USES OF BIOREDIBLE Ocular INSERT FOR DRUG DELIVERY

Description

1 / 80 “USES OF BIOERODIBLE OCULAR INSERT FOR DRUG DELIVERY”

[001] Divided from BR1120230046777, deposited on 09 / 13 / 2021. BACKGROUND OF THE INVENTION FIELD OF THE INVENTION

[002] This invention relates to implantable bioerodible inserts for delivering active pharmaceutical agents to the eye. The invention relates to methods of using such inserts to treat patients who need therapeutic relief, as well as methods of manufacturing such inserts. BACKGROUND

[003] Implantable drug delivery inserts have certain advantages over conventional drug delivery methods, such as oral administration or intravenous injection. For example, in conventional dosing methods, the concentration of a drug (active pharmaceutical ingredient) can vary considerably, reaching a maximum concentration (Cmax) soon after administration and then decreasing sharply. To maintain therapeutic levels, it may be necessary to administer the drug in high doses, which can temporarily result in potentially toxic high drug concentrations. As the drug is metabolized or eliminated by the body, the drug concentration may decrease to safe, therapeutic levels. When the drug level falls to subtherapeutic levels, another dose must be administered, and so the cycle repeats.Thus, one problem with conventional dosing is that, for certain types of drugs, a patient may be chronically exposed to undesirably high drug levels due to the repeated dosing cycles required for treatment. Furthermore, frequent dosing may be necessary, reducing patient adherence.

[004] Implantable drug delivery inserts can reduce the need for frequent dosing and avoid high systemic concentrations of Petition 870260060402, dated 06 / 19 / 2026, page 10 / 113 2 / 80 of the drug. However, achieving a constant dosing rate (so-called zero-order release) over an acceptable period is challenging.

[005] Furthermore, many implantable drug delivery inserts contain non-biodegradable materials that remain permanently in a patient's body even after all the drug has been administered. This can become problematic, particularly for drug delivery to an anatomical site with a small volume. Repeated therapeutic treatments via implantation may be limited due to the undesirable accumulation of the non-biodegradable portions of the implantable drug delivery device.

[006] Furthermore, it is extremely challenging to provide an implantable drug delivery device that is small enough to be implanted in a patient with minimal discomfort, but large enough to hold sufficient drug to provide sustained delivery of therapeutic levels of the drug.

[007] In view of these factors, there remains a need in the art to improve the design and method of preparation of implantable drug delivery devices that provide controlled and sustained release of a drug to a patient to achieve a desired local or systemic physiological or pharmacological effect.

[008] One ophthalmic condition for which improved drug delivery is needed is age-related macular degeneration (AMD). AMD is a leading cause of blindness worldwide, and the World Health Organization estimates that approximately 14 million people have developed blindness or been severely impaired due to AMD. AMD causes progressive loss of central vision attributable to degenerative and neovascular changes in the macula, a specialized area in the center of the retina. In general, macular degeneration can produce a slow or sudden loss of vision. Petition 870260060402, dated 06 / 19 / 2026, page 11 / 113 3 / 80

[009] There are two forms of AMD: dry AMD and wet AMD. Typically, AMD begins as dry AMD, characterized by the formation of drusen, yellow plaque-like deposits in the macula between the retinal pigment epithelium and the underlying choroid. About 15% of patients with dry AMD develop wet AMD, characterized by the formation of new blood vessels in the choroid (choroidal neovascularization) and vision loss.

[010] Dry macular degeneration is more common than wet AMD, with about 90% of AMD patients being diagnosed with dry AMD. The dry form of AMD can result from aging and thinning of macular tissues, pigment deposition in the macula, or a combination of both processes. The wet form of the disease generally leads to more severe vision loss. With wet AMD, new blood vessels grow under the retina and leak blood and fluids. This leakage causes retinal cells to die and creates blind spots in central vision.

[011] Although there is no cure for AMD, there are some treatments for wet AMD, but many of them are inconvenient or have significant side effects. BRIEF SUMMARY OF THE INVENTION

[012] According to various embodiments of the invention and after extensive experimentation, the inventors have developed a bioerodible drug delivery insert comprising an active pharmaceutical ingredient (API) and a bioerodible polymer. This insert is particularly useful for local delivery of an effective amount of the API to the eye. Furthermore, the insert provides sustained release of the API. In some respects, the insert provides sustained release during a period almost synchronized with the period required to complete the erosion of the insert in an eye.

[013] These inserts can be administered intraocularly, by Petition 870260060402, dated 06 / 19 / 2026, page 12 / 113 4 / 80 For example, via intravitreal, suprachoroidal and intracameral routes; or subconjunctival. For example, the inserts can be placed through a needle or cannula, for example, intravitreal injection. Thus, in some respects, the invention relates to a drug delivery insert that can deliver effective intraocular concentrations of the API while delivering low systemic concentrations of the API, for example, to reduce the risk of toxicity or other undesirable side effects.

[014] In some respects, the invention relates to methods for treating or preventing eye diseases by local (e.g., intraocular) administration of an API or a pharmaceutically acceptable salt thereof.

[015] In one embodiment, the invention relates to an ocular drug delivery insert comprising a solid matrix core comprising a matrix polymer and vorolanib or a pharmaceutically acceptable salt thereof, wherein the amount of vorolanib or pharmaceutically acceptable salt thereof in the insert is about 10% w / w about 98% w / w, wherein the drug release rate to the insert is about 0.01 μg / day to about 100 μg / day for at least 14 days and wherein the insert is capable of at least 20% erosion within 95 days. In another embodiment, the amount of vorolanib or pharmaceutically acceptable salt thereof in the insert is about 60% w / w about 98% w / w.

[016] In another embodiment, the insert further comprises a coating that substantially surrounds the core. In some embodiments, the amount of coating is about 5% by weight to about 20% by weight of the insert. In further embodiments, the insert further comprises a delivery port.

[017] In another embodiment, the insert is sized and shaped to pass through a needle or cannula of gauge 20 to 27 and the insert has a Petition 870260060402, dated 06 / 19 / 2026, p. 13 / 113 5 / 80 length of about 1 mm to about 10 mm. In yet another embodiment, the insert is sized and shaped to pass through a needle or cannula of gauge smaller than 25. In a further embodiment, the insert has a length of about 1 mm to about 6 mm.

[018] In some embodiments, the matrix polymer comprises PVA. In some embodiments, the matrix polymer consists of PVA. In some embodiments, the coating comprises PVA. In some embodiments, the coating consists of PVA.

[019] In some aspects, the coating comprises a different grade of PVA than the matrix polymer. In some embodiments, the coating comprises more than one covering comprising PVA, and the DH of the PVA in at least one covering differs from the DH of the PVA matrix polymer. In some embodiments, the MW of the PVA in the coating differs from the MW of the PVA matrix polymer. In further embodiments, the coating comprises at least two coverings comprising PVA, and at least one of the coverings comprises a different grade of PVA than at least one other covering. In still other aspects, the PVA in at least two coverings comprising PVA differs in DH. In some embodiments, the PVA in at least two coverings comprising PVA differs in MW.

[020] In yet another modality, the insert is capable of at least 90% erosion within 440 days.

[021] In one aspect, the drug release rate is from about 0.1 μg / day to about 20 μg / day. In another aspect of the insert, the drug release rate is from about 0.1 μg / day to about 10 μg / day. In yet another aspect of the insert, the drug release rate is from about 0.1 μg / day to about 2 μg / day.

[022] In one embodiment, the nucleus comprises about 200 μg to about Petition 870260060402, dated 06 / 19 / 2026, p. 14 / 113 6 / 80 of 2,000 μg of vorolanib or a pharmaceutically acceptable salt thereof.

[023] In another embodiment, the duration of release of vorolanib is at least about 90 days. In yet another embodiment, the duration of release of vorolanib is from about 60 days to about 270 days.

[024] In one aspect of the invention, the core comprises about 1% by w / w about 15% by w / w of PVA.

[025] In another aspect of the invention, the insert was cured for about 30 minutes to about 4 hours at about 130 °C to about 150 °C.

[026] In yet another aspect of the invention, the insert has approximately zero-order release rate kinetics.

[027] In one embodiment, the insert has a cylindrical shape. In a further embodiment, at least one end of the insert forms a delivery port.

