CAI-loaded bioerodible implant and methods of use thereof

Abstract

Provided herein are carboxy-amido-triazole (CAI) formulations, including bioerodible implants including CAI complexed with poly (D, L-lactic-co-glycolic acid) (PLGA), methods of production thereof and methods of use thereof. The methods of use include methods of treating ocular diseases characterized by neovascularization and pathological cellular proliferation and invasion, and specifically methods of treating age-related macular degeneration and methods of treating diabetic retinopathies.

Description

CAI-LOADED BIOERODIBLE IMPLANT AND METHODS OF USE THEREOFRELATED APPLICATION

[0001] This application claims priority to and benefit of U.S. Provisional Application No. 63 / 542,277, filed October 3, 2023, which is fully incorporated by reference herein.BACKGROUND OF THE INVENTIONFIELD OF THE INVENTION

[0002] The present disclosure relates to 5-amino-l-(3,5-dichloro-4-(4- chlorobenzoyl)benzyl)-lH-l,2,3-triazole-4-carboxamide (carboxy-amido-triazole or CAI), and more specifically to bioerodible implants or filament formulations of CAI, methods of preparation thereof, and methods of use therefore, including for the treatment of ocular disease.BACKGROUND INFORMATION

[0003] Carboxyamidotriazole derivatives were originally discovered as antiparasitic agents and then subsequently demonstrated to be antiproliferative agents and potential cancer therapeutics. The specific compound, 5-amino-[4-(4-chlorobenzoyl)-3,5- dichlorobenzyl]-l,2,3- triazole-4- carboxamide, has been demonstrated to have antiproliferative and antimetastatic activity that was linked to decrease of intracellular calcium by inhibition of non-voltage-gated calcium channels.

[0004] Tyrosine kinase and metalloproteinase pharmacological mechanistic activities and anti-angiogenesis activity relevant to antitumor efficacy have also been described for this compound. The current compound will be referred to in the following discussion using the acronym CAI which is generally used to describe the compound.

[0005] Clinical investigations have been conducted with CAI in the treatment of lifethreatening diseases. For example, CAI has been used in the treatment of a variety of refractory tumors including prostate cancer, lymphomas, glioblastoma, peritoneal cancer, fallopian tube cancer, epithelial ovarian cancer, advanced renal cell carcinoma, metastatic renal carcinoma and non-small cell lung cancer.

[0006] While these studies using CAI indicate that CAI has intrinsic clinical efficacy for many cancer types, the systemic oral dosage regimens and formulations used in a clinical setting to date have been associated with dose limiting side effects. CAI is highly plasma protein boundand the absorption through the GI tract is variable which produced a relatively narrow therapeutic window for effective inhibition of pathological neovascularization. Toxic effects (cerebellar ataxia, peripheral neuropathy and exacerbation of depression) have been observed in clinical studies at doses of CAI required to achieve circulating levels of free drug in serum.

[0007] Furthermore, clinical use of CAI by systemic administration has been associated with the loss of vision for which two cases have been described where no ocular pathophysiology was identified. Therefore, use of systemic CAI as currently applied in clinical investigations for cancer is effectively precluded for acute or chronic treatment of non-life- threatening conditions, in particular for the treatment of ocular diseases.

[0008] To treat certain ocular diseases, such as age-related macular degeneration (AMD), diabetic retinopathy or diseases with specific ocular manifestations, therapeutic treatments rely on blockade of growth factors by pharmacologic agents, or occlusion of the blood vessels using either threshold laser photocoagulation or subthreshold laser combined with a photoactivated dye.

[0009] Wet or neovascular age-related macular degeneration (wAMD or nAMD) is the most common cause of visual impairment among elderly patients in developed countries. Approximately 10% of patients with AMD will develop choroidal neovascularization (CNV), which is the hallmark of nAMD. CNV is formed by complex mechanisms that include vascular endothelial growth factor (VEGF), integrin, angiopoietin, Tie-2, platelet derived growth factor (PDGF), fibroblastic growth factor (FGF), Tissue Factor and other pathways. Intracellular calcium levels regulate many of these pathways. CNV can cause sub-retinal or sub-RPE fluid or blood accumulation, detachment and / or atrophy of the retinal pigment epithelium (RPE), and fibrosis which ultimately lead to severe vision loss.

[0010] Regular administration of intravitreal anti-VEGF medications significantly improves vision in 30% of patients and stabilizes vision in another 60% of patients. Without such treatment, patients with nAMD experience severe, irreversible vision loss. The first FDA-approved intravitreal anti-VEGF agent for nAMD was pegaptanib sodium, a VEGF (165)-specific antagonist. This has since been replaced by bevacizumab, ranibizumab, aflibercept, and faricimab. Ranibizumab is a recombinant humanized antibody fragment that binds all isoforms of VEGF. Bevacizumab, approved by FDA for metastatic colorectal carcinoma, is used off-label as a treatment for nAMD. Aflibercept acts as a VEGF receptor decoy, effectively trapping VEGF isoforms. Lampalizumab was also approved to treat nAMD, but its use has been limited secondaryto reports of occlusive vasculitis. Additionally, faricimab, an antibody with affinity for both VEGF and angiopoietin-2 has been approved for use in the U.S. as well. Finally, several ranibizumab biosimilar agents have also been recently approved by the FDA.

[0011] Most pharmacologic agent currently approved and most that are under development for the treatment of AMD act primarily by blocking VEGF. Even with effective VEGF blockade for nAMD over 50% of patients do not enjoy a 3-line improvement in vision and 30-40% of patients with Diabetic Macular Edema, DME, do not have a favorable response to anti-VEGF monotherapy. Moreover, the treatment burden of these injections is high where patients require 5- 8 treatments per eye per year to control their disease. Laser treatment requires either full-thickness retinal damage by thermal destruction or damage to medium and large choroidal vessels thereby precluding any potential visual recovery. Further, the subject is left with a scar and visual scotoma. Moreover, recurrences are common and visual prognosis is poor.

[0012] Although CAI produces potent anti angiogenic effects in multiple pre-clinical models and appears relatively safe after systemic administration in humans, the poor aqueous solubility of CAI means that novel methods of administration and targeted administration are required for providing safe and effective doses to treat non-life-threatening diseases, ocular diseases in particular.

[0013] High local concentrations of CAI may be required to treat acute disease symptoms while lower concentrations can be effective as maintenance therapy or prophylactic therapy.

[0014] Treatments using dosage regimens, routes of administration and formulations of CAI described to date do not have adequate safety and efficacy for treating severe proliferative diseases that are non-life-threatening.

[0015] There exists an unfulfilled need for new dosage regimens, routes of administration and formulations of CAI that can provide therapeutic effects on non-life- threatening proliferative diseases, such as ocular diseases that are characterized by neovascularization and pathological cellular proliferation and invasion.SUMMARY OF THE INVENTION

[0016] The present invention is based on the seminal discovery that CAI / PLGA complex in the form of a bioerodible implant can be used to release CAI over time in the eye. Provided herein are CAI formulations allowing safe and effective local concentrations to slow vascular outgrowth.Treatment may be advised from every week to every month, to few months, to yearly dosing with appropriate molecules in sustained delivery systems.

[0017] In one embodiment, the present invention provides a method of treating age-related macular degeneration (AMD) in a patient in need thereof including administering to the patient a bioerodible implant including 5-amino-[4-(4-chlorobenzoyl)- 3,5-dichlorobenzyl]-l,2,3-triazole- 4-carboxamide (carboxy-amido-triazole or CAI) complexed with poly(D,L-lactic-co-glycolic acid) (PLGA), thereby treating AMD.

[0018] In one aspect, the PLGA is a two-part copolymer system including (i) a lactic acid monomer and (ii) a glycolic acid monomer. In another aspect, administering includes ocular administration by intravitreal injection. In one aspect, administering includes administering a unique dose, administering a dose every 6 months, administering a dose every 9-12 months, or less. In another aspect, the implant releases a therapeutically effective amount of CAI over time. In some aspects, the therapeutically effective amount of CAI released from the implant is from about 1 pg to 10 pg per day. In other aspects, the therapeutically effective amount of CAI released from the implant is about 2 pg to 5 pg per day. In one aspect, delivering CAI over time includes delivering CAI over at least 50 days, at least 60 days, at least 75 days, at least 96 days, or more. In another aspect, complexing the CAI with PLGA includes using an extrusion process. In one aspect, the implant includes about 20% CAI by weight and about 80% PLGA by weight. In another aspect, the implant includes about 40% CAI by weight and about 60% PLGA by weight. In one aspect, the 20% or 40% CAI by weight further includes an additional therapeutic agent. In some aspects, the 20% or 40% CAI by weight further includes an additional VEGF binding molecule. In other aspects, the 20% or 40% CAI by weight further includes an additional complement inhibitor molecule.

