Fornix insert containing an active agent

Abstract

Disclosed in certain embodiments is a fomix insert comprising a material having a first distal surface and a second distal surface; the first distal surface affixed to a composition comprising a hydrogel and an active agent; the second distal surface comprising a plurality of microneedles extending away from the first distal surface; wherein the fomix insert is configured to be inserted into the fomix with the composition contacting the eyeball and the plurality of microneedles contacting the eyelid.

Description

FORNIX INSERT CONTAINING AN ACTIVE AGENTTECHNICAL FIELD

[0001] The present invention relates to compositions and methods for the treatment of ocular diseases. According to the present invention, ocular diseases are treated by administering an insert to the fornix and provides sustained release of an active agent suitable for ocular therapy.BACKGROUND

[0002] Effective fornix delivery of active agents to treat ocular disease would be beneficial to patients. However, it is very difficult to keep a fornix insert in place for extended periods of time. Fornix delivery' has been attempted with shapes such as rings or lobed structures designed to resist ejection but has suffered from patient discomfort and cosmetic issues. Bio-adhesion has also been tried to improve fornix insert retention, although long-term adhesion to mucous tissue can be problematic to patients. There is a medical need for a fornix insert with improved retention.

[0003] All references disclosed herein are hereby incorporated by' reference in their entireties for all purposes.OBJECTS AND SUMMARY OF THE INVENTION

[0004] It is an object of certain embodiments of the presen t invention to provide a fornix insert comprising an active agent that is effective for treating ocular diseases.

[0005] Another object of certain embodiments of the present invention is to provide methods of treatment of ocular diseases utilizing a fomix insert.

[0006] It is a further object of certain embodiments of the present invention to provide a method of preparing a fomix insert

[0007] One or more of these objects of the present invention and others are solved by one or more embodiments as disclosed and claimed herein.

[0008] In one embodiment, the present invention is directed to a fornix insert comprising a material having a first distal surface and a second distal surface; the first distal surface affixed to a composition comprising a hydrogel and an active agent; the second distal surface comprising aplurality of microneedles extending away from the first distal surface; wherein the fornix insert is configured to be inserted into the fornix with the composition contacting the eyeball and the plurality of microneedles contacting the eyelid.

[0009] Another embodiment of the present invention is directed to a method of treating an eye disease comprising administering a fornix insert as disclosed herein to the fornix wherein the composition contacts the eyeball and the plurality of microneedles contacts the eyelid.

[0010] Another embodiment of the present invention is directed to a method of preparing a fornix insert as disclosed herein. In certain embodiments, the method comprises affixing a composition comprising a hydrogel and an active agent to the first distal surface of a material having a first distal surface and a second distal surface; the second distal surface comprising a plurality of microneedles extending away from the first distal surface; wherein the fornix insert is configured to be inserted into the fornix with the composition contacting the eyeball and the plurality of microneedles contacting the eyelid

[0011] The individual aspects of the present invention are disclosed in the specification and claimed in the independent claims, while the dependent claims claim particular embodiments and variations of these aspects of the invention. Details of the various aspects of the present invention are provided in the detailed description below.

[0012] Throughout this application various references are cited. The disclosures of these references are hereby incorporated by reference into the present disclosure. In case of conflict, the disclosure in the present application prevails.BRIEF DESCRIPTION OF THE DRAWINGS

[0013] Figure 1 discloses the structure of an implan t according to an embodiment of the invention.

[0014] Figure 2 shows the fornix insert of an embodiment of the invention in place in a fornix with a microneedle face against the eyelid and a lubricious hydrogel surface facing the eyeball.DEFINITIONS

[0015] The term “ocular” as used in the present invention refers to the eye in general, or any part or portion of the eye or any disease of the eye (as in one aspect the present inventiongenerally refers to treating any diseases of the eye (“ocular diseases”), of various origin and nature.

[0016] The term “patient” herein includes both human and animal patients. The inserts according to the present invention are therefore suitable for human or veterinary medicinal applications. Generally, a “subject” is a (human or animal) individual to which an insert according to the present invention is administered, such as during a clinical study. A “patient” is a subject in need of treatment due to a particular physiological or pathological condition.

[0017] The term “biodegradable” refers to a material which becomes degraded 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, the insert composition comprising a hydrogel and an active agent that slowly biodegrades over time once deposited within the fornix. In certain embodiments biodegradation takes place at least in part via ester hydrolysis in the aqueous environment of the fornix. The composition slowly dissolves until it is fully resorbed.

[0018] A “hydrogel” is a three-dimensional network of hydrophilic natural or synthetic polymers (as disclosed herein) that can swell in water and hold an amount of water while maintaining or substantially maintaining its structure, e.g., due to chemical or physical crosslinking of individual polymer chains. Due to their high water content, hydrogels are soft and flexible, which makes them very similar to natural tissue. In the present invention the term “hydrogel” is used to refer both to a hydrogel in the hydrated state when it contains water (e.g. after the hydrogel has been formed in an aqueous solution, or after the hydrogel has been (re- jhydrated once inserted into the fornix and to a hydrogel in its dry (dried / 'dehydrated) state, also known as a xerogel, when it has been dried to a low water content of e.g. not more than 1% by weight. In the present invention, wherein an active principle is contained (e.g. dispersed) in a hydrogel, the hydrogel may also be referred to as a “matrix”.

[0019] The term “polymer network” describes a structure formed of polymer chains (of the same or different molecular structure and of the same or different molecular weight) that are crosslinked with each other. The types of polymers suitable for the purposes of the present invention are disclosed herein. Tire polymer network may also be formed with the aid of a crosslinking agent as also disclosed herein.

[0020] The term “amorphous” refers to a polymer or polymer network or other chemical substance or entity which does not exhibit crystalline structures in X-ray or electron scattering experiments.

[0021] The term “semi-crystalline” refers to a polymer or polymer network or other chemical substance or entity which possesses some crystalline character, i.e., exhibits some crystalline properties in X-ray or electron scattering experiments.

[0022] The term “crystalline” refers to a polymer or polymer network or other chemical substance or entity which has crystalline character as evidenced by X-ray or electron scattering experiments.

[0023] For the purposes of the present invention, active agents in all their possible forms, such as amorphous, crystaline, semi-crystaline, polymorphs or any pharmaceutically acceptable salts, anhydrates, hydrates, other solvates or derivatives of active agents, can be used.

[0024] The term “precursor” herein refers to those molecules or compounds that are reacted with each other and that are thus connected via crosslinks to form the polymer network and thus the hydrogel matrix. While other materials might be present in the hydrogel, such as active agents or buffers, they are not referred to as “precursors”.

[0025] The parts of the precursor molecules that are still present in the final polymer network are also called “units” herein. The “units” are thus the building blocks or constituents of the polymer network forming the hydrogel. For example, a polymer network suitable for use in the present invention may contain identical or different polyethylene glycol units as further disclosed herein.

