HK40118703A - Method of treating wet age-related macular degeneration - Google Patents

Description

Treatment methods for wet age-related macular degeneration

Background of the Invention

background

Age-related macular degeneration (“AMD”) is a leading cause of blindness worldwide. AMD causes progressive loss of central vision due to macular degeneration and/or neovascularization, specifically in the macula, the central region of the retina. Generally, macular degeneration results in slow or rapid vision loss. It is estimated that AMD affects nearly 200 million people worldwide, with advanced AMD affecting nearly 11 million of them.

There are two forms of AMD: dry AMD and wet AMD. Typically, AMD begins as dry AMD, characterized by the formation of drusen, which are yellow, patchy deposits in the macula between the retinal pigment epithelium and the underlying choroid. Dry AMD can develop into wet AMD.

Dry macular degeneration (AMD) is more common than wet AMD, with approximately 90% of AMD patients being diagnosed with dry AMD. Dry AMD can be caused by aging and thinning of the macular tissue, pigment deposition in the macula, or a combination of both processes.

The wet form of this disease typically causes more severe vision loss. Wet AMD is characterized by the formation of new blood vessels in the choroid (choroidal neovascularization), macular atrophy (geographic atrophy), and vision loss. In wet AMD, new blood vessels grow beneath the retina and leak blood and fluid. This leakage causes retinal cell death and creates blind spots in central vision.

A person may have AMD in one eye or both eyes, and the AMD in each eye may be at a different stage. Wet AMD usually occurs first in one eye, called unilateral wet AMD. Patients with wet AMD in one eye have a significant risk of developing choroidal neovascularization in their contralateral eye. Retrospective studies of patients with unilateral wet AMD treated with anti-vascular endothelial growth factor (VEGF) therapy, including those followed for at least three years after the start of treatment, found that in 38% of patients, contralateral conversion occurred in the first eye within a three-year window following the onset of wet AMD.

There are some treatments for wet AMD, but existing treatments are inconvenient or have significant adverse effects, and these treatments cannot cure wet AMD. Furthermore, there are currently no drugs to prevent wet AMD.

Summary of the Invention

Based on various embodiments of the present invention and after extensive experimentation, the inventors have invented a novel biodegradable drug delivery insert comprising an active pharmaceutical ingredient (API) and a biodegradable polymer, and a method of using this insert. This insert is particularly useful for the topical delivery of an effective amount of API to the eye. Furthermore, the insert provides sustained release of the API. In some aspects, the duration of sustained API release provided by the insert is almost synchronized with the duration required for complete dissolution of the insert in the eye.

Such inserts can be administered intraocularly, such as intravitreal, suprachoroidal, intraanterior chamber, or subconjunctival. For example, the insert can be placed via a needle or cannula for intravitreal injection. Therefore, in some aspects, the present invention relates to a drug delivery insert that delivers an effective intraocular concentration of API while simultaneously delivering a low systemic concentration of API to reduce the risk of toxicity or other undesirable side effects.

Therefore, in some aspects, the present invention relates to the use of inserts for treating or preventing the eye diseases described herein by topical (e.g., intraocular) application of an API or a pharmaceutically acceptable salt thereof.

In some embodiments, the present invention provides a method for treating wet age-related macular degeneration (AMD), the method comprising: assessing the presence of subfoveal intraretinal fluid (IRF) in an eye diagnosed with wet AMD, wherein the eye is in a human subject, and if subfoveal IRF is not detected, administering to the eye an ocular drug delivery insert comprising vorolanib or a pharmaceutically acceptable salt thereof, wherein the insert releases about 0.01 μg/day to about 100 μg/day of vorolanib for at least 60 days.

In other aspects, the present invention provides a method for treating wet AMD, the method comprising: administering an ocular drug delivery insert comprising voronib or a pharmaceutically acceptable salt thereof to an eye diagnosed with wet AMD, wherein the eye is in a human subject and no foveal IRF is detected in the eye at baseline, wherein the insert releases about 0.01 μg/day to about 100 μg/day of voronib for at least 60 days.

In other embodiments, the present invention provides a method for treating wet age-related macular degeneration (AMD), the method comprising: assessing the presence of subfoveal intraretinal fluid (IRF) in an eye diagnosed with wet AMD, wherein the eye is in a human subject, and if subfoveal IRF is not detected, administering to the eye an ocular drug delivery insert comprising voronib or a pharmaceutically acceptable salt thereof, wherein the insert has an average drug release rate of voronib of about 0.01 μg/day to about 100 μg/day over a 30-day period.

In other aspects, the present invention provides a method for treating wet AMD, the method comprising: administering an ocular drug delivery insert comprising voronib or a pharmaceutically acceptable salt thereof to an eye diagnosed with wet AMD, wherein the eye is in a human subject and no foveal IRF was detected in the eye at baseline, wherein the insert has an average drug release rate of voronib of about 0.01 μg/day to about 100 μg/day over a 30-day period.

In some embodiments, the present invention provides a method for treating a posterior ocular condition, the method comprising: assessing the presence of subfoveal intraretinal fluid (IRF) in an eye diagnosed with the posterior ocular condition, wherein the eye is in a human subject, and if subfoveal IRF is not detected, administering to the eye an ocular drug delivery insert comprising voronib or a pharmaceutically acceptable salt thereof, wherein the insert releases about 0.01 μg/day to about 100 μg/day of voronib for at least 60 days.

In other aspects, the present invention provides a method for treating a posterior ocular condition, the method comprising: administering an ocular drug delivery insert comprising voronib or a pharmaceutically acceptable salt thereof to an eye diagnosed with the posterior ocular condition, wherein the eye is in a human subject and no foveal IRF is detected in the eye at baseline, wherein the insert releases about 0.01 μg/day to about 100 μg/day of voronib for at least 60 days.

In some embodiments, the present invention provides a method for treating a posterior ocular condition, the method comprising: assessing the presence of subfoveal intraretinal fluid (IRF) in an eye diagnosed with the posterior ocular condition, wherein the eye is in a human subject, and if subfoveal IRF is not detected, administering to the eye an ocular drug delivery insert comprising voronib or a pharmaceutically acceptable salt thereof, wherein the insert has an average drug release rate of voronib of about 0.01 μg/day to about 100 μg/day over a 30-day period.

In other aspects, the present invention provides a method for treating a posterior ocular condition, the method comprising: administering an ocular drug delivery insert comprising voronib or a pharmaceutically acceptable salt thereof to an eye diagnosed with the posterior ocular condition, wherein the eye is in a human subject and no foveal IRF was detected in the eye at baseline, wherein the insert has an average drug release rate of voronib of about 0.01 μg/day to about 100 μg/day over a 30-day period.

Furthermore, the present invention provides a method for treating posterior ocular diseases, the method comprising: administering an ocular drug delivery insert comprising voronib or a pharmaceutically acceptable salt thereof to an eye diagnosed with a posterior ocular disease, wherein the CST in the eye is 500 μm or less, wherein the insert releases about 0.01 μg/day to about 100 μg/day of voronib for at least 60 days.

In other embodiments, the present invention provides a method for treating posterior ocular diseases, the method comprising: assessing whether the central retinal thickness (CST) in an eye diagnosed with the posterior ocular disease is 500 μm or less; if the CST is 500 μm or less, administering to the eye an ocular drug delivery insert comprising voronib or a pharmaceutically acceptable salt thereof, wherein the insert has an average drug release rate of voronib of about 0.01 μg/day to about 100 μg/day over a 30-day period.

In other embodiments, the present invention provides a method for treating a posterior ocular condition, the method comprising: administering an ocular drug delivery insert comprising voronib or a pharmaceutically acceptable salt thereof to an eye diagnosed with the posterior ocular condition, wherein the CST in the eye is 500 μm or 500 μm, wherein the insert has an average drug release rate of voronib of about 0.01 μg/day to about 100 μg/day over a 30-day period.

In some aspects of the approach, the posterior ocular condition is wet AMD.

In other aspects of the approach, the posterior eye condition is diabetic macular edema.

In other aspects of the method, the posterior eye condition is diabetic retinopathy.

In other embodiments of the method, the posterior eye condition is nonproliferative diabetic retinopathy.

In other embodiments of the method, the posterior ocular condition is retinal vein occlusion. In some embodiments, the ocular drug delivery insert is administered to the eye with a baseline CST of less than 500 μm, 400 μm, 350 μm, 300 μm, 250 μm, or 200 μm. In some embodiments, the ocular drug delivery insert is administered to the eye with a CST of less than 500 μm, 400 μm, 350 μm, 300 μm, 250 μm, or 200 μm on the day of insert administration.

In other embodiments, the ocular drug delivery insert is applied to an eye with a baseline CST of 500 μm or less, 400 μm or less, 350 μm or less, 300 μm or less, 250 μm or less, or 200 μm or less. In still other embodiments, the ocular drug delivery insert is applied to an eye with a CST of 500 μm or less, 400 μm or less, 350 μm or less, 300 μm or less, 250 μm or less, or 200 μm or less.

For example, if the baseline CST in the eye is 350 μm or less, an ophthalmic drug delivery insert is applied to that eye. Alternatively, if the CST in the eye on the day of application is 350 μm or less, an ophthalmic drug delivery insert is applied to that eye.

In some aspects of the method, the eyes were not treated with voronib.

In some aspects of the method, the insert comprises a solid matrix core containing voronib or a pharmaceutically acceptable salt thereof and a matrix polymer. In some embodiments, the matrix polymer is polyvinyl alcohol (PVA). In some embodiments, the amount of matrix polymer in the insert is from about 1% w/w to about 15% w/w.

In some embodiments of the method, the amount of voronib or a pharmaceutically acceptable salt thereof in the insert is from about 60% w/w to about 98% w/w. In other embodiments, the amount of voronib or a pharmaceutically acceptable salt thereof in the insert is from about 85% w/w to about 99% w/w.

In some embodiments of the method, the insert is capable of being etched away by at least 90% within 440 days. In other embodiments, the insert comprises about 200 μg to about 2000 μg of voronib or a pharmaceutically acceptable salt thereof.

In some embodiments of the method, the insert is administered via intravitreal injection through a 20- to 27 gauge needle or cannula. In some embodiments, the length of the insert is from about 1 mm to about 10 mm. In some embodiments, 1 to 6 inserts are injected. In other embodiments, the total amount of voronib in all inserts is from about 600 μg to about 6000 μg. In other embodiments of the method, one or more ocular drug delivery inserts deliver a total average daily dose of voronib from about 1 μg/day to about 50 μg/day for at least 90 days.

In other embodiments of the method, the insert releases approximately 0.1 μg/day to approximately 30 μg/day of voronib for at least 90 days. In still other embodiments, the insert releases approximately 0.1 μg/day to approximately 30 μg/day of voronib for at least 120 days.

In some embodiments of the method, the eye does not require supplemental treatment for at least 120 days from the date of application of the insert.

In other embodiments, the change in best corrected visual acuity (BCVA) relative to baseline at 120 days after insert application is a loss of ≤5 ETDRS letters. In still other embodiments, the change in best corrected visual acuity (BCVA) relative to baseline at 120 days after insert application is a loss of ≤10 ETDRS letters. In some embodiments, the change in best corrected visual acuity (BCVA) relative to baseline at 120 days after insert application is a loss of ≤15 ETDRS letters. In some embodiments, the change in best corrected visual acuity (BCVA) relative to baseline at 120 days after insert application is an increase of ≥5 ETDRS letters.

In other aspects of the method, the change in best-corrected visual acuity (BCVA) relative to baseline was an increase of ≥10 ETDRS letters on the 120-day post-insertion date. In still other aspects, the change in best-corrected visual acuity (BCVA) relative to baseline was an increase of ≥15 ETDRS letters on the 120-day post-insertion date. In other embodiments, the subject's IVI questionnaire composite score did not significantly increase relative to baseline for at least 180 days from the date of insert application.

This document describes additional embodiments of inserts that can be used in the methods of the present invention. Therefore, the methods described above are not limited to the application of inserts having only the characteristics described above (such as drug release rate and insert degradation rate).

For example, in some embodiments, the insert does not have a coating. In other embodiments, the matrix polymer is PVA.

In some embodiments, the insert comprises a coating substantially surrounding the core. In other embodiments, the insert also comprises a delivery port. In some embodiments, the coating comprises PVA.

In other embodiments, the matrix polymer is PVA and the coating contains a different grade of PVA than the matrix polymer.

In some aspects of the method, the insert is cured at about 60°C to about 120°C for about 200 minutes to about 1440 minutes.

In some embodiments of the method, the ocular drug delivery insert comprises a solid matrix core comprising a matrix polymer and voronib or a pharmaceutically acceptable salt thereof, wherein the amount of voronib or a pharmaceutically acceptable salt thereof in the insert is from about 10% w/w to about 98% w/w, and wherein the drug release rate of the insert is from about 0.01 μg/day to about 100 over 95 days. In another embodiment, the amount of voronib or a pharmaceutically acceptable salt thereof in the insert is from about 60% w/w to about 98% w/w.

In other embodiments, the insert further comprises a coating substantially surrounding the core. In some embodiments, the amount of coating is from about 5% w/w to about 20% w/w of the insert. In other embodiments, the insert further comprises a delivery port.

In some embodiments of the method, the ocular drug delivery insert comprises a solid matrix core containing an API and at least two different grades of PVA, wherein the drug release rate of the insert is from about 0.0001 μg/day to about 200 μg/day for at least 30 days, wherein the insert is capable of at least 20% erosion within 95 days, and wherein the insert is sized and shaped to fit through a 20 to 27 gauge needle or cannula. In some embodiments, the two different grades of PVA are selected from a mixture comprising the following list: a mixture of MW 78,000, 88% hydrolyzed and MW 78,000, 98% hydrolyzed; a mixture of MW 78,000, 88% hydrolyzed and MW 78,000, 99+% hydrolyzed; a mixture of MW 6,000, 80% hydrolyzed and MW 78,000, 98% hydrolyzed; a mixture of MW 6,000, 80% hydrolyzed and MW 78,000, 99+% hydrolyzed; a mixture of MW 78,000, 88% hydrolyzed and MW 125,000, 88% hydrolyzed; and a mixture of MW 6,000, 80% hydrolyzed and MW 125,000, 88% hydrolyzed.

In other embodiments of the method, the ocular drug delivery insert comprises (a) a solid matrix core comprising PVA and API, and (b) a coating comprising PVA substantially surrounding the core; wherein the insert comprises at least two different grades of PVA, wherein the insert is capable of being etched at least 20% within 95 days, and wherein the insert is sized and shaped to fit through a 20 to 27 gauge needle or cannula.

In some embodiments of the method, the ocular drug delivery insert comprises:

(a) A solid matrix core comprising PVA selected from the following: MW 6,000, 80% hydrolyzed; MW 9,000 to 10,000, 80% hydrolyzed; MW 25,000, 88% hydrolyzed; MW 25,000, 98% hydrolyzed; MW 30,000 to 70,000, 87% to 90% hydrolyzed; MW 78,000, 88% hydrolyzed; MW 78,000, 98% hydrolyzed; MW 78,000, 99+% hydrolyzed; MW 89,000 to 98,000, 99+% hydrolyzed; MW 85,000 to 124,000, 87% to 89% hydrolyzed; MW 108,000, 99 ⁺ % hydrolyzed; MW 125,000, 88% hydrolyzed; MW 133,000, 99% hydrolyzed; 146,000 to 186,000, 99+% hydrolyzed, and mixtures thereof; and API; and

(b) At least one PVA-containing coating substantially surrounding the core, wherein the PVA in the coating is selected from the following PVAs: MW 6,000, 80% hydrolyzed; MW 9,000 to 10,000, 80% hydrolyzed; MW 25,000, 88% hydrolyzed; MW 25,000, 98% hydrolyzed; MW 30,000 to 70,000, 87% to 90% hydrolyzed; MW 78,000, 88% hydrolyzed; MW 78,000, 98% hydrolyzed; MW 78,000, 99+% hydrolyzed; MW 89,000 to 98,000, 99+% hydrolyzed; MW 85,000 to 124,000, 87% to 89% hydrolyzed; MW 108,000, 99 ⁺ % hydrolyzed; MW 125,000 MW, 88% hydrolyzed; 133,000 MW, 99% hydrolyzed; 146,000 to 186,000 MW, 99+% hydrolyzed; and mixtures thereof;

The PVA in the core and at least one coating consists of different grades of PVA.

In some embodiments of the method, the coating comprises a different grade of PVA compared to the core PVA. In some embodiments, the DH of the PVA in the coating differs from the DH of the core PVA. In other embodiments, the MW of the PVA in the coating differs from the MW of the core PVA. In some embodiments, the coating comprises at least two coatings containing PVA, wherein at least one of the coatings contains a different grade of PVA than at least one other coating. In some embodiments, the DH of the PVA differs in at least two coatings. In some embodiments, the MW of the PVA differs in at least two coatings.

Additional embodiments of inserts that can be used in the methods of the present invention are described below.

Attached Figure Description

Figure 1 depicts an exemplary ocular drug delivery insert used in this invention.

Figure 2 depicts the average weight change of PVA membranes of different grades after immersion in PBS for 24 hours.

Figure 3 depicts a scale showing the relative membrane strength of the membranes being evaluated.

Figure 4A depicts the in vitro drug release curves showing the cumulative drug release percentage of the insert for formulation A, which is a coated formulation cured at 140°C for 4 hours.

Figure 4B depicts an in vitro drug release curve showing the cumulative amount (μg) of drug released from the insert of formulation A.

Figure 5 shows photographs of the etched formulation A inserts taken after immersion in the dissolving medium for 314 days and 447 days, with the photograph of the inserts on day 447 including the intact inserts for comparison.

Figure 6 depicts the in vitro drug release profile of an uncoated formulation A insert, which is identical to formulation A but without a coating.

Figure 7 shows photographs of the etched, uncoated Formulation A inserts collected after immersion in the dissolving medium for 287 and 352 days, with the photograph of the insert on day 352 including the intact insert for comparison.

Figure 8A depicts the in vitro drug release curves showing the cumulative drug release percentage of the formulation B insert, which is a coated formulation cured at 140°C for 30 minutes.

Figure 8B depicts the in vitro drug release curves showing the cumulative drug release (μg) of the insert of formulation B.

Figure 9 shows photographs of the etched Formulation B inserts collected after immersion in the dissolving medium for 59, 88, and 155 days.

Figure 10 depicts the in vitro drug release profile of formulation C insert, i.e., the uncured encapsulated formulation.

Figure 11 shows photographs of two samples of the etched formulation C insert collected after immersion in a dissolving medium at 37°C for 98 days and then at room temperature for 113 days.

Figure 12 shows a comparison of the in vitro drug release curves of formulations A, B, and C.

Figure 13A depicts the average amount of residual drug in the inserts over time in an in vivo study, where the inserts implanted in rabbit eyes were removed and analyzed at multiple time points to determine the amount of residual voronib in the inserts (μg). One curve shows the amount of inserts from eyes with 3 inserts implanted, and another curve shows the amount of inserts from eyes with 6 inserts implanted.

Figure 13B depicts the cumulative percentage of drug release from removed inserts over time from the same in vivo study. One curve shows the insert content from an eye with 3 inserts implanted, and another curve shows the insert content from an eye with 6 inserts implanted.