[0019] In another embodiment, the invention provides a method of treating an ocular disease in a patient in need thereof including administering to the patient a bioerodible implant including CAI complexed with PLGA, wherein the ocular disease is characterized by neovascularization, an increase in vascular permeability, and / or pathological cellular proliferation and invasion, thereby treating the ocular disease.

[0020] In one aspect, the ocular disease is selected from the group consisting of age-related macular degeneration (AMD), wet AMD, neovascular AMD, diabetic retinopathy, proliferative diabetic retinopathy, scotoma, glaucoma, low-tension glaucoma, angiomatous lesion, irisneovascularization and neovascular glaucoma, proliferative sickle cell retinopathy, myopic choroidal neovascular membrane, inflammatory choroidal neovascular membrane, polypoidal choroidal vasculopathy, subfoveal choroidal neovascular membrane, and choroidal neovascular membrane. In another aspect, the patient has previously been treated with cryotherapy, laser photo coagulation, an anti-VEGF, a Complement inhibitor or any combination thereof.

[0021] In an additional embodiment, the invention provides a method of treating age-related macular degeneration (AMD) and / or diabetic retinopathy in a patient in need thereof including administering to the patient a bioerodible implant including CAI complexed with PLGA, thereby treating AMD and / or the diabetic retinopathy.

[0022] In one embodiment, the invention provides a bioerodible implant including a) about 20-40 weight % CAI complexed with b) about 60-80 weight % PLGA, wherein the CAI / PLGA complex is formulated for intravitreal injection.

[0023] In one aspect, the PLGA is a two-part copolymer system including (i) a lactic acid monomer and (ii) a glycolic acid monomer. In another aspect, the implant has a length of about 1- 10 mm, and a diameter of about 400 pm. In one aspect, the implant releases a therapeutically effective amount of CAI of about 1 pg to 10 pg per day, for up to 96 days. In another aspect, the implant includes about 20% CAI by weight and about 80% PLGA by weight. In one aspect, the implant includes about 40% CAI by weight and about 60% PLGA by weight. In another aspect, the 20% or 40% CAI by weight further includes an additional therapeutic agent. In some aspects, the 20% or 40% CAI by weight further includes an additional VEGF binding molecule. In other aspects, the 20% or 40% CAI by weight further includes an additional complement inhibitor molecule.BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure l is a table illustrating CAI formulations of the invention.

[0025] Figure 2 is a table illustrating the physical measurements of the bioerodible implants produced in accordance with the methods of the invention, for the formulations of Figure 1.

[0026] Figure 3 is a table illustrating the content uniformity in the formulation described in Figure 1.

[0027] Figure 4 is a graph illustrating the in vitro release of CAI in a 20% CAI formulation, over a 56-day period.

[0028] Figure 5 is a graph illustrating the in vitro release of CAI in a 40% CAI formulation, over a 56-day period.

[0029] Figure 6 is a graph illustrating the in vitro cumulative release of CAI in both the 20% and the 40% formulations, over a 56-day period. The dose is illustrated as a percentage of total available drug load.

[0030] Figure 7 is a table illustrating the design of various sample formulations, with varyingPLGA monomer components.

[0031] Figure 8 is a graph illustrating the in vitro release of CAI from the formulation of Figure 7, over a 96-day period.

[0032] Figure 9 is a graph illustrating vitreous fluorometry results.

[0033] Figure 10 is a graph illustrating the compared drug release of a CAI / PLGA implant as compared to a dexamethasone / PLGA implant.DETAILED DESCRIPTION

[0034] The present invention is based on the seminal discovery that CAI / PLGA complex in the form of a bioerodible implant can be used to release CAI over time in the eye.

[0035] Before the present compositions and methods are described, it is to be understood that this invention is not limited to particular compositions, methods, and experimental conditions described, as such compositions, methods, and conditions may vary. It is also to be understood that the terminology used herein is for purposes of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only in the appended claims.

[0036] As used in this specification and the appended claims, the singular forms “a”, “an”, and “the” include plural references unless the context clearly dictates otherwise. Thus, for example, references to “the method” includes one or more methods, and / or steps of the type described herein which will become apparent to those persons skilled in the art upon reading this disclosure and so forth.

[0037] As used herein, the term “and / or” includes any and all combinations of one or more of the associated listed items.

[0038] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.

[0039] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the invention, it will be understood that modifications and variations are encompassed within the spirit and scope of the instant disclosure. The preferred methods and materials are now described.

[0040] The present disclosure provides CAI formulations, methods of preparation thereof, and methods of use thereof in the localized treatment of non-life-threatening diseases. In particular, the present disclosure provides for CAI bioerodible implant formulations, and further provides methods for treating ocular diseases characterized by neovascularization and pathological cellular proliferation and invasion, including administering to a patient a therapeutically effective amount of a CAI formulation (using novel delivery systems and combination therapies) that are effective and are associated with little or no adverse side effects. Previously recorded attempts to formulate a preparation of a clinically viable injectable dose form of CAI have encountered difficulties due to poor aqueous solubility of the CAI molecule and the need for use of toxic organic cosolvents in the preparation process. The present invention is based on the discovery that complexing CAI to PLGA using the methods described herein overcomes these limitations, including the need for use of cosolvents of any type. Unlike other molecules of similar molecular weight like Dexamethasone (OZURDEX®) that have been complexed to PLGA, the CAI / PLGA implant provides a long- acting controlled release of the drug over months of use, whereas the dexamethasone / PLGA implant releases its dexamethasone load in just a matter of days (as illustrated in FIGURE 10).

[0041] In one embodiment, the present invention provides a method of treating age-related macular degeneration (AMD) in a patient in need thereof including administering to the patient a bioerodible implant including 5-amino-[4-(4-chlorobenzoyl)- 3,5-dichlorobenzyl]-l,2,3-triazole- 4-carboxamide (carboxy-amido-triazole or CAI) complexed with poly(D,L-lactic-co-glycolic acid) (PLGA), thereby treating AMD.

[0042] Macular degeneration, or age-related macular degeneration (AMD), is a medical condition which may result in blurred or no vision in the center of the visual field. Early on thereare often no symptoms, but over time, however, some people experience a gradual worsening of vision that may affect one or both eyes. While it does not result in complete blindness, loss of central vision can make it hard to recognize faces, drive, read, or perform other activities of daily life. Visual hallucinations may also occur.

[0043] Macular degeneration typically occurs in older people and is caused by damage to the macula of the retina. The condition is diagnosed through a complete eye exam. Severity is divided into early, intermediate, and late types. The late type is additionally divided into “dry” and “wet” forms, with the dry form making up 90% of cases. The difference between the two forms is categorized by the change in the macula. Those with dry form AMD have drusen, cellular debris in their macula that gradually damages light-sensitive cells and leads to vision loss. In wet form AMD, blood vessels grow under the macula, causing blood and fluid to leak into the retina. There is no cure or treatment that restores the vision already lost. In the wet form, anti-VEGF medication injected into the eye or, less commonly, laser coagulation or photodynamic therapy may slow worsening.

[0044] Age-related macular degeneration is a main cause of central blindness among the working-age population worldwide. As of 2020, it affects more than 190 million people globally with the prevalence expected to increase to 288 million people by 2040 as the proportion of elderly persons in the population increases. It affects males and females equally, and it is more common in those of European or North American ancestry. CAI is essentially insoluble in aqueous solutions and in addition to the hydrophobicity of the molecule, it is also hygroscopic. Many attempts have been made to develop a stable durable CAI formulation for the treatment of ocular disease and most have been fraught with significant difficulties. The molecular weight and insolubility of CAI predicts an intravitreal half-life of approximately 6-8 hours, and when CAI is complexed with beta hydroxy cyclodextrin, the intravitreal half-life is only increased to 40 hours. When CAI was supercompressed into pellets with the hopes of producing a sustained release delivery system for the vitreous, some pellets rapidly expanded and cracked because of the hygroscopic nature of molecule, rendering these implants unusable. Multiple attempts were made before a stable nanoparticle formulation to enhance cellular uptake was achieved. However, despite many attempts, these nanoparticles could not be complexed to PLGA to generate a stable CAI-PLGA copolymer suspension. After these multiple failures were encountered with multiple candidate formulations, it was the CAI bioerodible implant described herein, developed via complexing CAIin powder form with various combinations of PLGA monomers, that yielded a stable, repeatable and controlled release configuration, contrary to the current state of knowledge about the compatibility of this small molecule compound with multiple controlled release chemistries.

[0045] The term “CAI” or “CAI compound” as used herein, refers to CAI as a free base and to CAI analogs, and CAI prodrugs, and to any salts such as acid salts thereof. The term “CAI formulation” as used herein refers to the implant of the invention, including a CAI compound complexed with PLGA.