[0026] The molecular weight of a polymer precursor as used for the purposes of the present invention and as disclosed herein may be determined by analytical methods known in the art. The molecular weight of polyethylene glycol may for example be determined by any method known in the art, including gel electrophoresis such as SDS-PAGE (sodium dodecyl sulphatepolyacrylamide gel electrophoresis), gel permeation chromatography (GPC), including GPC with dynamic light scattering (DLS), liquid chromatography (LC), as well as mass spectrometry such as matrix-assisted laser desorption / ionization-time of flight (MALDI-TOF) spectrometry or electrospray ionization (ESI) mass spectrometry. The molecular weight of a polymer, including a polyethylene glycol precursor as disclosed herein, is an average molecular weight (based on the polymer’s molecular weight distribution), and may therefore be indicated by means of various average values, including the weight average molecular weight (Mw) and the number average molecular weight (Mn). In the case of polyethylene glycol precursors as used in the present invention, the molecular weight indicated herein is the number average molecular weight (Mn).

[0027] The term “release” (and accordingly the terms “released”, “releasing” etc.) as used herein refers to the provision of agents such as an API from an insert of the present invention to the surrounding environment. The surrounding environment may be an in vitro or in vivo environment as described herein. Thus, whenever it is herein stated that the insert “releases” or “provides for (sustained) release” of an active agent, this not only refers to the provision of the active agent directly from the insert while the hydrogel has not yet (fully) biodegraded, but also refers to the continued provision of the active agent to the surrounding environment following full degradation of the hydrogel when remaining active agent is still present in this surrounding environment (e.g. in an agglomerated form) for an extended period of time and continues to exert its therapeutic effect. Accordingly, the “treatment period” referred to herein (i.e. , the period during which a certain therapeutic effect as described herein is achieved) may extend to a period of time even after the hydrogel has fully biodegraded.

[0028] The term “sustained release” is defined for the purposes of the present invention to refer to inserts which are formulated to make a drag available over an extended period of time, thereby allowing a reduction in dosing frequency compared to an immediate release dosage form (such as e.g. a solution of an active principle that is injected into the eye). Other terms that may be used herein interchangeably with “sustained release” are “extended release” or “controlled release”. “Sustained release” thus characterizes the release of an API that is contained in an insert according to the present invention.

[0029] As used herein, the term “about” in connection with a measured quantity, refers to the normal variations in that measured quantity, as expected by one of ordinary skill in the art in making the measurement and exercising a level of care commensurate with the objective of measurement and the precision of the measuring equipment.

[0030] As used herein, the singular forms "a," "an", and "the" include plural references unless the context clearly indicates otherwise.

[0031] The term "and / or" as used in a phrase such as "A and / or B" herein is intended to include both "A and B" and "A or B”.

[0032] Open terms such as "include," "including," "contain," "containing" and the like as used herein mean "comprising” and are intended to refer to open-ended lists or enumerations of elements, method steps, or the like and are thus not intended to be limited to the recited elements, method steps or the like but are intended to also include additional, unrecited elements, method steps or the like.

[0033] The terms “from A to B”, “of from A to B”, and “of A to B” are used interchangeably herein and all refer to a range from A to B, including the upper and lower limits A and B.

[0034] The terms “API”, “active (pharmaceutical) ingredient”, “active (pharmaceutical) agent”, “active (pharmaceutical) principle”, “(active) therapeutic agent”, “active”, and “drug” are used interchangeably herein and refer to the substance used in a finished pharmaceutical product (FPP) as well as the substance used in the preparation of such a finished pharmaceutical product, intended to furnish pharmacological activity or to otherwise have direct effect in the diagnosis, cure, mitigation, treatment or prevention of a disease, or to have direct effect in restoring, correcting or modifying physiological functions in a patient.

[0035] The active agent utilized herein can be any active agent suitable for ocular administration..

[0036] As used herein, the term “therapeutically effective” refers to the amount of drug or active agent needed to produce a certain desired therapeutic result after administration. The abbreviation “PBS” when used herein means phosphate-buffered saline.

[0037] The abbreviation “PEG” when used herein means polyethylene glycol.DETAILED DESCRIPTION

[0038] By virtue of certain embodiments of the present invention, disclosed is the use of microneedles to anchor a fornix insert in place by resisting shear at the insert-tissue interface. Shear is the primary mode of failure in retaining an insert within the fornix. Shear forced are generated by movement of the eyeball relative to the eyelid. Although the surfaces of conjunctival tissues are fairly lubricious, some friction is generated that can move an insert. The insert would have microneedles on one face and hydrogel (e.g., with embedded drug) on the other face. The hydrogel layer would provide a lubricious surface, minimizing friction generated shear forces. The insert could be bioresorbable or non-resorbable (removable).

[0039] In certain embodiments, the present invention is directed to a fornix insert comprising a material having a first distal surface and a second distal surface: the first distal surface affixed to a composition comprising a hydrogel and an active agent: the second distal surface comprising a plurality of microneedles extending away from the first distal surface;wherein the fornix insert is configured to be inserted into the fornix with the composition contacting the eyeball and the plurality of microneedles contacting the eyelid.

[0040] In certain embodiments, the material is a biocompatible polymer, ceramic or metal.

[0041] In certain embodiments, the material is biodegradable.

[0042] In certain embodiments, the first distal surface comprises a textured surface to facilitate affixation of the composition.

[0043] In certain embodiments, the first distal surface comprises a plurality of microneedles extending away from the second distal surface to facilitate affixation of the composition

[0044] In certain embodiments, the hydrogel material is biodegradable.

[0045] In certain embodiments, the hydrogel material is non-biodegradable.

[0046] In certain embodiments, the material comprises acrylonitrile butadiene styrene, polyester, polyethylene, silicone, polypropylene, polyimide or a combination thereof.

[0047] In certain embodiments, the hydrogel comprises polyethylene glycol, polyvinyl alcohol, polylactic glycolic acid, organogel or a combination thereof.

[0048] In certain embodiments, the hydrogel is cross-linked with a linking agent.

[0049] In certain embodiments, the linking agent is biodegradable or non-biodegradable.

[0050] In certain embodiments, the linking agent is trilysine.

[0051] In certain embodiments, the hydrogel is thermoset.

[0052] In certain embodiments, the length of the microneedles is from about 0.1 mm to about 1 mm.

[0053] In certain embodiments, the length of the microneedles is from about 0.4 mm to about 0.7 mm.

[0054] In certain embodiments, the aspect ratio (length / diameter) is from about 5: 1 to about 10: 1.

[0055] In certain embodiments, the microneedles are cylindrical, squared, or irregular shaped.

[0056] In certain embodiments, the microneedles are tapered.

[0057] In certain embodiments, the hydrogel comprises a polymer network comprising one or more crosslinked polymer units of polyethylene glycol, polyethylene oxide, polypropylene oxide, polyvinyl alcohol, poly (vinylpyrrolidinone), polylactic acid, polylactic-co-glycolic acid, random or block copolymers or combinations or mixtures of any of these, or one or more units of polyaminoacids, glycosaminoglycans, polysaccharides, or proteins.