Figure 14 is a bar graph comparing the percentage of corrected total lesion fluorescence (CTFL) over time at different drug doses in a pig model of laser-induced choroidal neovascularization.

Figure 15 shows the 6-month mean change in the optimal BCVA from subject screening visits in a Phase 1 clinical trial.

Figure 16 shows the 6-month mean change in CST from subject screening visits during a Phase 1 clinical trial.

Figure 17 is a graph showing the 6-month no-supplementation rate for each visit in a Phase 1 clinical trial.

Figure 18 is a graph showing the 12-month no-supplementation rate of each visit in the Phase 1 clinical trial.

Figure 19 is a graph showing the 12-month no-supplementation rate for each visit of subjects who did not have excess fluid at screening in a Phase 1 clinical trial.

Detailed Implementation

1. Active pharmaceutical ingredient (API)

The insert of this invention comprises the active pharmaceutical ingredient (API) voronibue. API is sometimes referred to herein as a "medicine". In some embodiments of this invention, the API is a pharmaceutically acceptable salt of voronibue.

Voronib has the chemical name (S,Z)-N-(1-(dimethylcarbamoyl)pyrrolidine-3-yl)-5-((5-fluoro-2-oxoindol-3-ylidene)methyl)-2,4-dimethyl _- 1H-pyrrolo-3 _- carboxamide. Synonyms include the term "X- ₈₂ ". Its molecular formula is _{C₂₃H₂₆FN₅O₃} . Voronib has a solubility of less than 10 μg/mL in water. Voronib has the following structure:

Voronib is an orally active multi-kinase inhibitor that can inhibit the activation of vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR).

Methods for manufacturing voronibu are described, for example, in U.S. Patent Nos. 7,683,057, 8,524,709, 8,039,470, and U.S. Publication No. 2019/0233403, each of which is incorporated herein by reference in its entirety.

As used herein, "voronibu or a pharmaceutically acceptable salt thereof" includes amorphous and crystalline forms, polymorphs, hydrates and solvates of voronibu or a pharmaceutically acceptable salt thereof.

In addition, this invention covers analogues, derivatives, pharmaceutically acceptable salts, esters, prodrugs, compound drugs and their protected forms that use APIs.

The term "pharmaceutically acceptable salt" refers to a salt that retains the biological efficacy and properties of the given compound and is not biologically or otherwise undesirable.

Pharmaceutically acceptable salts include salts with inorganic or organic acids, and salts with inorganic or organic bases. Those skilled in this art will recognize the various synthetic methods that can be used to prepare non-toxic, pharmaceutically acceptable salts.

Salts can be derived from inorganic acids, including hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and similar acids. Salts can also be derived from organic acids, including acetic acid, propionic acid, glycolic acid, gluconic acid, dihydroxynaphthyl acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, lactic acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid.

Pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Salts derived from inorganic bases include sodium, potassium, lithium, ammonium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines.

In addition, pharmaceutically acceptable salts include organic salts such as choline salts, glucosamine salts, tris(hydroxymethyl)aminomethane salts, meglumine salts, lysine salts, arginine salts, tributylamine salts, and benzathine salts.

In some embodiments, the API is an amorphous, crystalline, polymorphic, hydrated, or solvate.

Unless otherwise stated, the dosage described in this application (e.g., 100 μg) refers to the weight of the pharmacologically active fraction, not the weight of a given API salt or API ester. Therefore, for example, when the insert contains a pharmaceutically acceptable salt or ester of voronib, the weight must be adjusted to provide an amount of API salt equivalent to the amount of API described herein. In another embodiment, a drug release rate of 100 μg/day indicates that the insert releases 100 μg/day of the pharmacologically active fraction (e.g., voronib).

Before being formulated into inserts, the API may be milled to produce a fine particle size. In some embodiments, the API used to manufacture the inserts has a D ₉₀ of less than 200 μm, less than 100 μm, less than 50 μm, less than 40 μm, less than 30 μm, less than 20 μm, or less than 15 μm. In some embodiments, D ₉₀ is about 0.01 μm to about 100 μm, about 0.01 μm to about 80 μm, about 0.1 μm to about 50 μm, about 0.1 μm to about 20 μm, about 0.1 μm to about 15 μm, about 0.1 μm to about 12 μm, about 1 μm to about 50 μm, about 1 μm to about 30 μm, about 1 μm to about 25 μm, about 1 μm to about 20 μm, about 1 μm to about 15 μm, about 1 μm to about 12 μm, about 5 μm to about 10 μm, about 7 μm, about 8 μm, about 9 μm, about 10 μm, about 11 μm, or about 12 μm.

2. Ocular drug delivery inserts

"Ocular drug delivery inserts" are implantable devices that contain a drug and release it into the eye after implantation. "Ocular drug delivery inserts" encompasses all inserts described herein.

The ocular drug delivery insert comprises a core containing an API dispersed in a solid matrix. In some embodiments, the core is at least partially covered by a coating. In other embodiments, the insert consists only of the core. It is not surrounded by a coating or any kind of barrier surrounding the core. The insert is biodegradable.

In some embodiments, the insert comprises both a core and a coating. The coating is a layer that partially or completely surrounds the core. The coating is an outer layer that may be pre-formed into the desired shape (e.g., it may be a sleeve) before being placed to surround the core, or the coating may be formed by: co-extruding the core and coating, spraying the coating onto the core, or immersing the core in a coating material once or more (e.g., 1 to 10 coatings). If the core is coated, the coating may completely surround the core or may only partially surround the core.

The insert can be in various shapes, such as cylinder, rod, sphere, or disc. In some embodiments, the insert is cylindrical, and the coating covers the entire surface of the cylinder except for the end of the rod or cylinder. The end of the rod can serve as a delivery port. In some embodiments, one end of the cylinder is covered by the coating and the other end is uncovered. In some embodiments, one end is covered by a drug-impermeable cap, such as a silicone cap.

A rod is a solid geometry with parallel sides, where the length of one side is longer than the diameter or longest side of the cross-section. The cross-sectional shape can be circular, elliptical, square, rectangular, triangular, or a polygon such as a hexagon. Those skilled in the art will recognize that, due to the manufacturing process, the shape of the insert may not be precise; for example, the exterior may not be smooth or perfectly flat. For instance, the sides of a cylinder or rod may not be perfectly straight or perfectly parallel. The cross-section of a cylinder or rod may not be perfectly circular or elliptical. Cross-sections of other shapes may not precisely conform to the definition of that shape. For example, a square cross-section may not have perfectly straight sides, and the angles of its corners may not be precisely 90 degrees. A sphere or sphere may not be perfectly spherical.

a. matrix

In some embodiments, the core is a solid matrix comprising a matrix polymer and an API, which may be in solid form, such as powder, particles, or granules, dispersed throughout the matrix. The matrix components and the API form a homogeneous mixture in which the API is dispersed. The matrix is solid at room temperature and is biodegradable. The matrix helps control the API release rate, thus modulating the API release rate compared to unformulated API. In some embodiments, the matrix slows the drug release rate and provides longer drug delivery and less frequent dosing.

In some embodiments, the matrix also contains other pharmaceutically acceptable components. In other embodiments, the only material used to form the matrix is one or more matrix polymers.

The polymer used to form the matrix (“matrix polymer”) may include one or more of the following: polyvinyl alcohol (PVA), poly(caprolactone) (PCL), polyethylene glycol (PEG), poly(dl-lactide-co-glycolic acid) (PLGA), polyvinyl alcohol (PVA), poly(lactic acid) (PLA), poly(glycolic acid) (PGA), polyalkyl cyanoacrylate or copolymers thereof.

In some embodiments, the matrix polymer comprises PVA. In some embodiments, the only inert pharmaceutical component in the matrix is PVA.

Multiple grades of PVA can be used. The degree of hydrolysis (DH) of PVA can be from about 70% to about 99 ⁺ %, and the molecular weight (MW) can be from about 6,000 to 200,000, that is, the matrix polymer is PVA with a molecular weight of about 6,000 to 200,000, which is hydrolyzed from about 70 mol% to about ⁹⁹⁺ mol%. For example, DH can be approximately 70% to approximately 80%, approximately 80% to approximately 90%, approximately 80% to approximately 85%, approximately 88% to approximately 90%, approximately 90% to approximately 99 ⁺ %, approximately 98% to approximately 99 ⁺ %, approximately 80%, approximately 81%, approximately 82%, approximately 83%, approximately 84%, approximately 85%, approximately 86%, approximately 87%, approximately 88%, approximately 89%, approximately 90%, approximately 91%, approximately 92%, approximately 93%, approximately 94%, approximately 95%, approximately 96%, approximately 97%, approximately 98%, or approximately 99+ ^. %; and MW can be approximately 5000, approximately 6000, approximately 7000, approximately 8000, approximately 9000, approximately 10,000, approximately 15,000, approximately 18,000, approximately 20,000, approximately 25,000, approximately 30,000, approximately 40,000, approximately 50,000, approximately 60,000, approximately 70,000, approximately 75,000, approximately 78,000, approximately 80,000, approximately 85,000, approximately 90,000, approximately 100,000, approximately 108,000, approximately 110,000, approximately 120,000, approximately 125,000, approximately 130,000, approximately 133,000, approximately 140,000, approximately 146,000, approximately 150,000, approximately 160,000, approximately 170,000, approximately 180,000, approximately 186,000, approximately 190,000, or approximately 200,000. In some embodiments, MW may be about 5,000 to 10,000, about 6,000 to 10,000, about 9,000 to 10,000, about 10,000 to 30,000, about 10,000 to 25,000, about 25,000 to 50,000, about 30,000 to 70,000, about 60,000 to 80,000, about 70,000 to 80,000, approximately 75,000 to 80,000, approximately 75,000 to 100,000, approximately 89,000 to 98,000, approximately 85,000 to 124,000, approximately 100,000 to 150,000, approximately 146,000 to 186,000, or approximately 150,000 to 200,000. In some embodiments, the PVA is MW 6,000, 80% hydrolyzed; MW 9,000 to 10,000, 80% hydrolyzed; MW 25,000, 88% hydrolyzed; MW 25,000, 98% hydrolyzed; MW 30,000 to 70,000, 87% to 90% hydrolyzed; MW 78,000, 88% hydrolyzed; MW 78,000, 98% hydrolyzed; MW 78,000, 99+% hydrolyzed; MW 89,000 to 98,000, 99+% hydrolyzed; MW 85,000 to 124,000, 87% to 89% hydrolyzed; MW 108,000, 99 ⁺ % hydrolyzed; MW 125,000, 88% hydrolyzed; MW 133,000, 99% hydrolyzed; or MW 146,000 to 186,000, 99+% hydrolysis.

In other embodiments, the matrix polymer comprises a mixture of two, three, or four different grades of PVA. In some embodiments, the PVA is a mixture of two different grades of PVA. In some embodiments, the ratio of the two grades in the mixture is from 1:1 to 1:15. In some embodiments, the ratio of the two grades is 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, or 1:12 for the slower-etching PVA to the faster-etching PVA. The PVA etching rate can be measured as described in Example 1. For example, in some embodiments, the PVA mixture has a ratio of 1:9 6000MW, 80% DH to 125,000MW, 88% DH. In other embodiments, the ratio of the two grades in the mixture is 1:1 to 1:15 for the faster-etching PVA to the slower-etching PVA, such as 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, or 1:12.

Examples of PVA mixtures include mixtures of MW 6,000, 80% hydrolyzed and MW 78,000, 98% hydrolyzed; mixtures of MW 6,000, 80% hydrolyzed and MW 78,000, 99 ⁺ % hydrolyzed; mixtures of MW 78,000, 98% hydrolyzed and MW 78,000, 99 ⁺ % hydrolyzed; and mixtures of MW 6,000, 80% hydrolyzed and MW 125,000, 88% hydrolyzed.

MW and DH should be selected to provide the required drug release rate for a specific drug, an indication of the ocular drug delivery insert to be used, the required duration of drug release, and the required erosion rate.

The polymer solution used to form the core matrix may contain approximately 1% w/w to approximately 20% w/w, approximately 1% w/w to approximately 15% w/w, approximately 2% w/w to approximately 15% w/w, approximately 2% w/w to approximately 12% w/w, approximately 2% w/w to approximately 10% w/w, approximately 3% w/w to approximately 10% w/w, approximately 3% w/w to approximately 8% w/w, approximately 3% w/w to approximately 6% w/w, approximately 5% w/w to approximately 20% w/w, approximately 5% w/w to approximately 15% w/w, approximately 10% w/w to approximately 20% w/w, approximately 5% w/w to approximately 8% w/w, approximately 5% w/w to approximately 7% w/w, approximately 6% w/w to approximately 8% w/w, approximately 6% w/w Polymers such as PVA in solvents such as water or ethanol at a concentration of approximately 7% w/w, approximately 2% w/w, approximately 2.5% w/w, approximately 3% w/w, approximately 3.5% w/w, approximately 4% w/w, approximately 4.5% w/w, approximately 5% w/w, approximately 5.5% w/w, approximately 6% w/w, approximately 6.5% w/w, approximately 7% w/w, approximately 7.5% w/w, approximately 8% w/w, approximately 8.5% w/w, approximately 9% w/w, approximately 9.5% w/w, approximately 10% w/w, approximately 10.5% w/w, approximately 11% w/w, approximately 11.5% w/w, approximately 12% w/w, approximately 13% w/w, approximately 14% w/w, or approximately 15% w/w.

The polymer solution and API can be combined in ratios of approximately 0.5:1, approximately 1:1, approximately 1:1.2, approximately 1:1.5, approximately 1:1.7, or approximately 1:2 w/w API:polymer solution.

In some embodiments, the core comprises voronib or a pharmaceutically acceptable salt thereof and PVA. In some embodiments, the core consists of voronib or a pharmaceutically acceptable salt thereof and PVA.

In other embodiments, the PVA solution and API are combined in a ratio of approximately 1:1 w/w API:PVA solution.

In some embodiments, the PVA solution and API are combined in a ratio of approximately 1:2 w/w API:PVA solution.

In some embodiments, the core comprises about 0.1% w/w to about 90% w/w, about 0.1% w/w to about 80% w/w, about 0.1% w/w to about 70% w/w, about 0.1% w/w to about 60% w/w, about 0.1% w/w to about 50% w/w, about 0.1% w/w to about 40% w/w, about 0.1% w/w to about 30% w/w, about 0.1% w/w to about 25% w/w, about 0.1% w/w to about 20% w/w, and about 0. 1% w/w to about 15% w/w, about 0.1% w/w to about 10% w/w, about 1% w/w to about 20%, about 1% w/w to about 15%, about 1% w/w to about 10% w/w, about 1% w/w to about 9% w/w, about 1% w/w to about 8% w/w, about 1% w/w to about 7% w/w, about 1% w/w to about 6% w/w, about 2% w/w to about 10% w/w, about 2% w/w to about 8% w/w, about 2% w/w to about 6% w/w Approximately 3% w/w to approximately 90% w/w, approximately 3% w/w to approximately 75% w/w, approximately 3% w/w to approximately 60% w/w, approximately 3% w/w to approximately 40% w/w, approximately 3% w/w to approximately 20% w/w, approximately 3% w/w to approximately 15% w/w, approximately 3% w/w to approximately 10% w/w, approximately 3% w/w to approximately 8% w/w, approximately 3% w/w to approximately 7%, approximately 3% w/w to approximately 5% w/w, approximately 4% w/w to approximately 60% w/w, approximately 4% w/w to approximately 50%. Inert (non-API) components, such as matrix polymers, are present in weight percentages of approximately 4% w/w to approximately 40% w/w, approximately 4% w/w to approximately 25% w/w, approximately 4% w/w to approximately 20% w/w, approximately 4% w/w to approximately 15% w/w, approximately 4% w/w to approximately 10% w/w, approximately 4% w/w to approximately 8% w/w, approximately 4% w/w to approximately 7% w/w, approximately 5% w/w to approximately 10% w/w, approximately 5% w/w to approximately 8% w/w, or approximately 5% w/w to approximately 7% w/w. These weight percentages are based on the core dry weight (i.e., after any drying step in the process).

In some embodiments, the amount of matrix polymer in the core is about 0.1% w/w to about 90% w/w, about 0.1% w/w to about 80% w/w, about 0.1% w/w to about 70% w/w, about 0.1% w/w to about 60% w/w, about 0.1% w/w to about 50% w/w, about 0.1% w/w to about 40% w/w, about 0.1% w/w to about 30% w/w, about 0.1% w/w to about 25% w/w, about 0.1% w/w to about 20% w/w, about 0.1% w/w to about 15% w/w, about 0.1% w/w to about 10% w/w, about 1% w/w to about 20%, about 1% w/w to about 15%. %, about 1% w/w to about 10% w/w, about 1% w/w to about 9% w/w, about 1% w/w to about 8% w/w, about 1% w/w to about 7% w/w, about 1% w/w to about 6% w/w, about 2% w/w to about 10% w/w, about 2% w/w to about 8% w/w, about 2% w/w to about 6% w/w, about 3% w/w to about 90% w/w, about 3% w/w to about 75% w/w, about 3% w/w to about 60% w/w, about 3% w/w to about 40% w/w, about 3% w/w to about 20% w/w, about 3% w/w to about 15% w/w, about 3% w/w to about 10% w/w, about 3% w/w to about 8% w/w, about 3% w/w to about 7%, about 3% w/w to about 5% w/w, about 4% w/w to about 60% w/w, about 4% w/w to about 50% w/w, about 4% w/w to about 40% w/w, about 4% w/w to about 25% w/w, about 4% w/w to about 20% w/w, about 4% w/w to about 15% w/w, about 4% w/w to about 10% w/w, about 4% w/w to about 8% w/w, about 4% w/w to about 7% w/w, about 5% w/w to about 10% w/w, about 5% w/w to about 8% w/w, or about 5% w/w to about 7% w/w; or about 1%, 1.5%, 2% w/w, 2.5%w/w,3%w/w,3.5%w/w,4%w/w,4.5%w/w,5%w/w,5.5%w/w,6%w/w,6.5%w/w,7%w/w,7.5%w/w,8%w/w,8.5%w/w,9%w/w,9.5%w/w,10%w/w,1 0.5% w/w, 11% w/w, 11.5% w/w, 12% w/w, 15% w/w, 18% w/w, 20% w/w, 25% w/w, 30% w/w, 35% w/w, 40% w/w, 50% w/w, 55% w/w, 60% w/w, 65% w/w or 70% w/w. These weight percentages are based on the core dry weight (i.e., after any drying step in the process).

The term "insertion consists of" a core containing a solid matrix and an API, indicating that the entire insert is in the form of a solid matrix and an API. The matrix may also include additional components, but the insert does not have a shell, coating, cap, cover, tube, or other outer layer such that the exterior of the core is in direct contact with the liquid when the insert is immersed in a liquid environment, such as vitreous humor of the eye or an in vitro drug delivery medium.

b. Coating

In some embodiments of the invention, the insert comprises or consists of: (a) a core comprising an API and a solid matrix, and (b) a coating. In other embodiments, the insert does not comprise a coating.

In some embodiments, the coating is a diffusion membrane that is permeable to the API and acts as an active pharmaceutical ingredient. The diffusion membrane modulates the API release rate from the matrix. The diffusion membrane operates, for example, by regulating the flow rate of liquid entering the matrix and/or restricting the API from penetrating the matrix. In other embodiments, the coating increases the durability of the insert compared to an uncoated core, for example during processing, packaging, and/or dose delivery. In some embodiments, the coating modulates the API release rate and increases the durability of the insert.