[028] In another embodiment, the insert is produced by dissolving PVA in an aqueous solution to form a PVA solution, mixing the PVA solution with vorolanib or a pharmaceutically acceptable salt thereof to form a matrix mixture, extruding the mixture through a dispensing tip to form an elongated conformed matrix, curing the elongated conformed matrix at a temperature of about 140 °C to about 160 °C for about 30 minutes to about 2 hours, and segmenting the elongated conformed matrix.

[029] In other embodiments, the insert is produced by dissolving PVA in an aqueous solution to form a PVA solution, mixing the PVA solution with vorolanib or a pharmaceutically acceptable salt thereof to form a matrix mixture, extruding the mixture through a dispensing tip to form an elongated conformed matrix, coating the elongated conformed matrix with a PVA solution, curing the elongated conformed matrix at a temperature of about 140 °C to about 160 °C for about 30 minutes to about 2 Petition 870260060402, dated 06 / 19 / 2026, p. 15 / 113 7 / 80 hours, and segment the elongated shaped matrix.

[030] The invention also relates to a method for treating or preventing an eye condition in an individual who needs it, comprising injecting one or more inserts into the vitreous humor of an eye of the individual.

[031] Furthermore, the invention relates to a method for treating macular degeneration in an individual who needs it, comprising injecting one or more inserts into the vitreous humor of one of the individual's eyes. In some embodiments, the macular degeneration treated is age-related macular degeneration.

[032] In another aspect, the invention provides a method for producing an eye insert for drug delivery comprising dissolving PVA in an aqueous solution to form a PVA solution, mixing the PVA solution with vorolanib or a pharmaceutically acceptable salt thereof to form a matrix mixture, extruding the mixture through a dispensing tip to form an elongated conformed matrix, curing the elongated conformed matrix at a temperature of about 140 °C to about 160 °C for about 30 minutes to about 6 hours, and segmenting the elongated conformed matrix.

[033] In another aspect, the elongated shaped die is covered with a coating comprising PVA before curing the die.

[034] Furthermore, the invention relates to a method for treating a condition in an individual who needs it, wherein the condition is selected from the group consisting of: macular degeneration, retinal vein occlusion and diabetic retinopathy, comprising administering from about 0.01 μg / day to about 100 μg / day of vorolanib directly into one eye of the individual.

[035] In one embodiment, vorolanib or a pharmaceutically acceptable salt thereof is delivered by injecting one or more ocular drug delivery inserts comprising vorolanib or a pharmaceutically acceptable salt of Petition 870260060402, dated 06 / 19 / 2026, p. 16 / 113 8 / 80 right on target.

[036] In another modality, the insert is administered by intravitreal injection.

[037] In some embodiments, the insert is injected through a needle or cannula of smaller gauge than 25. In some embodiments no incision is required for injection.

[038] In some aspects, 1-6 inserts are injected.

[039] In some respects, each of the inserts comprises from about 200 μg to about 2000 μg.

[040] In some respects, the total amount of vorolanib in all injected inserts is from about 600 μg to about 6000 μg.

[041] In some embodiments, each of the one or more ocular drug delivery inserts has a drug release rate of about 0.1 μg / day to about 100 μg / day for at least 60 days.

[042] In some embodiments, one or more ocular drug delivery inserts deliver a total average daily dose of vorolanib of about 1 μg / day to about 50 μg / day for at least 30 days.

[043] In other embodiments, one or more ocular drug delivery inserts deliver a total average daily dose of vorolanib of about 1 μg / day to about 20 μg / day for at least 30 days.

[044] The invention also provides an ocular insert for drug delivery consisting of a solid matrix core comprising an API and at least two different grades of PVA, wherein the drug release rate to 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 pass through a 20 to 27 gauge needle or cannula. In some embodiments of this insert, the two different grades Petition 870260060402, dated 06 / 19 / 2026, p. 17 / 113 9 / 80 PVA is a blend selected from the list comprising: a blend of MW 78000, 88% hydrolyzed and MW 78000, 98% hydrolyzed; a blend of MW 78000, 88% hydrolyzed and MW 78000, 99+% hydrolyzed; a blend of MW 6000, 80% hydrolyzed and MW 78000, 98% hydrolyzed; a blend of MW 6000, 80% hydrolyzed and MW 78000, 99+% hydrolyzed; a blend of MW 78000, 88% hydrolyzed and MW 125000, 88% hydrolyzed; and a mixture of MW 6000, 80% hydrolyzed, and MW 125000, 88% hydrolyzed.

[045] In addition, the invention provides an eye insert for drug delivery comprising (a) a solid matrix core comprising PVA and an 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 at least 20% erosion within 95 days, and wherein the insert is sized and shaped to pass through a 20 to 27 gauge needle or cannula.

[046] In some embodiments of the insert, the cladding comprises a different grade of PVA than the PVA core. In some embodiments, the DH of the PVA in the cladding differs from the DH of the PVA core. In other embodiments, the MW of the PVA in the cladding differs from the MW of the PVA core. In still other embodiments, the cladding comprises at least two coverings comprising PVA, and at least one of the coverings comprises a different grade of PVA from at least one other covering. In further embodiments, the PVA in at least two coverings differs in DH. In some embodiments, the PVA in at least two coverings differs in MW.

[047] In other aspects of the insert, the amount of API in the insert is about 60% w / w about 98% w / w. In still other aspects, the core comprises about 20% w / w about 60% w / w of PVA. In additional embodiments, the amount of coating is about 5% w / w Petition 870260060402, dated 06 / 19 / 2026, p. 18 / 113 10 / 80 approximately 20% p / p of the insert. In other methods, the insert is capable of at least 90% erosion within 440 days.

[048] In some embodiments, the insert has approximately zero-order release rate kinetics and the drug release rate for the insert is from about 0.0001 μg / day to about 200 μg / day for at least 30 days. In still other embodiments, the drug release rate is from about 0.001 μg / day to about 100 μg / day for at least 30 days. In additional embodiments, the API release duration is at least about 90 days. In additional embodiments, the API release duration is from about 60 days to about 270 days.

[049] In some aspects of the insert, the insert was cured for about 30 minutes to about 4 hours at about 130 °C to about 150 °C.

[050] In other respects, the insert has a cylindrical shape. In another embodiment, at least one end of the insert forms a delivery port. In a further embodiment, the insert has a length of about 1 mm to about 10 mm, or is sized and shaped to pass through a needle or cannula of gauge smaller than 25.

[051] The invention also provides an ocular insert for drug delivery comprising:

[052] (a) a solid matrix core comprising a PVA selected from the group consisting of MW 6000, 80% hydrolyzed, MW 9000-10000, 80% hydrolyzed, MW 25000, 88% hydrolyzed, MW 25000, 98% hydrolyzed, MW 30000-70000, 87-90% hydrolyzed, MW 78000, 88% hydrolyzed, MW 78000, 98% hydrolyzed, MW 78000, 99% hydrolyzed, MW 89000-98000, 99% hydrolyzed, MW 85000-124000, 87-89% hydrolyzed, MW 108000, 99% hydrolyzed % hydrolyzed, MW 125,000, 88% hydrolyzed, MW 133,000, 99% hydrolyzed, MW 146,000-186,000, 99+% hydrolyzed, and mixtures thereof; and an API; and Petition 870260060402, dated 06 / 19 / 2026, page 19 / 113 11 / 80

[053] (b) at least one coating comprising PVA substantially surrounding the core, wherein the PVA in the coating is selected from a PVA selected from the group consisting of MW 6000, 80% hydrolyzed, MW 9000-10000, 80% hydrolyzed, MW 25000, 88% hydrolyzed, MW 25000, 98% hydrolyzed, MW 30000-70000, 87-90% hydrolyzed, MW 78000, 88% hydrolyzed, MW 78000, 98% hydrolyzed, MW 78000, 99% hydrolyzed, MW 89000-98000, 99% hydrolyzed, MW 85000-124000, 87-89 % hydrolyzed, MW 108000, 99+% hydrolyzed, MW 125,000, 88% hydrolyzed, MW 133000, 99% hydrolyzed, MW 146000-186000, 99+% hydrolyzed, and mixtures thereof;

[054] wherein the PVA in the core and the PVA in at least one coating have different degrees of PVA.

[055] In some forms, the insert comprises at least 2 PVA coverings and the DH of the PVA in the outermost covering is less than the DH of any PVA in the other coverings.

