Compound, compositions, and methods of use thereof

Abstract

Provided is a compound, compositions and methods for treating or preventing age-related macular regeneration (AMD) in patients in need thereof.

Description

COMPOUND, COMPOSITIONS, AND METHODS OF USE THEREOFCROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit under 35 U.S.C. §119(e) to U.S. Provisional Application Number 63 / 666,016, filed June 28, 2024, all of which are incorporated by reference.BACKGROUND

[0002] Although being relatively safe and efficient in treatment and prevention of coronary heart disease, statins have certain limitations in their use because of possible deleterious side effects, such as muscle weakness and renal failure. Statin therapy is contra-indicated in pregnant women and patients with liver disorders. Additionally, there is a significant patient population in whom statins are not effective, and so the need for an agent that will lower cholesterol extends beyond the number of patients currently taking statins to lower their cholesterol levels.

[0003] Research has also shown that both HDL cholesterol and triglycerides showed association with drusen (yellow spots) and early age-related macular degeneration (AMD). It has been suggested that the accumulation of drusen resembles the formation of atherosclerotic plaques seen in cardiovascular disease, with a similar composition of lipids and proteins, and higher levels of circulating HDL cholesterol raised the odds of larger drusen, whereas higher levels of triglycerides decreased the odds. Higher levels of LDL cholesterol were statistically significant in the association with early AMD.SUMMARY

[0004] Provided herein are alkyl-hydroxy derivatives of atorvastatin for enhanced potency and targeted delivery. In certain embodiments, provided is a compound of Formula I:or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein L is Ci-io alkylene.

[0005] In certain embodiments, provided is a compound of Formula IA:or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein n is 0, 1, 2, 3, 4, 5, 6, 7, or 8.

[0006] In certain embodiments, provided is a compound (Compound 1) having the name 3- hydroxypropyl (3R,5R)-7-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)-lH-pyrrol-l- yl)-3,5-dihydroxyheptanoate, and the structure:or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof.

[0007] In certain embodiments, the compound exhibits enhanced activity profiles when compared to atorvastatin. For example, the compound has exhibited superior potency as compared to atorvastatin. It is also contemplated that the compounds disclosed herein (e.g., Compound 1) have improved retinal pigment epithelium (RPE) permeability and / or localization in certain assays as compared to atorvastatin.

[0008] It is contemplated that compounds of the present disclosure (e.g., Compound 1) are not “active” unless or until the alkyl-hydroxy moiety is cleaved by a carboxylesterase (CES). CES is known to be produced by RPE, especially RPE under stress. Therefore if compounds of the present disclosure are administered, such as to the eye, there is potential to achieve a localized activity, such as within the RPE, rather than other cells within the retina that do not produce CES.

[0009] It is also contemplated that uptake of the compounds of the present disclosure (e.g., Compound 1) by RPE is enhanced when compared to ATV. If this is occurring, uptake may be mediated by a receptor, such as OATP1B1, which is known to take up ATV, resulting in targeted delivery to RPE.

[0010] The present disclosure, in one embodiment, provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound disclosed herein, e.g., Compound 1, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof.

[0011] The present disclosure, in one embodiment, provides an ocular implant comprising a compound disclosed herein, e.g., Compound 1, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, and a polymer matrix, wherein the compound is dispersed in the polymer matrix and the polymer matrix controls release of the compound.

[0012] The present disclosure, in one embodiment, provides a flowable composition comprising a compound disclosed herein, e.g., Compound 1, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, and a solvent or excipient, wherein the compound is dispersed in a solvent or excipient and the solvent or excipient controls release of the compound.

[0013] The present disclosure, in one embodiment, provides an extended release dosage form comprising a compound disclosed herein, e.g., Compound 1, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein the extended release form administers the compound at a substantially constant drug pressure over a predetermined time period.

[0014] The present disclosure, in one embodiment, provides an extended release dosage form for ocular administration of a compound disclosed herein, e.g., Compound 1, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, an ocular implant or flowable composition comprising the same.

[0015] The present disclosure, in one embodiment, provides a method for treating or preventing hypercholesterolemia in a patient in need thereof, comprising administering a compound disclosed herein, e.g., Compound 1, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, to the patient.

[0016] The present disclosure, in one embodiment, provides a method of treating or preventing age- related macular degeneration (AMD), comprising administering a compound disclosed herein, e.g., Compound 1 , or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, to a patient in need thereof, wherein the compound is administered to the eye in an extended release dosage form, such that the concentration of compound within the eye is substantially maintained at a concentration of from about 1-10 nM for a treatment period of least 1 month.

[0017] The present disclosure, in one embodiment, provides a method of treating or preventing a retinal disease or disorder, comprising administering a compound disclosed herein, e.g., Compound 1, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, to a patient in need thereof.

[0018] The present disclosure, in one embodiment, provides a method of treating or preventing age- related macular degeneration (AMD) comprising administering a compound disclosed herein, e.g., Compound 1 , or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixtureof stereoisomers, or prodrug thereof to a patient in need thereof, optionally wherein the administering is by intravitreal injection.

[0019] The present disclosure, in one embodiment, provides a method of reducing drusen size and / or number comprising administering comprising administering a compound disclosed herein, e.g., Compound 1 , or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof to a patient in need thereof, optionally wherein the administering is by intravitreal injection.

[0020] The present disclosure, in one embodiment, provides a method of preventing, reducing, or reversing complement activation in the eye comprising administering comprising administering a compound disclosed herein, e.g., Compound 1, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof to a patient in need thereof, optionally wherein the administering is by intravitreal injection.

[0021] The present disclosure, in one embodiment, provides a method of treating or preventing age- related macular degeneration (AMD), comprising administering an ultralow daily dose of a compound disclosed herein, e.g., Compound 1, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof to a patient in need thereof over the course of a treatment period.

[0022] The present disclosure, in one embodiment, provides a method for reducing low-density lipoprotein (LDL) in a patient in need thereof, comprising administering a compound disclosed herein, e.g., Compound 1, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, or a pharmaceutical composition or extended release dosage form comprising the same.BRIEF DESCRIPTION OF DRAWINGS

[0023] Fig. 1 shows Compound 1 demonstrated activity in a drusen model.

[0024] Fig. 2 shows Compound 1 is not toxic to RPE.

[0025] Fig. 3 and Fig. 4 show Compound 1 does not directly inhibit HMGCR activity.DETAILED DESCRIPTION

[0026] All numerical designations, e.g., pH, temperature, time, concentration, and molecular weight, including ranges, are approximations which are varied ( + ) or ( - ) by increments of 0.1 or 20%, or 10%. It is to be understood, although not always explicitly stated that all numerical designations are preceded by the term “about”. Reference to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se. In certain embodiments, the term “about” includes the indicated amount + 20%. In certain embodiments, the term “about” includes the indicated amount + 10%. In other embodiments, the term “about” includes the indicated amount + 5%. In certainother embodiments, the term “about” includes the indicated amount ± 1%. It also is to be understood, although not always explicitly stated, that the reagents described herein are merely exemplary and that equivalents of such are known in the art.

[0027] As used herein, the term “hypercholesterolemia” refers to a high blood cholesterol level. Hypercholesterolemia can be defined as the presence of high plasma cholesterol levels, with normal plasma triglycerides, as a consequence of the rise of cholesterol and apolipoprotein B (apoB)-rich lipoproteins, i.e., low-density lipoprotein (LDL).

[0028] As used herein, an “ocular implant” or “implant” refers to a solid device, which is structured, sized, or otherwise configured, to be delivered to an eye. Ocular implants in accordance with the present disclosure are generally biocompatible with physiological conditions of an eye and may not cause adverse side effects or immunological reaction. Ocular implants may be placed in an eye without disrupting vision of the eye. Non-limiting examples include extruded filaments or rods having a diameter and cut to a length suitable for placement in an ocular region of the eye, such as the posterior chamber. In some embodiments, the implants are biodegradable. In some embodiments, the ocular implant is suitable for intravitreal injection (or intravitreal implantation).

[0029] As used herein, an “ocular region” or “ocular site” refers generally to any area of the eyeball, including the anterior and posterior segment of the eye, and which generally includes, but is not limited to, any functional (e.g., for vision) or structural tissues found in the eyeball, or tissues or cellular layers that partly or completely line the interior or exterior of the eyeball. Specific examples of ocular regions in the eye include the anterior chamber, the posterior chamber, the vitreous cavity, the vitreous body, the choroid, the suprachoroidal space, the conjunctiva, the subconjunctival space, the sub-tenon space, the episcleral space, the intracorneal space, the epicorneal space, the sclera, the pars plana, surgically- induced avascular regions, the macula, and the retina.

[0030] An “intravitreal” implant is an implant that is sized for placement in the vitreous body of the eye. The ocular implants disclosed herein are typically syringeable.

[0031] As used herein, a “polymer” is intended to encompass both homopolymers (polymers having only one type of repeating unit) and copolymers (a polymer having more than one type of repeating unit).

[0032] As used herein, a “polymer matrix” refers to a substantially homogeneous mixture of polymers. In other words, the matrix does not include a mixture wherein one portion thereof is different from the other portion by ingredient, density, and etc. The mixture of polymers may be of the same type, e.g. two different PLA polymers, or of different types, e.g. PLA polymers combined with PLGA polymers.

[0033] As used herein, a “flowable composition” refers to a pharmaceutical composition having a consistency that allows the composition to flow readily (e.g., a liquid). The flowable composition can be a solution (e.g., dissolved in a carrier) or a suspension (i.e., particles in a carrier).

[0034] As used herein, “dispersed” means that the compound as disclosed herein is distributed, mixed, suspended, dissolved, and / or homogenized, within the polymer matrix of the ocular implant or the solvent of the flowable composition (e.g., benzyl benzoate). As such, the term dispersed includes solutions, emulsions, suspensions, and other dispersed systems.

[0035] “Substantially” in relation to the release profile or the release characteristic of compound means that the rate of release (e.g., the amount of a compound disclosed herein, e.g., Compound 1, released / unit of time) does not vary by more than 100%, or by more than 50%, over a treatment period. “Substantially” in relation to the blending, mixing or dispersing of an active agent (i.e., a compound disclosed herein, e.g., Compound 1) in a polymer, as in the phrase “substantially homogenously dispersed” means that there is a small difference in concentration of a compound disclosed herein, e.g., Compound 1, throughout the polymer matrix or solvent of the composition (e.g., a homogenous dispersal).

[0036] As used herein, the term “active agent” is intended to refer to a compound disclosed herein, e.g., Compound 1. In some embodiments, the active agent is administered in a composition; thus the term “active agent” also can include compositions comprising a compound disclosed herein, e.g., Compound 1.

[0037] The term “biodegradable,” as used herein, means that the ocular implant or flowable composition is capable of being broken down into innocuous products in the normal functioning of the body.

[0038] The term “non-biodegradable,” as used herein, means that the ocular implant or flowable composition is not capable of being broken down in the body.

[0039] “Alkylene” refers to a linear or branched saturated divalent hydrocarbon chain. As used herein, alkylene has 1 to 10 carbon atoms (i.e., Ci-io alkylene), 2 to 8 carbon atoms (i.e., C2-8 alkylene), 2 to 6 carbon atoms (i.e., C2-6 alkylene) or 2 to 4 carbon atoms (i.e., C2-4 alkylene).

[0040] “Pharmaceutically acceptable” refers to compounds, salts, compositions, dosage forms and other materials which are useful in preparing a pharmaceutical composition that is suitable for veterinary or human pharmaceutical use.

[0041] “Pharmaceutically acceptable excipient” includes without limitation any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier which has been approved by the United States Food and Drug Administration as being acceptable for use in humans or domestic animals.

[0042] “Pharmaceutically acceptable salt” refers to a salt of a compound that is pharmaceutically acceptable and that possesses (or can be converted to a form that possesses) the desired pharmacological activity of the parent compound. Such salts include acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citricacid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, lactic acid, maleic acid, malonic acid, mandelic acid, methanesulfonic acid, 2-napththalenesulfonic acid, oleic acid, palmitic acid, propionic acid, stearic acid, succinic acid, tartaric acid, p-toluenesulfonic acid, trimethylacetic acid, and the like, and salts formed when an acidic proton present in the parent compound is replaced by either a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as diethanolamine, triethanolamine, N-methylglucamine and the like. Also included in this definition are ammonium and substituted or quaternized ammonium salts. Representative nonlimiting lists of pharmaceutically acceptable salts can be found in S. M. Berge et al., J. Pharma Sci., 66(1), 1-19 (1977), and Remington: The Science and Practice of Pharmacy, R. Hendrickson, ed., 21st edition, Lippincott, Williams & Wilkins, Philadelphia, PA, (2005), at p. 732, Table 38-5, both of which are hereby incorporated by reference herein.

[0043] Compounds disclosed herein include isotopically labeled, solvates, hydrates, tautomers, stereoisomers and salt forms thereof.

[0044] Provided are also isotopically enriched analogs, i.e., compounds in which from 1 to n hydrogen atoms attached to a carbon atom may be replaced by deuterium atom or D, in which n is the number of hydrogen atoms in the molecule. As known in the art, the deuterium atom is a non-radioactive isotope of the hydrogen atom. Such compounds exhibit may increase resistance to metabolism, and thus may be useful for increasing the half-life of the compounds when administered to a mammal. See, e.g., Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism,” Trends Pharmacol. Sci., 5(12):524-527 (1984). Such compounds are synthesized by means well known in the art, for example by employing starting materials in which one or more hydrogen atoms have been replaced by deuterium.

[0045] The present disclosure also provides for prodrugs of the compounds disclosed herein. A “prodrug” is defined in the pharmaceutical field as a biologically inactive derivative of a drug that upon administration to the human body is converted to the biologically active parent drug according to some chemical or enzymatic pathway.Compounds

[0046] In certain embodiments, provided is a compound of Formula I:or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein L is Ci-io alkylene.

[0047] In certain embodiments, L is C2-10 alkylene. In certain embodiments, L is C2-8 alkylene. In certain embodiments, L is C2-7 alkylene. In certain embodiments, L is C2-6 alkylene. In certain embodiments, L is C3-6 alkylene. In certain embodiments, L is C35 alkylene.

[0048] In certain embodiments, provided is a compound of Formula IA:or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein n is 0, 1, 2, 3, 4, 5, 6, 7, or 8.

[0049] In certain embodiments, n is 1, 2, or 3. In certain embodiments, n is 1. In certain embodiments, n is 2. In certain embodiments, n is 3. In certain embodiments, n is 4. In certain embodiments, n is 5. In certain embodiments, n is 6. In certain embodiments, n is 7. In certain embodiments, n is 8.

[0050] In certain embodiments, provided is 3-hydroxypropyl (3R,5R)-7-(2-(4-fluorophenyl)-5- isopropyl-3-phenyl-4-(phenylcarbamoyl)-lH-pyrrol-l-yl)-3,5-dihydroxyheptanoate (Compound 1) having the structure:or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof.

[0051] In certain embodiments, provided is a compound of Table 1, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof:

[0052] Reference to the “compounds described herein,” including but not limited to, Compound 1, is intended to include isomers, stereoisomers and the like. As used herein, the term “isomers” refers to different compounds that have the same molecular formula but differ in arrangement and configuration of the atoms. Also as used herein, the term “a stereoisomer” refers to any of the various stereo isomeric configurations which may exist for a given compound disclosed herein and includes geometric isomers. It is understood that a substituent may be attached at a chiral center of a carbon atom. Therefore, the compound disclosed herein includes enantiomers, diastereomers, or racemates of the compound.

[0053] ‘ ‘Enantiomers” are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a “racemic” mixture.

[0054] The term is used to designate a racemic mixture where appropriate. “Diastereoisomers” are stereoisomers that have at least two stereocenters, but which are not mirror-images of each other.Methods of Treatment

[0055] Provided herein are methods for treating or preventing certain diseases or disorders associated with high or excess cholesterol levels in a patient. As used herein, the terms “treating,” “treatment,” and the like are used herein to mean obtaining a desired pharmacologic and / or physiologic effect. The effect may be prophylactic in terms of completely or partially preventing a disorder or sign or symptom thereof, and / or may be therapeutic in terms of a partial or complete cure for a disorder and / or adverse effect attributable to the disorder.

[0056] In certain embodiments, the invention provides methods of treating an individual comprising administering one or more pharmaceutical compositions as described herein. A “pharmaceutical composition” is intended to include the combination of one or more compounds disclosed herein, e.g., Compound 1, with one or more carriers, inert or active, making the composition suitable for therapeutic use in vitro, in vivo or ex vivo. “An effective amount” refers to the amount of an agent sufficient to induce a desired biological and / or therapeutic result. That result can be alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system.

[0057] In certain embodiments, the individual has age-related macular degeneration (AMD), hypercholesterolemia, mixed dyslipidemia, atherosclerosis, a risk of developing atherosclerosis, coronary heart disease, a history of coronary heart disease, early onset coronary heart disease, acute coronary syndrome, one or more risk factors for coronary heart disease, type II diabetes, type II diabetes with dyslipidemia, dyslipidemia, hypertriglyceridemia, hyperlipidemia, hyperfattyacidemia, hepatic steatosis, non-alcoholic steatohepatitis, or non-alcoholic fatty liver disease. It is also contemplated that the pharmaceutical compositions as described herein may be used to treat cancer, sepsis, infectious disease, glaucoma, and other ophthalmic diseases as well.

[0058] In certain embodiments, provided is a method for treating or preventing one or more diseases or disorders selected from age-related macular degeneration (AMD), hypercholesterolemia, mixed dyslipidemia, atherosclerosis, coronary heart disease, acute coronary syndrome, type II diabetes, dyslipidemia, hypertriglyceridemia, hyperlipidemia, hyperfattyacidemia, hepatic steatosis, non-alcoholic steatohepatitis, non-alcoholic fatty liver disease, cancer, sepsis, infectious disease, glaucoma, or other ophthalmic disease in a patient in need thereof, comprising administering a compound according to any one of claims 1-4, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, or the pharmaceutical composition of claim 5, to the patient.AMD / Drusen

[0059] The methods provided can be used to slow growth of and / or regress drusen (e.g., soft drusen), to slow growth of and / or regress drusenoid pigment epithelial detachments (PEDs), to slow and / or prevent atrophy of any or all layers of the retina (e.g. the RPE), to slow and / or prevent atrophy of one or morephotoreceptors, to slow and / or prevent loss of visual function, to improve visual acuity, to prevent AMD, to slow and / or prevent progression from early AMD to intermediate AMD, to slow and / or prevent progression from intermediate AMD to Geographic Atrophy and / or to wet AMD.