[0046] “Poly(D,L-lactic-co-glycolic acid)” or “PLGA” as used herein refers to a copolymer known for its biodegradability and biocompatibility. It is synthesized by means of ring-opening o- polymerization of two monomers, the cyclic dimer (l,4-dioxane-2, 5-diones) of glycolic acid, and lactic acid. During polymerization, successive monomeric units (of glycolic acid or lactic acid) are linked together in PLGA by ester linkages, thus yielding a linear, aliphatic polyester as a product. The biocompatibility of PLGA results from its composition, due to lactic and glycolic acid fermentation from sugars, making them less reactive in the body. PLGA degrades into non-toxic and non-reactive products that makes them useful for medical and pharmaceutical applications. PLGA is degraded by enzymatic reaction, where an esterase releases the lactic acid and glycolic acid, which are integrated in the Krebs cycle and degraded into carbon dioxide and water.

[0047] The term “therapeutically effective amount” as used herein, refers to the amount necessary to elicit the desired biological response such as amelioration or reduction in severity of a symptom by a percentage amount. In some embodiments, an effective amount of a CAI formulation is sufficient to ameliorate the severity of symptoms and / or complications associated with an ocular disease. The amelioration in symptom and / or complication severity may be a 1%, 5%, 10%, 15%, 20%, 25% 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98% or 99% decrease in severity. As detailed below, preferably, the therapeutically effective amount of CAI locally administered in the treatment of ocular disease is a dose of about 1 ug to 10 ug per day. More preferably the 1 ug to 10 ug is administered intravitreally. More preferably, the CAI compound is CAI free base complexed in a PLGA co-polymer matrix formulation.

[0048] The term “treatment” as used herein covers any treatment of an ocular disease in a patient, particularly a human, comprising administration of a CAI formulation of the present disclosure, and includes: (i) preventing the disease from occurring in a patient that may bepredisposed to the disease but has not yet been diagnosed as having it; (ii) inhibiting the disease, e.g., inhibiting occurrence of an additional disease; or arresting development, inducing remission, or maintaining remission of the disease; (iii) relieving the disease, e.g., causing regression of the disease or addressing by diminishing or reducing symptoms; or (iv) inhibiting recurrence of a disease.

[0049] The present disclosure features formulations of CAI compounds for treatment of ocular diseases. Such formulations serve to overcome bioavailability limitations of CAI as a poorly water-soluble compound and / or provide for the increased, with respect to an aqueous solution of free base CAI, bioavailability of free CAI drug to the targeted disease tissue and providing exposure to diseased tissue at a desired rate to achieve and maintain a therapeutically effective amount of CAI in a pharmacologically active concentration.

[0050] The implant described herein, which is interchangeably refers to as “bioerodible implant”, “implant”, “CAI implant”, “filament” and the like is meant to describe a biodegradable implant including a CAI compound complexed with PLGA. By “bioerodible” or “biodegradable”, it is meant that the implant, once inserted or administered, slowly degrades to provide a steady and controlled release over a prescribed time of the CAI compound complexed within it. The bioerodible implant formulation includes 5-amino-[4-(4-chlorobenzoyl)-3,5- dichlorobenzyl]- l,2,3-triazole-4-carboxamide (CAI) and poly(D,L-lactic-co-glycolic acid) (PLGA), wherein the CAI is preferably provided in powder form and the PLGA is comprised of a two-part copolymer system wherein one part (a monomer) of the two part copolymer is a lactic acid and the other part (also a monomer) of the two part copolymer is a glycolic acid.

[0051] The PLGA copolymer may have representative molecular weights ranging from 7 kDa to 17 kDa. The respective weights of the PLGA monomers may be selected to effect changes in the rate of the decay of the bioerodible implant formulation such that the bioerodible implant may last for longer periods of time, or shorter periods of time, thereby determining the total delivered dosage of the CAI compound.

[0052] Routes of administration contemplated herein for the delivery of bioerodible CAI implant formulations by local administration include, but are not limited to, ocular, intravitreal, peribulbar sub-Tenon, periocular, subconjunctival, retrobulbar, subretinal, suprachoroidal, and posterior juxta scleral routes. Such routes of administration may be performed by injection by syringe and using a needle or cannula or by needle- free systems, or in conjunction with drugdelivery systems exemplified by controlled release of CAI from a matrix comprising a contact lens or punctal plug, (for delivery of drug to a tissue of the eye), from a device, from an implant, for release of drug to proximal tissue.

[0053] Preferably, a CAI formulation is administered locally to ocular tissue via a route that attenuates ocular pathological disease processes without unduly compromising normal or healthy ocular function by acting directly in the eye (e.g., at the site of diseased tissue) in a controlled therapeutically effective and localized fashion.

[0054] In one aspect, administering includes ocular administration by intravitreal injection.

[0055] The bioerodible implant described herein is administered to release CAI over time. Depending on the CAI concentration in the implant, and the pathology to be treated, a patient may need a single implant injected once. In cases where a chronic disease is to be treated, with effects sought after for an extended period of time, the administration of an implant may be repeated once the initial (or preceding implant) has released all the CAI it was contained. For example, an implant may be injected every month, every 3 months, every 6 months, every 9 months, every 12 months, or more or less frequently.

[0056] In one aspect, an implant is administered only once. In other aspects, a first implant is administered and is replaced regularly or frequently to maintain the sustain release of CAI over longer periods of time. In some aspect, an implant is administered every month, every 2 months, every 3 month, every 4 months, every 5 months, every 6 months, every 7 months, every 8 months, every 9 months, every 10 months, every 11 months, every 12 months, every 15 months, every 18 months, every 21 months, every 24 months, or more or less frequently.

[0057] In one aspect, administering includes administering a dose unique to the patient, e.g., administering a dose every 3 months, every 6 months, administering a dose every 9-12 months, or more or less.

[0058] In another embodiment, the invention provides a method of treating ocular disease in a patient including administering to the patient a bioerodible implant including CAI complexed with PLGA, wherein the ocular disease is characterized by neovascularization, increased vascular permeability, and / or pathological cellular proliferation and invasion, thereby treating the ocular disease.

[0059] “Ocular disease(s)” as used herein, include but are not limited to diabetic retinopathy (DR), neovascular age-related macular degeneration (ARMD), diabetic macular edema (DME),cystoid macular edema (CME) and ocular tumors such as choroidal melanoma or retinoblastoma (RB), Retinopathy of Prematurity (ROP), Retinal Vascular Occlusions (RVO), corneal neovascularization, iris neovascularization, neovascular glaucoma, ischemic neural damage, uveitis, glaucoma, and pterygium, neovascular diseases of the retina such as hyperproliferative retinopathies, proliferative vitreoretinopathies and retinal degeneration associated with systemic diseases such as diabetes mellitus, ischemic and hypoxic conditions associated with retinal vein and artery occlusion (e.g., from sickle cell disease or thrombosis), retinal degeneration resulting from retinal detachment, and age-related macular degeneration.

[0060] The formulations of the present disclosure may also be used to treat ocular symptoms resulting from diseases or conditions that have both ocular and non-ocular symptoms. Some examples include AIDS- related disorders such as cytomegalovirus retinitis and disorders of the vitreous; von Hippel-Lindau Syndrome (a disease that has ocular and nonocular neovascularization); pregnancy-related disorders such as hypertensive changes in the retina; and ocular effects of various infectious diseases such as tuberculosis, syphilis, Lyme disease, parasitic disease, toxocara canis's, toxoplasmosis, ophthalmonyiasis, cysticercosis, and fungal infections. Examples of non-ocular diseases include, but are not limited to, rheumatoid arthritis, psoriasis, contact dermatitis, keratitis, conjunctivitis, scleritis, squamous cell carcinoma, condyloma, eczema, rosacea vascular proliferation associated with angioplasty, graft vs host disease (organ and tissue transplantation), glioblastoma, peripheral neuropathies, diabetic neuropathy, and collagen vasculitis.

[0061] In one aspect, the ocular disease is selected from age-related macular degeneration (AMD), wet AMD, neovascular AMD, diabetic retinopathy, proliferative diabetic retinopathy, scotoma, glaucoma, low-tension glaucoma, angiomatous lesion, iris neovascularization and neovascular glaucoma, proliferative sickle cell retinopathy, myopic choroidal neovascular membrane, inflammatory choroidal neovascular membrane, polypoidal choroidal vasculopathy, subfoveal choroidal neovascular membrane, and choroidal neovascular membrane.

[0062] In another aspect, the patient has previously been treated with another therapeutic regimen, for example, cryotherapy, laser photo coagulation, an anti-VEGF, a Complement inhibitor, or any combination thereof.

[0063] By “another therapeutic regimen”, it is meant that the patient has received a previous therapeutic intervention for the treatment of the ocular disease, such treatment may have beenefficient for a period of time, and then symptoms reappeared, which is now prompting the administration of the bioerodible implant of the invention, or the treatment may have been unsuccessful at providing any relief to the patient. Therapeutic interventions for ocular diseases are well-known in the art and can easily be identified depending on the ocular disease. Non limiting examples of therapeutic interventions available for AMD include cryotherapy, laser photo coagulation, an anti-VEGF, a Complement inhibitor, or any combination thereof.