[056] In other embodiments of the inserts of the invention, the API has a molecular weight of 1000 AMU or less and a water solubility of less than about 200 μg / ml at 25 °C. In other embodiments, the API is a VEGF inhibitor. In other embodiments, it is a TKI inhibitor. In still other embodiments, the API is vorolanib or a pharmaceutically acceptable salt thereof. In further embodiments, the API is axitinib or a pharmaceutically acceptable salt thereof. In still other embodiments, the API is a Tie-2 activator. In some embodiments, the API is razuprotafib or a pharmaceutically acceptable salt or zwitterion thereof.

[057] In some aspects of the methods of the invention, the individual has geographic atrophy, the individual is at risk of developing geographic atrophy, the individual has vision loss, the individual is at risk of developing vision loss, the individual has ischemic retinal vein occlusion or the individual has non-ischemic retinal vein occlusion. Petition 870260060402, dated 06 / 19 / 2026, page 20 / 113 12 / 80

[058] The invention also provides a method for inhibiting angiogenesis in an eye in an individual who needs it, comprising implanting into the vitreous of an eye of the individual one or more ocular inserts for drug delivery, wherein the number of inserts administered during the administration procedure is from 1 to 6 inserts, and wherein each of the one or more inserts has a drug release rate of about 0.01 μg / day to about 100 μg / day of vorolanib for at least 30 days.

[059] It also provides a method for inhibiting VEGFR and PDGFR in an individual who needs it, comprising implanting into the vitreous of one eye of the individual one or more ocular drug delivery inserts, wherein the number of inserts administered during the administration procedure is from 1 to 6 inserts, and wherein each of the one or more inserts has a drug release rate of about 0.01 μg / day to about 100 μg / day of vorolanib for at least 30 days.

[060] In addition, the invention provides a method for treating macular degeneration in an individual in need thereof, comprising implanting into the vitreous of one eye of the individual one or more ocular drug delivery inserts, wherein the number of inserts administered during the administration procedure is from 1 to 6 inserts, and wherein each of the one or more inserts has a drug delivery rate of about 0.01 μg / day to about 100 μg / day of vorolanib for at least 30 days. In some embodiments, the macular degeneration treated is age-related macular degeneration.

[061] In some embodiments, the treatment or administration methods further comprise administering a pharmaceutical composition comprising a therapeutically effective amount of a Tie-2 activator to the individual. In a further embodiment, the Tie-2 activator is razuprotafib or a salt. Petition 870260060402, dated 06 / 19 / 2026, page 21 / 113 13 / 80 pharmaceutically acceptable or zwitterion of the same. In still other embodiments, the treatment methods additionally comprise administering a pharmaceutical composition comprising a therapeutically effective amount of a steroidal anti-inflammatory agent to the individual.

[062] Furthermore, the invention provides a method of VE-PTP inhibition in an eye of an individual in need thereof, comprising injecting one or more inserts into the vitreous humor of an eye of the individual. In other aspects, the invention provides a method of treating glaucoma in an individual in need thereof, comprising injecting one or more inserts into the vitreous humor of an eye of the individual. In still other embodiments, the invention provides a method of treating elevated IOP in an individual in need thereof, comprising injecting one or more inserts into the vitreous humor of an eye of the individual. In yet another embodiment, the invention provides a method of reducing IOP in an individual in need thereof, comprising injecting one or more inserts into the vitreous humor of an eye of the individual. In some embodiments, the method further comprises administering a VEGF inhibitor.

[063] In some respects, the invention provides an insert for use in the treatment or prevention of an eye condition in an individual who needs it.

[064] In other respects, the invention provides an insert for use in inhibiting angiogenesis in an eye in an individual who needs it.

[065] In still other aspects, it provides an insert for use in inhibiting VEGFR and PDGFR in an eye in an individual who needs it.

[066] In some respects, the invention provides an insert for use in the treatment of age-related macular degeneration in an individual who needs it.

[067] In some respects, the invention provides an insert for use in Petition 870260060402, dated 06 / 19 / 2026, page 22 / 113 14 / 80 treatment of retinal vein occlusion in one eye of an individual who needs it.

[068] In some respects, the invention provides an insert for use in the treatment of diabetic retinopathy in one eye of an individual who needs it.

[069] In some embodiments, the invention provides an insert for use in VE-PTP inhibition in one eye of an individual who needs it.

[070] In some embodiments, the invention provides an insert for use in the treatment of glaucoma in one eye of an individual who needs it.

[071] In other embodiments, the invention provides an insert for use in the treatment of elevated IOP in an eye of an individual who needs it.

[072] In still other embodiments, the invention provides an insert for use in reducing IOP in an eye in an individual who needs it.

[073] In further embodiments, the invention provides an insert for use in the treatment of uveitis in one eye of an individual who needs it.

[074] In further embodiments, the invention provides an insert for use in the treatment of chronic non-infectious uveitis affecting the posterior segment of the eye in an eye of an individual who needs it.

[075] In some embodiments, the insert is injected through a needle or cannula of smaller gauge than 25. In some embodiments no incision is required for injection. BRIEF DESCRIPTION OF THE DRAWINGS

[076] Figure 1 represents an eye insert for drug delivery exemplifying the invention.

[077] Figure 2 represents graphs showing the average weight change of films of different PVA grades after 24 h of immersion in PBS.

[078] Figure 3 represents a scale showing the relative resistances. Petition 870260060402, dated 06 / 19 / 2026, page 23 / 113 15 / 80 of the films reviewed.

[079] Figure 4A represents the in vitro drug release profile showing the cumulative percentage of drug release from a Formulation A implant, which is a coated formulation cured at 140 °C for 4 hours.

[080] Figure 4B represents the in vitro drug release profile showing the cumulative amount (μg) of drug released from a Formulation A implant.

[081] Figure 5 shows photos of eroded Formulation A implants taken after immersion in dissolution medium for 314 and 447 days, and the photo of the 447-day implant includes an intact implant for comparison.

[082] Figure 6 represents the in vitro drug release profile for an implant of Uncoated Formulation A, which is the same as Formulation A but without a coating.

[083] Figure 7 shows photos of eroded implants of Uncoated Formulation A taken after immersion in dissolution medium for 287 and 352 days, and the photo of the 352-day implant includes an intact implant for comparison.

[084] Figure 8A represents the in vitro drug release profile showing the cumulative percentage of drug release from a Formulation B implant, which is a coated formulation cured at 140 °C / 30 minutes.

[085] Figure 8B represents the in vitro drug release profile showing the cumulative amount (μg) of drug release from a Formulation B implant.

[086] Figure 9 shows photos of eroded Formulation B implants taken after immersion in dissolution medium for 59, 88 and 155 days.

[087] Figure 10 represents the in vitro drug release profile of Formulation C, an uncured coated formulation.

[088] Figure 11 shows photos of two samples of eroded implants. Petition 870260060402, dated 06 / 19 / 2026, page 24 / 113 16 / 80 Formulation C samples were taken after immersion in a dissolution medium for 98 days at 37 °C, then 113 days at room temperature.

[089] Figure 12 represents a comparison of the in vitro drug release profiles of Formulations A, B and C.

[090] Figure 13A represents the average amount of drug remaining in an insert versus time for an in vivo study in which inserts that were implanted in rabbit eyes were explanted at various time points and tested to determine the amount (μg) of vorolanib remaining in the insert. One curve shows the insert levels of eyes in which 3 inserts were implanted, and the other shows the insert levels of eyes in which 6 inserts were implanted.

[091] Figure 13B represents the cumulative percentage of drug released versus time for explanted inserts from the same in vivo study. One curve shows the insert levels of eyes in which 3 inserts were implanted, and the other shows the insert levels of eyes in which 6 inserts were implanted. DETAILED DESCRIPTION OF THE INVENTION 1. Active Pharmaceutical Ingredient (API)

[092] The injection insert comprises an active pharmaceutical ingredient (API). An API is sometimes referred to as a “drug” in this document.