The coating may completely surround the core or may only partially surround the core. In some embodiments, the coating substantially covers the core, meaning the coating covers at least 70% of the core's surface area. In some embodiments, the coating covers at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% of the core's surface area. In other embodiments, the coating surrounds about 40% to about 98%, about 50% to about 98%, about 60% to about 98%, about 70% to about 95%, about 70% to about 98%, about 70% to about 100%, about 80% to about 95%, about 80% to about 96%, about 80% to about 98%, about 80% to about 99%, about 90% to about 99%, or about 90% to about 98% of the core's surface area. For cylindrical inserts, the surface area A is calculated as A = 2πrL + 2πr², where r is the radius and L is the length of the insert. In some embodiments, a region of the core remains uncoated to form a delivery port. In some embodiments, more than one area remains uncovered to form more than one delivery port.

The delivery port is permeable to the API.

In some embodiments, the insert is rod-shaped, such as a cylinder, and only the ends of the rod/cylinder are uncoated.

To provide an illustration of an embodiment of the ocular drug delivery insert of the present invention, FIG1 shows an axial cross-sectional view of an ocular drug delivery insert 100 according to an embodiment of the present invention. The insert 100 comprises a solid matrix core 105. The insert 100 also comprises a coating 110 that substantially surrounds the core 105. The insert 100 is further characterized by two delivery ports 115 located at opposite ends of the insert 100. In this particular embodiment, at least one delivery port 115 comprises a membrane permeable to the API contained in the core 105 to allow the API to be released from the delivery port 115.

In some embodiments, the coating is biodegradable, similar to the matrix.

The coating may contain polymeric and/or non-polymeric components. In some embodiments, the coating contains one or more polymers, such as polyvinyl alcohol (PVA), poly(caprolactone) (PCL), polyethylene glycol (PEG), poly(dl-lactide-co-glycolic acid) (PLGA), poly(lactic acid) (PLA), poly(glycolic acid) (PGA), polyalkyl cyanoacrylate, or copolymers thereof.

In embodiments where the core is coated, the coating may be formed from 1 to 10 layers of polymer. For example, the core may be coated with 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 layers. In some embodiments, each of the coatings comprises the same polymer as the other coatings. In some embodiments, each of the coatings is composed of the same polymer as the other coatings. In other embodiments where the coating is formed from more than one layer, at least two of the coatings comprise different polymers.

In some embodiments, the coating comprises PVA. In other embodiments, the coating is composed of PVA. In some embodiments, the only inert pharmaceutical component in the coating is PVA. In other embodiments, both the matrix polymer and the coating comprise PVA. In still other embodiments, both the matrix polymer and the coating are composed of PVA.

Multiple grades of PVA can be used. The degree of hydrolysis (DH) of PVA can be from about 70% to about 99 ⁺ %, and the molecular weight (MW) can be from about 6,000 to 200,000, that is, the matrix polymer is PVA with a molecular weight of about 6,000 to 200,000, which is hydrolyzed from about 70 mol% to about ⁹⁹⁺ mol%. For example, DH can be approximately 70% to approximately 80%, approximately 80% to approximately 90%, approximately 80% to approximately 85%, approximately 88% to approximately 90%, approximately 90% to approximately 99 ⁺ %, approximately 98% to approximately 99 ⁺ %, approximately 80%, approximately 81%, approximately 82%, approximately 83%, approximately 84%, approximately 85%, approximately 86%, approximately 87%, approximately 88%, approximately 89%, approximately 90%, approximately 91%, approximately 92%, approximately 93%, approximately 94%, approximately 95%, approximately 96%, approximately 97%, approximately 98%, or approximately 99+ ^. %; and MW can be approximately 5000, approximately 6000, approximately 7000, approximately 8000, approximately 9000, approximately 10,000, approximately 15,000, approximately 18,000, approximately 20,000, approximately 25,000, approximately 30,000, approximately 40,000, approximately 50,000, approximately 60,000, approximately 70,000, approximately 75,000, approximately 78,000, approximately 80,000, approximately 85,000, approximately 90,000, approximately 100,000, approximately 108,000, approximately 110,000, approximately 120,000, approximately 125,000, approximately 130,000, approximately 133,000, approximately 140,000, approximately 146,000, approximately 150,000, approximately 160,000, approximately 170,000, approximately 180,000, approximately 186,000, approximately 190,000, or approximately 200,000. In some embodiments, MW may be about 5,000 to 10,000, about 6,000 to 10,000, about 9,000 to 10,000, about 10,000 to 30,000, about 10,000 to 25,000, about 25,000 to 50,000, about 30,000 to 70,000, about 60,000 to 80,000, about 70,000 to 80,000, approximately 75,000 to 80,000, approximately 75,000 to 100,000, approximately 89,000 to 98,000, approximately 85,000 to 124,000, approximately 100,000 to 150,000, approximately 146,000 to 186,000, or approximately 150,000 to 200,000. In some embodiments, the PVA is MW 6,000, 80% hydrolyzed; MW 9,000 to 10,000, 80% hydrolyzed; MW 25,000, 88% hydrolyzed; MW 25,000, 98% hydrolyzed; MW 30,000 to 70,000, 87% to 90% hydrolyzed; MW 78,000, 88% hydrolyzed; MW 78,000, 98% hydrolyzed; MW 78,000, 99+% hydrolyzed; MW 89,000 to 98,000, 99+% hydrolyzed; MW 85,000 to 124,000, 87% to 89% hydrolyzed; MW 108,000, 99 ⁺ % hydrolyzed; MW 125,000, 88% hydrolyzed; MW 133,000, 99% hydrolyzed; or MW 146,000 to 186,000, 99+% hydrolysis.

In other embodiments, the PVA is a mixture of two, three, or four different grades of PVA. In some embodiments, the PVA is a mixture of two different grades of PVA. In some embodiments, the ratio of the two grades in the mixture is from 1:1 to 1:15. In some embodiments, the ratio of the two grades is 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, or 1:12 for the slower-etching PVA to the faster-etching PVA. The PVA etching rate can be measured as described in Example 1. For example, in some embodiments, the PVA mixture has a ratio of 1:9 6000MW, 80% DH to 125,000MW, 88% DH. In other embodiments, the ratio of the two grades in the mixture is 1:1 to 1:15 for the faster-etching PVA to the slower-etching PVA, such as 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, or 1:12.

Examples of PVA mixtures include mixtures of MW 6,000, 80% hydrolyzed and MW 78,000, 98% hydrolyzed; mixtures of MW 6,000, 80% hydrolyzed and MW 78,000, 88% hydrolyzed; mixtures of MW 6,000, 80% hydrolyzed and MW 78,000, 99 ⁺ % hydrolyzed; mixtures of MW 78,000, 88% hydrolyzed and MW 78,000, 98% hydrolyzed; mixtures of MW 78,000, 98% hydrolyzed and MW 78,000, 99 ⁺ % hydrolyzed; and mixtures of MW 6,000, 80% hydrolyzed and MW 125,000, 88% hydrolyzed.

In some embodiments, the core comprises a mixture of two different grades of PVA. In some embodiments, the coating comprises a mixture of two different grades of PVA. In other embodiments, both the core and the coating comprise a mixture of two different grades of PVA. When the coating comprises more than one PVA layer, one or more of the coatings may comprise a mixture of two different grades of PVA.

In embodiments where both the core and coating contain PVA, the core PVA and coating PVA may be of the same or different grades of PVA. As used herein, the term "different grades of PVA" refers to PVAs with different molecular weights (MW), different degrees of hydrolysis (DH), or different MW and DH. Furthermore, as used herein, a mixture of PVA grades is considered "different grades of PVA" if the PVA being compared to a mixture is not a mixture of the same precise PVA grade. For example, a mixture of 6,000, 80% hydrolyzed PVA and 78,000, 98% hydrolyzed PVA would be considered a different grade of PVA than a PVA composition containing only 78,000, 98% hydrolyzed PVA or a PVA composition containing 6,000, 80% hydrolyzed PVA and 125,000, 88% hydrolyzed PVA.

Therefore, the core PVA and the coating PVA may have the same MW and DH, or MW or DH may be different, or both MW and DH may be different. In some embodiments, the core comprises a PVA, and the insert comprises a coating that comprises a PVA, wherein the MW of the coating PVA is the same as the MW of the core PVA, and the DH of the coating PVA is lower than the DH of the core PVA. In some embodiments, the MW and DH of the coating PVA are each lower than the MW and DH of the core PVA.

In some embodiments, the coating is formed by more than one coating. When the insert coating comprises coatings of more than one PVA, PVAs having the same MW and DH can be used in the core and at least one coating. In other embodiments, the core comprises a PVA with a different MW and/or DH than the PVAs in at least one coating. In some embodiments, the core comprises a PVA with both a different MW and DH than the PVAs in at least one coating. In other embodiments, the PVAs in the core and the PVAs in at least one coating have the same MW but different DHs. In some embodiments, the DH of the PVAs in at least one coating is lower than the DH of the PVAs in the core. In other embodiments, the PVAs in the core and the PVAs in at least one coating have different MWs but the same DH. In some embodiments, the MW of the PVAs in at least one coating is lower than the MW of the PVAs in the core.

In some embodiments, the insert coating comprises a single PVA-containing coating. In other embodiments, the insert coating comprises more than one PVA-containing coating, and the PVA in each coating has the same MW and DH. In some embodiments, at least one coating comprises a PVA with a different MW and/or DH than the PVA in at least one other coating. In some embodiments, at least one coating comprises a PVA with a different MW and DH than the PVA in at least one other coating. In some embodiments, no two coatings contain the same grade of PVA, i.e., the PVA in each coating has a different MW and/or DH than the PVA in the other coatings.

In some embodiments where the insert coating comprises more than one PVA-containing coating, the PVA in the outermost coating is more soluble (in PBS) than the PVA in any of the other coatings. In some embodiments, the PVA in at least one of the coatings is more soluble than the core PVA.

In some embodiments, the insert comprises (a) a solid matrix core comprising PVA and API, and (b) a coating comprising PVA substantially surrounding the core; and the DH of the PVA in the coating is lower than the DH of the PVA in the core. In one embodiment of this insert, the insert comprises two PVA-containing coatings. In other embodiments, the insert comprises three PVA-containing coatings. In still other embodiments, the insert comprises four PVA-containing coatings. In still other embodiments, the insert comprises five PVA-containing coatings. In still still other embodiments, the insert comprises six PVA-containing coatings.

In embodiments with more than one coating, the first coating applied to the core is the innermost coating, and the last coating applied is the outermost coating. In some embodiments where the insert has more than one PVA coating, the DH of the PVA in the innermost coating is higher than the DH of the PVA in the outermost coating. In other embodiments where the insert has more than one PVA coating, the MW of the PVA in the innermost coating is higher than the MW of the PVA in the outermost coating. In some embodiments, the DH of the PVA in the outermost coating is lower than the DH of the PVA in the other coatings. In other embodiments, the MW and DH of the PVA in the outermost coating are lower than the MW and DH of the PVA in any of the other coatings.

In some aspects, the insert comprises (a) a PVA selected from the group consisting of: MW 6,000, 80% hydrolyzed; MW 9,000 to 10,000, 80% hydrolyzed; MW 25,000, 88% hydrolyzed; MW 25,000, 98% hydrolyzed; MW 30,000 to 70,000, 87% to 90% hydrolyzed; MW 78,000, 88% hydrolyzed; MW 78,000, 98% hydrolyzed; MW 78,000, 99+% hydrolyzed; MW 89,000 to 98,000, 99+% hydrolyzed; MW 85,000 to 124,000, 87% to 89% hydrolyzed; MW 108,000, 99 ⁺ % hydrolyzed; MW 125,000, 88% hydrolyzed; MW 133,000, 99% hydrolyzed; MW 146,000 to 186,000, 99+% hydrolyzed and mixtures thereof; and a solid matrix core of API; and (b) at least one PVA-containing coating substantially surrounding the core, wherein the PVA in the coating is selected from the group consisting of: MW 6,000, 80% hydrolyzed; MW 9,000 to 10,000, 80% hydrolyzed; MW 25,000, 88% hydrolyzed; MW 25,000, 98% hydrolyzed; MW 30,000 to 70,000, 87% to 90% hydrolyzed; MW 78,000, 88% hydrolyzed; MW 78,000, 98% hydrolyzed; MW 78,000, 99+% hydrolyzed; MW 89,000 to 98,000, 99+% hydrolyzed; MW The PVA comprises 85,000 to 124,000 MW, 87% to 89% hydrolyzed; 108,000 MW, 99 ⁺ % hydrolyzed; 125,000 MW, 88% hydrolyzed; 133,000 MW, 99% hydrolyzed; 146,000 to 186,000 MW, 99+% hydrolyzed; and mixtures thereof; wherein the PVA in the core and the PVA in at least one coating are of different grades of PVA. In other aspects of this insert, the insert comprises coatings of at least two PVAs, and the DH of the PVA in the outermost coating is lower than the DH of any of the PVAs in the other coatings.

This invention provides the ability to adjust the PVA grade for use in the manufacture of ophthalmic inserts. The PVA AMW and DH of the core and coating should be selected to provide the drug release rate, duration of drug release, and rate of degradation required for a specific drug, the indication that the ophthalmic insert will be used. Different eye diseases or conditions may require different durations of drug release. For example, a 12-month duration of drug release (as provided by formulation A) may be needed to treat diabetic retinopathy, while an insert may require less than a month to suppress ocular inflammation caused by injury or surgery.

The polymer solution used to form the coating may contain about 1% w/w to about 20% w/w, about 1% w/w to about 15% w/w, about 1% w/w to about 10% w/w, about 2% w/w to about 15% w/w, about 2% w/w to about 12% w/w, about 2% w/w to about 10% w/w, about 2% w/w to about 8% w/w, about 2% w/w to about 6% w/w, about 3% w/w to about 10% w/w, about 3% w/w to about 8% w/w, about 3% w/w to about 6% w/w, about 2% w/w, about 2.5% w/w, about 3 ... Polymers such as PVA in solvents such as water or ethanol, at a concentration of approximately 3.5% w/w, 4% w/w, 4.5% w/w, 5% w/w, 5.5% w/w, 6% w/w, 6.5% w/w, 7% w/w, 7.5% w/w, 8% w/w, 8.5% w/w, 9% w/w, 9.5% w/w, 10% w/w, 10.5% w/w, 11% w/w, 11.5% w/w, 12% w/w, 13% w/w, 14% w/w, or 15% w/w.

For inserts containing a PVA coating, the core may be covered by 1 to 10 coatings of PVA solution, that is, the insert may contain 1 to 10 PVA coatings. For example, the insert may contain 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 PVA coatings.

In some embodiments, the weight of the insert coating is approximately 0.1% w/w to approximately 60% w/w, approximately 0.1% w/w to approximately 40% w/w, approximately 0.1% w/w to approximately 20% w/w, approximately 1% w/w to approximately 40% w/w, approximately 1% w/w to approximately 30% w/w, approximately 1% w/w to approximately 20% w/w, approximately 1% w/w to approximately 10% w/w, approximately 1% w/w to approximately 6% w/w, approximately 3% w/w to approximately 20% w/w, approximately 3% w/w /w to about 10% w/w, about 3% w/w to about 6% w/w, about 5% w/w to about 30% w/w, about 5% w/w to about 25% w/w, about 5% w/w to about 20% w/w, about 5% w/w to about 15% w/w, about 5% w/w to about 10% w/w, about 10% w/w to about 25% w/w, about 10% w/w to about 20% w/w, about 10% w/w to about 18% w/w, or about 12% w/w to about 18% w/w. These weight percentages are based on the dry weight of the insert (i.e., after any drying step in the process).

In some embodiments, the total amount of inactive component in the insert is about 0.1% w/w to about 90% w/w, about 0.1% w/w to about 80% w/w, about 0.1% w/w to about 70% w/w, about 0.1% w/w to about 60% w/w, about 0.1% w/w to about 50% w/w, about 0.1% w/w to about 40% w/w, about 0.1% w/w to about 30% w/w, about 0.1% w/w to about 25% w/w, about 0.1% w/w to about 20% w/w, about 0.1% w/w to about 15% w/w, or about 0.1% w/w to about 10%. w/w, about 1% w/w to about 70% w/w, about 1% w/w to about 50% w/w, about 1% w/w to about 20%, about 1% w/w to about 15%, about 1% w/w to about 10% w/w, about 1% w/w to about 9% w/w, about 1% w/w to about 8% w/w, about 1% w/w to about 7% w/w, about 1% w/w to about 6% w/w, about 2% w/w to about 10% w/w, about 2% w/w to about 8% w/w, about 2% w/w to about 6% w/w, about 3% w/w to about 90% w/w, about 3% w/w to about 75% w/w, about 3% w /w to about 60% w/w, about 3% w/w to about 40% w/w, about 3% w/w to about 20% w/w, about 3% w/w to about 15% w/w, about 3% w/w to about 10% w/w, about 3% w/w to about 8% w/w, about 3% w/w to about 7%, about 3% w/w to about 5% w/w, about 4% w/w to about 60% w/w, about 4% w/w to about 50% w/w, about 4% w/w to about 40% w/w, about 4% w/w to about 25% w/w, about 4% w/w to about 20% w/w, about 4% w/w to about 15% w/w, about 4% w/w Approximately 10% w/w, approximately 4% w/w to approximately 8% w/w, approximately 4% w/w to approximately 7% w/w, approximately 5% w/w to approximately 40% w/w, approximately 5% w/w to approximately 30% w/w, approximately 5% w/w to approximately 25% w/w, approximately 5% w/w to approximately 20% w/w, approximately 5% w/w to approximately 15% w/w, approximately 5% w/w to approximately 7% w/w, approximately 10% w/w to approximately 25% w/w, approximately 10% w/w to approximately 22% w/w, approximately 15% w/w to approximately 25% w/w, approximately 15% w/w to approximately 22% w/w, or approximately 18% w/w to approximately 22% w/w. These weight percentages are based on the dry weight of the insert (i.e., after any drying step in the process).

In some embodiments, the amount of PVA in the insert is about 0.1% w/w to about 30% w/w, about 0.1% w/w to about 25% w/w, about 0.1% w/w to about 20% w/w, about 0.1% w/w to about 15% w/w, about 0.1% w/w to about 10% w/w, about 1% w/w to about 80% w/w, about 1% w/w to about 75% w/w, about 1% w/w to about 60% w/w, about 1% w/w to about 30% w/w, about 1% w/w to about 20%, about 1% w/w to about 15%, or about 1% w/w to about 10%. w/w, about 1% w/w to about 9% w/w, about 1% w/w to about 8% w/w, about 1% w/w to about 7% w/w, about 1% w/w to about 6% w/w, about 2% w/w to about 10% w/w, about 2% w/w to about 8% w/w, about 2% w/w to about 6% w/w, about 3% w/w to about 90% w/w, about 3% w/w to about 80% w/w, about 3% w/w to about 75% w/w, about 3% w/w to about 70% w/w, about 3% w/w to about 60% w/w, about 3% w/w to about 40% w/w, about 3% w/w w to about 20% w/w, about 3% w/w to about 15% w/w, about 3% w/w to about 10% w/w, about 3% w/w to about 8% w/w, about 3% w/w to about 7%, about 3% w/w to about 5% w/w, about 4% w/w to about 60% w/w, about 4% w/w to about 50% w/w, about 4% w/w to about 40% w/w, about 4% w/w to about 25% w/w, about 4% w/w to about 20% w/w, about 4% w/w to about 15% w/w, about 4% w/w to about 10% w/w, about 4% w/w to about 8% w/w, about 4% w/w to about 7% w/w, about 5% w/w to about 40% w/w, about 5% w/w to about 30% w/w, about 5% w/w to about 25% w/w, about 5% w/w to about 20% w/w, about 5% w/w to about 15% w/w, about 5% w/w to about 10% w/w, about 5% w/w to about 7% w/w, about 10% w/w to about 25% w/w, about 10% w/w to about 22% w/w, about 15% w/w to about 25% w/w, about 15% w/w to about 22% w/w, or about 18% w/w to about 22% w/w. These weight percentages are based on the dry weight of the insert (i.e., after any drying step in the process).