[0058] In certain embodiments, the polymer network comprises one or more crosslinked polyethylene glycol units having an average molecular weight in the range from about 2,000 to about 100,000 Daltons, or from about 10,000 to about 60,000 Daltons, or from about 15,000 to about 50,000 Daltons.

[0059] In certain embodiments, the polyethylene glycol units have an average molecular weight of about 20,000 Daltons.

[0060] In certain embodiments, the polymer network comprises one or more crosslinked 2- to 10-arm polyethylene glycol units, or one or more 4- to 8-arm polyethylene glycol units.

[0061] In certain embodiments, the polymer network comprises 4-arm polyethylene glycol units.

[0062] In certain embodiments, the polymer network is formed by reacting an electrophilic group-containing multi-arm-polymer precursor with a nucleophilic group- containing crosslinking agent.

[0063] In certain embodiments, the nucleophilic group is an amine group and the electrophilic group is an activated ester group.

[0064] In certain embodiments, the active agent comprises an NSAID, a corticosteroid, ant anti-glaucoma agent, a local anaesthetic, an ant-allergy agent, an anti-microbial, an antihistamine, an agent to treat dry eye, an agent to treat cystoid macular edema or a combination thereof.

[0065] In certain embodiments, the active agent is travoprost, dexamethasone, nepafenac, a quinolone, or bupivacaine.

[0066] In certain embodiments, the present invention is directed to a method of treating an eye disease comprising administering to a fornix insert as disclosed herein to the fornix wherein the composition contacts the eyeball and the plurality of microneedles contacts the eyelid.

[0067] In certain embodiments, the eye disease is inflammation, pain, dry eye, allergic conjunctivitis, glaucoma, infection, allergy, cystoid macular edema or a combination thereof.

[0068] In certain embodiments, the administration is post-surgery.

[0069] In certain embodiments, the administration is post cataract surgery.

[0070] In certain embodiments, the fornix insert is administered to the inferior fornix.

[0071] In certain embodiments, the fornix insert is administered to the superior fornix.

[0072] In certain embodiments, the fornix insert is maintained in the fornix for about 24 hours to about three months.

[0073] In certain embodiments, the fornix insert is maintained in the fornix for about 2 days to about 2 weeks.

[0074] In certain embodiments, the fornix insert is maintained in the fornix for about 1 week to about 1 month.

[0075] In certain embodiments, the fornix insert is maintained in the fomix for about 2 weeks to about 2 months.

[0076] In certain embodiments, the active agent administered by the inserts of the present invention can, e.g., have an aqueous solubility of less than about 2,000 pg / mL, less than about 1,500 pg / mL, less than about 1,000 pg / mL, less than about 800 pg / mL, less than about 600 pg / mL, less than about 500 pg''mL, less than about 400 pg / mL, less than about 300 pg / mL, less than about 200 pg / mL, less than about 100 pg / mL, less than about 75 pg / mL, less than about 50 pg / mL, less than about 25 pg / mL, less than about 10 pg / mL, less than about 5 pg / mL, less than about 1 pg''mL, less than about 0.5 pg / mL, less than about 0.4 pg / mL, less than about 0.3 pg / mL, less than about 0.2 pg / mL or less than about 0. 1 pg / mL.

[0077] In other embodiments, the active agents administered by the devices of the present invention can have an aqueous solubility of sparingly soluble (30-100 parts solvent needed for 1 part solute), slightly soluble (100-1,000 parts solvent needed for 1 part solute), very slightly soluble (1,000-10,000 parts solvent needed for 1 part solute) or practically insoluble or insoluble (>10,000 parts solvent needed for I part solute) as described in Remington, The Science and Practice of Pharmacy 22nd Edition 2012.

[0078] Ocular diseases that can be treated with the inserts and methods of the present invention may include any ophthalmic condition such as front of the eye conditions or back of the eye conditions.

[0079] Front of the eye conditions may be associated with cellular or subcellular components of the front of the eye anatomy such as the acellular tear film layer and its corresponding lipid aqueous mucin components. Front of the eye conditions may also be associated with the upper and lower eyelids including conditions of the meibomian gland and its corresponding cellular and tissue components such as the muscle, lipid producing holocrine, exocrine and endocrine glands and vascular and connective tissue components; and theconjunctiva and its corresponding cells including goblet cells, fibroblast cells, vascular and component blood cells. Front of the eye conditions 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 nerve its associated cells and ground substances. Front of the eye conditions may also include inflammation, diffuse lamellar keratitis, corneal diseases, edemas, or opacifications with an exudative or inflammatory component, eye conditions related to systemic autoimmune diseases, ocular surface disorders from dry eye (e.g., keratoconjunctivitis such as vernal keratoconjunctivitis, atopic keratoconjunctivitis and sicca keratoconjunctivitis), lid margin diseases, meibomian gland conditions, dysfunctional tear syndromes, anterior and posterior blepharitis, staphylococcal blepharitis, microbial infection, conjunctivitis (e.g., persistent allergic, giant papillary, seasonal intermittent allergic, perennial allergic, toxic and infectious conjunctivitis), conjunctival edema, anterior uveitis, inflammatory conditions, edema, genetic conditions of the cornea (e.g., corneal dystrophies such as keratoconus, posterior polymorphous dystrophy), Fuchs' dystrophies, aphakic and pseudophakic bullous keratopathy, scleral diseases, ocular cicatricial pemphigoid and pterygium.

[0080] Back of the eye conditions may be related to cellular or subcellular components of the back of the eye anatomy including the retina and all of the cells of the layers of the retina such as outer and inner photoreceptor layers, nuclear cell layers, amacrine and ganglion cells, macula, fovea, and vitreous. Additional components of the back of the eye include the ciliary body, iris, uvea and the retinal pigment cells. Back of the eye conditions may include conditions of the optic nerve (including corresponding cellular and sub cellular components such as the axons and associated innervations), glaucomas (e.g., primary open angle glaucoma, acute and chronic closed angle glaucoma and secondary glaucomas), myopic retinopathies, macular edema (including clinical macular edema or angiographic cystoid macular edema arising from conditions such as diabetes, exudative macular degeneration and macular edema associated with laser treatment of the retina), diabetic retinopathy, age-related macular degeneration, retinopathy of prematurity, retinal ischemia and choroidal neovascularization, genetic disease of the retina, pars planitis, Posner Schlossman syndrome, Bechet's disease, Vogt-Koyanagi-Harada syndrome, hypersensitivity reactions, toxoplasmosis chorioretinitis, inflammatory pseudotumor of the orbit, chemosis, conjunctival venous congestion, periorbital cellulitis, acute dacryocystitis, nonspecific vasculitis, sarcoidosis, and cytomegalovirus infection.

[0081] Specific active agents that can be utilized in the inserts and methods of the present invention include but are not limited to immunosuppressants, complement protein C5 agents (e.g., eculizumab or avacincaptad pegol), steroids, anti-inflammatories such as steroidal and nonsteroidal anti-inflammatories (e.g., COXI or COX 2 inhibitors), antivirals, antibiotics, antiglaucoma agents, anti-VEGF agents, analgesics and combinations thereof.