[093] In some embodiments, the API for the insert and methods of the invention is an API with a molecular weight of 1000 AMU or less, and a water solubility of less than about 200 μg / ml at 25 °C. In other embodiments, the water solubility of the API is less than about 100 μg / ml at 25 °C, less than about 75 μg / ml at 25 °C, less than about 50 μg / ml at 25 °C, less than about 10 μg / ml at 25 °C, or less than about 5 μg / ml at 25 °C. In some embodiments, the water solubility of the API at 25 °C is from about 0.1 μg / ml to about 200 μg / ml. Petition 870260060402, dated 06 / 19 / 2026, p. 25 / 113 17 / 80 about 0.1 μg / ml to about 150 μg / ml, about 0.1 μg / ml to about 100 μg / ml, about 0.1 μg / ml to about 75 μg / ml, about 0.1 μg / ml to about 50 μg / ml, about 0.1 μg / ml to about 20 μg / ml, about 0.1 μg / ml to about 10 μg / ml or about 0.5 μg / ml to about 50 μg / ml.

[094] The eye insert of the present invention can be used to deliver various classes of APIs. Examples of such classes of APIs and specific APIs include the following:

[095] In some embodiments, the API is a vascular endothelial growth factor (VEGF) inhibitor (sometimes also called an anti-VEGF), a kinase inhibitor such as a tyrosine kinase inhibitor (TKI), a vascular endothelial protein tyrosine phosphatase (VE-PTP) inhibitor, an Ang-1 inhibitor, an Ang-2 inhibitor, a Tie-2 activator, a Tie-2 agonist, or an mTOR inhibitor. APIs with one or more of these activities include altiratinib, rebastinib, afatinib, alectinib, apatinib, ASP-3026, axitinib, bafetinib, baricitinib, binimetinib, bosutinib, brigatinib, cabozantinib, canertinib, cediranib, CEP-11981, CEP37440, ceritinib, cobimetinib, copanlisib, crenolanib, crizotinib, CYT387, dabrafenib, damnacantal, dasatinib, doramapimod, enterctinib, erlotinib, everolimus, filgotinib, foretinib, fostamatinib, gefitinib, grandinin, ibrutinib, icotinib, idelalisib, imatinib, IPI-145, JSI-124, lapatinib, lenvatinib, lestaurtinib, linifanib, masitinib,motesanib, mubritinib, neratinib, nilotinib, nintedanib, pacritinib, palbociclib, Pazopanib, pegaptanib, perifosine, pexmetinib, PF06463922, ponatinib, PX-866, quizartinib, radotinib, razuprotafib (AKB-9778), regorafenib, ruxolitinib, selumetinib, semaxanib, sirolimus, sorafenib, sorafenib tosylate, staurosporine, sunitinib, sunitinib malate, SU6656, temsirolimus, TG101348, tivozanib, toceranib, tofacitinib, trametinib, TSR-011, vandetanib, vatalanib, vemurafenib, vorolanib and X-396.

[096] In some modalities, the API may be an anti-inflammatory agent. Petition 870260060402, dated 06 / 19 / 2026, page 26 / 113 18 / 80 steroidal, such as a steroid or corticosteroid, examples of which are not limited to fluocinolone acetonide, hydrocortisone, hydrocortisone acetate, triamcinolone acetonide, methylprednisolone, dexamethasone, medrisone, methylprednisolone, prednisolone 21-phosphate, prednisolone acetate, fluoromethasone and betamethasone.

[097] In other embodiments, the API is a prostaglandin or a prostaglandin analogue or agonist, such as bimatoprost, latanoprost, latanoprost bunod, tafluprost or travoprost.

[098] In still other forms, the API is an alpha-2 adrenergic receptor agonist, such as brimonidine, brimonidine tartrate, or brimonidine pamoate.

[099] In some respects, API is a beta-blocker like timolol.

[0100] In other respects, the API is a carbonic anhydrase inhibitor (CAI), like acetazolamide, brinzolamide, dorzolamide, or methazolamide.

[0101] In other respects, API is a rho kinase inhibitor like netarsudil.

[0102] Nonsteroidal anti-inflammatory drugs (NSAIDs) are also included. NSAIDs include diclofenac, etoldolac, fenoprofen, floctafenine, flurbiprofen, ibuprofen, indoprofen, ketoprofen, ketorolac, lomoxicam, morazone, naproxen, perisoxal, pirprofen, pranoprofen, suprofen, suxibuzone, tropesin, ximoprofen, zaltoprofen, zileuton, and zomepirac. COX-2 inhibitors, such as valdecoxib, rofecoxib, and celecoxib, are also included.

[0103] In some modalities, the API is a neuroprotective agent such as nimodipine; an antibiotic such as tetracycline, chlortetracycline, bacitracin, neomycin, polyrhinixin, gramicidin, oxytetracycline, chloramphenicol, gentamicin, or erythromycin; or an antibacterial agent such as a sulfonamide, sulfacetamide, sulfamethylol, sulfisoxazole, nitrofurazone, or sodium propionate.

[0104] In another embodiment, the API is a complement inhibitor, such as a C3 inhibitor, for example, APL-2 (pegcetacoplan) or a C5 inhibitor. Petition 870260060402, dated 06 / 19 / 2026, page 27 / 113 19 / 80

[0105] Anesthetics and analgesic agents such as lidocaine and related compounds are also included.

[0106] In some embodiments, the insert comprises more than one API.

[0107] In addition, the invention contemplates the use of analogues, derivatives, pharmaceutically acceptable salts, esters, prodrugs, codrugs and their protected forms of the API.

[0108] The term “pharmaceutically acceptable salt” of a given compound refers to salts that retain the biological efficacy and properties of the given compounds and that are not biologically or otherwise undesirable.

[0109] Pharmaceutically acceptable salts include salts with inorganic acids or organic acids and salts with inorganic bases or organic bases. Those skilled in the art will recognize various synthetic methodologies that can be used to prepare non-toxic pharmaceutically acceptable salts.

[0110] Salts may be derived from inorganic acids, including hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Salts may be derived from organic acids, including acetic acid, propionic acid, glycolic acid, gluconic acid, pamoic 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, salicylic acid, and the like.

[0111] In some forms, the salt is an acetonide salt.

[0112] 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. Petition 870260060402, dated 06 / 19 / 2026, page 28 / 113 20 / 80

[0113] In addition, pharmaceutically acceptable salts include organic salts such as choline, glucosamine, tris, meglumine, lysine, arginine, tributylamine and benzathine salts.

[0114] In some embodiments, the API is an amorphous form, a crystalline form, a polymorph, a hydrate or a solvate.

[0115] Except where otherwise specified, the doses described in this application (e.g., 100 μg) refer to the weight of the pharmacologically active chemical moiety, rather than the weight of a given API salt or API ester. Thus, for example, when the insert contains a pharmaceutically acceptable salt or ester of an API, for example, razuprotafib sodium, the weight should be adjusted to provide an amount of the API salt that is equivalent to the amount of the API described herein. For example, reference in this document to an insert containing 100 μg of razuprotafib sodium means that the insert contains an amount of the salt equivalent to 100 μg of the razuprotafib molecule. In another example, a Drug Release Rate of 100 μg / day means that the insert releases 100 μg / day of the pharmacologically active chemical moiety (e.g., vorolanib).

[0116] In some embodiments of the invention, the API is vorolanib or a pharmaceutically acceptable salt thereof.

[0117] Vorolanib has the chemical designation (S,Z)-N-(1-(Dimethylcarbamoyl)pyrrolidin-3-yl)-5-((5-fluoro-2-oxoindolin-3-ylidene)methyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide. Synonyms include the term “X-82”. The molecular formula is C23H26FN5O3. The solubility of vorolanib in water is less than 0.1 μg / ml. Vorolanib has the following structure: Petition 870260060402, dated 06 / 19 / 2026, page 29 / 113 21 / 80 H

[0118] As used in this document, “vorolanib or a pharmaceutically acceptable salt thereof” includes amorphous and crystalline forms, polymorphs, hydrates and solvates of vorolanib or its pharmaceutically acceptable salts.

[0119] Vorolanib is an orally active multikinase inhibitor and can inhibit the activation of vascular endothelial growth factor (VEGFR) and platelet-derived growth factor (PDGFR) receptors.

[0120] Methods for manufacturing vorolanib are described, for example, in U.S. Patent Nos. 7,683,057; 8,524,709; 8,039,470; and U.S. Publication Application No. 2019 / 0233403; each of which is incorporated herein by reference in its entirety.