[0060] Age-related changes to the retina and the choroid of the eye which contribute to and comprise the development of age-related macular degeneration (AMD) include changes in Bruch’s Membrane permeability, accumulation of drusen, the loss of rod photoreceptors, the thinning of the choroid, and the accumulation of lipofuscin and reportedly components thereof (e.g., A2E (N-retinylidene-N-retinyl- ethanolamine)) in the retinal pigment epithelium (RPE) as well as lipids in the sub-RPE basal lamina (sub-RPE-BL) space and anterior to and / or within Bruch’s membrane (BrM). Cholesterol rich lipoprotein particles and other constituents accumulate, forming basal linear deposits (BLinD) and drusen on the BrM. The RPE secretes apolipoproteins including but not limited to apolipoprotein B and / or E (apoB, apoE)-containing lipoprotein particles onto BrM, where they accumulate with age and eventually form a lipid-rich layer on BrM. This lipid-rich layer is frequently referred to as BLinD and / or a druse (plural drusen). Drusen negatively impact the health and function of the RPE as they inhibit nutrient exchange with the choroid and create a hypoxic environment for the highly metabolically active RPE. As the RPE is responsible for photoreceptor maintenance, the accumulation and increased thickness of drusen lead to RPE dysfunction and death, which in turn leads to death of photoreceptors and results in blindness. While anti-VEGF therapy has proven effective for treating the neovascular or “wet” form of AMD, the more common “dry” form has limited effective therapies and is a leading cause of blindness. Drusen underlie the pathogenesis of both wet and dry AMD and are thus an important target.

[0061] Drusen are extracellular deposits rich in lipids (e.g., esterified cholesterol (EC) and phospholipids) and lipoprotein components (e.g., apoB and / or apoE) and form in the sub-RPE-BL space between the RPE-BL and the inner collagenous layer of the BrM, possibly as a result of RPE secretion of EC-rich lipoprotein particles, which resemble low density lipoproteins (LDLs) and / or very low-density lipoproteins (VLDLs) basolaterally. “Hard” drusen are small, distinct and far away from one another, and may not cause vision problems for a long time, if at all. In contrast, “soft” drusen are large, have poorly defined edges, and cluster closer together. Soft drusen are more fragile than hard drusen, are oily upon dissection due to a high lipid constitution, and are a major risk factor for the development of advanced atrophic or neovascular AMD. Esterified cholesterol and phospholipids (in the form of lipoprotein particles of 50-80 nm diameter) accumulate in the BrM and the sub-RPE-BL space throughout adulthood and eventually aggregate as BLinD on the BrM or soft drusen in the sub-RPE-BL space of older eyes. Soft drusen and BLinD are two forms (a lump and a thin layer, respectively) of the same lipid-rich extracellular lesion containing lipoprotein-derived debris and specific to AMD. Lipid constituents of soft drusen and BLinD interact with reactive oxygen species to form pro-inflammatory peroxidized lipids (or lipid peroxides), which inhibit paraoxonase 1 activity, activate the complement system and elicit choroidal neovascularization. Furthermore, drusen contain immunogenic complement components. EC-rich, apoB / apoE-containing lipoproteins (e.g., LDLs, and / or LDL-like particles and / orVLDLs and / or VLDL-like particles) secreted by RPE cells are retained by a BrM that progressively thickens with age, until an oily layer forms on the BrM, with oxidation of lipids or other modifications followed by fusion of individual lipoproteins over time to form BLinD. An inflammatory response to the accumulated material ensues with activation of the complement system and other components of the immune system. Moreover, by altering the BrM with subsequent calcification and fracture, the accumulation of lipid-containing material leads to neovascularization in the sub-RPE-BL space and breakthrough to the subretinal space, the potential space between the photoreceptors and the RPE. Furthermore, the lipid-rich drusen in the sub-RPE-BL space and BLinD overlying the BrM block oxygen and nutrients (including vitamin A) from reaching the RPE cells and the photoreceptors (rods and cones) in the retina, which results in their atrophy / degeneration and eventually death.

[0062] Chronic inflammatory responses to the changes described above include complement- mediated pathways, infiltration by circulating macrophages, and activation of inflammasomes and microglia. Activation of the complement cascade leads to activation of the central component 3 (C3) and initiation of the terminal pathway with the cleavage of component 5 (C5) into C5a and C5b. The terminal pathway results in the assembly of a membrane attack complex (MAC), e.g., in the basal RPE membrane, the BrM or the choriocapillary endothelial cell membrane, by stepwise binding of C5b, C6, C7, C8 and polymerized C9 to form a pore in the lipid bilayer of the membrane. The MAC can lead to the dysfunction and death of the RPE, the BrM and / or the choriocapillary endothelium, with outer retinal atrophy ensuing. In addition, C5a elicits pro-inflammatory and pro-angiogenic effects, and combined with calcification and fracture of the BrM, can contribute to NV, including choroidal NV (CNV).

[0063] The early stage of AMD (which is atrophic AMD) is characterized by the presence of a few small to medium-size drusen and pigmentary abnormalities such as hyperpigmentation or hypopigmentation of the RPE. The intermediate stage of AMD is characterized by the presence of at least one of one large druse, multiple medium-size drusen, hyperpigmentation and / or hypopigmentation of the RPE, either without geographic atrophy (GA), or with geographic atrophy (GA) that does not extend to the center of the macula (non-foveal GA). GA represents the loss of photoreceptor, RPE and choriocapillaris, resulting in a sharply defined atrophic lesions visually resembling geographic areas on a map. In GA, RPE below the retina atrophies, which causes vision loss through the death of photoreceptors. RPE atrophy can result from a large accumulation of drusen and / or BLinD that contributes to the death of the overlying RPE, as the drusen become thick and the RPE is far removed from the choriocapillaris. Drusen may include calcification in the form of hydroxyapatite, and may progress to complete calcification, at which stage RPE cells have died. The RPE-BL thickens in a stereotypic manner to form basal laminar deposits (BLamD); RPE cells hence reside on a thick layer of BLamD. Junctions between the normally hexagonal-shaped RPE cells may be perturbed, and individual RPE cells may round up, stack and migrate anteriorly into the neurosensory retina, at which point the RPE cells become farther removed from their supply of nutrients and oxygen in the choriocapillaris. Once RPE cells begin the anterior migration, the overall RPE layer begins to atrophy.

[0064] Sub-RPE-BL drusen elevate the RPE off the BrM and thereby can cause mild vision loss, including metamorphopsia (a vision defect in which objects appear to be distorted) through disturbance of overlying photoreceptors and slowing of rod-mediated dark adaptation. Non-central GA spares the fovea and thus preserves central vision. However, patients with non-central GA can experience visual disturbances due to paracentral blind spots (scotomas), which can impair vision in dim light, decrease contrast sensitivity and impair reading ability.

[0065] The most advanced stage of nonexudative AMD is characterized by the presence of drusen and GA that extends to the center of the macula (central or subfoveal GA). Central GA involves the fovea and thus results in significant loss of central vision and visual acuity.

[0066] The advanced stage of AMD that becomes neovascular or “wet” AMD is characterized by neovascularization and any of its potential sequelae, including leakage (e.g., of plasma), plasma lipid and lipoprotein deposition, sub-RPE-BL, subretinal and intraretinal fluid, hemorrhage, fibrin, fibrovascular scars and RPE detachment. In CNV, new blood vessels grow up from the choriocapillaris and through the BrM, which causes vision loss via the aforementioned sequelae. There are three types of neovascularization (NV). Type 1 NV occurs in the sub-RPE-BL space, and new blood vessels emanate from the choroid under the macular region. Type 2 NV occurs in the subretinal space above the RPE, and new blood vessels emanate from the choroid and break through to the subretinal space. In types 1 and 2 NV, new blood vessels cross the BrM and may ramify in the pro-angiogenic cleavage plane created by soft drusen and BLinD. Type 3 NV (retinal angiomatous proliferation) occurs predominantly within the retina (intraretinal), but can also occur in the subretinal space, and new blood vessels emanate from the retina with possible anastomoses to the choroidal circulation. Type 3 NV is the most difficult subtype of NV to diagnose and has the most devastating consequences for photoreceptor health, but type 3 NV responds well to treatment with an anti-VEGF agent. A neovascular AMD patient can also have a combination of subtypes of NV, including type 1 plus type 2, type 1 plus type 3, and type 2 plus type 3. The approximate occurrence of the different subtypes of NV among newly presenting neovascular AMD patients is: 40% type 1, 9% type 2, 34% type 3, and 17% mixed (of the mixed, 80% type 1 plus type 2, 16% type 1 plus type 3, and 4% type 2 plus type 3). Another form of NV is polypoidal vasculopathy, which is of choroidal origin and is the most common form of NV among Asians, whose eyes generally have few drusen but may have BLinD. The RPE can become detached from the BrM in each subtype of NV. For instance, leakage of fluid from neovessels into the sub-RPE-BL space in type 1 NV can result in pigment epithelium detachment. The new blood vessels generated by NV are fragile, leading to leakage of fluid, blood and proteins below the macula. Leakage of blood into the subretinal space is particularly toxic to photoreceptors, and intraretinal fluid signifies a poor prognosis for vision. Bleeding and leaking from the new blood vessels, with subsequent fibrosis, can cause irreversible damage to the retina and rapid vision loss if left untreated.

[0067] In the early, intermediate and advanced stages of AMD, and in atrophic AMD and neovascularAMD, the progression and treatment of AMD can be monitored using various imaging methods known inthe art (called “diagnostic” methods herein for simplicity). Such imaging methods include structural Spectral Domain Optical Coherence Tomography (SDOCT), which reveals drusen and RPE and can allow quantification of total drusen volume and monitoring the progression of the disease), color fundus photography, fundus autofluorescence (which can detect fluorophores unique to drusen and basal linear deposits), quantitative fundus autofluorescence (qAF, which relies on both blue and green autofluorescence imaging), OCT- angiography (OCT- A, which can detect the presence of sub-RPE-BL, subretinal or intraretinal fluid consistent with active neovascularization), and fluorescein angiography (which can demonstrate the types of CNV lesions). Functional measures can assess cone -mediated vision (e.g., best-corrected visual acuity [BCVA, which persists until late in the disease] on Early Treatment Diabetic Retinopathy Study (ETDRS) or Snellen charts, contrast sensitivity using a Pelli-Robson chart and other methods, low-luminance visual acuity [visual acuity measured with a neutral-density filter to reduce retinal illuminance] and rod-mediated vision (e.g., rod intercept time on dark adaptation testing, which is a sensitive measure of macular function that tracks with progression of the early disease]). For example, treatment is expected to reduce loss of and / or keep stable, and / or improve, photopic (daylight) vision mediated by cone photoreceptors and scotopic (night) vision mediated by rod photoreceptors. As another example, the loss of RPE cells can be assessed by the area of hypoautofluorescence on qAF, which can demonstrate reduced RPE area loss or stability. GA area on qAF is an FDA-approved endpoint for this stage of AMD, and has been used to monitor the progression of non-central GA or central GA and response to investigational therapies in clinical trials. The health of RPE cells can also be assessed with SDOCT. The presence of hyper-reflective foci located vertically above drusen within the retina indicates migratory RPE cells or pigmented monocytic cells and constitute a strong predictor of future atrophy of RPE cells and photoreceptors. Poor RPE health can be an indicator of poor visual outcome in both nonexudative and exudative AMD.

[0068] As with dosage per administration, total dosage over a period of about 1 month, total dosage over a period of about 6 months, total dosage for the entire treatment regimen, dosing frequency and total number of administrations, the duration / length of treatment with the active agent can be adjusted if desired and can be selected by the treating physician to minimize treatment burden and to achieve desired outcome(s), such as reduction of lipid deposits to a desired level (e.g., the presence of a few medium-size drusen or the absence of any large druse) and elimination or reduction of geographic atrophy (non-central or central) to a desired level. In some embodiments, the treatment regimen with the active agent lasts for about 24 months or less, 18 months or less, 12 months or less, or 6 months or less. In further embodiments, the treatment regimen with the active agent lasts for about 18-24 months, 12-18 months, 6- 12 months, or 1-3 months. Treatment with the active agent can also last longer than 24 months (2 years), such as up to about 3 years, 4 years, 5 years or longer. In some embodiments, the treatment regimen with the active agent lasts for about 24, 21, 18, 15, 12, 9 or 6 months. In certain embodiments, the treatment regimen with the active agent lasts for about 6-12 or 12-24 months. In additional embodiments, the treatment regimen with the active agent lasts at least about 6, 12, 24 or 36 months or longer (e.g., at least about 12 months).

[0069] In some embodiments, the active agent (i.e., compound disclosed herein or composition comprising the same) is administered at an initial dose with a treatment regimen of about once per month, and then the dose interval is extended to greater than one month, e.g., every 6 weeks, or 2 months, or 3 months. In some embodiments, the active agent is administered at an initial dose with a treatment regimen of about once per month, and then the dose is tapered to a lower dose after the first 1-3 doses.

[0070] In some embodiments, the compound, or composition comprising the same, is administered in an interval of once per month, once per three months, once per six months, once per year, or a combination thereof. In some embodiments, the compound or composition is administered at a shorter interval for a time period (e.g., every 3 months for a total of 6-12 months), followed by a longer interval (e.g., once per year, or longer).

[0071] In some embodiments, the active agent is administered at least in the advanced stage of AMD. In certain embodiments, the active agent is administered at least in the advanced stage of AMD to treat or slow the progression of central geographic atrophy (GA), and / or to prevent or delay the onset of neovascular AMD. In further embodiments, the active agent is administered at least in the advanced stage of AMD to treat or slow the progression of neovascular AMD (including types 1 , 2 and / or 3 neovascularization) .

[0072] In additional embodiments, the active agent is administered at least in the intermediate stage of AMD. In certain embodiments, the active agent is administered at least in the intermediate stage of AMD to treat or slow the progression of non-central GA, and / or to prevent or delay the onset of central GA and / or neovascular AMD. In further embodiments, the active agent is administered at least in the early phase of intermediate AMD to prevent or delay the onset of non-central GA. The intermediate stage of AMD is characterized by the presence of at least one of one large druse, multiple medium-size drusen, hyperpigmentation and / or hypopigmentation of the RPE, either without geographic atrophy (GA), or with geographic atrophy (GA) that does not extend to the center of the macula (non-foveal GA). Reduction of confluent soft drusen in intermediate AMD using the active agent can result in decrease in the thickness and normalization of the Bruch’s membrane, as well as renewal of the overlying RPE cell layer due to improved exchange of incoming oxygen and nutrients and outgoing waste between the choriocapillaris and the RPE. Reduction of confluent soft drusen can be observed by SDOCT.

[0073] In further embodiments, the active agent is administered at least in the early stage of AMD. The active agent can be administered at an earlier stage (e.g., the early stage or the intermediate stage) of AMD to slow or stop the progression of AMD. In some embodiments, the active agent is administered at least in the early stage of AMD to prevent or delay the onset of non-central GA. The active agent does not need to eliminate or remove all or most of the abnormal lipid deposits from the eye to have a therapeutic or prophylactic effect in AMD. If a threshold amount of abnormal lipids is cleared from the eye, natural transport mechanisms, including traffic between the choriocapillaris endothelium and the RPE layer, can properly work again and can clear remaining abnormal lipids from the eye. Furthermore,lipids accumulate in the eye slowly over a period of years (although fluctuations in druse volume in a shorter time frame are detectable).

[0074] The active agent can be administered in a stage (e.g., the early, intermediate or advanced stage) of AMD for a length of time selected by the treating physician (e.g., at least about 1 month, at least about 2 months, at least about 3 months, 6 months, 12 months, 18 months, 24 months or longer) or until the disease has been successfully treated according to selected outcome measure(s) (e.g., elimination of all or most soft drusen or reduction of soft drusen volume to a certain level).

[0075] The implants and compositions provided herein can be employed for one or more of the following: 1) reduction of drusen (including soft drusen) size (e.g., diameter or volume), number or amount (e.g., by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 99%); 2) prevention or resolution of drusenoid PEDs (e.g., promotion of re-attachment of the RPE- BL to the BrM ICL, or flattening of a PED or decrease in the separation / distance between the detached RPE-BL and the BrM ICL by at least about 50%, 60%, 70%, 80%, 90%, 95% or 99%); 3) enhancement of the phagocytic function (e.g., phagocytosis of drusen and other undesired matter) of RPE cells (e.g., increase in the percentage of phagocytic RPE cells by at least about 33%, 50%, 66%, 80% or 100%); 4) prevention or curtailment of atrophy and death of RPE cells and photoreceptors (e.g., reduction of the area of noncentral and / or central geographic atrophy by at least about 30%, 40%, 50%, 60%, 70%, 80% or 90%); 5) prevention or forestalling of progression to or development of intermediate atrophic AMD, advanced atrophic AMD or neovascular AMD; 6) prevention or curtailment of vision loss (e.g., reduction of loss of visual acuity to no more than about 5, 4, 3, 2 or 1 letter); and 7) improvement of visual acuity (e.g., by at least about 3, 6, 9 or 12 letters).

[0076] In some embodiments, the compounds and compositions provided herein may be used to slow or retard disease progression (e.g., AMD) as measured by one or more of the following: 1) reduction or slowing of drusen formation (including soft drusen), such as size (e.g., diameter or volume), number, or amount (e.g., by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 99%); 2) prevention or resolution of drusenoid PEDs (e.g., promotion of re-attachment of the RPE- BL to the BrM ICL, or flattening of a PED or decrease in the separation / distance between the detached RPE-BL and the BrM ICL by at least about 50%, 60%, 70%, 80%, 90%, 95% or 99%); 3) enhancement of the phagocytic function (e.g., phagocytosis of drusen and other undesired matter) of RPE cells (e.g., increase in the percentage of phagocytic RPE cells by at least about 33%, 50%, 66%, 80% or 100%); 4) prevention or curtailment of atrophy and death of RPE cells and photoreceptors (e.g., reduction of the area of noncentral and / or central geographic atrophy by at least about 30%, 40%, 50%, 60%, 70%, 80% or 90%); 5) prevention or forestalling of progression to or development of intermediate atrophic AMD, advanced atrophic AMD or neovascular AMD; 6) prevention or curtailment of vision loss (e.g., reduction of loss of visual acuity to no more than about 5, 4, 3, 2 or 1 letter); and 7) improvement of visual acuity (e.g., by at least about 3, 6, 9 or 12 letters).

[0077] One or more of the active agents described herein can also be used to treat other eye diseases and disorders in addition to AMD. Non-limiting examples of other eye diseases and disorders that can be treated with one or more active agents described herein include age-related macular degeneration, macular drusen (small, intermediate, large), peripheral drusen, extramacular drusen, drusenoid pigment epithelial detachment (PED), drusenoid deposits, basal laminar deposits, basal linear deposits, doyne honeycomb retinal dystrophy, Malattia Leventinese, familial dominant drusen (or autosomal dominant drusen), cuticular drusen, serous detachment of RPE, drupelets, RPE atrophy, geographic atrophy, ellipsoid zone (EZ) attenuation, EZ loss, incomplete retinal pigment epithelial and outer retinal atrophy (iRORA), complete retinal pigment epithelial and outer retinal atrophy (cRORA), nascent geographic atrophy, retinal flecks, fundus flavimaculatus, Best disease, adult-onset vitelliform macular dystrophy, Best vitelliform macular dystrophy, autosomal recessive bestrophinopathy, vitelliform material, pattern dystrophy, autosomal dominant vitreoretinochoroidopathy, BEST1 gene mutation disorders, retinal emboli (in retinal artery occlusion), retinal exudates, retinal exudates secondary to retinal microaneurysm, familial exudative vitreoretinopathy (FEVR), synchysis scintillans (cholesterolosis bulbi), neuronal ceroid lipofuscinosis, Batten's Disease, retinitis pigmentosa, Bietti’s crystalline dystrophy juvenile macular degeneration (e.g., Stargardt disease), macular telangiectasia, maculopathy (e.g., age-related maculopathy (ARM) and diabetic maculopathy (DMP) (including partial ischemic DMP)), macular edema (e.g., diabetic macular edema (DME) (including clinically significant DME, focal DME and diffuse DME), Irvine-Gass Syndrome (postoperative macular edema), and macular edema following RVO (including central RVO and branch RVO)), retinopathy (e.g., diabetic retinopathy (including in patients with DME), Purtscher's retinopathy and radiation retinopathy), retinal artery occlusion (RAO) (e.g., central and branch RAO), retinal vein occlusion (RVO) (e.g., central RVO (including central RVO with cystoid macular edema (CME)) and branch RVO (including branch RVO with CME)), glaucoma (including low-tension, normal-tension and high-tension glaucoma), ocular hypertension, retinitis (e.g., Coats’ disease (exudative retinitis) or retinitis pigmentosa), chorioretinitis, choroiditis (e.g., serpiginous choroiditis), uveitis (including anterior uveitis, intermediate uveitis, posterior uveitis with or without CME, and pan-uveitis), retinal detachment (e.g., in von Hippel-Lindau disease), retinal pigment epithelium (RPE) detachment, bestrophinopathy, Doyne honeycomb / dominant drusen, and diseases associated with increased intra- or extracellular lipid storage or accumulation in addition to AMD.