In some embodiments, the present invention provides an insert having an extremely high drug content relative to the inactive component in the insert, which unexpectedly provides the insert with drug release capability over an extended period of time. In some embodiments, the amount of API in the insert is about 5% w/w to about 98% w/w, about 10% w/w to about 98% w/w, about 15% w/w to about 98% w/w, about 20% w/w to about 98% w/w, about 30% w/w to about 98% w/w, about 40% w/w to about 98% w/w, about 50% w/w to about 98% w/w, about 60% w/w to about 98% w/w, about 65% w/w to about 98% w/w, or about 70% w/w. Approximately 98% w/w, approximately 75% w/w to approximately 98% w/w, approximately 65% w/w to approximately 90% w/w, approximately 70% w/w to approximately 90% w/w, approximately 75% w/w to approximately 90% w/w, approximately 80% w/w to approximately 90% w/w, approximately 80% w/w to approximately 99% w/w, approximately 85% w/w to approximately 98% w/w, approximately 85% w/w to approximately 99% w/w, approximately 90% w/w to approximately 99% w/w, or approximately 90% w/w to approximately 98% w/w. These weight percentages are based on the dry weight of the insert (i.e., after any drying step in the process).

In some embodiments, the only inactive component in the insert is a polymer such as PVA.

The thickness of the coating around the core can be, for example, about 20 μm to about 400 μm, about 20 μm to about 300 μm, about 20 μm to about 200 μm, about 20 μm to about 100 μm, about 5 μm to about 75 μm, about 5 μm to about 50 μm, or about 5 μm to about 25 μm.

c. Shape and size of the insert

In some embodiments, when the insert is prepared for implantation in the vitreous body of the eye, the insert is no more than about 15 mm in any direction, or preferably no more than about 10 mm, so that the insert can be inserted through an incision of 15 mm or less.

In some embodiments, the insert may be shaped and sized for injection. In some embodiments, the insert is sized and shaped to fit through a cannula or needle of 20 gauge or smaller. This means that the insert can be injected through a cannula or needle of that gauge without abnormal force. The phrase “or smaller” in this context refers to a smaller outer diameter. A smaller outer diameter would correspond to a larger gauge number; for example, a 25 gauge needle has a smaller outer diameter than a 22 gauge needle.

In some embodiments, the insert is sized and shaped to fit through needles or cannulas of 20 to 27, 21 to 27, 22 to 27, 23 to 27, 24 to 27, 25 to 27, or 25.5 to 27.

In other embodiments, the insert is sized and shaped to fit through cannulas or needles of 20 or smaller, 22 or smaller, 23 or smaller, 24 or smaller, 25 or smaller, 25.5 or smaller, 26 or smaller, or 26.5 or smaller. Preferably, the insert is sized and shaped to fit through cannulas or needles smaller than 25, smaller than 26, or smaller than 27. In some embodiments, the insert is sized and shaped to fit through cannulas or needles of about 29 to about 25.5, such as about 28 to about 25.5, or about 28 to about 26. In some embodiments, the needle or cannula is about 22, 22s, 23, 24, or 25, but preferably about 25.5, 26, 26.5, 26s, 27, 27.5, 28, 28.5, 29, 29.5, 30, or 30.5.

In some embodiments, the insert is rod-shaped, cylindrical, or spherical, and may be less than about 12 mm in length and less than about 1 mm in diameter.

In some embodiments, the insert may be rod-shaped or cylindrical, and not exceeding 8 mm in length and 3 mm in diameter.

In some embodiments, the length of the insert is about 1 mm to 10 mm, 2 mm to 10 mm, 1 mm to 4 mm, 4 mm to 8 mm, 6 mm to 10 mm, 8 mm to 10 mm, 1 mm to 12 mm, 2 mm to 12 mm, or 4 mm to 12 mm; about 1 mm, about 1.5 mm, about 2 mm, about 2.5 mm, about 3 mm, about 3.5 mm, about 4 mm, about 4.5 mm, about 5 mm, about 5.5 mm, about 6 mm, about 6.5 mm, about 7 mm, about 7.5 mm, about 8 mm, about 8.5 mm, about 9 mm, about 9.5 mm, about 10 mm, about 10.5 mm, about 11 mm, about 11.5 mm, about 12 mm, about 12.5 mm, about 13 mm, about 13.5 mm, about 14 mm, about 14.5 mm, or about 15 mm.

In some embodiments, the diameter of the insert is about 0.1 mm to about 2 mm, about 0.1 mm to about 1 mm, about 0.1 mm to about 0.8 mm, about 0.1 mm to about 0.6 mm, about 0.1 mm to about 0.5 mm, about 0.3 mm to about 0.5 mm, about 0.3 mm to about 0.4 mm, about 0.2 mm to 0.4 mm, about 0.1 mm to 0.2 mm, or about 0.4 mm to about 0.6 mm; about 0.57 mm, about 0.50 mm, about 0.41 mm, about 0.42 mm, about 0.37 mm, about 0.34 mm, about 0.31 mm, about 0.26 mm, or about 0.15 mm.

d. Insert manufacturing

The insert can be manufactured by mixing an API with a matrix polymer. In some embodiments, the matrix polymer is a solution of one or more polymers in a solvent such as water or ethanol. The API, the matrix polymer solution, and any other matrix components are mixed to form a paste suitable for extrusion through a dispensing tip. The paste can be extruded through an 18 to 25 gauge sleeve or dispensing tip. In some embodiments, 21 to 23 or 23 to 26 gauge sleeves or dispensing tips are used. For example, the gauge of the sleeve or dispensing tip may be 20, 21, 22, 23, 24, 25, or 26. The extruded paste is referred to herein as an extrudate and is an elongated matrix or rod. The rod may be about 4 to 5 inches (about 10 to 13 cm) long. The extrudate is solid at room temperature. The extrudate may be coated with one or more additional layers. In some embodiments, the extrudate is dried at room temperature for at least 24 hours before coating.

During extrusion, extrusion parameters such as liquid pressure, flow rate, and temperature of the extruded material can be controlled. A suitable extruder can be selected to deliver co-extruded materials at pressures and flow rates sufficient to produce products that can be injected during segmentation and drying via needles or cannulas as described herein, at die head and outlet port or dispensing tip dimensions.

If a polymer solution is used and the extrudate is coated, the extruded API-polymer mixture is allowed to dry before coating. For example, the extrudate may be allowed to dry at room temperature for approximately 30 minutes to approximately 48 hours before coating.

The extrudate may be coated with one or more layers, although in some embodiments no coating is applied. The coating may be applied before segmenting into the desired insert length. Coating can be applied by immersing the extrudate in a liquid coating material and allowing it to dry or harden. This process can be repeated to add additional coatings. Alternatively, the coating may be sprayed onto the extrudate.

In other embodiments, the coating/outer layer may be pre-formed, for example, into a tubular shape, and an API-polymer paste may be extruded into the tube.

Depending on the polymer used for the substrate, the substrate may be cured. Curing can be achieved, for example, by heating in an oven, microwaving, or chemical treatment. In other embodiments, the substrate may not be cured. In practice, it may be allowed to dry at air temperature or at a temperature of about 80°C or lower.

In some embodiments, the substrate is uncured or cured by heating at a temperature below 80°C. In other embodiments, the substrate is cured at a temperature of about 80°C to about 160°C for about 10 minutes to about 300 minutes (5 hours), at a temperature of about 80°C to about 160°C for about 15 minutes to about 4 hours, at a temperature of about 120°C to about 160°C for about 15 minutes to about 4 hours, at a temperature of about 130°C to about 150°C for about 10 minutes to about 4 hours, at a temperature of about 140°C to about 160°C for about 10 minutes to about 30 minutes, and at a temperature of about 130°C to about 160°C for about 15 minutes to about 160°C for about 15 minutes to about 4 hours. Curing time is approximately 30 minutes to approximately 4 hours at 50°C, approximately 200 minutes to approximately 1440 minutes at approximately 60°C to approximately 120°C, approximately 300 minutes to approximately 600 minutes at approximately 60°C to approximately 100°C, approximately 400 minutes to approximately 500 minutes at approximately 80°C to approximately 90°C, approximately 600 minutes to approximately 1440 minutes at approximately 80°C to approximately 120°C, and approximately 800 minutes to approximately 1440 minutes at approximately 80°C to approximately 110°C.

In another embodiment, the matrix is cured at about 90°C for about 200 minutes to about 1600 minutes, at about 90°C for about 200 minutes to about 500 minutes, at about 90°C for about 500 minutes to about 1600 minutes, at about 90°C for about 240 minutes, at about 90°C for about 480 minutes, or at about 90°C for about 1440 minutes.

In some embodiments, the substrate is cured at about 100°C for about 200 minutes to about 1600 minutes, at about 100°C for about 200 minutes to about 500 minutes, at about 100°C for about 500 minutes to about 1600 minutes, at about 100°C for about 240 minutes, at about 100°C for about 480 minutes, or at about 100°C for 1440 minutes.

In some embodiments, the substrate is cured at about 110°C for about 30 minutes to about 1600 minutes, cured at about 110°C for about 30 minutes to about 200 minutes, cured at about 110°C for about 200 minutes to about 1600 minutes, cured at about 110°C for about 30 minutes, cured at about 110°C for about 60 minutes, cured at about 110°C for about 240 minutes, or cured at about 110°C for about 1440 minutes.

In other embodiments, the matrix is cured at about 140°C for about 10 minutes to about 4 hours, cured at about 140°C for about 10 minutes to about 1 hour, cured at about 140°C for about 15 minutes to about 30 minutes, cured at about 140°C for about 30 minutes to about 1 hour, cured at about 140°C for about 1 hour to about 4 hours, cured at about 140°C for about 1 hour to about 3 hours, cured at about 140°C for about 10 minutes to about 400 minutes, cured at about 140°C for about 30 minutes to about 400 minutes, cured at about 140°C for about 60 minutes to about 380 minutes, cured at about 140°C for about 60 minutes to about 300 minutes, cured at about 140°C for about 180 minutes to about 300 minutes, cured at about 140°C for about 220 minutes to about 280 minutes, cured at about 140°C for about 230 minutes to about 300 minutes, or cured at about 140°C for about 30 minutes to about 90 minutes.

Examples of curing temperatures include about 60°C to about 100°C, about 60°C to about 80°C, about 80°C to about 100°C, about 80°C to about 110°C, about 80°C to about 120°C, about 85°C to about 115°C, about 90°C to about 100°C, about 90°C to about 110°C, about 90°C to about 120°C, about 90°C to about 130°C, about 120°C to about 140°C, about 130°C to about 150°C, about 140°C to about 160°C, about 135°C to about 145°C, or about 140°C to about 150°C.

Examples of curing times include approximately 20 minutes to approximately 400 minutes, approximately 30 minutes to approximately 400 minutes, approximately 60 minutes to approximately 400 minutes, approximately 90 minutes to approximately 400 minutes, approximately 120 minutes to approximately 400 minutes, approximately 180 minutes to approximately 360 minutes, approximately 200 minutes to approximately 320 minutes, approximately 200 minutes to approximately 300 minutes, approximately 20 minutes to approximately 240 minutes, approximately 20 minutes to approximately 200 minutes, approximately 20 minutes to approximately 180 minutes, approximately 20 minutes to approximately 120 minutes, approximately 20 minutes to approximately 90 minutes, approximately 20 minutes to approximately 60 minutes, approximately 30 minutes to approximately 120 minutes, and approximately 60 minutes to approximately 180 minutes.

In addition, examples of curing times include approximately 10 minutes, approximately 15 minutes, approximately 20 minutes, approximately 30 minutes, approximately 45 minutes, approximately 60 minutes, approximately 75 minutes, approximately 90 minutes, approximately 105 minutes, approximately 120 minutes, approximately 150 minutes, approximately 180 minutes, approximately 210 minutes, approximately 240 minutes, approximately 270 minutes, approximately 300 minutes, approximately 330 minutes, approximately 360 minutes, approximately 390 minutes, approximately 420 minutes, approximately 450 minutes, approximately 480 minutes, approximately 510 minutes, approximately 540 minutes, approximately 570 minutes, approximately 600 minutes, approximately 630 minutes, approximately 660 minutes, approximately 690 minutes, approximately 720 minutes, or approximately 1440 minutes. The curing temperature can be, for example, room temperature, approximately 60°C, approximately 65°C, approximately 70°C, approximately 75°C, approximately 80°C, approximately 85°C, approximately 90°C, approximately 95°C, approximately 100°C, approximately 105°C, approximately 110°C, approximately 120°C, approximately 125°C, approximately 130°C, approximately 135°C, approximately 140°C, approximately 145°C, approximately 150°C, approximately 155°C, or approximately 160°C. After curing, the rod can be allowed to cool to room temperature before proceeding with other manufacturing steps. If a coating insert is to be applied, the coating can be applied before or after curing.

Drug release rates were evaluated for both uncoated and PVA-coated PVA matrix inserts. The inventors found that, generally, higher curing temperatures and longer curing times resulted in slower drug release rates and slower etching.

When all curing, cooling and/or coating and drying steps are completed, the rod is segmented into inserts approximately 1 mm to approximately 15 mm in length, for example, approximately 1 mm to approximately 10 mm, or approximately 2 mm to approximately 6 mm. For example, the rod may be segmented into inserts approximately 1 mm, approximately 1.5 mm, approximately 2 mm, approximately 2.5 mm, approximately 3 mm, approximately 3.5 mm, approximately 4 mm, approximately 4.5 mm, approximately 5 mm, approximately 5.5 mm, approximately 6 mm, approximately 6.5 mm, approximately 7 mm, approximately 7.5 mm, approximately 8 mm, approximately 8.5 mm, approximately 9 mm, approximately 9.5 mm, approximately 10 mm, approximately 10.5 mm, approximately 11 mm, approximately 11.5 mm, approximately 12 mm, approximately 12.5 mm, approximately 13 mm, approximately 13.5 mm, approximately 14 mm, approximately 14.5 mm, or approximately 15 mm in length.

The rod can be segmented, or otherwise cut into a series of shorter products using any suitable technique for cutting the rod, which may vary depending on whether the product is cured, uncured, or partially cured. For example, the segmentation table may employ pliers, scissors, a slicing knife, or any other technique. The applied technique may vary depending on the required configuration of each cut portion of the product. For example, a shearing operation may be suitable when open ends are required. However, pliers may be used when sealing the ends is required upon completion of the cut.

In some embodiments, the extrudate is impregnated with an aqueous PVA solution having the following PVA concentrations: about 1% w/w to about 20% w/w, about 1% w/w to about 15% w/w, about 1% w/w to about 10% w/w, about 2% w/w to about 10% w/w, about 2% w/w to about 8% w/w, about 2% w/w to about 6% w/w, and about 3% w/w to about 6% w/w. Approximately 2% w/w, approximately 2.5% w/w, approximately 3% w/w, approximately 3.5% w/w, approximately 4% w/w, approximately 4.5% w/w, approximately 5% w/w, approximately 5.5% w/w, approximately 6% w/w, approximately 6.5% w/w, approximately 7% w/w, approximately 7.5% w/w, approximately 8% w/w, approximately 8.5% w/w, approximately 9% w/w, approximately 9.5% w/w, or approximately 10% w/w.

The coated extrudate can then be air-dried. The dip-coating process can be repeated 1 to 10 times, preferably 1 to 6 or 1 to 5 times, with air drying between coatings. The coated extrudate can then be cured as described above. After cooling, the extrudate is then cut into inserts.

e. Insert characteristics

Some eye diseases, including those described in this article, may require treatment for the remainder of a patient's life. Currently available therapies require repeated treatment with therapeutic agents. However, recurrent therapies via implanted drug delivery devices are limited by the presence of non-biodegradable materials in these devices, as biodegradable residues accumulate in the eye. Therefore, providing implantable drug delivery devices that fully dissolve around the time the next device is needed, or shortly thereafter, would be extremely beneficial to patients.

However, designing a drug delivery device that delivers controlled release of therapeutic amounts of drug over extended periods, while also being capable of complete degradation within, for example, approximately several months or a year, is extremely challenging. Many materials that require effective controlled drug release over extended periods are either not biodegradable or degrade too slowly.

Furthermore, providing a drug delivery device that is small enough to be implanted in the patient's eye with minimal discomfort, while also containing a sufficient drug load to provide continuous drug delivery, significantly increases the challenges mentioned above. The difficulty in handling and fabricating such devices without significant breakage also adds to the challenge.

The inventors have overcome these challenges by providing a drug delivery device that is small enough to be implanted in the eye with minimal discomfort and capable of providing continuous drug delivery for several months, while also being sufficiently eroded at some point after the end of the drug delivery period. Furthermore, the inventors have discovered a method for providing devices with different drug delivery periods/durations and delivery rates. Moreover, such devices provide substantially linear release of the drug after the initial peak of drug delivery. Additionally, the insert has an exceptionally high drug content relative to the inactive components within the insert, which is unexpected given the insert's ability to provide drug release over an extended period.

i. Erosion of the insert:

In some embodiments, the insert is capable of complete erosion within 365 days. The ability of the insert to erode within a given time period can be evaluated using the following erosion assessment protocol. The sample insert is placed in a 10 mL glass vial containing 5 mL of phosphate-buffered saline (PBS), and the vial is incubated at 37°C. The PBS in the vial is replaced every 24 hours for each day of the time period of interest (e.g., 365 days, 200 days, 110 days). At the end of this period, the insert is removed from the vial, allowed to dry, and then visually inspected and weighed. The weight reduction compared to the original weight is calculated as follows:

For example, if the insert originally weighed 500 μg and weighed 200 μg after being incubated in PBS for 200 days according to the etching assessment protocol, then the insert's weight is 40% of its original weight, and it has lost 60% of its weight. It has undergone 60% etching over 200 days. The insert is considered completely etched when less than 10% of its original weight remains. In some embodiments, the insert is completely etched within 760 days, 730 days, 700 days, 660 days, 630 days, 600 days, 570 days, 540 days, 400 days, 365 days, 300 days, 280 days, 240 days, 210 days, 200 days, 180 days, 160 days, or 140 days. In other embodiments, using a corrosion assessment scheme, the insert was measured to be capable of corrosion of at least 5% within 60 days, at least 10% within 60 days, at least 15% within 60 days, at least 20% within 60 days, at least 25% within 60 days, at least 5% within 75 days, at least 10% within 75 days, at least 15% within 75 days, at least 20% within 75 days, at least 10% within 95 days, at least 15% within 95 days, and at least 20% within 95 days. %, at least 25% corrosion within 95 days, at least 30% corrosion within 95 days, at least 35% corrosion within 95 days, at least 40% corrosion within 95 days, at least 15% corrosion within 100 days, at least 20% corrosion within 100 days, at least 25% corrosion within 100 days, at least 30% corrosion within 100 days, at least 35% corrosion within 100 days, at least 20% corrosion within 110 days, at least 30% corrosion within 110 days, at least 40% corrosion within 110 days, at least 3% corrosion within 180 days 0%, at least 40% corrosion within 180 days, at least 50% corrosion within 180 days, at least 60% corrosion within 180 days, at least 30% corrosion within 220 days, at least 40% corrosion within 220 days, at least 50% corrosion within 220 days, at least 60% corrosion within 220 days, at least 70% corrosion within 220 days, at least 40% corrosion within 280 days, at least 50% corrosion within 280 days, at least 60% corrosion within 280 days, at least 70% corrosion within 280 days, within 280 days Internal corrosion of at least 80%, corrosion of at least 60% within 365 days, corrosion of at least 70% within 365 days, corrosion of at least 80% within 365 days, corrosion of at least 90% within 365 days, corrosion of at least 60% within 400 days, corrosion of at least 70% within 400 days, corrosion of at least 80% within 400 days, corrosion of at least 90% within 400 days, corrosion of at least 60% within 440 days, corrosion of at least 70% within 440 days, corrosion of at least 80% within 440 days, or corrosion of at least 90% within 440 days.

ii. Drug release rate:

The inventors discovered that curing temperature, curing duration, and insert surface area all affect the release rate. Increasing the diameter while keeping the length constant increases the release rate. When the diameter remains constant, increasing the length increases the release rate.