[0121] In some embodiments, the API is razuprotafib (AKB-9778), or a pharmaceutically acceptable salt or zwitterion thereof, for example, razuprotafib sodium, razuprotafib choline, razuprotafib glucosamine, razuprotafib tris, razuprotafib meglumine, razuprotafib lysine, razuprotafib arginine, razuprotafib tributylamine, razuprotafib benzathine. Razuprotafib is a potent and selective inhibitor of the catalytic activity of VE-PTP (vascular endothelial protein tyrosine phosphatase). Razuprotafib promotes TIE2 activation, increases ANG1-induced TIE2 activation, and stimulates the phosphorylation of signaling molecules in the TIE2 pathway, including Petition 870260060402, dated 06 / 19 / 2026, page 30 / 113 22 / 80 AKT, eNOS and ERK.

[0122] Razuprotafib has the chemical designation [4-[(2S)-2-[[(2S)-2(methoxycarbonylamino)-3-phenylpropanoyl]amino]-2-(2-thiophen-2-yl-1,3-thiazol-4-yl)ethyl]phenyl]sulfamic acid. The molecular formula is C26H26N4O6S3. Its registration number is 1008510-37-9. The chemical structure is:

[0123] Methods for manufacturing razuprotafib are described, for example, in U.S. Patent No. 7,622,593, which is incorporated by reference in its entirety.

[0124] In some embodiments of the invention, the API is axitinib or a pharmaceutically acceptable salt or ester thereof.

[0125] Axitinib has the chemical designation N-methyl-2-[3-((E)-2-pyridin-2-ylvinyl)-1H-indazol-6-ylsulfanyl]-benzamide. The molecular formula is C22H18N4OS and the molecular weight is 386.47 Daltons. The chemical structure is:

[0126] Axitinib has a pKa of 4.8. The solubility of axitinib in aqueous media above the pH range of 1.1 to 7.8 exceeds 0.2 pg / ml.

[0127] Methods for manufacturing Axitinib are described, for example, in Petition 870260060402, dated 06 / 19 / 2026, page 31 / 113 23 / 80 U.S. Patent Nos. 6,891,044 and 8,791,140, ​​each of which is incorporated by reference in its entirety.

[0128] Before insert formulation, API may be milled to produce a fine particle size. In some embodiments, the D90 for API for use in insert manufacture is 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, the D90 is from 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, 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, about 7 μm, about 8 μm, about 9 μm, about 10 μm, about 11 μm or about 12 μm. 2. Ocular Insert for Drug Delivery

[0129] An “ocular drug delivery insert” is a device that can be implanted in an eye, that contains a drug, and that can release the drug into the eye after implantation. “Ocular drug delivery insert” encompasses all inserts described in this document.

[0130] The ocular insert for drug delivery comprises a core comprising an API dispersed in a solid matrix. In some embodiments, the core is at least partially covered by a coating. The insert is bioerodible.

[0131] In other embodiments, the insert consists only of the core. It is not surrounded by a coating or any type of barrier that encircles the core.

[0132] In some embodiments, the insert comprises both a core and a coating. The coating is a layer that partially or completely surrounds the core. Petition 870260060402, dated 06 / 19 / 2026, p. 32 / 113 24 / 80 completely surrounds the core. The coating is an outer layer, which can be pre-formed into the desired shape (e.g., it can be a tube) before being placed around the core, or the coating can be formed, for example, by co-extrusion of core and coating, spraying the coating onto the core, or immersing the core in the coating material one or more times (e.g., 1-10 coats). If the core is coated, the coating can completely surround the core or only partially surround the core.

[0133] The insert may have a variety of different shapes, for example, a cylinder, rod, sphere, or disc. In some embodiments, the insert has a cylindrical shape, and the coating covers the entire surface of the cylinder except for the ends of the rod or cylinder. The ends of the rod may act as delivery ports. In some embodiments, one end of the cylinder is covered by the coating and the other is not. In some embodiments, one end is covered by a drug-impermeable cap, such as a silicone cap. A rod is a solid geometric figure with parallel sides, wherein the length of one side is greater than the diameter or the longest side of the cross-sectional shape. The cross-sectional shape may be a circle, oval, square, rectangle, triangle, or polygon, such as a hexagon.A person skilled in the art will recognize that due to manufacturing processes, the insert shape may not be precise; for example, the exterior may not be smooth and perfectly uniform. For instance, the sides of the cylinder or rod may not be perfectly straight or perfectly parallel. A cross-section of a cylinder may not be a perfect circle or oval. Cross-sections of other shapes may not precisely meet the definition of those shapes. For example, a square cross-section may not have perfectly straight sides, and the corner angles may not be exactly 90 degrees. Spheres or pellets may not be perfectly spherical. Petition 870260060402, dated 06 / 19 / 2026, page 33 / 113 25 / 80 a. Matrix

[0134] In some embodiments, the core is a solid matrix composed of a matrix polymer and an API, which may be present in solid form, such as a powder, particles, or granules, dispersed throughout the matrix. The matrix ingredients and the API form a homogeneous mixture in which the API is dispersed. The matrix is ​​solid at room temperature and is bioerodible. The matrix controls the release rate of the API, thus modifying the API release rate compared to the unformulated API. In some embodiments, the matrix slows the drug release rate and provides prolonged drug delivery and less frequent dosing.

[0135] In some embodiments, the matrix also comprises other pharmaceutically acceptable ingredients. In other embodiments, the only material used to form the matrix is ​​one or more matrix polymers.

[0136] The polymer used to form the matrix (the “matrix polymer”) may comprise one or more of the following: polyvinyl alcohol (PVA), poly(caprolactone) (PCL), polyethylene glycol (PEG), poly(dl-lactide-co-glycolide) (PLGA), polyvinyl alcohol (PVA), poly(lactic acid) (PLA), poly(glycolic acid) (PGA), polyalkyl cyanoacrylate or a copolymer thereof.

[0137] In certain embodiments, the matrix polymer comprises PVA. In some embodiments, the only inactive pharmaceutical ingredient in the matrix is ​​PVA.

[0138] Various grades of PVA can be used. The degree of hydrolysis (DH) of PVA can be about 70% to about 99+%, and the molecular weight (MW) can be about 6000-200,000, i.e., the matrix polymer is about 70 mol% to about 99+ mol% hydrolyzed PVA with a molecular weight of about 6000-200000. For example, the DH can be about 80% to about 90%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, Petition 870260060402, dated 06 / 19 / 2026, page 34 / 113 26 / 80 close to 88% to close to 90%, close to 90% to close to 99+%, close to 91%, close to 92%, close to 93%, close to 94%, close to 95%, close to 96%, close to 97%, close to 98% close to 99+% or close to 98% to close to 99+%; The MW could be close to 5000, close to 6000, close to 7000, close to 8000, close to 9000, close to 10000, close to 15000, close to 18000, close to 20000, close to 25000, close to 30000, close to 40000, close to 50000, close to 60000, close to 70000, close to 75000, close to 78000, close to 80000, close to 85000, close to 90000, close to 100000, close to 108000, close to 110000, close to 120000, close to 125000, close to 130000, close to 133000, about 140000, about 146000, about 150000, about 160000, about 170000, about 180000, about 186000, about 190000 or about 200000.In some forms, the MW can be approximately 5000-10000, approximately 6000-10000, approximately 9000-10000, approximately 10000-25000, approximately 25000-50000, approximately 30000-70000, approximately 60000-80000, approximately 70000-80000, approximately 75000-80000, approximately 75000-100000, approximately 89000-98000, approximately 85000-124000 or approximately 146000-186000. In certain forms, the PVA is 6000 MW, 80% hydrolyzed, 9000 MW, 10000 MW. 80% hydrolyzed, MW 25000, 88% hydrolyzed, MW 25000, 98% hydrolyzed, MW 30000-70000, 87-90% hydrolyzed, MW 78000, 88% hydrolyzed, MW 78000, 98% hydrolyzed, MW 78000, 99% hydrolyzed, MW 89000-98000, 99% hydrolyzed, MW 85000-124000, 87-89% hydrolyzed, MW 108000, 99% hydrolyzed, MW 125000, 88% hydrolyzed, MW 133000, 99% hydrolyzed or MW 146000-186000, 99+% hydrolyzed.

[0139] 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 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 of the most eroding PVA. Petition 870260060402, dated 06 / 19 / 2026, p. 35 / 113 27 / 80 slow to faster-eroding PVA. The PVA erosion rate can be measured as described in Example 1. For example, in some embodiments, the PVA mixture has a ratio of 1:9 for 6000 MW, 80% DH to 125000 MW, 88% DH. In other embodiments, the ratio of the two grades in the mixture is 1:1 to 1:15, for example, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11 or 1:12, from the fastest-eroding PVA to the slowest-eroding PVA.

