Extruded intraocular insert or implant and method of manufacture thereof - Patents.com

Abstract

The present invention relates to a method for preparing sustained release biodegradable intraocular inserts or implants comprising melt extruding or injection molding a polymer composition and an active agent to form an insert or implant suitable for administration within the body, for example, intraocular administration. The method includes feeding the polymer composition and the active agent into an extruder, mixing the ingredients in the extruder, extruding strands, and cutting the strands into unit dose inserts or implants.

Description

[Technical field]

[0001] The present invention relates to an extruded intraocular insert or implant, which may be suitable for insertion or implantation into the human body, for example, subcutaneous, subconjunctival, intracanalicular, intracameral, suprachoroidal, intrafornix or intravitreal administration, for a variety of diseases and disorders, including ocular diseases and disorders. [Background technology]

[0002] Intraocular inserts or implants are an important treatment option because they can provide long-term treatment without the need for ongoing repeated administration of eye drops.

[0003] The small scale manufacturing process for hydrogel intraocular inserts or implants involves forming a reaction mixture of a hydrogel precursor solution with suspended drug particles and injection molding the hydrogel into a tubular mold through a casting process.

[0004] For large-scale manufacturing processes, there are challenges in scaling up and streamlining the casting process due to limitations in manufacturing equipment.

[0005] There is a need in the art for intraocular inserts or implants and processes that can be efficiently scaled to accommodate large-scale manufacturing processes. Summary of the Invention

[0006] It is an object of certain embodiments of the present invention to provide an extruded intraocular insert or implant.

[0007] Another object of certain embodiments of the present invention is to provide a method for preparing an extruded intraocular insert or implant.

[0008] Another object of certain embodiments of the present invention is to provide a method of treating ocular diseases and conditions comprising administering the extruded intraocular inserts or implants disclosed herein.

[0009] One or more of the objects of the present invention may be achieved by the present invention, which in certain embodiments relates to a method of preparing a sustained release biodegradable intraocular insert or implant comprising extruding a polymer composition and an active agent to form an insert or implant suitable for intraocular administration.

[0010] In certain embodiments, the present invention relates to an intraocular insert or implant prepared by the methods disclosed herein.

[0011] In certain embodiments, the present invention relates to methods of treating ocular diseases comprising administering an intraocular insert or implant disclosed herein.

[0012] One or more of these objects, and others, of the present invention are solved by one or more embodiments of the present invention as disclosed and claimed herein. [Brief description of the drawings]

[0013] [Figure 1] 1 shows the in vitro release of melt extruded material. [Diagram 2] 1 shows an exemplary custom parallel twin screw configuration disclosed in the Examples. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0014] definition As used herein, the term "insert" refers to an object that contains an active agent, specifically a glucocorticoid, such as dexamethasone, that is administered into the human or animal body, for example, into the canaliculus of the eye, via an existing orifice, and remains there for a certain period of time while releasing the active agent into the surrounding environment. As used herein, the term "implant" refers to an object that contains an active agent, specifically a glucocorticoid, such as dexamethasone, that is administered into the human or animal body, for example, into the vitreous humor of the eye, via injection or surgical implantation, and remains there for a certain period of time while releasing the active agent into the surrounding environment. The insert or implant has any predetermined shape before it is inserted or implanted, and the general shape is maintained to some extent when the insert or implant is placed in the desired location, but the dimensions (e.g., length and / or diameter) of the insert or implant may change after administration due to hydration, as further disclosed herein. In other words, it is not a solution or suspension that is administered into the body, but an already shaped and coherent object. Thus, the insert or implant is fully formed before it is administered. Over time, the insert or implant may biodegrade (as disclosed herein), thereby changing its shape (e.g., expanding in diameter and decreasing in length) until it is completely dissolved / resorbed. As used herein, the term "insert" as in "implant" is used to refer to both an insert or implant in a hydrated (also referred to herein as "wet") state, when both the insert or implant contain water, e.g., after the insert or implant has been administered to the body, e.g., the eye, and (re)hydrated, or otherwise immersed in an aqueous environment, and an insert or implant in a dry (dried / dehydrated) state.

[0015] As used herein, the term "ocular" refers to the eye in general, or to any site or portion of the eye (as an "intraocular insert" or "intraocular implant" according to the invention refers in principle to an insert or implant that can be administered to any site or portion of the eye). The present invention, in certain embodiments, is directed to the intracanalicular administration of an intraocular insert, as further disclosed herein, and for example, to the treatment of dry eye disease (DED) or post-operative pain.

[0016] As used herein, the term "biodegradable" refers to a material or object (e.g., an intracanalicular insert or implant according to the present invention) that degrades in vivo, i.e., when placed in the human or animal body. In the context of the present invention, as disclosed in detail herein below, an insert or implant comprising a hydrogel, in which particles of an active agent are dispersed, slowly biodegrades over time once deposited in the body or eye (e.g., in the canalicular). In certain embodiments, biodegradation is at least partially achieved by ester hydrolysis in the aqueous environment provided by tears. In certain embodiments, the intracanalicular insert or implant of the present invention slowly softens and liquefies, and is eventually removed (discarded / washed away) through the nasolacrimal duct.

[0017] A "hydrogel" is a three-dimensional network of hydrophilic natural or synthetic polymers (as disclosed herein) that swells in water and retains a certain amount of water (e.g., more than 25%, more than 50%, more than 75%, or from 25% to about 90%, or from about 705 to about 99%) while maintaining or substantially maintaining its structure, e.g., by chemical or physical crosslinking of individual polymer chains. Hydrogels are soft and flexible due to their high water content, and thus closely resemble natural tissue. In the present invention, the term "hydrogel" is used to refer to both hydrogels in their hydrated state when they contain water (e.g., after they are formed in an aqueous solution, or once they are inserted or implanted in the eye or otherwise immersed in an aqueous environment and (re)hydrated), and in their dry (dried / dehydrated) state when they are dried to a low water content, e.g., 1% or less by weight, also called xerogels. In the present invention, when an active ingredient is contained (eg, dispersed) within a hydrogel, the hydrogel may also be referred to as a "matrix."

[0018] As used herein, the term "polymer network" describes a structure formed from polymer chains (of the same or different molecular structure and of the same or different average molecular weight) cross-linked to one another. Types of polymers suitable for the purposes of the present invention are disclosed herein. Polymer networks may also be formed utilizing cross-linking agents, as also disclosed herein.

[0019] The term "non-crystalline" refers to a polymer or polymer network that does not exhibit a crystalline structure in X-ray or electron scattering experiments.

[0020] The term "semi-crystalline" refers to a polymer or polymer network that has some crystalline properties, ie, that exhibits some crystalline properties in X-ray or electron scattering experiments.

[0021] The term "precursor" or "polymer precursor" as used herein refers to molecules or compounds that react with each other and, once reacted, thereby linking together through crosslinks to form a polymer network and thus the hydrogel matrix. Other materials, such as active agents, visualization agents, or buffers, may be present within the hydrogel, but are not referred to as "precursors."

[0022] The molecular weight of the polymer precursors used for the purposes of the present invention and disclosed herein can be quantified by analytical methods known in the art. For example, the molecular weight of polyethylene glycol can be quantified by any method known in the art, including gel electrophoresis, such as SDS-PAGE (sodium dodecyl sulfate-polyacrylamide gel electrophoresis), gel permeation chromatography (GPC) (including GPC with dynamic light scattering (DLS)), liquid chromatography (LC), and mass spectrometry (e.g., matrix-assisted laser desorption / ionization time-of-flight (MALDI-TOF) spectrometry or electrospray ionization (ESI) mass spectrometry). The molecular weight of a polymer (including the polyethylene glycol precursors disclosed herein) is an average molecular weight (based on the molecular weight distribution of the polymer) and therefore can be represented by various average values, including weight average molecular weight (Mw) and number average molecular weight (Mn). Any such average value can be used in the context of the present invention. In certain embodiments, the average molecular weight of the polyethylene glycol unit or other precursors disclosed herein is a number average molecular weight.

[0023] The portions of the precursor molecules that remain in the final polymer network are also referred to herein as "units." Thus, the "units" are the building blocks or constituents of the polymer network that forms the hydrogel. For example, polymer networks suitable for use in the present invention may contain identical or different polyethylene glycol units, as further disclosed herein.

[0024] As used herein, the term "crosslinker" refers to any molecule suitable for connecting precursors via crosslinks to form a polymer network and thus a hydrogel matrix. Crosslinkers can be low molecular weight compounds or polymeric compounds as disclosed herein.

[0025] The term "sustained release" is defined for the purposes of the present invention to refer to a pharmaceutical dosage form that is formulated to make the active agent available for an extended period of time after administration, e.g., a week or more, thereby allowing for reduced administration frequency compared to immediate release dosage forms, e.g., solutions of the active agent applied topically to the eye (e.g., glucocorticoid-containing eye drops). Other terms that may be used interchangeably with "sustained release" herein include "extended release" or "controlled release". In the context of the present invention, the term "sustained release" also includes a period during which the release of the active agent per day is constant, which may be followed by a period during which the release of the active agent is gradually reduced. In other words, during the "sustained release" period, the release rate is not necessarily constant or essentially constant, but may vary over time. In the context of the present invention, the term "tapered" or "tapering" refers to a decrease in the rate of release of an active agent, such as dexamethasone, over time, e.g., until the active agent is completely released.

[0026] As used herein, the term "visualization agent" refers to a molecule or moiety that may be included in the insert or implant of the present invention, which allows the insert or implant to be readily visualized in a non-invasive manner by illuminating the corresponding ocular site with a suitable light source when the insert is located within the body, for example, within the canaliculus of the eye.

[0027] As used herein, the term "ocular surface" includes the conjunctiva and cornea, as well as elements such as the lacrimal apparatus (including the lacrimal puncta and canaliculi) and associated eyelid structures. In the sense of the present invention, the ocular surface also includes the aqueous humor.

[0028] As used herein, the term "tears" or "tear film" refers to the clear fluid secreted by the lacrimal gland that lubricates the eye. Tears are composed of water, electrolytes, proteins, lipids, and mucin.

[0029] As used herein, the term "bilaterally" or "bilateral" (in the context of administration of the inserts or implants of the present invention) refers to administration of the inserts or implants to both eyes of a patient. Thus, "unilaterally" or "unilateral" refers to administration of the inserts or implants to only one eye. The inserts or implants may be inserted into the superior and / or inferior canaliculi of both eyes or one eye.

[0030] As used herein, terms such as "administration" or "administering" or "administered" in the context of the sustained release biodegradable insert or implant of the present invention refer to the process of inserting, injecting, or surgically implanting the insert or implant into the body or eye. In certain embodiments, the formulation is inserted into the canaliculus of the eye through the opening of the lacrimal punctum. Terms such as "administration" or "administering" or "administered" in the context of topical ophthalmic pharmacological products such as eye drops (not the subject of the present invention) refer to the topical application of these products to the eye.

[0031] As used herein, the term "insert stacking" or "stacking" refers to inserting a further insert or implant (e.g., into the canaliculus) on top of a first insert or implant while retaining the first insert or implant.In certain embodiments, the further insert or implant is placed on top of the first insert or implant after the active agent contained in the first insert or implant is essentially completely released, or after at least about 70% or at least about 80% or at least about 90% of the active agent contained in the first insert or implant is released.The stacking of inserts or implants allows, for example, long-term administration of active agent.