In some embodiments, the drug release rate of the insert is about 0.01 μg/day to about 100 μg/day, about 0.01 μg/day to about 90 μg/day, about 0.01 μg/day to about 80 μg/day, about 0.01 μg/day to about 70 μg/day, about 0.01 μg/day to about 50 μg/day, about 0.01 μg/day to about 20 μg/day, about 0.01 μg/day to about 10 μg/day, about 0.1 μg/day to about 100 μg/day, about 0.1 μg/day to about 150 μg/day, about 0.1 μg/day to about 60 μg/day, about 0.1 μg/day to about 50 μg/day, about 0.1 μg/day to about 40 μg/day, about 0.1 μg/day to about 30 μg/day, about 0.1 μg/day to about 20 μg/day, about 0.1 μg/day to about 10 μg/day, about 0.1 μg/day to about 5 μg/day, about 0.1 μg/day to about 2 μg/day, about 0.1 μg/day to about 1 μg/day, about 0.5 μg/day to about 15 μg/day, about 0.5 μg/day to about 10 μg/day, about 0.5 μg/day to about 20 μg/day, about 0.5 μg/day to about 30 μg/day, about 1 The release rates are approximately 1 μg/day to about 50 μg/day, about 1 μg/day to about 40 μg/day, about 1 μg/day to about 30 μg/day, about 1 μg/day to about 20 μg/day, about 1 μg/day to about 15 μg/day, about 1 μg/day to about 10 μg/day, about 5 μg/day to about 30 μg/day, about 5 μg/day to about 20 μg/day, or about 10 μg/day to about 30 μg/day. In some embodiments, this is the release rate after achieving steady-state release. In some embodiments, this is the release rate after 2, 3, 5, 8, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, 100, 105, or 110 days of drug release. In some embodiments, the drug release rate is the average drug release rate measured over a specified time period (e.g., 30 days, 60 days, 90 days, 120 days, or 180 days) by an in vitro drug release method (described below). As used herein, the term "average release rate" refers to the sum of the release rates of the ocular drug delivery insert over a period of time (e.g., 30 days) divided by the total number of days. The average release rate can be readily calculated by measuring the release rate on each day of the time period using the methods described herein.

Therefore, for example, in some embodiments, the ocular drug delivery insert has an average drug release rate of about 0.1 μg/day to about 150 μg/day over a 30-day period.

In some embodiments, the release rate of the insert, as measured by an in vitro drug release method, lasts for at least 14 days, at least 30 days, at least 60 days, at least 90 days, at least 100 days, at least 120 days, at least 180 days, at least 200 days, at least 240 days, at least 270 days, at least 300 days, or at least 365 days.

The amount of drug released was assessed using the following in vitro drug release method: the insert was placed in a 10 mL glass tube, and 5 mL of PBS was added to the tube. The tube was incubated in a 37°C water bath. Samples of the medium were collected on each day of the stated time period, and the release medium was replaced with fresh PBS. The amount of API released was quantified by HPLC as described in Example 2C.

The duration (total time) of API release by the insert can be up to about 365 days, about 260 days, or about 200 days, or the duration can be at least about 8 weeks, at least about 10 weeks, at least about 12 weeks, at least about 18 weeks, at least about 22 weeks, at least about 28 weeks, at least about 30 weeks, at least about 36 weeks, at least about 40 weeks, at least about 44 weeks, or at least about 52 weeks. Alternatively, the duration of API release can be at least about 28 days, at least about 42 days, at least about 56 days, at least about 120 days, at least about 168 days, at least about 180 days, at least about 200 days, at least about 224 days, at least about 270 days, at least about 300 days, at least about 365 days, or at least about 730 days. The in vitro drug release method described above can be used to determine whether the insert releases the drug within this duration.

In some embodiments, the insert of the present invention provides an initial rapid release or peak of the drug in vivo for a period of time before reaching a steady-state rate. In a preferred embodiment of the invention, the initial period of rapid release is much shorter than the total duration of API release (e.g., less than 10%). In some embodiments, this initial period is, for example, 1 to 120 days, 20 to 120 days, 80 to 120 days, 1 to 20 days, 2 to 50 days, 3 to 40 days, 5 to 60 days, 1 day, 2 days, 3 days, 4 days, 5 days, 8 days, 10 days, 12 days, 15 days, 20 days, 25 days, 30 days, 40 days, 50 days, 60 days, 70 days, 80 days, 90 days, 100 days, 105 days, or 110 days. In in vitro studies in rabbit eyes, the inventors found unexpectedly high initial peak drug release, indicating that the API was released from the insert more rapidly than expected before reaching a steady state. This peak is beneficial because it allows for rapid achievement of C- _maximum and balance, thus quickly delivering a therapeutically effective dose to the local area of the eye. After this peak, the API release rate stabilizes, delivering a therapeutically effective dose of API each day.

In a preferred embodiment, the insert of the present invention releases the API at a substantially constant rate (i.e., zero-order drug release kinetics, ^R² of 0.7 to 1) for a predetermined duration after implantation. For example, it may release the API at a substantially constant rate for about 14 days, about 28 days, about 42 days, about 56 days, about 168 days, about 180 days, about 224 days, about 270 days, about 300 days, or about 365 days. In some embodiments, the insert releases the API at a substantially constant rate for at least 14 days, at least 28 days, at least 42 days, at least 56 days, at least 120 days, at least 168 days, at least 180 days, at least 224 days, at least 270 days, at least 300 days, at least 365 days, at least 540 days, at least 600 days, or at least 730 days.

The duration of substantially constant API release from the insert can be within a period of about 1 to about 48 months, about 2 to about 36 months, about 2 to about 24 months, about 2 to about 12 months, or about 3 to about 9 months. In some aspects, the duration of substantially constant API release is about 60 days to about 730 days, about 60 days to about 540 days, about 60 days to about 365 days, about 60 days to about 300 days, about 60 days to about 270 days, about 90 days to about 365 days, about 90 days to about 270 days, about 180 days to about 365 days, or about 365 days to about 730 days. In some embodiments, it is at least about 12 weeks, at least about 18 weeks, at least about 22 weeks, at least about 24 weeks, at least about 30 weeks, at least about 32 weeks, at least about 36 weeks, at least about 40 weeks, at least about 44 weeks, at least about 48 weeks, or at least about 52 weeks. The in vitro drug release test described above can be used to determine whether the insert releases the drug during this duration.

3. Treatment methods

In some respects, the insert is applied to inhibit VEGFR and/or PDGFR in the eye of the desired subject. In other respects, the insert is applied to inhibit angiogenesis in the eye of the desired subject.

In other respects, the application of ocular drug delivery inserts is used to prevent or treat specific eye conditions or diseases of a person in need, such as to treat anterior eye conditions; prevent anterior eye conditions; treat posterior eye conditions; or prevent posterior eye conditions.

"Anterior ocular disorders" are diseases, ailments, or conditions that affect or involve the anterior (i.e., the part of the eye, also known as the anterior segment) area or structures of the eye, such as the periocular muscles or eyelids, or the fluid located on the anterior to posterior walls of the lens capsule or ciliary muscle. Therefore, anterior ocular disorders can affect or involve the conjunctiva, cornea, anterior chamber, iris, posterior chamber (located between the iris and lens), lens or lens capsule, and the blood vessels and nerves that vascularize or innervate the anterior ocular area or site. Anterior ocular disorders can include diseases, ailments, or conditions such as, but not limited to, glaucoma.

"Posterior ocular disorders" are diseases, ailments, or conditions that primarily affect or involve the posterior (i.e., the back of the eye, also known as the posterior segment) area or structures of the eye, such as the choroid or sclera (located in the posterior part of the plane passing through the posterior wall of the lens capsule), vitreous body, vitreous chamber, retina, optic nerve or optic disc, and the blood vessels and nerves that vascularize or innervate the posterior ocular area or site.

Posterior eye conditions can include diseases, ailments, or symptoms such as, but not limited to, acute macular optic nerve retinopathy; Behcet's disease; geographic atrophy; choroidal neovascularization; diabetic uveitis; histoplasmosis; infections such as those caused by fungi, bacteria, or viruses; macular degeneration such as neovascular macular degeneration, acute macular degeneration, age-related macular degeneration (AMD) (such as non-exudative (dry) AMD or exudative (wet) AMD (also known as late neovascular AMD)); edema such as macular edema, cystoid macular edema, or diabetic macular edema (DME); multifocal choroiditis; ocular trauma affecting the posterior part or position of the eye; ocular tumors; retinal conditions such as retinal vein occlusion, central retinal vein occlusion, diabetic retinopathy (including proliferative and non-proliferative diabetic retinopathy), proliferative vitreous disease. Vitreoretinal diseases (PVR), hypertensive retinopathy, retinal artery occlusion (such as central retinal artery occlusion (CRAO) and branch retinal artery occlusion (BRAO), retinal detachment, uveitis-related retinopathy; sympathetic ophthalmitis; Vogt-Koyanagi-Harada (VKH) syndrome; uveitis; posterior ocular conditions caused or affected by ocular laser treatment; or posterior ocular conditions caused or affected by: photodynamic therapy, photocoagulation, radiation retinal therapy, epiretinal membrane diseases, branch retinal vein occlusion, anterior ischemic optic neuropathy, non-retinal diabetic retinopathy, and retinitis pigmentosa. Glaucoma can also be considered a posterior ocular condition because the treatment goal is to prevent or reduce the incidence of vision loss attributable to damage or loss of retinal or optic nerve cells (e.g., through neuroprotection).

Therefore, the present invention provides a method for preventing or treating a variety of eye conditions by applying an ocular drug delivery insert to the eye of a person in need.

In some embodiments, the ocular condition is diabetic macular edema (DME). In other embodiments, the ocular condition is retinal vein occlusion, such as central retinal vein occlusion (“CRVO”) or branch retinal vein occlusion (“BRVO”). In still other embodiments, the ocular condition is non-ischemic retinal vein occlusion or ischemic retinal vein occlusion. In other embodiments, the condition is diabetic retinopathy. In still other embodiments, the condition is non-proliferative diabetic retinopathy.

In some embodiments, the insert is applied to prevent or treat vision loss in a person in need, such as vision loss associated with macular degeneration.

In other embodiments of the method for preventing or treating various eye conditions by administering an ocular drug delivery insert to the eye of a person in need, the eye condition is AMD.

Additionally, the present invention provides a method for providing neuroprotection to ocular tissues by administering an ocular drug delivery insert to the eye of a subject in need. For example, the present invention provides a method for providing neuroprotection in the posterior segment of the eye, and particularly in the retina. For example, the present invention provides a method for providing neuroprotection to the retina to prevent retinal diseases (such as dry AMD or wet AMD), or to slow the progression of retinal diseases (e.g., slowing the progression of dry AMD to wet AMD) or to slow the progression via stages of AMD. In another embodiment, the present invention provides a method for treating or preventing an eye disease by administering an ocular drug delivery insert to the eye of a subject in need, wherein the eye disease is characterized by retinal neuronal damage. In other embodiments, eye diseases characterized by retinal neuronal damage affect photoreceptors, such as geographic atrophy, glaucoma, diabetic macular edema, or retinal detachment.

4. Age-related macular degeneration

Age-related macular degeneration (AMD) is one of the most common causes of vision loss, affecting an estimated 200 million people worldwide. (Wong WL, Su X, Li X, et al. Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: a systematic review and meta-analysis. Lancet Glob. Health. 2014; 2:e106-116.). Advanced AMD, characterized by macular atrophy (called geographic atrophy) and choroidal neovascularization (CNV), affects nearly 11 million people. (Ibid.). Approximately two-thirds of cases of advanced AMD involve CNV, which manifests through fluid and blood exudation and often results in vision loss and fibrotic scarring when left untreated.

Age-related macular degeneration (AMD) can be divided into three stages, partly based on the number and size of drusen visible under the retina during retinal examination. Although dry AMD can be classified into early, intermediate, and late stages, wet AMD is always considered a late form of AMD. Wet AMD includes neovascular age-related macular degeneration, which is also a late form of AMD.

The table below describes four categories or stages of AMD as defined in the National Eye Institute's AREDS study based on the presence of certain AMD markers. See https://www.nei.nih.gov/research/clinical-trials/age-related-eye-disease-studies-aredsareds2/about-areds-and-areds2.

The patient may have AMD in only one eye (unilateral) or in both eyes (bilateral), but may be at different stages of AMD in each eye.

In cases where a subject has a unilateral disease or is in a more advanced stage of the disease, the subject's other eye is referred to herein as the "contralateral eye." The contralateral eye does not meet the diagnostic criteria for a disease already diagnosed in the other eye (such as wet AMD). For example, in subjects with unilateral wet AMD, there may be no signs of choroidal neovascularization in the contralateral eye.

Typically, there is no vision loss in early AMD, and only small drusen or a small number of medium-sized drusen are present. Individuals with early AMD have a low risk of progressing to late AMD within 5 years.

Subjects with intermediate AMD are at significant risk of developing advanced AMD. In intermediate AMD, multiple medium-sized drusen or at least one large drusen are found in one or both eyes, along with changes in the retinal pigment epithelium (RPE). Subjects may have some vision loss or no vision loss in the affected eye.

There are two types of advanced AMD: dry (non-neovascular or non-exudative) AMD and wet (neovascular or exudative) AMD. If a subject has large drusen in both eyes, rather than just one, they are more likely to progress to advanced AMD within 5 years. Subjects with advanced AMD may experience vision loss in the affected eye due to macular damage. Having advanced AMD in one eye significantly increases the risk of developing advanced AMD in the other eye.

In dry AMD, photoreceptors (light-sensitive retinal cells) gradually die off, impairing the eye's ability to sense light. This defect, along with lesions in the retinal pigment epithelium (RPE), the subcutaneous tissue that supports the retina, leads to vision loss. Complete loss of RPE cells in a region is called geographic atrophy.

In late-stage wet AMD, abnormal blood vessels develop beneath the retina, called choroidal neovascularization. These vessels can leak fluid or blood, thereby damaging surrounding tissues, including photoreceptors. Dry AMD can progress relatively slowly from early to late stages, or even not at all. However, wet AMD tends to progress rapidly, and leakage or hemorrhage beneath or into the retina can lead to sudden vision loss. It is also possible for the same eye to exhibit characteristics of both wet and dry AMD.

In intermediate or late-stage dry AMD, drusen deposits can expand and physically impact the photoreceptor and/or retinopathy of prematurity (RPE). Larger drusen can cause progressive tissue hypoxia and release factors such as VEGF and PLGF, which in turn stimulate increased vascular permeability, macular edema, exudation, and choroidal neovascularization (CNV) seen in wet AMD. These new vessels are initially fragile and may rupture, causing subretinal hemorrhage and photoreceptor toxicity. Progression of choroidal neovascularization can lead to discoid scar formation, also known as late-stage wet AMD. At this stage, neither drug nor surgical treatment provides any benefit.

Intravitreal injection of VEGF inhibitors can reduce the extent of CNV-induced exudation. Ranibizumab (Genentech, USA), bevacizumab (Genentech, USA), and aflibercept (Regeneron Pharmaceuticals, USA) are used worldwide to treat CNV secondary to AMD. However, such treatments carry the risk of rare but serious adverse events from intravitreal procedures and require monthly visits by a retinal specialist, which is a significant burden.

Various methods can be used to diagnose AMD, determine AMD stages, or monitor eye progression via AMD stages. Some diagnostic tools can detect changes in choroidal neovascularization or existing blood vessel formation.

For example, best-corrected visual acuity (BCVA) assessment can be used to evaluate and monitor changes in visual acuity as AMD progresses. In subjects with markers of AMD or at risk for AMD, changes in visual acuity can be monitored by assessing BCVA at different time points. Additionally, assessing BCVA at different time points before and during the administration of a specific AMD therapy can help determine whether the therapy effectively improves the detrimental effects of AMD on visual acuity, slows AMD progression, or stabilizes AMD. For example, an increase of at least 5 ETDRS letters in BCVA compared to baseline indicates that a specific therapy reduces the effects of AMD. An increase of, for example, at least 10 or at least 15 ETDRS letters indicates a more significant improvement. Visual stability in subjects with intermediate or advanced AMD, such as a loss of ≤15 ETDRS letters during treatment, indicates that the therapy has stabilized or slowed AMD progression. A loss of ≤10 or ≤5 ETDRS letters during treatment indicates a more significant effect on stabilizing or slowing AMD progression.

Individuals with early-stage AMD may experience vision loss in low light, low contrast, and/or altered light conditions, impacting their vision-related quality of life. The Impact of Vision Impairment (IVI) questionnaire, used to measure the impact of vision impairment on specific aspects of quality of life, has been found to be reliable. See Weih, L.M., Hassell, J.B. & Keeffe, J. Assessment of the impact of vision impairment. Investigative Ophthalmology & Visual Science 43, 927-935 (2002). The IVI has three vision-specific subscales: reading and information acquisition, mobility and independence, and emotional health. The composite score is the sum of scores from all three subscales. In some embodiments of the invention, the subjects' composite IVI questionnaire scores did not significantly increase relative to baseline over at least 180 days, at least 365 days, or at least 545 days.

Cycloplegic refraction using an ophthalmoscope can be used to detect the presence of drusen in the eye and quantify the number of drusen.

Fluorescein angiography (FA) or optical coherence tomography (OCT) can be used to detect choroidal neovascularization and monitor neovascular and exudative changes in AMD, such as an increase in lesion size. OCT can be frequency domain OCT (SD-OCT) or OCT-angiography (OCT-A).