[0078] The implants and compositions provided herein can provide prevention of loss, slowing of loss, or improvement, in one or more of the following: metamorphopsia on Amsler grid (resolve; no distortion in straight lines from previous distortion); metamorphopsia on ForeSee Home, notal vision device (resolve; line with no distortion viewed on the device, from previous line with distortion. The trend score no longer exceeds the test score change threshold); best corrected visual acuity (BCVA) or prevention of loss of BCVA (0-100 ETDRS letters); color vision (cone contrast test 0-100% of normal, 100% being normal. Farnsworth or Lanthony D-15: confusion index 1-3, with 1 being normal and 3 abnormal, total error score 11-40, 11 being normal and 40 abnormal); visual field testing (per eye: maximum is 160° inhorizontal plane and 135° in the vertical plane); scotoma / visual field loss (0 to 160° horizontal, 0 to 135°); macular sensitivity on microperimetry testing (MAIA MP: 0-36 dB, Nidek MP: 0-20 dB); dark adaptation (rod intercept time RIT from 0 to >30 min; normal RIT is considered <6.5 min, abnormal > 6.5 min); change in reading speed from baseline under standard and low luminance conditions (0-38 words / minute); contrast sensitivity (MARS chart has log scale abnormal 0 to 1.92 normal, Pelli Robson 0 abnormal to 2 normal); ellipsoid zone (EZ) attenuation or loss (0 to 28.3 mm2); full field electro- retinogram (ERG): a-wave implicit times (normal 15-16.5 Hz, abnormal >16.5 (to 19 Hz), flicker peak times (normal 29-30.5 Hz, abnormal 30.5 to 35 Hz); multifocal ERG testing: response amplitude normal 27-30 nV, abnormal <27 nV, implicit time normal < 29 ms, abnormal 29-33 ms; electro-oculogram (EOG) testing (Arden ratio: abnormal 0 to 1.8, 1.8 to 2 borderline, >2 normal); Size of window defects on fluorescein angiogram (GA) (0 to 17.5 mm2); NEI-VFQ (worst 0 worst to 100 best); low luminance questionnaire (worst 0 to 100 best, abnormal < 80); and functional reading independence (FRI; score 1- 4).

[0079] The compositions and methods provided herein can be employed to achieve one or more of the following: decrease in number of hyper-reflective foci (1- infinity, typically 5-20 per OCT 6x6 mm volume); decrease or prevention of increase in vitelliform material height / volume (height 0-1200 mm, typically around 200-250 mm and volume 0.5 mm3); decrease or prevention of increase in drusen volume (0 to 0.03 mm3normal, over 0.03 mm3at high risk of late AMD; range 0- 0.5 mm3; decreased unesterified cholesterol in the RPE; normalization of distribution of the esterified cholesterol from the Bruch’s membrane to the photoreceptor outer segments; decreased levels of 4-hydroxy-2-nonenal (HNE) adducts (lipid peroxidation by-products) in the retina; prevention of or regression of retraction of apical microvilli of RPE cells; prevention of pseudohyopyon (clinical assessment); decrease in or prevention of increase of yellows dots / flecks, punctate white opacities (typically 0 to 100); prevention of retinal arteriolar narrowing (narrow artery < 50 mm); prevention of optic nerve pallor (pallor scale 0 to 4); prevention or regression of thickening of cone outer segments (0 to 2.5 mm); decrease in hyperautofluorescent lesions (0 -100); prevention or decrease of sub-RPE fibrosis; prevention of RPE atrophy (0 to 28.3 mm2, measured on qAF imaging); prevention of pigment epithelial detachment (serous, vascular or drusenoid); prevention of geographic atrophy (0 to 17.5 mm2, measured on qAF imaging); prevention of choroidal neovascularization (as defined on FA by CNV and OCT by subretinal / intraretinal fluid); prevention of macular holes; decrease in or prevention of subretinal hemorrhage, subretinal fluid, intraretinal fluid; decrease in or prevention of macular edema (intraretinal cysts 0 to 200); prevention of iRORA, cRORA (by case definitions), treatment of neovascular AMD, prevention of neovascular AMD, slowed progression of neovascular AMD, prevention of progression of disease, slowing progression of disease, improved visual acuity, stabilization of visual acuity, improvement of visual field as measured using Amsler grid, reduction of drusen size, reduction of drusen volume, reduction in number of drusen, elimination of drusen, improvement in ocular coherence tomography metrics, reduction and / or elimination of basal laminar deposits, reduction of anti-VEGFtreatments, reduction of complement-related treatments, prevention of geographic atrophy, prevention of drusen formation, and reduction in rate of GA growth.

[0080] The implants and compositions provided herein can be employed to treat or prevent one or more of the following indications (e.g., retinal diseases and disorders): age-related macular degeneration, macular drusen (small, intermediate, large), peripheral drusen, extramacular drusen, drusenoid pigment epithelial detachment (PED), drusenoid deposits, basal laminar deposits, basal linear deposits, Doyne honeycomb retinal dystrophy (Malattia Leventinese, familial dominant drusen or autosomal dominant drusen), cuticular drusen, serous detachment of RPE, drupelets, RPE atrophy, geographic atrophy, total and partial ellipsoid zone (EZ) attenuation, EZ loss, incomplete retinal pigment epithelial and outer retinal atrophy (iRORA), complete retinal pigment epithelial and outer retinal atrophy (cRORA), nascent geographic atrophy, Stargardt disease, retinal flecks, fundus flavimaculatus, Best disease, bestrophinopathy, adult-onset vitelliform macular dystrophy, Best vitelliform macular dystrophy, autosomal recessive bestrophinopathy, vitelliform material, pattern dystrophy, autosomal dominant vitreoretinochoroidopathy, BEST1 gene mutation disorders, retinal emboli (in retinal artery occlusion), retinal exudates, Coat’s disease, retinal exudates secondary to retinal microaneurysm, familial exudative vitreoretinopathy (FEVR), synchysis scintillans (cholesterolosis bulbi), neuronal ceroid lipofuscinosis, Batten's Disease, retinitis pigmentosa, and Bietti’s crystalline dystrophy.

[0081] The implants and compositions of the present disclosure may also be used for treating an ocular disease is selected from the group consisting of glaucoma, diabetic retinopathy (DR), retinal vein occlusion (RVO), and retinopathy of prematurity (ROP).

[0082] In some embodiments, provided is a method of treating or preventing age-related macular degeneration (AMD), comprising administering an ultralow daily dose of a compound disclosed herein, e.g., Compound 1, to a patient in need thereof over the course of a treatment period.Hypercholesterolemia

[0083] As used herein, the term “hypercholesterolemia” refers to a high blood cholesterol level. Hypercholesterolemia can be defined as the presence of high plasma cholesterol levels, with normal plasma triglycerides, as a consequence of the rise of cholesterol and apolipoprotein B (apoB)-rich lipoproteins, called low-density lipoprotein (LDL). According to the WHO definition (1970), hypercholesterolemia would be included in Ila phenotype.

[0084] In certain embodiments, an LDL of less than 70 mg / dL has emerged as desirable in some very high-risk populations. In certain embodiments, an LDL of less than 100 mg / dL would now be considered optimal in such patients.

[0085] The limits to define hypercholesterolemia can be established according to plasma levels of total and LDL cholesterol (LDL-C) above the 95th percentile corrected for age and gender in each population.

[0086] Guidelines for lipid-lowering therapy were established in 2001 by Adult Treatment Panel III (ATP III) of the National Cholesterol Education Program (NCEP), and updated in 2004 (Grundy et al., Circulation, 2004, 110, 227-239). The guidelines include obtaining a complete lipoprotein profile, typically after a 9 to 12 hour fast, for determination of LDL-C, total cholesterol, and HDL-C levels. According to the most recently established guidelines, LDL-C levels of 130-159 mg / dL, 160-189 mg / dL, and greater than or equal to 190 mg / dL are considered borderline high, high, and very high, respectively. Total cholesterol levels of 200-239 and greater than or equal to 240 mg / dL are considered borderline high and high, respectively. HDL-C levels of less than 40 mg / dL are considered low.

[0087] In certain embodiments, the individual has been identified as in need of lipid-lowering therapy. In certain such embodiments, the individual has been identified as in need of lipid-lowering therapy according to the guidelines established in 2001 by Adult Treatment Panel III (ATP III) of the National Cholesterol Education Program (NCEP), and updated in 2004 (Grundy et al., Circulation, 2004, 110, 227-239). In certain such embodiments, the individual in need of lipid-lowering therapy has LDL-C above 190 mg / dL. In certain such embodiments, the individual in need of lipid-lowering therapy has LDL-C above 160 mg / dL. In certain such embodiments, the individual in need of lipid-lowering therapy has LDL-C above 130 mg / dL. In certain such embodiments, the individual in need of lipid-lowering therapy has LDL-C above 100 mg / dL. In certain such embodiments, the individual in need of lipid- lowering therapy should maintain LDL-C below 160 mg / dL. In certain such embodiments, the individual in need of lipid-lowering therapy should maintain LDL-C below 130 mg / dL. In certain such embodiments, the individual in need of lipid-lowering therapy should maintain LDL-C below 100 mg / dL. In certain such embodiments, the individual should maintain LDL-C below 70 mg / dL or even below 50 mg / dL.Extended Release Dosage Forms

[0088] In some embodiments, a compound disclosed herein, e.g., Compound 1 ,is administered to an eye of the patient as an extended release dosage form.

[0089] In some embodiments, the ultralow daily dose of a compound disclosed herein, e.g., Compound 1, (per eye) is about 20 pg or less, or about 18 pg or less, or about 16 pg or less, or about 15 pg or less, or about 14 pg or less, or about 13 pg or less, or about 12 pg or less, or about 11 pg or less, or about 10 pg or less, or about 9 pg or less, or about 8 pg or less, or about 7 pg or less, or about 6 pg or less, or about 5 pg or less, or about 4 pg or less, or about 3 pg or less, or about 2 pg or less, or about 1 pg or less, or about 0.1 pg or less , or about 0.1 pg or less, or about 0.01 pg or less, or about 0.005 pg or less.

[0090] In some embodiments, the ultralow daily dose of a compound disclosed herein, e.g., Compound 1, (per eye) is from about 0.001 pg to about 200 pg, or from about 0.005 pg to about 100 pg, or from about 0.01 pg to about 20 pg, or from about 0.05 pg to about 10 pg, or from about 0.1 pg to about 20 pg, or from about 0.1 pg to about 10 pg, or from about 0.001 pg to about 0.10 pg, or from about 0.001 pg to about 0.01 pg.

[0091] In some embodiments, the treatment period is 1-30 days, 4-52 weeks, 1-12 months, or 1-5 years.

[0092] Provided herein are extended release dosage forms for ocular administration of a compound disclosed herein, e.g., Compound 1„ comprising an ocular implant or flowable composition as described herein. Extended release dosage forms release a compound disclosed herein, e.g., Compound l,or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, from the ocular implant or flowable composition at a sustained rate, can either be sustained release or controlled release unit dosage forms.

[0093] In some embodiments, the extended release dosage form is a sustained release unit dosage form, where the unit dosage form maintains release (or administration) over a sustained period, but not at a constant rate.

[0094] Sustained release implies that the active agent is not released from the implant sporadically, in an unpredictable fashion. The term “sustained release” may include a partial “burst phenomenon” associated with deployment. In some example embodiments, an initial burst may be desirable, followed by a more gradual release thereafter. The release rate may be steady state (commonly referred to as “timed release” or zero order kinetics), that is the active agent (e.g., Compound 1) is released in even amounts over a predetermined time (with or without an initial burst phase), or may be a gradient release. Sustained release compositions have substantially constant release over a given time period.

[0095] In some embodiments, the extended release dosage form is a controlled release unit dosage form, where the unit dosage form maintains release (or administration) over a sustained period at a nearly constant rate.

[0096] Controlled release drug delivery systems are classified based on the mechanism of drug release from the dosage form into dissolution controlled, diffusion-controlled, water penetration-controlled (osmotic pressure-controlled and swelling-controlled), chemically controlled and nanoparticle-based systems.

[0097] In some embodiments, the extended release dosage form comprises a compound disclosed herein, e.g., Compound 1„ or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, wherein the extended release form administers the compound at a substantially constant drug pressure over a predetermined time period.

[0098] In some embodiments, the extended release dosage form comprises a lipid nanoparticle (LNP), wherein the compound is formulated in a lipid nanoparticle (LNP), Such particles can be utilized for topical administration.

[0099] As used herein, the term “lipid nanoparticle” refers to a colloidal system composed primarily of lipids, wherein the lipid molecules self-assemble into nanoparticles with a size typically ranging from about 10 to 200 nanometers in diameter. These nanoparticles possess a core-shell structure, with a compound disclosed herein, e.g., Compound 1„ or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, encapsulated within the lipidbilayer or aqueous core. The lipid composition can vary widely and may include phospholipids, or other lipidic materials, imparting stability, biocompatibility, and controlled release properties to the formulation. The lipid nanoparticles are intended to offer advantages such as enhanced cellular uptake, prolonged circulation time, and targeted delivery to specific tissues or cells.

[0100] In some embodiments, the extended release dosage form is a dissolution controlled drug delivery system. In a dissolution-controlled release system, drugs are either coated with or encapsulated within slowly dissolving polymeric membranes (reservoir systems) or matrices (monolithic systems), respectively. In reservoir systems, drugs are protected inside polymeric membranes with low solubility, where the rate-limiting step is dissolution.

[0101] In some embodiments, the extended release dosage form is a diffusion-controlled drug delivery system. In diffusion-controlled release systems, drugs are trapped in and released via diffusion through inert water-insoluble polymeric membranes (reservoir systems) or polymeric matrices (monolithic systems). These are classified into membrane control reservoir systems and monolithic matrix systems. The drug release is governed by Fick’s laws of diffusion. The rate-limiting step in diffusion-controlled systems is the diffusion of drugs. Diffusion-controlled systems are classified into membrane-controlled and monolithic or matrix systems. In membrane-controlled systems, the drug is contained in the core as a reservoir and is covered by a thin polymeric membrane. The membrane could be either porous or non- porous. The release of drugs is by diffusion through the membrane and the rate of release is governed by membrane thickness, porosity and physicochemical characteristics of drugs (partition coefficient, molecular size and diffusivity, protein binding and dosage). A common method to fabricate membrane- controlled reservoir systems includes encapsulation. The drug release is through diffusion when the outside layer that is exposed to the solution gets dissolved first, allowing drugs to diffuse out of the matrix.

[0102] In monolithic or matrix-controlled delivery systems, the drug is dispersed in a polymer matrix or solvent (e.g., benzyl benzoate). In monolithic systems, where a drug is dissolved, drugs are loaded below the solubility limit. As the size of the matrix decreases, the drug released decreases. Here the drug release is typically nonzero order, i.e., rate of absorption rate of elimination. In monolithic systems where the drugs are dispersed in the polymer matrix or solvent, drugs are typically loaded above the solubility limit.

[0103] In some embodiments, the extended release dosage form is a water penetration-controlled drug delivery system. These are classified as osmotic pressure-controlled drug delivery systems and swelling controlled drug delivery systems. The rate control is dependent on water penetration into the system.

[0104] In some embodiments, the extended release dosage form is an osmotic controlled drug delivery system. Osmotic drug delivery uses the osmotic pressure for controlled delivery of drugs by using osmogens. Osmosis refers to the process of movement of solvent from a lower concentration of solute towards a higher concentration of solute across the semipermeable membrane. Osmotic pressure is thepressure exerted by the flow of water through a semipermeable membrane separating two solutions with different concentrations of solute. These systems can be used for administration via injection.

[0105] Basic components of osmotic drug delivery systems include the drug which itself may act as osmogen; otherwise, osmogenic salt can be added to the formulation. A semipermeable membrane with sufficient wet strength and water permeability that is biocompatible and rigid in withstanding the pressure within the device is needed. Apart from that, an outer coating material that is permeable to water but impermeable to solute can be used. Polymers such as cellulose acetate, cellulose triacetate and ethyl celluloses are commonly used in osmotic drug delivery systems. The advantages of osmotic-controlled delivery systems include increased efficacy of the drug, controlled drug delivery and reduced dosing frequency. A simple osmotic delivery system is a pump that is made up of two compartments separated by a moving partition. Compartment one is filled with an osmotic agent covered by a semi-permeable membrane. Compartment 2 is covered by a hard rigid shell with a delivery orifice.

[0106] In some embodiments, the extended release dosage form is a swelling-controlled drug delivery system. In swelling-controlled drug delivery systems, the drug is dispersed or dissolved in the hydrophilic polymer when in a glassy (hard and rigid) state. In an aqueous environment, such as a physiological environment, or biological fluid (e.g., vitreous humor) liquid penetrates and swells the polymer matrix, which results in slow drug diffusion out of the polymer matrix. In certain embodiments, the polymer matrix comprises a hydrogel.

[0107] In some embodiments, provided is a chemically controlled drug delivery system. Chemically controlled delivery systems change their chemical structure when exposed to the biological milieu. These are typically made primarily from biodegradable polymers which degrade in the body as a result of natural biological processes, eliminating the need to remove the delivery system after exhausting an active agent from the system. These are classified into two types: Polymer-drug dispersion system and polymer-drug conjugate systems. In polymer-drug dispersion systems, the drug is dispersed (e.g., suspended or dissolved) in a biodegradable polymer matrix and released through degradation of polymers under physiological conditions. Two types of biodegradations are reported: bulk erosion, which is through breakdown of polymers in the bulk and, surface erosion which is due to the breakdown of polymers from the surface or dissolution of polymers from the surface. Various factors that affect degradation (bioerosion and bulk erosion) include chemical structure and composition, the presence of unexpected units or chain defects, configuration, and molecular weight.