[0082] Immunosuppressants include but are not limited to cyclosporine, rnTOR inhibitors (e.g., rapamycin, tacrilimus, temsirolimus, sirolimus, everolimus, KU-0063794, WYE-354, AZD8055, metformin, or Torin-2), cyclophosphamide, atoposide, thiotepa, methotrexate, azathioprine, mercaptopurine, interferons, infliximab, etanercept, mycophenolate mofetil, 15- deoxyspergualin, thalidomide, glatiramer, leflunomide, vincristine, cytarabine, pharmaceutically acceptable salts thereof and combinations thereof.

[0083] Non-steroidal anti-inflammatory compounds include inhibitors of the cyclooxygenase (COX) enzyme such as cyclooxygenase- 1 (COX-1) and cyclooxygenase-2 (COX-2) isozymes. General classes of non-steroidal anti-inflammatory compounds include salicylates, propionic acid derivatives, acetic acid derivatives, enolic acid derivatives, and anthranilic acid derivatives. Examples of non-steroidal anti-inflammatory compounds include acetylsalicylic acid, diflunisal, salsalate, ibuprofen, dex-ibuprofen, naproxen, fenoprofen, ketoprofen, dex-ketoprofen, flurbiprofen, oxaprozin, loxoprofen, indomethacin, tolmetin, sulindac, etodolac, ketorolac, diclofenac, aceclofenac, nabumetone, piroxicam, tenoxicam, tenoxicam, loroxicam, phenylbutazone, mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid, celecoxib, pharmaceutically acceptable salts thereof and combinations thereof.

[0084] Anti-inflammatory agents that may be utilized in the inserts and methods of the present invention may include agents that target inflammatory cytokines such as TNFa, IL-1, IL- 4, IL-5 or IL-17, or CD20. Such agents may include etanercept, infliximab, adalimumab, daclizumab, rituximab, tocilizumab, certolizumab pegol, golimumab, pharmaceutically acceptable salts thereof and combinations thereof.

[0085] Analgesics that may be utilized in the inserts and methods of the present invention include acetaminophen, acetaminosalol, aminochlorthenoxazin, acetylsalicylic 2-amino-4- picoline acid, acetylsalicylsalicylic acid, anileridine, benoxaprofen, benzylmorphine, 5- bromosalicylic acetate acid, bucetin, buprenorphine, butorphanol, capsaicin, cinchophen, ciramadol, clometacin, clonixin, codeine, desomorphine, dezocine, dihydrocodeine, dihydromorphine, dimepheptanol, dipyrocetyl, eptazocine, ethoxazene, ethylmorphine, eugenol,floctafenine, fosfosal, glafenine, hydrocodone, hydromorphone, hydroxypethidine, ibufenac, p- lactophenetide, levorphanol, meptazinol, metazocine, metopon, morphine, nalbuphine, nicomorphine, norlevorphanol, normorphine, oxycodone, oxymorphone, pentazocine, phenazocine, phenocoll, phenoperidine, phenylbutazone, phenylsalicylate, phenylramidol, salicin, salicylamide, tiorphan, tramadol, diacerein, actarit, pharmaceutically acceptable salts thereof and combinations thereof.

[0086] Antibiotic that may be utilized in the inserts 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, cioxacillin, dicloxacillin, flucloxacillin, mezlocillin, nafcillin, oxacillin, penicillin G, penicillin V, piperacillin, pivampicillin, pivmecillinam, ticarcillin, pharmaceutically acceptable salts thereof and combinations thereof. Cephalosporins may include cefacetrile, cefadroxil, cefalexin, cefaloglycin, cefalonium, cefaloridine, cefalotin, cefapirin, cefatrizine, cefazaflur, cefazedone, cefazolin, cefradine, cefroxadine, ceftezole, cefaclor, cefamandole, cefmetazole, cefonicid, cefotetan, cefoxitin, cefprozil, cefuroxime, cefuzonam, cefcapene, cefdaloxime, cefdinir, cefditoren, cefetamet, cefixime, cefmenoxime, cefodizime, cefotaxime, cefpimizole, cefpodoxime, cefteram, ceftibuten, ceftiofur, ceftiolene, ceftizoxime, ceftriaxone, cefoperazone, ceftazidime, cefclidine, cefepime, cefluprenam, cefoselis, cefozopran, cefpirome, cefquinome, ceftobiprole, ceftaroline, cefaclomezine, cefaloram, cefaparole, cefcanel, cefedrolor, cefempidone, cefetrizole, cefivitril, cefmatilen, cefmepidium, cefovecin, cefoxazole, cefrotil, cefsumide, ccfuracctimc. 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.

[0087] Antivirals that may be utilized in the inserts and methods of the present invention include nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, fusion inhibitors, integrase inhibitors, nucleoside analogs, protease inhibitors, and reverse transcriptase inhibitors. Examples of antiviral agents include, but are not limited to,abacavir, aciclovir, acyclovir, adefovir, amantadine, amprenavir, ampligen, arbidol, atazanavir, boceprevir, cidofovir, darunavir, delavirdine, didanosine, docosanol, edoxudine, efavirenz, emtricitabine, enfuvirtide, entecavir, famciclovir, fomivirsen, fosamprenavir, foscarnet, fosfonet, ganciclovir, ibacitabine, imunovir, idoxuridine, imiquimod, indinavir, inosine, interferon type III, interferon type II, interferon type I, interferon, lamivudine, lopinavir, loviride, maraviroc, moroxydine, methisazone, nelfmavir, nevirapine, nexavir, oseltamivir, peginterferon alfa-2a, penciclovir, peramivir, pleconaril, podophyllotoxin, raltegravir, ribavirin, rimantadine, ritonavir, pyramiding saquinavir, stavudine, tenofovir, tenofovir disoproxil, tipranavir, trifluridine, trizivir, tromantadine, truvada, valaciclovir, valganeiclovir. vicriviroc, vidarabine, viramidine, zalcitabine, zanamivir, zidovudine, pharmaceutically acceptable salts thereof and combinations thereof.

[0088] Steroidal anti-inflammatory agents that may be utilized in the inserts and methods of the present invention include dexamethasone, budensonide, triamcinolone, hydrocortisone, loteprednol, prednisolone, mometasone, fluticasone, rimexolone, fluoromethoIone, beclomethasone, flunisolide, pharmaceutically acceptable salts thereof and combinations thereof.