In some embodiments of the invention, no new choroidal neovascularization occurs within 6 months from the date of application, compared to a baseline. In other embodiments, as measured by OCT, existing choroidal neovascularization remains less than 5 mm in diameter for at least 6 months after application of the ocular drug delivery insert.

In some embodiments of the invention, the application of the ocular drug delivery insert avoids significant vision loss. For example, in some embodiments, the BCVA of the eye to which the insert is applied remains unchanged relative to baseline over a period of time, wherein this period is measured from the day of application of the ocular drug delivery insert. In other embodiments, the loss is ≤5 ETDRS letters. In still other embodiments, the loss is ≤10 ETDRS letters. In still other embodiments, the loss is ≤15 ETDRS letters. In some embodiments, the loss is increased by ≥5 ETDRS letters. The period may be at least 90 days, at least 180 days, at least 270 days, or at least 365 days.

In some embodiments of the invention, the application of the ocular drug delivery insert avoids an increase in central retinal thickness (CST), also known as foveal thickness (the average thickness of the macula within a central 1 mm ETDRS grid). For example, in some embodiments, the CST of the eye to which the insert is applied does not increase relative to baseline during a certain time period, wherein this time period is measured from the day of application of the ocular drug delivery insert. In other embodiments, the CST does not increase by more than 100 μm, 75 μm, 50 μm, 25 μm, or 15 μm during the time period. In some embodiments of the invention, the subject's IVI questionnaire composite score does not increase significantly relative to baseline during this time period.

In some embodiments of the method, no detectable choroidal neovascularization is observed in the eye to which the insert is administered for a period of time, wherein this period is measured from the day the ocular drug delivery insert is administered. In other embodiments, the eye to which the insert is administered does not progress to an AMD category higher than that of the eye at baseline for a period of time.

The time period can be 90 days, 180 days, 270 days, 365 days, or 545 days. The results of the specific test or evaluation method at the end of the time period are compared with the baseline.

In this article, the eye at the “baseline” can be assessed precisely before the administration of the ocular drug delivery insert, such as on day 0 (treatment day) or on one of the seven days prior to the day of administration (day -7 to day -1).

In some embodiments, the ocular drug delivery insert is applied to an eye with a baseline CST of less than 500 μm, 400 μm, 350 μm, 300 μm, 250 μm, or 200 μm. In some embodiments, the ocular drug delivery insert is applied to an eye with a baseline CST of 500 μm or less, 400 μm or less, 350 μm or less, 300 μm or less, 250 μm or less, 200 μm or less.

In some embodiments, the ocular drug delivery insert is applied to an eye with a CST of less than 500 μm, 400 μm, 350 μm, 300 μm, 250 μm, or 200 μm on the day of application. In some embodiments, the ocular drug delivery insert is applied to an eye with a CST of 500 μm or less, 400 μm or less, 350 μm or less, 300 μm or less, 250 μm or less, 200 μm or less.

In some embodiments of the invention, the eye is evaluated at baseline and subsequently at one or more time points, such as 30, 60, 90, 120, 150, 180, 210, 270, 300, 330 and/or 365 days after application, for signs of AMD (e.g., drusen, BCVA, CST, or neovascularization), with application performed on day 0. The eye may also be evaluated at additional time points.

In some embodiments, the present invention provides a method for treating wet age-related macular degeneration (AMD) comprising assessing the presence of subfoveal intraretinal fluid (IRF) in an eye diagnosed with wet AMD, wherein the eye is in a human subject, and if subfoveal IRF is not detected, administering an ocular drug delivery insert comprising voronib or a pharmaceutically acceptable salt thereof, as described in more detail herein. In other aspects, the present invention provides a method for treating wet AMD comprising administering the ocular drug delivery insert of the present invention to an eye of a human subject diagnosed with wet AMD, wherein subfoveal IRF is not detected in the eye at baseline.

The presence of central depression IRF can be detected by OCT.

When used in relation to a condition, the term "prevention" refers to administering a medication to prevent the onset of an eye condition in a subject or to delay the onset of an eye condition relative to a subject who has not received the medication. The term "mitigation" of the progression of a particular eye condition means the prevention of worsening of the condition in the subject relative to a subject who has not received the medication at the same stage of the disease.

The term "treatment" means to reduce, improve, or stabilize an existing, unwanted condition.

a. Application of ocular medication delivery insert

Administering the insert may involve inserting it into the subject's eye, such as into the aqueous humor or, preferably, the vitreous humor. Administering the insert may also involve surgically implanting it into or onto the eye, such as through a scleral implant, subconjunctival implant, suprachoroidal implant, extrascleral implant, or intravitreal implant. The insert may be surgically implanted into the subject's eye, for example, into the vitreous humor, subretinal, or onto the sclera. In some embodiments, the insert may be placed via injection through a needle or cannula. The insert allows for gradual release of the API within the eye, thus avoiding painful, frequent administration.

In some embodiments, the insert is injected into the subject's eye, preferably without an incision. In some aspects, the insert is injected into the vitreous humor of the eye. In a preferred embodiment, the application of the insert comprises intravitreal injection.

In some embodiments, a needle or cannula with a gauge of 20 to 27 is used for injection. In other embodiments, a needle or cannula with a gauge of 25 to 27 is used. In a preferred embodiment, a needle with a gauge smaller than 25 is used for injection, such as a needle with a gauge of 25.5, 26, 26.5, or 27.

In some embodiments of the application method of the present invention, local and/or subconjunctival anesthesia may be applied to the injection site prior to injection of the insert. Additionally, a broad-spectrum antimicrobial agent may be applied to the lower fornix. The insert may be placed suboptically and posterior to the equator of the eye. The conjunctiva may be movable such that the conjunctival and scleral needle entry sites are misaligned after needle withdrawal. The needle for injecting the insert may be inserted through the conjunctiva and sclera to the positive stop of the applicator, and the push rod may be pressed to deliver the insert to the dorsum of the eye.

In some embodiments, one or more inserts are applied once every 90 to 270 days, once every 90 to 180 days, once every 120 to 720 days, once every 270 to 720 days, once every 270 to 540 days, once every 360 to 720 days, once every 360 to 540 days, or once every 540 to 720 days.

b. Object

In some embodiments, the ocular drug delivery insert is administered to the eye of the subject. In some embodiments, the subject is a mammal. In other embodiments, the subject is a human.

c. Dosage

In some embodiments, the total dose of voronib delivered is about 0.0001 μg/day to about 200 μg/day, about 0.0001 μg/day to about 150 μg/day, about 0.0001 μg/day to about 100 μg/day, about 0.0001 μg/day to about 80 μg/day, about 0.0001 μg/day to about 50 μg/day, about 0.0001 μg/day to about 30 μg/day, about 0.0001 μg/day to about 10 μg/day, about 0.0001 μg/day to about 5 μg/day, about 0.0001 μg/day to about 1 μg/day, about 0.001 μg/day to about 200 μg/day, about 0.001 μg/day to about 150 μg/day, about 0. 0.001 μg/day to about 100 μg/day, about 0.001 μg/day to about 80 μg/day, about 0.001 μg/day to about 60 μg/day, about 0.001 μg/day to about 40 μg/day, about 0.001 μg/day to about 30 μg/day, about 1 μg/day to about 25 μg/day, about 0.001 μg/day to about 20 μg/day, about 0.001 μg/day to about 15 μg/day, about 0.001 μg/day to about 10 μg/day, about 0.001 μg/day to about 8 μg/day, about 0.005 μg/day to about 15 μg/day, about 0.005 μg/day to about 10 μg/day, about 0.01 μg/day to about 100 μg/day, about 0.01 μg/day to about 90 μg/day, about 0.01 μg/day to about 80 μg/day, about 0.01 μg/day to about 70 μg/day, about 0.01 μg/day to about 50 μg/day, about 0.01 μg/day to about 20 μg/day, about 0.01 μg/day to about 10 μg/day, about 0.1 μg/day to about 150 μg/day, about 0.1 μg/day to about 100 μg/day, about 0.1 μg/day to about 80 μg/day, about 0.1 μg/day to about 60 μg/day, about 0.1 μg/day to about 50 μg/day, about 0.1 μg/day to about 40 μg/day, about 0.1 μg/day to about 30 μg/day, about 0.1 μg/day to about 20 μg/day, about 0.1 The release rates are approximately 0.1 μg/day to about 5 μg/day, about 0.1 μg/day to about 2 μg/day, about 0.1 μg/day to about 1 μg/day, about 0.5 μg/day to about 15 μg/day, about 0.5 μg/day to about 10 μg/day, about 1 μg/day to about 50 μg/day, about 1 μg/day to about 40 μg/day, about 1 μg/day to about 30 μg/day, about 1 μg/day to about 20 μg/day, about 1 μg/day to about 15 μg/day, about 1 μg/day to about 10 μg/day, about 1 μg/day to about 5 μg/day, about 5 μg/day to about 30 μg/day, about 5 μg/day to about 20 μg/day, or about 10 μg/day to about 30 μg/day. In some embodiments, this is the release rate after steady-state release has been achieved. In some embodiments, this is the release rate after 2, 3, 5, 8, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, 100, 105, or 110 days of drug release.

This dosage can be achieved by administering, for example, 1 to 6 inserts in a single application, i.e., a single treatment for one eye. Therefore, for each eye of the subject, a single treatment may require the application of 1, 2, 3, 4, 5, or 6 inserts. In some embodiments, the subject may receive treatment for a single eye or both eyes. When a single treatment injects more than one insert, the inserts may be injected individually in separate injections, or several inserts may be injected in the same injection. For example, 1, 2, or 3 inserts may be injected in a single injection. When a single treatment will inject more than 3 inserts, it may be divided into several injections. For example, if a single treatment will inject 4 to 6 inserts, it may be divided into 2 or 3 injections of 2 to 3 inserts/injections.

Each insert may contain about 1 μg to about 3000 μg, about 1 μg to about 1000 μg, about 1 μg to about 500 μg, about 10 μg to about 2000 μg, about 10 μg to about 1000 μg, about 100 μg to about 500 μg, about 10 μg to about 800 μg, about 50 μg to about 600 μg, about 200 μg to about 2000 μg, about 600 μg to about 2000 μg, about 800 μg to about 2000 μg, about 800 μg to about 1500 μg, about 100 μg to about 500 μg, about 100 μg to about 300 μg, or about 300 μg to about 550 μg of voronib. For example, each insert may contain approximately 400 μg, approximately 420 μg, approximately 440 μg, approximately 480 μg, approximately 500 μg, approximately 520 μg, approximately 540 μg, approximately 560 μg, approximately 580 μg, approximately 600 μg, approximately 620 μg, approximately 640 μg, approximately 660 μg, approximately 680 μg, approximately 700 μg, approximately 720 μg, approximately 740 μg, approximately 780 μg, APIs, such as voronib, in quantities of approximately 800 μg, 820 μg, 840 μg, 860 μg, 880 μg, 900 μg, 920 μg, 940 μg, 960 μg, 980 μg, 1000 μg, 1020 μg, 1040 μg, 1045 μg, 1060 μg, 1080 μg, or 2000 μg.

The total amount of voronib in all inserts (total effective load) can be about 50 μg to about 1000 μg, about 200 μg to about 6000 μg, about 600 μg to about 6000 μg, about 800 μg to about 6000 μg, about 600 μg to about 5040 μg, about 600 μg to about 4500 μg, about 1000 μg to about 5400 μg, about 1000 μg to about 3000 μg, or about 2000 μg to about 4000 μg. For example, the total API amount of all inserts may be approximately 1400 μg, approximately 1420 μg, approximately 1500 μg, approximately 1600 μg, approximately 1800 μg, approximately 1900 μg, approximately 1980 μg, approximately 2000 μg, approximately 2040 μg, approximately 2080 μg, approximately 3000 μg, approximately 3120 μg, approximately 3180 μg, approximately 3240 μg, approximately 3400 μg, approximately 3600 μg, approximately 3800 μg, approximately 4000 μg, approximately 4140 μg, approximately 4160 μg, approximately 4180 μg, approximately 4200 μg, approximately 4400 μg, approximately 4600 μg, approximately 5000 μg, or approximately 5040 μg.

5. Combination - Induction therapy and maintenance therapy

The present invention also provides a method for treating posterior ocular conditions in an eye in need, comprising administering an agent that inhibits the activation of VEGF receptors, such as a VEGF ligand, VEGF inhibitor, or anti-VEGF, to the eye at a first time point (induction therapy), and administering an ocular drug delivery insert containing voronib or a pharmaceutically acceptable salt thereof to the eye at a second time point (maintenance therapy) to maintain the induction therapy.

In some embodiments, the posterior eye condition is selected from wet AMD, diabetic retinopathy (DR), macular edema following retinal vein occlusion (RVO), and diabetic macular edema (DME). In some embodiments, the posterior eye condition is neovascular age-related macular degeneration.

The first and second time points are suitable to be on different days. For example, the second time point may be at least about 1 week, at least about 2 weeks, at least about 4 weeks, at least about 8 weeks, or at least about 24 weeks after the first time point, suitablely at least 1 week, at least 2 weeks, at least 4 weeks, at least 8 weeks, or at least 24 weeks.

Generally, the agent used for induction therapy (induction therapy agent) is any standard care VEGF inhibitor (sometimes also called anti-VEGF). In some embodiments, the agent is a VEGF inhibitor selected from ranibizumab, bevacizumab, and aflibercept. In some embodiments, the VEGF inhibitor is administered by injection, such as via intravitreal injection. In some embodiments, the VEGF inhibitor is aflibercept for intravitreal use.

In some embodiments used to treat wet AMD, aflibercept is administered via intravitreal injection at a dose of about 2 mg or 2 mg (0.05 mL) every 4 weeks (about every 28 days, monthly). In some embodiments, monthly injections are administered for the first 12 weeks (3 months), followed by intravitreal injections of about 2 mg or 2 mg (0.05 mL) every 8 weeks (2 months) or every 12 weeks.

In some embodiments of the treatment of macular edema, aflibercept is administered at a dose of about 2 mg or 2 mg (0.05 mL) via intravitreal injection once every 4 weeks (about every 25 days, monthly).

In some embodiments for the treatment of diabetic macular edema (DME) or diabetic retinopathy (DR), for the first 5 injections, aflibercept is administered via intravitreal injection at a dose of about 2 mg or 2 mg (0.05 mL) every 4 weeks (about every 28 days, monthly). This is followed by intravitreal injection of about 2 mg or 2 mg (0.05 mL) every 8 weeks (2 months). In some embodiments, aflibercept is administered every 4 weeks (monthly) after the first 20 weeks (5 months).

In some embodiments, a VEGF inhibitor is administered to the eye monthly until the eye is dry or until no other visual or anatomical improvement beyond baseline is observed. The eye may then be evaluated periodically, such as every 2, 3, 4, 5, 6, 7, or 8 weeks. If fluid recurs, the VEGF inhibitor is administered to the eye again, and evaluation continues. In some embodiments, the treatment interval for the VEGF inhibitor may be extended from once monthly (every 4 weeks or 28 days) to once every 5 weeks or every 6 weeks. If the eye remains fluid-free for a given time interval, the period during which the eye remains fluid-free is designated as the treatment interval for the VEGF inhibitor (e.g., treatment every 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 weeks). Evaluation of the eye for fluid and/or vision will continue on a routine basis, such as every 2, 3, 4, 5, 6, 7, or 8 weeks, with the treatment interval adjusted to be the same as the fluid-free interval.

In some embodiments, the ocular drug delivery insert administered at a second time point (i.e., to an eye that has previously received induction therapy) comprises a solid matrix core comprising a matrix polymer and voronib or a pharmaceutically acceptable salt thereof, wherein the amount of voronib or a pharmaceutically acceptable salt thereof in the insert is from about 10% w/w to about 98% w/w, wherein the drug release rate of the insert is from about 0.01 μg/day to about 100 μg/day for at least 14 days, and wherein the insert is eroded by at least 20% within 95 days.

In other embodiments, the first dose of the ocular drug delivery insert is an initial dose, and subsequent doses are maintenance doses, as described herein.

Therefore, the present invention provides a method of treatment that can be described as a "maintenance therapy" for posterior ocular conditions. In most eyes, this treatment produces a less intensive treatment regimen than treatment with a VEGF inhibitor alone, and can keep most eyes visually and anatomically stable for six months or longer. In some embodiments, the eye is treated with one or more supplemental doses of a VEGF inhibitor after administration of one or more doses of an ocular drug delivery insert. In some embodiments of the invention, the VEGF inhibitor and the ocular insert of the present invention are administered simultaneously to the eye being treated. Hereinafter, simultaneous treatment means that the eye receiving the VEGF inhibitor contains an ocular insert that still releases voronib.

In some embodiments, a VEGF inhibitor is administered prior to the administration of a first dose of the ocular drug delivery insert as an initial dose, as described herein. In some embodiments, the first dose of the ocular drug delivery insert is administered to the eye treated with the VEGF inhibitor over a period of about 1 week, at least about 2 weeks, at least about 4 weeks, at least about 8 weeks, at least about 12 weeks, or at least about 24 weeks.

In some embodiments, a first dose of an ocular drug delivery insert is administered to an eye that has previously responded to at least 2, 3, 4, 5, 6, 7, or 8 intravitreal injections of a VEGF inhibitor.

In some embodiments, supplemental treatment is administered after the initial dose of the ocular drug delivery insert described herein, such as when the initial dose of the ocular drug delivery insert is present in the eye.

In some embodiments, supplemental treatment is administered after the administration of a maintenance dose of the ocular drug delivery insert described herein, such as when the maintenance dose ocular drug delivery insert is present in the eye.

In some embodiments, as described herein, aflibercept is administered as an induction therapy on day 1, week 4, and week 8. In some embodiments, a first dose of the ocular drug delivery insert is administered to an eye that has previously received induction therapy on day 1, week 4, and week 8, or 30 minutes after induction therapy in week 8.

In some embodiments, supplemental treatment with aflibercept is administered to the eye starting at week 12, the eye having previously received induction treatment with aflibercept on days 1, 4, and 8, and receiving the first dose of the ocular drug delivery insert 30 minutes after the induction treatment in week 8. In some embodiments, supplemental treatment with aflibercept is administered to the eye at week 12, wherein the BCVA is reduced by ≥5 letters for the best study measurement due to wet AMD and the CST is increased by ≥75 microns on the SD-OCT for the lowest study measurement, the BCVA is reduced by ≥10 letters for the best study measurement due to wet AMD, and the CST is increased by ≥100 microns on the SD-OCT for the lowest study measurement based on two consecutive visits or the presence of new or worsening visual impairment bleeding due to wet AMD.

In some embodiments, the first ocular drug delivery insert is applied to an eye with a CST less than 500 μm, 400 μm, 350 μm, 300 μm, 250 μm, or 200 μm. In some embodiments, the ocular drug delivery insert is applied to an eye with a CST less than 500 μm, 400 μm, 350 μm, 300 μm, 250 μm, or 200 μm. In some embodiments, the CST is 400 μm or less, 350 μm or less, or 300 μm or less.

6. Definition

As used in this specification and the claims, the following words and phrases are generally intended to have the meaning set forth below, unless otherwise indicated by the context in which they are used.

Unless the context clearly specifies otherwise, the singular forms “without quantifier” and “the/said” include a plural reference. For example, “matrix polymer” means one or more matrix polymers.