[0140] Examples of PVA blends include a blend of MW 6000, 80% hydrolyzed with MW 78000, 98% hydrolyzed; a blend of MW 6000, 80% hydrolyzed with MW 78000, 99+% hydrolyzed; a blend of MW 78000, 98% hydrolyzed with MW 78000, 99+% hydrolyzed; and a blend of MW 6000, 80% hydrolyzed with MW 125000, 88% hydrolyzed.

[0141] MW and DH should be selected to provide the desired drug release rate for the specific drug, the indication for which the ocular drug delivery insert will be used, the desired duration of drug release, and the desired erosion rate.

[0142] The polymer solution used to form the matrix may comprise from about 1% w / w to about 20% w / w, about 1% w / w, about 15% w / w, about 2% w / w, about 15% w / w, about 2% w / w, about 12% w / w, about 2% w / w, about 10% w / w, about 3% w / w, about 10% w / w, about 3% w / w, about 8% w / w, about 3% w / w, about 6% w / w, about 2% w / w, about 2.5% w / w, about 3% w / w, about 3.5% w / w, about 4 % by w / w, about 4.5% by w / w, about 5% by w / w, about 5.5% by w / w, about 6% by w / w, about 6.5% by w / w, about 7% by w / w, about 7.5% by w / w, about 8% by w / w, about 8.5% by w / w, about 9% w / w, about 9.5% w / w, about 10% w / w, about 10.5% w / w, about 11% w / w, about 11.5% w / w, about 12% w / w, about 13% w / w, about 14% w / w or about Petition 870260060402, dated 06 / 19 / 2026, p. 36 / 113 28 / 80 15% w / w of polymer, such as PVA, in a solvent, such as water or ethanol.

[0143] The polymer solution and the API can be combined in a ratio of, for example, about 0.5:1, about 1:1, about 1:1.2, about 1:1.5, about 1:1.7 or about 1:2 w / w of API:polymer solution.

[0144] In some embodiments, the core comprises vorolanib or a pharmaceutically acceptable salt thereof and PVA. In some embodiments, the core consists of vorolanib or a pharmaceutically acceptable salt thereof and PVA.

[0145] In some embodiments, the core comprises axitinib or a pharmaceutically acceptable salt thereof and PVA. In some embodiments, the core consists of axitinib or a pharmaceutically acceptable salt thereof and PVA.

[0146] In additional embodiments, the PVA and API solutions are combined at a ratio of approximately 1:1 in p / p of API:PVA solution.

[0147] In additional embodiments, the PVA and API solutions are combined at a ratio of approximately 1:2 in p / p of API:PVA solution.

[0148] In some forms, the core comprises approximately 0.1% p / p approximately 90% p / p, approximately 0.1% p / p approximately 80% p / p, approximately 0.1% p / p approximately 70% p / p, approximately 0.1% p / p approximately 60% p / p, approximately 0.1% p / p approximately 50% p / p, approximately 0.1% p / p approximately 40% p / p, approximately 0.1% p / p approximately 30% p / p, approximately 0.1% p / p approximately 25% p / p, approximately 0.1% p / p approximately 20% p / p, approximately 0.1% p / p approximately 15% p / p, approximately 0.1% p / pa approximately 10% p / p, approximately 3% p / pa approximately 90% p / p, approximately 3% p / pa approximately 75% p / p, approximately 4% p / pa approximately 60% p / p, approximately 4% p / pa approximately 50% p / p, approximately 4% p / pa approximately 40% p / p, approximately 4% p / pa approximately 25% p / p, approximately 1% p / pa approximately 10% p / p, approximately 1% p / pa approximately 9% p / p, approximately 1% p / pa approximately 8% p / p, approximately 1% p / pa approximately 7% in p / p,approximately 1% in p / pa (approximately), Petition 870260060402, dated 06 / 19 / 2026, p. 37 / 113 29 / 80 of 6% w / w, approximately 2% w / p, approximately 8% w / w, approximately 2% w / p, approximately 6% w / w or approximately 3% w / p, approximately 5% w / w of inactive ingredients (non-API), such as a matrix polymer. These weight percentages are based on the dry weight of the core (i.e., after any drying steps in processing).

[0149] In some embodiments, the amount of matrix polymer in the core is from about 0.1% to about 90% w / w, about 0.1% w / p, about 80% w / w, about 0.1% w / p, about 70% w / w, about 0.1% w / p, about 60% w / w, about 0.1% w / p, about 50% w / w, about 0.1% w / p, about 40% w / w, about 0.1% w / p, about 30% w / w, about 0.1% w / p, about 25% w / w, about 0.1% w / p, about 20% w / w, about 0.1% w / p p / pa approximately 15% p / p, approximately 0.1% p / pa approximately 10% p / p, approximately 3% p / pa approximately 90% p / p, approximately 3% p / pa approximately 75% p / p, approximately 4% p / pa approximately 60% p / p, approximately 4% p / pa approximately 50% p / p, approximately 4% p / p approximately 40% p / p, approximately 4% p / p approximately 25% p / p, approximately 1% p / pa approximately 10% p / p, approximately 1% p / pa approximately 9% p / p, approximately 1% p / pa approximately 8% p / p,approximately 1% p / pa approximately 7% p / p, approximately 1% p / pa approximately 6% p / p, approximately 2% p / pa approximately 8% p / p, approximately 2% p / pa approximately 6% p / p, or approximately 3% p / pa approximately 5% p / p; or about 1% w / w, 1.5% w / w, 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 % in p / w, 7 % in p / w, 7.5 % in p / w, 8 % in p / w, 8.5 % in p / w, 9 % in p / w, 9.5 % in p / w, 10 % in p / w, 10.5 % in p / w, 11 % in p / w, 11.5 % in p / w, 12 % in p / w, 15% in p / p, 18% p / p, 20% p / p, 25% p / p, 30% p / p, 35% p / p, 40% p / p, 50% p / p, 55% p / p, 60% p / p, 65% p / p, or approximately 70% p / p. These percentages by weight are based on the dry weight of the kernel (or, Petition 870260060402, dated 06 / 19 / 2026, page 38 / 113 30 / 80 (i.e., after any drying steps in processing).

[0150] The term “the insert consists of” a core comprising a solid matrix and API means that the entire insert is in the form of a solid matrix and API. The matrix may also include additional ingredients, but the insert does not have an outer casing, coating, cap, cover, tube, or other outer layer, so that when immersed in a fluid environment, such as the vitreous humor of the eye or an in vitro drug delivery medium, the exterior of the core is in direct contact with that fluid. b. Coating

[0151] 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.

[0152] In some embodiments, the coating is permeable to the passage of the API and acts as a diffusion membrane for the active pharmaceutical ingredient. A diffusion membrane can modify the API release rate from the matrix. The diffusion membrane can operate, for example, by modifying the fluid flow in the matrix and / or limiting the passage of the API out of 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 certain embodiments, the coating modifies the API release rate and increases the durability of the insert.

[0153] The coating may completely surround the core or only partially surround the core. In some embodiments, the coating substantially covers the core, meaning that it 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%, at least 95%, about 70% to about 100%, about 70% to about 95%, about 80% Petition 870260060402, dated 06 / 19 / 2026, p. 39 / 113 31 / 80 to about 95%, about 80% to about 96%, about 80% to about 99%, about 90% to about 99%, or about 90% to about 98% of the core 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 98%, or about 80% to about 98% of the core surface area. For a cylindrical insert, 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 designs, an area of ​​the core is left uncovered by a sheath to form a delivery port. In some designs, more than one area is left uncovered to form more than one delivery port.

[0154] The delivery port is API-permeable.

[0155] In some embodiments, the insert has a rod shape, for example, cylindrical, and only the two ends of the rod / cylinder are not coated.

[0156] To provide an illustration of an embodiment of the ocular drug delivery insert of the invention, Figure 1 shows a longitudinal cross-sectional view of an ocular drug delivery insert 100 according to an embodiment of the invention. The insert 100 comprises a solid matrix core 105. The insert 100 further comprises a coating 110, which substantially surrounds the core 105. The insert 100 also features two delivery ports 115 which are situated at opposite ends of the insert 100. In this particular embodiment, at least one of the delivery ports 115 comprises a membrane permeable to the API contained in the core 105 to allow the API to be released from the delivery port (or ports) 115.