[0108] The extended release dosage forms described herein minimize the frequency of intravitreal administration. In some embodiments, the extended release dosage form is configured to substantially maintain a desired intravitreal concentration of compound over the course of a treatment period. In some embodiments, the intravitreal concentration of compound is substantially maintained at least about 10 nM, or from about 10 nM to about 5 pM, or about 100 nM, over the course of the treatment period. In some embodiments, the treatment period is 1-30 days, 4-52 weeks, 1-12 months, or 1-5 years.

[0109] In some embodiments, the intravitreal concentration of compound is substantially maintained at least about 0.001 pg / mL, or about 0.005 pg / mL, or not more than about 0.01 pg / mL, or not more than about 0.05 pg / mL, or between about 0.001-0.01 pg / mL over the course of the treatment period. In some embodiments, the treatment period is 1-30 days, 4-52 weeks, 1-12 months, or 1-5 years.

[0110] In some embodiments, to achieve the required therapeutic concentration of a compound disclosed herein, e.g., Compound 1„ or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, and to maintain the concentration of a compound disclosed herein, e.g., Compound 1, for a desired treatment period, the unit dosage form is made up of two parts. The first which contains a loading dose and the second part which contains a maintenance dose. The desired response can be achieved by the loading dose (the initial burst dose causes a rapid onset of the pharmacological effect) and a maintenance dose release is administered at a slow and steady rate (following the zero-order kinetics) to maintain the desired pharmacological effect. In some embodiments, the rate of maintenance dose at which the compound is administered substantially equals the rate of the drug output, however, this is not required in the extended release dosage forms described herein.

[0111] The present disclosure, in one embodiment, provides extended release dosage forms for ocular administration of a compound disclosed herein, e.g., Compound 1„ or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof. In some embodiments, the extended release dosage form is an ocular implant. In some embodiments, the extended release dosage form is a flowable composition.

[0112] Accordingly, in some embodiments, provided herein is an ocular implant comprising a compound disclosed herein, e.g., Compound 1„ or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, and a polymer matrix, wherein the compound is dispersed in the polymer matrix and the polymer matrix controls release of the compound.

[0113] In some embodiments, provided herein is a flowable composition comprising a compound disclosed herein, e.g., Compound 1„ or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, and a solvent or excipient, wherein the compound is dispersed in a solvent or excipient and the solvent or excipient controls release of the compound.

[0114] In some embodiments, provided herein is a method of treating or preventing age-related macular degeneration (AMD), comprising administering a compound disclosed herein, e.g., Compound 1,, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, to a patient in need thereof, wherein the compound is administered to the eye in an extended release dosage form. In some embodiments, the compound concentration within the eye is substantially maintained at a concentration of greater than about 10 nM for the duration of a treatmentperiod, such as at least 1 month, or 3 months, or 6 months, or 1 year. In some embodiments, the compound concentration within the eye refers to the intravitreal concentration of compound within one of the eyes.

[0115] In some embodiments, both eyes are treated. In some embodiments, one eye of a patient is treated.

[0116] In some embodiments, provided herein is a method of treating or preventing age-related macular degeneration (AMD) comprising administering a compound disclosed herein, e.g., Compound 1„ or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, to a patient in need thereof, wherein the administering is by intravitreal injection.

[0117] In some embodiments, provided herein is a method of reducing drusen size and / or number comprising administering a compound disclosed herein, e.g., Compound 1„ or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, to a patient in need thereof, wherein the administering is by intravitreal injection.

[0118] In some embodiments, provided herein is a method of preventing, reducing, or reversing complement activation in the eye comprising administering a compound disclosed herein, e.g., Compound 1,, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, to a patient in need thereof, wherein the administering is by intravitreal injection.

[0119] The implants and compositions provided herein can be used employed to treat or prevent one or more of the following indications (e.g., retinal diseases and disorders), such as, but not limited to, age- related macular degeneration, macular drusen (small, intermediate, large), peripheral drusen, extramacular drusen, drusenoid pigment epithelial detachment (PED), drusenoid deposits, basal laminar deposits, basal linear deposits, doyne honeycomb retinal dystrophy, Malattia Leventinese, familial dominant drusen (or autosomal dominant drusen), cuticular drusen, serous detachment of RPE, drupelets, RPE atrophy, geographic atrophy, ellipsoid zone (EZ) attenuation, EZ loss, incomplete retinal pigment epithelial and outer retinal atrophy (iRORA), complete retinal pigment epithelial and outer retinal atrophy (cRORA), nascent geographic atrophy, retinal flecks, fundus flavimaculatus, Best disease, adultonset vitelliform macular dystrophy, Best vitelliform macular dystrophy, autosomal recessive bestrophinopathy, vitelliform material, pattern dystrophy, autosomal dominant vitreoretinochoroidopathy, BEST1 gene mutation disorders, retinal emboli (in retinal artery occlusion), retinal exudates, retinal exudates secondary to retinal microaneurysm, familial exudative vitreoretinopathy (FEVR), synchysis scintillans (cholesterolosis bulbi), neuronal ceroid lipofuscinosis, Batten's Disease, retinitis pigmentosa, Bietti’s crystalline dystrophy juvenile macular degeneration (e.g., Stargardt disease), macular telangiectasia, maculopathy (e.g., age-related maculopathy (ARM) and diabetic maculopathy (DMP) (including partial ischemic DMP)), macular edema (e.g., diabetic macular edema (DME) (including clinically significant DME, focal DME and diffuse DME), Irvine-GassSyndrome (postoperative macular edema), and macular edema following RVO (including central RVOand branch RVO)), retinopathy (e.g., diabetic retinopathy (including in patients with DME), Purtscher's retinopathy and radiation retinopathy), retinal artery occlusion (RAO) (e.g., central and branch RAO), retinal vein occlusion (RVO) (e.g., central RVO (including central RVO with cystoid macular edema (CME)) and branch RVO (including branch RVO with CME)), glaucoma (including low-tension, normal-tension and high-tension glaucoma), ocular hypertension, retinitis (e.g., Coats’ disease (exudative retinitis) or retinitis pigmentosa), chorioretinitis, choroiditis (e.g., serpiginous choroiditis), uveitis (including anterior uveitis, intermediate uveitis, posterior uveitis with or without CME, and pan-uveitis), retinal detachment (e.g., in von Hippel-Lindau disease), retinal pigment epithelium (RPE) detachment, bestrophinopathy, Doyne honeycomb / dominant drusen, and diseases associated with increased intra- or extracellular lipid storage or accumulation in addition to AMD.

[0120] The implants and compositions of the present disclosure may also be used for treating an ocular disease is selected from the group consisting of glaucoma, diabetic retinopathy (DR), retinal vein occlusion (RVO), and retinopathy of prematurity (ROP).

[0121] In some embodiments, a compound disclosed herein, e.g., Compound l,has low solubility in the flowable composition or polymer matrix of an ocular implant. Accordingly, a compound disclosed herein, e.g., Compound 1, can be milled or pelleted in solid form and dispersed in the carrier (e.g., benzyl benzoate or polymer). In some embodiments, the average size of the active agent is 2 pm or less, 1.5 pm or less, or 1 pm or less, in size.

[0122] In some embodiments, a compound disclosed herein, e.g., Compound 1, is present in particles, which particles are dispersed in the polymer matrix or the benzyl benzoate.

[0123] In some embodiments, a compound disclosed herein, e.g., Compound 1, has high solubility in either the solvent(s) or excipient(s) of the flowable composition or the polymer matrix. In instances where a compound disclosed herein, e.g., Compound 1, is soluble in a benzyl benzoate formulation, sterilization may be performed via filtration, which then avoids terminal sterilization by means such as gamma irradiation or e-beam.Ocular Implants

[0124] In some embodiments, provided herein is an ocular implant comprising a compound disclosed herein, e.g., Compound 1, and a polymer matrix, wherein a compound disclosed herein, e.g., Compound 1, is dispersed (i.e., dissolved or suspended) in the polymer matrix. In the ocular implants, the polymer matrix is what controls release, and thus administration, of a compound disclosed herein, e.g., Compound 1,-

[0125] It is contemplated that any polymer can be used to provide the polymer matrix, provided that the polymer matrix is biocompatible, specifically biocompatible within the eye, e.g., the vitreous humor. In some embodiments, suitable polymers for use in the polymer matrix includes polymers used in extended release drug delivery systems, such as synthetic polymers, natural polymers, or stimuli-responsive polymers.

[0126] Exemplary, non-limiting, synthetic polymers include polyhydroxy ethyl methacrylate poly (2-hydroxyethyl methacrylate), ethyl cellulose, hydroxypropyl methyl cellulose (HPMC), eudragits, polylactic acid (PLA), polylactic-co-glycolic acid (PLGA), polycaprolactone, polyvinyl Pyrrolidone (PVP), poly methyl methacrylate (PMMA), poly-(N-Isopropyl acrylamide) (PNIPAM), poly(ethylenimine), cyclodextrin (a, P, y), or carbomers.

[0127] Exemplary, non-limiting, natural polymers include alginates, starches, dextrans, cellulose, gums (acacia, tragacanth, guar gum), chitosan, hyaluronic acid, collagen, gelatine, microbial polymers (polyhydroxy butyrate), or arginine derivatives.

[0128] Exemplary, non-limiting, stimuli-responsive polymers include pH-responsive polymers (e.g., polyacids (such as PLA, polymethacrylate, poly aspartate, alginates, polystyrene sulphonic acid, and the like), polybases (such as chitosan, poly-L-lysine, poly allylamine, polyethylene amine, polyamidoamine dendrimer, and the like), thermoresponsive polymers (e.g., poly-(N-isopropyl acrylamide) (PNIPAM), poly-(N-vinylcaprolactam), poly(N,N-dimethyl acrylamide), poly (methyl vinyl ether), and the like), electric responsive polymers (e.g., sulfonated polystyrenes, poly(thiophene)s, poly(ethyl oxazoline)s, and the like), ultrasound responsive polymers (e.g., ethylene-vinyl acetate), or light responsive polymers (e.g., modified poly(acrylamide)s).

[0129] In some embodiments, the ocular implant is non-biodegradable.

[0130] In some embodiments, the polymer matrix is swellable in vivo.

[0131] In some embodiments, the ocular implant is biodegradable.

[0132] Non-limiting examples of biodegradable polymers include polyesters, poly (]-hydroxy acids), polylactide, poly glycolide, poly(I-caprolactone), polydioxanone, poly (hydroxy alkanoates), poly(hydroxypropionates), poly (3 -hydroxypropionate), poly(hydroxybutyrates), poly(3- hydroxybutyr ate) , poly (4-hydroxybutyr ate) , poly (hydroxypentanoates) , poly (3 -hydroxypentanoate) , poly(hydroxy valerates), poly (3 -hydroxy valerate), poly(4-hydroxy valerate), poly(hydroxy octanoates), poly (2-hydroxy octanoate), poly (3 -hydroxy octanoate), polysalicylate / polysalicylic acid, polycarbonates, poly(trimethylene carbonate), poly(ethylene carbonate), poly(propylene carbonate), tyrosine-derived polycarbonates, L-tyrosine -derived polycarbonates, polyiminocarbonates, poly(DTH iminocarbonate), poly (bisphenol A iminocarbonate), poly (amino acids), poly (ethyl glutamate), poly(propylene fumarate), poly anhydrides, poly orthoesters, poly(DETOSU-l,6HD), poly(DETOSU-t-CDM), polyurethanes, polyphosphazenes, polyimides, polyamides, nylons, nylon 12, polyoxyethylated castor oil, poly(ethylene glycol), polyvinylpyrrolidone, poly(L-lactide-co-D-lactide), poly(L-lactide-co-D,L-lactide), poly(D- lactide-co-D,L-lactide), poly(lactide-co-glycolide), poly(lactide-co-I-caprolactone), poly(glycolide-co-I- caprolactone), poly(lactide-co-dioxanone), poly(glycolide-co-dioxanone), poly(lactide-co-trimethylene carbonate), poly(glycolide-co-trimethylene carbonate), poly(lactide-co-ethylene carbonate), poly(glycolide-co-ethylene carbonate), poly(lactide-co-propylene carbonate), poly(glycolide-co- propylene carbonate), poly(lactide-co-2-methyl-2-carboxyl-propylene carbonate), poly(glycolide-co-2-methyl-2-carboxyl-propylene carbonate), poly(lactide-co-hydroxybutyrate), poly(lactide-co-3- hydroxybutyrate), poly(lactide-co-4-hydroxybutyrate), poly(glycolide-co-hydroxybutyrate), poly(glycolide-co-3-hydroxybutyrate), poly(glycolide-co-4-hydroxybutyrate), poly(lactide-co- hydroxy valerate), poly(lactide-co-3-hydroxyvalerate), poly(lactide-co-4- hydroxy valerate), poly(glycolide-co-hydroxyvalerate), poly(glycolide-co-3-hydroxyvalerate), poly(glycolide-co-4- hydroxy valerate) , poly(3 -hydroxybutyr ate-co-4-hydroxybutyr ate) , poly (hydroxybutyrate-co- hydroxy valerate), poly(3-hydroxybutyrate-co-3-hydroxyvalerate), poly(3- hydroxybutyrate-co-4- hydroxy valerate), poly(4-hydroxybutyrate-co-3-hydroxyvalerate), poly(4- hydroxybutyrate-co-4- hydroxy valerate), poly(I-caprolactone-co-fumarate), poly(I-caprolactone-co-propylene fumarate), poly(ester-co-ether), poly(lactide-co-ethylene glycol), poly(glycolide-co-ethylene glycol), poly(I- caprolactone-co-ethylene glycol), poly(ester-co-amide), poly(DETOSU-l,6HD-co-DETOSU-t-CDM), poly(lactide-co-cellulose ester), poly(lactide-co-cellulose acetate), poly(lactide-co-cellulose butyrate), poly(lactide-co-cellulose acetate butyrate), poly(lactide-co-cellulose propionate), poly(glycolide-co- cellulose ester), poly(glycolide-co-cellulose acetate), poly(glycolide-co-cellulose butyrate), poly(glycolide-co-cellulose acetate butyrate), poly(glycolide-co-cellulose propionate), poly(lactide-co- glycolide-co-I-caprolactone), poly(lactide-co-glycolide-co-trimethylene carbonate), poly(lactide-co-I- caprolactone-co-trimethylene carbonate), poly(glycolide-co-I-caprolactone-co-trimethylene carbonate), poly(3-hydroxybutyrate-co-3-hydroxyvalerate-co-4- hydroxybutyrate), poly(3-hydroxybutyrate-co-4- hydroxyvalerate-co-4-hydroxybutyrate), collagen, casein, polysaccharides, cellulose, cellulose esters, cellulose acetate, cellulose butyrate, cellulose acetate butyrate, cellulose propionate, chitin, chitosan, dextran, hyaluronic acid, starch, modified starch, and copolymers and blends thereof, wherein lactide includes L-lactide, D-lactide and D,L-lactide.

[0133] RESOMERS® identified by an “RG” or “DLG” in the product name, such as RG752S, is a poly(D,L-lactide-co-glycolide) or PLGA.

[0134] The synthesis of various molecular weights of DLG with various D,L-lactide-glycolide ratios is possible. In one embodiment, DLG, such as 1A, with an inherent viscosity of approximately 0.05 to approximately 0.15 dL / g can be used. In another embodiment, DLG, such as 2A, with an inherent viscosity of approximately 0.15 to approximately 0.25 dL / g can be used. Poly(D,L-lactide-co-glycolide) or PLGA copolymers can be synthesized at different ratios of lactide to glycolide, such as a lactide: glycolide ratio of 75:25. These copolymers can be an ester-terminated PLGA copolymer, as identified by the terminal “S” in the product name, or an acid-terminated PLGA copolymer, as identified by the terminal “H” in the product name.

[0135] In some embodiments, the ocular implant of the disclosure comprises at least one PLGA, wherein each PLGA is independently selected from the group consisting of RG502, RG502S, RG502H, RG503, RG503H, RG504, RG504H, RG505, RG506, RG653H, RG752H, RG752S, RG753H, RG753S, RG755, RG755S, RG756, RG756S, RG757S, RG750S, RG858, and RG858S.

[0136] In some embodiments, the polymer matrix comprises poly(D, L-lactide-co-glycolide) (PGLA) having a molar ratio (D,L LA: GA) of 50:50, an inherent viscosity range (dl / g) of 0.1 - 0.3, 0.2 - 0.4, 0.4- 0.6, 0.6 - 0.8, 0.8 - 1.0, 1.0 - 1.2, or 1.2 - 1.4, and acid / ester end group, such as Viatel™ DLG 5002, 5003, 5005, 5007, 5009, 5011, or 5013 A / E.

[0137] In some embodiments, the polymer matrix comprises poly(D, L-lactide-co-glycolide) (PGLA) having a molar ratio (D,L LA: GA) of 55:45, an inherent viscosity range (dl / g) of 0.2 - 0.4 or 0.4 - 0.6, and acid / ester end group, such as Viatel™ DLG 5503 or 5505 A / E.

[0138] In some embodiments, the polymer matrix comprises poly(D, L-lactide-co-glycolide) (PGLA) having a molar ratio (D,L LA: GA) of 65:35, an inherent viscosity range (dl / g) of 0.2 - 0.4, and acid / ester end group, such as Viatel™ DLG 6503 A / E.

[0139] In some embodiments, the polymer matrix comprises poly(D, L-lactide-co-glycolide) (PGLA) having a molar ratio (D,L LA: GA) of 75:25, an inherent viscosity range (dl / g) of 0.1 - 0.3, 0.2 - 0.4, 0.4- 0.6, 0.6 - 0.8, 0.8 - 1.0, 1.0 - 1.2, or 1.2 - 1.4, and acid / ester end group, such as Viatel™ DLG 7502, 7503, 7505, 7507, 7509, 7511, or 7513 A / E.

[0140] In some embodiments, the polymer matrix comprises poly(D, L-lactide-co-glycolide) (PGLA) having a molar ratio (D,L LA: GA) of 85:15, an inherent viscosity range (dl / g) of 0.1 - 0.3, 0.2 - 0.4, 0.4- 0.6, 0.6 - 0.8, 0.8 - 1.0, 1.0 - 1.2, or 1.2 - 1.4, and acid / ester end group, such as Viatel™ DLG 8502, 8503, 8505, 8507, 8509, 8511, or 8513 A / E.

[0141] In some embodiments, the polymer matrix comprises poly(D, L-lactide) (PDLLA) having an inherent viscosity range (dl / g) of 0.1 - 0.3, 0.2 - 0.4, 0.4 - 0.6, 0.6 - 0.8, 0.8 - 1.0, 1.0 - 1.2, or 1.2 - 1.4, and acid / ester end group, such as Viatel™ DL 02, 03, 05, 07, 09, 11, or 13 A / E.

[0142] In some embodiments, the biodegradable polymer comprises a poly(lactic-co-glycolic acid) (PLGA), wherein the PLGA is selected from the group consisting of RG502, RG503H, RG503, RG752S, RG753S, RG755S, RG756S, and RG858S. In some embodiments, the biodegradable polymer comprises a poly(lactic-co-glycolic acid) (PLGA), wherein the PLGA is selected from the group consisting of RG502, RG503, RG752S, RG753S, RG755S, RG756S, and RG858S.