[0032] As used herein, the term "plug" refers to a device capable of preventing tear drainage by causing blockage of the tear duct(s) ("duct blockage"). Thus, plugs enhance tear retention, which helps keep the eye moist. Plugs can be classified as "punctal plugs" and "intracanalicular plugs". Intracanalicular plugs are also referred to in the literature as "canalicular plugs". Both plug classifications are inserted through the superior and / or inferior puncta of the eye. Because punctal plugs remain in the punctal opening, they are easily visible and therefore removable without significant difficulty. However, punctal plugs may exhibit poor retention and, because they are exposed and positioned, they may be more easily contaminated by microorganisms, resulting in infection. In contrast, intracanalicular plugs are essentially invisible and are placed in both the vertical and horizontal parts of the canaliculus, resulting in better retention compared to punctal plugs. However, currently available intracanalicular plugs may not be easily removable and / or may increase the risk of movement due to a loose fit. Commercially available plugs are often made from collagen, acrylic polymers, or silicone.

[0033] The term "canaliculus (plural canaliculi)" or alternatively "lacrimal duct", as used herein, refers to the lacrimal canaliculus, i.e., the small channel in each eyelid that drains lacrimal fluid (tear fluid) from the lacrimal punctum into the nasolacrimal duct. As such, the canaliculus forms part of the lacrimal apparatus that drains tears from the ocular surface into the nasal cavity. The canaliculus in the upper eyelid is referred to as the "superior canaliculus" or "upper canaliculus" and the canaliculus in the lower eyelid is referred to as the "inferior canaliculus" or "lower canaliculus". Each canaliculus includes a vertical region that leads to the lacrimal punctum (referred to as the "vertical canaliculus") and a horizontal region that leads to the vertical canaliculus (referred to as the "horizontal canaliculus"), which joins the nasolacrimal duct.

[0034] The term "punctum" (plural puncta) refers to lacrimal punctum, which is an opening at the edge of the eyelid that corresponds to the entrance of the canaliculus. After tears are produced, some of the fluid evaporates during blinking and some is drained through the punctum. Because both the upper and lower eyelids exhibit puncta, these puncta are referred to as "superior puncta" or "upper puncta," "lower puncta" or "lower puncta."

[0035] The term "intracanalicular insert" refers to an insert that can be administered into the upper and / or lower canaliculus of the eye, particularly into the upper and / or lower canaliculus vertical part of the eye, through the upper and / or lower lacrimal punctum. The insert is placed in the canaliculus, thus blocking tear drainage through blockage of the lacrimal gland, as also observed with intracanalicular plugs. The intracanalicular insert of the present invention can be inserted bilaterally or unilaterally into the lower and / or upper canaliculus vertical part of the eye. According to the present invention, the intracanalicular insert is a sustained release biodegradable insert.

[0036] The terms "API", "active pharmaceutical ingredient", "active drug", "active pharmaceutical ingredient", "(active) therapeutic agent", "active", and "drug" are used interchangeably herein and refer to substances used in finished pharmaceutical products (FPPs), and in the preparation of such finished pharmaceutical products, which are intended to provide pharmacological activity or otherwise have a direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to have a direct effect in the repair, correction, or modification of a patient's physiology.

[0037] For purposes of the present invention, the active agents can be used in all their possible forms, including any active agent polymorphs, or pharma- ceutically acceptable salts, anhydrates, hydrates, other solvates, or derivatives of the active agent. Whenever an active agent is referred to by name in this description or claims, such pharma- ceutically acceptable polymorphs, salts, anhydrates, solvates (including hydrates), or derivatives of the active agent are also referred to, even if not expressly stated.

[0038] As used herein, the term "therapeutically effective" refers to the amount of a drug or active agent (eg, a glucocorticoid) required upon administration to produce a desired therapeutic response or result.

[0039] As used herein, the term "average" refers to the central or typical value in a collection of data, and is calculated by dividing the sum of the values ​​in the collection by the number of data.

[0040] As used herein, the term "about" in connection with a measured quantity refers to normal variation in that measured quantity that would be expected by one of ordinary skill in the art in making the measurement and exercising a level of care depending on the purpose of the measurement and the precision of the measuring device.

[0041] As used herein, the term "at least about" in reference to a measured amount refers to normal variation in the measured amount and an amount higher than the measured amount that would be expected by one of ordinary skill in the art in making the measurement and exercising a level of care depending on the purpose of the measurement and the precision of the measuring device.

[0042] As used herein, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0043] The term "and / or" as used herein in expressions such as "A and / or B" is intended to include both "A and B" as well as "A or B."

[0044] As used herein, open terms such as "include," "including," "contain," "containing," and the like, mean "comprising" and are intended to refer to an open-ended list or enumeration of elements, method steps, etc., and thus are not limited to the listed elements, method steps, etc., but are intended to include additional unlisted elements, method steps, etc.

[0045] The term "up to," when used herein in conjunction with a value or number, is intended to include the respective value or number. For example, the term "up to 25 days" means "up to and including 25 days."

[0046] All documents disclosed herein are hereby incorporated by reference in their entirety for all purposes (in the case of any conflict, the present specification will control).

[0047] In certain embodiments, the present invention relates to a method of preparing a sustained release biodegradable intraocular insert or implant, comprising melt extruding or injection molding a polymer composition and an active agent to form an insert or implant suitable for administration to the body, for example, to the eye.

[0048] In other embodiments, the method includes feeding the polymer composition and the active agent into an extruder, mixing the ingredients in the extruder, extruding the strands, and cutting the strands into unit dose inserts or implants.

[0049] In certain embodiments, the polymer composition and the active agent are fed separately to the extruder. In other embodiments, the polymer composition and the active agent are fed simultaneously to the extruder. In certain embodiments, the polymer composition is premixed, such as by melt mixing, before being introduced into the extruder. Mixing can be performed, for example, by using an orbital mixer, an acoustic mixer, or a V-shell blender. In certain embodiments, the polymer composition and the active agent are melt mixed, milled, and then fed into the extruder.

[0050] In certain embodiments, the method further includes cooling the strands, for example, prior to cutting the strands.

[0051] In certain embodiments, the method further comprises extending the strand, eg, prior to severing the strand.

[0052] In certain embodiments, the stretching is performed under wet or humid conditions, heated conditions, or a combination thereof. In other embodiments, the stretching is performed under dry conditions, heated conditions, or a combination thereof. In certain embodiments, strands stretched after crosslinking in a humid environment, such as a humidity chamber, may have shape memory or partial shape memory when dried and placed in an aqueous environment. In certain embodiments, strands that are stretched or otherwise caused to have a smaller diameter immediately after extrusion and while still warm before crosslinking may not have shape memory.

[0053] In certain embodiments, the extruded composition is subjected to a curing step, such as exposure to humidity. If one reactant is a salt, such as an amine salt, the salt is insoluble in the dried polymer melt. In this case, curing is achieved by exposing the dried extruded composition to humidity, allowing the extruded composition to absorb water from the environment, thereby dissolving the salt and allowing it to react to crosslink the precursor and form the matrix. In certain embodiments, curing crosslinks the polymer composition.

[0054] In certain embodiments, the method further comprises drying the strands after stretching the strands.

[0055] In other embodiments, any of the steps of the methods disclosed herein may be performed simultaneously or sequentially in any order.

[0056] In certain embodiments, the method further includes melting the polymer in an extruder at a temperature below the melting point of the active agent. The optimal temperature of the molten polymer is determined by experimentation depending on its extrusion properties. In certain embodiments, the unmolten active agent remains unchanged throughout this melt extrusion process. In certain embodiments, the extrusion is performed at a temperature above the melting points of the polymer and the active agent. This can result in a color change and / or a change in morphology of the active agent, for example, from amorphous to crystalline. The temperature can be, for example, less than about 180°C, less than about 150°C, less than about 130°C, less than about 120°C, less than about 100°C, less than about 90°C, less than about 80°C, less than about 70°C, less than about 60°C, less than about 50°C. In some embodiments, the temperature is about 50°C to about 80°C. In other embodiments, the temperature is about 50°C to about 200°C, about 60°C to about 180°C, or about 80°C to about 140°C. Exemplary temperatures are about 40°C to about 90°C. According to certain embodiments of the present invention, the temperature is kept as low as possible to protect the excipient powders and active ingredients and optimize stability. In certain embodiments, the active agent is axitinib and the polymer is melted in the extruder at a temperature of 57°C to about 200°C, about 65°C to about 150°C, or about 70°C to about 90°C. In certain embodiments, the active agent is dexamethasone and the polymer is melted in the extruder at a temperature of 57°C to about 250°C, about 65°C to about 175°C, or about 70°C to about 90°C. In certain embodiments, the active agent is cyclosporine and the polymer is melted in the extruder at a temperature of 57°C to about 145°C, about 65°C to about 120°C, or about 70°C to about 90°C. In certain embodiments, the active agent is bupivacaine and the polymer is melted in the extruder at a temperature of 57°C to about 105°C, about 65°C to about 95°C, or about 70°C to about 90°C.

[0057] In certain embodiments, the extruded composition is dried in strand form or unit dose state. In certain embodiments, drying is performed after stretching the strands. Drying may be, for example, evaporative drying at ambient temperature or may include heat, vacuum, or a combination thereof.

[0058] In certain embodiments, the hydrogel strands are stretched by a stretch factor ranging from about 1.1 to about 10, 1.2 to about 6, or about 1.5 to about 4.

[0059] In certain embodiments, the strands are cut into segments having an average length of about 20 mm, 17 mm, 15 mm, 12 mm, 10 mm, 8 mm, 5 mm, 4 mm, 3 mm, 2 mm, 1 mm, or 0.5 mm or less, and in certain embodiments, the size is about 0.5 mm to about 10 mm, about 1 mm to about 8 mm, or about 1.5 mm to about 5 mm.

[0060] In certain embodiments, the active agent is suspended in the polymeric composition.

[0061] In certain embodiments, the active agent is uniformly dispersed in the polymeric composition.

[0062] In certain embodiments, the extrusion process is carried out without a solvent (e.g., water). In certain embodiments, a solvent is used in an amount of less than about 10% w / w, less than about 5% w / w, or less than about 1% w / w. The solvent can be, for example, water or oil. The oil can increase the release rate of lipophilic active agents. The oil can be a biocompatible vegetable oil, synthetic oil, or mineral oil, a liquid fatty acid or triglyceride composition, or it can be a hydrophobic biodegradable liquid polymer, or a combination thereof. In certain embodiments, the oil is selected from the group consisting of triethyl citrate, acetyl triethyl citrate (ATEC), acetyl tributyl citrate (ATBC), alpha-tocopherol (vitamin E), alpha-tocopherol acetate, vegetable oils such as sesame oil, olive oil, soybean oil, sunflower oil, coconut oil, canola oil, rapeseed oil, nut oils such as hazelnut, walnut, pecan, almond, cottonseed oil, corn oil, safflower oil, linseed oil, ethyl oleate, castor oil and its derivatives (Cremo), and the like. The lipids may include lipids that are liquid at or below 37° C., such as saturated or unsaturated fatty acids, monoglycerides, diglycerides, triglycerides (Myglyols®), phospholipids, glycerophospholipids, sphingolipids, sterols, prenol, polyketides, hydrophobic biodegradable liquid polymers (such as low molecular weight PLGA, PGA, or PLA), low melting point waxes, such as vegetable, animal, or synthetic waxes, lanolin, jojoba oil, or combinations thereof.

[0063] In certain embodiments, the content uniformity of the unit dose insert or implant is within 10%, 5%, or 1%.

[0064] In certain embodiments, the duration of the dosage form is from about 1 day to about 1 year, from about 2 days to about 9 months, or from about 7 days to about 6 months after administration, which can be increased or decreased based on factors such as crosslinking.