[0064] In an additional embodiment, the invention provides a method of treating age-related macular degeneration (AMD) and / or diabetic retinopathy in a patient including administering to the patient a bioerodible implant including CAI complexed with PLGA, thereby treating AMD and / or the diabetic retinopathy.

[0065] In one embodiment, the invention provides a bioerodible implant including a) about 20-40 weight % CAI complexed with b) about 60-80 weight % PLGA, wherein the CAI / PLGA complex is formulated for intravitreal injection.

[0066] The bioerodible or biodegradable implant described herein includes from about 20% to 40% by weight of CAI. In some aspects, the implant includes about 20 weight % CAI. In other aspects, the implant includes about 40 weight % CAI.

[0067] In various aspects, the implant includes a weight percent of CAI that ranges from about20 weight % to 40 weight %. In some aspect, the implant includes about 15-25 weight % CAI. In other aspects, the implant includes about 20-30 weight% CAI. In some aspects, the implant includes about 25-35 weight % CAI. In other aspects, the implant includes about 30-40 weight % CAI. In some aspect, the implant includes about 25-45 weight % CAI. For example, the implant can include, about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 227, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44 or 45 weight % CAI.

[0068] The bioerodible or biodegradable implant described herein includes from about 60% to 80% by weight of PLGA. In some aspects, the implant includes about 60 weight % PLGA. In other aspects, the implant includes about 80 weight % PLGA.

[0069] In various aspects, the implant includes a weight percent of PLGA that ranges from about 60 weight % to 80 weight %. In some aspect, the implant includes about 55-65 weight % PLGA. In other aspects, the implant includes about 60-70 weight% PLGA. In some aspects, the implant includes about 65-75 weight % PLGA. In other aspects, the implant includes about 70-80 weight % PLGA. In some aspect, the implant includes about 75-85 weight % PLGA. For example,the implant can include, about 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, or 85 weight % PLGA.

[0070] In some aspect, the implant includes essentially CAI and PLGA, e.g., the implant does not include any additional component. In one aspect, the implant includes about 20 weight % CAI and about 80 weight % PLGA. In another aspect, the implant includes about 40 weight % CAI and about 60 weight % PLGA.

[0071] In some aspects, the implant includes from about 20 to 40 weight % CAI and from about 60 to 80 weight % PLGA. For example, the implant includes about 15 weight % CAI and 85 weight % PLGA, 16 weight % CAI and 84 weight % PLGA, 17 weight % CAI and 83 weight % PLGA, 18 weight % CAI and 82 weight % PLGA, 19 weight % CAI and 81 weight % PLGA, 20 weight % CAI and 80 weight % PLGA, 21 weight % CAI and 79 weight % PLGA, 22 weight % CAI and 78 weight % PLGA, 23 weight % CAI and 77 weight % PLGA, 24 weight % CAI and 76 weight % PLGA, 25 weight % CAI and 75 weight % PLGA, 26 weight % CAI and 74 weight % PLGA, 27 weight % CAI and 73 weight % PLGA, 28 weight % CAI and 72 weight % PLGA, 29 weight % CAI and 71 weight % PLGA, 30 weight % CAI and 70 weight % PLGA, 31 weight % CAI and 69 weight % PLGA, 32 weight % CAI and 68 weight % PLGA, 33 weight % CAI and 67 weight % PLGA, 34 weight % CAI and 66 weight % PLGA, 35 weight % CAI and 65 weight % PLGA, 36 weight % CAI and 64 weight % PLGA, 37 weight % CAI and 63 weight % PLGA, 38 weight % CAI and 62 weight % PLGA, 39 weight % CAI and 61 weight % PLGA, 40 weight % CAI and 60 weight % PLGA, 41 weight % CAI and 59 weight % PLGA, 42 weight % CAI and 58 weight % PLGA, 43 weight % CAI and 57 weight % PLGA, 44 weight % CAI and 56 weight % PLGA or 45 weight % CAI and 55 weight % PLGA.

[0072] In one aspect, the PLGA is a two-part copolymer system including (i) a lactic acid monomer and (ii) a glycolic acid monomer.

[0073] In another aspect, PLGA content includes ester monomer and acid monomer. In some aspect, the ratio of ester monomer ranges from about 20% to 50%, and the ratio of acid monomer ranges from about 50% to 80%.

[0074] In some aspects, the PLGA content includes about 15-25 % ester monomer. In other aspects, the implant includes about 20-30% ester monomer. In some aspects, the implant includes about 25-35% ester monomer. In other aspects, the implant includes about 30-40% ester monomer. In some aspect, the implant includes about 35-45% ester monomer. In some aspects, the implantincludes about 40-50% ester monomer. In other aspects, the implant includes about 45-55% ester monomer. For example, the implant can include, about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, or 55% ester monomer. In some aspects, the implant includes about 25-35% ester monomer. In other aspects, the implant includes about 30-40% ester monomer.

[0075] In other aspects, the PLGA content includes about 45-55 % acid monomer. In other aspects, the implant includes about 50-60% acid monomer. In some aspects, the implant includes about 55-65% acid monomer. In other aspects, the implant includes about 60-70% acid monomer. In some aspect, the implant includes about 65-75% acid monomer. In some aspects, the implant includes about 70-80% acid monomer. In other aspects, the implant includes about 75-85% acid monomer. For example, the implant can include, about 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, or 85% acid monomer.

[0076] In some aspects, the implant includes about 25-35% ester monomer. In other aspects, the implant includes about 30-40% ester monomer. Those ranges and values apply to any CAI / PLGA implant described herein, including any ratio of CAI / PLGA as described herein (e.g., those values and ranges apply to any CAI / PLGA implant including about 15-45% CAI and about 50-85% PLGA

[0077] In one aspect, the PLGA weight percent includes about 20% ester monomer and about 80% acid monomer. In another aspect, the PLGA weight percent includes about 50% ester monomer and about 50% acid monomer. For example, in a CAI / PLGA implant including about 20 weight % CAI and about 80 weight % PLGA, the 80 weight % PLGA can include 20% ester monomer and about 80% acid monomer or about 50% ester monomer and about 50% acid monomer. In a CAI / PLGA implant including about 40 weight % CAI and about 60 weight % PLGA, the 60 weight % PLGA can include 20% ester monomer and about 80% acid monomer or about 50% ester monomer and about 50% acid monomer.

[0078] In some aspects, the PLGA ester and acid monomer ratio includes about 15 % ester monomer and 85 % acid monomer, 16 % ester monomer and 84 % acid monomer, 17 % ester monomer and 83 % acid monomer, 18 % ester monomer and 82 % acid monomer, 19 % ester monomer and 81 % acid monomer, 20 % ester monomer and 80 % acid monomer, 21 % ester monomer and 79 % acid monomer, 22 % ester monomer and 78 % acid monomer, 23 % estermonomer and 77 % acid monomer, 24 % ester monomer and 76 % acid monomer, 25 % ester monomer and 75 % acid monomer, 26 % ester monomer and 74 % acid monomer, 27 % ester monomer and 73 % acid monomer, 28 % ester monomer and 72 % acid monomer, 29 % ester monomer and 71 % acid monomer, 30 % ester monomer and 70 % acid monomer, 31 % ester monomer and 69 % acid monomer, 32 % ester monomer and 68 % acid monomer, 33 % ester monomer and 67 % acid monomer, 34 % ester monomer and 66 % acid monomer, 35 % ester monomer and 65 % acid monomer, 36 % ester monomer and 64 % acid monomer, 37 % ester monomer and 63 % acid monomer, 38 % ester monomer and 62 % acid monomer, 39 % ester monomer and 61 % acid monomer, 40 % ester monomer and 60 % acid monomer, 41 % ester monomer and 59 % acid monomer, 42 % ester monomer and 58 % acid monomer, 43 % ester monomer and 57 % acid monomer, 44 % ester monomer and 56 % acid monomer, 45 % ester monomer and 55 % acid monomer, 46 % ester monomer and 54 % acid monomer, 47 % ester monomer and 53 % acid monomer, 48 % ester monomer and 52 % acid monomer, 49 % ester monomer and 51 % acid monomer, 50 % ester monomer and 50 % acid monomer, 51 % ester monomer and 49 % acid monomer, 52 % ester monomer and 48 % acid monomer, 53 % ester monomer and 47 % acid monomer, 54 % ester monomer and 46 % acid monomer, or 55 % ester monomer and 45 % acid monomer.

[0079] In another aspect, the implant has a length of about 1-10 mm, and a diameter of about 400 pm.