[0089] Anti-glaucoma agents that may be utilized in the inserts and methods of the present invention include beta-blockers such as atenolol propranolol, metipranolol, betaxolol, carteolol, levobetaxolol, levobunolol timolol, pharmaceutically acceptable salts thereof and combinations thereof; adrenergic agonists or sympathomimetic agents such as epinephrine, dipivefrin, clonidine, aparclonidine, brimonidine, pharmaceutically acceptable salts thereof and combinations thereof; parasympathomimetics or cholingeric agonists such as pilocarpine, carbachol, phospholine iodine, physostigmine, pharmaceutically acceptable salts thereof and combinations thereof; carbonic anhydrase inhibitor agents, including topical or systemic agents such as acetozolamide, brinzolamide, dorzolamide; methazolamide, ethoxzolamide, dichlorphenamide, pharmaceutically acceptable salts thereof and combinations thereof; mydriatic-cycloplegic agents such as atropine, cyclopentolate, succinylcholine, homatropine, phenylephrine, scopolamine, tropicamide, pharmaceutically acceptable salts thereof and combinations thereof; prostaglandins such as prostaglandin F2 alpha, antiprostaglandins, prostaglandin precursors, or prostaglandin analog agents such as bimatoprost, latanoprost, travoprost, unoprostone, tafluprost, pharmaceutically acceptable salts thereof and combinations thereof.

[0090] Anti-VEGF agents that may be utilized in the inserts and methods of the present invention include bevacizumab, pegaptanib, ranibizumab, brolucizumab, pharmaceutically acceptable salts thereof and combinations thereof.

[0091] In certain embodiments, the active principle contained in an insert of this aspect of the invention is a TKI. Examples for suitable TKIs are axitinib, sorafenib, sunitinib, nintedanib, pazopanib, regorafenib, cabozantinib, and vandetanib. In particular embodiments, the TKI used in this and other aspects of the present invention is axitinib.

[0092] The active agent may be dispersed or distributed in the hydrogel. In certain embodiments, the active agent is homogeneously or essentially homogeneously dispersed in the hydrogel. The hydrogel may prevent the active agent from agglomerating and may provide a matrix for the active agent (e.g., in particle form) for sustained release.

[0093] In certain embodiments of the invention, the active agent may be particles that are microencapsulated. The term “microcapsule” (also referred to as “microparticle”) is sometimes defined as a roughly spherical particle with a size varying between e.g. about 50 nm to about 2 mm. Microcapsules have at least one discrete domain (or core) of active agent encapsulated in a surrounding material, sometimes also referred to as a shell. One suitable agent (without limiting the present disclosure to this) for microencapsulating the active agent, for the purposes of the present invention, is poly (lactic-co-glycolic acid).

[0094] In other embodiments, the active agent particles are not microencapsulated and are thus dispersed in the hydrogel and thus in the isert of the invention as they are, i.e., without being admixed to or adjoined with or microencapsulated by another material such as (but not limited to) poly (lactic-co-glycolic acid).

[0095] In one embodiment, the active agent particles may be micronized particles. In another embodiment, the active agent particles, may not be micronized. Micronization refers to the process of reducing the average diameter of particles of a solid material. Particles with ■ Field Cod reduced diameters may have inter alia higher dissolution and erosion rates, which increases the 1 Field Cod bioavailability of active pharmaceutical ingredients and may have in certain embodiments a Field CodeField Cod positive impact on release kinetics.The polymer network:

[0096] In certain embodiments, the hydrogel may be formed from precursors having functional groups that form crosslinks to create a polymer network. These crosslinks between polymer strands or arms may be chemical (i.e., may be covalent bonds) and / or physical (such as ionic bonds, hydrophobic association, hydrogen bridges etc.) in nature.

[0097] The polymer network may be prepared from precursors, either from one type of precursor or from two or more types of precursors that are allowed to react. Precursors are chosen in consideration of the properties that are desired for the resultant hydrogel. There are various suitable precursors for use in making the hydrogels. Generally, any pharmaceutically acceptable and crosslinkable polymers forming a hydrogel may be used for the purposes of the present invention. The hydrogel and thus the components incorporated into it, including the polymers used for making the polymer network, should be physiologically safe such that they do not elicit e.g. an immune response or other adverse effects. Hydrogels may be formed from natural, synthetic, or biosynthetic polymers.

[0098] Natural polymers may include glycosaminoglycans, polysaccharides (e.g. dextran), polyaminoacids and proteins or mixtures or combinations thereof.