[0065] In certain embodiments, the polymorphic form of the active agent is unchanged or substantially unchanged. In certain embodiments, the purity of the active agent after curing is greater than 99%, greater than 99.5%, or greater than 99.9% compared to the active agent before extrusion. Purity is measured by chemical decomposition of the active agent.

[0066] In certain embodiments, the active agent has a median (D50) particle size of less than about 100 μm, less than about 50 μm, less than about 25 μm, or less than about 10 μm.

[0067] In certain embodiments, the active agent has a D50 particle size of less than about 10 μm and / or a D99 particle size of less than about 50 μm, or a D90 particle size of about 5 μm or less, and / or a D98 particle size of about 10 μm or less.

[0068] In certain embodiments, the polymer composition comprises one or more units of polyethylene glycol, polyethylene oxide, polypropylene oxide, polyvinyl alcohol, poly(vinylpyrrolidone), polylactic acid, polylactic-glycolic acid copolymers, random or block copolymers, polycaprolactone, ethylene vinyl acetate, or any combination or mixture thereof, or a polyamino acid, a glycosaminoglycan, a polysaccharide, a protein, a cellulose polymer (e.g., hydroxypropylmethylcellulose), povidone, poloxamer, an acrylic polymer (e.g., polymethacrylate), or a combination thereof.

[0069] In certain embodiments, the polymer composition comprises an electrophilic group-containing multi-arm polyethylene glycol.

[0070] In certain embodiments, the polymer composition further comprises a nucleophilic group-containing crosslinker.

[0071] In certain embodiments, the crosslinker comprises an amine group.

[0072] In a particular embodiment, the electrophilic-containing multi-arm polymer precursor is 4a20kPEG-SG and the crosslinker is trilysine acetate.

[0073] In certain embodiments, the polymer composition further comprises a visualization agent, hi other embodiments, the polymer composition further comprises a radiopaque agent, for example for x-ray or magnetic resonance imaging.

[0074] In certain embodiments, the visualization agent is a fluorophore.

[0075] In certain embodiments, the intraocular insert or implant is suitable for intracanalicular, suprachoroidal, intracameral, intrafornix, or intravitreal administration, which may be done manually, with the insert or implant tool or device, or by injection.

[0076] In certain embodiments, the active agent is selected from dexamethasone, travoprost, cyclosporine, axitinib, bupivacaine, ropivacaine, lidocaine, and various polymorphs, co-crystals, salts, or prodrug forms.

[0077] In certain embodiments, the extrusion process excludes water.

[0078] In certain embodiments, the present invention relates to an intraocular insert or implant prepared by the methods disclosed herein.

[0079] In certain embodiments, the present invention relates to methods of treating ocular diseases comprising administering an intraocular insert or implant disclosed herein.

[0080] One or more of these objects, and others, of the present invention are solved by one or more embodiments of the present invention as disclosed and claimed herein.

[0081] Implants and active ingredients In certain embodiments, the inserts or implants disclosed herein are suitable for ocular delivery, for example, to a route selected from punctal, intravitreal, subconjunctival, intrascleral, subretinal, suprachoroidal, periocular, periocular, retrobulbar, intracorneal, posterior subtenon delivery, anterior subtenon delivery, cul-de-sac delivery, or fornix delivery. Administration can be, for example, injection with a needle or insertion with a delivery device to the selected ocular delivery route.

[0082] The needle can be of a gauge selected from, for example, 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.

[0083] In certain embodiments, administration may be with improved devices 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.

[0084] In alternative embodiments where the ocular delivery pathway is accessible from outside the eye, administration can optionally be performed without the use of a needle, for example manually or with the assistance of tweezers, applicators, or other administration delivery aids.

[0085] An active agent administered by the implants of the present invention may have a water solubility of, for example, less than about 2,000 μg / mL, less than about 1,500 μg / mL, less than about 1,000 μg / mL, less than about 800 μg / mL, less than about 600 μg / mL, less than about 500 μg / mL, less than about 400 μg / mL, less than about 300 μg / mL, less than about 200 μg / mL, less than about 100 μg / mL, less than about 75 μg / mL, less than about 50 μg / mL, less than about 25 μg / mL, less than about 10 μg / mL, less than about 5 μg / mL, less than about 1 μg / mL, less than about 0.5 μg / mL, less than about 0.4 μg / mL, less than about 0.3 μg / mL, less than about 0.2 μg / mL, or less than about 0.1 μg / mL.

[0086] In other embodiments, the active agents administered by the devices of the invention can have an aqueous solubility that is poorly soluble (requiring 30-100 parts solvent to 1 part solute), slightly soluble (requiring 100-1,000 parts solvent to 1 part solute), very slightly soluble (requiring 1,000-10,000 parts solvent to 1 part solute), or virtually insoluble or insoluble (requiring more than 10,000 parts solvent to 1 part solute) as described in Remington, The Science and Practice of Pharmacy 22nd Edition 2012.

[0087] Ocular conditions that can be treated by the implants and methods of the present invention can include any ophthalmic condition, such as a condition of the anterior segment of the eye or a condition of the posterior segment of the eye.

[0088] The state of the anterior segment of the eye may be associated with the cellular or subcellular components of the anterior anatomical structures of the eye, such as the acellular tear film and its corresponding lipid aqueous mucin components. The state of the anterior segment of the eye may also be associated with the upper and lower eyelids, including the state of the meibomian gland and its corresponding cellular and tissue components, such as muscle, lipid producing holocrine, exocrine and endocrine glands, and vascular and connective tissue components, and the state of the conjunctiva and its corresponding cellular components, such as goblet cells, fibroblasts, vascular and blood cell components. The state of the anterior segment of the eye may further be associated with the corneal layers of the eye, including the layers of epithelial cells, stromal cells, and fibroblasts, corneal endothelial cells, corneal nerves and their associated cells, and the stroma. Conditions of the anterior segment of the eye may also include inflammation, diffuse lamellar keratitis, corneal disease, edema, or opacities with an exudative or inflammatory component, ocular conditions associated with systemic autoimmune disease, ocular surface disorders due to dry eye (e.g., keratoconjunctivitis such as vernal keratoconjunctivitis, atopic keratoconjunctivitis, and keratoconjunctivitis sicca), eyelid margin disease, meibomian gland disease, lacrimal dysfunction syndrome, anterior and posterior blepharitis, staphylococcal blepharitis, microbial infections, conjunctivitis (e.g., , persistent allergic, giant papillary conjunctivitis, seasonal intermittent allergic conjunctivitis, perennial allergic conjunctivitis, toxic and infectious conjunctivitis), chemosis, anterior uveitis, inflammatory conditions, chemosis, inherited conditions of the cornea (e.g. corneal dystrophies such as keratoconus, posterior polymorphous dystrophy), Fuchs' dystrophy, aphakic and pseudophakic bullous keratopathy, diseases of the sclera, ocular cicatricial pemphigoid and pterygium.

[0089] Conditions of the posterior segment of the eye may relate to the cellular or subcellular components of the anatomical structures of the posterior segment of the eye, including the retina and all cells of the retinal layers, such as the outer and inner photoreceptor layers, the nuclear cell layer, the amacrine and ganglion cells, the macula, the fovea, and the vitreous. Additional components of the posterior segment of the eye include the ciliary body, iris, uvea, and retinal pigment cells. Conditions of the posterior segment of the eye may relate to the condition of the optic nerve (including the corresponding cellular and subcellular components, such as axons and associated innervations), glaucoma (e.g., primary open-angle glaucoma, acute and chronic angle-closure glaucoma, and secondary glaucoma), myopic retinopathy, macular edema (including clinical or angiographic cystoid macular edema resulting from conditions such as diabetes, exudative macular degeneration, and macular edema associated with laser treatment of the retina), diabetic retinopathy, and the like. These may include retinopathy, age-related macular degeneration, retinopathy of prematurity, retinal ischemia and choroidal neovascularization, genetic disorders of the retina, pars planitis, Posner-Schlossman syndrome, Behçet's disease, Vogt-Koyanagi-Harada syndrome, hypersensitivity reactions, toxoplasmic chorioretinitis, orbital inflammatory pseudotumor, chemosis, conjunctival venous congestion, periorbital cellulitis, acute dacryocystitis, nonspecific vasculitis, sarcoidosis, and cytomegalovirus infection.

[0090] Particular active agents that may be utilized in the implants and methods of the present invention include, but are not limited to, immunosuppressants, complement protein C5 agents (e.g., eculizumab or avacincaptad pegol), anti-inflammatory agents such as steroids, steroidal and non-steroidal anti-inflammatory agents (e.g., COX1 or COX2 inhibitors), antiviral agents, antibiotics, anti-glaucoma agents, anti-VEGF agents, analgesics, and combinations thereof.

[0091] Immunosuppressants include, but are not limited to, cyclosporine, mTOR inhibitors (e.g., rapamycin, tacrylimus, temsirolimus, sirolimus, everolimus, KU-0063794, WYE-354, AZD8055, metformin, or Torin-2), cyclophosphamide, atoposide, thiotepa, methotrexate, azathioprine, mercaptopurine, interferon, infliximab, etanercept, mycophenolate mofetil, 15-deoxyspargalin, thalidomide, glatiramer, leflunomide, vincristine, cytarabine, pharma- ceutically acceptable salts thereof, and combinations thereof.

[0092] Nonsteroidal anti-inflammatory compounds include inhibitors of cyclooxygenase (COX) enzymes, such as cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) isoenzymes. General classes of nonsteroidal anti-inflammatory compounds include salicylates, propionic acid derivatives, acetic acid derivatives, enolic acid derivatives, and anthranilic acid derivatives. Examples of nonsteroidal anti-inflammatory compounds include acetylsalicylic acid, diflunisal, salsalate, ibuprofen, dexibuprofen, naproxen, nepafenac, fenoprofen, ketoprofen, dexketoprofen, flurbiprofen, oxaprozin, loxoprofen, indomethacin, tolmetin, sulindac, etodolac, ketorolac, diclofenac, aceclofenac, nabumetone, piroxicam, tenoxicam, tenoxicam, roloxicam, phenylbutazone, mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid, celecoxib, pharmaceutically acceptable salts thereof, and combinations thereof.

[0093] 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 TNFα, IL-1, IL-4, IL-5, IL-17, or CD20. Such agents may include etanercept, infliximab, adalimumab, daclizumab, rituximab, tocilizumab, certolizumab pegol, golimumab, pharma- ceutically acceptable salts thereof, and combinations thereof.

[0094] Analgesics that may be utilized in the implants and methods of the present invention include acetaminophen, acetaminosalol, aminochlorthenoxazine, acetylsalicyl 2-amino-4-picolinate, acetylsalicylsalicylic acid, anileridine, benoxaprofen, benzylmorphine, 5-bromosalicylacetic acid, bucetin, buprenorphine, butorphanol, capsaicin, cinchophen, ciramadol, clometacin, clonixin, codeine, desomorphine, dezocine, dihydrocodeine, dihydromorphine, dimepheptanol, dipyrocetyl, eptazocine, ethoxazene, ethylmorphine, eugenol, fumarate, furanol ... Includes loctafenine, fosfosal, glafenine, hydrocodone, hydromorphone, hydroxypethidine, ibufenac, p-lactophenetide, levorphanol, meptazinol, metazocine, metopon, morphine, nalbuphine, nicomorphine, norlevorphanol, normorphine, oxycodone, oxymorphone, pentazocine, phenazocine, fenocol, phenoperidine, phenylbutazone, phenylsalicylic acid, phenylramidol, salicin, salicylamide, thiorphan, tramadol, diacerein, actarit, pharma- ceutically acceptable salts thereof, and combinations thereof.