As used herein, the terms “bioerode,” “bioerosion,” “biodegradation,” and “biodegradation” refer to the gradual division, dissolution, or disintegration of an insert in a biological system over a period of time, for example by one or more physical or chemical degradation methods, such as enzymatic activity, hydrolysis, ion exchange, or dissolution by dissolution, emulsion formation, or microcell formation.

The term "room temperature" means 22°C. "Solid at room temperature" means a solid at a temperature of 22°C.

When the term “about” is used in conjunction with a numerical value or range, it modifies the value or range by extending the upper and lower limits of the stated value. Generally, unless a different difference is specified (e.g., ±30%, ±20%, ±5%, ±1%, ±0.5%, etc.), the term “about” is used herein to modify numerical values that are higher or lower than the stated value by a difference of 10% above or below (higher or lower), i.e., ±10%.

The term “and/or” means and covers each of the individually listed items, as well as any and all possible combinations of one or more of the listed items.

The terms “comprising,” “consisting of,” and “substantially constitute” have their common, generally accepted meanings under patent law. When the term “comprising” is used in this specification or claims, it is intended to be inclusive in a manner similar to how the term “comprising” is interpreted as a transitional term in the claims.

The terms “optional” and “optionally” indicate that the situation described below may or may not occur, and therefore the description includes both the scenario in which the situation occurs and the scenario in which the situation does not occur.

When the features or aspects of the content or claims are disclosed in accordance with the description of the Markush group, the described group includes any single member of the Markush group as well as subgroups.

Those skilled in this art will understand that all terms such as “at most,” “at least,” “greater than,” and “less than” include the listed numbers and refer to a range that can be subsequently broken down into subranges. Finally, those skilled in this art will understand that a range includes each individual member and includes the range endpoints. For example, a group with 1 to 3 members means a group with 1, 2, or 3 members. Similarly, a group with 1 to 5 members means a group with 1, 2, 3, 4, or 5 members, and so on.

As used herein, the term “substantially all” means the majority of the total, such as at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%.

The term %w/w indicates the proportion of a particular substance in a mixture as measured by weight or mass. Therefore, for example, for an insert whose core contains at least about 8% w/w of inactive ingredient, the total weight of the inactive ingredient in the core is at least about 8% of the total weight of the core. For example, if the total core weight is 100 mg, then the inactive ingredient in this core will weigh at least 8 mg.

The term %w/v indicates the percentage of a component's weight (such as a solute) in the total volume of the solution. A 2% w/v PVA solution would mean 2 grams of PVA in 100 mL of solution. A 2% w/w PVA solution would mean 2 grams of PVA in 100 mg of solution.

All cited patents, publications, scientific publications, and books are incorporated herein by reference in their entirety.

Although various aspects and embodiments have been disclosed herein, other aspects and embodiments will be apparent to those skilled in the art.

Example

Example 1

Films were made from PVA of the grades listed in the table below, and their etching rate and strength were then evaluated.

To form the membrane, a 4.5% PVA aqueous solution was poured into a dish and air-dried at room temperature. Once dry, the membrane was cut into 1×1 square samples. Six samples of each membrane were then cured at 100°C for 3 hours, 140°C for 30 minutes, or 140°C for 4 hours, as described in the table below. After curing, the sample membrane squares were weighed and imaged. Each sample was then immersed in PBS at room temperature for 24 hours. The samples were then removed from the PBS, and four of the PVA grades were oven-dried at 50°C for 2 hours, while two of the PVA grades were air-dried on paper towels at room temperature, as described in the table below. The samples were then weighed and imaged again.

The weighted average weight change after immersion in PBS for 24 hours was calculated and is shown in the curves in Figure 2. The degree of PVA hydrolysis (DH) and molecular weight (MW) determine the membrane solubility. PVA membranes of 6000/80%, 25,000/88%, 125,000/88%, and 6000/80%-125,000/88% mixtures dissolved at the end of day 1 under all tested curing conditions. The 78,000/98% membrane persisted the longest. The relative membrane strengths of the tested membranes are depicted in Figure 3.

Example 2A

The insert is prepared according to the parameters in the table below:

The insert was manufactured by mixing voronib with a 78,000/98% PVA aqueous solution at the w/w voronib:PVA solution ratio specified in the table above. The mixture was then extruded from 20, 21, or 23 gauge dispensing tips and dried at room temperature.

For the coated inserts, the extrudate is then dipped in a 78,000/98% PVA solution and air-dried. The dip-coating process is repeated to achieve the number of coatings specified in the table above. The coating process involves dipping the extrudate in the PVA solution, allowing 5 minutes of room temperature drying between the first layers, and then a further 10 minutes of drying time before dipping to form the final layer/coating. The coated extrudate is then cured as described in the table. After cooling to ambient temperature, the extrudate is cut into inserts of 2 mm, 3.5 mm, 5 mm, 6 mm, or 8 mm lengths.

Example 2B

The drug release rate of the inserts was tested in vitro. Each insert sample was placed in a 10 mL glass tube, and 5 mL of PBS was added to the tube. The tube was incubated in a 37°C water bath. Samples of the release medium were collected at 12 to 24 hour intervals, and the release medium was replaced with fresh PBS. The amount of voronib released was quantitatively measured by HPLC according to the method described in Example 2C. The in vitro release rate was tested, and the average release rate was determined from the cumulative release comparison time.

Example 2C

Analyze the API content of the insert samples. Cut the insert sample for testing into four pieces and place all four pieces in labeled scintillation vials. Aspirate 3.0 mL of methanol into each vial and place the vial under a cabinet. Repeat this procedure for all samples. Place the sample vials in a sonic vibrator, add an appropriate amount of water, and sonicate the samples for 30 minutes. Repeat the sonication treatment five more times, cooling the sonic vibrator between treatments. Additional sonication treatments may be performed as needed to ensure complete API dissolution. HPLC was performed with the following parameters: column: ZORBAX Eclipse XDB-C18; 4.6 × 150 mm; 5 μm; mobile phase A: water + 0.1% phosphoric acid; mobile phase B: acetonitrile + 0.1% phosphoric acid; gradient method; stop time 30 min; UV: 214 nm.

Example 2D

Evaluate the etching of the sample insert. Place the sample insert in a 10 mL glass vial containing 5 mL of phosphate-buffered saline (PBS) and incubate the vial at 37°C without stirring. Replace the PBS in the vial every 24 hours for each day of the period of interest. At the end of the period, remove the sample from the vial, weigh it, and photograph it.

The drug release rate curves of the coated 4.5% PVA formulation, designated Formulation A, cured at 140°C for 4 hours, are shown in Figures 4A (cumulative drug release %) and 4B (cumulative drug release (μg)). The drug release rate curve of the uncoated Formulation A insert is shown in Figure 6. Photographs of the etched Formulation A insert, collected after immersion in the dissolving medium for 314 and 447 days, are shown in Figure 5. The 447-day photograph includes the intact insert for comparison. Photographs of the etched uncoated Formulation A insert, collected after immersion in the dissolving medium for 287 and 352 days, are shown in Figure 7. The 352-day photograph includes the intact insert for comparison.

The drug release rate curves of the coated 4.5% PVA formulation, referred to as Formulation B, cured at 140°C for 30 minutes, are shown in Figure 8 (cumulative drug release %) and Figure 8B (cumulative drug release (μg)). Photographs of the etched Formulation B inserts, collected after immersion in the dissolving medium for 59, 88, and 155 days, are shown in Figure 9.

The drug release rate curves for the uncured coated 4.5% PVA formulation, referred to as Formulation C, are shown in Figure 10. Two photographs of different samples of the etched Formulation C insert, collected after immersion in the dissolution medium at 37°C for 98 days followed by immersion at room temperature for 113 days, are shown in Figure 11.

The comparison of drug release curves for formulations A, B, and C is shown in Figure 12.

Formulation A releases the drug more slowly and degrades more slowly than formulations B and C. Formulation C releases the drug more quickly and degrades more quickly than formulations A and B.

Example 3

Prepare inserts containing more than one level of PVA based on the parameters in the table below:

The insert was manufactured by mixing voronirb with an aqueous PVA solution at a ratio of 1:1 w/w voronirb:PVA solution to form a paste. The mixture was then extruded from a 21-gauge dispensing tip to form rods approximately 4 to 5 inches in length and dried at room temperature. The extruded rods cured as described in the table above.

The extrudate is dipped into an aqueous PVA solution and allowed to dry at room temperature. For inserts with more than one coating, the coating process involves dipping the extrudate into a PVA solution, allowing 5 minutes of room temperature drying between the first layers, and then allowing at least 10 minutes of drying time before dipping again to form the final layer/coating.

After the final coating, allow the coated rod to cure under the conditions described in the table above. After cooling to ambient temperature, use a razor blade to cut the coated rod into 8mm long inserts.

API release is measured according to the method described in Example 2B.

The API content was measured according to the method described in Example 2C.

The insertion etching was evaluated according to the method described in Example 2D.

Prepare inserts containing more than one level of PVA based on the parameters in the table below:

The insert was manufactured by mixing voronirb with an aqueous PVA solution at a ratio of 1:1 w/w voronirb:PVA solution to form a paste. The mixture was then extruded from a 21-gauge dispensing tip to form rods approximately 4 to 5 inches in length and dried at room temperature. The extruded rods cured as described in the table above.

The extrudate is dipped into an aqueous PVA solution and allowed to dry at room temperature. For inserts with more than one coating, the coating process involves dipping the extrudate into a PVA solution, allowing 5 minutes of room temperature drying between the first layers, and then allowing at least 10 minutes of drying time before dipping again to form the final layer/coating.

After the final coating, allow the coated rod to cure under the conditions described in the table above. After cooling to ambient temperature, use a razor blade to cut the coated rod into 8mm long inserts.

API release is measured according to the method described in Example 2B.

The API content was measured according to the method described in Example 2C.

The insertion etching was evaluated according to the method described in Example 2D.

Example 4

The insert is prepared according to the parameters in the table below:

Mix the API and PVA aqueous solution at the API:PVA solution ratio specified in the table to form a paste. Extrude the paste through a 20 to 23 gauge dispensing tip to form rods approximately 4 to 5 inches long and allow to dry at room temperature. The extruded rods cure before or after coating as described in the table above.

The extrudate is impregnated in an aqueous PVA solution for coating. The coating process involves impregnating the extrudate in the PVA solution, allowing 5 minutes of room temperature drying between the first layer and a subsequent drying time of at least 10 minutes before impregnation to form the final layer/coating. After the final coating, the extrudate is cured by a coating bar according to the table above or allowed to dry at room temperature for 24 hours.

Use a razor blade to cut the coated stick into inserts 2mm, 3.5mm, 5mm, or 6mm long.

API release is measured according to the method described in Example 2B.

The API content was measured according to the method described in Example 2C.

The insertion etching was evaluated according to the method described in Example 2D.

Example 5A - Pharmacokinetic Study

Intravitreal pharmacokinetic studies were conducted in male Dutch belted rabbits. The aim of this study was to characterize the plasma and ocular tissue pharmacokinetics of the voronib insert following bilateral intravitreal injections on day 1. Animals were evaluated for up to 24 months after placement of the intravitreal insert.

The following table describes the group-assigned dose levels and treatments.

Following anesthesia, voronib inserts measuring 0.37 mm in diameter and 3.5 mm in length, designed to deliver the drug for at least 6 months, were injected into the vitreous cavity of each eye of 52 male Dutch rabbits using a syringe. The low-dose group (1) received 3 inserts per eye, for a total dose of 630 μg per eye. The high-dose group (2) received 6 inserts per eye in two separate injections (3 inserts per injection), for a total dose of 1,260 μg per eye.

Before each predetermined sacrifice point, a whole blood sample was collected from each of the two target animals in each group via marginal ear vein puncture. The voronib content and its metabolites were tested in the samples. Both animals in each group were euthanized at 6, 12, 24, and 48 hours on day 1, at day 7 and 14, and at 1, 2, 4, 6, 8, 16, and 24 months. Vitreous fluid and ocular tissue were collected from both eyes for analysis of drug distribution in ocular tissues. Inserts were collected, and samples from the liver and kidneys were collected to assess tissue distribution.

Results: At steady state, the vitreous concentration of voronib was 56 ng/mL for the low dose of 630 μg and 97 ng/mL for the high dose of 1,260 μg (approximately dose-proportional). Retinal/choroidal concentrations were 49 ng/g and 89 ng/g, respectively. A peak release period was observed in the first 90 days, followed by a steady state. Steady state was reached on day 105. The maximum concentrations observed in the vitreous and retinal/choroidal regions appeared to be almost dose-proportional. No significant changes in plasma concentrations were observed after 99 days. Until day 180, for the 630 μg dose, _{the maximum} vitreous concentration (C) was 232 ng/mL, _{the maximum time} to reaction (T) was 336 h, and _{the final} AUC was 315.5 μg·h/mL. Until day 180, for the 1260 μg dose, _{the maximum} vitreous concentration (C) was 1697 ng/mL, _{the maximum} T was 720 h, and _{the final} AUC was 1583.2 μg·h/mL.

Figure 13A depicts the average amount of remaining drug in the insert over time. For the insert, it was removed and analyzed at multiple time points to determine the amount of voronib remaining in the insert. Figure 13B depicts the cumulative percentage of drug release from the removed insert over time.

Example 5B - Pharmacokinetic Study

Another intravitreal pharmacokinetic study was conducted in male Dutch rabbits. The aim of this study was to evaluate the plasma and ocular pharmacokinetics of the voronib insert following bilateral intravitreal injections in the rabbit eye. Animals were evaluated for up to 12 months after the placement of the intravitreal insert.

Voronib inserts were administered to the eyes of Dutch rabbits via intravitreal injection. Group 1 eyes received one insert containing 643 μg of voronib, and Group 2 eyes received two inserts containing a total of 900 μg of voronib. Blood samples were collected monthly at days 2, 7, 14, and 28, and subsequently from 2 to 12 months. The inserts were recovered at days 2, 7, and 14, and subsequently at months 1, 2, 4, 6, 8, 10, and 12. Residual voronib content was determined in all explants using high-performance liquid chromatography (HPLC). The voronib release rate was estimated based on the residual content in the explants. Plasma and ocular tissues were separated, and voronib and its metabolites were analyzed using HPLC-MS/MS.

Results: The insert released voronib at an average rate of 8.1%/month in Group 1 and 7.8%/month in Group 2 over 12 months. Release profiles show near-zero order kinetics over 8 months, indicating consistent daily release of micrograms of drug with concentrations in target ocular tissues (choroid and retina) exceeding the IC50 for VEGFR2. Beyond 8 months, the release rate rapidly decreased, resulting in target ocular tissue concentrations below the IC50 (<10 ng/ml) at 10 months. The order of voronib exposure was choroid = retina = vitreous humor > aqueous humor > plasma. Between 8 and 10 months, there was an 85%–99% decrease in mean voronib concentrations in ocular tissues and plasma.

The voronib insert achieves sustained and consistent zero-order release of voronib in the rabbit eye for 8 months, followed by a rapid decrease over 10 months. The voronib insert is being investigated in a phase 2 clinical trial for wAMD and diabetic retinopathy, with a trial planned for diabetic macular edema.

Example 6 - Toxicological and Pharmacokinetic Studies

An 18-month intravitreal toxicity study of the insert was also conducted in 80 Dutch rabbits (40 males and 40 females). Animals were evaluated at 6 and 18 months after intravitreal insertion. The aim was to characterize the ocular toxicity, plasma pharmacokinetics, and biodegradation of the voronib insert following bilateral intravitreal injection.

The tables below describe the group assignments and dose levels. For the toxicology group, animals were sacrificed at 6 and 18 months. For plasma pharmacokinetic analysis, blood samples were collected on days 1, 3, and 7, and subsequently at 1, 2, 3, 4, 5, 6, 12, 14, 16, and 18 months.

Following anesthesia, voronib inserts measuring 0.37 mm in diameter and 3.5 mm in length, designed to deliver the drug for at least 6 months, were injected into the vitreous cavity of each eye of Dutch rabbits using a syringe. The placebo group (1) received two placebo inserts in each eye via injection. The low-dose group (2) received two inserts in each eye. The intermediate-dose group (3) received three inserts in each eye via two separate injections. The high-dose group (4) received four inserts in each eye via two separate injections (two inserts per injection). The highest-dose group (5) received six inserts in each eye via two separate injections (three inserts per injection).

Whole blood was collected via peripheral auricular vein puncture at predetermined time points. Clinical pathology and plasma pharmacokinetics of the samples were analyzed. Animals were euthanized according to the aforementioned timeline. A complete total necropsy was performed on all animals euthanized or found dead during the study period. Organs were weighed and tissues were collected. Ocular tissue was collected solely for histopathology.

Conclusion: Plasma pharmacokinetic and toxicological studies provide safety evidence for vitreous _maximum C and AUC after 18 and 24 months of exposure, respectively. Furthermore, at the tested time points, voronib levels in the vitreous and retina/choroid remained significantly higher than the _IC50 of VEGFR.

No adverse findings were attributed to voronib, and no adverse findings were found for a maximum of 6 inserts. The No-Seeed Adverse Effect Level (NOAEL) for the inserts was determined to be 6 inserts/eye (1260 μg/eye).

The most frequently observed event was yellow discoloration of the lens, which appeared to be dose-related and attributed to the color of the API. No histopathological/microscopic findings were found related to the lens discoloration. The second most frequent event was focal, speckled, or linear lens opacity, which appeared to be primarily related to the number of injections and, to a lesser extent, to the number of inserts.

Initially, mild inflammation (<2+ aqueous humor cells or vitreous cells) was observed in all groups. By 3 months, all inflammatory cells had gradually subsided and cleared. The highest observed inflammatory event was observed in the placebo group (2 drug-free inserts).

Although some temporary changes were observed, intraocular pressure (IOP) remained unchanged relative to baseline.

Voronib plasma concentrations were in the low pg/mL range.

Example 7 - Safety and Efficacy

The safety and efficacy of voronib inserts were evaluated in a porcine (miniature pig) model of laser-induced choroidal neovascularization (CNV). The primary objective of this study was to assess the long-term safety and inhibitory effects on vascular permeability and angiogenesis of voronib inserts in a porcine model of laser-induced choroidal neovascularization (CNV).

The experimental design is described in the table below:

On laser treatment days (groups 1–4), animals were treated with an 810 nm diode laser delivered via indirect ophthalmoscopy. Approximately six single laser points were located between the retinal veins. Both eyes were treated according to the timelines in the table above.

On the day of intravitreal injection, anesthetize the animals and prepare the eyes aseptically. Gently grasp the conjunctiva with Colibri forceps and inject (using a 25G syringe needle) 2 to 3 mm posterior to the superior limbus (through the pars plana), with the needle pointing slightly posteriorly to avoid contact with the lens. Allow the animals to recover normally from the procedure. Four to six hours later, administer topical drops of antibiotic ophthalmic solution to the pigs, followed by two more days of BID, with doses at least 6 hours apart. Administer the medication to the animals immediately following day 0 after laser CNV induction or seven days before laser CNV induction, according to the timeline in the table above. Animals in groups 5 and 6 did not undergo the laser CNV procedure and received implantation on day 0.

During environmental adaptation and throughout the study, animal mortality and morbidity, as well as general health, were assessed, with particular attention to the eyes. Animal weight was collected before treatment and necropsy, and animals in groups 5 and 6 were weighed monthly.