[0099] Synthetic polymers may generally be any polymers that are synthetically produced from a variety of feedstocks by different types of polymerization, including free radical polymerization, anionic or cationic polymerization, chain-growth or addition polymerization, condensation polymerization, ring-opening polymerization etc. Hie polymerization may be initiated by certain initiators, by light and / or heat, and may be mediated by catalysts.[000100] Generally, for the purposes of the present invention one or more synthetic polymers of the group comprising one or more units of polyalkylene glycol, such as polyethylene glycol (PEG), polypropylene glycol, poly(ethylene glycol)-block-poly(propylene glycol) copolymers, or polyethylene oxide, polypropylene oxide, polyvinyl alcohol, poly (vinylpyrrolidinone), polylactic acid, polylactic-co-glycolic acid, random or block copolymers or combinations / mixtures of any of these can be used, while this list is not intended to be limiting.[000101] To form covalently crosslinked polymer networks, the precursors may be covalently crosslinked with each other. In certain embodiments, precursors with at least two reactive centers (for example, in free radical polymerization) can serve as crossl inkers since each reactive group can participate in the formation of a different growing polymer chain.[000102] The precursors may have biologically inert and hydrophilic portions, e.g., a core. In the case of a branched polymer, a core refers to a contiguous portion of a molecule joined to arms that extend from the core, where the arms carry a functional group, which is often at the terminus of the arm or branch. Multi-armed PEG precursors are examples of such precursors and are further disclosed herein below.[000103] Thus a hydrogel for use in the present invention can be made e.g. from one multiarmed precursor with a first (set of) functional group(s) and another multi-armed precursor having a second (set of) functional group(s). By way of example, a multi-armed precursor may have hydrophilic arms, e.g., polyethylene glycol units, terminated with primary amines (nucleophile), or may have activated ester end groups (electrophile). The polymer network according to the present invention may contain identical or different polymer units crosslinked with each other.[000104] Certain functional groups can be made more reactive by using an activating group. Such activating groups include (but are not limited to) carbonyldiimidazole, sulfonyl chloride, aryl halides, sulfosuccinimidyl esters, N-hydroxysuccinimidyl ester, succinimidyl ester, epoxide, aldehyde, maleimides, imidoesters, acrylates and the like. The N-hydroxysuccinimide esters (NHS) are useful groups for crosslinking of nucleophilic polymers, e.g., primary amine- terminated or thiol-terminated polyethylene glycols. An NHS-amine crosslinking reaction may be carried out in aqueous solution and in the presence of buffers, e.g., phosphate buffer (pH 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).[000105] In certain embodiments, each precursor may comprise 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 a crosslinker has only nucleophilic functional groups such as amines, the precursor polymer may have electrophilic functional groups such as N-hydroxysuccinimides. On the other hand, if a crosslinker has electrophilic functional groups such as sulfosuccinimides, then the functional polymer may have nucleophilic functional groups such as amines or thiols. Thus, functional polymers such as proteins, poly (allyl amine), or amine-terminated di-or multifunctional polyfethylene glycol) can be also used to prepare the polymer network of the present invention.[000106] In one embodiment a first reactive precursor has about 2 to about 16 nucleophilic functional groups each (termed functionality), and a second reactive precursor allowed to reactwith the first reactive precursor to form the polymer network has about 2 to about 16 electrophilic functional groups each. Reactive precursors having a number of reactive (nucleophilic or electrophilic) groups as a multiple of 4, thus for example 4, 8 and 16 reactive groups, are particularly suitable for the present invention. Any number of functional groups, such as including any of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 groups, is possible for precursors to be used in accordance with the present invention, while ensuring that the functionality is sufficient to form an adequately cross I inked network.PEG hydrogels:[000107] In a certain embodiments of the present invention, the polymer network forming the hydrogel contains polyethylene glycol (PEG) units. PEGs are known in the art to form hydrogels when crosslinked, and these PEG hydrogels are suitable for pharmaceutical applications e.g. as matrix for drugs intended to be administered to all parts of the human or animal body.[000108] The polymer network of the hydrogel inserts of the present invention may comprise one or more multi-arm PEG units having from 2 to 10 arms, or 4 to 8 arms, or 4, 5, 6, 7 or 8 arms. The PEG units may have a different or the same number of arms. In certain embodiments, the PEG units used in the hydrogel of the present invention have 4 and / or 8 arms. In certain particular embodiments, a combination of 4- and 8-arm PEG units is utilized.[000109] The number of arms of the PEG used contributes to controlling the flexibility or softness of the resulting hydrogel. For example, hydrogels formed by crosslinking 4-arm PEGs are generally softer and more flexible than those formed from 8-arm PEGs of the same molecular weight. In particular, if stretching the hydrogel prior to or after drying as disclosed herein below in the section relating to the manufacture of the insert is desired, a more flexible hydrogel may be used, such as a 4-arm PEG, optionally in combination with another multi-arm PEG, such as an 8-arm PEG as disclosed above.[000110] In certain embodiments of the present invention, polyethylene glycol units used as precursors have an average molecular weight in the range from about 2,000 to about 100,000 Daltons, or in a range from about 10,000 to about 60,000 Daltons, or in a range from about 15,000 to about 50,000 Daltons. In certain particular embodiments the polyethylene glycol units have an average molecular weight in a range from about 10,000 to about 40,000 Daltons, or ofabout 20,000 Daltons. PEG precursors of the same average molecular weight may be used, or PEG precursors of different average molecular weight may be combined with each other. The average molecular weight of the PEG precursors used in the present invention is given as the number average molecular weight (Mn), which, in certain embodiments, may be determined by MALDI.[000111] In a 4-arm PEG, each of the arms may have an average arm length (or molecular weight) of the total molecular weight of the PEG di vidcd by 4. A 4a20kPEG precursor, which is one precursor that can be utilized in the present invention thus has 4 arms with an average molecular weight of about 5,000 Daltons each. An 8a20k PEG precursor, which may be used in addition to the 4a20kPEG precursor in the present invention, thus has 8 arms each having an average molecular weight of 2,500 Daltons. Longer arms may provide increased flexibility as compared to shorter arms. PEGs with longer arms may swell more as compared to PEGs with shorter arms. A PEG with a lower number of arms also may swell more and may be more flexible than a PEG with a higher number of arms. In certain particular embodiments, combinations of PEG precursors w’ith different numbers of arms, such as a combination of a 4- arm PEG precursor and an 8-arrn precursor, may be utilized in the present invention. In addition, longer PEG arms have higher melting temperatures when dry, which may provide more dimensional stability during storage. For example, an 8 -arm PEG with a molecular weight of 15,000 Dalton crosslinked with trilysine may not be able to maintain a stretched configuration at room temperature, whereas a 4-arm 20,000 Dalton PEG crosslinked with an 8-arm 20,000 Dalton PEG may be dimensionally stable in a stretched configuration at room temperature.[000112] When referring to a PEG precursor having a certain average molecular weight, such as a 15kPEG- or a 20kPEG-precursor, the indicated average molecular weight (i.e., a Mn of 15,000 or 20,000, respectively) refers to the PEG part of the precursor, before end groups are added (“20k” here means 20,000 Daltons, and “15k” means 15,000 Daltons - the same abbreviation is used herein for other average molecular weights of PEG precursors). In certain embodiments, the Mn of the PEG part of the precursor is determined by MALDI. The degree of substitution with end groups as disclosed herein may be determined by means of *H-NMR after end group functionalization.[000113] In certain embodiments, electrophilic end groups for use with PEG precursors for preparing the hydrogels of the present invention are N-hydroxysuccinimidyl (NHS) esters, including but not limited to: “SAZ” referring to a succinimidylazelate end group, “SAP”referring to a succinimidyladipate end group, “SG” referring to a succinimidylglutarate end group, and “SS” referring to a succinimidylsuccinate end group.[000114] In certain embodiments, nucleophilic end groups for use with PEG precursors for preparing the hydrogels of the present invention are amine (denoted as “NEb”) end groups. Thiol (-SH) end groups or other nucleophilic end groups are also possible.[000115] In certain preferred embodiments, 4-arm PEGs with an average molecular weight of about 20,000 Daltons and an electrophilic end group as disclosed above and 8-arm PEGs also with an average molecular weight of about 20,000 Daltons and with a nucleophilic end group as disclosed above are crosslinked for forming the polymer network and thus the hydrogel according to the present invention.[000116] Reaction of nucleophilic group-containing PEG units and electrophilic group- containing PEG units, such as amine end-group containing PEG units and activated ester-group containing PEG units, results in a plurality of PEG units being crosslinked by a hydrolyzable linker having the formula:, wherein m is an integer from 0 to 10, and specifically is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In one particular embodiment, m is 6, e.g. in the case a SAZ-end group-containing PEG is used. For a SAP-end group, m would be 3, for a SG-end group, m would be 2 and for an SS-end group m would be 1. All crosslinks within the polymer network may be the same, or may be different.