[218] The implants of the present invention may thus have different densities. The densities of the final implants (i.e., in their dry state) may be controlled and determined by various factors, including but not limited to the concentration of the ingredients in the wet composition when forming the hydrogel, and certain conditions during manufacturing of the implant. For example, the density of the final implant in certain embodiments can be increased by means of sonication or degassing, e.g. using vacuum, at certain points during the manufacturing process.

[219] In certain embodiments, implants according to the invention contain a therapeutically effective amount of active agent prodrug for release over an extended period of time, but are nevertheless relatively small in length and/or diameter. This is advantageous both in terms of ease of administration (injection) as well as in terms of reducing possible damage to ocular tissue and reducing a possible impact of the patient's vision while the implant is in place. In certain embodiments, the implants of the present invention combine the benefits of a suitably high dose of the active agent prodrug (i.e., a therapeutically effective dose adjusted to a particular patient's need) with a relatively small implant size. Dimensions of the implant and dimensional change upon hydration through stretching:

[220] If not formulated for in situ implant formation, the dried implant may have different geometries, depending on the method of manufacture, such as the use of mold or tubing into which the mixture comprising the hydrogel precursors including the active agent prodrug is cast prior to complete gelling. The implant according to the present invention may include a "fiber" (which term is used interchangeably herein with the term "rod"), wherein the fiber is an object that has in general an elongated shape. The implant (or the fiber) may have different geometries, with specific dimensions as disclosed herein.

[221] In one embodiment, the implant is cylindrical or has an essentially cylindrical shape. In this case, the implant has a round or an essentially round cross-section. [222] In other embodiments of the invention, the implant is non-cylindrical, wherein the implant is optionally elongated in its dry state, wherein the length of the implant is greater than the width of the implant, wherein the width is the largest cross sectional dimension that is substantially perpendicular to the length. In certain embodiments, the width may be about 0.1 mm to about 3.5 mm, or 1 mm to 10 mm. Various geometries of the outer implant shape or its cross-section may be used in the present invention. For example, instead of a round diameter fiber or rod (i.e. , a cylindrical implant), a cross-shaped fiber (i.e., wherein the cross-sectional geometry is cross-like) may be used. Other cross-sectional geometries, such as oval or oblong, rectangular, triangular, starshaped etc. may generally be used. In certain embodiments, the fiber may also be twisted. In embodiments where the implant is administered to tiny location sites such as, e.g., the eye by means of a needle, the dimensions of the implant (i.e., its length and diameter) and its cross-sectional geometry must be such as to enable loading the implant into the needle, particularly a fine-diameter needle such as a 25-gauge or 27-gauge needle as further disclosed herein.

[223] The polymer network, such as the PEG network, of the hydrogel implant according to certain embodiments of the present invention may be semi-crystalline in the dry state at or below room temperature, and amorphous in the wet state. Even in the stretched form, the dry implant may be dimensionally stable at or below room temperature, which may be advantageous for loading the implant into the needle and for quality control.

[224] Upon hydration of the implant in the eye (which can be simulated by immersing the implant into PBS, pH 7.2 at 37 °C) the dimensions of the implant according to the invention may change: generally, the diameter of the implant may increase, while its length may decrease or at least may stay essentially the same. An advantage of this dimensional change is that, while the implant in its dry state is sufficiently thin to be loaded into a fine diameter needle (such as a 25-, or 27-, or in some cases even a smaller diameter needle, such as a 30-gauge needle) to be injected into the eye, once it has been placed in eye, e.g , in the vitreous humor, the implant may become shorter to beter fit within the limited, small volume of the eye. The needles used for injection of the implants of the present invention as disclosed herein, such as the 25- or 27-gauge needles in certain embodiments, are small in diameter (and e.g. may have an inner diameter of about 0.4 mm). As the implant also may become softer upon hydration, injuries of any ocular tissue can be prevented or minimized even when the implant comes into contact with such tissue. In certain embodiments, the dimensional change is enabled at least in part by the "shape memory" effect introduced into the implant by means of stretching the implant in the longitudinal direction during its manufacture (as also disclosed below in the section "Method of manufacture"). In certain embodiments, the stretching may either be performed in the dry or in the wet state, i.e., after drying the hydrogel implant, or before drying. It is noted that if no stretching is performed, and the hydrogel implant is only dried and cut into a desired length, the implant may increase in both diameter and length upon hydration. If this is not desired, the hydrogel fiber may be dry or wet stretched.

[225] In pre-formed dried hydrogels, a degree of molecular orientation may be imparted by dry-stretching the material then allowing it to solidify, locking in the molecular orientation. This can be accomplished in certain embodiments by drawing the material (optionally while heating the material to a temperature above the melting point of the crystallizable regions of the material), then allowing the crystallizable regions to crystallize. Alternatively, in certain embodiments the glass transition temperature of the dried hydrogel can be used to lock in the molecular orientation for polymers such as PVA that have a suitable glass transition temperature. Still another alternative is to stretch the get prior to complete drying (also referred to as "wet stretching") and then drying the material white under tension. The molecular orientation provides one mechanism for anisotropic swelling upon introduction into a hydrating medium such as the vitreous. Upon hydration the implant of certain embodiments will swell only in the radial dimension, while the length will either decrease or be essentially maintained. The term "anisotropic swelling" means swelling preferentially in one direction as opposed to another, as in a cylinder that swells predominantly in diameter, but does not appreciably expand (or does ever contract) in the longitudinal dimension.

[226] The degree of dimensional change upon hydration may depend inter alia on the stretch factor. As an example, stretching at e.g. a stretch factor of about 1.3 (e.g. by means of wet stretching) may have a less pronounced effect or may not change the length during hydration to a large extent. In contrast, stretching at e.g. a stretch factor of about 1.8 (e.g. by means of wet stretching) may result in a markedly shorter length during hydration. Stretching at e.g. a stretch factor of 4 (e.g. by means of dry stretching) could result in a much shorter length upon hydration (such as, for example, a reduction in length from 15 to 8 mm). One skilled in the art will appreciate that other factors besides stretching can also affect swelling behavior.

[227] Among other factors influencing the possibility to stretch the hydrogel and to elicit dimensional change of the implant upon hydration is the composition of the polymer network. In the case PEG precursors are used, those with a lower number of arms (such as 4-armed PEG precursors) contribute to providing a higher flexibility in the hydrogel than those with a higher number of arms (such as 8-armed PEG precursors). If a hydrogel contains more of the less flexible components (e.g. a higher amount of PEG precursors containing a larger number of arms, such as the 8-armed PEG units), the hydrogel may be firmer and less easy to stretch without fracturing. On the other hand, a hydrogel containing more flexible components (such as PEG precursors containing a tower number of arms, such as 4-armed PEG units) may be easier to stretch and softer, but also swells more upon hydration. Thus, the behavior and properties of the implant once it has been placed into the eye (i.e., once the hydrogel becomes (re-)hydrated) can be tailored by means of varying structural features as well as by modifying the processing of the implant after it has been initially formed.

[228] Implants of the invention may however also have dimensions (i.e., lengths and/or diameters) differing from the dimensions disclosed herein. The dried implant dimensions inter alia depend on the amount of active agent prodrug incorporated as well as the ratio of active agent prodrug to polymer units and can also be controlled by the diameter and shape of the mold or tubing in which the hydrogel is allowed to gel. Furthermore, the diameter of the implant is further determined inter alia by (wet or dry) stretching of the hydrogel strand once formed. The dried strand (after stretching) is cut into segments of the desired length to form the implant; the length can thus be chosen as desired.

[229] In the following, embodiments of implants with specific dimensions are disclosed. Whenever the dimensional ranges or values disclosed herein relate to the length and the diameter of an implant, the implant is cylindrical or essentially cylindrical. However, all values and ranges disclosed herein for lengths and diameters of cylindrical implants may equally be used for lengths and widths, respectively, of non-cylindrical implants as also disclosed herein.

[230] In certain embodiments, an implant of the present invention may have in its dry state a length of less than about 17 mm. In specific embodiments, the length of an implant in its dry states may be less than about 15 mm, or less than or equal to about 12 mm, or less than or equal to about 10 mm, or less than or equal to about 8.5 mm. In specific embodiments, an implant of the present invention may have in its dry state a length of about 12 to about 17 mm, or may have in its dry state a length of about 6 mm to about 10 mm or specifically of about 6 mm to about 9 mm.

R31] In certain embodiments, an implant of the present invention may have in its dry state a diameter of about 0.1 mm to about 0.5 mm. In certain other embodiments, an implant in its dry state may have a diameter of about

0.2 mm to about 0.5 mm. In specific embodiments, an implant in its dry state may have a diameter of about 0.2 mm to about 0.4 mm, or of about 0.3 mm to about 0.4 mm. In specific embodiments, ah implant of tfie present invention may have a diameter in the dry state of about 0.2 mm to about 0.3 mm, or of about 0.3 mm to about 0.4 mm.

[232] In particular embodiments, an implant in its dry state may have a length of about 6 mm to about 10 mm and a diameter of about 0.2 to about 0.4 mm.

[233] In certain embodiments, an implant of the present invention may have in its wet/hydrated state a length of about 6 mm to about 12 mm. In certain other embodiments, an implant of the present invention may have in its ; wet/hydrated state a length of equal to or less than about 10 mm, or of about 6 mm to about 10 mm. In specific embodiments, an implant of the present invention in its wet/hydrated state may have a length of about 6 mm to about 8 mm.

[234] In certain embodiments, an implant of the present invention may have in its wet/hydrated state a diameter of equal to or less than about 0.8 mm, or of about 0.5 mm to about 0.8 mm, or of about 0.65 mm to about 0.8 mm. In specific embodiments, an implant of the present invention may have a diameter in its wet/hydrated state of about 0.7 mm to about 0.8 mm. [23S] In particular embodiments, an implant in its wet/hydrated state may have a length of equal to or less than about 10 mm and a diameter of equal to or less than about 0.8 mm.

[236] In embodiments of the present invention, the diameter of an implant in its dry state must be such that the implant can be loaded into a thin-diameter needle as disclosed herein, such as a 25-gauge or 27-gauge needle.

Specifically, in one embodiment an implant may have a diameter such that it can be loaded into a 25-gauge needle, or that it can be loaded into a 27-gauge needle without afflicting any damage to the implant while loading, and such that the implant remains stably in the needle during further handling (including packaging, sterilization, shipping etc.). [237] Whenever herein a length or a diameter of an inplant of the invention in the wet/hydrated state is disclosed (in mm), this disclosure refers to the implant's length or the diameter, respectively, determined after 24 hours at 37 °C at pH 7.2. It is understood that in this context a pH of 7.2 comprises a pH range of about 7.2 to about 7.4.

[238] The dimensions of an implant may further change (e.g. the length may increase slightly again) over the course of time ( i.e. , after 24 hours) when the implant remains in these conditions. However, whenever hydrated dimensions of an implant are reported herein, these are measured after 24 hours at a pH of 7.2 at 37 °C in PBS as disclosed above.

[239] In case several measurements of the length or diameter of one implant are conducted, or several datapoints are collected during the measurement, the average (i.e., mean) value is reported as defined herein. The length and diameter of an implant according to the invention may be measured e.g., by means of microscopy, or by means of an (optionally automated) camera system.

[240] In certain embodiments, an implant of the present invention may have a ratio of the diameter in the hydrated state to the diameter in the dry state of less than about 5 mm, or less than about 4 mm, or less than about 3.25 mm, or less than about 2.5 mm, or less than about 2.25 mm, or less than about 2.10 mm.

[241] In certain same or other emtxxiiments, an implant of the present invention may have a ratio of the length in the dry state to the length in the hydrated state of greater than about 0.7, or greater than about 0.8, or greater than about 0,9, or greater than about 1.0. In certain specific embodiments, the ratio of the length of an implant in the dry state to the length of the implant in the hydrated state may be greater than about 1.5, or even greater than about 2.0. This ratio of length in the dry state to length in the hydrated state may apply in addition to, or independently of, the ratio of the diameter in the hydrated state to the diameter in the dry state disclosed above.

[242] In certain embodiments, a small diameter in the dry state may be advantageous as the implant may fit into a small diameter needle for injection as disclosed herein, such as a 25-gauge or a 27-gauge needle. Also, only moderate swelling upon hydration may be advantageous for the implant to not occupy too much space in the vitreous humor. A relatively shorter length of the implant may be advantageous in reducing the potential likelihood for contact with the retina, if used in the eye.

[243] In one embodiment, an implant of the present invention contains from about 160 pg to about 250 pg, or from about 180 pg to about 220 pg, or about 200 pg active agent prodrug, is in the form of a fiber (or cylinder) and has a length of about 14.5 mm to about 17 mm, or of about 15 mm to about 16.5 mm and a diameter of about 0.20 mm to about 0.30 mm in the dried state. Such an implant may decrease in length and increase in diameter upon hydration in vivo in the eye, such as in the vitreous humor, or in vitro (wherein hydration in vitro is measured in phosphate-buffered saline at a pH of 7.2 at 37 °C after 24 hours) to a length of about 6.5 mm to about 8 mm or of about 7 mm to about 8.5 mm, and a diameter of about 0.65 mm to about 0,8 mm, or of about 0.70 to about 0.80 mm. In one embodiment, this dimensional change may be achieved by dry stretching as disclosed herein at a stretch factor of about 2 to about 5, or a stretch factor of about 3 to about 4.5. [244] In another embodiment, an implant of the present invention contains from about 480 pg to about 750 pg, or from about 540 pg to about 660 pg, or about 600 pg of active agent prodrug, is in the form of a fiber (cylinder) and in its dried state may have a length of in the range of from about 6 mm or about 7 mm to about 12 mm and a diameter of about 0.25 mm to about 0.50 mm, or a length of about 7 mm to about 10 mm, or of about 8 mm to about 11 mm, and a diameter of about 0.3 mm to about 0.4 mm. In specific embodiments, an implant of the present invention that contains from about 480 pg to about 750 pg, or from about 540 pg to about 660 pg, or about 600 pg of prodrug, is in the form of a fiber (cylinder) and in its dried state may have a length of from about 7 mm to about 10 mm, such as from about 7 mm to about 9 mm, and a diameter of from about 0.3 mm to about 0,4 mm, such as from about 0.35 mm to about 0.39 mm.

[245] Such an implant may increase in diameter upon hydration in vivo in the eye, such as in the vitreous humor, or in vitro (wherein hydration in vitro is measured in phosphate- buffered saline at a pH of 7.2 at 37 °C after 24 hours) while its length may be essentially maintained or may be reduced, or only slightly increased to a length of e.g. in the range of from about 6 mm or about 9 mm to about 12 mm and a diameter of about 0.5 mm to about 0.8 mm, or a length of about 9.5 mm to about 11.5 mm and a diameter of from about 0.65 mm to about 0.75 mm or about 0.8 mm in its hydrated state. In specific embodiments, an implant of the present invention that contains from about 480 pg to about 750 pg, or from about 540 pg to about 660 pg, or about 600 pg of active agent prodrug and is in the form of a fiber (cylinder) in its hydrated state (i.e., at a pH of 7.2 at 37 °C after 24 hours as explained above) may have a length of from about 6 mm to about 10.5 mm, such as from about 6.5 mm to about 8.5 mm, and a diameter from about 0.7 mm to about 0.8 mm.

[246] In one embodiment, the length of an implant of the present invention that contains from about 480 pg to about 750 pg, or from about 540 pg to about 660 pg, or about 600 pg of active agent prodrug in the dried state is no longer than 10 mm, and in the hydrated state (as measured in phosphate- buffered saline at a pH of 7.2 at 37 °C after 24 hours) is also no longer or not substantially longer than about 10 mm, or no longer than about 9 mm, or no longer than about 8 mm.

[247] In one or more embodiment(s), tfie above-ctesaibed dimensional change can be achieved by wet stretching at a stretch factor of about 0.5 to about 5, or a stretch factor of about 1 to about 4, or a stretch factor of about 1.3 to about 3.5, or a stretch factor of about 1.7 to about 3, or a stretch factor of about 2 to about 2.5. In other embodiments the implant of the present invention containing from about 480 pg to about 750 pg, or from about 540 pg to about 660 pg, or about 600 pg of active agent prodrug may be longer than about 12 mm in the dry state, but may end up being shorter than about 10 mm or about 9 mm in the hydrated state.

[248] In certain embodiments, the stretching thus creates a shape memory, meaning that the implant upon hydration when administered into the eye, e.g., into the vitreous cavity, will shrink in length and widen in diameter until it approaches (more or less) its equilibrium dimensions, which are determined by the original molded dimensions and compositional variables. While the narrow dry dimensions facilitate administration of the product through a small gauge needle, the widened diameter anc shortened length after administration yield a shorter implant (such as about 9 to 10 mm long, or at least not much longer than that) in the posterior chamber of the eye relative to the eye diameter minimizing potential contact with surrounding eye tissues. Thus, in one aspect the present invention also relates to a method of imparting snape memory to a hydrogel fiber comprising an active agent prodrug dispersed in the hydrogel by stretching the hydrogel fiber in the longitudinal direction. In another aspect the present invention relates to a method of manufacturing an implant comprising a hydrogel comprising an active agent prodrug dispersed therein, wherein the implant changes its dimensions upon administration to the eye, the method comprising preparing a fiber of the hydrogel and stretching the fiber in the longitudinal direction.

In vitro release:

[249] The in vitro-release of active agent prodrug from the implants of the invention can be determined by various methods. Briefly, one method to determine the in vitro release of the active agent prodrug from the implant is under (phosphate-buffered saline, pH 7.2) at 37 °C, with daily replacement of PBS in a suitable volume comparable to the volume at the implantation site.

[250] In certain embodiments of the invention, an implant according to the invention may release on average about 0.1 pg to about 3 pg, or about 0.25 pg to about 2.5 pg, or about 0.1 pg to about 2 pg, or may release about 0.25 pg to about 1.5 pg per day in vitro in PBS at pH 7.2 and 37 °C for a period of 30 days. [251] In other embodiments of the invention, an implant according to the invention may release on average about

0.1 mg to about 3 mg, or about 0.25 mg to about 2.5 mg, or about 0.1 mg to about 2 mg, or may release about 0.25 mg to about 1.5 mg per day in vitro In PBS at pH 7.2 anc 37 °C for a period of 30 days.

[252] In one embodiment, an implant according to the invention containing about 200 pg active agent prodrug, may release on average in vitro about 0.01 pg to about C.15 pg of active agent prodrug per day in phosphate- buffered saline at pH 7.2 and 37 °C for a period of 30 da/s.

[253] In one embodiment, an implant according to the invention containing about 600 pg active agent prodrug may release on average in vitro about 0.3 pg to about 0.5 pg of active agent prodrug per day in phosphate-buffered saline at pH 7.2 and 37 °C for a period of 30 days.

[254] In one embodiment, an implant according to the invention containing about 200 mg active agent prodrug, may release on average in vitro about 0.01 mg to about 0.15 mg of active agent prodrug per day in phosphate- buffered saline at pH 7.2 and 37 °C for a period of 30 days.

[255] In one embodiment, an implant according to the invention containing about 600 mg active agent prodrug may release on average in vitro about 0.3 mg to about 0.5 mg of active agent prodrug per day in phosphate-buffered saline at pH 7.2 and 37 °C for a period of 30 days. [256] In an accmM<in^itro^st, the release of the active agent prodrug from the implant can be determined in a 25:75 ethanol/water mixture (v/v) at 37 °C. This accelerated in vitro test can be completed in about 2 weeks. [257] In one embodiment, an implant according to the invention containing about 200 pg active agent prodrug releases in vitro about 35 % to about 45 % of the active agent prodrug in 3 days, about 65 % to about 75 % of the active agent prodrug in 7 days, and about 90 % to about 100 % of the active agent prodrug in 12 to 13 days in a 25:75 ethanol/water mixture (v/v) at 37 °C.

[258] In one embodiment, an implant according to the invention containing about 600 pg active agent prodrug releases in vitro about 40 % to about 60 % of the active agent prodrug in 2 days, about 65 % to about 85 % of the active agent prodrug in 4 days, and about 75 % to about 90 % of the active agent prodrug in 6 days in a 25:75 ethanol/water mixture (v/v) at 37 °C. An implant according to the invention containing about 600 pg active agent prodrug may also release in vitro about 45 % to about 55 % of the active agent prodrug in 2 days, about 70 % to about 80 % of the active agent prodrug in 4 days, and about 80 % to about 90 % of the active agent prodrug in 6 days in a 25:75 ethanol/water mixture (v/v) at 37 °C.

[259] In another embodiment, an implant according to the invention containing about 200 mg active agent prodrug releases in vitro about 35 % to about 45 % of the active agent prodrug in 3 days, about 65 % to about 75 % of the active agent prodrug in 7 days, and about 90 % to about 100 % of the active agent prodrug in 12 to 13 days in a 25:75 ethanol/water mixture (v/v) at 37 °C.

[260] In still another embodiment, an implant according to the invention containing about 600 mg active agent prodrug releases in vitro about 40 % to about 60 % of the active agent prodrug in 2 days, about 65 % to about 85 % of the active agent prodrug in 4 days, and about 75 % to about 90 % of the active agent prodrug in 6 days in a 25:75 ethanol/water mixture (v/v) at 37 °C. An implant according to the invention containing about 600 mg active agent prodrug may also release in vitro about 45 % to about 55 % of the active agent prodrug in 2 days, about 70 % to about 80 % of the active agent prodrug in 4 days, and about 80 % to about 90 % of the active agent prodrug in 6 days in a 25:75 ethanol/water mixture (v/v) at 37 °C.

[261] Finally, the release of active agent prodrug from implants of the present invention can also be determined under For this real-time test, release of the active agent prodrug is determined in PBS (pH 7.2)/0.01% NaF at 37 °C with an octanol top layer on the PBS. This is one method to qualitatively simulate release of the active agent prodrug from the implant into the vitreous humor and from there resorption of the active agent prodrug Into ocular tissue.

[262] In one embodiment, an implant according to the invention containing about 200 pg active agent prodrug releases in vitro about 25 % to about 35 % of the active agent prodrug in 2 months, about 47 % to about 57 % of the active agent prodrug in 3 months, about 70 % to about 80 % of the active agent prodrug in 5 months, and about 90 % to about 100 % of the active agent prodrug in 7 months in phosphate buffered saline at a pH of 7.2, at 37 °C and with an octanol top layer.

[263] In another embodiment, an implant according to the invention containing about 200 mg active agent prodrug releases in vitro about 25 % to about 35 % of the active agent prodrug in 2 months, about 47 % to about 57 % of the active agent prodrug in 3 months, about 70 % to about 80 % of the active agent prodrug in 5 months, and about 90 % to about 100 % of the active agent prodrug in 7 months in phosphate buffered saline at a pH of 7.2, at 37 °C and with an octanol top layer.

[264] The in vitro release tests, especially the accelerated in vitro release test described herein, may be used inter alia to compare different implants (e.g., of different production batches, of different composition, and of different dosage strength etc.) with each other, for example for the purpose of quality control or other qualitative assessments. The release rates disclosed herein can also be obtained with different amounts of active

In vivo release and persistence:

[265] For short term treatments, the implant of embodiments of the invention comprising hydrophobic opioid prodrugs provides fast-acting pain relief for extended periods of time, such as 5 days to 2 months, or 5 days to 1 month, or 5 days to 3 weeks, such as 5 or 6 days to 2 weeks, with an efficacy profile similar to the parent API.

[266] In an embodiment, the hydrogel implant biodeg -ades in a time period that is longer than the drug elution time and less than 1 month, ft can be administered by one-time post-surgical implantation, e.g., by a physician, and its dosing can be varied, proportional to patient size and tolerance. Furthermore, the implants may be stored at room temperature (25°C) or in a refrigerator for more than 1 year.