A complete ocular examination (OE) (modified Hackett and McDonald) was performed using a slit-lamp biological microscope and indirect ophthalmoscope to assess ocular surface morphology, anterior and posterior segment inflammation, and cataract formation. Retinal changes were examined by a veterinary ophthalmologist at the time points indicated in the experimental design. Pupil dilation was performed during the ocular examination using topical 1% tropicamide HCl.

Fluorescein angiography was performed in both eyes of anesthetized animals at the time points indicated in the experimental design table.

Full-field electroretinography (ERG) was performed on both eyes of the animals at baseline and 3 months after administration (groups 5-6 only). Animals were anesthetized after dark adaptation on the day of ERG measurement. ERG was induced by a short flash of light at 0.33 Hz delivered at maximum intensity using a mini-Ganzfeld light stimulator. Each animal was magnified, filtered, and averaged twenty responses. Standard ERG measurements were performed on the animals according to ISCEV standards, including dark (0.01 candle), dark (3 candle), and bright (25 candle) measurements.

Animals were euthanized at the time points specified in the experimental design table, after final data collection. Histological evaluation was performed on eyes from groups 5 and 6.

Results: Overall, dose-related efficacy was observed and no clinical toxicity was noted. Fluorescein angiography analysis in all groups (1–4) showed reduced corrected total lesion fluorescence (CTLF) values from day 7 to day 28, with the largest reduction in CTLF values observed in animals treated with aflibercept followed by higher doses, and similar reductions in CTLF values observed in the remaining groups. In both groups that underwent ERG, the ERG b-wave amplitude decreased relative to baseline up to day 84; however, this may be attributed to difficulties in obtaining ERG data.

The eyes examined showed partial inflammation, which may have been more severe in animals given high doses of the insert. The implantation procedure may have contributed to the increased inflammation observed in the high-dose group.

Aflibercept and the placebo insert performed as expected, with aflibercept having a normal efficacy level in this model and the placebo insert being well tolerable.

As shown in Figure 14, lesions in Group 2 (medium dose) and Group 3 (high dose) animals (who received the insert 7 days prior to laser CNV) never reached the size of lesions in untreated eyes. This indicator insert prevented lesions from reaching the size seen in untreated eyes. Figure 14 is a bar graph comparing the percentage of corrected total lesion fluorescence (CTFL) over time in Groups 1 through 4.

in conclusion:

In PK studies, voronib plasma concentrations were in the low pg/mL range. Dose-related efficacy was observed, and no clinically observed toxicity was found. Therefore, the insert of the present invention can locally deliver a safe and therapeutically effective stable level of voronib over a sustained period of time, while producing negligible systemic voronib levels. Furthermore, the insert is completely biodegradable. Additionally, the insert appears to have a preventative effect against lesion growth.

Example 8: A Phase 1, multicenter, prospective, open-label dose-escalation study of an ocular drug delivery insert for an EYP-1901 tyrosine kinase inhibitor (TKI) in subjects with wet AMD.

A Phase 1 open-label, dose-escalation clinical trial of the ocular drug delivery insert of the present invention was conducted to evaluate the safety of voronib-containing ocular drug delivery inserts in managing subjects with neovascular (wet) age-related macular degeneration (AMD). Interim 6-month results have been evaluated and reported.

At the start of the study, 17 participants were recruited, all of whom had previously been treated for wet AMD. Prior to the screening visit, participants in this study had been diagnosed with wet AMD in the study eye for at least 4 months. To be included, participants had to have received at least 3 prior injections of an anti-VEGF product, such as bevacizumab (Genentech), ranibizumab (Genentech), or aflibercept (Regeneron), in the study eye within the previous 6 months, with a BCVA between 25 letters (20/320 Snellen equivalent) and 75 letters (20/32 Snellen equivalent).

For subjects with unilateral wAMD, the affected eye was designated as the study eye; for subjects with bilateral wAMD, the study eye was the more severely affected eye that met the inclusion/exclusion criteria, i.e., the eye with a worse BCVA, or, if equal, the clinically determined more severely affected eye as determined by the investigator. If the eyes were symmetrically affected, the study eye was the right eye.

One week after screening and standard care anti-VEGF injections, subjects received one injection of the study drug, namely an ocular drug delivery insert containing voronib and PVA. The study included four dose groups: low-dose, low-intermediate-dose, intermediate-dose, and high-dose. A 25-gauge needle was used for the low-dose injection, and a 22-gauge needle was used for the other injections.

The release duration of the active pharmaceutical ingredient (voronib) is expected to be at least 9 months. There was no reinjection of the study drug during the first 6 months of the trial.

After the injection on day 0 of the study, the subjects recovered on day 7, day 14, day 28 and every 4 weeks thereafter until month 12.

The assessments included BCVA as evaluated by ETDRS, anterior/posterior segment ocular examination, IOP, fluorescein angiography (FA), color fundus photography (CFP), treatment-induced ocular and non-ocular adverse events (TEAE), clinical laboratory assessments (hematology, serum chemistry, coagulation and urinalysis), vital sign measurements (see details in the accompanying study procedures and assessment forms), frequency domain-optical coherence tomography (SD-OCT), and OCT-angiography (OCT-A) at study sites where equipment was available.

The primary endpoint was to assess safety and determine the maximum tolerated dose for treating neovascular (wet) AMD based on treatment-induced ocular (study eye and contralateral eye) and non-ocular adverse events (TEAEs), including clinical laboratory results. Secondary endpoints included BCVA and CST as measured by OCT. Researchers also assessed the number of eyes that did not require supplemental (previously referred to as “rescue” in our study protocol) at various time points and the extent of reduction in anti-VEGF treatment load following EYP-1901 administration.

Following intravitreal injection of the EYP-1901 insert, if at least one of the following criteria is met, FDA-approved anti-VEGF therapy or off-label bevacizumab for wet AMD may be administered at the investigator's discretion:

• Due to new or worsening visually impairing hemorrhages relative to baseline (day 0) in wet AMD, or

• CST increase relative to baseline (day 0) >75 μm, or

• In cases of intraretinal/subretinal fluid and/or hemorrhage, a loss of ≥10 ETDRS letters relative to baseline (day 0) is considered a cause of BCVA loss.

If the above guidelines for complementary treatment are not met, researchers can still determine whether complementary medicines are necessary for the best interests of the subject's health.

6-month Conclusions: The interim 6-month results of this study showed positive safety data, with no dose-limiting toxicities (DLTs), no reported serious ocular adverse events (SAEs), and no reported drug-related systemic SAEs. Most reported ocular adverse events were mild and predictable. All ocular AEs were ≤ grade 2, with only grade 3 AEs not drug-related. Across all dose groups, 76% of subjects did not receive supplementation for up to 4 months, and 53% did not receive supplementation for up to 6 months, with a median duration of supplementation of 6 months across all subjects. At the 6-month visit, stable best-corrected visual acuity (BCVA) with a mean change of -2.5 letters and central retinal thickness (CST) with a mean change of -2.7 μm were obtained over 6 months. Three of the 17 subjects required supplementation at month 1, but these subjects will also be considered as second-best responders to standard-of-care anti-VEGF therapy. The total treatment load at 6 months was reduced by 79% across all groups, and 8 of the 17 subjects remained without supplementation, with one subject remaining without supplementation for up to 9 months. The average change in BCVA for screening visits is shown in the curve in Figure 15. The average change in CST for screening visits is shown in the curve in Figure 16. The no-supplementation rate for each visit is shown in the curve in Figure 17.

Example 9

Six months of data (longitudinal records of each enrollee) from the DAVIO study (described in Example 8 above) were compared using a statistical analysis system (SAS) to compare certain parameters with outcomes. The data were analyzed to determine whether several baseline characteristics in the subjects predicted the efficacy of the investigational drug (EYP-1901) in wet AMD. The baseline subject characteristics (parameters) assessed included the presence of subfoveal IRF at baseline in the study eyes. The presence of subfoveal IRF at baseline in the study eyes was associated with an increased number of supplemental treatments (p≤0.05).

Example 10

The results of the DAVIO study (described in Example 8 above) showed positive safety data, with no dose-limiting toxicities (DLTs), no reported serious ocular adverse events (SAEs), and no reported drug-related systemic SAEs. Most of the reported ocular adverse events were mild and unrelated to EYP-1901. Visual acuity and OCT were stable. Treatment load was reduced by 75% at 6 months and by 73% at 12 months. Following a single dose of EYP-1901 (n=17), 53% of eyes did not require supplemental injections for up to 6 months and 35% of eyes did not require supplemental injections for up to 12 months, as shown in the curves in Figure 18. As used herein, supplemental injection refers to the same concept as supplemental treatment described in Example 8 above in the administration of standard care VEGF therapy.

During the study, patients who received 2,060 μg or 3,090 μg of EYP-1901 (n=6) and had no excess fluid at screening experienced a 92% reduction in treatment load at 6 months and an 89% reduction at 12 months. Patients who received any dose of EYP-1901 (n=9) and had no excess fluid at screening were not given supplemental injections for up to 4 months; 67% of patients were not given supplemental injections for up to 6 months and 56% were not given supplemental injections for up to 12 months, as shown in the curves in Figure 19.

Claims (52)

1. A method for treating wet age-related macular degeneration (AMD), the method comprising: Assess the presence of subfoveal intraretinal fluid (IRF) in eyes diagnosed with wet AMD, wherein the eyes are human subjects, and If no foveal IRF is detected, an ocular drug delivery insert containing voronib or a pharmaceutically acceptable salt thereof is administered to the eye, wherein the insert releases about 0.01 μg/day to about 100 μg/day of voronib for at least 60 days. 2. A method for treating wet AMD, the method comprising: An ocular drug delivery insert containing voronibu or a pharmaceutically acceptable salt thereof is administered to an eye diagnosed with wet AMD, wherein the eye is in a human subject and no foveal IRF is detected in the eye at baseline, wherein the insert releases about 0.01 μg/day to about 100 μg/day of voronibu for at least 60 days. 3. A method for treating wet age-related macular degeneration (AMD), the method comprising: Assess the presence of subfoveal intraretinal fluid (IRF) in eyes diagnosed with wet AMD, wherein the eyes are human subjects, and If no foveal IRF is detected, an ocular drug delivery insert containing voronib or a pharmaceutically acceptable salt thereof is administered to the eye, wherein the insert has an average drug release rate of voronib of about 0.01 μg/day to about 100 μg/day over a 30-day period. 4. A method for treating wet AMD, the method comprising: An ocular drug delivery insert containing voronib or a pharmaceutically acceptable salt thereof is administered to an eye diagnosed with wet AMD, wherein the eye is in a human subject and no foveal IRF is detected in the eye at baseline, wherein the insert has an average drug release rate of voronib of about 0.01 μg/day to about 100 μg/day over a 30-day period. 5. The method according to any one of claims 1 to 4, wherein the eye has not been treated with voronib. 6. The method according to any one of claims 1 to 4, wherein the insert comprises a solid matrix core comprising the voronib or a pharmaceutically acceptable salt thereof and a matrix polymer. 7. The method according to claim 6, wherein the matrix polymer is polyvinyl alcohol (PVA). 8. The method of claim 6, wherein the amount of matrix polymer in the insert is from about 1% w/w to about 15% w/w. 9. The method according to any one of claims 1 to 8, wherein the amount of voronib or a pharmaceutically acceptable salt thereof in the insert is from about 60% w/w to about 98% w/w. 10. The method according to any one of claims 1 to 8, wherein the amount of voronib or a pharmaceutically acceptable salt thereof in the insert is from about 85% w/w to about 99% w/w. 11. The method according to any one of claims 1 to 8, wherein the insert is capable of being eroded by at least 90% within 440 days. 12. The method according to any one of claims 1 to 8, wherein the insert comprises about 200 μg to about 2000 μg of voronib or a pharmaceutically acceptable salt thereof. 13. The method according to any one of claims 1 to 8, wherein the insert is administered via intravitreal injection through a 20 to 27 gauge needle or cannula. 14. The method of claim 13, wherein the length of the insert is from about 1 mm to about 10 mm. 15. The method according to any one of claims 1 to 14, wherein the insert further comprises a coating substantially surrounding the core. 16. The method of claim 15, wherein the insert further comprises a delivery port. 17. The method of claim 16, wherein the coating comprises PVA. 18. The method of claim 17, wherein the matrix polymer is PVA and the coating comprises a different grade of PVA than the matrix polymer. 19. The method of claim 13, wherein 1 to 6 inserts are injected. 20. The method of claim 19, wherein the total amount of voronib in all said inserts is from about 600 μg to about 6000 μg. 21. The method of claim 7, wherein the insert is cured at about 60°C to about 120°C for about 200 minutes to about 1440 minutes. 22. The method according to claim 1 or 2, wherein the insert releases about 0.1 μg/day to about 30 μg/day of voronib for at least 90 days. 23. The method according to claim 1 or 2, wherein the insert releases about 0.1 μg/day to about 30 μg/day of voronib for at least 120 days. 24. The method of claim 20, wherein one or more ocular drug delivery inserts deliver a total average daily dose of voronib of about 1 μg/day to about 50 μg/day for at least 90 days. 25. The method according to any one of claims 1 to 8, wherein the eye does not require supplemental treatment for at least 120 days from the date of application of the insert. 26. The method according to any one of claims 1 to 8, wherein the eye does not require supplemental treatment for at least 6 months from the date of application of the insert. 27. The method according to any one of claims 1 to 8, wherein the eye does not require supplemental treatment for at least 12 months from the date of application of the insert. 28. The method according to any one of claims 1 to 8, wherein on a day 120 days after the application of the insert, the change in the best corrected visual acuity (BCVA) of the eye relative to the baseline is a loss of ≤5 ETDRS letters. 29. The method according to any one of claims 1 to 8, wherein on a day 120 days after the application of the insert, the change in the best corrected visual acuity (BCVA) of the eye relative to the baseline is a loss of ≤10 ETDRS letters. 30. The method according to any one of claims 1 to 8, wherein on a day 120 days after the application of the insert, the change in the best corrected visual acuity (BCVA) of the eye relative to the baseline is a loss of ≤15 ETDRS letters. 31. The method according to any one of claims 1 to 8, wherein on a day 120 days after the application of the insert, the change in the best corrected visual acuity (BCVA) of the eye relative to the baseline is an increase of ≥5 ETDRS letters. 32. The method according to any one of claims 1 to 8, wherein on a day 120 days after the application of the insert, the change in the best corrected visual acuity (BCVA) of the eye relative to the baseline is an increase of ≥10 ETDRS letters. 33. The method according to any one of claims 1 to 8, wherein on a day 120 days after the application of the insert, the change in the best corrected visual acuity (BCVA) of the eye relative to the baseline is an increase of ≥15 ETDRS letters. 34. The method according to any one of claims 1 to 8, wherein for at least 180 days from the date of application of the insert, the subject's overall IVI questionnaire score did not increase significantly relative to the baseline. 35. The method according to any one of claims 1 to 8, wherein the baseline CST in the eye to which the ocular drug delivery insert is applied is less than 400 μm. 36. The method according to any one of claims 1 to 8, wherein the baseline CST in the eye to which the ocular drug delivery insert is applied is 350 μm or less. 37. The method according to any one of claims 1 to 8, wherein the CST in the eye on the day of application of the ocular drug delivery insert is less than 400 μm or less. 38. The method according to any one of claims 1 to 8, wherein the CST in the eye on the day of application of the ocular drug delivery insert is 350 μm or less. 39. A method for treating posterior ocular conditions, the method comprising: Assess whether the central retinal thickness (CST) in the eye diagnosed with the aforementioned posterior ocular condition is 500 μm or less. If the CST is 500 μm or less, an ocular drug delivery insert containing voronib or a pharmaceutically acceptable salt thereof is administered to the eye, wherein the insert releases about 0.01 μg/day to about 100 μg/day of voronib for at least 60 days. 40. A method for treating posterior ocular conditions, the method comprising: An ocular drug delivery insert comprising voronibue or a pharmaceutically acceptable salt thereof is administered to an eye diagnosed with the aforementioned posterior ocular condition, wherein the CST in the eye is 500 μm or less, and wherein the insert releases about 0.01 μg/day to about 100 μg/day of voronibue for at least 60 days. 41. A method for treating posterior ocular conditions, the method comprising: Assess whether the central retinal thickness (CST) in the eye diagnosed with the aforementioned posterior ocular condition is 500 μm or less. If the CST is 500 μm or less, an ocular drug delivery insert containing voronib or a pharmaceutically acceptable salt thereof is administered to the eye, wherein the insert has an average drug release rate of voronib of about 0.01 μg/day to about 100 μg/day over a 30-day period. 42. A method for treating posterior ocular conditions, the method comprising: An ocular drug delivery insert comprising voronib or a pharmaceutically acceptable salt thereof is administered to an eye diagnosed with the aforementioned posterior ocular condition, wherein the CST in the eye is 500 μm or less, and wherein the insert has an average drug release rate of voronib of about 0.01 μg/day to about 100 μg/day over a 30-day period. 43. A method for treating posterior ocular conditions, the method comprising: Assess the presence of subfoveal intraretinal fluid (IRF) in eyes diagnosed with the aforementioned posterior ocular condition, wherein the eyes are human subjects, and If no foveal IRF is detected, an ocular drug delivery insert containing voronib or a pharmaceutically acceptable salt thereof is administered to the eye, wherein the insert releases about 0.01 μg/day to about 100 μg/day of voronib for at least 60 days. 44. A method for treating posterior ocular conditions, the method comprising: An ocular drug delivery insert comprising voronibue or a pharmaceutically acceptable salt thereof is administered to an eye diagnosed with the aforementioned posterior ocular condition, wherein the eye is in a human subject and no foveal IRF is detected in the eye at baseline, wherein the insert releases about 0.01 μg/day to about 100 μg/day of voronibue for at least 60 days. 45. A method for treating posterior ocular conditions, the method comprising: Assess the presence of subfoveal intraretinal fluid (IRF) in eyes diagnosed with the aforementioned posterior ocular condition, wherein the eyes are human subjects, and If no foveal IRF is detected, an ocular drug delivery insert containing voronib or a pharmaceutically acceptable salt thereof is administered to the eye, wherein the insert has an average drug release rate of voronib of about 0.01 μg/day to about 100 μg/day over a 30-day period. 46. A method for treating posterior ocular conditions, the method comprising: An ocular drug delivery insert containing voronibue or a pharmaceutically acceptable salt thereof is administered to an eye diagnosed with the aforementioned posterior ocular disease, wherein the eye is a human subject and no foveal IRF is detected in the eye at baseline, wherein the insert has an average drug release rate of voronibue of about 0.01 μg/day to about 100 μg/day over a 30-day period. 47. The method according to any one of claims 39 to 46, wherein the posterior ocular condition is wet AMD. 48. The method according to any one of claims 39 to 46, wherein the posterior eye condition is diabetic macular edema. 49. The method according to any one of claims 39 to 46, wherein the posterior eye condition is diabetic retinopathy. 50. The method according to any one of claims 39 to 46, wherein the posterior eye condition is nonproliferative diabetic retinopathy. 51. The method according to any one of claims 39 to 46, wherein the posterior eye condition is retinal vein occlusion. 52. The method according to any one of claims 39 to 46, wherein the ocular drug delivery insert is applied to an eye in which the CST is 350 μm or less.