[000117] In certain preferred embodiments, the SAZ end group is utilized in the present invention. This end group may provide for increased duration in the eye, and the insert of certain embodiments of the present invention comprising a hydrogel comprising PEG-SAZ units is biodegraded in the eye, only after an extended period of time, e.g., 9 to 12 months as further disclosed below, and may in certain circumstance persist even longer. The SAZ group is more hydrophobic than e.g. the SAP-, SG- or SS-end groups because of a higher number of carbon atoms in the chain (m being 6, and the total of carbon atoms between the amide group and the ester group being 7).[000118] In certain preferred embodiments, a 4-arm 20,000 Dalton PEG precursor is combined with an 8-arm 20,000 Dalton PEG precursor, such as a 4-arm 20,000 Dalton PEG precursor having a SAZ group (as defined above) combined with an 8-arm 20,000 Dalton PEG precursor having an amine group (as defined above). These precursors are also abbreviatedherein as 4a20kPEG-SAZ and 8a20kPEG-NH2, respectively. The chemical structure of4a20kPEG-SAZ is:wherein R represents a pentaerythritol core structure. The chemical structure of 8a20kPEG-NH2 (with a hexaglycerol core) is:In the above formulae, n is determined by the molecular weight of the respective PEG-arm.[000119] In certain embodiments, the molar ratio of the nucleophilic and the electrophilic end groups reacting with each other is about 1 : 1, i.e., one amine group is provided per one SAZ group. In the case of 4a20kPEG-SAZ and 8a20kPEG-NH2 this results in a weight ratio of about 2: 1 , as the 8-arm PEG contains double the amount of end groups as the 4-arm PEG. However, an excess of either the electrophilic (e.g. the NHS end groups, such as the SAZ) end groups or of the nucleophilic (e.g. the amine) end groups may be used. In particular, an excess of the nucleophilic, such as the amine-end group containing precursor may be used, i.e., the weight ratio of 4a20kPEG-SAZ and 8a20kPEG-NH2 may also be less than 2:1.[000120] Each and any combination of electrophilic- and nucleophilic -group containing PEG precursors disclosed herein may be used for preparing the insert according to the present invention. For example, any 4-arm or 8-arm PEG-NHS precursor (e.g. having a SAZ, SAP, SG or SS end group) may be combined with any 4-arm or 8-arm PEG-NH2 precursor (or any other PEG precursor having a nucleophilic group). Furthermore, the PEG units of the electrophilic- and the nucleophilic group-containing precursors may have the same, or may have a different average molecular weight.[000121] Another nucleophilic group-containing crosslinking agent may be used instead of a PEG-based crosslinking agent. For example, a low-molecular weight amine linker can be used,such as trilysine (or a trilysine salt or derivative, such as trilysine acetate) or other low-molecular weight multi-arm amines.[000122] In certain embodiments, the nucleophilic group-containing crosslinking agent may be bound to or conjugated with a visualization agent. A visualization agent is an agent that contains a fluorophoric or other visualization-enabling group. Fluorophores such as fluorescein, rhodamine, coumarin, and cyanine may for example be used as visualization agents. The visualization agent may be conjugated with the crosslinking agent e.g. through some of the nucleophilic groups of the crosslinking agent. Since a sufficient amount of the nucleophilic groups are necessary' for crosslinking, “conjugated” or “conjugation” in general includes partial conjugation, meaning that only a part of the nucleophilic groups are used for conjugation with the visualization agent, such as about 1% to about 20%, or about 5% to about 10%, or about 8% of the nucleophilic groups of the crosslinking agent may be conjugated with a visualization agent. In other embodiments, a visualization agent may also be conjugated with the polymer precursor, e.g. through certain reactive (such as electrophilic) groups of the polymer precursors.Additional ingredients:[000123] The insert of the present invention may contain, in addition to the polymer units forming the polymer network as disclosed above and the active principle, other additional ingredients. Such additional ingredients are for example salts originating from buffers used during the preparation of the hydrogel, such as phosphates, borates, bicarbonates, or other buffer agents such as triethanolamine. In certain embodiments of the present invention sodium phosphate buffers (specifically, mono- and dibasic sodium phosphate) are used.[000124] Optionally, preservatives may be used for the inserts of the present invention. However, in certain embodiments, the inserts of the present invention are free of preservatives, such as anti-microbial preservatives (including, but not limited to benzalkonium chloride (BAK), chlorobutanol, sodium perborate, and stabilized oxychloro complex (SOC)), or are substantially free of such preservatives.Formulation:[000125] In certain embodiments, the compositions of the inserts according to the present invention in their dry state may contain from about 15% to about 80%, such as from about 25%to about 75% by weight active agent and from about 15% to about 80%, such as from about 20% to about 60% by weight polymer units, or in particular embodiments from about 35% to about 65% by weight active agent and from about 25% to about 50% by weight polymer units (dry composition). In specific embodiments, the inserts according to the present invention may contain from about 45% to about 55% by weight active agent and from about 37% to about 47% by weight polymer units (dry composition), with the active agent and the polymer units being selected from those disclosed herein above. In other specific embodiments, the inserts according to the present invention in their dry state may contain from about 55% to about 75% by weight active agent and from about 20% to about 40% by weight polymer units (dry composition), with the active agent and the polymer units being selected from those disclosed herein above. In other specific embodiments, the inserts according to the present invention in their dry state may contain from about 30% to about 45% by weight active agent and from about 47% to about 70% by weight polymer units (dry composition), with the active agent and the polymer units being selected from those disclosed herein above.Therapy[000126] In certain embodiments the ocular disease treated by the present invention involves angiogenesis.[000127] In other embodiments the ocular disease may be mediated by one or more receptor tyrosine kinases (RTKs), such as VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-a / p, and / or by c-Kit. [000128] In some embodiments the ocular disease is a retinal disease including Choroidal Neovascularization, Diabetic Retinopathy, Diabetic Macula Edema, Retinal Vein Occlusion, Acute Macular Neuroretinopathy, Central Serous Chorioretinopathy, and Cystoid Macular Edema; wherein the ocular disease is Acute Multifocal Placoid Pigment Epitheliopathy, Behcet’s Disease, Birdshot Retinochoroidopathy, Infectious (Syphilis, Lyme, Tuberculosis, Toxoplasmosis), Intermediate Uveitis (Pars Planitis), Multifocal Choroiditis, Multiple Evanescent White Dot Syndrome (MEWDS), Ocular Sarcoidosis, Posterior Scleritis, Serpignons Choroiditis, Subretinal Fibrosis, Uveitis Syndrome, or Vogt-Koyanagi-Harada Syndrome; wherein the ocular disease is a vascular' disease or exudative diseases, including Coat’s Disease, Parafoveal Telangiectasis, Papillophlebitis, Frosted Branch Angitis, Sickle Cell Retinopathy and other Hemoglobinopathies, Angioid Streaks, and Familial Exudative Vitreoretinopathy; or wherein the ocular disease results from trauma or surgery, including Sympathetic Ophthalmia,Uveitic Retinal Disease, Retinal Detachment, Trauma, Photodynamic Laser Treatment, Photocoagulation, Hypoperfusion During Surgery’, Radiation Retinopathy, Bone Marrow Transplant Retinopathy, or Retinopathy Rhodopsin-mediated autosomal dominant retinitis pigmentosa, Bestl related retinal diseases, Leber congentital amaurosis, Stargardt macular dystrophy or Inherited retinal disease.[000129] In alternative embodiments the fornix insert can be applied in treating ocular conditions associated with tumors. Such conditions include e.g., Retinal Disease Associated with Tumors, Solid Tumors, Tumor Metastasis, Benign Tumors, for example, hemangiomas, neurofibromas, trachomas, and pyogenic granulomas, Congenital Hypertrophy? of the RPE, Posterior Uveal Melanoma, Choroidal Hemangioma, Choroidal Osteoma, Choroidal Metastasis, Combined Hamartoma of the Retina and Retinal Pigmented Epithelium, Retinoblastoma, Vasoproliferative Tumors of the Ocular Fundus, Retinal Astrocytoma, or Intraocular Lymphoid Tumors.[000130] In general, the ocular inserts of the present invention can also be applied for treatment of any ocular disease involving vascular leakage.[000131] In certain embodiments the ocular disease is one selected from the list consisting of neovascular age-related macular- degeneration (AMD), diabetic macula edema (DME), and retinal vein occlusion (RVO). In particular embodiments the ocular disease is neovascular age- related macular degeneration.[000132] In some embodiments the treatment is effective in reducing the central subfield thickness (CSFT) as measured by optical coherence tomography in a patient whose central subfield thickness is elevated. Elevated within that context means that the CSFT is higher in the patient when compared to other individuals not suffering from the specific ocular disease. The elevated CSFT may be caused by retinal fluid such as sub- or intraretinal fluid. The reduction of CSFT in a patient may be determined with respect to a baseline CSFT measured in that patient prior to the start of the treatment, i.e., prior to the administration of the insert of the present invention.[000133] In certain embodiments, the total dose of active agent, per eye administered once for the treatment period may be contained in one or more inserts. In certain embodiments the dose per eye administered once for the treatment period is contained in one insert. In other embodiments the total dose per eye administered once for the treatment period is contained in e.g. two inserts. In yet other embodiments the dose per eye administered once for the treatmentperiod is contained in e.g. three inserts. In one embodiment, an insert is administered to both the superior fornix and the inferior fornix. In another embodiment, more than one insert is administered to one or more of the superior and inferior fornix.