[0095] Antibiotics 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 B, neomycin C, neomycin E, streptomycin, paramomycin, pharmaceutically acceptable salts thereof, and combinations thereof. Penicillins may include amoxicillin, ampicillin, bacampicillin, carbenicillin, cloxacillin, dicloxacillin, flucloxacillin, mezlocillin, nafcillin, oxacillin, penicillin G, penicillin V, piperacillin, pivampicillin, pivmecillinam, ticarcillin, pharmaceutically acceptable salts thereof, and combinations thereof. Cephalosporins are cefatrile, cefadroxil, cephalexin, cephaloglycin, cephalonium, cephaloridine, cephalothin, cephapirin, cefatrizine, cefazaflur, cefazedone, cefazolin, cephradine, cefroxadine, ceftezole, cefaclor, cefamandole, cefmetazole, cefonicid, cefotetan, cefoxitin, cefprozil, cefuroxime, cefuzonam, cefcapene, cefdaloxime, cefdinir, cefditoren, cefetamet, cefixime, cefmenoxime, cefodizime, cefotaxime, cefpimizole, cefpodoxime, and cefoxitin. ceftaram, ceftibuten, ceftiofur, ceftiolene, ceftizoxime, ceftriaxone, cefoperazone, ceftazidime, cefclidine, cefepime, cefluprenam, cefoselis, cefozopran, cefpirome, cefquinome, ceftobiprole, ceftaroline, cefaclomezine, cephaloram, cefaparole, cefcanel, cefedrol, cefenpidone, cefetrizole, cefibitril, cefmatilen, cefmepidium, cefovecin, cefoxazole, cefrotil, cefsumide, ceflastim, ceftioxide, pharmaceutically acceptable salts thereof, and combinations thereof.Fluoroquinolones may include ciprofloxacin, levofloxacin, gatifloxacin, moxifloxacin, ofloxacin, norfloxacin, pharmaceutically acceptable salts thereof, and combinations thereof. Macrolides may include azithromycin, erythromycin, clarithromycin, dirithromycin, oxithromycin, telithromycin, pharmaceutically acceptable salts thereof, and combinations thereof.

[0096] Antiviral agents that may be utilized in the implants and methods of the present invention include nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, fusion inhibitors, integrase inhibitors, nucleoside analogues, protease inhibitors, and reverse transcriptase inhibitors. Examples of antiviral agents include abacavir, acyclovir, adefovir, amantadine, amprenavir, ampligen, arbidol, atazanavir, boceprevir, cidofovir, darunavir, delavirdine, didanosine, docosanol, edoxudine, efavirenz, emtricitabine, enfuvirtide, entecavir, famciclovir, fomivirsen, fosamprenavir, foscarnet, phosphonet, ganciclovir, ibacitabine, immunovir, idoxuridine, imiquimod, indinavir, inosine, interferon type III, interferon type II, interferon type I, interferon, lamivudine, lopinavir, lopinavir, including, but not limited to, viridan, 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, valacyclovir, valganciclovir, vicriviroc, vidarabine, viramidine, zalcitabine, zanamivir, zidovudine, pharmaceutically acceptable salts thereof, and combinations thereof.

[0097] Steroidal anti-inflammatory agents that may be utilized in the implants and methods of the present invention include dexamethasone, budesonide, triamcinolone, hydrocortisone, loteprednol, prednisolone, mometasone, fluticasone, rimexolone, fluorometholone, beclomethasone, flunisolide, pharma- ceutically acceptable salts thereof, and combinations thereof.

[0098] 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, levobetaxolol, levobunolol, timolol, and the like, pharmaceutical acceptable salts thereof, and combinations thereof; adrenergic or sympathomimetics such as epinephrine, dipivefrin, clonidine, apclonidine, brimonidine, and the like, pharmaceutical acceptable salts thereof, and combinations thereof; parasympathomimetics or cholinergic agents such as pilocarpine, carbachol, phosphoryl iodine, physostigmine, and the like, pharmaceutical acceptable salts thereof, and combinations thereof; acetozolamide, brinzolamide, doxorubicin, tetracycline ... carbonic anhydrase inhibitors, including topical or systemic agents such as luzolamide, methazolamide, etoxolamide, dichlorphenamide, pharmaceutically acceptable salts thereof and combinations thereof; mydriatic cycloplegics, such as atropine, cyclopentolate, succinylcholine, homatropine, phenylephrine, scopolamine, tropicamide, pharmaceutically acceptable salts thereof and combinations thereof; prostaglandins, such as prostaglandin F2 alpha, antiprostaglandins, prostaglandin precursors, or prostaglandin analogues, such as bimatoprost, latanoprost, travoprost, unoprostone, tafluprost, pharmaceutically acceptable salts thereof and combinations thereof.

[0099] Anti-VEGF agents that may be utilized in the implants and methods of the present invention include bevacizumab, pegaptanib, ranibizumab, brolucizumab, pharmaceutically acceptable salts thereof, and combinations thereof.

[0100] In certain embodiments, the active ingredient contained in the implant of this aspect of the present invention is a TKI.Examples of suitable TKIs are axitinib, sorafenib, sunitinib, nintedanib, pazopanib, regorafenib, cabozantinib and vandetanib.In certain embodiments, the TKI used in this and other aspects of the present invention is axitinib.Details of axitinib, its chemical structure, polymorphs, solvates, salts, and properties such as solubility are described in the definition section above.

[0101] In certain embodiments, the active agent is dexamethasone and an insert or implant that provides an in vitro release of dexamethasone of one or more of: (i) about 30% to about 70% or about 40% to about 65% at 1 hour, (ii) about 60% to about 90% or about 65% to about 85% at 2 hours, or (iii) greater than about 85% or greater than about 90% at 4 hours. In vitro release is measured in water at 37° C. using an Acquity BEH C8 column or equivalent, or in pH 4 phosphate buffered saline (PBS) using a Mettler Toledo UV5 spectrometer or equivalent.

[0102] Polymer Compositions or Networks Hydrogels may be formed from precursors that have functional groups that form crosslinks to form a polymer network. These crosslinks between the polymer strands or arms may be chemical (i.e., may be covalent) and / or physical (e.g., ionic bonds, hydrophobic associations, hydrogen bridges, etc.) in nature.

[0103] The polymer network can be prepared from either one type of precursor or from two or more types of precursors that can react. The precursor is selected with consideration of the properties desired for the resulting hydrogel. There are a variety of suitable precursors for use in the preparation of hydrogels. Generally, any medicamentously acceptable crosslinkable polymer that forms a hydrogel can be used for the purposes of the present invention. The hydrogel and the components incorporated therein (including the polymers used to prepare the polymer network) should be physiologically safe, e.g., so as not to induce an immune response or other adverse effects. The hydrogel can be formed from natural polymers, synthetic polymers, or biosynthetic polymers.

[0104] Natural polymers may include glycosaminoglycans, polysaccharides (eg, dextran), polyamino acids, and proteins, or mixtures or combinations thereof, although this list is not intended to be limiting.

[0105] Synthetic polymers can generally be any polymers that are synthetically produced from various 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. Polymerization may be initiated by specific initiators, light and / or heat, or mediated by catalysts. Synthetic polymers may be used in certain embodiments to reduce allergenic potential in dosage forms that do not contain any components of human or animal origin.

[0106] Generally, for the purposes of the present invention, one or more synthetic polymers from the group including one or more units of polyethylene glycol (PEG), polyethylene oxide, polypropylene oxide, polyvinyl alcohol, poly(vinylpyrrolidinone), polylactic acid, polylactic-co-glycolic acid, random or block copolymers, or any combination / mixture thereof can be used, although this list is not intended to be limiting.

[0107] The precursors can be covalently crosslinked with each other to form a covalently crosslinked polymer network. In certain embodiments, precursors having at least two reactive centers (e.g., in free radical polymerization) can function as crosslinkers, since each reactive group can participate in the formation of a different growing polymer chain.

[0108] The precursor may have a biologically inert and hydrophilic portion, e.g., a core. In the case of a branched polymer, the core refers to a continuous portion of the molecule connected to arms extending from the core, where the arms often have functional groups at the ends of the arms or branches. Multi-arm PEG precursors are examples of such precursors and are used in certain embodiments of the invention as further disclosed herein.

[0109] Hydrogels for use in the present invention can be made, for example, from one multi-arm precursor having a first functional group(s) and another (e.g., multi-arm) precursor having a second functional group(s). By way of example, the multi-arm precursor may have hydrophilic arms (e.g., polyethylene glycol units) terminated with primary amines (nucleophilic) or may have activated ester end groups (electrophilic). The polymer network according to the present invention may comprise identical or different polymer units crosslinked to each other. The precursors may be high molecular weight building blocks (e.g., polymers with functional groups as further disclosed herein) or low molecular weight building blocks (e.g., small amines, thiols, esters, etc., also as further disclosed herein).

[0110] Certain functional groups can be made more reactive by using activating groups. Such activating groups include (but are not limited to) carbonyldiimidazole, sulfonyl chloride, aryl halides, sulfosuccinimidyl esters, N-hydroxysuccinimidyl (abbreviated as "NHS") esters, succinimidyl esters, benzotriazolyl esters, thioesters, epoxides, aldehydes, maleimides, imidoesters, acrylates, and the like. NHS esters are useful groups for crosslinking with nucleophilic polymers, such as primary amine- or thiol-terminated polyethylene glycols. The NHS-amine crosslinking reaction may be carried out in aqueous solution in the presence of a buffer solution, such as phosphate buffer (pH 5.0-7.5), triethanolamine buffer (pH 7.5-9.0), borate buffer (pH 9.0-12), or sodium bicarbonate buffer (pH 9.0-10.0).

[0111] In certain embodiments, each precursor may contain only nucleophilic or only electrophilic functional groups, so long as both nucleophilic and electrophilic precursors are used in the crosslinking reaction. Thus, for example, if the crosslinker has only nucleophilic functional groups (e.g., amines), the precursor polymer may have electrophilic functional groups (e.g., N-hydroxysuccinimide). On the other hand, if the crosslinker has electrophilic functional groups such as sulfosuccinimide, the functional polymer may have nucleophilic functional groups such as amines or thiols. Thus, functional polymers (e.g., proteins, poly(allylamine), or amine-terminated di- or multifunctional poly(ethylene glycol)) can also be used to prepare the polymer networks of the present invention.

[0112] In one embodiment of the invention, the precursors for the polymer network forming the hydrogel in which the glucocorticoid is dispersed to form the insert or implant according to the invention each have from about 2 to about 16 nucleophilic functional groups (referred to as functionality), and in another embodiment, the precursors each have from about 2 to about 16 electrophilic functional groups (referred to as functionality). Reactive precursors having a number of reactive (nucleophilic or electrophilic) groups that is a multiple of 4, thus, for example, 4, 8, and 16 reactive groups, are particularly suitable for the invention. However, any number of functional groups (e.g., containing any of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 groups) is possible in order to ensure that the precursor can be used according to the invention while still having sufficient functionality for the formation of a suitable crosslinked network.

[0113] PEG hydrogel In certain embodiments of the invention, the polymer network forming the hydrogel comprises polyethylene glycol (PEG) units, which are known in the art to form hydrogels when crosslinked, and these PEG hydrogels are suitable for pharmaceutical applications, e.g., as matrices for drugs intended to be administered to any site of the human or animal body.