[0157] In some forms, such as the matrix, the coating is bio-erodible.

[0158] The coating may comprise polymeric and / or non-polymeric ingredients. Petition 870260060402, dated 06 / 19 / 2026, p. 40 / 113 32 / 80 polymeric. In some embodiments, the coating comprises one or more polymers such as polyvinyl alcohol (PVA), poly(caprolactone) (PCL), polyethylene glycol (PEG), poly(d,l-lactide-co-glycolide) (PLGA), poly(lactic acid) (PLA), poly(glycolic acid) (PGA), polyalkyl cyanoacrylate or a copolymer thereof.

[0159] In embodiments where the core is coated, the coating can be formed from 1-10 polymer coatings. For example, the core can be coated with 1 coating, 2 coatings, 3 coatings, 4 coatings, 5 coatings, 6 coatings, 7 coatings, 8 coatings, 9 coatings, or 10 coatings. In some embodiments, each of the coatings comprises the same polymer as the other coatings. In certain embodiments, each of the coatings consists of the same polymer as the other coatings. In other embodiments where the coating is formed from more than one coating, at least two coatings comprise different polymers.

[0160] In certain embodiments, the coating comprises PVA. In other embodiments, the coating consists of PVA. In some embodiments, the only inactive pharmaceutical ingredient in the coating is PVA. In other embodiments, the matrix polymer comprises PVA and the coating comprises PVA.

[0161] Various grades of PVA can be used. The degree of hydrolysis (DH) of PVA can be about 70% to about 99+%, and the molecular weight (MW) can be about 6000-200,000, i.e., the matrix polymer is about 70 mol% to about 99+ mol% hydrolyzed PVA with a molecular weight of about 6000-200000. For example, the DH may be from about 80% to about 90%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 88 % to about 90%, about 90% to about 99+%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98% about 99+% or about 98 to about 99+%; and the MW Petition 870260060402, dated 06 / 19 / 2026, page 41 / 113 33 / 80 can be about 5000, about 6000, about 7000, about 8000, about 9000, about 10000, about 15000, about 18000, about 20000, about 25000, about 30000, about 40000, about 50000, about 60000, about 70000, about 75000, about 78000, about 80000, about 85000, about 90000, about 100000, about 108000, about 110000, about 120000, about 125000, about 130000, about of 133000, about 140000, about 146000, about 150000, about 160000, about 170000, about 180000, about 186000, about 190000 or about 200000. In some embodiments, or MW can be about 5000-10000, about 6000-10,000, about 9000-10000, about 10000-25000, about 25000-50000, about 30000-70000, about 60000-80000, about 70000-80000, about 75000-80000, about 75000100000, about 89000-98000, about 85000-124000 or about 146000186000.In certain models, the PVA is MW 6000, 80% hydrolyzed, MW 9000-10000, 80% hydrolyzed, MW 25000, 88% hydrolyzed, MW 25000, 98% hydrolyzed, MW 30000-70000, 87-90% hydrolyzed, MW 78000, 88% hydrolyzed, MW 78000, 98% hydrolyzed, MW 78000, 99% hydrolyzed, MW 89000-98000, 99% hydrolyzed, MW 85000-124000, 87-89% hydrolyzed, MW 108000, 99% hydrolyzed, MW 125000, 88% hydrolyzed, MW 133000, 99% hydrolyzed or MW 146000-186000, 99+% hydrolyzed.

[0162] In other embodiments, PVA is a mixture of two, three, or four different grades of PVA. In some embodiments, PVA is a mixture of two different grades of PVA. In some embodiments, the ratio of the two grades in the mixture is 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 from the slower-eroding PVA to the faster-eroding PVA. The PVA erosion rate can be measured as described in Example 1. For example, in some embodiments, the PVA mixture has a ratio of 1:9 at 6000 MW, 80% DH to 125000 MW, 88% DH. In others Petition 870260060402, dated 06 / 19 / 2026, p. 42 / 113 In the 34 / 80 modalities, the ratio of the two grades in the mixture is 1:1 to 1:15, for example, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11 or 1:12, from the fastest-eroding PVA to the slowest-eroding PVA.

[0163] Examples of PVA mixtures include a mixture of MW 6000, 80% hydrolyzed with MW 78000, 98% hydrolyzed; a mixture of MW 6000, 80% hydrolyzed with MW 78000, 88% hydrolyzed; a mixture of MW 6000, 80% hydrolyzed with MW 78000, 99+% hydrolyzed; a mixture of MW 78000, 88% hydrolyzed with MW 78000, 98% hydrolyzed; a mixture of MW 78000, 98% hydrolyzed with MW 78000, 99+% hydrolyzed; and a mixture of MW 6000, 80% hydrolyzed, with MW 125000, 88% hydrolyzed.

[0164] In certain 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 still other embodiments, the core and the coating comprise a mixture of two different grades of PVA. When the coating comprises more than one PVA covering, one or more of the coverings may comprise a mixture of two different grades of PVA.

[0165] In embodiments in which both the core and the cladding comprise PVA, the core PVA and the cladding PVA may be of the same or different grades of PVA. As used in this document, the term different grades of PVA means that the PVA differs in molecular weight (MW), degree of hydrolysis (DH), or both MW and DH. Furthermore, as used in this document, a mixture of PVA grades is a “different grade of PVA” if the PVA with which the mixture is compared is not a mixture of the exact same grades of PVA, for example, a mixture of 6000, 80% hydrolyzed PVA with MW 78000, 98% hydrolyzed PVA, could be considered a different grade of PVA from a PVA composition that contains only MW 78000, 98% hydrolyzed PVA or that contains a mixture of MW 6000, 80% hydrolyzed PVA with MW 125000, 88% hydrolyzed PVA. Petition 870260060402, dated 06 / 19 / 2026, page 43 / 113 35 / 80

[0166] Thus, the PVA core and the cladding PVA may have the same MW and DH, or they may differ in MW or DH, or they may differ in both MW and DH. In some embodiments, the core comprises PVA, and the insert comprises a cladding comprising PVA, wherein the MW of the cladding PVA is equal to the MW of the core PVA, and the DH of the cladding PVA is less than the DH of the core PVA. In some embodiments, the MW and DH of the cladding PVA are each less than the MW and DH of the core PVA.

[0167] In some embodiments, the cladding is formed from more than one covering. When the insert cladding comprises more than one PVA covering, PVA with the same MW and DH may be used for the core and at least one of the coverings. In other embodiments, the core comprises a PVA that differs in MW and / or DH from the PVA in at least one covering. In some embodiments, the core comprises a PVA that differs in both MW and DH from the PVA in at least one covering. In other embodiments, the PVA in the core and the PVA in at least one covering have the same MW, but differ in DH. In some embodiments, the DH of the PVA in at least one covering is less than the DH of the PVA in the core. In other embodiments, the PVA in the core and the PVA in at least one covering differ in MW, but have the same DH. In some embodiments, the MW of the PVA in at least one covering is less than the MW of the PVA in the core.

[0168] In some embodiments, the insert coating comprises a single covering comprising PVA. In other embodiments, the insert coating comprises more than one covering comprising PVA, and the PVA in each covering has the same MW and DH. In some embodiments, at least one covering comprises PVA that differs in MW and / or DH from the PVA in at least one other covering. In some embodiments, at least one covering comprises PVA that differs in MW and DH from the PVA in at least one other covering. In some Petition 870260060402, dated 06 / 19 / 2026, page 44 / 113 36 / 80 modalities, neither of the two coverages comprises the same degree of PVA, that is, the PVA in each coverage differs in MW and / or DH from the other coverages.

[0169] In embodiments where the insert coating comprises more than one coating comprising PVA, 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.

[0170] In certain embodiments, the insert comprises (a) a solid matrix core comprising PVA and an API, and (b) a coating comprising PVA that substantially surrounds the core; and the DH of the PVA in the coating is less than the DH of the PVA in the core. In one embodiment of this insert, the insert comprises 2 coatings comprising PVA. In other embodiments, the insert comprises 3 coatings comprising PVA. In still other embodiments, the insert comprises 4 coatings comprising PVA. In further embodiments, the insert comprises 5 coatings comprising PVA. In still other embodiments, the insert comprises 6 coatings comprising PVA.