[0143] In some embodiments, the ocular implant comprises one PLGA. In some embodiments, the PLGA has a ratio of PLA and PLG of about 65:35. The polymers used to form the implants of the disclosure have independent properties associated with them that when combined provide the properties needed to provide sustained release of a therapeutically effective amount of an active agent. A few of the primary polymer characteristics that control active agent release rates are the molecular weight distribution, polymer endgroup (i.e., acid or ester), and the ratio of polymers and / or copolymers in the polymer matrix. The present disclosure provides an example of a polymer matrix that possess desirable active agent release characteristics by manipulating one or more of the aforementioned properties to develop a suitable ocular implant. Exemplary formulations are shown in Table 1, below.Table 1: Formulations

[0144] Suitable polymeric materials or compositions for use in the implants include those materials which are compatible, which is biocompatible, with the eye so as to cause no substantial interference with the functioning or physiology of the eye.

[0145] The polymeric materials may be cross-linked or non-cross-linked, for example not more than lightly cross-linked, such as less than about 5%, or less than about 1% of the polymeric material being cross-linked. For the most part, besides carbon and hydrogen, the polymers will include at least one of oxygen and nitrogen, advantageously oxygen. The oxygen may be present as oxy, e.g. hydroxy or ether, carbonyl, e.g. non-oxo-carbonyl, such as carboxylic acid ester, and the like. The nitrogen may be present as amide, cyano and amino. The polymers set forth in Heller, Biodegradable Polymers in Controlled Drug Delivery, In: CRC Critical Reviews in Therapeutic Drug Carrier Systems, Vol. 1, CRC Press, Boca Raton, Fla. 1987, pp 39-90, which describes encapsulation for controlled drug delivery, may find use in the present implants.

[0146] Of additional interest are polymers of hydroxyaliphatic carboxylic acids, either homopolymers or copolymers, and polysaccharides. Polyesters of interest include polymers of D-lactic acid, L-lactic acid, racemic lactic acid, glycolic acid, polycaprolactone, and combinations thereof. Generally, by employing the L-lactate or D-lactate, a slowly eroding polymer or polymeric material is achieved, while erosion is substantially enhanced with the lactate racemate.

[0147] Among the useful polysaccharides are, without limitation, calcium alginate, and functionalized celluloses, particularly carboxymethylcellulose esters characterized by being water insoluble, a molecular weight of about 5 kD to 500 kD, for example.

[0148] Other polymers of interest include, without limitation, polyvinyl alcohol, polyesters, polyethers and combinations thereof which are biocompatible and may be biodegradable and / or bioerodible.

[0149] Some exemplary characteristics of the polymers or polymeric materials for use in the present disclosure may include biocompatibility, compatibility with the therapeutic component, ease of use of thepolymer in making the drug delivery systems of the present disclosure, a half-life in the physiological environment of at least about 6 hours, or greater than about one day, not significantly increasing the viscosity of the vitreous, and water insolubility.

[0150] The biodegradable polymeric materials which are included to form the matrix are desirably subject to enzymatic or hydrolytic instability. Water soluble polymers may be cross-linked with hydrolytic or biodegradable unstable cross-links to provide useful water insoluble polymers. The degree of stability can be varied widely, depending upon the choice of monomer, whether a homopolymer or copolymer is employed, employing mixtures of polymers, and whether the polymer includes terminal acid groups.

[0151] Equally important to controlling the biodegradation and / or erosion of the polymer and hence the extended release profile of the implant is the relative average molecular weight of the polymeric composition employed in the implant. Different molecular weights of the same or different polymeric compositions may be included in the implant to modulate the release profile. In certain implants, the relative average molecular weight of the polymer will range from about 9 to about 64 kD, usually from about 10 to about 54 kD, and more usually from about 12 to about 45 kD.

[0152] In some implants, copolymers of glycolic acid and lactic acid are used, where the rate of biodegradation is controlled by the ratio of glycolic acid to lactic acid. The most rapidly degraded copolymer has roughly equal amounts of glycolic acid and lactic acid. Homopolymers, or copolymers having ratios other than equal, are more resistant to degradation. The ratio of glycolic acid to lactic acid will also affect the brittleness of the implant, where a more flexible implant is desirable for larger geometries. The % of polylactic acid in the polylactic acid poly glycolic acid (PLGA) copolymer can be 0-100%, about 15-85%, or about 35-65%. In some implants, a 50 / 50 PLGA copolymer is used.

[0153] The biodegradable polymer matrix of the ocular implant may comprise a mixture of two or more biodegradable polymers. For example, the implant may comprise a mixture of a first biodegradable polymer and a different second biodegradable polymer. One or more of the biodegradable polymers may have terminal acid groups.

[0154] In an embodiment, the ocular implants can have an aspect ratio of width-to-length from 1 : 1 to greater than 1:30. In some embodiments, the width-to-length aspect ratio of the ocular implant is between 1:2 to 1:25. In some embodiments, the width-to- length aspect ratio of the ocular implant is between 1:5 to 1:20. In some embodiments, the width-to-length aspect ratio of the ocular implant is between 1:10 to 1:20. In some embodiments, the width-to-length aspect ratio of the ocular implant is between 1:15 to 1:20.

[0155] In some embodiments, the implant has a diameter of about 100 pm to about 500 pm, or about 250 pm to about 400 pm, 100 pm to about 300 pm, 250 pm to about 300 pm, (e.g., about 250 pm or less, about 300 pm or less, about 325 pm or less, about 350 pm or less, about 375 pm or less, or about 400 pm or less). In some embodiments, the implant has a diameter of about 300 pm or less.

[0156] In some embodiments, the implant has a length of about 1 mm to about 10 mm, or about 2 mm to about 8 mm, or about 2 mm to about 7 mm, or about 2 mm to about 6 mm, or about 10 mm or less, or about 9 mm or less, or about 8 mm or less, or about 7 mm or less, or about 6 mm or less, or about 5 mm or less, or about 4 mm or less, or about 3 mm or less, or about 2 mm or less, or about 1 mm or less.

[0157] In some embodiments, the implant is rod-shaped. In some embodiments, the term “rod-shaped,” refers to an implant that is elongated, narrow, and substantially cylindrical in form, much like a rod or a stick. In some embodiments, the implant is rod-shaped and has a diameter of about 100 pm to about 500 pm, and a length of about 2 mm to about 6 mm.

[0158] In some embodiments, the implant has a diameter of about 250 pm to about 400 pm; and a length of about 2 mm to about 6 mm. In some embodiments, the implant has a diameter of about 250 pm to about 300 pm; and a length of about 2 mm to about 6 mm.

[0159] In some embodiments, the implant has a volume of from about 0.1 mm3to about 1 mm3. In some embodiments, the implant has a volume of about 0.1 mm3, or about 0.15 mm3, or about 0.16 mm3, or about 0.2 mm3, or about 0.25 mm3, or about 0.3 mm3, or about 0.35 mm3, or about 0.4 mm3, or about 0.45 mm3, or about 0.5 mm3, or about 0.55 mm3, or about 0.6 mm3, or about 0.65 mm3, or about 0.7 mm3, or about 0.75 mm3, or about 0.8 mm3, or about 0.85 mm3, or about 0.9 mm3, or about 0.95 mm3, or about 1 mm3.

[0160] In some embodiments, the implant is rod-shaped and has a volume of from about 0.1 mm3to about 1 mm3. In some embodiments, the implant has a volume of about 0.1 mm3, or about 0.15 mm3, or about 0.16 mm3, or about 0.2 mm3, or about 0.25 mm3, or about 0.3 mm3, or about 0.35 mm3, or about 0.4 mm3, or about 0.45 mm3, or about 0.5 mm3, or about 0.55 mm3, or about 0.6 mm3, or about 0.65 mm3, or about 0.7 mm3, or about 0.75 mm3, or about 0.8 mm3, or about 0.85 mm3, or about 0.9 mm3, or about 0.95 mm3, or about 1 mm3.

[0161] The ocular implants disclosed herein may have a diameter sufficient for administration with a needle for administration by surgical implantation. For needle-injected implants, the implants may have any appropriate length so long as the diameter of the implant permits the implant to move through a needle. For example, implants having a length of about 6 mm to about 7 mm have been injected into an eye. The implants administered by way of a needle have a diameter that is less than the inner diameter of the needle. In some embodiments, the diameter is less than about 500 pm. The vitreous chamber in humans is able to accommodate relatively large implants of varying geometries, having lengths of, for example, 1 to 10 mm. In some embodiments, the implant is a pellet, such as a cylindrical pellet, e.g., rodshaped.

[0162] In some embodiments, the implant may also be at least somewhat flexible so as to facilitate both insertion of the implant in the eye, such as in the vitreous, and accommodation of the implant. In some embodiments, the total weight of the implant is about 250-5,000 pg, or about 500-1,000 pg. For example, an implant may be about 500 pg, or about 1 ,000 pg.

[0163] Thus, implants can be prepared where the center may be of one material and the surface may have one or more layers of the same or a different composition, where the layers may be cross-linked, or of a different molecular weight, different density or porosity, or the like. For example, where it is desirable to quickly release an initial bolus of drug (e.g., a loading dose), the center may be a polylactate coated with a polylactate-polyglycolate copolymer, so as to enhance the rate of initial degradation. Alternatively, the center may be polyvinyl alcohol coated with polylactate, so that upon degradation of the polylactate exterior the center would dissolve and be rapidly washed out of the eye.

[0164] The implants may be of any geometry including fibers, sheets, films, microspheres, spheres, circular discs, plaques, rods, and the like. The upper limit for the implant size will be determined by factors such as toleration for the implant, size limitations on insertion, ease of handling, etc. Where sheets or films are employed, the sheets or films will be in the range of at least about 0.5 mmx0.5 mm, usually about 3-10 mmx5-10 mm with a thickness of about 0.1-1.0 mm for ease of handling. Where fibers are employed, the fiber diameter may be in the range of about 0.05 to 3 mm and the fiber length will generally be in the range of about 0.5-10 mm. Spheres may be in the range of about 0.5 pm to 4 mm in diameter, with comparable volumes for other shaped particles.

[0165] In some embodiments, the implant is other than spherically shaped. In some embodiments, the implant is not a nanoparticle.

[0166] The size and form of the implant can also be used to control the rate of release, period of treatment, and drug concentration at the site of implantation. Larger implants may deliver a proportionately larger dose, but depending on the surface to mass ratio, may have a slower release rate. The particular size and geometry of the implant are chosen to suit the site of implantation. The rate of release of a compound disclosed herein, e.g., Compound 1, from an ocular implant may depend on several factors, including but not limited to, the surface area of the implant, a compound disclosed herein, e.g., Compound 1, content, and water solubility of the therapeutic agent, and speed of polymer degradation.

[0167] In some embodiments, the ocular implant comprises initially at least about 95% to about 99% (e.g., about 95%, about 96%, about 97%, about 98%, and about 99%) of the polymer matrix. In some embodiments, the ocular implant comprises initially at least 95% of the polymer matrix. In some embodiments, the ocular implant comprises initially at least about 80% to about 95% (e.g., about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, and about 95%) of the polymer matrix.

[0168] The proportions of the active agent component, polymer(s), and any other modifiers may be empirically determined by formulating several implants with varying proportions. A USP approved method for dissolution or release test can be used to measure the rate of release (USP 23; NF 18 (1995) pp. 1790-1798). For example, using the infinite sink method, a weighed sample of the implant is added to a measured volume of a solution containing 0.9% NaCl in water, where the solution volume will be such that the drug concentration after release is less than 5% of saturation. The mixture is maintained at 37°C.and stirred slowly to maintain the implants in suspension. The appearance of the dissolved drug as a function of time may be followed by various methods known in the art, such as spectrophotometrically, HPLC, mass spectroscopy, etc. until the absorbance becomes constant or until greater than 90% of the drug has been released.

[0169] In some embodiments, the biodegradable ocular implant is a sterile biodegradable ocular implant. As used herein, “sterile” refers to the composition meeting the requirements of sterility enforced by medicine regulatory authorities, such as the MCA in the UK or the FDA in the US. Tests are included in current versions of the compendia, such as the British Pharmacopoeia and the US Pharmacopoeia. In some embodiments, the biodegradable ocular implant is a substantially pure biodegradable ocular implant. In some embodiments, the biodegradable ocular implant is a medical-grade biodegradable ocular implant.Flowable Compositions

[0170] There are provided herein formulations that are of limited solubility in biological media, are biocompatible, and in some embodiments, biodegradable (referred to as “LSBB”), which may also be syringeable, for controlled and sustained release of an active agent or a combination of active agents. Solid, gel, or injectable controlled-sustained release systems can be fabricated by combining LSBB and an active agent. Systems can combine more than one biodegradable component as well as more than one active agent. Gels can be produced by vortex or mechanical mixing. Injectable formulations can be made by pre-mixing in a syringe or mixing of the LSBB and the active agent before or at the time of administration. Formulations may serve as coating for stents or other implants by, for example, dipping the stent in a liquid form of the formulation and then drying it. In another aspect, the solid form generally contains about 1% to about 60% of an LSBB, the gel form generally contains about 20% to about 80% of an LSBB, and an injectable form (which may be a gel or liquid form) generally contains about 30% to about 99.9% of an LSBB. In an aspect of the present disclosure, the excipient is also biodegradable or bioerodible.

[0171] Examples of solvents or excipients that may be useful as biocompatible, biodegradable and / or bioerodible excipients include, but are not limited to: (i) d-a-tocopherol; d,l-a-tocopherol; d-(3- tocopherol; d,l-P-tocopherol; d-r|-tocopherol; and d,l-r|-tocopherol (including acetate, hemisuccinate, nicotinate, and succinate-PEG ester forms of each of the foregoing); tocotrienol isomers, and their esters; (ii) benzyl alcohol; (iii) benzyl benzoate; (iv) diethylene glycol dibenzoate; (v) triethylene glycol dibenzoate; (vi) dibenzoate esters of poly(oxyethylene) diols, such as those having a molecular weight of up to about 400 g / mol; (vii) propylene glycol dibenzoate; (viii) dipropylene glycol dibenzoate; (ix) tripropylene glycol dibenzoate; (x) dibenzoate esters of poly (oxypropylene) diols having a molecular weight of up to about 3000 g / mol; (xi) poly(oxypropylene) diols, such as those having a molecular weight of up to about 3000 g / mol; (xii) dimethyl sulfone; (xiii) triethyl, tripropyl, and tributyl esters of O-acetylcitrate; (xiv) triethyl, tripropyl, tributyl esters of citric acid; and (xv) liquid to semisolid polycarbonate oligomers, such as, but not limited to, those prepared by the polymerization oftrimethylene carbonate (poly(l,3-propanediol carbonate)) or the ester exchange polymerization of diethylene carbonate with aliphatic diols or poly oxyalkane diols (poly(di-l,2-propylene glycol carbonate) or poly(tri-l,2-propylene glycol carbonate)).

[0172] Another example of biodegradable / biocompatible excipients useful in the present disclosure are “tocols.” Tocols refers to a family of tocopherols and tocotrienals and derivatives thereof, because tocopherols and tocotrienals are derivatives of the simplest tocopherol, 6-hydroxy-2-methyl-2- phytylchroman. Tocopherols are also known as a family of natural or synthetic compounds commonly called Vitamin E. Alpha-tocopherol is the most abundant and active form of this class of compounds. Other members of this class include P-, y-, and 5-tocopherols and a-tocopherol derivatives such as tocopheryl acetate, succinate, nicotinate, and linoleate. Useful tocotrienols include d-5-tocotreinols, and d-[>-, d-y- tocotrienols, and their esters.

[0173] Benzyl benzoate (CAS 120-51-4, FW 212.3) is a relatively nontoxic liquid which when applied topically in the eye results in no damage. Grant, Toxicology of the Eye 185 (2d ed., 1974). Its oral Ldso in humans is estimated to be 0.5 g / kg-5.0 g / kg. Gosselin et al., II Clin Tox of Commercial Prod. 137 (4th ed., 1976). In vivo, benzyl benzoate is hydrolyzed to benzoic acid and benzyl alcohol. The benzyl alcohol is subsequently oxidized to benzoic acid, which is then conjugated with glucuronic acid and excreted in the urine as benzoylglucuronic acid. To a lesser extent, benzoic acid is conjugated with glycine and excreted in the urine as hippuric acid. Handbook of Pesticide Toxicology 1506 (Hayes & Laws, eds., 1991). U.S. Patent No. 7,906,136 and Lim, Jennifer I., Marcia Niec, and Vernon Wong. "One year results of a phase 1 study of the safety and tolerability of combination therapy using sustained release intravitreal triamcinolone acetonide and ranibizumab for subfoveal neovascular AMD." British Journal of Ophthalmology 99.5 (2015): 618-623 are incorporated herein by reference their entirety.

[0174] In addition to the active agent and the drug release sustaining component, the compositions disclosed herein may optionally include one or more buffering agents, preservatives, antioxidants, or other excipients, or combinations thereof. Suitable water soluble buffering agents include, without limitation, alkali and alkaline earth carbonates, phosphates, bicarbonates, citrates, borates, acetates, succinates and the like, such as sodium phosphate, citrate, borate, acetate, bicarbonate, carbonate and the like. These agents are advantageously present in amounts sufficient to maintain a pH of the system of between 2 to 9 or 4 to 8. Suitable water soluble preservatives include sodium bisulfite, sodium bisulfate, sodium thiosulfate, ascorbate, benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric acetate, phenylmercuric borate, phenylmercuric nitrate, parabens, methylparaben, polyvinyl alcohol, benzyl alcohol, phenylethanol and the like and mixtures thereof. These buffering agents, preservatives, antioxidants, and other excipients may be present in amounts of from 0.001 to 10% by weight of the implant. Examples of antioxidant agents include ascorbate, ascorbic acid, alpha-tocopherol, mannitol, reduced glutathione, various carotenoids, cysteine, uric acid, taurine, tyrosine, superoxide dismutase, lutein, zeaxanthin, cryptoxanthin, astaxanthin, lycopene, N-acetyl-cysteine, carnosine, gamma-glutamylcysteine, quercitin, lactoferrin, dihydrolipoic acid, citrate, Ginkgo Biloba extract, tea catechins, bilberry extract, vitamins E or esters of vitamin E, and retinyl palmitate.Active Agent Dosing and Release Kinetics

[0175] The amount of a compound disclosed herein, e.g., Compound 1, loaded in the implant or composition may vary and can be adjusted based on any factor(s), such as, but not limited to, release kinetics, compound potency, desired clinical outcome, patient needs, etc.

[0176] In some embodiments, the implant or composition as disclosed herein administered (per eye) comprises a total amount of a compound disclosed herein, e.g., Compound 1, in a range of about 0.1 pg to about 10 mg, 0.1 pg to about 5 mg, 0.1 pg to about 2 mg, 0.1 pg to about 1.5 mg, or 1 pg to about 1 mg (e.g., about 1 pg, about 10 pg, about 25 pg, about 50 pg, about 75 pg, about 100 pg, about 125 pg, about 150 pg, about 175 pg, about 200 pg, about 225 pg, about 250 pg, about 275 pg, about 300 pg, about 325 pg, about 350 pg, about 375 pg, about 400 pg, about 425 pg, about 450 pg, about 475 pg, about 500 pg, about 525 pg, about 550 pg, about 575 pg, about 600 pg, about 625 pg, about 650 pg, about 675 pg, about 700 pg, about 725 pg, about 750 pg, about 775 pg, about 800 pg, about 825 pg, about 850 pg, about 875 pg, about 900 pg, about 925 pg, about 950 pg, and about 975 pg).