[0080] The implant can be manufactured to have any size. The implant can be manufactured individually, one at a time, to an exact final length, and be ready to be injected (e.g., such implant can be referred to as an injected implant or ready to be injected implant). Alternatively, the implant can be manufactured as a long length implant, or ready to be cut implant (e.g., the manufactured implant is longer than a ready to be injected implant and needs to be cut to the size of a ready to be injected implant. In some aspects, the injected implant has a length that is less than about 10 mm. For example, the injected implant has a length of about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10mm. In various aspects, the injected implant has a length of about 5-6mm. In other aspects, the implant, the manufactured long-length implant has a length of about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 mm or any other increment of 5mm, such that an injectable implant of about 5mm can be cut out of the long-length implant. In other aspects, the manufactured long-length implant has a length of about 6, 12, 18, 24, 30, 36, 42, 48, 54, 60, 66, 72, 78, 84, 90,96, or 102 mm or any other increment of 6mm, such that an injectable implant of about 6mm can be cut out of the long-length implant.

[0081] In various aspects, the implant has a length ranging from about l-10mm, 5- 15mm, 10-20mm, 15-25mm, 20-30mm, 35-45mm, 40-50 mm, or 45-55mm. In other aspects, the implant has a length ranging from about l-5mm, 5-10mm, 10-15mm, 15-20mm, 20-25mm, 25-30mm, 30- 35mm, 35-40mm, 40-45mm, 45-50mm or 50-55mm. For example, the implant has a length of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, or 55mm or more.

[0082] The diameter of the implant is generally limited by the size of the needle used for the ocular administration of the implant. In various aspects, the implant is administered using a 22- gauge syringe needle and is therefore less than about 400pm. In other aspects, the implant has a diameter that ranges from about 300-500 pm. In one aspect, the implant has a diameter of about 400pm.

[0083] In another aspect, the implant releases a therapeutically effective amount of CAI over time.

[0084] In some aspects, the therapeutically effective amount of CAI released from the implant is from about 1 pg to 10 pg per day. In other aspects, the therapeutically effective amount of CAI released from the implant is from about 1 pg to 20 pg per day. In some aspects, the therapeutically effective amount of CAI released from the implant is about 1-10, 1-15, or 1-20 pg per day. In other aspects, the therapeutically effective amount of CAI released from the implant is about 1-5, 5-10, 10-15, or 15-20pg per day. In some aspects, the therapeutically effective amount of CAI released from the implant is about 1-10, 5-15, or 10-20pg per day. For example, the therapeutically effective amount of CAI released from the implantl, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20pg per day. In one aspect, the therapeutically effective amount of CAI released from the implant is about 2 pg to 5 pg per day.

[0085] In one aspect, delivering CAI over time includes delivering CAI over at least 60 days, at least 75 days, at least 96 days, or more. In some aspects, the delivery / release of CAI using the CAI / PLGA implant described herein allows the release of CAI for at least 7 days. In some aspects, the delivery / release of CAI using the CAI / PLGA implant described herein allows the release of CAI for at least 14 days. In some aspects, the delivery / release of CAI using the CAI / PLGA implantdescribed herein allows the release of CAI for at least 21 days. In some aspects, the delivery / release of CAI using the CAI / PLGA implant described herein allows the release of CAI for at least 28 days. In some aspects, the delivery / release of CAI using the CAI / PLGA implant described herein allows the release of CAI for at least 35 days. In some aspects, the delivery / release of CAI using the CAI / PLGA implant described herein allows the release of CAI for at least 42 days. In some aspects, the delivery / release of CAI using the CAI / PLGA implant described herein allows the release of CAI for at least 49 days. In some aspects, the delivery / release of CAI using the CAI / PLGA implant described herein allows the release of CAI for at least 56 days. In some aspects, the delivery / release of CAI using the CAI / PLGA implant described herein allows the release of CAI for at least 63 days. In some aspects, the delivery / release of CAI using the CAI / PLGA implant described herein allows the release of CAI for at least 70 days. In some aspects, the delivery / release of CAI using the CAI / PLGA implant described herein allows the release of CAI for at least 77 days. In some aspects, the delivery / release of CAI using the CAI / PLGA implant described herein allows the release of CAI for at least 84 days. In some aspects, the delivery / release of CAI using the CAI / PLGA implant described herein allows the release of CAI for at least 91 days. In some aspects, the delivery / release of CAI using the CAI / PLGA implant described herein allows the release of CAI for at least 96 days. For example, delivery / release of CAI using the CAI / PLGA implant described herein allows the release of CAI for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26,27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52,53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78,79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 98, 99, 100 or more days.

[0086] In one aspect, the implant releases a therapeutically effective amount of CAI of about 1 pg to 10 pg per day, for up to 96 days. The implant described herein releases a sustained effective amount of CAI over a period of time.

[0087] In some aspects, the delivery / release of CAI using the CAI / PLGA implant described herein allows the release of about 1 pg to 20 pg per day CAI for at least 7 days. In some aspects, the delivery / release of about 1 pg to 20 pg per day CAI using the CAI / PLGA implant described herein allows the release of about 1 pg to 20 pg per day CAI for at least 14 days. In some aspects, the delivery / release of about 1 pg to 20 pg per day CAI using the CAI / PLGA implant describedherein allows the release of about 1 .g to 20 gg per day CAI for at least 21 days. In some aspects, the delivery / release of about 1 pg to 20 pg per day CAI using the CAI / PLGA implant described herein allows the release of CAI for at least 28 days. In some aspects, the delivery / release of about 1 pg to 20 pg per day CAI using the CAI / PLGA implant described herein allows the release of CAI for at least 35 days. In some aspects, the delivery / release of about 1 pg to 20 pg per day CAI using the CAI / PLGA implant described herein allows the release of about 1 pg to 20 pg per day CAI for at least 42 days. In some aspects, the delivery / release of about 1 pg to 20 pg per day CAI using the CAI / PLGA implant described herein allows the release of about 1 pg to 20 pg per day CAI for at least 49 days. In some aspects, the delivery / release of about 1 pg to 20 pg per day CAI using the CAI / PLGA implant described herein allows the release of about 1 pg to 20 pg per day CAI for at least 56 days. In some aspects, the delivery / release of about 1 pg to 20 pg per day CAI using the CAI / PLGA implant described herein allows the release of about 1 pg to 20 pg per day CAI for at least 63 days. In some aspects, the delivery / release of about 1 pg to 20 pg per day CAI using the CAI / PLGA implant described herein allows the release of about 1 pg to 20 pg per day CAI for at least 70 days. In some aspects, the delivery / release of about 1 pg to 20 pg per day CAI using the CAI / PLGA implant described herein allows the release of about 1 pg to 20 pg per day CAI for at least 77 days. In some aspects, the delivery / release of about 1 pg to 20 pg per day CAI using the CAI / PLGA implant described herein allows the release of about 1 pg to 20 pg per day CAI for at least 84 days. In some aspects, the delivery / release of about 1 pg to 20 pg per day CAI using the CAI / PLGA implant described herein allows the release of about 1 pg to 20 pg per day CAI for at least 91 days. In some aspects, the delivery / release of about 1 pg to 20 pg per day CAI using the CAI / PLGA implant described herein allows the release of about 1 pg to 20 pg per day CAI for at least 96 days. For example, delivery / release of about 1 pg to 20 pg per day CAI using the CAI / PLGA implant described herein allows the release of about 1 pg to 20 pg per day CAI for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 227,28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53,54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79,80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 98, 99, 100 or more days.

[0088] In another aspect, the 20% or 40% CAI by weight further includes an additional therapeutic agent.

[0089] By “additional therapeutic agent” it is meant that the weight percent of CAI in the CAI / PLGA implant can include CAI and optionally one or more therapeutic agent that are not CAI. The additional therapeutic agent can be any therapeutic agent known in the art as useful for the treatment of ocular diseases. Non limiting examples of additional therapeutic agents include VEGF binding molecule, complement inhibitor molecule, and combination thereof. In some aspects, the 40% CAI by weight further includes an additional VEGF binding molecule. In other aspects, the 40% CAI by weight further includes an additional complement inhibitor molecule.

[0090] In some aspects, the implant includes CAI and PLGA, and optionally one or more additional agents. The one or more agents can include any other drug, small molecules and the like that can be used for the treatment of the ocular disease of interest. In some aspects, the one or more agents are added to the CAI portion of the implant. That is, the weight percent of PLGA does not change, but rather it is the weight percent of CAI that is modified to include a desired weight percent of the additional agent(s).

[0091] As discussed above, in one aspect, the implant includes about 20 weight % CAI and about 80 weight % PLGA; in such cases, the 20 weight % CAI further include one or more additional agent. In another aspect, the implant includes about 40 weight % CAI and about 60 weight % PLGA; in such cases, the 40 weight % CAI further include one or more additional agent.

[0092] Concurrent administration" and "concurrently administering," as used herein, includes administering a formulation of the present disclosure in a therapeutic method suitable for use with the methods of the present disclosure in the treatment of ocular diseases.