[0114] The polymer network of the hydrogel insert or implant of the invention may include one or more multi-armed PEG units having 2-10 arms, or 4-8 arms, or 4, 5, 6, 7 or 8 arms. In certain embodiments, the PEG units used in the hydrogels of the invention have 4 arms. In certain embodiments, the PEG units used in the hydrogels of the invention have 8 arms. In certain embodiments, PEG units having 4 arms and PEG units having 8 arms are used in the hydrogels of the invention. In certain embodiments, one or more 4-armed PEGs are utilized.

[0115] The number and molecular weight of the PEG arms used contribute to controlling the flexibility or softness of the resulting hydrogel. For example, hydrogels formed by crosslinking 4-arm PEG are generally softer and more flexible than those formed from 8-arm PEG of the same molecular weight. Also, higher molecular weight for a particular number of arms usually increases softness. In particular, as disclosed later in this specification in the section on making inserts or implants, if it is desired to stretch the hydrogel before drying (or even after drying), a softer hydrogel, such as 4-arm PEG, may be used, optionally in combination with another multi-arm PEG (e.g., 8-arm PEG as disclosed above, or another (different) 4-arm PEG).

[0116] In certain embodiments of the invention, the polyethylene glycol units used as precursors have an average molecular weight (Mn) in the range of about 2,000 to about 100,000 daltons, or in the range of about 10,000 to about 60,000 daltons, or in the range of about 15,000 to about 50,000 daltons. These polymers usually have a narrow polydispersity, such as Mw / Mn less than 1.1. In certain particular embodiments, the polyethylene glycol units have an average molecular weight in the range of about 10,000 to about 40,000 daltons. In a specific embodiment, the polyethylene glycol units used to prepare the hydrogels according to the invention have an average molecular weight of about 20,000 daltons. Polyethylene glycol precursors of different molecular weights may be combined with each other. When referring herein to a PEG material having a particular average molecular weight, for example about 20,000 daltons, a ±10% variation is intended to be included, i.e., a reference to a material having an average molecular weight of about 20,000 daltons also refers to such materials having average molecular weights of about 18,000 to about 22,000 daltons. As used herein, the abbreviation "k" in the context of molecular weight means 1,000 daltons, i.e., "20k" means 20,000 daltons.

[0117] In a 4-arm ("4a") PEG, in certain embodiments, each of the arms may have an average arm length (or molecular weight) that is the total molecular weight of the PEG divided by 4. Thus, the 4a20k PEG precursor, which is a particularly suitable precursor for use in the present invention, has 4 arms with an average molecular weight of about 5,000 Daltons each and a total molecular weight of 20,000 Daltons. Thus, the 8a20k PEG precursor, which may be used in combination with or instead of the 4a20k PEG precursor in the present invention, has 8 arms ("8a") with an average molecular weight of 2,500 Daltons each and a total molecular weight of 20,000 Daltons. Longer arms may be more flexible than shorter arms. PEGs with longer arms may swell more than PEGs with shorter arms. Also, PEGs with fewer arms may swell more and may be more flexible than PEGs with more arms. In certain embodiments, only 4-arm PEG precursors are utilized in the present invention. In certain other embodiments, a combination of 4-arm PEG precursors and 8-arm precursors is utilized in the present invention. In addition, longer PEG arms result in a higher melting point when dry, which may enhance dimensional stability during storage.

[0118] In certain embodiments, electrophilic end groups for use with PEG precursors for the preparation of hydrogels of the invention are N-hydroxysuccinimidyl (NHS) esters, including, but not limited to, NHS dicarboxylate esters (e.g., succinimidyl malonate, succinimidyl maleate, succinimidyl fumarate), "SAZ" (referring to succinimidyl azelate end groups), "SAP" (referring to succinimidyl adipate end groups), "SG" (referring to succinimidyl glutarate end groups), "SS" (referring to succinimidyl succinate end groups), and "SGA" (referring to succinimidyl glutarate end groups).

[0119] In certain embodiments, nucleophilic end groups for use with electrophilic group-containing PEG precursors for the preparation of the hydrogels of the invention are amine (denoted as "NH") end groups. Thiol (-SH) end groups or other nucleophilic end groups are also possible.

[0120] In certain preferred embodiments of the invention, 4-arm PEG having an average molecular weight of about 20,000 Daltons and electrophilic end groups as disclosed above (e.g., SAZ, SAP, SG, and SS end groups, especially SG end groups) are crosslinked to form a polymer network and thus a hydrogel according to the invention. Suitable PEG precursors are available from a number of sources, such as Jenkem Technology.

[0121] For example, the reaction of a nucleophilic group-containing crosslinker with an electrophilic group-containing PEG unit, e.g., an amine group-containing crosslinker with an activated ester group-containing PEG unit, may result in a plurality of PEG units of the formula: [ka] where m is an integer from 0 to 10, specifically 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. For SAZ end groups, m is 6, for SAP end groups, m is 3, for SG end groups, m is 2, and for SS end groups, m is 1.

[0122] In certain embodiments, the polymer precursors used to form hydrogels according to the invention may be selected from 4a20kPEG-SAZ, 4a20kPEG-SAP, 4a20kPEG-SG, 4a20kPEG-SS, 8a20kPEG-SAZ, 8a20kPEG-SAP, 8a20kPEG-SG, 8a20kPEG-SS, or mixtures thereof, with one or more PEG or lysine-based amine groups selected from 4a20kPEG-NH2, 8a20kPEG-NH2, and trilysine, or trilysine salts or derivatives, such as trilysine acetate. In certain embodiments, the salt form is protective and is removed in water, and the crosslinking reaction occurs when the polymers are melted and mixed. Crosslinking may occur faster when non-salts are used. In certain embodiments, an additional inlet / feed port on the extruder allows for the introduction of a crosslinker just prior to extrusion.

[0123] In certain embodiments, the present invention utilizes SG end groups, which may result in a shorter time for the hydrogel to biodegrade in an aqueous environment, such as in tears, than other end groups, such as SAZ end groups. SAZ end groups may be less susceptible to ester hydrolysis than SG end groups, since they provide a higher number of carbon atoms in the linker and are therefore more hydrophobic.

[0124] In a particular embodiment, a 4-arm 20,000 dalton PEG precursor with SG end groups (as defined above) is crosslinked with a crosslinker having one or more reactive amine end groups. This PEG precursor is abbreviated herein as 4a20kPEG-SG. The schematic chemical structure of 4a20kPEG-SG is reproduced below. [ka] In this formula, n is determined by the molecular weight of each PEG arm.

[0125] In certain embodiments, the crosslinking agent (also referred to herein as "crosslinker") used is a low molecular weight component containing a nucleophilic end group (e.g., an amine or thiol end group). In certain embodiments, the nucleophilic group-containing crosslinking agent is a low molecular weight amine having a molecular weight of less than 1,000 Da. In certain embodiments, the nucleophilic group-containing crosslinking agent contains two, three, or more primary aliphatic amine groups. Suitable crosslinking agents for use in the present invention include (but are not limited to) spermine, spermidine, lysine, dilysine, trilysine, tetralysine, polylysine, ethylenediamine, polyethyleneimine, 1,3-diaminopropane, 1,3-diaminopropane, diethylenetriamine, trimethylhexamethylenediamine, 1,1,1-tris(aminoethyl)ethane, pharma- ceutically acceptable salts, hydrates, or other solvates thereof, and derivatives thereof (e.g., conjugates (so long as there are sufficient nucleophilic groups for crosslinking)), and any mixtures thereof. A specific cross-linking agent for use in the present invention is trilysine, or a trilysine salt or derivative, such as trilysine acetate. Other low molecular weight multi-arm amines may also be used. The chemical structure of trilysine is reproduced below: [ka]

[0126] In a very specific embodiment of the invention, the 4a20kPEG-SG precursor is reacted with trilysine acetate to form the polymer network.

[0127] In certain embodiments, the nucleophilic group-containing crosslinker is bound to or conjugated with a visualization agent. Fluorophores, such as fluorescein, rhodamine, coumarin, and cyanine, can be used as visualization agents disclosed herein. In a specific embodiment of the present invention, fluorescein is used as the visualization agent. The visualization agent can be conjugated to the crosslinker, for example, via some of the nucleophilic groups of the crosslinker. Because a sufficient amount of nucleophilic groups is required for crosslinking, generally "conjugated" or "conjugation" includes partial conjugation, meaning that only some of the nucleophilic groups are used for conjugation with the visualization agent, for example, about 1% to about 20%, or about 5% to about 10%, or about 8% of the nucleophilic groups of the crosslinker can be conjugated to the visualization agent. In a specific embodiment, the crosslinker is trilysine acetate and is conjugated to fluorescein.

[0128] In other embodiments, the visualization agent may be conjugated to the polymer precursor, for example, via certain reactive (e.g., electrophilic) groups of the polymer precursor. In certain embodiments, the crosslinker or the polymer precursor itself may contain, for example, a fluorophoric group or other visualization capable group.

[0129] The present invention contemplates conjugating the visualization agent to the polymer precursor(s) or crosslinker disclosed below, which will retain the visualization agent within the hydrogel while the active agent is released into the tear fluid, allowing for a convenient and non-invasive method of confirming the presence of the insert within the canaliculus.

[0130] In certain embodiments, the molar ratio of nucleophilic and electrophilic end groups reacting with each other is about 1:1, i.e., one amine group is provided for every electrophilic group (e.g., SG group). In the case of 4a20kPEG-SG and trilysine (acetate), the molar ratio of the two components is about 1:1, since trilysine has four primary amine groups that can react with the electrophilic SG ester groups. However, an excess of either the electrophilic end group (e.g., NHS end group such as SG) precursor or the nucleophilic (e.g., amine) end group precursor may be used. In particular, an excess of nucleophilic end group (e.g., amine end group)-containing precursor or crosslinker may be used. In certain embodiments, the molar ratio of electrophilic group-containing precursor:nucleophilic group-containing crosslinker, e.g., 4a20kPEG-SG:trilysine acetate, is about 1:2 to about 0.5:1, or about 1:2 to about 2:1.

[0131] Finally, in an alternative embodiment, the amine coupling agent may be another PEG precursor having the same or a different number of arms and the same or a different arm length (average molecular weight) as 4a20kPEG-SG, but having a terminal amine group, i.e., 4a20kPEG-NH2.

[0132] Additional Ingredients The insert or implant of the present invention may contain other additional components in addition to the polymeric units forming the polymer network as disclosed above and the active ingredient. Such additional components are, for example, salts resulting from the buffer used during the preparation of the hydrogel, such as phosphates, borates, bicarbonates, or other buffers, such as triethanolamine. In a particular embodiment of the present invention, sodium phosphate buffers are used, specifically sodium phosphate monobasic and sodium phosphate dibasic.

[0133] In a specific embodiment, the insert or implant of the present invention does not contain an antimicrobial preservative, or at least does not contain a significant amount of an antimicrobial preservative.

[0134] In a further specific embodiment, the insert or implant of the present invention does not contain any components of animal or human origin, but only synthetic components.