[0177] In some embodiments, the implant or composition as disclosed herein comprises a dose of an active agent in a range of about 10 pg to about 500 pg.

[0178] In some embodiments, the implant or composition as disclosed herein comprises about 500 pg to about 4 mg (e.g., about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, and about 3.5 mg) of a compound disclosed herein, e.g., Compound 1. In some embodiments, the implant or composition comprises about 150 pg to about 250 pg of a compound disclosed herein, e.g., Compound 1.

[0179] In certain embodiments, the implant or composition as disclosed herein comprises about 165 pg to about 220 pg (e.g., about 165 pg, about 170 pg, about 175 pg, about 180 pg, about 185 pg, about 190 pg, about 195 pg, about 200 pg, about 205 pg, about 210 pg, about 215 pg, and about 220 pg) of a compound disclosed herein, e.g., Compound 1. In some embodiments, the dose is about 300 pg to about 500 pg of a compound disclosed herein, e.g., Compound 1. In some embodiments, the dose is about 400 pg to about 500 pg of a compound disclosed herein, e.g., Compound 1. In some embodiments, the dose is about 300 pg to about 550 pg of a compound disclosed herein, e.g., Compound 1. In some embodiments, the dose is about 300 pg to about 600 pg of a compound disclosed herein, e.g., Compound 1.

[0180] In certain embodiments, the implant or composition as disclosed herein comprises about 330 pg to about 500 pg (e.g., about 330 pg, about 335 pg, about 340 pg, about 345 pg, about 350 pg, about 355 pg, about 360 pg, about 365 pg, about 370 pg, about 375 pg, about 380 pg, about 385 pg, about 390 pg, about 395 pg, about 400 pg, about 405 pg, about 410 pg, about 415 pg, about 420 pg, about 425 pg, about 430 pg, about 435 pg, about 440 pg, about 445 pg, about 450 pg, about 455 pg, about 460 pg, about 465 pg, about 470 pg, about 475 pg, about 480 pg, about 485 pg, about 490 pg, about 495 pg, and about 500 pg) of a compound disclosed herein, e.g., Compound 1.

[0181] In some embodiments, the implant or composition as disclosed herein comprises about 200 pg to about 400 pg (e.g., about 200 pg, about 210 pg, about 220 pg, about 230 pg, about 240 pg, about 250 pg, about 260 pg, about 270 pg, about 280 pg, about 290 pg, about 300 pg, about 310 pg, about 320 pg, about 330 pg, about 340 pg, about 350 pg, about 360 pg, about 370 pg, about 380 pg, about 390 pg, about 400 pg) of a compound disclosed herein, e.g., Compound 1.

[0182] In some embodiments, the implant or composition as disclosed herein comprises about 175 pg of a compound disclosed herein, e.g., Compound 1. In some embodiments, when a compound disclosed herein, e.g., Compound 1 is present as a salt, the amount of a compound disclosed herein, e.g., Compound 1 is calculated based on the molecular weight of the compound perse (e.g., the free acid or free base).

[0183] Exemplary implants are described in Table 2, below.Table 2: Formulations

[0184] It will be understood to one of skill in the art that the weight percent (wt%) of compound can be adjusted to provide the desired release profile using methods known in the art. For example, such calculations typically take into account one or more known or experimentally determinable factors, such as, but not limited to, molecular weight, activity, efficacy, and / or half-life of the compound, degradation rate of the polymer matrix or flowable composition, release rate of compound from the polymer matrix or flowable composition (e.g., swellability, hydrophilicity or hydrophobicity), and the like.

[0185] The methods provided herein can comprise administering an implant or composition as disclosed herein to the patient once weekly, once every two weeks, once every four weeks, once every six weeks, once every two months, once every three months, once every four months, once every five months, once every six months, once every seven months, once every eight months, once every nine months, once every ten months, once every eleven months, once every twelve months, once every eighteen months, once every two years, once every three years, once every four years, once every five years, once everysix years, once every seven years, once every eight years, once every nine years, once every ten years, or a number or a range between any two of the values.

[0186] In certain embodiments, the amount of compound released during the first hours or days after administration is higher than the target daily dose (e.g., during the initial burst release period) and as the implant or composition is substantially degraded and the concentration of compound in the remaining portion of the implant or composition is diminished, the daily dose will be lower than the target daily dose.

[0187] In certain embodiments, the total target daily dose (per eye) is from about 0.001 pg / mL (mass of compound per mL of vitreous fluid) to 10 pg / mL, or from about 0.001 pg / mL to 1 pg / mL, or from about 0.001 pg / mL to 0.10 pg / mL, or from about 0.001 pg / mL to 0.01 pg / mL per eye per day. In certain embodiments, the total target daily dose (per eye) is from about 0.001 pg / mL to 0.01 pg / mL (mass of compound per mL of vitreous fluid).

[0188] In certain embodiments, the target amount of compound maintained in the eye for the duration of the treatment period ranges from about 0.001 pg / mL to 0.1 pg / mL (mass of compound per mL of vitreous fluid). In certain embodiments, the target amount of compound maintained in the eye for the duration of the treatment period is about 0.001 pg / mL, or about 0.002 pg / mL, or about 0.003 pg / mL, or about 0.004 pg / mL, or about 0.005 pg / mL, or about 0.006 pg / mL, or about 0.007 pg / mL, or about 0.008 pg / mL, or about 0.009 pg / mL, or about 0.1 pg / mL (mass of compound per mL of vitreous fluid).

[0189] In certain embodiments, the target concentration of compound maintained in the eye for the duration of the treatment period ranges from about 1 nM to 20 nM. In certain embodiments, the target concentration of compound maintained in the eye for the duration of the treatment period is about 1 nM, or about 2 nM, or about 3 nM, or about 4 nM, or about 5 nM, or about 6 nM, or about 7 nM, or about 8 nM, or about 9 nM, or about 10 nM.

[0190] It will be understood that each eye may be treated independently in that the same dose or treatment may not be administered to both eyes of the patient.

[0191] In certain embodiments, the active agent comprises as a % w / w of the implant or composition as disclosed herein: about 1% to about 90%, or about 1% to about 80%, or about 1% to about 70%, or about 1% to about 60%, or about 1% to about 55%, or about 1% to about 50%, or about 1% to about 45%, or about 1% to about 40%, or about 1% to about 35%, or about 1% to about 30%, or about 1% to about 25%, or about 1% to about 20%, or about 1% to about 15%, or about 1% to about 10%, or about 1% to about 5%, or about 5% to about 90%, or about 5% to about 80%, or about 5% to about 70%, or about 5% to about 60%, or about 5% to about 55%, or about 5% to about 50%, or about 5% to about 45%, or about 5% to about 40%, or about 5% to about 35%, or about 5% to about 30%, or about 5% to about 25%, or about 5% to about 20%, or about 5% to about 15%, or about 5% to about 10%, or about 10% to about 90%, or about 10% to about 80%, or about 10% to about 70%, or about 10% to about 60%, or about 10% to about 55%, or about 10% to about 50%, or about 10% to about 45%, or about 10% to about 40%, orabout 10% to about 35%, or about 10% to about 30%, or about 10% to about 25%, or about 10% to about 20%, or about 10% to about 15%, or about 15 % to about 90%, or about 15% to about 80%, or about 15% to about 70%, or about 15% to about 60%, or about 15% to about 55%, or about 15% to about 50%, or about 15% to about 45%, or about 15% to about 40%, or about 15% to about 35%, or about 15% to about 30%, or about 15% to about 25%, or about 15% to about 20%, or about 20% to about 90%, or about 20% to about 80%, or about 20% to about 70%, or about 20% to about 60%, or about 20% to about 55%, or about 20% to about 50%, or about 20% to about 45%, or about 20% to about 40%, or about 20% to about 35%, or about 20% to about 30%, or about 20% to about 25%, or about 30% to about 90%, or about 30% to about 80%, or about 30% to about 70%, or about 30% to about 60%, or about 30% to about 55%, or about 30% to about 50%, or about 30% to about 45%, or about 30% to about 40%, or about 30% to about 35%, or about 40% to about 90%, or about 40% to about 80%, or about 40% to about 70%, or about 40% to about 60%, or about 40% to about 55%, or about 40% to about 50%, or about 40% to about 45%, or about 45% to about 90%, or about 45% to about 80%, or about 45% to about 75%, or about 45% to about 70%, or about 45% to about 65%, or about 45% to about 60%, or about 45% to about 55%, or about 45% to about 50%, or about 50% to about 90%, or about 50% to about 80%, or about 50% to about 70%, or about 50% to about 60%, or about 50% to about 55%, or about 25% to about 40%, or about 28% to about 35%, or about 30%, to about 33%, or about 39% to about 45%.

[0192] In certain embodiments, the implant or composition as disclosed herein administers a daily dose of compound in an amount of from about 0.001 pg to about 1 pg; or about 1 pg to about 500 pg; or about 1 pg to about 400 pg; or about 1 pg to about 300 pg; or about 1 pg to about 200 pg; or about 1 pg to about 100 pg; or about 1 pg to about 90 pg; or about 1 pg to about 80 pg; or about 1 pg to about 70 pg; or about 1 pg to about 60 pg; or about 1 pg to about 50 pg; or about 1 pg to about 40 pg; or about 1 pg to about 30 pg; or about 1 pg to about 20 pg; or about 1 pg to about 10 pg or about 10 pg to about 100 pg; or about 10 pg to about 50 pg; or about 10 pg to about 35 pg; or about 10 pg to about 31 pg; or about 14 pg to about 26 pg; or about 20 pg to about 40 pg; or about 25 pg to about 35 pg; or about 28 pg to about 31 pg; or about 14 pg; or about 19 pg; or about 26 pg; or about 29 pg; or about 42 pg.

[0193] In certain embodiments, the polymer matrix or solvent comprises as a % w / w of the overall implant composition: about 5% to about 95% w / w, or about bout 5% to about 90% w / w, or about 5% to about 80%, or about 5% to about 70%, or about 5% to about 60%, or about 10% to about 90% w / w, or about 10% to about 80%, or about 10% to about 70%, or about 10% to about 60%, or about 20% to about 90%, or about 20% to about 80%, or about 20% to about 70%, or about 20% to about 60%, or about 30% to about 90%, or about 30% to about 80%, or about 30% to about 70%, or about 30% to about 60%, or about 40% to about 90%, or about 40% to about 80%, or about 40% to about 70%, or about 40% to about 60%, or about 50% to about 90%, or about 50% to about 80%, or about 50% to about 70%, or about 50% to about 60%, or about 60% to about 90%, or about 60% to about 85%, or about 65% to about 85%, or about 60% to about 80%, or about 60% to about 70%; or about 45% to about 80%, or about 45% to about 75%, or about 45% to about 70%, or about 45% to about 65%, or about 45% to about 60%, or about 45%to about 55%, or about 45% to about 50%, or about 70% to about 80%, or about 65% to about 85%, or about 85% to about 95%, or about 92.5% to about 95%, or about 55% to about 70% w / w of the implant composition.

[0194] Release of the active agent from a polymer matrix or solvent may be a function of several processes, including diffusion out of the polymer, degradation of the polymer and / or erosion or degradation of the polymer. Some factors which influence the release kinetics of active agent from the implant or composition can include the size and shape of the implant or a depot of the composition, the size of the active agent particles, the solubility of the active agent, the ratio of active agent to polymer(s) or solvent(s), the method of manufacture, the surface area exposed, and the erosion rate of the polymer(s) or solvent(s). For example, degradation or erosion by hydrolysis (among other mechanisms) can occur, and therefore, any change in the composition of the implant that enhances water uptake by the implant will likely increase the rate of hydrolysis, thereby increasing the rate of polymer degradation and erosion, and thus, increasing the rate of active agent release. Equally important to controlling the biodegradation, and hence the extended release profile of the implant, is the relative average molecular weight of the polymeric composition employed in the implant. Different molecular weights of the same or different polymers may be included in an implant to modulate the release profile.

[0195] The release kinetics of the implant or composition described herein can be dependent in part on the surface area implant or composition administered. A larger surface area may expose more active agent to ocular fluid, and may cause faster erosion of the implant or composition and dissolution of the active agent in the fluid. Therefore, the size and shape of an implant may also be used to control the rate of release, period of treatment, and active agent concentration at the site of implantation.

[0196] As discussed herein, the polymer matrix of the ocular implant may swell or degrade at a rate effective to sustain release of an effective amount of compound for weeks, months, or years after implantation into an eye. For a homopolymer such as PLA, the drug release is also determined by (a) the lactide stereoisomeric composition (i.e., the amount of L- vs. D,L-lactide) and (b) molecular weight. Three additional factors that determine the degradation rate of PLGA copolymers are: (a) the lactide: glycolide ratio, (b) the lactide stereoisomeric composition (i.e., the amount of L- vs. DL-lactide), and (c) molecular weight. The lactide: glycolide ratio and stereoisomeric composition are generally considered most important for PLGA degradation, as they determine polymer hydrophilicity and crystallinity. For instance, PEGA with a 1 : 1 ratio of lactic acid to glycolic acid degrades faster than PEA or PGA, and the degradation rate can be decreased by increasing the content of either lactide or glycolide. Polymers with degradation times ranging from weeks to years can be manufactured simply by customizing the lactide: glycolide ratio and lactide stereoisomeric composition.

[0197] The release rate of an active agent from an implant may be empirically determined using a variety methods. A USP approved method for dissolution or release test can be used to measure the rate of release (USP 23; NF 18 (1995) pp. 1790-1798). For example, using the infinite sink method, a weighed sample of the drug delivery system (e.g., implant) is added to a measured volume of a solutioncontaining 0.9% NaCl in water (or other appropriate release medium such as phosphate buffered saline), where the solution volume will be such that the drug concentration after release is less than 20%, or less than 5%, of saturation. The mixture is maintained at 37°C. and stirred slowly to ensure drug release. The amount of drug released in to the medium as a function of time may be quantified by various methods known in the art, such as spectrophotometrically, by HPLC, mass spectroscopy, etc.

[0198] In some embodiments, greater than about 95%, or greater than about 90%, or greater than about 85%, or greater than about 80% of the compound is released from the ocular implant when placed in phosphate buffered saline (PBS) in about 1 month to about 12 months (about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about 13 months, about 14 months, about 15 months, about 16 months, about 17 months, about 18 months).

[0199] In some embodiments, less than 90% (e.g., about 90%, about 85%, about 80%, about 75%, about 70%, about 65%, about 60%, about 55%, about 50%, about 45%, about 40%, about 35%, about 30%, about 25%, about 20%, about 15%, about 10%, and about 5%) of the compound is released from the ocular implant when placed in phosphate buffered saline (PBS) in about 1 month to about 12 months (about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months).

[0200] Over the course of treatment, the biodegradable polymer matrix degrades releasing the active agent. Once the active agent has been completely released, the polymer matrix is expected to be gone. Complete polymer matrix degradation may take longer than the complete release of the active agent. Polymer matrix degradation may occur at the same rate as the release of the active agent. For example, the ocular implant may be designed to release an effective amount of active agent for approximately one month, two months, three months, four months, five months, six months, seven months, eight months, nine months, ten months, eleven months, twelve months, or longer. In aspects, the ocular implant is designed to release an effective amount of active agent for one month, two months, three months, four months, five months, or six months. In other aspects, the ocular implant is designed to release an effective amount of active agent for three months, four months, five months, or six months. In aspects, the ocular implant releases active agent for longer than 6 months. In aspects, the ocular implant releases active agent for a period of time between about 6 months and one year.

[0201] The therapeutically effective amount and the frequency of administration of, and the duration of treatment with, a particular active agent for the treatment of AMD or another eye disorder may depend on various factors, including the eye disease, the severity of the disease, the potency of the active agent, the mode of administration, the age, body weight, general health, gender and diet of the subject, and the response of the subject to the treatment, and can be determined by the treating physician. In some embodiments, the dosing regimen of one or more, or all, of the active agent(s) comprises one or more loading doses followed by one or more maintenance doses. The one or more loading doses are designed to establish a relatively high or therapeutically effective level of the active agent at the target site(s)relatively quickly, and the one or more maintenance doses are designed to establish a therapeutically effective level of the active agent for the period of treatment. The loading dose can be provided, e.g., by administering a dose that is greater than (e.g., 2, 3, 4 or 5 times greater than) the maintenance dose, or by administering a dose substantially similar to the maintenance dose more frequently (e.g., 2, 3, 4 or 5 times more frequently) at the beginning of treatment.Administration and Dosing

[0202] In some embodiments, the compound is administered as a pharmaceutical composition, which can comprise any number of excipients. Excipients that can be used include carriers, surface active agents, thickening or emulsifying agents, solid binders, dispersion or suspension aids, solubilizers, colorants, flavoring agents, coatings, disintegrating agents, lubricants, sweeteners, preservatives, isotonic agents, and combinations thereof. The selection and use of suitable excipients is taught in Gennaro, ed., Remington: The Science and Practice of Pharmacy, 20th Ed. (Lippincott Williams & Wilkins 2003), the disclosure of which is incorporated herein by reference.

[0203] In certain embodiments, the pharmaceutical composition is suitable for parenteral administration (e.g., intravenous, intramuscular, subcutaneous, spinal, intravitreal, and the like), oral, topical mucosal, or epidermal (e.g., by injection or infusion).

[0204] In certain embodiments, the pharmaceutical composition is suitable for parenteral administration. The phrase “parenteral administration” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural, intravitreal, and intrastemal injection and infusion. Alternatively, the pharmaceutical composition can be administered via a non-parenteral route, such as a topical, epidermal or mucosal route of administration, e.g., intranasally, orally, vaginally, rectally, sublingually or topically.

[0205] In certain embodiments, the compound, or pharmaceutical composition comprising the same, is formulated as an ocular implant. In some embodiments, the ocular implant is sized for implantation in an ocular region. The ocular implant can be configured for local, e.g., ophthalmic, administration. Local administration of an active agent can deliver the agent to the target site(s) more effectively, avoid first- pass metabolism and require a lower administration dose of the agent, and thereby can reduce any side effect caused by the agent. As the pathological events of AMD occur in the eye, the active agent(s) used to treat AMD can be locally administered to the eye for more effective treatment.

[0206] Potential routes / modes of local administration include without limitation topical, intraaqueous (the aqueous humor), peribulbar, retrobulbar, suprachoroidal, subconjunctival, intraocular, periocular, subretinal, intrascleral, posterior juxtascleral, trans-scleral, sub-Tenon’s, intravitreal and / or transvitreal. Subretinal administration administers an active agent below the retina, such as, e.g., the subretinal space, the RPE, the sub-RPE-BL space or the choroid, or any combination or all thereof. Potential sites of localadministration include, but are not limited to, the anterior chamber (aqueous humor) and the posterior chamber of the eye, the vitreous humor (vitreous body), the retina (including the macula and / or the photoreceptor layer), the subretinal space, the RPE, the sub-RPE-BL space, the choroid (including the BrM and the choriocapillaris endothelium), the sclera, and the sub-Tenon’s capsule / space. In some embodiments, an active agent is delivered across the sclera and the choroid to the vitreous humor, from where it can diffuse to the target tissue(s), e.g., the retina (e.g., photoreceptors), the subretinal space, the RPE, the sub-RPE-BL space or the BrM, or any combination or all thereof. In other embodiments, an active agent is delivered across the sclera and the choroid to the target tissue(s), e.g., the retina (e.g., photoreceptors), the subretinal space, the RPE and / or the sub-RPE-BL space, from where it can diffuse to the BrM if the BrM is a target tissue. In further embodiments, an active agent is administered intraocularly into the anterior or posterior chamber of the eye, the vitreous humor, the retina or the subretinal space, for example.