[0093] In some embodiments, the bioerodible implant formulation further includes a CAI load, measured as a weight percentage of the CAI relative to the total formulation weight, that may vary in order to provide varied amounts of clinically relevant, or therapeutically effective, doses of the CAI compound. These CAI loading ranges may vary from 10% CAI by weight relative to the total formulation weight to 80% CAI by weight, relative to the total formulation, but preferably in the range from 20% by weight to 50% by weight.

[0094] In some embodiments, the bioerodible implant formulation further includes an additional therapeutic compound or substance, chosen from a group consisting of a VEGF binding molecule and a tyrosine receptor kinase inhibitor. In some embodiments, the VEGF binding molecule is selected from the group consisting of ranibizumab, aflibercept, faricimab, biologies or biosimilars of these molecules.

[0095] In some embodiments, the bioerodible implant formulation further includes an additional therapeutic compound or substance, chosen from a group consisting of a complement inhibitor. In some embodiments, the complement inhibitor molecule is selected from the group consisting of Avacincaptad pegol or Pegcetacoplan.

[0096] The bioerodible formulation can be prepared by various forming processes, including molding; which includes the process types of compression molding, melt molding, transfer molding and injection molding, and by extrusion; which include the process types of hot extrusion, hooker extrusion, hydrostatic extrusion, impact extrusion and ram extrusion. The choice of forming process to be used is generally based on the desired outcome in terms of implant size, shape, form factor, materials including their physical properties, melting points, size, shape and drug loading of the final bioerodible implant to be manufactured.

[0097] The preferred embodiment of the present invention utilizes a ram extrusion process, although other extrusion processes may also be used. Ram extrusion offers the advantages of being simple to operate and easy to control and is optimal for producing long, continuous cylindrical profiles in polymer matrix materials. Unlike screw-type extruders where the material matrix is both mixed and pushed out of the extrusion die by the action of the turning screw, a ram extruder takes fully pre-mixed matrix material and uses a plunger mechanism to push the material in bulk into and through the extrusion die creating the long, continuous length of bioerodible implant material. The long continuous segments of extruded material can then be stored for later use, and then cut to length post-extrusion, which allows for the flexibility to create multiple implant lengths of the bioerodible implant, on demand.

[0098] The ram extrusion process is primarily controlled by two parameters, plunger speed and extrusion temperature. The plunger speed setting is based on the size of the extrusion die that the extrudate is pushed through and the extrusion temperature is set based on the melting point of the materials being extruded. In the preferred embodiment of the present invention, the melting point of the CAI compound is much higher than the melting point of the polymer materials it is mixed and extruded with. Therefore, the extrusion / melt temperature is dictated by the polymer melt temperature and the CAI compound is not affected, denatured or otherwise compromised by the implant extrusion process. In the preferred embodiment, the extrusion temperature is set in the range of 64°C - 68°C. The corresponding plunger speed is set to 5 pl / min.

[0099] The input to the ram extrusion process is the mixture, in powder form, of the CAI compound and the components of the chosen PLGA copolymer materials, which are cryomilled to achieve particle sizes appropriate for extrusion processing and which improves bulk flow through the extruder. The formulation of the desired drug loading of the CAI compound with the final bioerodible implant is set by varying the relative weights (masses) of the CAI compound and the chosen copolymer materials. As previously described, the preferred embodiment of the present invention includes CAI loading in the range from 20% to 50% by weight of the extruded implant. The chosen formulation of weighed powders is dried to eliminated excess moisture, then input to the ram extruder to produce the bioerodible implants in the manner described previously for the preferred embodiment.

[0100] Presented below are examples discussing CAI / PLGA bioerodible implants contemplated for the discussed applications. The following examples are provided to further illustrate the embodiments of the present invention but are not intended to limit the scope of the invention. While they are typical of those that might be used, other procedures, methodologies, or techniques known to those skilled in the art may alternatively be used.EXAMPLESEXAMPLE 1GENERATION OF BIOERODIBLE CAI LOADED IMPLANTS

[0101] In preliminary work, formulations and bioerodible implants t were produced in accordance with the descriptions provided above. Two formulations were produced, one targeted for a 20% drug loading by weight of the CAI compound in the resulting implant, and the other targeting 40% by weight of the CAI compound. Extrusion die sizes were set to produce bioerodible implants with a target diameter of 400 gm. This target diameter corresponds with the ability to deliver the implants through a 22-gauge syringe needle, which conforms to a typical syringe size used in human intravitreal injections implants in a clinic setting. Figure 1 shows the representative formulations produced. Some of the physical properties of the implants are summarized in Figure 2.

[0102] Final implant lengths were the result of a cut-to-length process from the continuous extrusion output, as described above.

[0103] Representative implant samples were randomly selected for evaluation of resultant content for each formulation, known as a content assay and uniformity. Samples were prepared by dissolving the sample implants in acetonitrile and measuring the resultant drug load using standard HPLC methods. Figure 3 shows the results of the content assays for samples of both formulations.

[0104] Results demonstrated that the process was highly capable of producing repeatable results, with minimum variability, in terms of content uniformity across multiple samples, for both formulations.

[0105] Additional samples from both formulation groups were then tested for their ability to deliver the CAI compound over time and in clinically relevant doses. This testing, In Vitro Release Testing (IVRT), was conducted over a 56-day period to assess the physico-kinetic properties of the implants in the process of the PLGA copolymer breakdown (erosion) and stable release of the CAI compound. Testing was performed by placing samples of each formulation (n=3 replicates) in individual vials in a medium of 1% beta-cyclodextrin to produce sink conditions and maintained at 37°C temperature on an active shaker table. The solution media were sampled at prescribed time intervals and the amount of CAI compound present in solution was measure using standard HPLC methods.

[0106] Results of the IVRT testing for both formulations, showing average amount of CAI compound released per day out to 56 days of testing, are presented in Figure 4 for the 20% formulation and Figure 5 for the 40% formulation.

[0107] Results of the IVRT testing showing the cumulative amount of CAI (as a percent of the total drug load) released per day out to 56 days of testing is presented in Figure 6 for the both the 20% and 40% formulations.

[0108] The test results demonstrated that the unique combination of drug, drug load and copolymer materials, processed in the specified manner using the process descriptions provided, produced the two formulations in a configuration appropriate for a CALbased bioerodible implant for use in the treatment of chronic ocular diseases.

[0109] The implant formulations produced demonstrated that the process to produce them was stable and repeatable, and that in turn produced stable and highly linear results in terms of drug release. The dotted lines in Figure 6 represent the corresponding best fit linear models for each formulation, whose r2 values approximate 0.9. The implants achieved highly accurateimplementation in terms of the physical characteristics, including both dimensional stability and accuracy of drug loading.

[0110] The IVRT results demonstrate that both formulations produced highly linear release profiles and profiles that were consistently proportional to the drug loading at each time point. Across the 56-day test period, the implants achieved an average drug release of 2.8 pg / day CAI and 4.8 pg / day CAI for the 20% and 40% formulations, respectively. There were no nonlinearities in the release response. In terms of cumulative drug release, both formulations released only about 63% of their total drug load by the day 56 time point. Based on a continued linear approximation of the release curve, this suggests the release would last approximately 3 months (89 days) before all drug content is released at the average rate.[0U1] In subsequent work, the combination of polymer materials was extended to be complexed with CAI in order to demonstrate that the drug delivery could be extended for longer release periods and still deliver clinically relevant doses of CAI on an extended basis.

[0112] For this effort, five (5) different PLGA polymer components (monomers) were identified and combined with CAI in 4 different formulations in a Design of Experiments configuration. Each formulation had a different ratio by weight of the monomer components, but all used a constant amount of CAI by weight and a constant total weight of 1,000 mg, therefore providing the ability to isolate changes in release performance based on differences in the type and amount of the monomers themselves. The resulting matrix of CAI and polymer component formulations is shown in Figure 7.

[0113] Multiple samples of each of the formulations (designated FV2, FV3, FV4 and FV5) were produced using the same process as described for the initial experiments, i.e., a RAM extrusion method. After visual inspection, weights and physical dimensions were confirmed, the samples were placed on test using the same In Vitro Release (IVR) test apparatus and method as described above.

[0114] Figure 8 demonstrates the results of the IVR testing, performed out to 96 days of continuous exposure.

[0115] Figure 8 also includes results of the original formulation of 40% CAI (“FV1S”) to provide further comparative results. Overall, these results demonstrate that careful selection of specific polymer components in conjunction with the inherent properties of the CAI molecule characteristics can provide a stable and predictable outcome in terms of controlled drug release.The controlled release times were proportional to the combination of degradation times of the selected monomers and were unaffected by complexing to CAI for a given process. Varying the combination of PLGA monomers provides the opportunity to tune the IVR response depending on the desired outcome of drug release, the clinical indication and the overall desired degradation time.