[267] In certain embodiments for medium to long term treatments, the sustained release biodegradable implant biodegrades in the human or animal body within about 2 weeks and up to about IS months, such as 3 or 4 weeks, to about 15 months, or 1 to about 15 months or 2 to 14 months after administration; or the implant biodegrades in the human or animal body within about 4 to about 13 months after administration, such as within about 9 to about 12 months after administration.

[268] In the embodiments of the invention, the implant after administration to the human or animal body releases a therapeutically effective amount of hydrophobic opioid or opioid prodrug over a period of at least about 5 days, such as 6 days, or 7 days, or 5 days to 2 months, or 5 days to 1 month, or 5 days to 3 weeks, such as 5 or 6 days to 2 weeks, or for at least about 1 month, at least about 2 months, at least about 3 months, at least about 6 months, at least about 9 months, at least about 10 months, at least about 11 months, or at least about 12 months after administration, for example, the implant after administration to the human or animal body releases a therapeutically effective amount of hydrophobic prodrug over a period o' at least 1 week, or 2 weeks, or 3 weeks, or 1 month, or 6 months, or the implant after administration to the human or animal body releases a therapeutically effective amount of hydrophobic opioid or opioid prodrug over a period of at least 1 week to 9 months.

[269] In some embodiments, the implants disclosed herein are suitable for subcutaneous delivery, or delivery in surgically created space or injury, or ocular delivery to a route selected from, e.g., punctal, intravitreal, subconjunctival, mtrascleral, subretinal, suprachoroidal, periocular, peribulbar, retrobulbar, intracorneal, posterior sub-tenon's delivery, anterior sub-tenon's delivery, cul-de-sac delivery, or fornix delivery. The administration can be, e.g., by injection with a needle or insertion with a delivery device into the selected ocular delivery route. [270] The needle can be a gauge selected from, e.g., 18 gauge, 19 gauge, 20 gauge, 21 gauge, 22 gauge, 23 gauge, 24 gauge, 25 gauge, 26 gauge, T7 gauge, 28 gauge, 29 gauge, 30 gauge, 31 gauge, 32 gauge or 33 gauge.

[271] In certain embodiments, the administration can be with a modified device as described in U.S. Patent No. 8,808,225; U.S. Patent No. 10,722,396; U.S. Patent No. 10,390,901; U.S. Patent no. 10,188,550; U.S. Patent No. 9,956,114; U.S. Patent No. 9,931,330; U.S. Patent Application Publication No. 2019/0290485; U.S. Patent Application

Publication No. 2019/0000669; and U.S. Patent Application Publication No. 2018/0042767.

[272] In alternative embodiments, the administration can optionally be performed without a needle, e.g., manually or with the aid of forceps, applicator or other delivery aid.

[273] In an embodiment of the present invention, when the dried implant of the present invention is administered to an implantation site, e.g., the eye, such as the vitreous humor, it becomes hydrated and changes its dimensions as disclosed above, and is then over time biodegraded until it has been fully resorbed. When the implant is biodegraded, such as through ester hydrolysis, it gradually may swell and soften, then become smaller, softer and more liquid until it is fully dissolved and no longer visible. As recognized by the inventors from animal studies, an implant according to the invention may persist about 2 to about 6 months, or about 5 to about 6 months in rabbit eyes. If in certain embodiments two or more implants are administered to achieve a desired total dose, they are equally biodegraded over time.

[274] In the human eye, such as In the vitreous humor, the implant of the invention in certain embodiments biodegrades within about 2 to about 15 months after administration, or within about 4 to about 13 months after administration, or within about 9 to about 12 months after administration, specifically within about 9 to about 10.5 months after administration,

[275] In one embodiment, the implant after administration to an implantation site, such as e.g., the vitreous humor, releases (as defined herein) the active agent prodrug, such as a therapeutically effective amount of prodrug, over a period of at least about 3 months, at least about 6 months, at least about 9 months, at least about 10 months, at least about 11 months, or at least about 12 months, or at least about 13 months or longer after administration. In particular embodiments, the implant releases the active agent prodrug, for a period of about 6 to about 9 months.

[276] In one embodiment of the invention, the implant provides for a treatment period of at least about 3 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 12 months, or at least about 13 months or longer after administration of the (i.e., a single) implant. In one embodiment, the implant comprises a hydrogel and dexamethasone isonicotinate, or another ester of dexamethasone as disclosed herein, dispersed within the hydrogel. With its low solubility of about 0.5 pg/mL in PBS, such a hydrogel implant can release the dexamethasone over extended periods of time, such as at least about 6 months, at least about 9 months, or for at least about 12 months. [277] In one embodiment of the invention, active agent prodrug is released from the implant at an average rate of about 0.1 pg/day to about 10 pg/day, or about 0.5 pg/day to about 7 pg/day, or about 0.5 pg/day to about 2 pg/day, or about 1 pg/day to about 5 pg/day in e.g., the vitreous humor, over a time period of at least 3, or at least 6, or at least 9, or at least 11, or at least 12, or at least 13 days or months. In particular embodiments the release of active agent prodrug is maintained for about 6 to about 9 days or months after administration of the implant.

[278] In one embodiment of the invention, active agent prodrug is released from the implant at an average rate of about 0.1 mg/day to about 10 mg/day, or about 0.5 mg/day to about 7 mg/day, or about 0.5 mg/day to about 2 mg/day, or about 1 mg/day to about 5 mg/day in e.g., the vitreous humor, over a time period of at least 3, or at least 6, or at least 9, or at least 11, or at least 12, or at least 13 days, or months. In particular embodiments the release of active agent prodrug is maintained for about 6 to about 9 days or months after administration of the implant.

[279] Pre-clintoal studies in animals as well as clinical studies in humans with hydrogel implants comprising different active agent prodrugs, have shown that the implants of the invention may continuously release therapeutically effective amounts of active agent prodrug over an extended period of time, until the implants are fully biodegraded. In certain embodiments, the entire amount of active agent prodrug contained in the implant is released from the implant prior to complete biodegradation of the implant. No undissolved active agent prodrug particles would remain (and/or agglomerate) near the site of the former implant or elsewhere after complete biodegradation of the implant. ^:

[280] In one embodiment, the persistence of the hydrogel within an aqueous environment and in the human or animal body depends inter alia on the hydrophobicity of the carbon chain in proximity to the degradable ester group.

In the implants used herein, this carbon chain may comprise 7 carbon atoms as it stems from the SAZ functional group of the 4a20k PEG precursor. This may provide an extended persistence in the body of up to about 9 to about 12 months, or from about 9 to about 10.5 months. In other embodiments, different precursors than the 4a20kPEG- SAZ and the 8a20kPEG-NH> may be used to prepare hydrogel implants that biodegrade in the body and have similar or different persistence, for example for degradation within several weeks up to 1 or 2 months.

[281] In certain embodiments, the hydrogel implant softens over time as it degrades, which may depend inter alia on the structure of the linker that crosslinks the PEG units in the hydrogel. An implant as used in the example of the present application formed from a 4a20kPEG-SAZ and an 8a20kPEG-NHz softens rather slowly over time.

Mechanism : of release i [282] Without wishing to be bound by theory, the mechanism of release of the active agent prodrug from an implant of the invention may be explained as follows: In embodiments of the invention, release of the active agent prodrug into the human or animal body is dictated by diffusion and drug solubility, as enzymes being large molecule proteins are normally not able to penetrate into the hydrogel. An exemplary active agent prodrug according to the present invention is a hydrophobic prodrug. The solubility of the prodrug can be selected to be very tow in physiological medium (less than 100 pg/ml, less than 50 pg/mL, or less than 10 pg/mL, or less than 1 pg/mL, such as about 0.4 to about 0.5 pg/ml in PBS at pH 7.4). In embodiments of the present invention, the active agent prodrug is confined in a biodegradable hydrogel having a particular geometry and surface. Hydrogels release small molecule drugs mainly via two different mechanisms, the degradation rate of the hydrogel matrix in vivo, and diffusion of the prodrug, that is highly controlled by the prodrug solubility in the water within the hydrogel, Therefore, specifically for hydrophilic drugs, the use of a hydrophobic prodrug allows for an additional release control mechanism. The current invention uses a hydrogel matrix, but controls drug solubility itself so the drug can only be released from the hydrogel matrix at a desired rate. This Is achieved by chemical modification of the active agent to form a prodrug. This is a fundamentally different purpose than prodrugs have been designed for until now.

[283] In embodiments of the present invention, the drug-delivery system or implant comprises a hydrogel made of a polymer network and a drug dispersed within the hydrogel. The drug gradually gets dissolved in fluid penetrating into the hydrogel matrix and diffuses out of the hydrogel into the body. This may happen first at the outer region of the hydrogel (i.e., the drug particles that are located in the outermost region of the hydrogel get dissolved and diffuse out first, the innermost last) that is in contact with the liquid environment of the body. Thereby, in certain embodiments, the outer region of the hydrogel becomes devoid of drug particles. This region is therefore also called the "clearance zone", which is limited to disso ved drug only, with a concentration at or below the solubility of the drug. In certain embodiments, this low surface concentration may protect tissue (such as retinal or other cells) from potential drug toxicity by physically separating drug particles from the tissue should the implant get in contact with such tissue. In other embodiments, upon hydration the "clearance zone" is an outer region that has a concentration of active agent prodrug that is less than the active agent prodrug in an inner region of the hydrated hydrogel.

[284] In embodiments with clearance zones, because drug has dissolved and has diffused out of the clearance zone, this area of the hydrogel develops voids and becomes softer and weaker. Concurrently with the drug diffusing out of the hydrogel, the hydrogel may also be slowly degraded by means of, e.g., ester hydrolysis in the aqueous environment of the eye. This degradation occurs uniformly throughout the bulk of the hydrogel. At advanced stages of degradation, distortion and erosion of the hydrogel begins to occur. As this happens, the hydrogel becomes softer and more liquid (and thus its shape becomes distorted) until the hydrogel finally dissolves and is resorbed completely. This process is schematically shown on Fig. 4.

[285] In one embodiment, the entire amount of active agent prodrug is released prior to the complete degradation of the hydrogel. As the hydrogel may hold the active agent prodrug particles in place and prevent them from agglomeration, the release of active agent prodrug from the hydrogel can be faster as long as the hydrogel has not yet fully degraded. When the hydrogel has fully degraded, remaining prodrug particles are slowly dissolved, but without diffusion control by the hydrogel. Therefore, complete release of the active agent prodrug prior to full degradation of the hydrogel can be desired in embodiments of the invention.

[286] In embodiments of the invention, the hydrophobic prodrug can be selected from an ester or amide derivative of an active principle, or from any other derivative of an active principle having at least one hydrolyzable bond. The ester and/or amide derivative or other hydrolyzable derivative of the active principle is formed by reacting hydrophilic groups on the active principle, such as hydroxyl, thiol, carboxyl or amine groups, with at least one of an organic add, alcohol, thiol, or amine to form hydrophobic moieties on the active principle, resulting in a reduced water solubility of the prodrug over the unmodified active principle . In embodiments of the present invention, the hydrophobic prodrug, i.e., derivative of the active principle, can be hydrolyzed, with or without enzymatic action, in vivo to form or release the active principle or active metabolite. This allows to further control, e.g. stow down, the release and/or bioavailability over time of the hydrophobic prodrug or active agent from the hydrogel matrix by an additional mechanism. Release of the prodrugs versus the unmodified drug is governed not only by diffusion processes, but also by prodrug solubility as described herein. Furthermore, different types of hydrophobic derivatization of the active agent, for example, by forming esters with long or short chain aliphatic hydrocarbons can be used to further control the active agent release after the prodrug has diffused out of the hydrogel, due to different hydrolysis rates of different ester or amide derivatives. As an example, longer alkyl chain esters may have lower hydrolysis rates than shorter chain alkyl esters or amides, and aromatic carboxylic acid ester derivatives often have less solubility in water than alkyl ester derivatives.

[287] This prodrug solubility influence on release rate may be combined with release modifying mechanisms due to hydrogel degradation and/or development of clearance zones as described above, and/ or hydrolysis rates of the prodrug to form the active metabolite.

[288] The use of hydrophobic hydrolyzable prodrugs as described herein offers essentially two mechanisms of release control: via reduced aqueous solubility of the prodrug versus the active principle itself, allowing to control diffusion rates from the hydrogel matrix to the surrounding tissue, and controlling hydrolysis rates of the prodrug itself as s second factor influencing the release kinetics o^f the active principle.

[289] As shown in Examples 6 to 8, exemplary prostaglandin prodrugs such as Travoprost triacetate, Tafluprost ^: diacetate and latanoprost triacetate require two different enzymes to completely release the free acid active metabolites, and exemplary derivatization with acetate esters shows both solubility reduction and slowing down of the release of free acid by additionally required hydrolysis steps in vivo. This offers a further control of active agent release rate, that in embodiments of the invention can be combined with hydrogel degradation rate.

[290] This whole process makes it possible in certain embodiments to advantageously maintain the therapeutic effect of the implant of the present invention over an extended period of time, such as at least 3 months, or at least 6 months, or at least 9 months, or at least 11 months, or at least 12 months, or at least 13 months, or at least 14 months, or even longer, such as up to 15 months. The implants according to embodiments of the present invention may need to be injected only at much greater intervals of time, which is advantageous for the patient for a number of reasons as already disclosed above in the section "Objects and Summary".

Specific implant embodiments

[291] In some first embodiments, the polymer network contains polyethylene glycol units comprising multi-arm polyethylene glycol units, such as 4-arm and/or 8-arm polyethylene glycol units having an average molecular weight in the range of from about 10,000 Daltons to about 60,000 Daltons. In this embodiment, the polymer network of this implant is formed by reacting 4a20kPEG-SAZ with 8a20kPEG-NH_Jz at a weight ratio of about 2: 1.

[292] In this embodiment the hydrogel when formed and before being dried (i.e., the wet composition) contains about 6.5% to about 7.5% polyethylene glycol, representing the polyethylene glycol weight divided by the fluid weight x 100. Also, in this embodiment the implant in a cried state contains from about 45% to about 55% by weight active agent prodrug and from about 37% to about 47% by weight polyethylene glycol units, or from about 47% to about 52% by weight prodrug and from about 40% to about 45% by weight polyethylene glycol units, such as about 49% to about 50% by weight active agent prodrug and about 42% by weight PEG units, or about 47% by weight active agent prodrug and about 44% by weight PEG units (dry composition), the balance being sodium phosphate. The implant furthermore in its dried state may contain no more than about 1% by weight water, or not more than about 0.25% by weight water.

[293] In this embodiment, the implant containing active agent prodrug releases in vitro about 0.01 pg to about 0.15 pg of active agent prodrug per day in phosphate-buffered saline at 37 °C for a period of 30 days. Furthermore, in this embodiment the implant releases in vitro about 35 % to about 45 % of the active agent prodrug in 3 days, about 65 % to about 75 % of the active agent prodrug in 7 days, and about 90 % to about 100 % of the active agent prodrug in 12 to 13 days in a 25:75 ethanol/water (v/v) mixture at 37 °C. In this embodiment the implant may also release in vitro about 25 % to about 35 % of the active agent prodrug in 2 months, about 47 % to about 57 % of the active agent prodrug in 3 months, about 70 % to about 80 % of the active agent prodrug in 5 months, and about 90 % to about 100 % of the active agent prodrug in 7 months in phosphate buffered saline at a pH of 7.2, at 37 °C and with an octanol top layer.

[294] In this embodiment, the implant containing active agent prodrug may be in the form of a fiber (or cylinder) and may have a length of less than about 20 mm, or less than about 17 mm, or of about 15 mm to about 16.5 mm and a diameter of about 0.20 mm to about 0.30 mm in its dried state and may decrease in length and increases in diameter upon hydration in vivo in the vitreous humor or in vitro (wherein hydration in vitro is measured in phosphate-buffered saline at a pH of 7.2 at 37 °C after 24 hours) to a length of about 6.5 mm to about 8 mm and a diameter of about 0.70 mm to about 0.80 mm in the hydrated state. This dimensional change upon hydration may be achieved by imparting shape memory to the implant by cry stretching the implant in the longitudinal direction as explained in more detail elsewhere herein, by a stretch factor of about 2 to about 5, or a stretch factor of about 3 to about 4.5. In other embodiments, the implant may be non-cylindrical.

In this embodiment, the implant may have a ratio of the diameter in the hydrated state to the diameter in the dry state of less than about 3.25 mm, and/or a ratio of the length in the dry state to the length in the hydrated state of greater than about 1.5.

[296] The total weight of an implant as disclosed in this embodiment in its dry state may be from about 0.3 mg to about 0.6 mg, such as from about 0.4 mg to about 0.5 rrg. Such an implant in the dry state may contain about 10 pg to about 15 pg of active agent prodrug per 1 mm final length, and may contain from about 200 pg to about 300 pg active agent prodrug per mm³.

[297] In this embodiment, prior to administration, the implant containing an active agent prodrug is loaded into a 25-gauge needle or a 27 -gauge needle (or an even smaller gauge needle, such as a 30-gauge needle) for injection into the vitreous humor.

[298] In certain embodiments, the sustained release biodegradable implant is an intravitreal implant, is cylindrical and has in its dry state a length of less than about 17 mm and a diameter of about 0.2 mm to about 0.3 mm, and in its hydrated state (after 24 hours in phosphate-buffered saline at a pH of 7.2 at 37 °C) has a length of from about 6.5 mm to about 8 mm and a diameter of from about 0.7 mm to about 0.8 mm, and wherein the hydrogel comprises crosslinked 4a20k and 8a20k PEG units, wherein the crosslinks between the PEG units include a group represented by the following formula wherein m is 6.

[299] Alternatively, an implant of this particular first embodiment may also be non-cylindrical as disclosed herein. Furthermore, the hydrophobic active agent prodrug of this first embodiment may be at least one of an opioid prodrug, a prostaglandin prodrug, an integrin inhibitor prodrug, or a TKI inhibitor prodrug.

[300] In another, second embodiment, the implant, the polyethylene glycol units comprise multi-arm polyethylene glycol units, such as 4-arm and/or 8-arm polyethylene glycol units having an average molecular weight in the range of from about 10,000 Daltons to about 60,000 Daltons. In this embodiment, the polymer network of the implant comprises 4a20kPEG and 8a20kPEG units and is formed by reacting 4a20kPEG-SAZ with 8a20kPEG-NH₂, in a weight ratio of about 2:1.

[301] In this embodiment, the implant in a dried state may ^: contain from about 45% to about 55% by weight active agent prodrug and from about 37% to about 47% by weight polyethylene glycol units, or may contain from about 60% to about 75% by weight active agent prodrug and from about 21% to about 31% polyethylene glycol units, such as from about 63% to about 72% by weight active agent prodrug and from about 23% to about 27% polyethylene glycol units (dry composition), the balance being sodium phosphate. In certain specific embodiments the implant may contain about 68% to about 69% active agent prodrug and about 26% polyethylene glycol units (dry composition), the balance being sodium phosphate. The implant may contain no more than about 1 % by weight water, or not more than about 0.25 % by weight water.

[302] In this embodiment, this implant containing active agent prodrug releases in vitro about 0.3 pg to about 0.5 pg of active agent prodrug per day in phosphate-buffered saline at 37 °C for a period of 30 days. Furthermore, this implant releases in vitro about 40 % to about 60 % of the active agent prodrug in 2 days, about 65 % to about 85 % of the active agent prodrug in 4 days, and about 75 % to about 90 % of the active agent prodrug in 6 days in a 25:75 (v/v) ethanol/water mixture at 37 °C, In this embodiment, this implant may also release in vitro about 45 % to about 55 % of the active agent prodrug in 2 days, about 70 % to about 80 % of the active agent prodrug in 4 days, and about 80 % to about 90 % of the active agent prodrug in 6 days in a 25:75 ethanol/water (v/v) mixture at 37 °C. >

[303] In this embodiment, the implant may be in the form of a fiber (or cylinder) and may have in its dried state a length of less than about 20 mm, or less than about 17 mm, or less than about 15 mm, or less than or equal to about 12 mm, such as about 7 mm to about 12 mm and a diameter of about 0.25 mm to about 0.50 mm, or a length of from about 7 mm or about 8 mm to about 11 mm and a diameter of about 0.3 mm to about 0.4 mm, or about 0,3 to about 0.7 mm, and may increase in diameter upon hydration in vivo in the vitreous humor or in vitro (wherein hydration in vitro is measured in phosphate-buffered saline at a pH of 7.2 at 37 °C after 24 hours). In specific embodiments, an implant containing about 600 pg of active agent prodrug in its dried state may have a length of less than or equal to about 10 mm, or less than or equal to about 8.5 mm, or from about 7 mm to about 9 mm, or from about 7 mm to about 8.5 mm and a diameter of from about 0.3 mm to about 0.4 mm, such as from about 0.35 mm to about 0.39 mm.

[304] The dimensions of this implant after hydration in vivo or in vitro (wherein in vitro hydration is measured in phosphate-buffered saline at a pH of 7.2 at 37 °C after 24 hours) may be a length of less than or equal to about 10 mm, such as from about 6 mm or about 9 mm to about 12 mm and a diameter of about 0.5 mm to about 0.8 mm, or a length of about 9.5 mm to about 11.5 mm, or a length of not more than about 10 mm or not more than about 9 mm, and a diameter of from about 0.65 mm to about 0.75 mm or to about 0.80 mm. In specific embodiments, an implant containing active agent prodrug in its hydrated state (wherein hydration in vitro is measured in phosphate- buffered saline at a pH of 7.2 at 37 °C after 24 hours) may have a length of from about 6 mm to about 10.5 mm, such as from about 6.5 mm to about 8.5 mm, and a diameter of from about 0.7 mm to about 0.8 mm. In particular embodiments, a length of about 10 mm or less, such as about 9 mm or less when hydrated in the vitreous humor of the eye is an acceptable length given the limited volume of the eye.

J30SJ This dimensional change upon hydration may be achieved by wet stretching in the longitudinal direction prior to drying as disclosed in more detail below by a stretch factor of about 0.5 to about 5, or a stretch factor of about 1 to about 4, or a stretch factor of about 1.3 to about 3.5, or a stretch factor of about 1.7 to about 3, or a stretch factor of about 2 to about 2.5.

[306] In this embodiment, the implant containing active agent prodrug may have a ratio of the diameter in the hydrated state to the diameter in the dry state of less than about 2.25 mm and/or a ratio of the length in the dry state to the length in the hydrated state of greater than 0.75.

[307] The total weight of an implant as disclosed herein may in the dry state be from about 0.8 mg to about 1.1 mg, such as from about 0.9 mg to about 1.0 mg. Such an implant in the dry state may contain about 70 pg to about 85 pg of active agent prodrug per 1 mm final length, and may contain from about 500 pg to about 800 pg active agent prodrug per mm³.

[308] In this embodiment, the preferred shape of the implant is cylindrical or essentially cylindrical (and may also be referred to as a fiber). In other embodiments, the implant may be non-cylindrical. Prior to administration, this implant containing active agent prodrug is loaded into a 25-gauge (or a smaller gauge, such as a 27-gauge) needle for injection into the eye, e.g., the vitreous humor.

[309] In a particular embodiment, the sustained release biodegradable implant of the present invention is an intravitreal implant is cylindrical and has in its dry state a length of less than or equal to 10 mm and a diameter of about 0.3 mm to about 0.4 mm, and in its hydrated state (after 24 hours in phosphate- buffered saline at a pH of 7.2 at 37 °C) has a length of from about 6 mm to about 10.5 mm and a diameter of from about 0.6 mm to about 0.8 mm, and wherein the hydrogel comprises crosslinked 4a20k and 8a20k PEG units, wherein the crosslinks between the PEG units include a group represented by the following formula wherein m is 6.