[0207] The biodegradable implants may be inserted into the eye by a variety of methods, including placement by forceps, by trocar, or by other types of applicators, after making an incision in the sclera. In some instances, a trocar or applicator may be used without creating an incision. In various embodiments, the implant is administered as an intravitreal administration. An intravitreal administration refers to drug administration into the vitreous humor of the eye. In some embodiments, the implant is administered locally to the back of the eye. In some embodiments, the implant is injected into the intravitreal space using a needle and applicator. Delivery of such implants disclosed herein include delivery through a 20 gauge needle or smaller diameter needle. In aspects, the needles can be thin- walled or ultra-thin walled. In one embodied delivery method the needle is a 20 gauge, 21 gauge, 22 gauge, 23 gauge, 24 gauge, 25 gauge, 26 gauge, 27 gauge, 28 gauge, 29 gauge, 30 gauge, 31 gauge, 32 gauge, 33 gauge, or 34 gauge needle. In aspects, the needles can be thin- walled or ultra-thin walled.

[0208] The implants of the present disclosure may be inserted into the eye by a variety of methods using a suitable ocular implant delivery device. One example may include the device disclosed in U.S. Pat. No. 6,899,717, the relevant disclosure of which is herein incorporated by reference. In one embodiment, the implant is placed in the eye(s) using an intraocular delivery apparatus, the apparatus comprising an elongate housing and a cannula extending longitudinally from the housing, the cannula having a proximal end and a distal sharp end and having a lumen extending therethrough, the lumen having an inner diameter sufficient to receive the implant and permit passage of the implant through the lumen and into the eye of the patient. The apparatus may further comprise a push rod or plunger operably connected with a user-actuated linkage for ejecting the implant through the lumen into the eye. Another embodiment of the present disclosure is an apparatus for delivering a biodegradable ocular implant into the eye of a patient, the apparatus comprising an ocular implant according to any of those described herein, an elongate housing and a cannula extending longitudinally from the housing, the cannula having a proximal end, a distal sharp end, and a lumen extending therethrough, the lumen having an inner diameter sufficient to receive the ocular implant and permit translation of the implant through the lumen and intothe eye of the patient. The cannula may be a 20 gauge, 21 gauge, 22 gauge, 23 gauge, 24 gauge, 25 gauge, 26 gauge, 27 gauge, 28 gauge, 29 gauge, 30 gauge, 31 gauge, 32 gauge, 33 gauge, or 34 gauge needle, or may otherwise be described as having inner and outer diameters equivalent to those of a 20 gauge, 21 gauge, 22 gauge, 23 gauge, 24 gauge, 25 gauge, 26 gauge, 27 gauge, 28 gauge, 29 gauge, 30 gauge, 31 gauge, 32 gauge, 33 gauge, or 34 gauge needle. The needle, in addition, may be a thin-wall or ultra-thin-wall needle.

[0209] For placement e.g. in the vitreous cavity of the eye, useful implantation methods include advancing the needle through the pars plana at a location approximately 3.5-4 mm from the limbus of the eye. For smaller diameter needles, e.g., 25 gauge or smaller diameter needle, the needle can be inserted from any angle relative to the eye and still produce acceptable self-sealing results. For larger gauge needles, e.g., 23 gauge and above, self-sealing results can be enhanced by inserting the needle at angle relative to the eye surface. For example, good results are achieved by inserting the angle at an angle of 45° or less relative to the eye surface. Also, slightly improved results can be seen in some cases by orienting the bevel of the needle downward with respect to the eye surface. Another advantageous method involves a so-called “tunnel technique” approach. In this technique, the patient's eye is restrained from moving using e.g. a cotton swab or forceps, and the needle is advanced into the sclera at an angle approaching parallel relative to the eye surface. In this technique, the bevel will usually be oriented upward with respect to the eye surface. Once the tip is advanced sufficiently far enough into the scleral layer, usually such that the bevel portion is at least disposed within the scleral layer, the angle of the needle is adjusted to a more downward angle into the eye, and the needle is further advanced.Methods of Preparation

[0210] Various methods may be used to produce the implants. Methods include, but are not limited to, solvent casting, phase separation, interfacial methods, molding, compression molding, injection molding, extrusion, co-extrusion, heat extrusion, die cutting, heat compression, and combinations thereof. In certain embodiments, the implants are molded, such as in polymeric molds. Useful techniques include extrusion methods (for example, hot melt extrusion), compression methods, pellet pressing, solvent casting, print technology, hot embossing, soft lithography molding methods, injection molding methods, heat press methods and the like. As previously discussed, an ocular implant according to this disclosure may be configured as a rod, wafer, sheet, film, or compressed tablet. Cast films or sheets can be ground into microparticles, which may be useful in some applications. Biodegradable microspheres formed by an emulsion method and having any of the formulations described herein may also find use in a method according to this disclosure.

[0211] In some embodiments, the ocular implant of this disclosure is a solid rod-shaped implant formed by an extrusion process (an extruded rod) and is sized for placement in the anterior chamber of the eye. Methods for making an ocular implant by an extrusion process are familiar to those of skill in the art.See, for example, US 2008 / 0145403 and US 2005 / 0244464. An extruded implant (e.g., an extruded rod) can be made by a single or double extrusion method. Choice of technique, and manipulation of techniqueparameters employed to produce the implants can influence the release rates of the drug. Room temperature compression methods may result in an implant with discrete microparticles of drug and polymer interspersed. Extrusion methods may result in implants with a progressively more homogenous dispersion of the drug within a continuous polymer matrix, as the production temperature is increased. The use of extrusion methods may allow for large-scale manufacture of implants and result in implants with a homogeneous dispersion of the drug within the polymer matrix.

[0212] The use of extrusion methods allows for large-scale manufacture of implants and results in implants with a homogeneous dispersion of the drug within the polymer matrix. When using extrusion methods, the polymers and active agents that are chosen are stable at temperatures required for manufacturing, usually at least about 50°C. Extrusion methods use temperatures of about 25°C. to about 150°C, or about 60°C. to about 130°C.The temperature used during an extrusion method should be high enough to soften the polymer but low enough to avoid substantial loss of active agent activity. In this regard, extrusion methods may use temperatures of 50°C. to 130°C, or an extrusion temperature of between 50°C. and 80°C, or from 55°C. to 70°C. For example, the extrusion temperature used to make an active agent-containing implant may be 60°C. to 75°C, or from 60°C. to 70°C. Low temperatures such as these may be used for some active agents to preserve potency through to the final extruded implant.

[0213] Different extrusion methods may yield implants with different characteristics, including but not limited to the homogeneity of the dispersion of the active agent within the polymer matrix. For example, using a piston extruder, a single screw extruder, and a twin screw extruder may produce implants with progressively more homogeneous dispersion of the active agent. When using one extrusion method, extrusion parameters such as temperature, feeding rate, circulation time, pull rate (if any), extrusion speed, die geometry, and die surface finish will have an effect on the release profile of the implants produced.

[0214] In one variation of producing implants by a piston or twin-screw extrusion methods, the drug and polymers, including any polyethylene glycol if called for, are first mixed at room temperature and then heated to an appropriate temperature to soften the mixture or transform the mixture to a semi-molten state for a time period of 0 to 1 hour, for 1 to 10 minutes, 1 minute to 30 minutes, 1-5 minutes, 5 minutes to 15 minutes, or 10 minutes. The implants are then extruded at a temperature of between 50°C. and 80°C. In some variations, the temperature of extrusion may range from 60-75°C, or from 60-65°C. In some screw extrusion methods, the powder blend of active agent and polymer is added to a single or twin screw extruder preset at a temperature of 50°C. to 130°C, and directly extruded as a filament or rod with minimal residence time in the extruder. The extruded filament is then cut to a length suitable for placement in the anterior chamber or vitreous of the eye. The total weight of the implant will of course be proportional to the length and diameter of the implant, and implants may be cut to a desired target weight and therefore dosage of the active agent. For example, an intracameral implant in accordance with this disclosure may be cut to a target weight of between 20 and 150 pg (±5%). In some embodiments, theimplants are cut to a target weight of 50 pg (±5%), 75 pg (±5%), or 100 pg (±5%), wherein 20% of the implant by weight is active agent.

[0215] In one embodiment, the method for making the implants involves dissolving the appropriate polymers and active agent in a solvent. Solvent selection will depend on the polymers and active agents chosen. For the implants described herein, dichloromethane (DCM) can be an appropriate solvent. Other solvents may include methylene chloride and ethyl acetate. Once the polymers and active agent(s) have been dissolved, the resulting mixture is cast into a die of an appropriate shape. Once cast, the solvent used to dissolve the polymers and active agent(s) is evaporated at a temperature between 20°C. and 30°C, or about 25 °C. The polymer can be dried at room temperature or even in a vacuum. For example, the cast polymers including active agents can be dried by evaporation in a vacuum. Once the cast polymers are dried, they can be processed into an implant using any method known in the art to do so. In an example embodiment, the dried casted polymer can be cut and / or ground into small pieces or particles and extruded into rounded or squared rod shaped structures at a temperature between 50°C. and 80°C.

[0216] Implants that are compatible with loading and ejection from apparatus according to the present disclosure can be formed by a number of known methods, including phase separation methods, interfacial methods, extrusion methods, compression methods, molding methods, injection molding methods, heat press methods and the like. Particular methods used can be chosen, and technique parameters varied, based on desired implant size and drug release characteristics.

[0217] In manufacturing an implant, it may be desirable to pre-load the implant into the cannula. Pre- loaded apparatus provide added convenience for the user and avoid unnecessary handling of implants. Further, such loading can be done under sterile conditions, thereby ensuring delivery of a sterilized implant. In some embodiments, the implant can be pre-loaded into the cannula assembly and the loaded cannula assembly incorporate into the nose cone. In this fashion, loaded nose cone / cannula assemblies can be pre-assembled, for later incorporation with the housing assembly. In some embodiments, the implant can be preloaded in the cannula and then later assembled onto the housing assembly. In an alternative variation on this embodiment, the cannula can have two separate parts, with one part of the cannula retained within the housing that then communicates with the other external portion of the cannula that is subsequently connected to the housing. In such a variation, an implant can further be preloaded in the cannula part retained within the housing. In any case, push rods and linkages of the appropriate lengths are provided dependent on the length of the particular loaded implant, such that complete ejection of the particular implant can be assured.

[0218] Label plates, or other locations on the housing, can include the appropriate information relative to particular implant loaded. Given this interchangeability, unique apparatus for the delivery of selected implants can be easily manufactured, simply by providing the particular cannula, plunger, and linkage system for the selected implant. The remaining components of the apparatus remain the same. The name plate or housing itself can be labeled to correspond to the selected implant, thus identifying the apparatus with the loaded implant.

[0219] When the apparatus is assembled with the implant pre-loaded, it may further be desirable that the implant be positioned just proximal of the opening at the cannula tip. In this fashion, the introduction of air into the eye can be avoided when the implant is ejected, as could otherwise occur where the implant located further within the cannula lumen and an air bubble or air pocket allowed to exist between the cannula tip and the implant and ejection of the implant were to force the air bubble or air pocket into the eye. One method to accomplish this is to load the implant distally into the cannula followed by the plunger, with the plunger length designed to push the implant to the desired pre-actuation position. When the cannula assembly is then installed onto the housing, the plunger and thus the implant is advanced to the desired position. To guard against inadvertent premature release of the implant, the cannula can have a slight bend incorporated into the tip such that enough friction exists between the inner wall of the cannula and the implant to hold the implant in place, but at the same time, the frictional force is easily overcome by action of the plunger to eject the implant upon actuation of the apparatus.

[0220] Other cannula designs can likewise achieve the desired effect of avoiding the introduction of air into the eye upon ejection of the implant. For example, the implant can be positioned proximally of the cannula tip but with sufficient tolerance between the implant and cannula wall to provide for air exhaust past the implant as it is moved through the cannula. Adequate tolerances are those that retain air in front of the implant at close to ambient pressure as the implant is moved along the cannula. Because fluid pressure within the eye is typically slightly positive relative to ambient pressure, air at ambient pressure will not enter the eye.

[0221] Loaded apparatus according to the disclosure can be packaged to include a safety cap extending over the cannula and securing to the housing. This will provide a measure of safety during handling of the apparatus. The button or other depression mechanism of the apparatus can also include a notch which receives the rim of the safety cap. In this configuration, the safety cap will then also operate to guard against unintentional depression of the button or other depression mechanism and ejection of the implant.

[0222] As can be appreciated, an implant delivery apparatus according to the disclosure that is provided loaded with the desired implant is of great benefit to the physician user. Such apparatus can be provided sterile packaged for a single use application. The user need not ever handle the implant itself. As previously mentioned, the apparatus provides for a controlled ejection of the implant. The configuration and design of the apparatus also helps to achieve uniform placement of implants from patient to patient. Further, when the apparatus is configured to deliver a micro-implant, the apparatus provides a selfsealing method for delivery, as previously discussed. This has enormous benefit to the physician and patient in that the entire implant procedure can safely, easily, and economically be performed in a physician's office, without the need for more costly surgical support currently required for implant delivery.

[0223] In embodiments, the implant and delivery device may be combined and presented as a kit for use.The implant may be packaged separately from the delivery device and loaded into the delivery device just prior to use. Also, the implant may be loaded into the delivery device prior to packaging. In this case,once the kit is opened, the delivery device is ready for use. Components may be sterilized individually and combined into a kit, or may be sterilized after being combined into a kit. In some embodiments, the ocular implant is a sterile ocular implant. As used herein, “sterile” refers to the composition meeting the requirements of sterility enforced by medicine regulatory authorities, such as the MCA in the UK or the FDA in the US. Tests are included in current versions of the compendia, such as the British Pharmacopoeia and the US Pharmacopoeia. In some embodiments, the ocular implant is a substantially pure ocular implant. In some embodiments, the ocular implant is a medical-grade ocular implant. In some embodiments, the ocular implant is administered into the intravitreal space every 3 to 12 months.Examples

[0224] Solvents, reagents and starting materials were purchased from commercial vendors and used as received unless otherwise described. All reactions were performed at room temperature unless otherwise stated. Starting materials were purchased from commercial sources or synthesized according to the methods described herein or using literature procedures or the present disclosure.

[0225] Abbreviations: d: daysDCM: dichloromethaneDIPA: diisopropylamineDMSO-de: dimethyl sulfoxide deEDCI: l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride h: hoursHC1: hydrochloric acidMS: mass spectrometryNMR: nuclear magnetic resonanceRT : room temperatureTHF: tetrahydrofuranExample 1: Synthesis of Compound 1

[0226] Step l : EDCI (340 mg, 1.77 mmol) was added to a solution of Intermediate 1A’ (600 mg, 1.0 mmol), propanediol (0.74 mL, 10.2 mmol) and DIPA (0.7 mL, 5.0 mmol) in DCM (4 mL). The resultant reaction solution was stirred at RT for 2d then diluted with DCM (50 mL) then washed with water followed by saturated aqueous NaCl. The organic portion was evaporated in vacuo and the residue was purified by ISCO combiflash using a gradient of 0% DCM to 30% methanol over 20 min to afford 0.4g (60%) of 3-hydroxypropyl 7-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)-lH-pyrrol- l-yl)-3,5-dihydroxyheptanoate (Intermediate 1A).

[0227] Step 2: Intermediate 1A (120 mg, 0.182 mmol) was dissolved in THF (3mL) and IN HC1 (3mL) was added. The resultant solution was stirred for 6 h. The reaction solution was dissolved in lOOmL of water and extracted with ethyl acetate (3 X 100 mL). The combined organic portions were dried over anhydrous Na2SC>4, filtered and concentrated in vacuo. Purification of the residue by ISCO combiflash using DCM / methanol solvent afforded 50 mg (45 %) of Compound 1 as an oil. ’H NMR (300 MHz, DMSO-d6) d 9.81 (s, 1H), 7.50 (d, J=8.0Hz, 2H), 7.21 (qd, J=10.7, 9.7, 7.3Hz, 5H), 7.06 (d, J=2.8Hz, 4H), 7.05-6.89 (m, 3H), 4.74 (d, J=5.3Hz, 1H), 4.63 (d, J=5.0 Hz, 1H), 4.52 (t, J=5.2Hz, 1H), 4.04 (t, J=6.6 Hz, 2H), 3.98-3.63 (m, 2H), 3.51 (s, 2H), 3.20 (q, J=6.9Hz, 1H), 2.44-2.17 (m, 2H), 1.70 (q, J=6.4Hz, 1H), 1.46-1.63 (m, 4H), 1.22-1.45 (m, 6H). MS: m / e 639.39 (M + Na).

[0228] The remaining compounds are prepared in a similar manner to Compound 1.Example 2: Drusen Assay

[0229] Retinal Pigmented Epithelium Cell Culture: Human embryonic stem-cell-derived retinal pigmented epithelium (hESC-RPE) cells were cultured on transwell inserts for at least 4 weeks in a serum-free XVIVO culture medium. After 4 weeks, polygonal, pigmented monolayers of hESC-RPE were visualized by phase contrast and bright-field microscopy, indicating appropriately matured RPE cells.

[0230] Drusen Assay: The matured hESC-RPE inserts were then pre-incubated with varying concentrations of Atorvastatin (ATV) or Compound 1 (ranging from 1 pM to 12.3 nM) in both the top and bottom insert compartments for 24 hours in an incubator set at 37 °C with 5% CO2. On the following day, the medium was exchanged with fresh culture medium containing ATV or Compound 1 and 5% human serum (HS) for an additional 48-hour incubation to elicit the Drusen formation.

[0231] Immunostaining: The efficacy of ATV and Compound 1 in reducing Drusen was evaluated via immunostaining for APOE4 and C5b-9, the indicators of lipoprotein particles in Drusen and Drusen- mediated complement activation, respectively. The hESC-RPE monolayers (the whole insert) were fixed with 4% paraformaldehyde for 10 minutes at room temperature. Following fixation, inserts were individually removed from plates and cut out of their holders using a scalpel yielding individual membranes with hESC-RPE monolayers. Membranes were transferred to 24-well plates for storage in phosphate-buff ered saline with calcium and magnesium (PBS+ / +). Fixed membranes were incubated with a block solution containing 1% bovine serum albumin (BSA) and 0.1% Triton-X-100 in PBS+ / + for 1 hour at room temperature. After the blocking incubation period, membranes were incubated overnight at 4 oC with a primary antibody solution containing 1% BSA, goat anti-APOE4 antibody (1:250), and mouse anti-C5b-9 antibody (1:250). On the following day, membranes were washed thrice for 10 min with PBS+ / + and incubated with a secondary antibody solution containing 1% BSA, AlexaFluor donkey anti-goat 546 (1:200), and AlexaFluor donkey anti-mouse 488 (1:200) for 1 hour at room temperature in the dark. After the secondary antibody incubation, membranes were washed thrice for 10 min with PBS+ / + and counterstained with Hoechst solution (1:1000) in PBS+ / + for 10 min at room temperature. Membranes were then washed once with PBS+ / +, transferred to microscope slides, and mounted using ProLong Gold anti-fade solution and coverslips.