[0116] To demonstrate the clinical effectiveness of this unique combination of carboxyamidotriazole and selective PLGA monomers, a pre-clinical animal study was performed. New Zealand White Rabbits, a validated model of neovascular retinal disease, were used to compare the clinical effectiveness of a single PLGA implant dose of CAI to the current standard of care for nAMD treatment, aflibercept (tradename Eylea™). Three study arms (groups) were employed; one arm treated with the CAI bioerodible implant formulated for a 60-day treatment, one arm treated with an intravitreal injection of aflibercept and the third arm acting as a sham injection control group. Both treatment arms were induced with standard dose injections of the vascular endothelial growth factor (VEGF) protein to induce abnormal retinal blood vessel growth and significant increases in vascular permeability in the to be treated eyes.

[0117] Clinical performance (effectiveness) was measured at 30 days and 60 days (primary endpoint) using a standardized vitreous fluorescence photometry (microscopy) technique to measure changes in retinal vascular permeability, and to compare the anti-permeability effect of the standard-of-care single intravitreal injection treatment (aflibercept) vs. the single CAI treatment delivered in the controlled release form of the bioerodible implant. Additional effectiveness measures included the use of comparative fundus photography. Safety measures included the clinical evaluation of injection sites, intra-ocular pressure measurements, lack of adverse events and sacrifice histology of the retinal tissue.

[0118] At the 60-day primary endpoint, the results demonstrated that the bioerodible CAI implant was clinically, statistically superior to the standard of care aflibercept treatment in its antipermeability effect. Figure 9 shows the comparative results of the quantitative Vitreous Fluorometry measurements. This figure represents the measured amount of injected fluorescein that has leaked into the vitreous after VEGF induction, and post treatment with either aflibercept or the CAI-loaded implant. By Day 60, the results demonstrate that the single CALloaded implant has not only reduced the amount of measured fluorescein in the vitreous, but also the amount of reduction is significantly greater than the amount of reduction achieved by the aflibercepttreatment. This is a very significant and unexpected result given the longstanding assumptions about aflibercepf s effectiveness. These effectiveness results were further supported by the qualitative comparison of fundus imaging of all treatment eyes.

[0119] Additionally, all safety measures indicated that the Bioerodible CAI implant was a safe treatment option. With no injection site reactions, no infections, no adverse events and no changes in intra-ocular pressures, all clinical safety indicators were positive. Results of the sacrifice histology showed no demonstrable difference between the retinal layers of the CAI treated eyes vs. the aflibercept treated eyes and vs. the contralateral untreated (control) eyes. No evidence of inflammatory infiltrates nor toxicity were present in any eye.

[0120] These compelling clinical results demonstrate for the first time that a non-anti-VEGF treatment, i.e., a CAI-loaded bioerodible implant, performs clinically statistically better than the standard of care aflibercept intravitreal injection in a well validated model of neovascular AMD.

[0121] And in conjunction with the unique processing and selection of the monomers of the PLGA polymer family, a bioerodible, CAI-loaded implant has demonstrated for the first time that it can be formulated and delivered in a manner uniquely defined to provide clinically relevant dosing of CAI to the retina, resulting a safe and more effective treatment method than previously believed to have been possible.EXAMPLE 2DIABETIC COMPLICATIONS

[0122] Patient A is determined to be experiencing an acute relapse of diabetes, e g., diabetic ketoacidosis. Patient A has a history of diabetes over the past 20 years, with increasing debilitation from progressive diabetic retinopathy, nephropathy, and neuropathy. Patient A has not yet had pan-retinal laser photocoagulopathy but has been treated with focal laser for macular edema. Retinal examination and fluorescein angiography reveal Patient A has Proliferative Diabetic retinopathy that has not progressed to threshold criteria for pan-retinal photo coagulation per the Diabetic Retinopathy Study (DRS) guidelines.

[0123] According to the subject invention, Patient A will require scheduling of a follow-up visit and injection of a CAI PLGA implant in an attempt to delay or remove the need for panretinal laser photocoagulation.

[0124] Patient A is given a direct intravitreal injection the CAI-PLGA-implant and this isfollowed by weekly retinal examination follow-up to determine disease course and confirm necessity for pan-retinal laser photocoagulation. Intravitreal injections may be supplemented or replaced by other appropriate routes of administration, and this could be dictated by the patient’s clinical presentation, health, expected treatment compliance profile, and appropriateness of local, systemic, or controlled release treatment. CAI treatment would be targeted to be tapered off to prophylactic systemic or controlled release therapy, as the condition improves sufficiently.EXAMPLE 3PROLIFERATIVE DIABETIC RETINOPATHY

[0125] A 62-year-old male with Proliferative Diabetic Retinopathy and threshold high-risk characteristics presents with vitreous hemorrhage. The patient also has atrial fibrillation and ischemic cardiomyopathy that requires oral anti-coagulants. The patient is intolerant to topical pan-retinal photocoagulation and multiple co-morbidities preclude frequent enough visits for anti- VEGF therapy. Because of this acute event, intravitreal injection of CAI-PLGA implant is given to induce neovascular regression. The patient’s vitreous hemorrhage resolves and he is maintained with intravitreal injections of CAI-PLGA implant every 6 months.EXAMPLE 4CENTRAL SCOTOMA SECONDARY TO NEOVASCULAR AMD

[0126] A 78-year-old woman with a two-week history of central scotoma. She developed a large disciform scar in the contralateral eye after several sessions of photodynamic therapy. Upon exam and fluorescein angiography, a predominately classic sub-foveal membrane is noted. Intravitreal injection of CAI-PLGA implant is given and neovascular regression occurs. She is then maintained on intravitreal injections of CAI-PLGA implant every 6 months.EXAMPLE 5NEOVASCULAR AMD PROPHYLAXIS

[0127] A 67-year-old white male who has had three years of poor vision secondary to a disciform scar associated with nAMD in one eye. The contralateral eye has high-risk drusen and parafoveal pigmentation. Intravitreal injection of CAI-PLGA implant is given every 9-12 monthsto the better-sighted eye to prophylax against neovascularization.EXAMPLE 6GLAUCOMA COMPLICATION

[0128] An 82-year- o 1 d woman with low-tension glaucoma. She has a history of hypotony maculopathy in the left eye after trabeculectomy with visual acuity loss to 20 / 200 secondary to hypotony maculopathy associated with an intraocular pressure of 7 to 8 mmHg. In the right eye, she is progressively cupping with a Cup / Disc ratio 0.85 despite maximal medical treatment and an intraocular pressure of 11 mmHg. Intravitreal injection of CAI-PLGA implant is given every 9-12 months is given in order to maximize neuroprotection.EXAMPLE 7PROLIFERATIVE DIABETIC RETINOPATHY PARTIAL TREATMENT RESPONSE

[0129] 28-year-old noncompliant diabetic male who initially presented with aggressive Proliferative Diabetic Retinopathy. Pan-retinal Photo coagulation was performed, and despite anti- VEGF injections every 2 months there is recurrent residual Vitreous Hemorrhaging from a small active frond of neovascularization that is within heavy panretinal photocoagulation scars. Because of the persistent bleeding, intravitreal injection of CAI-PLGA implant is given to induce neovascular regression. The patient’s Vitreous Hemorrhage resolves and he is maintained with intravitreal injections of a CAI-PLGA implant every 6 months.EXAMPLE 8PROLIFERATIVE DIABETIC RETINOPATHY PERSISTENT VITREOUS HEMORRHAGE

[0130] A 37-year-old white male who is with Proliferative Diabetic Retinopathy and has undergone 2 Pars Plana Vitrectomy surgeries for vitreous hemorrhage. He has a heavy pattern of pan-retinal photo coagulation scars and it is thought that he has neovascularization arising from the sclerotomy sites, and / or the pars plana, which is causing persistent hemorrhage. Intravitreal injection of CAI-PLGA implant is given to induce neovascular regression. The patient’s vitreous hemorrhage resolves and he is maintained with intravitreal injections of a CAI-PLGA implant every 6 months.EXAMPLE 9VISION LOSS FROM ANGIOMATOUS LESION

[0131] A 16-year-old female who presents with a several month history of vision loss and is found to have a large angiomatous lesion that is causing a subtotal retinal detachment. The lesion has not responded to anti-VEGF treatment and secondary to the lesion size it is not amenable for cryotherapy and / or standard laser photocoagulation. Intravitreal injection of a CAI-PLGA implant is given to induce neovascular regression. The subretinal fluid resolves and she is maintained with intravitreal injections of a CAI-PLGA implant every 6 months.EXAMPLE 10IRIS NEOVASCULARIZATION AND NEOVASCULAR GLAUCOMA