[310] Alternatively, an implant of this second embodiment may also be non-cylindrical as disclosed herein. Furthermore, the hydrophobic active agent prodrug of this second embodiment may be at least one of an opioid prodrug, a prostaglandin prodrug, an integrin inhibitor prodrug, or a TKI inhibitor prodrug.

[311] In one embodiment, the sustained release biodegradable drug delivery system comprises a hydrogel and a hydrophobic prodrug of a steroid, such as dexamethasone, dispersed within the hydrogel, wherein the solubility of the prodrug is less than 100 pg/mL, as measured in phosphate-buffered saline (PBS) at 37 °C and pH 7.4. The system can be an intravitreal implant, or a canicular insert, for prolonged delivery of the steroid, such as dexamethasone, to extend the duration of therapy. The hydrophobic prodrug of dexamethasone may be an isonicotinate ester, or a dipropionate ester, or any one of the other dexamethasone derivatives mentioned herein before. As an exemplary embodiment, a sustained release biodegradable drug delivery system comprises a hydrogel and dexamethasone isonicotinate dispersed within the hydrogel. With its low solubility of about 0.5 pg/mL in PBS, such a hydrogel implant can release the dexamethasone over extended periods of time, such as at least about 6 months, at least about 9 months, or for at least about 12 months.

Opioid prodrug implants: <

[312] In certain embodiments, the implants disclosed nerein comprise a hydrogel and a hydrophobic opioid or opioid prodrug dispersed within the hydrogel. The hydrophobic opioid or opioid prodrug can be at least one of hydrocodone, buprenorphine, or a hydrophobic ester or ether derivative of an opioid agonist or antagonist selected from the group consisting of morphine, dihydromorphine, desmorphine, normorphine, oxycodone, hydromorphone, buprenorphine, codeine, dihydrocodeine, nalbuphine, nalorphine, naloxone, naltrexone, etorphine, dihydroetorphine, pharmaceutically acceptable salts thereof, or combinations thereof.

[313] Opioids may be hydrophobically modified by derivatization of hydroxyl groups at the morphinone structure to form esters with carboxylic acids, such as aliphatic, aromatic or heteroaromatic carboxylic acids, or to form ethers with alcohols such as aliphatic, aromatic or heteroaromatic alcohols. The chain length and/or number of carbon atoms can be varied to adjust hydrophobicity/lipophilicity of the resulting opioid prodrug. The numbering of positions in the morphine structure is as shown below.

[314] Hydrophobic ester, or ether, derivatives or prodrugs of opioids include aliphatic carboxylic acid ester, or aliphatic, aromatic or heteroaromatic ether, or aromatic or heteroaromatic carboxylic acid ester, which may be mono- or diesters, or mono- or diethers, depending on the number of hydroxyl groups in the opioid, pharmaceutically acceptable salts thereof, or combinations thereof.

[315] Aliphatic carboxylic acid esters may be selected from a linear or branched Cz to Cio, such as Cz to Cs, or & to Co, alkanoic acid ester such as an ethanoyl, propanoyl, iso-butanoyl, butanoyl, pentanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, or decanoyl ester, or isomers thereof, such as a butanoyl ester, pharmaceutically acceptable salts thereof, or combinations thereof.

[316] Aromatic carboxylic acid esters may be selected from a C? to Cn, such as C?, or C«N, mono- or polycyclic aromatic or heteroaromatic carboxylic acid ester, such as benzoyl, naphthalenoyl, or nicotinoyl ester, and these may optionally be substituted with at least one linear or branched Ci to Cio, such as Cz to Cs, or Q to «, alkyl or alkenyl group, pharmaceutically acceptable salts thereof, or combinations thereof.

[317] In certain embodiments, the hydrophobic opioid prodrug may be selected from aliphatic or aromatic carboxylic acid di-esters such as 3,6-di-Opropanoyl, or 3,6-di-O-butanoyl, or 3,6-di-O-hexanoyl, or 3,6-di-O benzoate, or 3,6-di-Onicotinoyl esters of at least one of morphine, dihydromorphine, normorphine, nalbuphine, nalorphine, pharmaceutically acceptable salts thereof, or combinations thereof. [318] In other embodiments, the hydrophobic opioid prodrug may be selected from aliphatic or aromatic carboxylic acid esters that may include a mono-ester selected from 3-O-propanoyl, or 3-O-butanoyl, or 3-O-hexanoyl, or 3-Obenzoate, or 3-Onicotinoy! esters of at least one of morphine, dihydromorphine, desmorphine, normorphine, hydromorphone, buprenorphine, nalbuphine, nalorphine, naloxone, naltrexone, etorphine, dihydroetorphine, pharmaceutically acceptable salts thereof, or combinations thereof.

[319] In further embodiments, the hydrophobic opioid prodrug may be selected from aliphatic or aromatic carboxylic acid esters including a mono-ester selected from fr-O-propanoyl, or 6-Obutanoyl, or 6-O-hexanoyl, or 6-0- benzoate, or 6-Onicotinoyl esters of at least one of normorphine, codeine or dihydrocodeine, pharmaceutically acceptable salts thereof, or combinations thereof; or wherein the aliphatic or aromatic carboxylic acid ester is a mono-ester selected from 14-0-propanoyl, or 14-O-butanoyl, or 14-O-hexanoyl, or 14-O-benzoate, or 14-O-nicotinoyl esters of oxycodone, or pharmaceutically acceptable salts thereof, or combinations thereof.

[320] In certain embodiments, the sustained release biodegradable implant comprises a hydrophobic opioid prodrug selected from at least one of the following compounds:

or pharmaceutically acceptable salts thereof, or combinations thereof.

[321] Three of these compounds - morphine, oxycodone and hydromorphone - are readily esterified to yield hydrophobic prodrugs. The fourth candidate, hydrocodone, does not possess hydroxyl groups, so it can be used in embodiment of the invention based on its inherent solubility at physiological conditions without further derivatization. The benzoyl and butanoyl prodrugs offer favorable properties based on literature data for the parent morphine, indicating they have acceptable hydrophobicity for sustained delivery over the target timeframe, see Drustrup, J.; Fullerton, A.; Christrup, L; Bundgaard, H. Utilization of Prodrugs to Enhance the Transdermal Absorption of Morphine. Int. J. Pharm. 1991, 71 (1-2), 105-116. Also, their potency and enzymatic conversion rates to morphine are known. 3 hydroxy (phenolic) ester convert more quickly than the 6 position (allylic) esters. [322] Oxycodone, for example, can only be esterified at the 14 position and is expected to hydrolyze at a rate slower than either morphine ester, since it is more sterically hindered and lacks an allylic group. Hydromorphone can only be esterified at the 3 position, so it is expected to hydrolyze at a fest rate, similar to the morphine 3 position ester. Hydrocodone has no available hydroxyl groups, so it will be released in its native state from a hydrogel matrix implant and requires no conversion to a parent molecule. Thus, by selecting the appropriate opioid prodrug, a range of hydrolysis rates from these prodrug compounds can be designed.

[323] Aliphatic ethers may be selected from a linear or branched C? to Cw, such as G to G, or G to Q,, alkyl ether such as an ethyl, propyl, iso-butyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, or decyl ester, or isomers thereof, such as a butyl ester, pharmaceutically acceptable salts Hereof, or combinations thereof, derived from the corresponding alcohols. ^{: :}

[324] Aromatic ethers may be selected from a G to Cw, such as C₆, or GN (pyridyl), mono- or polycyclic aromatic or heteroaromatic ether, such as benzyl, naphthalenoyl, or nicotmoyl ether, and these aromatic or heteroaromatic groups may optionally be substituted with at least one linear or branched G to Cw, such as G to G, or G to cs, alkyl or alkenyl group, pharmaceutically acceptable salts thereof, or combinations thereof.

[325] In certain embodiments, the hydrophobic opioid prodrug may be selected from aliphatic or aromatic diethers such as 3,6-di- Opropyl, or 3,6-di- O-butyl, or 3,6-di-O-hexyl, or 3,6-di-O-benzyl, or 3,6-di-Opyridyl ethers of at least one of morphine, dihydromorphine, normorphine, nalbuphine, nalorphine, pharmaceutically acceptable salts thereof, or combinations thereof.

[326] In other embodiments, the hydrophobic opioid prodrug may be selected from aliphatic or aromatic ethers that may include a mono-ether selected from 3-O-propyl, or 3-Obutyl, or 3-Ohexyl, or 3-Obenzyl, or 3-O-pyridyl ethers of at least one of morphine, dihydromorphine, desmorphine, normorphine, hydromorphone, buprenorphine, nalbuphine, nalorphine, naloxone, naltrexone, etorphine, dihydroetorphine, pharmaceutically acceptable salts thereof, or combinations thereof.

[327] In further embodiments, the hydrophobic opioid prodrug may be selected from aliphatic or aromatic ethers including a mono-ether selected from 6-0-propyl, or 6-Obutyl, or 6-O-hexyl, or 6-O-benzyl, or 6-Opyridyi ethers of at least one of normorphme, codeine or dihydrocodeine, pharmaceutically acceptable salts thereof, or combinations thereof; or wherein the aliphatic or aromatic ether is a mono-ether selected from 14- Opropyl, or 14-0-butyl, or 14- Ohexyl, or 14-Obenzyl, or 14-Opyridyl ethers of oxycodone, or pharmaceutically acceptable salts thereof, or combinations thereof.

[328] Prodrugs, being more hydrophobic than the parent molecule, can penetrate the blood-brain barrier (BBB) more readily, resulting in higher cerebrospinal fluid (CSF) concentrations and a higher apparent potency in vivo. For example, IV injection of the prodrug diacetylmorphine (heroin) is known to be more potent than the parent compound, morphine, because a significant fraction of unconverted, or partially converted prodrug crosses the BBB prior to full conversion by enzymes in the CSF, see Owen, J. A.; Nakatsu, K. Diacetylmorphine (Heroin) Hydrolases in Human Blood. Can. J. Physiol. Pharmacol. 1983, 61 (8), 870-875.

A slow, sustained release into the tissue surrounding the implant will allow more of the conversion to occur before reaching the BBB. On the other hand, a slower conversion rate, as is expected for the drug esterified in the 6 or 14 positions, e.g., the oxycodone prodrugs, could allow more of the unconverted prodrug to cross the BBB. If more of the prodrug crosses the BBB, the efficiency of delivery to the CNS will increase; thus, the apparent potency will increase and the required drug release rate from the implant will decrease. This circumstance may allow more prolonged treatment time, if desired, or smaller injection volume to achieve the same treatment time with less drug. [329] In an embodiment, the implant is used for the treatment of pain, such as moderate to severe pain, for example post-surgical pain, and the opioid is selected from prodrugs of parent opioid API indicated for moderate to severe pain, for example post-surgical pain. The implant may have a suitable form for being injectable or instillable as a subcutaneous implant, by minimally invasive administration, such as by needles. In certain embodiments, the hydrophobic opioid prodrug may be combined with a loading dose of the parent API. The implant of embodiments of the present invention is, since it is used under controlled conditions, an abuse-deterrent configuration that enhances safety and/or tolerability of the opioid analgesic, and minimal local tissue response can be expected.

[330] For short term treatments, the implant of embodiments of the invention comprising hydrophobic opioid prodrugs provides fast-acting pain relief for extended periods of time, such as 5 days to 2 months, or 5 days to 1 month, or 5 days to 3 weeks, such as 5 or 6 days to 2 weeks, with an efficacy profile similar to the parent API. [331] In an embodiment, the hydrogel implant biodeg -ades in a time period that is longer than the drug elution time and less than 1 month. It can be administered by one-time post-surgical implantation, e.g., by a physician, and its dosing can be varied, proportional to patient size and tolerance. Furthermore, the implants may be stored at room temperature (25°C) or in a refrigerator for more than 1 year.

[332] In certain embodiments for medium to long term treatments, the sustained release biodegradable implant biodegrades in the human or animal body within about 2 weeks and up to about 15 months, such as 3 or 4 weeks, to about 15 months, or 1 to about 15 months or 2 to 14 months after administration; or the implant biodegrades in the human or animal body within about 4 to about 13 months after administration, such as within about 9 to about 12 months after administration.

[333] In the embodiments of the invention, the implant after administration to the human or animal body releases a therapeutically effective amount of hydrophobic opioid or opioid prodrug over a period of at least about 5 days, such as 6 days, or 7 days, or 5 days to 2 months, or 5 days to 1 month, or 5 days to 3 weeks, such as 5 or 6 days to 2 weeks, or for at least about 1 month, at least about 2 months, at least about 3 months, at least about 6 months, at least about 9 months, at least about 10 months, at least about 11 months, or at least about 12 months after administration, for example, the implant after administration to the human or animal body releases a therapeutically effective amount of hydrophobic prodrug over a period o' at least 1 week, or 2 weeks, or 3 weeks, or 1 month, or 6 months, or the implant after administration to the human or animal body releases a therapeutically effective amount of hydrophobic opioid or opioid prodrug over a period of at least 1 week to 9 months.

[334] In some embodiments, the implants disclosed herein are suitable for subcutaneous delivery, or delivery in surgically created space or injury, or ocular delivery to a route selected from, e.g., punctal, intravitreal, subconjunctival, intrascleral, subretinal, suprachoroidal, periocular, peribulbar, retrobulbar, intracorneal, posterior sub-tenon's delivery, anterior sub-tenon's delivery, cul-de-sac delivery, or fornix delivery. The administration can be, e.g., by injection with a needle or insertion with a delivery device into the selected ocular delivery route.

[335] The needle can be a gauge selected from, e.g., 18 gauge, 19 gauge, 20 gauge, 21 gauge, 22 gauge, 23 gauge, 24 gauge, 25 gauge, 26 gauge, 27 gauge, 28 gauge, 29 gauge, 30 gauge, 31 gauge, 32 gauge or 33 gauge. [336] In certain embodiments, the administration can be with a modified device as described in U.S. Patent No.

8,808,225; U.S. Patent No. 10,722,396; U.S. Patent No. 10,390,901; U.S. Patent no. 10,188,550; U.S. Patent No. 9,956,114; U.S. Patent No. 9,931,330; U.S. Patent Application Publication No. 2019/0290485; U.S. Patent Application Publication No. 2019/0000669; and U.S. Patent Application Publication No. 2018/0042767.

[337] In alternative embodiments, the administration can optionally be performed without a needle, e.g., manually or with the aid of forceps, applicator or other delivery aid.

[338] The opioid or opioid prodrug administered by the drug delivery systems of the present invention can, e.g., have an aqueous solubility of less than about less than about 100 pg/mL, less than about 75 pg/mL, less than about 50 pg/mL, less than about 25 pg/mL, less than about 10 pg/mL, less than about 5 pg/mL, less than about 1 pg/mL, less than about 0,5 pg/mL, less than about 0.4 pg/mL, less than about 0.3 pg/mL, less than about 0.2 pg/mL or less than about 0.1 pg/mL, measured in PBS at pH 7.4 and 37°C. In some embodiments, the opioid prodrug is substantially insoluble in water,

[339] In other embodiments, the active agent prodrugs administered by the devices of the present invention can have an aqueous solubility classified as very slightly soluble (1,000-10,000 parts solvent needed for 1 part solute) or practically insoluble or insoluble (>10,000 parts solvent needed for 1 part solute) as described in Remington, The Science and Practice of Pharmacy 22nd Edition 2012.

[340] In addition to the opioid prodrugs, in certain embodiments the implant may in combination include a further active agent prodrug such as antibiotics, or antivirals, or steroidal or non-steroidal anti-inflammatory agents, as described herein above.

The disclosed amounts of active agent prodrug, such as the opioid or opioid prodrug, including the mentioned variances, refer to both the final content of the active principle in the implant, as well as to the amount of active principle used as a starting component per implant when manufacturing the implant. The doses disclosed herein can also be applicable to other active agent prodrugs in certain embodiments.

[342] As will be disclosed in more detail herein below, in certain embodiments of the invention the total dose of the active agent prodrug to be administered to a patient, may be contained in two, three or more implants administered COTCurrently. Ffor example, a dose of about 400 pg of opioid prodrug may be administered in one Implant containing about 400 pg opioid prodrug, or in two implants e.g., each containing about 200 pg opioid prodrug and so on. Of course, one may not only combine two or more identical implants (or implants containing the _: identical dose), but also two or more different implants (or implants containing different doses) in order to arrive at a desired total dose. In a particular embodiment, a total opioid prodrug of from about 480 pg to about 750 pg, or from about 540 pg to about 660 pg, or of about 600 pg, Is contained in one implant and only one such implant is administered to a patient in need of such treatment in accordance with the invention. In another embodiment, a total dose of higher than about 600 pg, such as from about 800 pg to about 1250 pg, or from about 900 pg to about 1100 pg, or of about 1000 pg, or a total dose from about 960 pg to about 1500 pg, or from about 1080 pg to about 1320 pg, or of about 1200 pg, or a total dose from about 1440 pg to about 2250 pg, or from about 1620 pg to about 1980 pg, or of about 1800 pg is contained in one implant and only one such implant is administered to a patient in need of such treatment in accordance with the invention. In other embodiments, the total dose administered to a patient in accordance with the present invention may he contained in two or more implants (containing the same or different amounts of API) administered concurrently.

[343] The opioid prodrag is contained in the implant of the invention and is dispersed or distributed as particles in the hydrogel that is comprised of a polymer network, In certain embodiments, the particles are homogeneously or essentially homogeneously dispersed in the hydrogel. The hydrogel may prevent the particles from agglomerating and may provide a matrix for the particles which holds them in the desired location in the eye while slowly releasing drag.

[344] In certain embodiments of t he invention, the opioid prodrag particles may De microencapsulated. The term " microcapsule" (also referred to as “mlcfoparttcle"} is Sometimes defined as a roughly spherical particle with a size varying between e.g., about 50 nm to about 2 moi. Microcapsules have at least one discrete domain (or core) of active agent prodrag encapsulated In a surrounding material,- sometimes also referred to as a shell. One suitable agent (without limiting the present disclosure to tills) for microencapsulating the active agent prodrug, for the purposes of the present invention, is poly (lactic-co-glycoiic acid).

[345] In other embodiments, the opioid prodhig particles are not microencapsulated and are thus dispersed in the hydragel and thus in the implant of the invention as they are, i.e., without being admixed to or adjoined with or microencapsulated by another material such as (but not limited to) poly (lactic-co-giycolic acid), [34$] In one embodiment, the active agent prodrug particles, such as the opioid prodrug partides, may be mlcrontzed particles. In another embodiment, the active agent prodrug particles may not be micronised. Micranization refers to the process of reducing the average diameter of particles of a solid material. Particles with reduced diameters may have inter aha higher dissolution and erosion rates, which increases the bioavailability of active pharmaceutical ingredients and may have in certain embodiments a positive impact on release kinetics. Furthermore, micronized particles may have a reduced tendency to agglomerate during manufacturing operations, in the composite materials field, particle size is known to affect the mechanical properties when combined with a matrix, with smaller particles providing superior reinforcement for a given mass fraction. Thus, a hydrogel matrix filled with micronized opioid prodrug particles may have improved mechanical properties (e.g„ brittleness, strain to failure, etc.) compared to a similar mass fraction of larger active agent prodrug particles. Such properties are important in manufacturing, during implantation, and during degradation of the Implant. Micronizatlon may also promote a more homogeneous distribubon of the active ingredient In the Chosen dosage form ar matrix. The particle size distribution can be measured by methods known in the art,, including sieving, laser diffracifon or dynamic light scattering. In certain embodiments of the invention the active agent prodrug, such as the opioid prodrug, particles used In preparing the implants of the present invention may have a d90 of less than about 100 pm and/or a d30 of less than about SO pm, or a d90 of less than about 75 pm and/or a d50 or fess than about 20 pm as determined by laser diffraction. In specific embodiments, the d90 of the opioid pradrug, may be iess than about 30 pm, iess than about 20 gm as determined by laser diffraction. In very particular embodiments, the d90 of the active agent pradrag, such as opioid pradrug, is less than about 10 pm as determined by laser diffraction. In these or other embodiments, the d50 of the active agent prodrug, such as opioid prodrug, particles used in preparing the implants of the present invention may be. iess than about 5 pm as determined by laser diffraction. In these or other embodiments, the dlO of the active agent prodrug, such as the opioid prodrug, particles used in the present invention may be less than about

3 pm as determined by laser diffraction. In certain embodiments, the dlOO of the active agent prodrug, such as the opioid prodrug, partides used in the preparation of the implants of the present invention may be iess than about 20 pm as determined by laser diffraction. The "d9G" (also referred to as ^sD90" herein) value means that 90 voiume-% of ail particles within the measured bulk material (which has a certain particle size distribution) have a particle size below the indicated value. For example, a d90 particle size of less than about 10 pm means that 90 volume-% of the particles in the measured bulk material have a particle size below about 10 pm. Corresponding definitions apply to other “d" values, such as the "diQ", ^udSO* or the "dlOO" values (also referred to herein as the "D10", "D50" and "D100" values, respectively), in certain other embodimerits also prodrug particles with diameters above this specification may be used, [347] Micronized opioid prodrug particles may be purchased per specification from the supplier, or may be prepared e,g,, according to the following exemplary procedure (similar to the method disclosed in WO 2016/183296 Al, Example 13): I860 ml of sterile Water For injection (WFI) is measured into a 2 L beaker and placed on a stir plate stirring at 68© RPM with a stir bar, creating B large WFI vortex in the center of the beaker. One 80 ml BD syringe containing opioid prodrug dissolved in a suitabie solvent that is miscible with water, e,g,, ethanol, is placed on a syringe pump which is clamped above the WFI beaker, A hypodermic needle (21G, BD) is connected to the syringe and aimed directly into the center of the vortex tor dispensation of the prodrug solution. The syringe pump is then run at 7.5 mL/min in order to add the opioid prodrug solution dropwise to the WH to precipitate micronized opioid prodrug. After micronization, the opioid prodrug is filtered, e,g.„ through a 0.2 pm vacuum filter and rinsed with WFI. After filtration, the opioid prodrug powder is collected from the filter e.g,, by using a spatula and: vacuum dried for an extended period of time, such as for about 12 or about 24 hours, in order to remove excess water and solvent. Another exemplary method of mfcronizing opioid: prodrug is disclosed tn Example 9 of WO 2017/091749. The described method of micronization is not limiting, and other methods of micronteing the active agent prodrug such as opioid pradrug may equally be used. The disclosed micranizatton method (or other methods) may also be used for other actives than opioid prodrugs. [348] Another aspect of the present inventkm is a sustained release biodegradable implant comprising a hydrogel and a hydrophabic apioid or apioid prodrug, wherein hydraphabic apioid or apioid prodrug particles are dispersed within the hydrogel, and wherein the implant: in its dry state has a total weight of about 0.2 mg to about 1.5 mg. [349] In certain embodiments, the total weight (also referred to herein as "total mass") of ah implant according to the present invention In its dry state may he from about 400 pg to about 1,2 tog. In certain specific embodiments, the total weight of an implant according to the invention in its dry state may be from about 0.3 mg to about 0.6 mg, such as from about 0.4 mg to about 0.5 mg, or may be from about 0.8 mg to about 1,1 mg, such as from about 0.9 mg to about 1.0 mg.

[350] AH features (Individuaiiy or any combinations of features) disclosed herein with respect to ar> implant according to the present invention may be used to characterize the sustained release biodegradable implant comprising a hydrogel a hydrophobic opioid or opioid prodrug, wherein active agent prodrug particles are dispersed within the hydrogel, and wherein the implant in its dry state has a total weight of about 0.2 mg to about 1.5 mg.