[0135] In certain embodiments, the insert or implant of the present invention comprises a visualization agent. The visualization agent used according to the present invention is any agent that can be conjugated to a component of the hydrogel or encapsulated in the hydrogel and is visible or can be visualized, for example, when exposed to a certain wavelength of light, or is a contrast agent. Visualization agents suitable for use in the present invention include, but are not limited to, for example, fluorescein, rhodamine, coumarin, cyanine, europium chelate complex, boron dipyrromethene, benzofurazan, dansyl, bimane, acridine, triazapentalene, pyrene, and derivatives thereof. Such visualization agents are commercially available (for example, from TCI). In certain embodiments, the visualization agent is a fluorophore, for example, fluorescein. The fluorescein-containing insert or implant can be visualized by illuminating it with blue light. The fluorescein in the intracanalicular insert will emit light when excited with blue light, and the presence of the insert can be confirmed. In a specific embodiment, the visualization agent is conjugated to one of the components that form the hydrogel. For example, a visualization agent, such as fluorescein, is conjugated to a crosslinker such as trilysine or a salt or derivative of trilysine (e.g., trilysine acetate) or to a PEG moiety, such as by reacting NHS-fluorescein with trilysine acetate. Conjugation of the visualization agent prevents it from eluting or being released from the insert.

[0136] In other embodiments, the formulation may include a plasticizer (e.g., stearic acid or glyceryl behenate) or a pore former (e.g., mannitol, sorbitol, or calcium carbonate). The inclusion of a plasticizer may improve the extrudability / flowability of the formulation, while the use of a pore former may increase the surface area upon dissolution and increase the release rate.

[0137] compound In certain embodiments, an insert or implant according to the invention comprises an active agent, a polymer network made from one or more polymer precursors disclosed herein in the form of a hydrogel, and optional additional components such as visualization agents, salts, etc. (e.g., phosphates used as buffers, etc.) that remain in the insert or implant from the production process. In certain embodiments, the insert or implant does not contain a preservative.

[0138] In some embodiments, the insert or implant according to the invention comprises, on a dry basis, about 5% to about 80% by weight of active agent, and about 15% to about 95% by weight of polymeric units, such as those disclosed above. In other embodiments, the insert or implant according to the invention comprises, on a dry basis, about 30% to about 70% by weight of active agent, and about 25% to about 60% by weight of polymeric units, such as those disclosed above. In further embodiments, the insert or implant according to the invention comprises, on a dry basis, about 30% to about 60% by weight of active agent, and about 30% to about 60% by weight of polymeric units, such as those disclosed above.

[0139] In certain embodiments, the insert or implant according to the invention may contain about 0.1% to about 1% by weight of a visualization agent, such as fluorescein, on a dry basis. In certain embodiments, the insert or implant according to the invention may also contain about 0.5% to about 5% by weight of one or more buffer salt(s) (separately or together) on a dry basis. In such embodiments, the insert or implant may contain about 0.01% to about 2% by weight or about 0.05% to about 0.5% by weight of a surfactant on a dry basis.

[0140] The amounts of active agent and polymer(s) may be varied and other amounts of active agent and polymer hydrogels beyond those disclosed herein may be used to prepare inserts or implants according to the present invention.

[0141] In certain embodiments, the maximum amount (wt %) of drug in the formulation is about twice the amount of polymer (e.g., PEG) units, although in certain cases the maximum amount of drug may be higher, for example, so long as the mixture including the precursor, visualization agent, buffer, and drug (before the hydrogel is fully gelled) can be extruded uniformly and / or so long as the hydrogel is still sufficiently extensible as disclosed herein and / or sufficiently increases in diameter upon hydration, also as disclosed herein.

[0142] In certain embodiments, a solids content of about 20% to about 50% (w / v) (where "solids" refers to the combined weight of the polymer precursor(s), optional visualization agent, salts, and drugs in solution) is utilized to form the hydrogel of an insert or implant according to the present invention.

[0143] In certain embodiments, the water content of the hydrogel in its dry (dehydrated / dried) state may be low, for example, about 1% water or less by weight, and in certain embodiments, the water content may be even lower, in some cases about 0.25% or less, or even about 0.1% or less by weight.

[0144] The dimensions of the insert or implant and the change in dimensions upon hydration due to stretching The dried insert or implant can have various geometric shapes depending on the manufacturing method, for example the size and shape of the mold or extrusion die that molds or extrudes the mixture containing the hydrogel precursor containing glucocorticoid before curing.In one embodiment, the insert or implant has an essentially cylindrical or essentially circular cross section.The shape of the insert or implant produced by extrusion can also be described as a fiber, strand, or rod.

[0145] Other shapes of the shape or cross section of the outer insert or implant may be used, such as an armed star shape, a gear shape, a ribbon shape (e.g., a flattened rectangle), a circular or semicircular shape, or a trapezoidal shape. For example, instead of round fibers, elliptical (or oblong) fibers may be used. The exact cross-sectional shape is not critical since tissue will form around the insert or implant when it hydrates within the canaliculus, as long as its diameter expands to the average hydrated diameter as disclosed herein.

[0146] The polymer network, such as the PEG network of a hydrogel insert or implant according to certain embodiments of the present invention, can be semi-crystalline in the dry state at or below room temperature and amorphous in the wet state. Even in an expanded form, the dry insert or implant can be dimensionally stable at or below room temperature, which can be advantageous for administration of the insert or implant into a target tissue and for quality control.

[0147] In certain embodiments, this dimensional change is possible, at least in part, due to a "shape memory" effect that is introduced into the insert or implant by longitudinally stretching the insert or implant during manufacture, as also disclosed herein. In certain embodiments, this stretching can be performed in a wet state, i.e., before drying. However, in certain other embodiments, stretching of the hydrogel strands (once cured) may be performed in a dry state (i.e., after drying the hydrogel strands). It should be noted that if no stretching is performed, the insert or implant may simply swell due to uptake of water, but may not achieve or may achieve less of the dimensional change of increasing diameter and decreasing length disclosed herein. This may result in, for example, a less than optimal fixation of the insert or implant in the canaliculus, leading to the removal of the insert or implant through the nasolacrimal duct or lacrimal punctum (possibly even before the full dose of active agent is released). If this is not desired, the hydrogel fibers may be, for example, dry or wet stretched to expand their diameter upon rehydration.

[0148] In the case of the hydrogels of the present invention, some degree of molecular orientation can be imparted by stretching the material and then solidifying it, fixing the molecular orientation. Molecular orientation provides one mechanism for anisotropic swelling when the insert or implant is contacted with a hydration medium (e.g., tear fluid). Upon hydration, the insert or implant of certain embodiments of the present invention swells only in the radial dimension, while the length decreases or is essentially maintained. The term "anisotropic swelling" refers to preferential swelling in one direction and not in another, such that in a cylindrical shape the diameter swells predominantly, while the longitudinal dimension swells very little (or even shrinks).

[0149] The extent of the dimensional change upon hydration may depend, inter alia, on the stretching factor. As a mere example to illustrate the effect of stretching, stretching (e.g., by wet stretching) with a stretching factor of, for example, about 1.3 may not have a significant effect or may not significantly change the length and / or diameter upon hydration. In contrast, stretching (e.g., by wet stretching) with a stretching factor of, for example, about 1.8 may result in a shorter length and / or an increased diameter upon hydration. Stretching (e.g., by dry stretching) with a stretching factor of, for example, about 3 or 4 may result in a much shorter length and a much larger diameter upon hydration. Those skilled in the art will understand that factors other than stretching may also affect swelling behavior.

[0150] Other factors that affect the ability of the hydrogel to stretch and change the dimensions of the insert or implant upon hydration include the composition of the polymer network. When PEG precursors are used, precursors with fewer arms (e.g., 4-arm PEG precursors) contribute to greater flexibility of the hydrogel than precursors with more arms (e.g., 8-arm PEG precursors). If the hydrogel contains more components with less flexibility (e.g., a higher amount of PEG precursors with a greater number of arms (e.g., 8-arm PEG units)), the hydrogel may be stiffer and less easily stretched without breaking. On the other hand, hydrogels with more flexible components (e.g., PEG precursors with fewer arms (e.g., 4-arm PEG units)) may be easier to stretch and softer, but may also swell more upon hydration. Thus, once the insert or implant is administered and rehydrated, the behavior and properties of the insert can be tailored not only by changing the structural features, but also by modifying the processing of the insert or implant after it is initially formed.

[0151] The dimensions of the dried insert or implant depend, inter alia, on the amount of glucocorticoid incorporated and the ratio of glucocorticoid:polymer units, and can be further controlled by the diameter and shape of the mold or tube in which the hydrogel is gelled. The diameter of the dried insert or implant can be further controlled by (wet or dry) stretching of the hydrogel strands once formed as disclosed herein. The dried hydrogel strands (after stretching) are cut into segments of the desired length to form the insert. Thus, the length can be selected as needed.

[0152] Release of active substances and biodegradation of inserts In certain embodiments, the persistence, i.e., time to disappearance in vivo or in vitro, of the inserts or implants of the present invention has been found to be increased compared to other methods such as casting. In one embodiment, the present invention relates to a sustained release biodegradable intraocular insert or implant comprising a hydrogel and an active agent, the insert or implant releasing a therapeutically effective amount of the active agent over a period of about 1 day to about 14 months or more. In other embodiments, the release is 30 days or less, 2 months or less, 3 months or less, 6 months or less, 9 months or less, 11 months or less, 12 months or less, 13 months or less, 14 months or less, or 15 months or less.

[0153] Further embodiments In certain embodiments, the formulation comprises from about 1% to about 80% by weight of active ingredient and from about 20% to about 80% by weight of polyethylene glycol.

[0154] In certain embodiments, the polyethylene glycol comprises 4a20k SG, 4a20k SAP, 4a20k SAZ, 8a20k NH3+, TLA crosslinker, or a combination thereof.

[0155] The active ingredient can be, for example, dexamethasone, cyclosporine, axitinib, bupivacaine, ropivacaine, or other suitable active ingredients used to treat various ocular disorders or diseases.

[0156] In certain embodiments, the batch size of the formulation may be from about 25 g to about 300 g, while in other embodiments, the batch size may be up to 1 kg or more.

[0157] In certain embodiments, mixing of the materials prior to extrusion includes hand mixing (e.g., in a sealable plastic bag), mixing in a mechanical mixer such as a FlakTek Speed ​​Mixer or V-Shell Blender, or mixing with a sonic mixer such as a Resodyn Acoustic Mixer.

[0158] In certain embodiments, the powder feed rate to the extruder is from about 2 g / min to about 10 g / min. The powder feeder can be a plunger feeder, or a K-Tron or Brabender feeder.

[0159] In certain embodiments, the extrusion temperature is from about 20° C. to about 150° C., or from about 40° C. to about 90° C. In certain embodiments, the polyethylene glycol is melted and the active ingredient is not melted.

[0160] In certain embodiments, the extruder die size is from about 0.3 mm to about 3 mm and different shapes (eg, cross or star) are available to optimize surface area.

[0161] In certain embodiments, the extruder screw speed is from about 50 rpm to about 200 rpm. EXAMPLES

[0162] The following examples are included to demonstrate certain aspects and embodiments of the claimed invention, although those of ordinary skill in the art will appreciate that the following descriptions are illustrative only and should not be construed as limiting the invention in any way.