[0132] A 68-year-old diabetic male with adult-onset diabetes and central retinal vein occlusion develops iris neovascularization and neovascular glaucoma with intraocular pressure of 42 mmHg. His pressure responds to topical drops and intravitreal anti-VEGF. However, two weeks after anti-VEGF therapy, he develops vitreous hemorrhage and recurrent elevated intraocular pressure of 46 mmHg. Intravitreal injection of a CAI-PLGA implant is given to induce neovascular regression. The vitreous hemorrhage resolves and the intraocular pressure normalized. He is then maintained with intravitreal injections of a CAI-PLGA implant every 6 months.EXAMPLE 11PROLIFERATIVE SICKLE CELL RETINOPATHY

[0133] A 40-year-old male with a history of Traction Retinal Detachment and vision loss in one eye from proliferative sickle cell retinopathy. The patient developed a Vitreous Hemorrhage in the fellow eye and has only incomplete regression following peripheral scatter laser. Intravitreal injection of a CAI-PLGA implant is given to induce neovascular regression, and the vitreous hemorrhage resolves. He is then maintained with intravitreal injections of a CAI-PLGA implant every 6 months.EXAMPLE 12MYOPIC CHOROIDAL NEOVASCULAR MEMBRANE COMPLICATIONS

[0134] A 44-year-old white male with a history of Choroidal Neovascular Membrane secondary to high myopia. One eye has Fuch’s spots and 20 / 200 vision. The second eye is affected with a subfoveal Choroidal Neovascular Membrane and 20 / 80 vision. A single injection Intravitreal injection of a CAI-PLGA implant is given to induce neovascular regression. The vision returns to 20 / 40 and no further treatment is needed.EXAMPLE 13INFLAMMATORY CHOROIDAL NEOVASCULAR MEMBRANE COMPLICATIONS

[0135] A 32-year-old female with multifocal choroiditis and macular scarring in one eye after several sessions of Photodynamic Therapy. She presents in the second eye with decreased vision t o 2 0 / 1 0 0 and a subfoveal Choroidal Neovascular Membrane. A periocular injection of 20 mg of triamcinolone and a single Intravitreal injection of a CAI-PLGA implant is given to hasten neovascular regression. The vision returns to 20 / 30 and no further treatment is needed.EXAMPLE 14POLYPOIDAL CHOROIDAL VASCULOPATHY COMPLICATIONS

[0136] A 55-year-old female with Polypoidal Choroidal Vasculopathy and macular scarring in one after large sub-macular hemorrhage. The fellow eye develops a peripapillary choroidal neovascular membrane with hemorrhage and vision loss to 20 / 40. Intravitreal injection of a CAI- PLGA implant is given to induce neovascular regression, the subretinal hemorrhage resolves and vision improves to 20 / 25. She is then maintained with intravitreal injections of a CAI-PLGA implant every 6 months.EXAMPLE 15TRAUMATIC CHOROIDAL NEOVASCULAR MEMBRANE COMPLICATIONS

[0137] An 18-year-old male is struck by a baseball to the eye and 3 months later develops a subfoveal choroidal neovascular membrane with vision loss to 20 / 70. A single Intravitrealinjection of a CAI-PLGA implant is given to hasten neovascular regression. The vision returns to 20 / 30 and no further treatment is needed.EXAMPLE 16PSEUDOXANTHOMA ELASTICUM CHOROIDAL NEOVASCULAR MEMBRANE COMPLICATIONS

[0138] A 62-year-old male develops a choroidal neovascular membrane in one eye and despite multiple anti-VEGF injections, vision diminishes to 20 / 400. The other eye develops a choroidal neovascular membrane with vision loss to 20 / 200. Intravitreal injection of a CAI-PLGA implant is given to induce neovascular regression, the subretinal fluid resolves and vision improves to 20 / 20. He is then maintained with intravitreal injections of a CAI-PLGA implant every 6 months.

[0139] Although the invention has been described with reference to the above examples, it will be understood that modifications and variations are encompassed within the spirit and scope of the invention. Accordingly, the invention is limited only by the following claims.

Claims

What is claimed is:

1. A method of treating age-related macular degeneration (AMD) in a patient in need thereof comprising administering to the patient a bioerodible implant comprising 5-amino-[4-(4- chlorobenzoyl)- 3,5-dichlorobenzyl]-l,2,3-triazole-4-carboxamide (carboxy-amido-triazole or CAI) complexed with poly(D,L-lactic-co-glycolic acid) (PLGA), thereby treating AMD.

2. The method of claim 1, wherein the PLGA is a two-part copolymer system comprising (i) a lactic acid monomer and (ii) a glycolic acid monomer.

3. The method of claim 1, wherein administering comprises ocular administration by intravitreal injection.

4. The method of claim 1, wherein administering comprises administering a unique dose, administering a dose every 6 months, administering a dose every 9-12 months, or less.

5. The method of claim 1, wherein the implant releases a therapeutically effective amount of CAI over time.

6. The method of claim 5, wherein the therapeutically effective amount of CAI released from the implant is from about 1 pg to 10 pg per day.

7. The method of claim 6, wherein the therapeutically effective amount of CAI released from the implant is about 2 pg to 5 pg per day.

8. The method of claim 5, wherein delivering CAI over time comprises delivering CAI over at least 50 days, at least 60 days, at least 75 days, at least 96 days, or more.

9. The method of claim 1, wherein complexing the CAI with PLGA comprises using an extrusion process.

10. The method of claim 1 , wherein the implant comprises about 20% CAI by weight and about 80% PLGA by weight.

11. The method of claim 1 , wherein the implant comprises about 40% CAI by weight and about60% PLGA by weight.

12. The method of claim 10 or 11, wherein the 20% or 40% CAI by weight further comprises an additional therapeutic agent.

13. The method of claim 10 or 11, wherein the 20% or 40% CAI by weight further comprises an additional VEGF binding molecule.

14. The method of claim 10 or 11, wherein the 20% or 40% CAI by weight further comprises an additional complement inhibitor molecule.

15. A method of treating an ocular disease in a patient in need thereof comprising administering to the patient a bioerodible implant comprising 5-amino-[4-(4-chlorobenzoyl)- 3,5- dichlorobenzyl]-l,2,3-triazole-4-carboxamide (carboxy-amido-triazole or CAI) complexed with poly(D,L-lactic-co-glycolic acid) (PLGA), wherein the ocular disease is characterized by neovascularization, an increase in vascular permeability, and / or pathological cellular proliferation and invasion, thereby treating the ocular disease.

16. The method of claim 14, wherein the ocular disease is selected from the group consisting of age-related macular degeneration (AMD), wet AMD, neovascular AMD, diabetic retinopathy, proliferative diabetic retinopathy, scotoma, glaucoma, low-tension glaucoma, angiomatous lesion, iris neovascularization and neovascular glaucoma, proliferative sickle cell retinopathy, myopic choroidal neovascular membrane, inflammatory choroidal neovascular membrane, polypoidal choroidal vasculopathy, subfoveal choroidal neovascular membrane, and choroidal neovascular membrane.

17. The method of claim 14, wherein the patient has previously been treated with cryotherapy, laser photo coagulation, an anti-VEGF, a Complement inhibitor or any combination thereof.

18. A method of treating age-related macular degeneration (AMD) and / or diabetic retinopathy in a patient in need thereof comprising administering to the patient a bioerodible implant comprising 5-amino-[4-(4-chlorobenzoyl)- 3, 5-di chlorobenzyl]-!, 2, 3-triazole-4-carboxamide (carboxy-amido-triazole or CAI) complexed with poly(D,L-lactic-co-glycolic acid) (PLGA),thereby treating AMD and / or the diabetic retinopathy.

19. A bioerodible implant comprising: a) about 20-40 weight % 5-amino-[4-(4-chlorobenzoyl)- 3,5-dichlorobenzyl]-l,2,3-triazole-4- carboxamide (carboxy-amido-triazole or CAI) complexed with b) about 60-80 weight % poly(D,L-lactic-co-glycolic acid) (PLGA), wherein the CAI / PLGA complex is formulated for intravitreal injection.

20. The implant of claim 19, wherein the PLGA is a two-part copolymer system comprising (i) a lactic acid monomer and (ii) a glycolic acid monomer.

21. The implant of claim 19, wherein the implant has a length of about 1-10 mm, and a diameter of about 400 pm.

22. The implant of claim 19, wherein the implant releases a therapeutically effective amount of CAI of about 1 pg to 10 pg per day, for up to 96 days.

23. The implant of claim 19, wherein the implant comprises about 20% CAI by weight and about 80% PLGA by weight.

24. The implant of claim 19, wherein the implant comprises about 40% CAI by weight and about 60% PLGA by weight.

25. The implant of claim 23 or 24, wherein the 20% or 40% CAI by weight further comprises an additional therapeutic agent.

26. The implant of claim 23 or 24, wherein the 20% or 40% CAI by weight further comprises an additional VEGF binding molecule.

27. The implant of claim 23 or 24, wherein the 20% or 40% CAI by weight further comprises an additional complement inhibitor molecule.

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