1.1, Manufacture of the Implant

Manufacturing process;

[351] Most active agents can readily be formed into fully reversable prodrugs. Active agent molecules having at least one hydroxyl, thiol or amine functionality can be estenfied ar amidated with aliphatic or aromatic carboxylic acids by standard chemical reactions and methods known to a skilled person. Similarly., active agent molecules having at least one carboxyl functionality can be esterffied by hydrocarbon alcohols or thiols, or amidated with amines,

[352] For example, most opioids can readily be formed into fully reversable prodrugs. These prodrugs can be designed with controltebly reduced solubility by esterification of hydroxyl groups on the starting molecule. The synthesis of opioid prodrugs as used herein can be done by methods known in principle, using standard synthetic Chemistry methods, for example by reacting hydroxyi-grcups at parent Opioids with aliphatic carboxylic acid: anhydrides, or benzoylation of the hydroxyl groups with benzoyl chiatide or similar compounds, or by Schoten- Baumann reaction. Such esterifieatian methods are described, inter alia, in, e.g., Owen, j. A.; Elliott, j.; ihamandas, K.; Nakatsu, K. Morphine Diesters. I. Synthesis and Action on Guinea Pig Ileum. Can. 3. Physiol. Pharmacol. 1984, 62 (4), 446-451; or Beni, S.; lath, G.; N&szei, 8.; Hosztafr, S. Preparation of Benzoate Esters of Morphine and Its Derivatives. Monatshefte Fur Chem. - Chem. Mon. 2012, 143 (10), 1431-1440; or Drustrup, J,; Fullerton, A,; Christrup, L; Bundgaard, H. Utilization of Prorirogs to Enhance the Transdermal Absorption of Morphine, Inf, 3. Pharm. 1991, 71 (1-2), 105-116; al! of which are Incorporated: herein by reference.

[353] In certain embodiments, the present invention also relates to a method of manufacturing a sustained release biodegradable Implant as disdosed herein. Generally, the method comprises the steps of forming a hydrogel comprising a polymer network and active agent prodrug particles dispersed within the hydrogel, shaping the hydrogel and drying the hydrogel, in certain embadiments the method comprises the steps of forming a hydrogel comprising a polymer network from reactive group-containing: precursors (e.g., comprising PEG units) and active agent prodrug particles dispersed In the hydrogel, shaping the hydrogel and drying the hydrogel, more specifically the polymer network is formed by mixing and reacting an etectrophUic group-containing multi-arm PEG precursor with a nucleophilic group-containing multi-arm PEG precursor or another nucleophilic group-containing crosslinking agent (precursors and crosslinking agent as disclosed herein in the sections "The polymer network" and "PEG hydrogels") in a buffered solubon in the presence of active agent prodreg particles and allowing the mixture to gel to form the hydrogel. In embodiments of the invention, the hydrogel is shaped Into a hydrogel strand as disclosed herein, by tasting the mixture into a tubing prior to complete gelling of the hydrogel, in certain embodiments, the hydrogel strand is stretched in the longitudinal direction prior to ar after drying as further disclosed herein.

[354] In embodiments of the invention, different fabrication methods for the implant itself may be employed, including casting, extrusion, injection molding and 3D printing. The choice of fabrication method will depend on the final product configuration or form factor. The form factor, along with drug solubility, is a major controller Crf drag release rate, driven by the release kinetics of the individual drug compound from the hydrogel, A wet-cast process is described In Example 1 hereinafter, Manufacturing of the implant by extrusion methods such as hot melt extrusion (HME) can be done as described in detail In WO 2023/197478 Al. Example 9 describes an exemplary embodiment thereof,

[355] In one embodiment the active agent prodrug may be used in micronized form for preparing the implant as disclosed: herein, and may have a particle diameter as also disclosed herein in the section ’’The active principle*, in certain specific embodiments, Use active agent prodrug may have a dSO of less than about 30 gm, or less than about 10 pro. Using micronized active agent prodrug may have the effect of reducing the tendency of the active agent prodrug particles to agglomerate during casting of the hydrogel strands. In another embodiment, the active agent prodrug may be used in non-micronized form for preparing trie implant.

[356] The precursors for forming the hydrogel of certain embodiments have been disclosed in detail above in the section relating to the implant itself. In case PEG precursors are used to prepare a crosslinked PEG network, the method of manufacturing toe implant in certain embodiments may comprise mixing and reacting an electrophilic group-conta suing polymer precursor, such as an electrophilic group-Conteining mulfi-Brm polyethylene glycol, Such as WOkPEG-SAZ, with a nucleophilic group-conteining polymer precursor or other cross-linking agent, such as a nucleophilic group-contatning multi-arm polyethylene glycol, such as 8a20kPEG"NH?, in a buffered solution in toe presence of the tyrosine kinase inhibitor, and allowing the mixture to gel. In certain embodiments, the molar ratio of the electrophilic groups to the nucleophilic groups in the PEG precursors is about 1;1, but the nucleophilic groups (such as the amine groups) may also be used in excess of the electrophilic groups. Other precursors, including other electrophilic group-containing precursors and other nucleophilic group-containing precursors or crosslinking agents may be used as disclosed in the section "The polymer network" and the section "PEG hydrogels" herein, [357] certain embodiments, a mixture of the electrophilic group-containing precursor, the nucleophilic group- containing precursor or other crosslinking agent, the active agent prodrug and optionally buffer (and optionally additional ingredients as disclosed in toe section “AdditionBl ingredients") is prepared. This may happen in a variety of orders, including but not limited to first preparing separate mixtures of the electrophilic and the nucleophilic group-containing precursors each in buffer solution, then combining one of the buffer/precursor mixtures, such as the buffer/nucieophliic group-containing precursor mixture, with toe active agent prodrug and subsequently combining this active agent prodrug -containing buffer/ precursor mixture with the other buffer/precursor mixture (in this case the bufifer/electrophilic group-containing precursor mixture}. After a mixture of ail components has been prepared fire., after all components have been combined and the wet composition has been formed), the mixture is cast into a suitable mold or tubing prior to complete gelling of die hydrogel in order to provide the desired final shape of the hydrogel. The mixture is then allowed to gel. The resulting hydrogel is then dried, [383] The viscosity of the wet hydrogel composition to be cast into a mold or tubing may depend /rfter ate on the coricentratian and the solids content: of the hydrogel composition, but: may also depend on external conditions such as the temperature. Castability of the wet hydrogel: composition especially in case the composition Is cast into fine- diameter tubing, may be improved by decreasing the. viscosity of the wet composition, Including (but hat: limited to) decreasing the concentration of ingredients in the solvent and/or decreasing the solids content, or ether measures such as increasing the temperature etc. Suitable solids contents are disclosed herein in the section "Formulation'’,

[359] In case the implant should have the final shape of a fiber (such as a cylinder), the reactive mixture may be cast into a fine diameter tubing (of e.g, an inner diameter of about 1.0 mm to about 1.5 mm), such as a PU or silicone tubing, in order to provide for the extended cylindrical shape, or extruded through a suitably dimensioned extrusion die. Different geometries and diameters of the tubing or extrusion die may be used, depending on the desired final cross-sectional geometry of the hydragel fiber, its initial diameter (which may still be decreased by means of stretching), and depending also on the ability of the reactive mixture to uniformly fill the tubing.

[360] Thus, the inside of tee tubing or die may have a round geometry or a non-round geometry*, such as a crossshaped (ar other) geometry, By means of a cross-shaped geometry, the surface of the implant may be increased.

Also, in certain embodiments, the amount of active agent prodrug incorporated in the implant may be increased with such cross-shaped geometry. Overall, by using a cross -shaped geometry, release of the API from the implant may in certain embodiments be increased. Other crass-sectional geometries of the implant may be used as disclosed herein.

[361] In certain embodiments, after the hydrogel has formed and has been left to cure to complete gelling, the hydrogei strand may be tongitudinally stretched in the wet or dry state as already disclosed in detail herein e,g. in the section relating to tee dimensional change of the implant upon hydration. In certain embodiments, a stretching factor (also referred to herein as "stretch factor") may be in a range of about 1 to about 4.5, or about 1.3 to about

3.5, or about 2 to about 2,5, or within other ranges also as disclosed herein (e.g, in, but not limited to, the section "Dimensions of the implant and dimensional change upon hydration through stretching”. The stretch factor indicates the ratio of the length of a certain hydrogel strand after stretching to the length of the hydrogel strand prior to stretching. For example, a stretch factor of 2 for dry stretching means that the length of the dry hydrogel strand after (dry) stretching Is twice the length of the dry hydrogel strand before the stretching. The same applies to wet stretching. When dry stretching is performed in certain embodiments, the hydrogel is first dried and then stretched. When wet stretching: is performed in certain embodiments, tee hydrogel is stretched in the wet (undried) state arid then left to dry under tension. Optionally, heat may be applied upon stretching. Further optionally, the hydrogel fiber may additionally* be twisted. In certain embodiments, the stretching and/or drying may be performed when the hydrogei Is still in the tubing. Alternatively, the hydrogei may be removed from the tubing prior to being stretched. In certain embodiments, the implant maintains its dimensions evert after stretching as tong as it is kept in the dry state at or below room temperawe.

[362] After stretching and drying the hydrogel strand is removed from the tubing (ft sttll: located inside the tubing) and cut into segments of a length desired for the final Implant in its dry state, such as disclosed herein (if cut within the tubing, the cut segments are removed from the tubing after cutting), A particularly desired length of the implant in the dry state for the purposes of the present invention is for exampfe a length of equal to or less than about 12 mm, or equal to or less than about 10 mm, as disclosed herein,

[363] In certain embodiments, the final prepared implant is then loaded into a fine diameter needle. In certain embodiments, the needle has a gauge size of from 22 to 30, such as gauge 22, gauge 23, gauge 24, gauge 25, gauge 26, gauge 27, gauge 28, gauge 29 or gauge 30. In specific embodiments, the needle is a 25- or 27 -gauge needle, or an even smaller gauge needle, such as a 30-gauge needie, depending on the diameter of the dried (and optionally stretched) implant,

[364] In certain embodiments, the needles containing implant are then separately packaged and sterilized e.g. by means of gamma irradiation, [365] In certain embodiments, an injection device, such as a syringe or another injection device, may he separately packaged and sterilized e.g. by means of gamma irradiation as disclosed below for the kit (which is another aspect of the present invention, see the section "Injectton device and kit"),

[366] A particular embodiment of a manufacturing process by casting according to the invention is disclosed in detail in Example 1, [PEG] Tipping the needle:

[367] In one embodiment, after the implant has been loaded into the needle the tip of the needle is dipped into a melted low-molecular weight PEG, Alternatively, molten PEG may be injected: or placed/dripped into tee needle tip lumen. This tow-molecular PEG is liquid (molten) at body temperature, hut solid at room temperature. After applying the, molten PEG to the needle tip,, either by dipping or dripping, upon cooling tee needle a hardened small drop or section (also referred to herein as "tip") of PEG remains at and in the top of the needle which occludes the needle lumen. The location of this tip/plug is shown in fig, SB.

[368] The low-molecular weight PEG used to this embodiment may be a linear PEG and may have an average molecular weight of up to about 1509, or up to about 1000, or may have an average molecular weight of about 400, about 600, about 800 or about 1000. Also mixtures of PEGS of different average molecular weights as disclosed may be used. In specific embodiments the average molecular weight of the PEG used for this purpose of tipping the needle Is about 1000, This Ik (1000) molecular weight PEG has a melting point between about 33 °C and about 40 ®C and melts at body temperature when the needle is injected into the eye. [369] Alternatively to the PEG materials, arty other material for tipping the irrtedion needle may be used that is water soluble and biocompatible (i.e., that may be used in contact with the human or animal body encl does not elicit topical or systemic adverse effects, e.g, that is not irritating) and that is solid or hardened at room temperature but liquid or substantially liquid or at least soft at body temperature. Alternatively to PEG, also the following materials may e.g, be used (without being limited to these): potakamers or poloxamer blends that rne.lt/are liquid at body temperature; crystallized sugars or salts (such as trehalose or sodium chloride)., agarose, cellulose, polyvinyl alcohol, poly(latiic‘co-glycalic acid), a UV-curing polymer, chitosan or combinations of mixtures thereof.

[370] The. plug Qr tip aids in keeping the implant in plate within the needle during packaging, storage and shipping and also further protects the implant from prematurely hydrating: during handling as it occludes the needle lumen, ft also prevents premature rehydration of the implant within the needle due to moisture ingress during the administration procedure, i.e., during the time the physician prepares the needle and injector for administration, and also at the time when the implant is about to be injected and the needle punctures into the eye (as the positive pressure in the eye could cause at least some premature hydration of the implant just before it is actually injected). The tip or plug additionally provides lubricity when warmed to body temperature and exposed to moisture and thereby allows successful deployment of the implant. Moreover, by occluding the needle lumen, the needle tipping minimizes the potential for tissue injury, i.e., tissue coring, a process by which pieces of tissue are removed by a needle as it passes through the tissue.

[371] In order to apply the PEG (or other material) tip/plug to the needle lumen, in one embodiment the needle containing the implant: may be manually or by means of an automated apparatus dipped into a container of molten PEG (or the respective other material). The needle may be held dipped in the molten material for a few seconds to enable the molten material to flow upward into the needle through capillary action. The dwell time, the dip depth and the temperature of the molten material determine the final size or length of the tip/plug. In certain embodiments, the length of the PEG (or other) tip/plug at the top end of the needle may be from about 1 to about 5 mm, such as from about 2 to about 4 mm. In certain embodiments, in case a Ik PEG is used the weight of the tip/plug may be from about 0.1 mg to about 0.6 mg, such as from atrout 0.15 mg to aboiit 0.55 mg. It was demonstrated that implants according to the present invention can be successfully deployed in vivo and in vitro from an injector carrying a needle with a Ik PEG tip as disclosed herein.

[372] The tipping of an injection needle as disclosed herein may also be used for the injection of other implants or other medicaments or vaccines to be injected into the human or animal body (including other locations within the eye, or other areas or tissue of the body) by means of a needle, where the effect of protection of the implant (or medicament or vaccine) from moisture and the protective effect on tissue into which the implant (or medicament or vaccine) is injected is desirable and advantageous.

Stretching: [373] The shape memory effect of the stretching has already been disclosed in detail above with respect to the properties of the implant. In certain embodiments., the degree of shrinking: upon hydration depends inter on the stretch factor as already disclosed above.

[374] In certain embodiments, the present inventfon thus also relates to a method of imparting shape memory to a hydrogel strand comprising an active agent prodrug dispersed in the hydrogel by stretching the hydrogel strand in the longitudinal direction,

[375] Likewise, in certain embodiments., the present invention thus also relates to a method of manufacturing an implant comprising a hydrogel comprising an active agent prodrug dispersed therein, wherein the implant changes its dimensions upon administration to the eye, the method comprising preparing a strand of the hydrogel and stretching it in the longitudinal direction.

[376] Stretch factors for use in these methods of the invention may be utilized as already disclosed above. The described method of manufacture Including the stretching methods are not limited to implants comprising opioids,, but may also be used for hydrogels comprising other active pharmaceutical agents, or for implants comprising hydrogels that are not formed from PEG units, but from other polymer units as disclosed herein above that are capable of forming a hydrogel.

[377] in embodiments where the implant contains prodrug in an amount in a range from about 160 pg to about 250 pg, or in an amount of about: 200 pg, the stretching may be performed after drying the hydrogel by a stretch factor of about 2 to about 5, or a stretch factor of about 3 to about 4,5 (dry stretching).

[373] In certain embodiments where the impiant contains prodrug in an amount in a range from about 488 yg to about 750 pg, or in an amount of about 600 pg, the stretching may be performed in a wet state prior to drying the hydrogel by a stretch factor of about 0.5 to about 5, or a stretch factor of about 1 to about 4, or a sb'etch factor of about 1.3 to about 3,5, or a stretch factor of about 1,7 to about 3, Or a stretch factor of about 2,0 to 2.5 (wet stretching).

III. Injection device and kit

[373] In certain embodiments, the present invention is further directed to a kit (which may also be referred to as a "system") comprising one or more sustained: release biodegradable tmplant(s) as dis-closed above or manufactured in accordance with the methods as disclosed above and one or more needie(s) for injection, wherein the one or more rteedle(s) is/are each pre-loaded with one sustained release biodegradable implant in a dried state. In certain embodiments the needle(s) has a gauge size of from 22 to 30, such as 22, 23, 24, 25, 26, 27, 28, 29, or 38 gauge, in specific embodiments, the needles may be 25- or 27-gauge needle(s) or may be smaller gauge, such as SO-gauge needte(s). The diameter of foe needle is chosen based on the final diameter of the implant in the dried (and optionally' stretched) state. [380] In one embodiment the kit comprises one or more, such as two or three 22- to 30-gauge, sudi as 25- or 27-gauge needie(s) each loaded with an implant containing prodrug in an amount in the range from about 180 pg to about 220 pg, or in an amount of about 200 yg„

[381] In yet another embodiment the kit comprises one 25-gauge needle loaded with an implant containing: prodrug in an amount in the range from about 540 pg to abort 060 pg, or in an amount of about 600 pg< in another embodiment, the kit comprises one 27-gauge needle loaded with an Implant containing active agent prodnsg.

[382] If two or more implants are contained in the kit, these implants may be identical or different, and may contain identical or different doses of active agent prodrug.

[383] In certain embodiments, the lumen of the needle containing the implant may be occluded by a material that is solid at room temperature but soft or liquid at: body temperature, such as a 1 k PEG material, as disclosed herein in detail m the section "Manufacture of the Implant" and specifically the subsection "(PEG) Tipping the needle" thereof.

[384] The kit may further contain an injection device for injecting the Implant(s) at an implantation site of a patient, such as into the vitreous humour, or a surgical incision site of the patient. Tn certain embodiments the injection device is provided and/or packaged separately from the one or more needie(s) loaded with implant, in such embodiments the injection device must be connected to the one or more needte(s) loaded with implant prior to injection.

[385] In certain embodiments the number of injection devices provided separately in the kit equate the number of needles loaded with the implant provided in the kit. In these embodiments the injection devices are only used once for injection of one implant, [386] in other embodiments the kit contains one or more injection device(s) for injecting the implant into the eye of a patient, such as into the vitreous humour of the patient, wherein each injection device is or is not pre-connected to a needle loaded with implant. The present invention thus in one aspect also relates to a pharmaceutical product comprising a sustained release biodegradable implant loaded in a needle and an injection device, wherein the needle is pre-connected to the injection device. In case the needle is not yet pre-connected to the injection device, the physician administering the implant needs to remove both the needle containing the implant and the injection device from the packaging and connect the needle to the injection device to be able to inject the implant into the patient's eye or another Implantation site,

[387] In some embodiments the injection device contains a push wire to deploy the implant from the needle into the implantation site. The push wire may be a Nitinol push wire or may be a stainless steei/Tefton push wire. The push wire allows deploying the implant from the needle more easily.

[388] In other embodiments the injection device and/or the injection needle may contain a stop feature that controls the injection depth. [389] In some embodiments the injection device is or comprises a modified Hamilton glass syringe that may t» placed into a plastic syringe housing, Such as inside an injection molded housing. A push wire, such as a Nitinol wire, is inserted into the syringe and ad vances with the plunger of the syringe during deployment of toe implant. To facilitate entry of the nitinol push wire into the needle, a hub insert may be added into the needle hub. Figures SA and SB show one emtojiment of an injector according to the present: invention for injecting an implant into the vitreous humor of a patient. This depicted embodiment of an Injector comprises a Hamilton syringe body and a Mitino! push wire to deploy the implant. Figure SA shews the Hamilton syringe body inside of an injection maided casing. Figure SB shoves a schematic view of the components of this embodiment of the injector . In certain embodiments, the injector comprising the Hamilton syringe body and the plastic housing parte are pre-assembled in a kit according to the invention and the injector is ready tor use (without or without mounted needle containing the implant). In other embodiments, the injector must be assembled by the physician prior to mounting the needle contain I ng the implant,

[399] In other embodiments, the injection device is an injection molded injector. A schematic exploded view of an embodiment of such injection molded injector is shown in Fig- 6A-6H. In this case the number of assembly steps by the physician just prior to administering the implant: to a patient, is reduced.

[391] The kit may further comprise one or more doses, in particular one dose of an additional: active agent prodrug, ready for injection, The additional active agent grading may be provided in a separate Injection device connected to a needle, or may be provided as a solution or suspension in a sealed vial, from which toe solution or suspension may be aspirated through a needle Into a syringe or other injection device prior to administration. [392] The kit may further comprise an operation manual for the physician who is irsjedtng the implants). The kit: may further comprise a package insert with product-related information.

[393] In addition to toe kit, the present invention in one aspect is also directed to an injection device per se that is suitable for injecting a sustained release biodegradable implant according to the invention into toe body. The injection device may contain means for connecting toe Injection device to a needle, wherein toe needle Is pre-loaded with the implant. The injection device may further contain a push wire to deploy the implant from the needle into the implantation site when the injection device has been connected to the needle, which push wire may be made of Mitino! or staintess steeliTefion or another suitable material. The injection device may further be obtainable by affixing toe wire to the plunger and: encasing it between two snap fit injector body parts and: securing the plunger with a dip. An injection device and a needle pre-loaded with implant in accordance with certain embodiments of the present invention is depicted in Fig, 1,

[394] As illustrated in Fig- 1, in some embodiments, the injection device (e.g., implant injector device) may include a first assembly and: a second assembly that are packaged separately (e.g., in separate enclosures), Fig, BC is an exploded view of the first: assembly and Fig, 69 is an exploded view of the second assembly.

[395] Referring to Fig, AC, the first assembly inciudes a body farming a first interior volume, a plunger including a first distal end disposed within the first interior volume, a wire including a first distal end secured to the first distal end of the plunger, and a plunger clip. The plunger clip is configured to interface with the plunger and the body to prevent actuation of the plunger. The body may include a first body half and a second body half configured to interconnect with each other. The body may include a living hinge that interfaces with a protrusion of the plunger responsive to actuation of the plunger. The living hinge may allow actuation of the plunger responsive to application of a threshold force.

[396] Referring the Fig, 6D, the second assembly indudes a cowl farming a second interior volume, a needle including a base and a lumen, a cowl cap disposed within the base, and a needle shield configured to secure to the cowl and te be disposed around a portion of the lumen, An implant is configured to be. disposed within the. lumen of the needle. The cowl may include a first cowl half and a second cowl half configured to interconnect with each other. The second assembly may further include a polymer tip (e.g., PEG tip) disposed on a second distal end of the lumen.

The implant is secured in the lumen between the cowl cap and the polymer tip. The polymer tip is configured to liquefy (e.g., dissolve) within a user to allow the implant to be injected into the user.