Claims

CLAIMS1 . A fornix insert comprising a material having a first distal surface and a second distal surface; the first distal surface affixed to a composition comprising a hydrogel and an active agent; the second distal surface comprising a plurality of microneedles extending away from the first distal surface; wherein the fornix insert is configured to be inserted into the fornix with the composition contacting the eyeball and the plurality of microneedles contacting the eyelid.

2. The fornix insert of claim 1, wherein the material is a biocompatible polymer, ceramic or metal.

3. The fornix insert of any of claims 1 or 2, wherein the material is biodegradable.

4. The fornix insert of claim 1 , wherein the first distal surface comprises a textured surface to facilitate affixation of the composition.

5. The fornix insert of claim 1, wherein the first distal surface comprises a plurality' of microneedles extending away from the second distal surface to facilitate affixation of the composition6. The fornix insert of any preceding claim, wherein the hydrogel material is biodegradable.

7. The fornix insert of any preceding claim, wherein the hydrogel material is non- biodegradable.

8. The fornix insert of claim 1, wherein the material comprises acrylonitrile butadiene styrene, polyester, polyethylene, silicone, polypropylene, polyimide or a combination thereof.

9. The fornix insert of claim 1, wherein the hydrogel comprises polyethylene glycol, polyvinyl alcohol, polylactic glycolic acid, organogel or a combination thereof.

10. The fornix insert of claim 1, wherein the hydrogel is cross-linked with a linking agent.11 . The fornix insert of claim 10, wherein the linking agent is biodegradable or non- biodegradable.

12. The fornix insert of claim 11, wherein the linking agent is trilysine.

13. The fornix insert of claim 1, wherein the hydrogel is thermoset.

14. The fornix insert of claim 1, wherein the length of the microneedles is from about 0. 1 mm to about 1 mm.

15. The fornix insert of claim 1, wherein the length of the microneedles is from about 0.4 mm to about 0.7 mm.

16. The fornix insert wherein the aspect ratio (Icngth / diameter) is from about 5:1 to about 10: 1.

17. The fornix insert of claim 1, wherein the microneedles are cylindrical, squared, or irregular shaped.

18. The fornix insert of claim 1, wherein the microneedles are tapered.

19. The fornix insert of claim 1, wherein the hydrogel comprises a polymer network comprising one or more crosslinked polymer units of polyethylene glycol, polyethylene oxide, polypropylene oxide, polyvinyl alcohol, poly (vinylpyrrolidinone), polylactic acid, polylactic-co-glycolic acid, random or block copolymers or combinations or mixtures of any of these, or one or more units of polyaminoacids, glycosaminoglycans, polysaccharides, or proteins.

20. The fornix insert of claim 19, wherein the polymer network comprises one or more crosslinked polyethylene glycol units having an average molecular weight in the rangefrom about 2,000 to about 100,000 Daltons, or from about 10,000 to about 60,000 Daltons, or from about 15,000 to about 50,000 Daltons.

21. The fornix insert of claim 20, wherein the polyethylene glycol units have an average molecular weight of about 20,000 Daltons.

22. The fornix insert of claim 19, wherein the polymer network comprises one or more crosslinked 2- to 10-arm polyethylene glycol units, or one or more 4- to 8-arm polyethylene glycol units.

23. The fornix insert of claim 22, wherein the polymer network comprises 4-arm polyethylene glycol units.

24. The fornix insert of claim 19, wherein the polymer network is formed by reacting an electrophilic group-containing multi-arm-polymer precursor with a nucleophilic group- containing crosslinking agent.

25. The fornix insert of claim 24, wherein the nucleophilic group is an amine group and the electrophilic group is an activated ester group.

26. The fornix insert of claim 1, wherein the active agent comprises an NSAID, a corticosteroid, ant anti-glaucoma agent, a local anaesthetic, an anti-allergy agent, an antimicrobial, an antihistamine, an agent to treat dry eye, an agent to treat cystoid macular edema or a combination thereof.

27. The fornix insert of claim 1, wherein the active agent is travoprost.

28. The fornix insert of claim 1, wherein the active agent is dexamethasone.

29. The fornix insert of claim 1, wherein the active agent is nepafenac.

30. The fornix insert of claim 1, wherein the active agent is a quinolone.

31. A method of treating an eye disease comprising administering to a fornix insert of any of claims 1-30 to the fornix wherein the composition contacts the eyeball and the plurality of microneedles contacts the eyelid.

32. The method of claim 31, wherein the eye disease is inflammation, pain, dry eye, allergic conjunctivitis, glaucoma agent, infection, allergy, cystoid macular edema or a combination thereof.

33. The method of any of claims 31 or 32, wherein the administration is post-surgery.

34. The method of claim 33, wherein the administration is post cataract surgery.

35. The method of any of claims 31-34, wherein the fornix insert is administered to the inferior fomix.

36. The method of any of claims 31-34, wherein the fomix insert is administered to the superior fornix.

37. The method of any of claims 31-36, wherein the fomix insert is maintained in the fornix for about 24 hours to about three months.

38. The method of any of claims 31-36, wherein the fornix insert is maintained in the fomix for about 2 days to about 2 weeks.

39. The method of any of claims 31-36, wherein the fornix insert is maintained in the fomix for about 1 week to about 1 month.

40. The method of any of claims 31-36, wherein the fornix insert is maintained in the fomix for about 2 weeks to about 2 months.

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