[0163] Example 1 Running the extrusion using the MiniCTW extruder The melt extrusion process begins with obtaining the necessary raw materials. This includes reactive polymers (4a20K PEG SG and fluorescein-tagged trilysine acetate (TLA)), API, and disodium phosphate. Alternatively, TLA can be replaced with PEG amine salt. These materials are first combined in melt or powder form and mixed for 10 minutes to obtain a homogenous pelletized, granulated, or mixed powder material. The materials are then fed into a MiniCTW melt extruder (Thermofisher, Inc.) set at a temperature (50-55°C) and screw rotation speed (20 rpm). The materials may be recirculated in the barrel of the twin-screw mixer extruder for 10 minutes to ensure homogeneity before extrusion. The materials may then be extruded from the extruder die onto a conveyor belt at a speed of 1000 RPM (1.4 in / sec). The draw speed determines the diameter of the extrudate. Drawing keeps the material straight, allowing it to cool and harden before it is cut off from the extruder and collected for downstream processing. After extrusion, the material can be placed in a humidity chamber to crosslink (usually overnight, 16-24 hours). After crosslinking, the wet, 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 as the liquid casting process. This process is carried out with the exclusion of water during extrusion, thus facilitating activation of the PEG crosslinking reaction. Since no heat is required to promote the crosslinking reaction, extrusion was carried out at a low temperature of 50-55°C. Exposure to a controlled water vapor environment (>95% humidity) after extrusion allows enough water to penetrate the strands and activate the hardening reaction. The wet strands, once crosslinked, become rubber and can be stretched three times their original length. Evaporative drying with a nitrogen sweep leaves a semi-crystalline solid that, although not cast, has the same molecular and physical structure and properties as the dried Dextenza® (dexamethasone intracanalicular insert) strands.

[0164] Table 1 provides an overview of these steps and discusses example equipment for each step and an example setting for each step. [Table 1-1] [Table 1-2] Product configuration:

[0165] Using the procedure described above, a dexamethasone composition containing the ingredients in Table 2 was prepared. [Table 2]

[0166] result: FIG. 1 shows the in vitro release of example melt extruded materials compared to dextenza, and the results before and after gamma sterilization.

[0167] After completing processing of these batches (including drying and cutting), the dry / wet dimensions of the plugs were analyzed and compared to Dextenza®. These results are shown in Table 3. The analytical results of the melt extruded product were comparable to Dextenza®, as shown in Table 4. [Table 3] [Table 4]

[0168] Example 2 Extrusion run using Leistritz Nano-16 extruder Formulation: Cyclosporine - batch size of 75g 38.1 g of micronized cyclosporine and 32.2 g (50.8%) of 4a20k PEG SG (42.9%) were placed in a 250 mL bottle and sealed under nitrogen. 0.94 g of trilysine acetate (TLA) and 3.8 g of disodium phosphate salt were placed in a glass vial and sealed under nitrogen. The materials were mixed and added to the plunger feeder. Air was reduced by beating with a rubber mallet. A parallel twin screw was set up using the custom configuration in Figure 2. The two shaded elements are for increasing shear, mixing, and degassing of the formulation. The downward arrow in the diagram indicates that the vent was open. The plunger temperature was set to "COLD" using a water jacket, with zone #1 set to 70 °C, zone #2 set to 50 °C, zone #3 set to 40 °C, and zone #4 set to 50 °C at the die opening. The die opening was circular with a diameter of 1.5 mm. The screw was set at 100 rpm and the powder feed rate was 5 cc / min. The extrudate was collected by a Dorner 2200 series conveyor belt operating at 4.4 FPM and fed into a Conair CPC 1-12 SD brand combination puller / cutter. The extrudate strand segments were cut into 20 cm pieces and stored in plastic tubes under a nitrogen purged environment for further processing.

[0169] Example 3 Extrusion run using Leistritz Nano-16 extruder Formulation: Axitinib - batch size of 50g 34.1 g of micronized dexamethasone (alternative API, 67.8%) and 10.1 g of 4a20k PEG SAZ (20.0%) were placed in a 250 mL bottle and sealed under nitrogen. 5.1 g of 8a20k NH3+ salt and 1.0 g of sodium phosphate dibasic salt were placed in a glass vial and sealed under nitrogen. The materials were mixed and added to the plunger feeder. Air was reduced by beating with a rubber mallet. A parallel twin screw was set up using the custom configuration in Figure 2. Note that the two shaded elements were selected to increase shear, mixing, and degassing of the formulation. The down arrow in the diagram indicates that the vent was open. The plunger temperature was set to "COLD" using a water jacket, with zone #1 set to 70°C, zone #2 set to 50°C, zone #3 set to 40°C, and zone #4 set to 50°C at the die opening. The die opening was circular with a diameter of 1.5 mm. The screw was set at 100 rpm and the powder feed rate was 5 cc / min. The extrudate was collected by a Dorner 2200 series conveyor belt operating at 3.8 FPM and fed into a Conair CPC 1-12 SD brand combination puller / cutter. The extrudate strand segments were cut into 20 cm pieces and stored in plastic tubes under a nitrogen purged environment for further processing.

[0170] Example 4 Extrusion run using Leistritz Nano-16 extruder Formulation: Dexamethasone - batch size of 50g 22.5 g of micronized dexamethasone (44.8%) and 25.0 g of 4a20k PEG SG (50.0%) were placed in a 250 mL bottle and sealed under nitrogen. 0.7 g of trilysine acetate (TLA) and 1.8 g of disodium phosphate salt were placed in a glass vial and sealed under nitrogen. The materials were mixed and added to the plunger feeder. Air was reduced by beating with a rubber mallet. A parallel twin screw was set up using the custom configuration in Figure 2. Note that the two shaded elements were selected to increase shear, mixing, and degassing of the formulation. The down arrow in the diagram indicates that the vent was open. The plunger temperature was set to "COLD" using a water jacket, with zone #1 set to 70°C, zone #2 set to 50°C, zone #3 set to 40°C, and zone #4 set to 50°C at the die opening. The die opening was circular with a diameter of 1.5 mm. The screw was set at 100 rpm and the powder feed rate was 5 cc / min. The extrudate was collected by a Dorner 2200 series conveyor belt operating at 3.4 FPM and fed into a Conair CPC 1-12 SD brand combination puller / cutter. The extrudate strand segments were cut into 20 cm pieces and stored in plastic tubes under a nitrogen purged environment for further processing.

[0171] Example 5 Extrusion run using Leistritz Nano-16 extruder Formulation: Cyclosporine (SG) - 150g batch size 26.0g of micronized cyclosporine (52.0%) and 21.0g of 4a20k PEG SAP (42.0%) were placed in a 100g FlakTek cup and sealed under nitrogen. 0.6g of trilysine acetate (TLA) and 2.4g of disodium phosphate salt were placed in a glass vial and sealed under nitrogen. This was repeated twice for both containers. The materials were mixed in a FlakTek speed mixer at 1000 rpm for 2x15 seconds. The mixed materials were added to a K-Tron T20 powder feeder. A parallel twin screw was set up using the custom configuration in Figure 2. Note that the two shaded elements were selected to increase shear, mixing, and degassing of the formulation. The down arrow in the figure indicates that the vent was open. The plunger temperature was set to "COLD" using a water jacket, with zone #1 at 40°C, zone #2 at 70°C, zone #3 at 40°C, and zone #4 at the die opening at 50°C. The die opening was circular with a diameter of 1.1 mm. The screw was set at 150 rpm, and the powder feed rate was 2 to 3 g / min. A Dorner 2200 series conveyor belt collecting the extrudate was operated at 3.8 FPM and fed into a Conair CPC 1-12 SD brand combination puller / cutter. The extrudate strand segments were cut into 21.6-inch pieces and stored in plastic tubes under a nitrogen purged environment for further processing.

[0172] Example 6 Extrusion run using Leistritz Nano-16 extruder Formulation: Axitinib - batch size of 35g 23.8g of micronized axitinib (69.0%) and 9.3g of 4a20k PEG SAZ (27.0%) were placed in a 100g FlakTek cup and sealed under nitrogen. 0.3g of trilysine acetate (TLA) and 1.1g of disodium phosphate salt were placed in a glass vial and sealed under nitrogen. The materials were mixed in a FlakTek Speed ​​Mixer at 1000 rpm for 2x15 seconds. The mixed materials were added to the plunger feeder. Air was reduced by tapping with a rubber mallet. A parallel twin screw was set up using the custom configuration in Figure 2. Note that the two shaded elements were selected to increase shear, mixing, and degassing of the formulation. The down arrow in the figure indicates that the vent was open. The plunger temperature was set to "COLD" using a water jacket, with zone #1 at 40°C, zone #2 at 70°C, zone #3 at 40°C, and zone #4 at the die opening at 50°C. The die opening was circular with a diameter of 0.7 mm. The screw was set at 150 rpm and the powder feed rate was 5 cc / min. A Dorner 2200 series conveyor belt collecting the extrudate was operated at 12 FPM and fed into a Conair CPC 1-12 SD brand combination puller / cutter. The extrudate strand segments were cut into 21.6-inch pieces and stored in plastic tubes under a nitrogen purged environment for further processing.

[0173] Example 7 Extrusion run using Leistritz Nano-16 extruder Formulation: Cyclosporine (SAP) - batch size of 150g 26.0g of micronized cyclosporine (52.0%) and 21.0g of 4a20k PEG SAP (42.0%) were placed in a 100g FlakTek cup and sealed under nitrogen. 0.6g of trilysine acetate (TLA) and 2.4g of disodium phosphate salt were added to a glass vial and sealed under nitrogen. This was repeated twice for both containers. The materials were mixed in a FlakTek Speed ​​Mixer at 1000 rpm for 2x15 seconds. The mixed materials were added to a K-Tron T20 powder feeder. A parallel twin screw was set up using the custom configuration in Figure 2. Note that the two shaded elements were selected to increase shear, mixing, and degassing of the formulation. The down arrow in the figure indicates that the vent was open. The plunger temperature was set to "COLD" using a water jacket, with zone #1 at 40°C, zone #2 at 70°C, zone #3 at 40°C, and zone #4 at the die opening at 50°C. The die opening was circular with a diameter of 1.1 mm. The screw was set at 150 rpm and the powder feed rate was 4 g / min. The Dorner 2200 series conveyor belt collecting the extrudate was operated at 3.8 FPM and fed into a Conair CPC 1-12 SD brand combination puller / cutter. The extrudate strand segments were cut into 21.6-inch pieces and stored in plastic tubes under a nitrogen purged environment for further processing.

[0174] Example 8 Extrusion run using Leistritz Nano-16 extruder Formulation: Bupivacaine (4a40k SG / TLA) - batch size of 37.8g 24.57g micronized bupivacaine (65%) and 12.67g 4a40k PEG SG (33.5%) were placed in a cup, sealed under nitrogen, and mixed in a FlakTek at 1000 rpm for 30 seconds. 0.188g TLA (0.49%) and 0.39g disodium phosphate salt (1.0%) were placed in a glass vial, sealed under nitrogen. The materials were mixed in a FlakTek speed mixer at 1000 rpm for 2x30 seconds. They were added to the plunger feeder. A parallel twin screw was set up using the custom configuration in Figure 2. Note that the two shaded elements were selected to increase shear, mixing, and degassing of the formulation. The down arrow in the figure indicates that the vent was open. The plunger temperature was set to "COLD" using a water jacket, with zone #1 at 60°C, zone #2 at 80°C, zone #3 at 60°C, and zone #4 at the die opening at 80°C. The die opening was circular with a diameter of 1.1 mm. The screw was set at 150 rpm and the powder feed rate was 4 g / min. The Dorner 2200 series conveyor belt collecting the extrudate was operated at 34 FPM and fed into a Conair CPC 1-12 SD brand combination puller / cutter. The extrudate strand segments were cut into 12 inch pieces and stored in plastic tubes under a nitrogen purged environment for further processing.