[397] In some embodiments, the second assembly is made from materials that include less moisture and/or undergoes conditioning (e.g,, nitrogen conditioning) prior to being sealed in an enclosure to prevent the implant from absorbing moisture. In some embodiments, the first assembly is made from materials teat include more moisture and/or does not undergo conditioning prior to being sealed in an enclosure since the implant is not included in the enclosure with the first assembly,

[398] The first assembly may be removed from a first enclosure of Fig. 1 and a second assembly may be removed from a second enclosure of Fig. 1. Referring to Fig. 6E, the first assembly and the second assembly may be aligned. One or more exterior recesses of the first assembly may align with one or more interior protrusions of the second assembly. The first assembly and second assembly may include markings (e.g,, arrows) to indicate how to align the first assembly and the second assembly. Referring to Fig, 8F, the cow! of the second assembly is secured to the body of the first assembly (e.g., via the interior protrusions of the cowl entering the exterior recesses of the body). Referring to Fig, 66, the needle shield is removed from the cowl of the second assembly and the plunger clip is removed from the body and plunger of the first assembly. Referring to Fig, 6H, the plunger of the first assembly is actuated (e.g., pushed into the body of the first assembly) to deploy the implant from the lumen of the needle of the second assembly. In some embodiments, the body has a living hinge that allows actuation of the plunger responsive to a threshold force being applied to the plunger, in some embodiments, the lumen of toe needle has a polymer tip (e,g,, a polymer, such as PEG, disposed at least in the distal end of the lumen) blocking the Implant from being deployed from the lumen, insertion of toe lumen with a polymer tip into a user may prevent coring of tissue of the user (e.g., cutting a piece of tissue the diameter of the inside of the lumen to later be deployed into the user). The lumen may be inserted in a user for a threshold amount sf time (e.g., 1 to 5 seconds) to liquefy (e,g., dissolve) the polymer bp. After the polymer fip is liquefied, the Imptent may be deployed from the lumen via actuation of toe plunger. XV, Therapy [399] The sustained drug delivery system of embodiments of the invention can be used for treatment of a variety of medical conditions or diseases in a patient. The systems or implants of embodiments of the invention allow troatment of diseases over prolonged periods if time, providing a steady release of an active agent, such as a substantially constant release. Frequent renewal or reimplantation may be avoided, increasing patient compliance. [400] in embodiments of the invention, the sustained release drug delivery system comprising the hydrogel and the hydrophobic prodrog is configured for use as a medicament.. such as for use in treating a disease or medical condition of a patient. In an embodiment, the method for treating a disease or medical condition of a patient comprises administering the hydrogel to the patient in order to release the hydrophobic prodrug over an extended period of time. [401] A treatment method of an embodiment of the invention comprises an ocular treatment, in such a treatment, the drug delivery system or implant is used to release the active agent prodrug over an extended period of time In the eye, in an embodiment thereof, the disease or medical condition to be treated is an eye disease, or ocular disease, such as back-of-the-eye diseases such as any ocular disease of the posterior segment that affects the vasculature and integrity of the retina, macula or choroid leading to visual acuity disturbances, loss of sight or blindness, particularly disease states of the posterior segment resulting from age, trauma, surgical interventions, such as age-related macular degeneration (AMD) cystoid macular edema (CME), diabetic macular edema (DME), posterior uveitis, and diabetic retinopathy.

[402] The treatment method can also involve treatment of glaucoma, ocular hypertension, hyphema, presbyopia, cataract, retinal vein occlusion, inflammation, myosis, mydriasis, conjunctivitis, intraocular infections, choroidal neovascularization (CNV), intraocuiar tumors, and retinal neuroinflammation. For treating ocular hypertension., pradrugs of prostaglandin analogs such as those described herein can be used, for example selected from one of travoprast: acetate, latanoprost: acetate, travoprost benzoate, or lateuoprost benzoate.

[403] The ocular disease may further be one of retinal neovascularization, choroidal neovascularization, Wet AMD, Dry AMD, retina! vein occlusion, diabetic macular edema, retinal degeneration, corneal graft rejection, retinoblastoma, melanoma, glaucoma, autoimmune uveitis, uveitis, proliferative vitreoretinopathy, and comeal degeneration, acute and chronic macular neuroretinopathy, central serous chorioretinopathy, macular edema, acute multifocal piacoid pigmerit epiiheliopathy., Behcet's disease, birdshot retinachoroidopathy, posterior uveitis, posterior sderitls, serpiginous choroiditis, subretinai fibrosis, uveitis syndrome, V&gt-Koyanagi-Harada syndrome, retinal arterial occlusive disease, central retinal vein occlusion, disseminated intravascular coagulopathy, branch retinal vein occlusion, hypertensive fundus changes, ocular ischemic syndrome, ietinai arterial microaneurysms, Coat's disease, parafoveal telangiectasis., hemi-retinal vein occlusion, papiiiophiebitis, carotid artery disease (CAD), frosted branch angiitis, sickle tell retinopathy, angioid streaks, familial exudative vitfeoretinopathy, Safes disease, proliferative vitteal retinopathy, diabetic retinopathy, retinal disease associated with tumors, congenital hypertrophy of the retinal pigment epitheiium (RPE), posterior uveal melanoma, choroidal hemangioma, choroidal osteoma, choroidal metastasis, combined hamartoma of the retina and retinal pigmented epithelium, retinoblastoma, vasoproiiferative tumors of the ocular fundus, retinal astrocytoma, intraocular lymphoid tumors, myopic retinal degeneration, acute retinal pigment epithelitis, glaucoma, endophthalmitis, cytomegalovirus retinitis, retinal cancers, retinitis pigmentosa, Leber's Congenita! Amaurosis. Choroideremta, x-linked retinitis pigmentosa, best vltelliform macular dystrophy, x- lihked retinoschisis, achromatopsia CNGA3, achromotopsia CIMG83, LHON, Stargardt disease, Usher syndrome, Norrie disease, Batoet-Biedi syndrome, and red-green color blindness.

[404] in certain embodiments, the present invention is thus directed to a method of treating an ocular disease in a patient in need thereof, the method comprising administering to the patient the sustained release biodegradable implant comprising the hydrogel and an active agent prodrug having a solubility of less than 100 pg, 'ml in PSS at pH7.4 and 37°C.

[405] In other embodiments, the present invention Is tows directed to method of t reating cancer in a patient in need thereof, the method comprising administering to the patient the sustained release biodegradable implant comprising the hydrogel and dispersed therein a hydrophobic prodrug of a tyrosine kinase inhibitor, the prodrug having a solubility of fess than WO pg/ml, as measured in PBS at pH7.4 and sy^c.

[406] in some embodiments, the present invention is directed to a method of treating an integrin mediated disease In a patient in need thereof, the method comprising administering to the patient the sustained release biodegradable implant comprising the hydrogel and dispersed therein a hydrophobic prodrug of an integrin Inhibitor compound, the prodrug having a solubility of less than 100 pg/ml, as measured In PS5 at pH7.4 and 37°C.

[407] In certain embodiments, the present invention is further directed to a method of treating pain, such .as moderate to severe pain, tor example post-operative pain, in a patient in need thereof, toe method comprising administering to the patient the sustained release biodegradable implant comprising the hydragel and an active agent prodrug such as a hydrophobic opioid or hydrophobic opioid prodrug as disclosed above.

[408] in specific embodiments, the present invention is directed to a method of treating pain, such as moderate to severe pain, for example post-operative or post-surgical pain, in a patient in need thereof, the method comprising administering to the patient a sustained release biodegradable implant comprising a hydrogel and an active agent prodrug, wherein active agent prodrug particles are dispersed within the hydrogel.

[405] In certain embodiments, the hydrophobic opioid is one of hydrocodone and buprenorphine. In other embodiments, the hydrophobic opioid prodrug fs selected from at least one of dibenzoylmorphine, dibutanoylmorphtne, benzoy toxycodone, butanoyloxycodone, benzoyihydromorphone, and butanoylmorphone, or the other opioid prodrugs mentioned above.

Combination therapy

[4X0] The methods described in this section can also compose administration of the drug delivery system in combination with another agent, also termed “coinbinatibn therapy," [411] In one embodiment, the combination therapy comprises administering the hydrogel in combination with one or more additional agents or prodrugs either on the same or different day. In one embodiment, the additional agent or prodrug to be administered in a combination therapy can be a liquid fotmuiation of the agent or prodrag, or it may be comprised in an oral dosage form. Thus, the additional agent or prodrug can be any small molecule, large molecule, a protein, a nanoparticie, or any ether of the active agents or active agent prodrugs described herein.

[412] The additional agent to be administered in a combination therapy , may also be a diagnostic agent.

Diagnostic agents have been described above and may be substances used to examine the body In order to detect impairment of its normal functions. In some cases, diagnostic agents may bg agents with a functional purpose, such as for use in the detection of ocular deformities, ailments, and pathophysiological aspects. Administration

[413] In embodiments of the treatment method, the dose administered once for the treatment period is contained in one implant or in two or more implants administered concurrently. In certain embodiments of the method, the implant is administered by injection into the human or animal body.

[414] In an embodiment, the dose administered once for a treatment period of at least at least 5 days, or for 3 months is at least about 150 pg, such as from about 150 pg to about 1800 pg, or from about 150 pg to about 1200 μg of the active agent prodrug.

[415] In certain embodiments, the dose of the active agent prodrug, administered once for (i,e., during) the treatment period is in the range of about 200 pg to about 800 pg. In certain embodiments the dose is in the range from about 160 pg to about 250 pg, or from about 180 to about 220 pg, or of about 200 pg. In yet other specific embodiments this dose is in the range from about 320 pg to about 500 pg, or from about 360 pig to about: 440 pg, or of about 400 pg. In yet other embodiments this dose is in the range from about 480 pg to about 750 pg, or from about 540 pg to about 660 pg, or of about 600 pg. In yet other embodiments this dose is In the range from about 640 pg to about 1000 pg, or from about 72G pg to about 880 pg, or of about 800 pg. In yet other embodiments this dose is in the range from about 800 pg to about 1250 pg, or from about 900 pg to about 1100 pg, or of about 1000 pg. In yet other embodiments this dose is in range from about 960 pg to about 1500 pg, or from about 1080 pg to about 1320 pg, or of about 1200 pg.

[416] In certain embodiments of the method, the Implant releases a therapeutically effective amount of hydrophobic prodrug over a period of at least about 5 days, such as 6 days, or 7 days, or 5 days to 2 months, or 5 days to 1 month, or 5 days to 3 weeks, such as 5 or 6 days to 2 weeks, or for Bt least about: 1 month, at least about 2 months, at least about 3 months, at least about 6 months, at least about 9 months, at least about 10 months, at least about 11 months, or at least about 12 months after administration.

[417] Ih some embodiments, ths implant after administration to the human or animal body releases a therapeutically effective amount of hydrophobic prodrug over a period of at least 1 week, or 2 weeks, or 3 weeks, or 1 month, or 6 months. In other embodiments, the implant after administration to the human or animal body releases a therapeutically effective amount of hydrophobic protirug over a period of at least 1 week to 9 months.

[418] In certain embodiments, the treatment period with an implant of the present invention is least 3 months, at least 4.5 months, at least 6 months, at least 9 months, at least 11 months, at least 12 months, at least 13 months, at least: 14 months or even longer, and may for example be about 6 to about 9 months.

[419] For the injection of drug-delivery systems or implants according to the present invention into the human or animal body it is generally desirable to use implants having B therapeutically effective dose of active agent prodrug (f.e„ one that is appropriate in view of particular patient's type and severity of condition) in a relatively small implant in order to facilitate administration (injection) as well as to reduce possible damage to body tissue while the implant is in place. In certain embodiment, the implants of the present invention advantageously combine the benefits of a suitably high dose of the active agent prodrug (i.e., a therapeutically effective dose adjusted to a particular patient's need) with a relatively small implant size,

[420] In certain embodiments, the implant may be administered by means of an injection device according to the present invention connected to a needle pre-loaded with implant as disclosed herein, or may be administered by means of another injection device suitable to be connected to a needle pre-loaded with an implant as disclosed herein, such as a (modified) Hamilton syringe. In other embodiments, a hollow microneedle may be used for suprachoroldal: administration as disclosed in US 8,388,225 which is incorporated by reference herein.

[421] In embodiments wherein two or more implants are administered, the implants are generally administered concurrently as disclosed herein above. The implants administered concurrently can be the same or different. In cases where an administration during the same session is not possible e.g. due to administration complications or patient-related reasons a successive administration during two or more different sessions may alternatively be applied, such as for instance administration of two implants 7 days apart. This may still be considered, as a "concurrent" administration in the context of the present invention,

[422] In certain embodiments the dry implants are loaded in a needle, such as a needle with a gauge size of from 22 to 23, such as a 25-gauge or a 27-gauge needle, or a smaller gauge needle, for injection and are administered to the body, through this needle. In one embodiment, the injector used for injecting the implant into the eye is an injection device according to another aspect of the present invention as disclosed above.

[423] The method of ocular treatment of certain embodiments comprising administering the drug delivery system or Implant may comprise any one of l.ntravitreal, intracameral, subconjunctival, retrobulbar, sub-tenon, subretinal, and suprachoreidal injections. Administration of the drug-delivery system of certain embodiments may also be topical, intradermal, or oral.

[424] In certain embodiments, the drug delivery system is formulated for direct injection at a treatment site of a patient, and may be administered for example by parenteral administration, intratumoral injection, injection into the eye such as intravitreal, intracameral, subconjunctival, retrobulbar, sub-tenon, subretinal, or suprachoroidal injecS tons. In aspects thereof, the drug delivery system is administered by direct injection, by oral application, or incorporated in implants. In certain embodiments, direct injection places a depot and delivers a drug for local or systemic administration. Direct injection may include injecting or implanting a preformed hydrogel at a treatment site, and can further include injection of precursors of the hydrogel or mixtures thereof for in situ forming an active agent prodrug releasing gel depot for delivering a prodrag for local or systemic administtation.

[425] The implant can generally be administered by means of administration routes selected from subcutaneous, intraocular., intracavai, intracamerai, punctal, iniravitreal, subconjunctival, intrascleral, subretinal, episcleral, subconjunctival, choroidal, suprachoroidal, periocular, peribulbar, retrobulbar, intracorneal, retinal, subretinal, intracanalicular, posterior sub-tenon's delivery, anterior sub-Tenon's delivery, cul-de-sac delivery, fornix delivery, or an implant for introduction into the anterior chamber, the vitreous, in the posterior subtenon's space (Inferior fornix), sub-tenon, or a lens, a surface of the cornea or the conjunctiva, puncta (canaliculus, upper/iower canaliculus), ocular fornix, upper/tower ocular fornix, subtenon space, cancer tissue, organ, prostate, breast, joint space, subdural, dental, subcutaneous, carpal tunnel, perivascular, surgically created space or injury, void space, and potential space, for example by injection to these locations. [426] In certain embodiments, the drug-delivery system can be implanted or administered to a body space of a patient by any one of subcutaneously, intramuscularly, intrathecally, epidurally, intraperitoneally, indaderrnaily, subcutaneously, intercostally, intra-artlcularly, intrasynovially, intraspihally, orally, nasally, rectally, intratuffloral, or intravaginal administration. Intra-articuiar administration is to a joint selected from knee, elbow, hip, sternoclavicular, temporomandibular., carpal, tarsal, wrist, ankle, intervertebral disk, or Hgamentum flavum. [427] In certain embodiments of the present invention an insert can be administered to certain parts of the body using an inserter or applicator without crossing a barrier or a membrane, thus, providing a minimally invasive method of administration. Exemplary administration routes thereof are canalicular, fornix inserts, buccal, nasal, optic, vaginal, anal administration,

[428] In certain embodiments, the treatment period is at least 5 days, such as one week, or at feast 2 weeks, or at least 1 month, or at least 2 months, or at least 3 months, but may be at least 4.5 months, at least 6 months, at least 9 months, at least 11 months or at least 12 months. In particular embodiments, the treatment period is at least

6 months, at least 9 months, at least 11 months, at least 12 months, at least 13 months, or at least: 14 months. In certain embodiments, the treatment period may also be longer, such as up to about IS months. "Treatment period" according to one embodiment of the invention means that a certain therapeutic effect, l.e., analgesia, of an implant of the present invention once administered is maintained, essentially maintained or partially maintained over that period of time. In other words, only one injection (of the implant of the present invention) is required in certain embodiments for maintaining a sufficient analgesic effect during the extended period of time referred to herein as "treatment period". An advantage is that the necessity and/or frequency of foe administration of medication during the treatment period is very low. In certain embodiments, no medication is necessary during: the treatment period, such as a treatment period of from about 6 to about 9 months after administration of the implant In certain other embodiments, medication only has to be administered rarely, such as 1, 2 or 3 times during the treatment period. [429] Once injected the implants of certain embodiments of the invention (comprising the hydrogel and the drug) biodegrade within an extended period of time as disclosed above, e,g,, about 9 to 12 months. In certain embodiments, the entire amount of active agent prodrug is dissolved prior to complete degradation of the hydrogel.

In situ applications

[430] In certain embodiments of the invention, the sustained release drug delivery system is administered in a way that the hydrogel including the hydrophobic pradrug is formed in situ at a treatment site of a patient. Since gelation can occur under mild physiologic conditions, geiatiOn may be done within the patient 's body. In aspects thereof, the hydrogel is formed in situ at a treatment site of a patient by combining, at the treatment site or immediately before, a first formulation comprising a first mixture including a first precursor and an active agent prodrug and a second formulation comprising a second mixture including a second precursor forming a hydrogel with the first precursor, and allowing the combined formulation mixture to gel in site at the treatment site by crosslinking reactions.

[431] In an aspect, the first formulation and the second formulation are combined shortly before administering the formulation mixture at the treatment site. In certain embodiments for treatment by in situ gelation of the hydrogel, the first formulation is in a first syringe, the second formulation in a second syringe, and the two formulations are combined in a Y-type mixer before direct injection at the treatment site. Alternatively, the first formulation and the second formulation are each administered at the treatment site, for example by separate injections, thereby combining the formulations at the treatment site, and allowing the combined formulations to gel in situ at the treatment site.

[432] Administration for in situ gel formation can be done by any one of subcutaneously, intramuscularly, intfathecaily, epidurally, intraperitoneally, intradermally, subcutaneously, intercostally, intfa-artiCuiariy, intrasynovially, intraspinaiiy, orally, nasally, rectaily, Intratumorai, or intravaginal administration. In certain embodiments thereof, administration for in situ gel formation example includes parenteral administration, intratumorai injection, injection into the eye such as Intravitreal, intracamerai, subconjunctival, retrobulbar, subtenon, subretinal, or suprachoroidal injections.

V. Release control methods

[433] In embodiments of the present invention there is further provided a method for controlling drug release rate from a hydrogel matrix comprising derivatizing hydrophilic drugs to form hydrophobic prodrugs. The method uses temporarily appending hydrophobic groups (promdieties) to the patent drug molecule bo block hydrophilic mdieties thereof can be used to reduce the rate of prodrug release from a hydrogel matrix. The hydrophobic moleties are the ester, thiol or amide forming groups reacted with at least one hydroxyl, thiol, carboxyl or amine group on the active principle, as described herein before, AS an example, the solubility of dexamethasone (free alcohol) in f>85 at pH 7.4 and 37°C is about 75 pg/ml, for dexamethasone valerate it is about 10>7 ug/mL, for dexamethasone acetate it is about 9 pg/mL, far dexamethasone dipropionate it is about 1.2 pg/mL, and for dexamethasone isonicotinate it is about 0,5 pg/mL, Thus, by selecting a prodrug with a more or less reduced solubility, as compared to the active principle itself, can be used to control active agent release from the hydroget implant by different diffusion rates due to solubility differences.

[434] This method can also be used to convert drugs considered hydrophobic to more hydrophobic forms for the purpose of further stowing do wn release from a hydrogel matrix. Once released from the hydrogel, the hydrophobic prodrug can be transfermed back into the active form of the drug by removal of the hydrophobic groups. Removal can be accomplished by local enzymes, such as carbaxyesterases, or by simple hydrolysis.

[435] One case, where such release control method is desirable is opioid prodrugs for the treatment of pain, such as moderate to severe pain, for example post-operative pain. In an embodiment of the present invention, pain, such as post-operative pain, can be treated by administering an implant that Is biodegradable and provides sustained retease of an opioid prodrug. In another exemplary embodiment of this invention, the slow delivery of an integrin inhibitor or a tyrosine kinase inhibitor to toe eye to treat retinal diseases can be accomplished. Another exemplary embodiment of this invention Is to slow the release rate of prostaglandin analog drugs to the eye to treat glaucoma or ocular hypertension.

EXAMPLES

[436] The following Examples are included to demonstrate certain aspects and embodiments of the invention as described in the claims. It should be appreciated by those of skill in toe art, however, that the following description is illustrative only and should not be taken In any way as a restriction of the invention.

Example 1; Preparation of 3,6- O-Pt benzoyl morphine implants (proohetTcl

[437] The implants of the present application are (essentially) cylindrical (and are also referred to herein as "fibers""), with the morphine prodrug homogeneously dispersed and entrapped within a PEG-based hydrogel matrix to provide sustained release of 3,8-O-Dibenz^'lmofphine based on its low aqueous solubility in the body,

[438] The polymer network of the implants can be formed In a so-called wet-ost process by reacting 2 parts 4a20K PEG-SAZ (a 20 kDa PEG with 4 arms with a N-hydroxysuccinimidyl reactive end group, sometimes also referred to as **NHS" end group) with 1 part 8a20K PEG NH2 (a 20 kDa PEG with 8 arms with an amine end group}. Therefore, a polyurethane tubing is cut into appropriate length pieces. After that, an 8a20K PEG NHZ sodium phosphate dibasic solution Is prepared and sterile filtered to remove endotoxins as well as other particles over

0,2 pm (pore size of the filter). The desired volume of toe PEG amine solution is then weighed into a syringe. Next, corresponding amounts of 3,6-O-Dtbenzoylmorphine depending on the desired final dose in the implant were weighed into another syringe. The powdered 3,fi-£>Dibenzoylmorphine syringe and the PEG amine syringe are mixed carefolly to suspend and disperse the particles. The syringe comprising the suspension mixture is then sonicated to break up any powdered agglomerates. After that, a 4a2«3K PEG SAZ sodium phosphate monobasic solution is prepared and sterile filtered as described for the. PEG amme solution. The desired volume of PEG SAZ solution is then weighed into another syringe. In the next step, the ingredients of both syringes (4a20K PEG SAZ sodium phosphate monobasic solution and 3,6-crDibenzoyimorphine -8a20K PEG NH2 mixture) are mixed to initiate the reaction until gelation occurs. The liquid suspension is cast through the prepared polyurethane tubing before the material crosslinks and solidifies. Gelling time can be confirmed by perfonming a gel tap test. The gel-comprising tubing is then placed into a high humidity curing chamber for 2 hours in order to prevent premature drying of the hydrogel prior to hydrogel gelation, in the chamber., the hydrogel S.S-auibenzoylmorphine suspension in the tubing is allowed to cross-link to campletian creating a highly reacted and uniform gel, thus forming a hydrogel strand.

[439] After curing,, different implant stretching methods can be performed as disclosed herein. Implants are either dry stretched er wet stretched as outlined below. For dry stretching, strands are cut into shorter segments after curing and the strands are dried for 48 to 96 hours. After drying, dried strand segments are removed from the tubing and placed on clamps of a custom stretcher. The strands are then slowly dry stretched: at a controlled rate to achieve the desired diameter that fits into a small gauge needie (stretch factor of about 2 to about 5, or about 3 to about 4.5). The stretching step is preferably performed in an oxygen and moisture free environment to protect the product.

For wet stretching, strands are placed on clamps of a custom stretcher . The strands are then slowly wet stretched at a controlled rate to achieve the desired diameter that fits into a small gauge needle (stretch factor of about 1 to about 3, or about 1.3 to about 2.6). After stretching, the strands are dried under tension under the conditions as described for the dry stretching process,

[440] The stretching creates a shape memory, meaning that the implant upon hydration when administered into the human or animal body wifi rapidly shrink in length and widen in diameter until it approaches its original wet casted dimension. While the narrow dry dimensions facilitate administration of the product through a smaller gauge needle, the widened diameter and shortened length after administration yield a shorter implant (in certain embodiments not much longer than about 10 mm) in the body, minimizing potential contact with surrounding tissues. In general, the degree of shrinking upon hydration depends mt'erMaon the stretch factor. For instance, stretching at e.g. a stretch factor of about 1,3 (wet stretching) will have a less pronounced effect or will not Change the length during hydration to a large extent, in contrast, stretching at e.g. a stretch factor of about 1.8 (wet stretching) will result in a markedly shorter length during hydration, Stretching at e.g, a stretch factor of about 4 (dry stretching) could result in a much shorter length upon hydration (such as, for example, a reduction in length from about 15 to about S mm).