[0232] Imaging and Quantification: Slides were imaged using a Leica SP8 Scanning Resonant Confocal Microscope using identical settings and laser power. At least 3 fields of view were collected per sample. Fiji (Image J) software was used for processing all the images. All images were processed with the parameters described below: Contrast adjustment - the value of contrast for the APOE4 channel was set to 150 to 255, and the C5b-9 channel was set to 70 to 255 to improve the accuracy of object observation. Thresholding - the cutoff value of the threshold for the APOE4 channel was set as 110, and the C5b-9 channel was set as 80 to identify the pixels as real expressions. Measurements of the total positive puncta area were then exported as a .csv file for analysis. All images were taken in triplicate per treatment. Results are presented as mean + SEM and were graphed using Graph Pad PRISM vlO. Statistical significance was established using one-way ANOVA tests followed by Tukey’s multiple comparisons test.

[0233] The data show that Compound 1 effectively reduces drusenoid deposits. It is also more potent that ATV, noted by the activity at low concentration of 10 nM, while ATV loses activity below about 100 nM.Example 3: In Vitro HMG-CoA Reductase (HMGCR) Activity Assay

[0234] In Vitro HMGCR Activity Assay: The in vitro HMGCR activity assay was performed following the instruction of a commercial kit purchased from Sigma- Aldrich (Catalog number CS1090). The assay is based on a spectrophotometric measurement of the decrease in absorbance at 340 nm, which represents the oxidation of NADPH by the catalytic subunit of HMGCR in the presence of its substrate, HMG-CoA. Samples with 5% human serum (HS) incubation were prepared 24 hours before the measurement. HSwas diluted by XVI VO culture medium to form a 5% HS / XVIVO medium. ATV and Compound 1 were diluted by 5% HS / XVIVO medium to 200 pM solutions and were incubated overnight in an incubator set at 37 °C with 5% CO2. All the reagents from the kit were thawed at room temperature and transferred onto ice. The concentrated assay buffer was diluted by ultrapure water 5-fold to prepare IX assay buffer which was used to reconstitute NADPH. For samples without 5%HS incubation, ATV and Compound 1 were diluted by IX assay buffer to prepare 200 pM ATV or Compound 1 solution. The IX assay buffer was equilibrated to 37 °C before preparing a master mixture of each sample. All the reagents for the master mixture were added in the following order: IX assay buffer, prepared ATV or Compound 1 solution (final concentration to 1 pM), reconstituted NADPH (final concentration to 400 pM), HMG- CoA substrate (0.3 mg / mL as final concentration), and recombinant enzyme of HMGCR catalytic subunit (6 pg). Samples without ATV or Compound 1 served as positive controls and samples with only substrate were used to represent blank baseline. The mixture was immediately transferred in triplicate per sample to a UV-compatible 96-well plate. The plate was immediately inserted into the plate reader and the absorbance at 340 nm was measured using the BioTek Cytation 5 Cell Imaging Multimode Reader (Agilent) prewarmed at 37 °C. The measurement was conducted with an orbital plate shaking at 300 rpm, followed by a kinetic program set with a 40-second interval for 40 minutes.

[0235] Data Analysis and Graph Preparation: The absorbance at 340 nm at each time point was recorded and exported as an Excel file. All the values were subtracted from the average of the blank baseline value (samples with only substrate) and the value from each well was further normalized to its value at the first time point. Results are presented as mean + SEM and graphed using Graph Pad PRISM vlO. The activity of HMGCR was calculated according to the following equation (TV as total volume = 0.2 mL, V as volume of enzyme = 0.002 mL, LP as light path = 0.55 cm), representing the ability to convert NADPH in pmol / min / mg-protein. The values were then normalized to positive control which represents 100% HMGCR activity. Results are presented as mean + SEM and graphed using Graph Pad PRISM vlO.12.44 x V x 0.6 X LP

[0236] The data show that Compound 1 is not active unless incubated with human serum, which is known to contain CES. Compound 1 is also not biochemically active at 10 nM, suggesting enhanced uptake in RPE that results in increased potency in the drusen model.Example 4: Toxicity Evaluation of Atorvastatin and Atorvastatin-Prodrug in the RPE Model

[0237] Retinal Pigmented Epithelium Cell Culture: Human induced pluripotent stem-cell-derived retinal pigmented epithelium (hiPSC-RPE) cells were cultured on a 96-well black polystyrene plate with a clear bottom for at least 4 weeks in a serum-free XVIVO culture medium. Maturation of hiPSC-RPE was confirmed by observing polygonal and pigmented monolayers under phase contrast and bright-field microscopy.

[0238] Incubation of Atorvastatin or Atorvastatin-prodrug: The matured iPSC-RPE was incubated with 10 uM of ATV or Compound 1 (triplicates per sample) diluted by serum-free XVIVO culture medium. The viability assay was performed at the following time points: before treatment, 24 hours, 3 days, 7 days, and 11 days. The medium was exchanged with fresh cultured medium containing ATV or Compound 1 after each measurement and the cells were continued incubated in an incubator set at 37 °C with 5% CO2.

[0239] hiPSC-RPE Viability Assay: The cell viability assay was performed following the instruction of a commercial kit, CellTiter-FluorTM, purchased from Promega (Catalog number G6080). The viability assay was conducted at indicated time points. To prepare a 2X reaction reagent, the assay buffer was thawed at 37 °C and the GF-AFC substrate was added to the assay buffer. Cells treated with 0.2% Triton- X-100 for 30 minutes served as negative controls of the viability assay. Cells without any treatment were the positive controls, and wells without any cells seeded were used as Blank backgrounds. At each viability measurement, the medium was exchanged with fresh culture medium, and an equal volume of 2X reaction reagent was added. The plate was then incubated for 30 minutes in an incubator set at 37 °C with 5% CO2. After the incubation period, the fluorescence signal from each well (405 nm excitation and 505 nm emission) was measured using the GloMax® Discover Microplate Reader (Promega).

[0240] Data Analysis and Graph Preparation: The data was exported as an Excel file from the microplate reader. All the values were subtracted from the average of the Blank background value and normalized to non-treated controls to generate the relative fold change in viability. This value from each well was further normalized to its normalized value at the first time point measurement to reduce the possible well variation across the plate. Results are presented as mean + SEM and graphed using Graph Pad PRISM vlO.Example 5: Manufacture of Ocular Implants

[0241] 0.3 mm x 6 mm implants can be manufactured at a target drug load of 40% Compound 1 using the 3 selected Viatel polymers: DLG 7502 A, DLG 7502 E, and DL 03 E. Two extrusion cycles can be utilized to promote homogeneity of the API in the polymer.

[0242] Materials: Compound 1, Milled Viatel DLG 7502 A, Milled Viatel DLG 7502 E, and Milled Viatel DL 03 E.

[0243] First Extrusion - Compounding Extrusion: Milled Viatel polymers are removed from the freezer and allowed to reach ambient temperature before opening. Polymer and API are added to a Max 40 speedmixer cup at a target API loading of 40% w / w. The blend is speedmixed for 5 sec. at 2000rpm, manually shaken / mixed, then speedmixed again for 5 sec. at 2000rpm. The blend is manually fed into the miniCTW extruder with assistance of the manual feeding piston, extruded at a set screw speed through a 3 mm die, and drawn down to a target OD of 2.5 mm (determined by the conveyer speed). Extruded strands are pelletized to a target length of 2.5 mm (pelletizer pull speed: 1.85, cut speed: 3.95), sealed in a foil pouch with desiccants, and stored in the refrigerator.Powder Blend Compositions:Compounding Extrusion Parameters:

[0244] Milling Compounded Pellets: Compounded pellets are milled to powder form using the rotary grinder (coffee grinder). Milled powder is collected in a sterilization pouch, sealed in a foil pouch with desiccants, and stored in the refrigerator.

[0245] Second Extrusion - Final Strand Extrusion: The milled API-loaded polymers are removed from the refrigerator and allowed to reach ambient temperature before opening. Material is added to the force feeder hopper (water cooling set temp: 10 °C) and run for -5-10 minutes at a speed of 100 to prime the screw. The feeder is then attached to the feed port of the extruder. The extruder screws and the force feeder are started simultaneously and material is extruded through a 0.5 mm die. Extruder speed is adjusted as necessary to produce a stable extruder torque and output rate. Once stable, the extruder is switched to “constant torque” mode using the current measured torque. The extruded material is drawn down to the target OD of 0.30 mm (determined by the conveyor speed) and cut to approximately 6” lengths. After enough in-spec strands are collected, the conveyer speed is decreased to collect some strands at a target OD of 0.40 mm in case they are needed in the future. Extrusion is continued until enough strands are collected for evaluation. Any remaining unused powder is returned to refrigerated storage. Extruded strands from each formulation are collected in 3 plastic storage tubes (0.3 mm strands,0.4 mm strands, and strands of various OD collected during process adjustments). The tubes containing the strands are sealed in a foil pouch with desiccants and stored in the refrigerator.

[0246] Cutting & Packaging Implants: The extruded strands are removed from the refrigerator and allowed to reach ambient temperature before opening. For each formulation, 0.30 mm OD strands are used to cut n=20 implants to a target length of 6 mm.

[0247] Implant Dimensions (Using USB Digital Microscope):

[0248] Implant Weights (Using n=10 implant composite):Example 6: Bioresorbable Polymer Implant

[0249] The following formulations can be used to manufacture implants using a hot melt extrusion process (Details in Example 5).

[0250] Implant diameter can be maintained at 300 pm to allow for administration via a 25G needle. Components are shown in the Table below.

[0251] Formulations using a hot melt ram extrusion process. The implant diameter is maintained at a value of 250 um to 300 um for administration via a 25G needle. Components are shown in the Table below.Example 7: Benzyl Benzoate Composition

[0252] Solution formulations of various concentrations can be prepared by placing 10 g of benzyl benzoate in 20 mL scintillation vials and adding a specified amount of Compound 1 to the same vial. A vortex mixer was used to mix and dissolve Compound 1 in benzyl benzoate. Solutions concentrations prepared ranged from 1 mg / mL to 10 mg / mL Compound 1 in benzyl benzoate.

[0253] In vitro drug release rate studies are performed by placing 25 pL or 50 pL of Compound 1 solution in a vial containing buffer and drawing a sample from the vial at various time points and determining the concentration of atorvastatin in the buffer 18-day data indicate that sustained release ofatorvastatin is feasible and tunable based on concentration of drug in benzyl benzoate and droplet volume of the formulation.* * *

[0254] The present disclosure is not to be limited in scope by the specific embodiments described which are intended as single illustrations of individual aspects of the disclosure, and any compositions or methods which are functionally equivalent are within the scope of this disclosure. It will be apparent to those skilled in the art that various modifications and variations can be made in the methods and compositions of the present disclosure without departing from the spirit or scope of the disclosure. Thus, it is intended that the present disclosure cover the modifications and variations of this disclosure provided they come within the scope of the appended claims and their equivalents.

[0255] All publications and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.

Claims

What is claimed is:

1. A compound of Formula I:or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof; wherein L is Ci-io alkylene.

2. A compound of Formula IA:or a pharmaceutically acceptable salt, isotopically enriched analog, or prodrug thereof, wherein n is 0, 1, 2, 3, 4, 5, 6, 7, or 8.

3. A compound according to Table 1, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof.

4. A compound (Compound 1) having the structure:or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof.

5. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound according to any one of claims 1-4, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof.

6. An ocular implant comprising a compound according to any one of claims 1-4, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, or the pharmaceutical composition of claim 5, and a polymer matrix, wherein the compound is dispersed in the polymer matrix and the polymer matrix controls release of the compound.

7. A flowable composition comprising a compound according to any one of claims 1-4, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, or the pharmaceutical composition of claim 5, and a solvent or excipient, wherein the compound is dispersed in a solvent or excipient and the solvent or excipient controls release of the compound.

8. The flowable composition of claim 5, wherein the solvent or excipient is benzyl benzoate.

9. An extended release dosage form comprising a compound according to any one of claims 1-4, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, or the pharmaceutical composition of claim 5, wherein the extended release form administers the compound at a substantially constant drug pressure over a predetermined time period.

10. A method for treating or preventing one or more diseases or disorders selected from age-related macular degeneration (AMD), hypercholesterolemia, mixed dyslipidemia, atherosclerosis, coronary heart disease, acute coronary syndrome, type II diabetes, dyslipidemia, hypertriglyceridemia, hyperlipidemia, hyperfattyacidemia, hepatic steatosis, non-alcoholic steatohepatitis, non-alcoholic fatty liver disease, cancer, sepsis, infectious disease, glaucoma, or other ophthalmic disease in a patient in need thereof, comprising administering a compound according to any one of claims 1-4, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, the pharmaceutical composition of claim 5, the ocular implant of claim 6, the flowable composition of claim 7 or 8, or the extended release dosage form of claim 9, to the patient.

11. A method for treating or preventing hypercholesterolemia in a patient in need thereof, comprising administering a compound according to any one of claims 1-4, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, the pharmaceutical composition of claim 5, the ocular implant of claim 6, the flowable composition of claim 7 or 8, or the extended release dosage form of claim 9, to the patient.

12. A method of treating or preventing age-related macular degeneration (AMD), comprising administering a compound according to any one of claims 1-4, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, or the pharmaceutical composition of claim 5, the ocular implant of claim 6, the flowable composition of claim 7 or 8, or the extended release dosage form of claim 9, to a patient in need thereof, wherein the compound or composition is administered to the eye in an extended release dosage form, such that the concentration of compound within the eye is substantially maintained at a concentration of greater than about 10 nM for a treatment period of least 1 month.

13. A method of treating or preventing a retinal disease or disorder, comprising administering a compound according to any one of claims 1-4, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, the pharmaceuticalcomposition of claim 5, the ocular implant of claim 6, the flowable composition of claim 7 or 8, or the extended release dosage form of claim 9, to a patient in need thereof.

14. The method of claim 13, wherein the retinal disease or disorder is age-related macular degeneration, macular drusen (small, intermediate, large), peripheral drusen, extramacular drusen, drusenoid pigment epithelial detachment (PED), drusenoid deposits, basal laminar deposits, basal linear deposits, doyne honeycomb retinal dystrophy, Malattia Leventinese, familial dominant drusen (or autosomal dominant drusen), cuticular drusen, serous detachment of RPE, drupelets, RPE atrophy, geographic atrophy, ellipsoid zone (EZ) attenuation, EZ loss, incomplete retinal pigment epithelial and outer retinal atrophy (iRORA), complete retinal pigment epithelial and outer retinal atrophy (cRORA), nascent geographic atrophy, retinal flecks, fundus flavimaculatus, Best disease, adult-onset vitelliform macular dystrophy, Best vitelliform macular dystrophy, autosomal recessive bestrophinopathy, vitelliform material, pattern dystrophy, autosomal dominant vitreoretinochoroidopathy, BEST1 gene mutation disorders, retinal emboli (in retinal artery occlusion), retinal exudates, retinal exudates secondary to retinal microaneurysm, familial exudative vitreoretinopathy (FEVR), synchysis scintillans (cholesterolosis bulbi), neuronal ceroid lipofuscinosis, Batten's Disease, retinitis pigmentosa, Bietti’s crystalline dystrophy, juvenile macular degeneration (e.g., Stargardt disease), macular telangiectasia, maculopathy (e.g., age-related maculopathy (ARM) and diabetic maculopathy (DMP) (including partial ischemic DMP)), macular edema (e.g., diabetic macular edema (DME) (including clinically significant DME, focal DME and diffuse DME), Irvine-Gass Syndrome (postoperative macular edema), and macular edema following RVO (including central RVO and branch RVO)), retinopathy (e.g., diabetic retinopathy (including in patients with DME), Purtscher's retinopathy and radiation retinopathy), retinal artery occlusion (RAO) (e.g., central and branch RAO), retinal vein occlusion (RVO) (e.g., central RVO (including central RVO with cystoid macular edema (CME)) and branch RVO (including branch RVO with CME)), glaucoma (including low-tension, normal-tension and high-tension glaucoma), ocular hypertension, retinitis (e.g., Coats’ disease (exudative retinitis) or retinitis pigmentosa), chorioretinitis, choroiditis (e.g., serpiginous choroiditis), uveitis (including anterior uveitis, intermediate uveitis, posterior uveitis with or without CME, and pan-uveitis), retinal detachment (e.g., in von Hippel-Lindau disease), retinal pigment epithelium (RPE) detachment, bestrophinopathy, Doyne honeycomb / dominant drusen, and diseases associated with increased intra- or extracellular lipid storage or accumulation in addition to AMD.

15. The method of claim 13 or 14, wherein the administering is by intravitreal injection.

16. A method of treating or preventing age-related macular degeneration (AMD) comprising administering a compound according to any one of claims 1-4, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, the pharmaceutical composition of claim 5, the ocular implant of claim 6, the flowable composition of claim 7 or 8, or the extended release dosage form of claim 9, to a patient in need thereof.

17. The method of claim 16, wherein the, wherein the administering is by intravitreal injection.

18. A method of reducing drusen size and / or number comprising administering a compound according to any one of claims 1-4, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, the pharmaceutical composition of claim 5, the ocular implant of claim 6, the flowable composition of claim 7 or 8, or the extended release dosage form of claim 9, to a patient in need thereof wherein the administering is by intravitreal injection.

19. A method of preventing, reducing, or reversing complement activation in the eye comprising administering a compound according to any one of claims 1-4, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, the pharmaceutical composition of claim 5, the ocular implant of claim 6, the flowable composition of claim 7 or 8, or the extended release dosage form of claim 9, to a patient in need thereof, wherein the administering is by intravitreal injection.

20. The method of any one of claims 16-19, wherein the compound is administered in an interval of once per month, once per three months, once per six months, once per year, or a combination thereof.

21. A method of treating or preventing age-related macular degeneration (AMD), comprising administering an ultralow daily dose of a compound according to any one of claims 1-4, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, prodrug thereof, the pharmaceutical composition of claim 5, the ocular implant of claim 6, the flowable composition of claim 7 or 8, or the extended release dosage form of claim 9, to a patient in need thereof over the course of a treatment period.

22. The method of claim 21, wherein the compound is administered to an eye of the patient as an extended release dosage form.

23. The method of claim 21 or 22, wherein the ultralow daily dose of compound per eye is about 20 pg or less.

24. The method of claim 22 or 23, wherein the ultralow daily dose of compound per eye is from about 0.01 pg to about 20 pg.

25. The method of any one of claims 22-24, wherein the treatment period is 1-30 days, 4-52 weeks, 1-12 months, or 1-5 years.

26. A method for reducing low-density lipoprotein (LDL) in a patient in need thereof, comprising administering a compound according to any one of claims 1-4, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, or prodrug thereof, the pharmaceutical composition of claim 5, the ocular implant of claim 6, the flowable composition of claim 7 or 8, or the extended release dosage form of claim 9.

27. The method of claim 26, wherein the compound is administered orally.

28. The method of claim 26, wherein the compound is administered systemically.

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