[0175] Example 9 Extrusion run using Leistritz Nano-16 extruder Formulation: Axitinib (4a20k SAZ / TLA) - batch size of 35g 14.13g of micronized axitinib (39.8%) and 20.07g of 4a20k PEG SAZ (57.5%) were placed in a cup, sealed under nitrogen, and mixed in a FlakTek at 1000 rpm for 30 seconds. 0.60g of TLA (1.68%) and 0.37g of disodium phosphate salt (1.0%) were placed in a glass vial, sealed under nitrogen, and mixed in a FlakTek Speed ​​Mixer at 1000 rpm for 2x30 seconds. The mixed materials are added to a plunger powder feeder. A parallel twin screw is set up using the custom configuration in Figure 2. Note that the two shaded elements were selected to increase shear, mixing, and degassing of the formulation. The down arrow in the figure indicates that the vent is open. The plunger temperature was set to "COLD" using a water jacket, with zone #1 at 40°C, zone #2 at 70°C, zone #3 at 70°C, and zone #4 at the die opening at 50°C. The die opening was circular with a diameter of 0.5 mm. The screw was set at 150 rpm and the powder feed rate was 4 g / min. A Dorner 2200 series conveyor belt was run collecting the extrudate and feeding it into a Conair CPC 1-12 SD brand combination puller / cutter. The extrudate strand segments were cut into 12 inch pieces and stored in plastic tubes under a nitrogen purged environment for further processing.

[0176] Example 10 Extrusion run using Leistritz Nano-16 extruder Formulation: Dexamethasone (4a20k SG / TLA) - batch size of 36.4g 18.21g of micronized dexamethasone (50.0%) and 17.35g of 4a20k PEG SG (47.6%) were placed in a cup, sealed under nitrogen, and mixed in a FlakTek at 1000 rpm for 30 seconds. 0.51g of TLA (1.39%) and 0.38g of disodium phosphate salt (1.0%) were placed in a glass vial, sealed under nitrogen, and mixed in a FlakTek Speed ​​Mixer at 1000 rpm for 2x30 seconds. The mixed materials were added to the plunger powder feeder. A parallel twin screw was set up using the custom configuration in Figure 2. Note that the two shaded elements were selected to increase shear, mixing, and degassing of the formulation. The down arrow in the figure indicates that the vent was open. The plunger temperature was set to "COLD" using a water jacket, with zone #1 at 60°C, zone #2 at 80°C, zone #3 at 60°C, and zone #4 at the die opening at 50°C. The die opening was circular with a diameter of 1.1 mm. The screw was set at 150 rpm and the powder feed rate was 5 cc / min. A Dorner 2200 series conveyor belt was run collecting the extrudate and feeding it into a Conair CPC 1-12 SD brand combination puller / cutter. The extrudate strand segments were cut into 12 inch pieces and stored in plastic tubes under a nitrogen purged environment for further processing.

[0177] Example 11 Extrusion run using Leistritz Nano-16 extruder Formulation: Dexamethasone (4a20k SG / TLA) - batch size of 33.3g 21.65g of micronized dexamethasone (65.0%) and 17.35g of 4a20k PEG SG (33.0%) were placed in a cup, sealed under nitrogen, and mixed in a FlakTek at 1000 rpm for 30 seconds. 0.33g of TLA (0.9%) and 0.35g of disodium phosphate salt (1.0%) were placed in a glass vial, sealed under nitrogen, and mixed in a FlakTek Speed ​​Mixer at 1000 rpm for 2x30 seconds. The mixed materials were added to the plunger powder feeder. A parallel twin screw is set up using the custom configuration in Figure 2. Note that the two shaded elements were selected to increase shear, mixing, and degassing of the formulation. The down arrow in the figure indicates that the vent was open. The plunger temperature was set to "COLD" using a water jacket, with zone #1 at 60°C, zone #2 at 80°C, zone #3 at 60°C, and zone #4 at the die opening at 50°C. The die opening was circular with a diameter of 1.1 mm. The screw was set at 150 rpm and the powder feed rate was 5 cc / min. A Dorner 2200 series conveyor belt was run collecting the extrudate and feeding it into a Conair CPC 1-12 SD brand combination puller / cutter. The extrudate strand segments were cut into 12 inch pieces and stored in plastic tubes under a nitrogen purged environment for further processing.

[0178] Example Input Ranges Compound: API 1~80% by weight, PEG 20~80% by weight PEG: 4a20k SG, 4a20k SAP, 4a20k SAZ, 8a20k NH3+, TLA crosslinker API: dexamethasone, cyclosporine, axitinib (examples do not show bupivacaine and ropivacaine) Batch size: 25-300g using Nano-16 Powder Mixing: Hand mixing in Ziploc bags and FlakTek (note I have also tried a V-shell blender and Resodyn acoustic mixing) Powder feed rate: 2-10g / min using plunger feeder, K-Tron, and Brabender feeder Screw geometry: one set has been used for all tests at Leistritz so far, but the screw can also be modified to add mixing / degassing segments. Temperature profile: 40-90°C, goal is to melt the PEG but not the API, keeping the temperature as low as possible to protect excipient powders and optimize stability. Die size: round is 0.3~3mm, other cross / star shapes to optimize surface area. Screw speed: 50~200rpm

[0179] Example Equipment Used Leistritz Nano-16 brand twin screw extruder Conair CPC1-12SD Brand Combined Puller / Cutter Dorner 2200 brand conveyor belt K-Tron T20 Brand Powder Feeder Flak Tek Speed ​​Mixer

Claims

1. A method for preparing a sustained-release biodegradable intraocular insert or implant, comprising extruding a water-soluble polymer composition comprising polyethylene glycol and an active pharmaceutical agent to form an insert or implant suitable for intraocular administration.

2. 10. The method of claim 1, wherein the method comprises feeding the polymer composition and the active pharmaceutical agent into an extruder.

3. mixing the ingredients in the extruder; extruding the strands; cutting the strands into unit dose inserts or implants; The method of claim 2 further comprising:

4. 3. The method of claim 2, wherein the polymer composition and the active pharmaceutical agent are fed separately to the extruder.

5. 3. The method of claim 2, wherein the polymer composition and the active pharmaceutical agent are mixed before being fed into the extruder.

6. 6. The method of claim 5, wherein the polymer composition and active pharmaceutical agent are melt mixed and milled before being fed into the extruder.

7. The method of claim 3 further comprising cooling the strands before cutting the strands.

8. The method of claim 3 further comprising stretching the strands before cutting the strands.

9. 9. The method of claim 8, wherein the stretching is performed (i) under wet conditions, humid conditions, heated conditions, or a combination thereof, or (ii) under dry conditions, heated conditions, or a combination thereof.

10. The method of claim 3 , wherein the extruded composition is subjected to a curing step.

11. The method of claim 10 , wherein the curing step comprises exposure to moisture.

12. The method of claim 10 wherein said curing crosslinks said polymer composition.

13. The method of claim 3 further comprising melting the polymer in the extruder at a temperature below the melting point of the active agent.

14. The method of claim 3 , wherein the extrusion is performed at a temperature above the melting point of the polymer and the active agent.

15. The method of claim 3 further comprising dewatering the strands.

16. 16. The method of claim 15, wherein the drying (i) occurs after stretching the strands, or (ii) is evaporation at ambient temperature, or (iii) is drying at ambient temperature, or (iv) comprises drying, heating, vacuum, or a combination thereof.

17. The method of any preceding claim, wherein two or more steps are performed simultaneously.

18. The method of claim 8, wherein the hydrogel strands are stretched with a stretch factor ranging from 1 to 6.

19. 4. The method of claim 3, wherein the strands are cut into segments having an average length of 50 mm or less, 10 mm or less, 4 mm or less.

20. The method of claim 19, wherein the segments are cylindrical or substantially cylindrical.

21. The method of claim 3 , wherein the active pharmaceutical agent is suspended in the polymer extrudate.

22. 17. The method of any of claims 1 to 16, wherein the extrusion is carried out (i) in the absence of a solvent, or (ii) in the absence of water.

23. The method of claim 3 , wherein the active agent is uniformly dispersed in the polymer extrudate.

24. 4. The method of claim 3, wherein the unit dose insert or implant has a content uniformity within 15%, within 10%, within 5%, or within 1%.

25. 10. The method of claim 1, wherein the duration of the dosage form is from 7 days to 6 months after intraocular administration.

26. 10. The method of claim 1, wherein the extrusion does not (i) result in a chemical or physical change of the active agent, or (ii) result in a change of the polymorphic form of the active agent.

27. 10. The method of claim 1, wherein the purity of the activator after curing is greater than 99%, greater than 99.5%, or greater than 99.9% compared to the activator before extrusion.

28. The method of claim 1, wherein (i) the average particle size of the active agent is less than 100 μm, or (ii) the active agent has a D50 particle size of less than 10 μm and / or a D99 particle size of less than 50 μm, or a D90 particle size of 5 μm or less, and / or a D98 particle size of 10 μm or less.

29. 10. The method of claim 1, wherein the polymer composition further comprises one or more units of polyethylene oxide, polypropylene oxide, polyvinyl alcohol, poly(vinylpyrrolidinone), polylactic acid, polylactic-co-glycolic acid, random or block copolymers, polycaprolactone, ethylene vinyl acetate, or any combination or mixture thereof, or a polyamino acid, glycosaminoglycan, polysaccharide, or protein.

30. 10. The method of claim 1, comprising a multi-arm polyethylene glycol.

31. 31. The method of claim 30, wherein the polymer composition further comprises a nucleophilic group-containing crosslinker.

32. 32. The method of claim 31 , wherein the cross-linking agent comprises an amine group.

33. 33. The method of claim 32, wherein the electrophilic-group-containing multi-arm polymer precursor is 4a20kPEG-SG and the crosslinker is trilysine acetate.

34. The method of claim 1 , wherein the polymer composition further comprises a visualization agent.

35. 35. The method of claim 34, wherein the visualization agent is a fluorophore.

36. 10. The method of claim 1, wherein the intraocular insert or implant is suitable for intracanalicular, intracameral, suprachoroidal, intrafornix, or intravitreal administration.

37. 17. The method of any of claims 1 to 16, wherein the active pharmaceutical agent is selected from axitinib, dexamethasone, travoprost, bupivacaine, or cyclosporine.

38. The method of claim 1 further comprising forming the extrudate by injection molding.

39. 39. The method of claim 38, comprising injecting the extrudate into a cavity of a mold and allowing the extrudate to cool and harden into the shape of the cavity.

40. 40. The method of claim 39, wherein the mold comprises steel or aluminum.

41. (i) the active agent is axitinib, and the method further comprises melting the polymer in the extruder at a temperature of 57°C to 200°C, 65°C to 150°C, or 70°C to 90°C. (ii) the active agent is dexamethasone, and further comprising melting the polymer in the extruder at a temperature of 57°C to 250°C, 65°C to 175°C, or 70°C to 90°C; (iii) the active agent is cyclosporine, and further comprising melting the polymer in the extruder at a temperature of 57°C to 145°C, 65°C to 120°C, or 70°C to 90°C. (iv) the active agent is bupivacaine, and further comprising melting the polymer in the extruder at a temperature of 57°C to 105°C, 65°C to 95°C, or 70°C to 90°C. (v) the active agent is dexamethasone and the insert or implant provides an in vitro release of 30% to 70% or 40% to 65% of dexamethasone in 1 hour; (vi) the active agent is dexamethasone and the insert or implant provides an in vitro release of 60% to 90% or 65% to 85% of dexamethasone in 2 hours; or (vii) The method of claim 1, wherein the active agent is dexamethasone and the insert or implant provides an in vitro release of greater than 85% or 90% of dexamethasone in 4 hours.

42. An intraocular insert or implant prepared by the method of any one of claims 1 to 16.

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