[441] Stretched hydragel strands are removed from the stretcher and then cut to the desired final length. The implant fibers are then placed on the inspection station. If the implants passed the quality control, they are loaded into a 25 or 27 gauge needle (e.g., an FDA-approved 25G UTW to" having an Inner diameter of about 0.4 mm, or a 25G UTW rora 27G TW 1.25” needle) using a customized vacuum device and capped safely to avoid any needle tip damage.

[442] The loaded needles are placed into a glove box for 6 to 9 days to remove any moisture (the remaining water content In the Implant is intended to not exceed 1% water). All steps from then on are performed in the glove box. The loaded needle is dipped into a melted low-molecular weight Ik PEG to tip the needle. Upon coaling a hardened small drop of PEG remains, which provides lubricity, keeps the implant in place within the needle, allows successful depioyment and prevents premature rehydratfon of the implant within the needle during administration. Moreover, PEG tipping is minimizing tissue injUEy i.e. tissue coring, a process by which pieces of tissue are removed by a needle as it passes through the tissue. The PEG-tipped: needles are then again inspected, needles which do not meet the quality requirernents are discarded. Passed needles are again capped to ensure the needles are not suffering any additional damage. Needles are then individually pouched and sealed to prevent them from moisture and keep them sterile. The injection device, for instance a modified Hamilton glass syringe, has a push wire (e.g., a Mitinoi push wire) that allows deploying the implant from the needle more easily. The injection needle may contain a stop feature that controls the injection depth. The. injection device can be Separately packaged and seaied under nitrogen in toll pouches in the same way as described for the needle (Figure 1), or could be pre-assembled with the implant-loaded needle or within a preloaded injector. The packaged needles and Injection devices are removed from the glove box and stored refrigerated (2-8 °C) prior to sterilization using gamma irradiation. After sterilization the packages are stored refrigerated (2-S °Q or frozen protected from light prior to use and are equilibrated 30 min to room temperature prior to injection.

[443] Administration of the implants occurs via injection at the implantation site. After injection, the implants hydrate in situ. Upon hydration upon contact with the body fluids, the implant softens and increases in diameter and may also shrink in length. By trapping opioid prodrug into the hydrogel, a defined and limited localization of the (pro)drug in the body can be provided. The hydrogel matrix of the implant Is formulated to biodegrade via ester hydrolysis in the aqueous environment of the body. Opioid prodrug releases for a sustained period from the hydrogel by diffusion into the body at the implantation site and then into toe surrounding tissues based on the drag's low solubility under physiological conditions (Figure 4). The drug release rate fEom the implants is inter alia inffeenced by diffusion, drug clearance, body fluid viscosity', concentration gradients within and proximate to the implant, implant dose, implant surface area and geometry, as well as the number cf implants and their localization within the body.

Example 2; Preparation of Travoprost prodrugs

[444] Travoprost acetate and travoprost benzoate prodrugs have been synthesized by reacting travoprost with the corresponding acid anhyilrides, Materials have been obtained from Sigma Aldrich.

[445] Travoprost acetate was prepared by dissolving 0.5 g of travoprost oil in 5 mL dichioromethane (DCM), 472 of acetic anhydride, and 0.72 mt of triethanolamine and 10.2 mg of 4-dimethyiaminopyridisne (DMA?) were added as a nucleophilic esterification catalyst The solution was stirred at room temperature (25^<*C) for 24 hours, yieidtng a brown solution, 5 mt of saturated aqueous ammonium chloride were added and extracted with 3x10ml of DCM. The combined organic layers were washed with 20 ml of saturated aqueous sodium bicarbonate and further 10 mt. of DCM were added. The organic layer was dried with anhydrous MgSCM, vacuum filtered to remove solids and concentrated in vacuo to about 2Qm( volume, dried with Nz purge overnight, and isolated by TIC plating using methylene chloride for dissolution and acetonitrile for eiution. 97% Yield, ’H-NMR (400 MHz, CD2CI2, T« 293.15 K, 5): 1.20 (fe, 6H, -COO-CH-(CH3)2), 1.98 (S, 3H, -O-CO-CH3), 2.05 (s, 3H, -O-CO-CH3), 2.07 (s, 3H, -O-CO-CH3), 4.05-4.15 (m, 2H, -CH2-COO-CH-(CH3)2), 4.85-5.00 (m, 2H, -O-CH-CH=CH-), 5.05 (m, 1H, -CH-(CH3)2), 5.30-5.40 (m, 2H, -OOC-(CH2)3-CH=CH-), 5.65-5.80 (m, 2H, -OCC-CH-CH2-CH-OCO-), 7.05-7.50 (4H, Ar) ppm.

[446] Travoprost benzoate was prepared in the same manner from a reaction mixture including 0.5 g of travoprost dissolved in 5 ml dichloromethane (DCM), 1137 pL of benzoic anhydride, and 0.72 ml of triethanolamine ^: and 10.9 mg of 4-dimethylaminopyridine (DMAP), and 9 mL instead of 20 ml saturated aqueous sodium bicarbonate was used. 97% Yield, ‘H-NMR (400 MHz, CD_:Ch, T = 293.15 K, 5): 1.16-1.22 (m, 6H, -COO-CH-(CH3)2), 1.33 (t, 2H, -COO-CH-CH2-CH-OOC-), 1.40-1.60 (m, 2H, CH=CH-CH2-CH2-CH2-), 2.65-2.75 (m, 1H, ArCO-O-CH-), 2.95-3.05 (m, 1H, ArCO-O-CH-), 4.20-4.40 (m, 2H, -CH2-CH2-COO-), 4.85-5.00 (m, 1H, -COO-CH-(CH3)2), 5.50-5.60 (m, 2H, -CH- CH2-CH=CH-), 5.90-6.00 (m, 2H, -CH-CH =CH-HCOR-), 6.00-6.10 (m, 1H, ArCO-O-CHR-CH2-O-), 7.10-8.20 (19H, Ar) ppm. ftaialglllaparation of Latanoprost prodruq

[449] Latanoprost acetate prodrug has been synthesized by reacting latanoprost with acetic acid anhydride following the procedure as described in Example 2. Methylene chloride has been used instead of DCM. 97% Yield, ‘H-NMR (400 MHz, CD2CI2, T = 293.15 K, 6): 1.20 (S.-„ 6H, -COO-CH-(CH3)2), 1.96 (S, 3H, -O-CO-CH3), 2.03 (S, 3H, - 0-C0-CH3), 2.05 (s, 3H, -O-CO-CH3), 4.76-4.84 (m, 1H, -CO-O-CH-), 4.86-4.92 (m, 1H, -CO-O-CH-), 4.98-5.04 (m, 1H, -CO-O-CH-(CH2)2-Ar), 5.30-5.44 (m, 2H, -CH=CH-), 7.15-7.35 (5H, Ar) ppm.

[450] Scheme 2:

SiatlfeliJPfabilitY determination

[451] The solubility in PBS 7.4 at 37° C of the prodrugs travoprost acetate and travoprost benzoate as prepared in Example 2, and, as a control, travoprost were determined as follows:

[452] Standard solutions of all three APIs were prepared for UPLC calibration curves (UPLC integrated peak area versus concentration in pg/mL). The APIs where weighed and dissolved in acetonitrile to provide standard stock solutions. A series of dilution from standard stock solution was prepared. Calibration curves were obtained with corresponding sets of standards. Then, saturated solutions of all three APIs in PBS xl pH 7.4 were prepared. Each API sample was weighed and 5mL of PBS xl pH 7.4 were added. The samples were placed in 37°C for 24hrs. Then, time for dissolution/equilibrium at room temperature was allowed and the sample analyzed with UPLC, and the API solubility was determined with the calibration curve. The results were as shown in Table 1 below: [453] Table 1: Solubility Results [454] The results show that esterification of the three free hydroxyl groups of the prostaglandin analog travoprost (travoprost itself is already a solubility reduced prodrug, namely a mono-isopropyl ester of the active metabolite travoprost free acid, see structures below) can significantly reduce the solubility.

[455] Scheme 3:

[456] Travoprost is a prodrug including an isopropyl ester that is enzymatically hydrolyzed by carboxylesterase 1 (CES1) to produce the travoprost free acid active metabolite.

[457] Travoprost acetate (isopropyl ester plus 3 acetate ester groups, see formula above) prepared as in Example

2 above has been enzymatically hydrolyzed at the same prodrug concentration with assay systems of purified human carboxylesterase enzymes 1 and 2 separately. The conditions were as follows:

Assay system.: hrCES-1 or hrCES-2 with a concentration of 0.1 mg protein/mL at 37 °C

Assay buffer: 100 mM KPCh, pH 7,4

MgClj 5mM

Single incubation of prodrug sample in each hrCES-1 or hrCE-S2 Prodrug sample concentration 1 pM ,

Incubation time points: 0, 15, 30, 60 and 120 min (n=l)

Positive control: known substrate for each isoform evaluated in parallel

Sample treatment: Centrifugation at 1,640^ (3,000 rpm) for 10 minutes at 4°C

Analysis of samples by LC-MS/MS using PARR Data analysis:

The percent remaining of the prodrug is calculated using the following equation:

% Remaining of prodrug = 100 x At/A_c where, At is the peak area ratio (prodrug to IS) at time t and Ao is the peak area ratio (prodrug to IS) at time zero. The elimination rate constant of prodrug is estimated from first-order reaction kinetics: where, Co and Ct are the concentrations of the prodrug (expressed as the peak area ratios of prodrug to IS) at time zero and incubation time t (mm) and k is the elimination rate constant (min ^-1). The elimination half-life t_v? of the prodrug (if applicable) is calculated using the following equation before the plot starts to plateau: _: : where, ti,z is the half-life (min), and k is the elimination rate constant (min ^-1).

The in vitro intrinsic clearance of the prodrug (if applicable) is calculated using the following equation: where, CLnt is the in vitro intrinsic clearance, k is the elimination rate constant (min ^-1), and P is the enzyme concentration in the incubation medium (mg protein/mL).

All intrinsic clearance parameters were estimated using GraphPad® Prism (GraphPad Software, San Diego, CA, USA) and Microsoft Office Excel (Microsoft Corporation, Redmond, WA, USA). Based on the formation of PNP, the hrCES enzymes used in the study were shown to be metabolically active.

[458] The results are summarized in Table 2 below.

[459] Table 2: Hydrolysis of travoprost prodrugs

[4®0] In this series of in vitro hydrolysis experiments, it could be shown that travoprost triacetate could not be completely hydrolyzed to travoprost free acid, the active metabolite, in the presence of carboxylesterase 1 (CES-1) enzyme only. CES-1 only hydrolyzes the isopropyl ester at the carboxyl end of the travoprost molecule. Likewise, it could be shown that CES-2 hydrolyzes the acetate esters, but not the isopropyl ester. Thus, esterification of the hydroxyl groups of the travoprost molecule offers a possibility to not only significantly change the solubility of the (pro)drug, but provides further mechanisms to control active agent release by requiring more than one enzyme for hydrolyzing promoiety bonds in the prodrug.

[461] Table 3 below shows the active metabolite travoprost free acid from the acetate ester prodrug.

[462] Table 3

[463] The results in Table 3 shows appearance only of fully hydrolysed Travoprost acid (all 4 ester groups hydrolysed), ft appears that hrCES-2 is not specific to the isopropyl ester, but also hydrolyses the acetate ester. It could be shown by UPLC data that the aliphatic esters are hydrolysing at a fast rate, while the alpha unsaturated ester appears to be slower to hydrolyse. Extrapolating the 120 minute travoprost free acid values to 100 % hydrolysis gives a delay time of about 6.5 days to quantitative hydrolysis, which offers a further control of active agent release rate. E xample 7: Tafluprost prodrug stability

[464] Tafluprost diacetate prodrug (prostaglandin analog with only aliphatic ester groups) has been analyzed for enzymatic hydrolysis rates in the same experimental setup as given in Example 5 for Travoprost acetate. The results are summarized in Tables 4 and 5 below.

[465] Table 4

[466] Table 5

[467] The results in Table 5 shows appearance only of fully hydrolysed Tafluprost acid (all 3 ester groups hydrolysed). Tafluprost itself (isopropyl ester) was fully hydrolysed by hrCES-1, and partially by hrCES-2. The tafluprost diacetate ester was completely hydrolysed by both enzymes in several hydrolysis steps, with relatively higher intrinsic clearance by hrCES-2. Extrapolating the 120 minute tafluprost free acid values to 100 % hydrolysis gives a delay time of about 3.8 days to quantitative hydrolysis, which offers a further control of active agent release rate.

Example: Latanoprost prodrug stability

[468] Latanoprost triacetate prodrug has been analyzed for enzymatic hydrolysis rates in the same experimental setup as given in Example 5 for Travoprost acetate. The results are summarized in Tables 6 and 7 below.

[469] Table 6

[470] Table 7

[471] The results in Table 7 shows appearance only of fully hydrolysed Latanoprost acid (all 3 ester groups hydrolysed). Latanoprost itself (isopropyl ester) was fully hydrolysed by hrCES-1, and only very slowly by hrCES-2. The Latanoprost triacetate ester was completely hydrolysed by both enzymes in several hydrolysis steps, with relatively higher intrinsic clearance by hrCES-2. Latanoprost free acid was not detected within 2 hours, suggesting partial or very slow multiple hydrolysis steps, and showing a potential to substantially slow down release of the active metabolite from this triacetate prodrug.

Example-9: Dexamethasone isonicotinate hydrogel

[472] The melt extrusion process begins with obtaining the necessary raw materials. This includes the reactive polymers (8al5K PEG SAP and trilysine acetate (TLA)), the API, and Sodium Phosphate Dibasic. Alternatively, the TLA can be substituted with a PEG amine salt. These materials are first combined and mixed for 10 minutes in the melt or powder form to provide a homogenous pelletized, granulated or blended powder material. The material is then loaded into a MiniCTW melt extruder (ThermoFisher, Inc.) , which has been set to temperature (50-55'C) and screw rotation speed (20 rpm). The material may be recirculated within the barrel of the twin-screw mixing extruder for 10 minutes to confirm homogeneity before extrusion. Material can then be extruded through the die of the extruder onto a conveyer belt at a speed of 1000RPM (1.4in/sec). The rate of drawing determines the diameter of _: the extrudate. Drawing keeps material straight and allows it to cool and harden before being cut away from the extruder and collected for downstream processing. After extrusion, material can be placed in a humidity chamber to crosslink, typically overnight, for a period of 16-24 hours. After crosslinking, the damp, rubbery material can be stretched to its final length and then dried overnight, at which point it is ready to be cut and inspected in the same manner it would be in a liquid casting process. The process is performed with the exclusion of water during extrusion, which facilitates activation of the PEG crosslinking reaction. The extrusion was run at low temperature, 50-55’C, since heat is not required to drive a crosslinking reaction. Exposure to a controlled water vapor environment (>95% humidity) after extrusion allows enough water to penetrate the strand to activate the curing reaction. The dampened strand, once crosslinked, is a rubber, which can be stretched at 3X. Evaporative drying with nitrogen sweep leaves a semi-crystalline solid with tie same molecular and physical structure and properties of dried Dextenza® (Dexamethasone intracanalicular insert) strand, albeit not by casting. [473] Table 8 outlines these steps, and considers exemplary equipment for each step as well as exemplary settings for each step.

Table 8: Laboratory bench top process steps

Product Composition:

[474] Using the procedures above, a dexamethasone isonicotinate composition was prepared with the components of Table 9 and extruded. Table 9:

Result#:

[475] Table 10 below summarizes the properties of the obtained extruded hydrogel strands.

Table 10:

[476] The hydrogel steadily released about 9 pg of the dexamethasone isonicotinate in PBS buffer (pH 7.4, 37°C) within 4 days, i.e. about 2.2 pg/day. By linear extrapolation, the implant could be active for about 300 days.

The invention is further described by the following numbered aspects: 1. A sustained release biodegradable drug delivery system comprising a hydrogel and a hydrophobic prodrug dispersed within the hydrogel, wherein the solubility of the prodrug is less than 100 pg/mL, as measured in phosphate-buffered saline (PBS) at 37 °C and pH 7.4.

2. The system of aspect 1, wherein the hydrophobic prodrug has a solubility of less than 50 pg/mL, or less than 10 pg/mL, or less than 1 pg/mL, as measured in phosphate-buffered saline (PBS) at 37 °C and pH 7.4. 3. The system of aspect 1 or 2, wherein the system is selected from an implant and a formulation forming the hydrogel in situ after administration to a patient. 4. The system of any one of aspects 1 to 3, wherein the hydrophobic prodrug is an ester or amide derivative of an active principle.

5. The system of aspect 4, wherein the ester and/or amide derivative of the active principle is a reaction product formed by reacting hydrophilic groups, such as hydroxyl, thiol, carboxyl or amine groups, on the active principle with at least one of an organic acid, alcohol or amine to form hydrophobic moieties on the active principle.

6. The system of aspect 5, wherein the ester and/or amide derivative of the active principle can be hydrolyzed in vivo to form the active principle.

7. The system of any one of the previous aspects, wherein the hydrophobic prodrug or ester and/or amide derivative is at least one of an aliphatic carboxylic acid ester, an aliphatic carboxylic acid thio ester, an aliphatic carboxylic acid amide, an aromatic carboxylic acid ester, an aromatic carboxylic acid thioester, an aromatic carboxylic acid amide, an heteroaromatic carboxylic acid ester, and an heteroaromatic carboxylic acid amide of the active principle, or any combinations thereof.

8. The system of any one of the previous aspects, wherein the hydrophobic prodrug is selected from the group of a monoester, a diester, a multi-ester, a monoamide, a diamide, and a multi-amide of the active principle, depending on the number of reactive hydroxyl, carboxyl and/or amine groups in the active principle, pharmaceutically acceptable salts thereof, or any combinations thereof.

9. The system of any one of the previous aspects, wherein the aliphatic carboxylic acid ester, thioester or amide is the reaction product of one or more hydroxyl, thiol, carboxyl and/or amine groups in the active principle with one or more linear or branched, optionally substituted C2 to CIO alkanoic adds, optionally substituted C3 to CIO cycloalkanoic adds, linear or branched, optionally substituted Cl to CIO alkyl alcohols or thiols, optionally substituted

C3 to CIO cycloalkyl alcohols or thiols, optionally substituted Cl to CIO alkyl amines, or optionally substituted C3 to CIO cycloalkyl amines, or combinations thereof.

10. The system of any one of the previous aspects, wherein the aromatic carboxylic acid ester, thioester or amide is the reaction product of one or more hydroxyl, thiol, carboxyl and/or amine groups or any group subject to esterification or amidation in the active principle to create a degradable functional group with one or more optionally substituted C7 to C14 mono- or polycyclic aromatic or heteroaromatic carboxylic acids, one or more optionally substituted C7 to C14 mono- or polycyclic aromatic or heteroaromatic alcohols, or one or more optionally substituted C7 to C14 mono- or polycyclic aromatic or heteroaromatic thiols, pharmaceutically acceptable salts thereof, or combinations thereof. 11. The system of any one of the previous aspects, wherein the hydrophobic prodrug is an aliphatic, aromatic, or heteroaromatic (thio)ester or amide derivative of an active principle selected from at least one of a therapeutically active agent or a diagnostically active agent, or combinations thereof.

12. The system of aspect 10, wherein the active principle is selected from steroids; non-steroidal antiinflammatory drugs (NSAIDS) such as Diclofenac, Ibuprofen, Meclofenamate, Mefanamic A, Salsalate, Sulindac, Tolmetin, Ketoprofen, Diflunisal, Piroxicam, Naproxen, Etodolac, Flurbiprofen, Fenoprofen C, Indomethacin,

Celecoxib, Ketorolac, Nepafenac; intraocular pressure lowering drugs; antibiotics such as Ciprofloxacin; pain reliever such as Bupivacaine or opioids; calcium channel blockers such as Nifedipine; complement inhibitors such as Avacincaptad pegol; cell cycle inhibitors such as Simvastatin; proteins such as insulin; small molecule hydrophilic drags, including carboxylic acid salts and amine salts; small molecule hydrophobic drugs, hydrophilic peptides arid protein drugs, such as insulin, single chain antibody fragments, Fab fragments, IgG antibodies, fusion antibodies, etc.; aptamers; particularly Bupivacaine (BPV-HCI or base), Ropivacaine (RPV), Dexamethasone, Travoprost, Axitinib, non-steroidal anti-inflammatory drugs (NSAIDS), steroids, antibiotics, pain relievers, calcium-channel blockers, cell cycle inhibitors, chemotherapeutics, anti-viral drugs, anesthetics, hormones, anticancer drugs, antineoplastic agents, viruses, viruses for gene delivery such as AAV, etc., or any combinations thereof. i

13. The system of any of the preceding aspects, wherein the hydrophobic prodrug is an opioid comprising at least one of hydrocodone, buprenorphine, or a hydrophobic ester or amide derivative of an opioid agonist or antagonist selected from the group consisting of morphine, dihydromorphine, desmorphine, normorphine, oxycodone, hydromorphone, buprenorphine, codeine, dihydrocodeine, nalbuphine, nalorphine, naloxone, naltrexone, etorphine, dihydroetorphine, pharmaceutically acceptable salts thereof, or combinations thereof.

14. The system of aspect 13, wherein the aliphatic or aromatic carboxylic acid ester is a di-ester selected from 3,6-di-O-propanoyl, or 3,6-di-O-butanoyl, or 3,6-di-O-hexanoyl, or 3,6-di-O-benzoate, or 3,6-di-O-nicotinoyl esters of at least one of morphine, dihydromorphine, normorphine, nalbuphine, nalorphine, pharmaceutically acceptable salts thereof, or combinations thereof. 15. The system of aspect 13, wherein the aliphatic or aromatic carboxylic acid ester is a mono-ester selected from 3-O-propanoyl, or 3-O-butanoyl, or 3-O-hexanoyl, or 3-O-benzoate, or 3-O-nicotinoyl esters of at least one of morphine, dihydromorphine, desmorphine, normorphine, hydromorphone, buprenorphine, nalbuphine, nalorphine, naloxone, naltrexone, etorphine, dihydroetorphine, pharmaceutically acceptable salts thereof, or combinations thereof. 16. The system of aspect 13, wherein the aliphatic or aromatic carboxylic acid ester is a mono-ester selected from 6-0-propanoyl, or 6-0-butanoyl, or 6-O-hexanoyl, or 6-O-benzoate, or 6-0-nicotinoyl esters of at least one of normorphine, codeine or dihydrocodeine, pharmaceutically acceptable salts thereof, or combinations thereof; or wherein the aliphatic or aromatic carboxylic acid ester is a mono-ester selected from 14-0-propanoyl, or 14-0- butanoyl, or 14-0-hexanoyl, or 14-0-benzoate, or 14-0-nicotinoyl esters of oxycodone, or pharmaceutically acceptable sate thereof, or combinations thereof.

17. The system of any one of aspects 1 to 12, wherein the hydrophobic prodrug is a derivative of dexamethasone selected from the list of dexamethasone valerate, dexamethasone acetate (flurnepredniSblone), dexamethasone cipecilate, dexamethasone diethylaminoacetate, dexamethasone dipropionate, dexamethasone tebutate (dexamethasone tert-butylacetate), dexamethasone succinate, dexamethasone isonicotinate, dexamethasone linoleate, dexamethasone metasulphobenzoate, dexamethasone acefurate, dexamethasone palmitate, dexamethasone phosphate, dexamethasone sulfate, dexamethasone pivalate, and dexamethasone troxundate, preferably an ester of dexamethasone such as dexamethasone isonicotinate, dexamethasone dipropionate, or dexamethasone tebutate.

18. The system of any one of aspects 1 to 12, wherein the hydrophobic prodrug is an aliphatic, aromatic, or heteroaromatic ester or amide of a prostaglandin analog such as travoprost.

19. The system of any of the preceding aspects, wherein the hydrophobic prodrug has a solubility in water at 25

°C of 100 pg/mL or less, 50 pg/mL or less, 50 pg/mL or less, or 10 pg/ml or less, such as 5 pg/ml or less, or 2 pg/ml or less, such as 1 pg/ml or less. : 20. The system of any of the preceding aspects, wherein the hydrophobic prodrug is substantially insoluble in water.

21. The system of any of the preceding aspects, wherein the hydrophobic prodrug is included in the hydrogel in particle form, optionally wherein the hydrophobic prodrug particles are dispersed within the hydrogel.

22. The system of aspect 21, wherein the hydrophobic prodrug particles are micronized particles.

23. The system of aspects 21 or 22, wherein the hydrophobic prodrug particles are encapsulated in a hydrogel shell. r

24. The system of aspect 22, wherein the encapsulated hydrophobic prodrug particles are dispersed within the hydrogel.

25. The system of any of the preceding aspects, wherein the system is an implant in a dried state prior to administration and becomes hydrated once administered or implanted into the human or animal body.

26. The system of any of the preceding aspects, wherein the hydrogel comprises a covalently crosslinked polymer network comprising one or more units of polyethylene glycol, polyethylene oxide, polypropylene oxide, polyvinyl alcohol, poly ( vinylpyrrolich none), polylactic add, polylactic-co-glycolic add, random or block copolymers or combinations or mixtures of any of these, or one or more units of polyaminoacids, glycosaminoglycans, polysaccharides, or proteins.

22. The system of aspect 26, wherein the hydrogel comprises a polymer network that comprises crosslinked polymer units that are identical or different i

28. The system of aspect 26, wherein crosslinked polymer units comprise or consist of one or more crosslinked polyethylene glycol units.

29. The system of any of aspects 26 to 28, wherein the polymer network comprises polyethylene glycol units having an average molecular weight in the range from about 2,000 to about 100,000 Daltons.

30. The system of aspect 29, wherein the polyethylene glycol units have an average molecular weight in the range from about 10,000 to about 60,000 Daltons.

31. The system of aspect 29, wherein the polyethylene glycol units have an average molecular weight in the range from about 20,000 to about 40,000 Daltons.

32. The system of aspect 31, wherein the polyethylene glycol units have an average molecular weight of about 20,000 Daltons.

33. The system of any of aspects 26 to 32, wherein the polymer network comprises one or more crosslinked multi-arm polymer units. i

34. The system of aspect 33, wherein the multi-arm polymer units comprise one or more 2- to 10-arm polyethylene glycol units, such as 4- to 8-arm polyethylene glycol units.

35.^: The system of aspect 34, wherein the multi-arm polymer units comprise one or more 4-arm polyethylene glycol units.

36. The system of any of aspects 26 to 35, wherein the polymer network comprises both 4-arm and 8-arm polyethylene glycol units.

37. The system of any of aspects 26 to 36, wherein the polymer network is formed by reacting an electrophilic group-containing multi-arm-polymer precursor with a nucleophilic group-contaming multi-arm polymer precursor.

38. The system of any of aspects 26 to 37, wherein the electrophilic group is an amine group. 39. The system of any of aspects 26 to 38, wherein the nucleophilic group is an activated ester group.

®. The system of aspect 39, wherein the nucleophilic group is an N-hydroxysuccinimidyl ester (NHS) group, wherein the ester is derived from an alpha-omega dicarboxylic linear aliphatic hydrocarbon, such as succinic add, glutaric acid, adipic add and azelate add.

41. The system of aspect 37, wherein the nucleophilic group is selected from N-hydroxysuccinimidyl monoesters of at least one linear, optionally mono- or di-unsaturated, C2 to C20 dicarboxylic acid, such as oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, azelaic acid, sebacic acid, dodecanoic add, thapsic acid, maleic acid, fumaric acid, and the like.

42. The system of any of aspects 34 to 41, wherein the 4-arm polyethylene glycol units are 4a20kPEG units and the 8-arm polyethylene glycol units are 8a20kPEG unite,

43. The system of aspect 42, wherein the polymer network is obtained by reacting 4a20kPEG-SAZ with 8a20kPEG-NH2 in a weight ratio of about 2: 1 or less (SAZ = N-hydroxysuccinimidyl azelate group).

44. The system of any the preceding aspects, wherein the implant in a dried state contains from about 25% to about 75% by weight of the hydrophobic prodrug and from about 20% to about 60% by weight polymer units.

45. The system of aspect 44, wherein the implant in a dried state contains from about 35% to about 65% by weight of the hydrophobic prodrug and from about 25% to about 50% by weight polymer unite.

46. The system of aspect 45, wherein the system or implant in a dried state contains from about 45% to about 55% by weight of the hydrophobic prodrug and from about 37% to about 47% by weight polymer units.

47. The system of any of the preceding aspects, wherein the system contains one or more salts selected from phosphate, borate, or carbonate salts.

48. The system of aspect 47, wherein the system contains phosphate salt optionally originating from phosphate buffer used during the preparation of the hydrogel. )

49. The system of any of the preceding aspects, wherein the hydrogel in a wet state contains about 3% to about 20% polyethylene glycol representing the polyethylene glycol weight divided by the fluid weight multiplied by 100. ^C

50. The system of aspect 49, wherein the hydrogel contains about 7.5% to about 15% polyethylene glycol representing the polyethylene glycol weight divided by the fluid weight multiplied by 100.

51. The system of any of the preceding aspects, wherein the implant in a dried state contains not more than about 1 % by weight water.

52. The system of any of the preceding aspects, wherein the implant has an essentially cylindrical shape, or a cross shape. I

53. The system of any of the preceding aspects, wherein the implant is in the form of a fiber.

54. The system of any of the preceding aspects, wherein the system or implant is administered to the body through a needle.

55. The system of aspect 54, wherein the needle is a 25- or 27-gauge needle.

56. The system of any of the preceding aspects, wherein upon hydration in vivo in the human or animal body, or in vitro, the diameter of the implant is increased, or the length of the implant is decreased while its diameter is increased. 57. The system of aspect 56, wherein hydration is measured in vitro in phosphate-buffered saline at a pH of 7.4 at 37 °C after 24 hours.

58. The system of any of the preceding aspects, wherein the implant biodegrades by hydrolysis and/or enzymatic cleavage in the human or animal body within about 2 weeks to about 15 months, such as 3 or 4 weeks to about 15 months, or 1 to about 15 months or 2 to 14 months after administration.

59. The system of aspect 58, wherein the implant biodegrades in the human or animal body within about 4 to about 13 months after administration.

60. The system of aspect 59, wherein the implant biodegrades in the human or animal body within about 9 to about 12 months after administration. 61, The system of any of the preceding aspects, wherein the implant after administration to the human or animal body releases a therapeutically effective amount of hydrophobic prodrug over a period of at least about 5 days, such as 6 days, or 7 days, or 5 days to 2 months, or 5 days to 1 month, or 5 days to 3 weeks, such as 5 or 6 days to 2 weeks; or for at least about 1 month, at least about 2 months, at least about 3 months, at least about 6 months, at least about 9 months, at least about 10 months, at least about 11 months, or at least about 12 months after administration.

62. The system of aspect 61, wherein toe implant after administration to toe human or animal body releases a therapeutically effective amount of hydrophobic prodrug over a period of at least 1 week, or 2 weeks, or 3 weeks, or 1 month, or 6 months. 63. The system of aspect 62, wherein the implant after administration to the human or animal body releases a therapeutically effective amount of hydrophobic prodrug over a period of at least 1 week to 9 months.

64. The system of any of the preceding aspects, wherein hydrophobic prodrug is released from the implant after administration at an average rate of about 0.1 pg/day to about 30 pg/day.

65. The system of aspect 64, wherein hydrophobic prodrug is released from the implant at an average rate of about 0.5 pg/day to about 30 pg/day; or at an average rate of 0.5 mg/day to about 30 mg/day.

66. The system of aspect 65, wherein hydrophobic prodrug is released from the implant at an average rate of about 1 pg/day to about 20 pg/day; or at an average rate of about 1 mg/day to about 20 mg/day.

67. The system of any of the preceding aspects, wherein the implant biodegrades in the human or animal body prior to complete solubilization of the hydrophobic prodrug particles contained in toe implant. 68, The system of any of the preceding aspects, wherein the entire amount of the hydrophobic prodrug contained in the implant is released prior to the complete degradation of the implant in the human or animal body. 69. The system of any of the preceding aspects, wherein the implant is obtainable by preparing a mixture containing hydrogel precursors and the hydrophobic procrug, filling the mixture into a tubing, allowing the hydrogel to gel in the tubing to provide a hydrogel shaped as a fiber, and stretching the hydrogel fiber. 70. The system of aspect 69, wherein the fiber has been stretched and/or twisted prior to or after drying.

71. The system of aspect 70, wherein the fiber has been stretched by a stretch factor in the longitudinal direction of from about 1.0 to about 4.5.

72. The sustained release implant of any one of aspects 3 to 71, wherein the hydrogel comprises a polymer network comprising polyethylene glycol units, and wherein toe implant is in a dried state prior to administration. 73, The implant of aspect 72, wherein the polymer network is formed by reacting 4a20kPEG-SAZ with 8a20kPEG-NH2.

74, The implant of aspect 73, wherein the hydrogel when formed and before being dried contains 7.5% polyethylene glycol, representing the polyethylene glycol weight divided by the fluid weight multiplied by 100. 75. The implant of any of aspects 72 to 74, wherein the implant in a dried state contains from about 45% to about 55% by weight hydrophobic prodrug and from about 37% to about 47% by weight polyethylene glycol units.

76. The implant of any of aspects 72 to 75, wherein the implant in a dried state contains not more than about 1

% by weight water.

77. The implant of any of aspects 72 to 76, wherein the polymer network is formed by reacting 4a20kPEG-SAZ with 8a20kPEG-NH2 in a weight ratio of about 2:1 or less,

78. The implant of any of aspects 72 to 77, wherein the implant releases in vitro about 0.01 pg to about 0.15 pg of hydrophobic prodrug per day in phosphate-buffered saline at 37 °C for a period of 30 days.

79. The implant of any of aspects 72 to 78, wherein the implant releases in vitro about 35 % to about 45 % of the hydrophobic prodrug in 3 days, about 65 % to about 75 % of the hydrophobic prodrug in 7 days, and about 90 % to about 100 % of the hydrophobic prodrug in 12 to 13 days in a 25:75 ethanol/water mixture (v/v) at 37 °C.

80. The implant of any of aspects 72 to 79, wherein the implant releases in vitro about 25 % to about 35 % of the hydrophobic prodrug in 2 months, about 47 % to about 57 % of the hydrophobic prodrug in 3 months, about 70 % to about 80 % of the hydrophobic prodrug in 5 months, and about 90 % to about 100 % of the hydrophobic prodrug in 7 months in phosphate buffered saline at a pH of 7.2, at 37 °C and with an octanol top layer. 81. The implant of any of aspects 72 to 80, wherein the implant is in the form of a fiber that has an average length of about 15 mm to about 16.5 mm and an average diameter of about 0.20 mm to about 0.30 mm in its dried state.

82. The implant of aspect 81, which decreases in length and increases in diameter upon hydration in vivo in the human or animal body or in vitro, wherein hydration in vitro is measured in phosphate-buffered saline at a pH of 7.2 at 37 °C after 24 hours.

83. The implant of aspect 72 to 80, wherein the implant in its hydrated state has an average length of about 6.5 to about 8 mm and an average diameter of about 0.70 to about 0.80 mm.

84. The implant of any of aspects 72 to 83, wherein the implant is obtainable by preparing a mixture containing hydrogel precursors and hydrophobic prodrug, filling the mixture into a tubing, allowing the hydrogel to gel in the tubing to provide a hydrogel shaped as a fiber, and stretching the hydrogel fiber.

85. The implant of aspect 84, wherein the fiber is stretched after drying by a factor of about 2 to about 5.

86. The implant of aspect 85, wherein the fiber is stretched after drying by a factor of about 3 to about 4.5.

87. The implant of any of aspects 72 to 86, wherein the implant in a dried state is loaded in a needle, such as a 25-gauge needle or a 27-gauge needle, suitable for injection into the human or animal body. 88. A sustained release biodegradable implant containing a hydrophobic opioid prodrug dispersed in a hydrogel, wherein the hydrogel comprises a polymer network, whe'ein the solubility of the opioid prodrug is less than 100 pg/mL, as measured in phosphate-buffered saline (PBS) at 37 °C and pH 7.4. 89. The implant of aspect 88, wherein the hydrophobic opioid prodrug is an aliphatic or aromatic acid ester of an opioid agonist or antagonist selected from the group consisting of morphine, oxycodone, hydromorphone, buprenorphine, codeine, dihydrocodeine, naloxone, naltrexone, etorphine, dihydroetorphine, or combinations thereof.

90. The implant of aspect 89, wherein the polymer network comprises crosslinked polyethylene glycol units. 91. The implant of any of aspects 88 to 90, wherein the polyethylene glycol units comprise 4-arm and/or 8-arm polyethylene glycol units having an average molecular weight in the range from about 10,000 Daltons to about 60,000 Daltons.

92. The implant of aspect 91, wherein the polyethylene glycol units comprise 4a20kPEG units.

93. The implant of aspect 92, wherein the polymer network is formed by reacting 4a20kPEG-SAZ with 8a20kPEG-NH2.

94. The implant of aspect 93, wherein the weight ratio of 4a20kPEG-SAZ to 8a20kPEG-NH2 is about 2:1 or less.

95. The implant of any of aspects 88 to 94, wherein the implant in a dried state contains from about 45% to about 55% by weight hydrophobic opioid prodrug and from about 37% to about 47% by weight polyethylene glycol units. 96. The implant of any of aspects 88 to 95, wherein the implant in a dried state contains not more than about

1% by weight water.

97. The implant of any of aspects 87 to 95, wherein the implant is in the form of a fiber that in its dried state has an average length of about 7 mm to about 12 mm and an average diameter of about 0.25 mm to about 0.50 mm. 98. The implant of aspect 97, wherein the implant is in the form of a fiber that in its dried state has an average length of about 8 mm to about 11 mm and an average diameter of about 0.3 mm to about 0.4 mm.

99. The system or implant of any of the previous asdects, wherein the implant is for administration to a route selected from subcutaneous, intraocular, intracaveal, intracameral, punctal, intravitreal, subconjunctival, intrascleral, subretinal, episcleral, subconjunctival, choroidal, suprachoroidal, periocular, peribulbar, retrobulbar, intracorneal, retinal, subretinal, intracanalicular, posterior sub-Tenon's delivery, anterior sub-Tenon's delivery, cul-de-sac delivery, fornix delivery, or an implant for introduction into the anterior chamber, the vitreous, in the posterior subtenon's space (Inferior fornix), sub-tenon, or a lens, a surface of the cornea or the conjunctiva, puncta (canaliculus, upper/lower canaliculus), ocular fornix, upper/lower ocular fornix, subtenon space, cancer tissue, organ, prostate, breast, joint space, subdural, dental, subcutaneous, carpal tunnel, perivascular, surgically created space or injury, void space, and potential space. ^: T

100. The implant of aspect 97 to 99, which increases in diameter upon hydration in vivo in the human or animal body or in vitro, wherein hydration in vitro is measured in phosphate-buffered saline at a pH of 7.2 at 37 °C after 24 hours.

101. The implant of aspect 100, wherein the implant in its hydrated state has an average length of about 9 mm to about 12 mm and an average diameter of about 0.5 mm to about 0.8 mm,

102. The implant of aspect 101, wherein the implant in its hydrated state has an average length of about 9.5 mm to about 11.5 mm and an average diameter of about 0.65 mm to about 0.75 mm or has an average length in its hydrated state of not more than about 10 mm or not more than about 9 mm. 103. The implant of any of aspects 88 to 102, wherein the implant releases in vitro about 0.3 pg to about 0.5 pg of hydrophobic opioid prodrug per day in phosphate-buffered saline at 37 °C for a period of 30 days.

104. The implant of any one of aspects 88 to 103, wherein the implant releases in vitro about 40 % to about 60 % of the hydrophobic opioid prodrug in 2 days, about 65 % to about 85 % of the hydrophobic opioid prodrug in 4 days, and about 75 % to about 90 % of the hydrophobic opioid prodrug in 6 days in a 25:75 ethanol/water mixture (v/v) at 37 °C. I

105. The implant of aspect 104, wherein the implant releases in vitro about 45 % to about 55 % of the hydro- phobic opioid prodrug in 2 days, about 70 % to about 80 % of the hydrophobic opioid prodrug in 4 days, and about 80 % to about 90 % of the hydrophobic opioid prodrug in 6 days in a 25:75 ethanol/water mixture (v/v) at 37 °C. 106. The sustained release biodegradable implant of any of aspects 88 to 105, wherein the implant is obtainable by preparing a mixture containing hydrogel precursors and hydrophobic opioid prodrug, filling the mixture into a tubing, allowing the hydrogel to gel in the tubing to provide a hydrogel shaped as a fiber, and stretching the hydrogel fiber.

107. The implant of aspect 106, wherein the fiber is wet-stretched prior to drying by a factor of about 0.5 to about 5,

108. The implant of aspect 107, wherein the fiber is wet-stretched prior to drying by a factor of about 1 to about

109. The implant of aspect 108, wherein the fiber is wet-stretched prior to drying by a factor of about 1.5 to about 3.5. 110. The implant of aspect 109, wherein the fiber is wet-stretched prior to drying by a factor of about 1.7 to about 3.

111. The implant of any of aspects 88 to 110, wherein the implant in a dried state is loaded in a needle for injection into the human or animal body.

112. The implant of aspect 111, wherein the implant in a dried state is loaded in a 25-gauge or a 27-gauge needle.

113. The system or implant of any of the preceding aspects, wherein the hydrogel comprises a polymer network which Is semi-crystalline in the dry state at or below room temperature, and amorphous in the wet state.

114. The system or implant of any of the preceding aspects, wherein the implant has undergone wet or dry stretching during manufacture, and wherein the implant in the stretched form is dimensionally stable when in the dry state at or below room temperature. :

115. A method for treating a disease or medical condition of a patient, comprising administering the system or implant of any one of aspects 1 to 114 to a patient, releasing the hydrophobic prodrug over an extended period of time. _:

116. A method of treating an ocular disease in a patient in need thereof, the method comprising administering to the patient the sustained release biodegradable system or implant of any one of aspects 1 to 114 comprising the hydrogel and dispersed therein a hydrophobic prodrug having a solubility of less than 100 pg/mL, as measured in PBS at pH7.4 and 37°C. :

117. The method of aspect 115, wherein the hydropnobic prodrug is an ester, thioester or amide derivative of a prostaglandin analog such as bimatoprost, latanoprost, tfavoprost, tafluprost, Or latanoprbstene bunOd. 118. A method of treating cancer in a patient in need thereof, the method comprising administering to the patient a sustained release biodegradable implant comprising a hydrogel and dispersed therein a hydrophobic prodrug of a tyrosine kinase inhibitor, the prodrug having a solubility of less than 100 pg/mL, as measured in PBS at pH7.4 and 37°C.

119. A method of treating an integrin mediated disease in a patient in need thereof, the method comprising administering to the patient a sustained release biodegradable implant comprising a hydrogel and dispersed therein a hydrophobic prodrug of an integrin inhibitor compound, the prodrug having a solubility of less than 100 pg/mL, as measured in PBS at pH7.4 and 37°C.

120. A method of treating pain in a patient in need thereof, the method comprising administering to the patient the sustained release biodegradable implant according to any of aspects 3 to 114, comprising a hydrogel and a hydrophobic opioid or hydrophobic opioid prodrug having a solubility of less than 100 pg/mL, as measured in PBS at pH7.4 and 37°C. :

121. The method of aspect 120, wherein the hydrapnobic opioid is one of hydrocodone and buprenorphine.

122. The method of aspect 121, wherein the hydropnobic opioid prodrug is selected from at least one of dibenzoylmorphine, dibutanoylmorphine, benzoyloxycodane, butanoyloxycodone, benzoylhydromorphone, and butanoylmorphone.

123. The method of aspect 122, wherein the delivery route is selected from subcutaneous, intraocular, intracaveal, intracameral, punctal, intravitreal, subconjunctival, intrascleral, subretinal, episcleral, subconjunctival, choroidal, suprachoroidal, periocular, peribulbar, retrobulbar, intracorneal, retinal, subretinal, intracanalicular, posterior sub-Tenon's delivery, anterior sub-Tenon's delivery, cul-de-sac delivery, fornix delivery, or an implant for introduction into the anterior chamber, the vitreous, in the posterior subtenon's space (Inferior fornix), sub-tenon, or a lens, a surface of the cornea or the conjunctiva, puncta (canaliculus, upper/lower canaliculus), ocular fornix, upper/lower ocular fornix, subtenon space, cancer tissue, organ, prostate, breast, joint space, subdural, dental, subcutaneous, carpal tunnel, perivascular, surgically created space or injury, void space, and potential space.

124. The method of any of aspects 115 to 123, wherein the dose administered once for the treatment period is contained in one implant or in two or more implants administered concurrently.

125. The method of any of aspects 115 to 124, wherein the implant is administered by injection into the human or animal body.

126. The method of any of aspects 115 to 125, wherein the treatment period is at least 2 months, at least 4.5 months, at least 6 months, at least 9 months, at least 11 months or at least 12 months.

127. The method of aspect 126, wherein the treatment period is at least 6 months, at least 9 months, or at least 11 months.

128. The method of any of aspects 115 to 127, wherein the hydrophobic opioid or hydrophobic opioid prodrug is dispersed in the hydrogel which comprises a polymer network formed by reacting 4a20kPEG-SAZ with 8a20kPEG- NH2, and wherein the implant is in a dried state prior to administration.

129. The method of aspect 128, wherein the hydrogel when formed and before being dried contains about 7.5% polyethylene glycol, representing the polyethylene glycol weight divided by the fluid weight multiplied by 100.

130. The method of any of aspects 115 to 129 wherein the treatment period is at least 9 months. 131. The method any of aspects 120 to 130, wherein the implant is administered by injection into the human or animal body by means of a 25- or a 27-gauge needle.

132. A method of manufacturing a sustained release biodegradable drug delivery system or implant according to any of aspects 1 to 114, the method comprising the steps of forming a hydrogel comprising a polymer network and hydrophobic opioid or hydrophobic opioid prodrug particles dispersed in the hydrogel, shaping the hydrogel, and drying the hydrogel.

133. The method of aspect 132, wherein the hydropnobic opioid or hydrophobic opioid prodrug particles are _: micronized and/or encapsulated and/or homogeneously dispersed within the hydrogel.

134. The method of any of aspects 132 or 133, wherein the polymer network is formed by crosslinking multi-arm polyethylene glycol units in a buffered solution.

135. The method of any of aspects 132 to 134, wherein the hydrogel comprises a polymer network that is formed by mixing and reacting an electrophilic group-containing multi-arm polyethylene glycol with a nucleophilic group-containing multi-arm polyethylene glycol in a buffered solution in the presence of the hydrophobic opioid or hydrophobic opioid prodrug and allowing the mixture to gel.

136. The method of aspect 135, comprising reacting 4a20kPEG-SAZ with 8a20kPEG-NH2 in a weight ratio of about 2:1.

137. The method of aspect 135 or 136, wherein the method comprises the steps of filling the mixture into a mold or tubing poor to complete gelling in order to provide the desired final shape of the hydrogel, allowing the mixture to gel, and drying the hydrogel.

138* The method of aspect 137, wherein the mixture is filled into a fine diameter tubing in order to prepare a hydrogel fiber.

139. The method of aspect 138, wherein the inside of the tubing has a round geometry.

140. The method of aspect 139, wherein the inside of the tubing has a non-round geometry.

141. The method of aspect 140, wherein the inside of the tubing has a cross-shaped geometry.

142. The method of any of aspects 13S to 141, wherein the method further comprises stretching the fiber and/or twisting the fiber.

143. The method of aspect 142, wherein the stretching is performed prior to or after drying the hydrogel.

144. The method of aspect 143, wherein the fiber is stretched by a stretch factor of about 1 to about 4.5.

145. The method of aspect 144, wherein the stretching is performed after drying the hydrogel by a stretch factor of about 2 to about 5 or a stretch factor of about 3 to about 4.5.

146. The method of aspect 145, wherein the stretching is performed in a wet state prior to drying the hydrogel at a stretch factor of about 0.5 to about 5, or a stretch factor of about 1 to about 4, or a stretch factor of about 1.3 to about 3,5, or a stretch factor of about 1.7 to about 3.

147. The method of any of aspects 132 to 146, wherein the method further comprises loading the implant in a dried state into a needle.

148. The method of aspect 147, wherein the needle is a 25- or 27-gauge needle.

149. A method of imparting shape memory to a hydrogel fiber comprising a hydrophobic prodrug dispersed in the hydrogel by stretching the hydrogel fiber in the longitudinal direction. 150. A method of manufacturing an implant comprising a hydrogel comprising hydrophobic prodrug dispersed therein, wherein the implant changes its dimensions upon administration to the human or animal body, the method comprising preparing a fiber of the hydrogel and stretching the fiber in the longitudinal direction.

151. The method of aspect 149 or 150, wherein the method comprises the step of drying the hydrogel, wherein the fiber is stretched in the longitudinal direction prior to or after said drying (wet or dry stretching).

152. The method of any of aspects 149 to 151, wherein the fiber is stretched by a factor of about 0.5 to about

5, or a factor of about 1 to about 4.5, or a factor of about 3 to about 4.5 or a factor of about 1 to about 2.

153. The method of any of aspects 149 to 152, wherein the hydrogel comprises a polymer network comprising crosslinked polyethylene glycol units. 154. The method of any of aspects 149 to 153, wherein the fiber upon hydration fully or partly returns to approximately its original length and/or original diameter that it had prior to the stretching.

155. The method of any of aspects 149 to 154, wherein the change in dimensions is an increase in diameter, or an increase in diameter together with a decrease in length.

156. A kit comprising one or more sustained release biodegradable drug delivery system(s) or implant(s) according to any of aspects 1 to 114 or manufactured in accordance with the method of any of aspects 150 to 155, and one or more needle(s), wherein the one or more needle(s) is/are each pre-loaded with one sustained release biodegradable implant in a dried state.

157. The kit of aspect 156, wherein the needle(s) is/are 25- or 27-gauge needle(s).

158. The kit of aspect 156 or 157, wherein the kit comprises one or more 25- or 27-gauge needle(s) each loaded with an implant. ^:

159. The kit of aspect 158, wherein the kit comprises one 25-gauge or 27— gauge needle loaded with an implant.

160. The kit of any of aspects 156 to 159, further containing an injection device for injecting the implant into the body of a patient. 161. The kit of aspect 160, wherein the injection device is provided in the kit separately from the one or more needle(s) loaded with implant.

162. The kit of aspect 161, wherein the injection device is pre-connected to a needle loaded with implant.

163. The kit of aspect 161 or 162, wherein the injection device contains a push wire to deploy the implant from the needle into the human or animal body. 164. An injection device suitable for injecting a sustained release biodegradable drug delivery system or implant according to any of aspects 1 to 114 into the human or animal body.

165. The injection device of aspect 164 containing means for connecting the injection device to a needle,

166. The injection device of aspect 164 or 165, wherein the needle is pre-loaded with the implant.

167. The injection device of any of aspects 164 to 166 containing a push wire to deploy the implant from the needle into the eye when the injection device has been connected to the needle.

168. The injection device of aspect 167, wherein the push wire is made of Nitinol or stainless steel/Teflon.

169. The injection device of aspect 167 or 168, obta nable by affixing the wire to the plunger and encasing it between two snap fit injector body parts and securing the plunger with a clip. 170. A pharmaceutical product comprising the sustained release biodegradable drug delivery system or implant of any of aspects 1 to 114 loaded in a needle and an injection device according to any of aspects 163 to 168.. wherein the needle is pre-connected to the injection device.

171. A sustained release biodegradable drug delivery system or implant according to any of aspects 1 to 114 for use In treating an ocular disease, or far treating pain, such as moderate to severe palp, or post-operative pain, in a patient in need thereof according to the method of any of aspects 115 to 131.

172. A use of a sustained retease biodegradable drug delivery system or implant according to any of aspects 1 to 114 in the preparation of a medicament for the treatment of an ocular disease or treatment of pain in a patient in need thereof according to the method of any of aspects 115 to 131.

Claims

1. A sustained release biodegradable drug delivery system comprising a hydrogel and a hydrophobic prodrug dispersed within the hydrogel., wherein the solubility' of the prodrug is less than 100 pg/rnl, as measured In phosphate-buffered saline (PBS) at 37 °C and pH 7.4.

2. The system of claim 1, wherein the hydrophobic prodrug has a solubility of less than 50 pg/ml, or less than 10 pg/mL, or less than 1 pg/ml, as measured in phosphate- buffered saline (PBS) at 37 °C and pH 7.4.

3. The system of claim 1 er 2, wherein the system is selected from an implant and a formulation forming foe hydrogel in situ after administration to a patient.

4. The system of any one of claims 1 to 3, wherein the hydrophobic prodrug is an ester or amide derivative of an active principle.

5. The system of claim 4, wherein the ester and/or amide derivative of the active principle is a reaction product formed by reacting hydrophilic groups, such as hydroxyl, thiol, carboxyl or amine groups, on the active principle with at least one of an organic acid, alcohol or amine to form hydrophobic moleties on the active principle.

6. The system of claim 5, wherein the ester and/ot amide derivative of the active principle can be hydrolyzed in vivo to form the active principle.

7. The system of any one of the previous claims, wherein the hydrophobic prodrug or ester and/or amide derivative is at least one of an aliphatic carboxylic acid ester, an aliphatic carboxylic acid thio ester, an aliphatic carboxylic acid amide, an aromatic carboxylic acid ester, an aromatic carboxylic acid thioester, an aromatic carboxylic acid amide, ars heteroaromatic carboxylic acid ester, and an heteroaromatic carboxylic acid amide of the active principle, or any combinations thereof,

8. The system of any one of the previous claims, wherein the hydrophobic prodrug is selected from the group qf a monoestet , a diestet, a multi-ester, a monoamide, a diamide, and a multi-amide of the active principle, depending on the number of reactive hydroxyl, carboxyl and/or amine groups in the active principle, pharmaceutically acceptable salts thereof, or any combinations thereof,

9. The system of any one of the previous claims, whereto the hydrophobic prodrug is an aliphatic, aromatic, or heteroaromatic (thio)ester or amide derivative of an active principle selected from at least one of a therapeutically active agent or a diagnostically active agent., or combinations thereof.

10. The system of ciaim 10, wherein the active principle is selected from steroids; non-steroidal antiinflammatory drugs (NSAiEJS) such as Diclofenac, Ibuprofen, Meclofenamete, fdefanamic A, Saisaiate, Sulindac, Tolmetin, Ketoprofen, Dsflurusai, Piroxfcam, Naproxen, Etodolac, Flurbiprofen,. Fenoprofen C, Indomethacin, Ceiecoxib, Ketorolac, Nepafenac; intraocular pressure towering drugs; antibiotics such as Qpraffoxacin; pain reliever such as Bupivacaine or opioids; calcium channel blockers such as Nifedipine; complement Inhibitors such as Avacincaptad pegoi; ceil cycle inhibitors such as Simvastatin; proteins such as insulin; small molecule hydrophilic drugs, including carboxylic add salts and amine salts; small molecule hydrophobic drugs, hydrophilic peptides and protein drugs, such as insulin, single chain antibody fragments. Fab fragments, IgG antibodies, fusion antibodies, ete,; aptamers; particularly Bupivacaine (BPV-HCI or base), Ropivacaine (RPV), Dexamethasone, Travoprost, Axltlnib, non-steroidal anti-inflammatory drugs

(NSAIDS), steroids,, antibiotics, pain relievers, caldum-cbahnel blockers, cell cycle inhibitors, chemotherapeutics,. anti-viral drugs, anesthetics, hormones, anticancer drugs, antineoplastic agents, viruses, viruses for gene delivery such as AAV, etc,, or any combinations thereof,

11. The system of any of the preceding claims, wherein the hydrophobic prodrug is an apioid comprising at least one of hydrocodone, buprenorphine, or a hydrophobic ester or amide derivative of an opioid agonist or antagonist selected from the group consisting of morphine, dihydromorphine, desmorphtne, nermorphlne, oxycodone, hydromorphone, buprenorphine, codeine, dihydrocodeine, nalbuphine, nalorphine, naloxone, naltrexone, etorphine, dihydroetorphine, pharmaceutically acceptable salts thereof, or combinations thereof.

12. The system of claim 11, wherein the aliphatic or aromatic carboxylic acid ester is a di-ester selected from 3,8-di-t>propanoyi, or 3,6-dl-O-butanoyi, or 3,6-di-tThexanoyl, or 3,6-dl-O-benzoate, or 3,6-dj-Onicotinoyl esters of at least one of morphine, dihydromorphine, normorphine, nalbuphine, nalorphine, pharmaceutically acceptable salts thereof, or combinations thereof.

13. The system of claim 11, wherein the aliphatic or aromatic carboxylic acid ester is a mono-ester selected from 3-O-propanoyl, or 3-<9-butanoyl, or 3-O-hexanoyl, or 3-0 benzoate, or 3 -CMcotinoyl esters of at least one of morphine, dihydromorphine, desmorphine, normorphine, hydromorphone, buprenorphine, nalbuphine, nalorphine, naloxone, naltrexone, etorphine, dihydroetorphine, pharmaceutically acceptable salts thereof, or combinations thereof, or wherein the aliphatic or aromatic carboxylic acid ester is a monoester selected from 8-i>propanoyl, or S-O-butanoyl, or 6-ahexanoyl, or 6-Obenzoate, or 6-C.Tnicotinayl esters of at least one of norfftorphine,, codeine or dihydrocodeine, pharmaceutically acceptable salts thereof, or combinations thereof; or wherein the aliphatic or aromatic carboxylic acid ester is a mono-ester selected from 14-£Tpropanoyl, or 14-£>butanoyl, or 14-£>hexanoyl, or 14- O- benzoate, or 14-Omcotirroyl esters of oxycodone, or pharmaceutically acceptable salts thereof, or combinations thereof,

14. The system of any one of claims 1 to 10, wherein the hydrophobic prodrug is a derivative of dexamethasone selected from the list of dexamethasone valerate, dexamethasone acetate (flumeprednisolone), dexamethasone clpecilate, dexamethasone diethylaminoacetate, dexamethasone dipropionate, dexamethasone tebutate (dexamethasone tert-butyiacetate), dexamethasone succinate, dexamethasone isonicotinate, dexamethasone linoleate, dexamethasone metasulphobenzoate, dexamethasone acefurate, dexamethasone palmitate, dexamethasone phosphate, dexamethasone seif ate, dexamethasone pivalate, and dexamethasone troxundate, preferably an ester of dexamethasone such as dexamethasone isonicotinate, dexamethasone dipropionate, or dexamethasone tebutate,

15, The system of any one of claims 1 to 12, wherein the hydrophobic prodrug is an aliphatic, aromatic, or heteraaromato ester or amide of a prostaglandin analog such aS travoprost,

16, The system of any of the, preceding claims, wherein the hydrophobic prodrug has a solubility in water at 25 °C of 100 yg/mL or less, 50 pg/ml or less, 50 pg/mL or less, or 10 pg/ml or less, such as 5 pg/ml or less, or 2 pg/rni or less, such as 1 pg, /ml or less.

17, The system of any of the pre-ceding claims, wherein the hydrophobic prodrug is included in the hydragel in particle form, optionally wherein the hydrophobic prodrug particles are dispersed within the hydrogel.

18. The system of any of fee preceding claims, wherein the hydrogel comprises a covalently crosslinked polymer network comprising one or more units of polyethylene glycol, polyethylene oxide, polypropylene oxide, polyvinyl alcohol, poly (viny Ipyrrolidinone), poiyiactic acid, poiyfactic-co-glycoiic acid, random or block capotymers or combinatioris or mixtures of any of these, or one or more units of polyaminoacfds, glycosaminoglycans, polysaccharides, or proteins.

19. The system of claim 18, wherein the hydrogel comprises a polymer network that comprises crosslinked polymer units that ate identical or different, wherein the crosslinked polymer units comprise or consist of one or more crosslinked polyethylene glycol units.

20. The system of any of claims 18 or 19, wherein the polymer network comprises polyethylene glycol units having a weight average molecular weight in the range from about 2,000 to about 100,000 Daltons, or from about 10,000 to about 60,000 Daltons, or from about 20,000 to about 40, 000 Daltons, of about 20,000 Daltons.

21, The system of any of claims 18 to 20, wherein the polymer network comprises one or more crosslinked mufti-arm polymer units, such as one or more 2- to 10-arm polyethylene glycol units, such as 4- to 8-arm polyethylene glycol units, or one or more 4-arm polyethylene glycol units, one or more 8-arm polyethylene -glycol units, or both 4-arm and 8-arm polyethylene glycol units.

22, The system of any of claims 18 to 21, wherein the polymer network is formed by reacting an electrophilic group-containing mulfearm-pblymer precursor with a nucleophilic group-eontaining multi-arm poiymer precursor.

23, The system of claim 22, wherein the nucleophilic group is an hi-hydroxy'succinimidyi ester (OHS) group, wherein the ester is derived from an alpha-omega dicattoxylic linear aliphatic hydro-carton, such as sucdnic acid, glutaric acid, adipic acid and azelaic acid, or wherein the nucleophilic group is selected from M- hydroxysisccmimidyl monoesters of at least one linear, optionally mono- or di-unsaturated, Cz to C20 dicarboxylic acid, such as oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, azelaic acid, sebacic acid, dodecanoic acid, thapsic acid, maleic acid, fumaric acid, and the like.

24, The system of any the preceding claims., wherein the implant in a dried state contains from about 25% to about 75% by weight of the hydrophobic prodrug and from about 20% to about 60% by weight polymer units, or from about 35% to about 65% by weight of the hydrophobic prodrug and from about 25% to about 50% by weight polymer units, or from about 45% to about 55% by weight of the. hydrophobic prodrug and from abort 37% to about 47% by weight polymer units.

25, The system Of any of toe preceding claims, wherein the system contains one or more salts selected from phosphate, borate, or carbonate salts.

26, The system of any of toe preceding claims, wherein the implant has an essentially cylindrical shape, or a cross shape, or Is in the form of a fiber.

27, The system of any of the preceding claims, wherein the implant biodegrades or is capable of biodegrading by hydrolysis and/or enzymatic cleavage in the human or animal body within about 2 weeks to about 15 months, such as 3 or 4 weeks to about 15 months, or 1 to about 15 months or 2 to 14 months after administration., or within about 4 to about 13 months after administration, or within about 9 to about 12 months after administration.

The system of any of the preceding claims, wherein the implant after administration to the human or animal body releases a therapeutically effective amount of hydrophobic prodrug over a period of at least about 5 days, such as 6 days, or 7 days, or 5 days to 2 months, or 5 days to 1 month, or 5 days to 3 weeks, such as 5 or 6 days to 2 weeks; or for at least about 1 month, at least about 2 months, at least about 3 months, at least about 6 months, at least about 9 months, at least about 10 months, at least about 11 months, or at least about 12 months after administration, or wherein the implant after administration to the human or animal body releases a therapeutically effective amount of hydrophobic prodrug over a period of at least 1 week, or 2 weeks, or 3 weeks, or 1 month, or 6 months, or wherein the implant after administration to the human or animal body releases a therapeutically effective amount of hydrophobic prodrug over a period of at least 1 week to 9 months,

28. The system of any of the preceding claims, wherein hydrophobic prodrug is released from the implant after administration at an average rate of about 0,1 pg/day to about 30 pg/day, such as an average rate of about

0.5 pg/day to about 30 pg/day; or at an average rate of 0.5 mg/day to about 30 mg/day, or at an average rate of about 1 pg/day to about 20 pg/day; or at an average rate of about i mg/day to about 20 mg/day.

29. The system of any of the preceding claims, wherein the implant is obtainable by preparing a mixture containing hydrogel precursors and the hydrophobic prodrog, filling the mixture into a tubing., allowing the hydrogel to gel in the tubing to provide a hydrogel shaped as a fiber, arid stretching the hydrogel fiber, preferably wherein the fiber has been stretched and/or twisted prior to or after drying.

30, The system or impiant of any of the previous claims, wherein the implant is adapted for administration to a route selected from subcutaneous, intraocular, intracaveal, intracamera!, punctel, intravitreaiy subconjunctival, intrascierai, subretinaf, episcleral, subconjunctival, choroidal, suprachoroidal, periocular, peribulbar, retrobulbar, intracarneai, retina!, subreiinai.. intracanalicuiaf, posterior sub-Tefioo's delivery, anterior sub-Tenon's delivery, cul-de-sac delivery, fomlx delivery, or an Implant for introduction into the anterior chamber, the vitreous, in the posterior subtenon's space (Inferior fornix), sub-tenon, or a lens, a surface of the cornea or the conjunctiva, puncta (canaliculus, upper/lower canaliculus), ocular fornix, upper /lower ocular fornix, subtenon space, cancer tissue, organ, prostate, breast, joint space, subdural, dental, subcutaneous, carpal tunnel, perivascular, surgically created space or injury', void space, and potential space.

31, The system or implant of any of the preceding claims, wherein the hydrogel comprises a polymer network which is semi-crystalline in the dry state at or below room temperature, and amorphous in the wet state.

32. A method far treating a disease or medical condition of a patient, comprising administering the system or

Implant of any one of claims 1 to 31 to a patient, releasing the hydrophobic prodrug over an extended period of time.

33. A method of treating an ocular disease in a patient in need thereof, the method comprising administering to the patient the sustained release biodegradable system or implant of any one of claims 1 to 31 comprising the hydrogel and dispersed therein a hydrophobic prodrug having a solubility' of less than 10Q pg/ml, as measured in PBS at pH7,4 and 37°C.

34. The method of claims 32 or 33, wherein the hydrophobic prodrug is a derivative of dexamethasone selected from the list of dexamethasone valerate, dexamethasone acetate (humeprednisolone), dexamethasone cipecilate, dexamethasone diethylaminoacetate, dexamethasone dipropionate, dexamethasone tebutate (dexamethasone hatebutylacetate), dexamethasone succinate, dexamethasone isonicotinate, dexamethasone linoleate, dexamethasone metasulphobenzoate, dexamethasone acefurate, dexamethasone palmitate, dexamethasone phosphate, dexamethasone sulfate, dexamethasone pivalate, and dexamethasone troxundate, preferably an ester of dexamethasone such as dexamethasone isonicotinate, dexamethasone dipropionate, or dexamethasone tebutate.

35, A method of treating cancer in a patient in need thereof, the method comprising administering to the patient a sustained release biodegradable implant comprising a hydrogel and dispersed therein a hydrophobic prodrug of a tyrosine kinase inhibitor, tne prodrug having a solubility of less than 1® pg/mt, as measured in PBS at pH7.4 and 37®C.

36. A method of treating an integrin mediated disease in a patient in need thereof, the method comprising administering to the patient a sustained release biodegradable implant comprising a hydrogel and dispersed therein a hydrophobic prodrug of an integrin inhibitor compound, the prodrug having a solubility of less than 100 pg/ml, as measured in PSS at pH7.4 and 37®C.

37. A method of treating pain in a patient in need thereof, the method comprising administering to the patient the Sustained release biodegradable implant according to any of claims 3 to 31, comprising a hydrogel and a hydrophobic opioid or hydrophobic Opioid prodrug having a solubility of less than 100 pg/mL, as measured in PBS at pH7.4 and 37°C

38. The method of any one of claims 32 to 37, wherein the delivery route is selected from subcutaneous, intraocular, intracaveal, intracamerai, punctai, intravitreai, subconjunctivai, Intrascierai, subretfnal, episcleral, sutKonjunctivai, choroidal, suprachoroidal, periocular, peribulbar, retrobulbar, intracorneal, retinal, subretinal, intracanalicuiar, posterior sub-Tenon’s delivery, anterior sub- Tenon's delivery, cul-de-sac delivery,, fornix delivery, or an implant for introduction into the anterior chamber, the vitreous, in the posterior subtenon’s space (inferior fornix), sub-tenon, or a lens, a surface of the cornea or the conjunctiva, puncta (canaliculus, upper/lower canaliculus), ocular fornix, upper/itrwer ocular fornix, subtenon space, cancer tissue, organ, prostate, breast, joint space, subdural, dental, subcutaneous, carpal tunnel, perivascular, surgically created space or injury, void space, and potential space,

39. The method of any of claims 32 to 38, wherein the dose administered once for the treatment period is contained: in one implant or in two or more implants administered concurrently.

40. The method of any of daims 32 to 39, wherein the implant is administered by injection into the human or animal body.

41. The method of any of claims 32 to 40, wherein the treatment period is at least 2 months, at least 4.5 months, at least 6 months, at least 9 months, at least 11 months or at least 12 months.

42. The method any of ciaims 38 to 41, wherein the implant is administered by injection into the human or animal body by means of a 25- or a 27-gauge needle.

43. A method of manufacturing a sustained release biodegradable drug deli very system or implant according to any of claims 1 to 31, the method comprising the steps of forming a hydrogel comprising a polymer network and hydrophobic opioid or hydrophobic opioid prodrug particles dispersed in the hydrogel, shaping the hydrogel, and drying the hydrogel.

44. The method of claim 43, wherein the hydrophobic apioid or hydrophobic opioid prodrug partides are micronized and/or encapsulated and/or hamagerteousiy dispersed within the hydrogel.

45. The method of claim 43or 44, wherein the method comprises the Steps of filling the mixture into a mold or tubing prior to complete gelling in order to provide the desired final shape of the hydrogel, allowing the mixture to gel, and drying the hydrogel, or extruding the mixture through an extruder die.

46. The method of claim 45, wherein the m ixture is filled into a fine diameter tubing or extruded through a die in order to prepare a hydrogel fiber,

47. A kit comprising one or more sustained release biodegradable drug delivery' system(s) or implant(s) according to any of claims 1 to 31 or manufactured irt accordance with the method of any of claims 43 to 46, and one or more needle(s), wherein the one or more needie(s) is/are each pre-loaded with one sustained release biodegradable implant in a dried state.

48. An injection device suitable for injecting a sustained release biodegradable drug delivery system or implant according to any of claims 1 to 31 into the human or animal body.

49. A pharmaceutical product comprising the sustained release biodegradable drug delivery system or implant of any of claims 1 to 31 loaded in a needle and an injection device according to claim 48, wherein the needle is pre-connected to the injection device.

50. A sustained release biodegradable drug delivery¹ system or implant according to any of claims 1 to 31 for use in treating an ocular disease, or for treating pain, such as moderate to severe pain, or post-operative pain, in a patient in need thereof.