[0171] In multi-layered insert designs, the first coating applied to the core is the innermost coating, and the last coating applied is the outermost coating. In some designs of these multi-layered PVA inserts, the DH of the PVA in the innermost coating is higher than the DH of the PVA in the outermost coating. In other designs of these multi-layered PVA inserts, the MW of the PVA in the innermost coating is higher than the MW of the PVA in the outermost coating. In some designs, the DH of the PVA in the outermost coating is lower than the DH of the PVA in each of the other coatings. In other designs, 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. Petition 870260060402, dated 06 / 19 / 2026, page 45 / 113 37 / 80

[0172] In some respects, the insert comprises (a) a solid matrix core coating a PVA selected from the group consisting of MW 6000, 80% hydrolyzed, MW 9000-10000, 80% hydrolyzed, MW 25000, 88% hydrolyzed, MW 25000, 98% hydrolyzed, MW 30000-70000, 87-90% hydrolyzed, MW 78000, 88% hydrolyzed, MW 78000, 98% hydrolyzed, MW 78000, 99% hydrolyzed, MW 89000-98000, 99% hydrolyzed, MW 85000-124000, 87-89% hydrolyzed, MW 108000, 99% hydrolyzed, MW 125000, 88% hydrolyzed, MW 133000, 99% hydrolyzed, MW 146000-186000, 99% hydrolyzed, and mixtures thereof;and an API, and (b) at least one coating comprising PVA that substantially surrounds the core, wherein the PVA in the coating is selected from a PVA selected from the group consisting of MW 6000, 80% hydrolyzed, MW 9000-10000, 80% hydrolyzed, MW 25000, 88% hydrolyzed, MW 25000, 98% hydrolyzed, MW 30000-70000, 87-90% hydrolyzed, MW 78000, 88% hydrolyzed, MW 78000, 98% hydrolyzed, MW 78000, 99% hydrolyzed, MW 89000-98000, 99% hydrolyzed, MW 85000-124000, 87-89 % hydrolyzed, MW 108000, 99+% hydrolyzed, MW 125000, 88% hydrolyzed, MW 133000, 99% hydrolyzed, MW 146000-186000, 99+% hydrolyzed, and mixtures thereof; wherein the PVA in the core and the PVA in at least one coating are different grades of PVA. In other respects, in this insert, the insert comprises at least 2 PVA coatings and the DH of the PVA in the outermost coating is less than the DH of any PVA in the other coatings.

[0173] The invention provides the ability to adapt the grades of PVA used to manufacture the ocular insert. The MW and DH of core and coating PVA should be selected to provide the desired drug release rate for the specific drug, the indication for which the ocular insert will be used, the desired duration of drug release, and the desired erosion rate. Different drug release durations may be desired for different eye diseases or conditions. For example, a duration of 12 months (as provided by Petition 870260060402, dated 06 / 19 / 2026, page 46 / 113 38 / 80 Formulation A) with drug release may be desirable for the treatment of diabetic retinopathy, while a duration of less than one month may be desirable for an insert to inhibit ocular inflammation caused by injury or surgery.

[0174] The polymer solution used to form the coating may comprise from about 1% w / w to about 20% w / w, about 1% w / w, about 15% w / w, about 2% w / w, about 15% w / w, about 2% w / w, about 12% w / w, about 2% w / w, about 10% w / w, about 3% w / w, about 10% w / w, about 3% w / w, about 8% w / w, about 3% w / w, about 6% w / w, about 2% w / w, about 2.5% w / w, about 3% w / w, about 3.5% w / w, about 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 of polymer, as PVA,in a solvent, such as water or ethanol.

[0175] For inserts comprising a PVA coating, the same may be covered with 1-10 coatings of a PVA solution, i.e., the insert may comprise 1-10 PVA coatings. For example, the insert may comprise 1 coating, 2 coatings, 3 coatings, 4 coatings, 5 coatings, 6 coatings, 7 coatings, 8 coatings, 9 coatings or 10 coatings of PVA.

[0176] In some embodiments, the weight of the insert coating is about 0.1% w / w about 60% w / w, about 0.1% w / w about 40% w / w, about 0.1% w / w about 20% w / w, about 1% w / w about 40% w / w, about 1% w / w about 30% w / w, about 1% w / w about 20% w / w, about 1% w / w about 10% w / w, about 5% w / w about 30% w / w, about 5% w / w about 25% w / w Petition 870260060402, dated 06 / 19 / 2026, p. 47 / 113 39 / 80 p / p, approximately 5% p / pa approximately 20% p / p, approximately 5% p / pa approximately 15% p / p, approximately 10% p / pa approximately 25% p / p, approximately 10% p / pa approximately 20% p / p, approximately 10% p / pa approximately 18% p / p or approximately 12% p / pa approximately 18% p / p of the insert. These percentages by weight are based on the dry weight of the insert (i.e., after any drying steps in processing).

[0177] In some embodiments, the total amount of inactive ingredients in the insert is approximately 1% w / w, approximately 70% w / w, approximately 1% w / w, approximately 50% w / w, approximately 3% w / w, approximately 90% w / w, approximately 3% w / w, approximately 75% w / w, approximately 4% w / w, approximately 60% w / w, approximately 4% w / w, approximately 50% w / w, approximately 4% w / w, approximately 40% w / w, approximately 4% w / w, approximately 25% w / w, approximately 5% w / w, approximately 40% w / w, approximately 5% w / w, approximately 30% w / w, approximately 5% p / pa approximately 25% p / p, approximately 5% p / pa approximately 20% p / p, approximately 5% p / pa approximately 15% p / p, approximately 10% p / pa approximately 25% p / p, approximately 10% p / pa approximately 22% p / p, approximately 15% p / pa approximately 25% p / p, approximately 15% p / pa approximately 22% p / p or approximately 18% p / pa approximately 22% p / p.These percentages by weight are based on the dry weight of the insert (i.e., after any drying steps in processing).

[0178] In some embodiments, the amount of PVA in the insert is approximately 1% p / p approximately 80% p / p, approximately 1% p / p approximately 75% p / p, approximately 3% p / p approximately 80% p / p, approximately 3% p / p approximately 70% p / p, approximately 4% p / p approximately 60% p / p, approximately 4% p / p approximately 50% p / p, approximately 4% p / p approximately 40% p / p, approximately 4% p / p approximately 25% p / p, approximately 5% p / p approximately 40% p / p, approximately 5% p / p approximately % p / p, approximately 5% p / p p / pa approximately 25% in p / p, approximately 5% in p / pa approximately 20% in p / p, approximately 5% in p / pa approximately 15% Petition 870260060402, dated 06 / 19 / 2026, p. 48 / 113 40 / 80 w / w, approximately 10% w / p, approximately 25% w / w, approximately 10% w / p, approximately 22% w / w, approximately 15% w / p, approximately 25% w / w, approximately 15% w / p, approximately 22% w / w, or approximately 18% w / p, approximately 22% w / w. These percentages by weight are based on the dry weight of the insert (i.e., after any drying steps in processing).

[0179] In some embodiments, the invention provides an insert that has a very high drug content, relative to the inactive ingredients in the insert, which is surprising given the insert's ability to provide drug release over extended periods. In some embodiments, the amount of API in the insert is approximately 5% p / pa approximately 98%, approximately 10% p / pa approximately 98%, approximately 15% p / pa approximately 98%, approximately 20% p / pa approximately 98%, approximately 30% p / pa approximately 98%, approximately 40% p / pa, approximately 65% ​​p / pa approximately 90% p / pa, approximately 70% p / pa approximately 90% p / pa, approximately 75% p / pa approximately 90% p / pa or approximately 80% p / pa approximately 90% p / pa.These percentages by weight are based on the dry weight of the insert (i.e., after any drying steps in processing).

[0180] In some embodiments, the only inactive ingredient in the insert is a polymer such as PVA.

[0181] The thickness of the covering 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. Insert Format and Dimensions Petition 870260060402, dated 06 / 19 / 2026, p. 49 / 113 41 / 80

[0182] In some embodiments, when the insert is prepared for implantation within the vitreous of the eye, the insert does not exceed about 15 mm or, preferably, does not exceed about 10 mm in either direction, so that the insert can be inserted through an incision of 15 mm or less.

[0183] In some embodiments, the insert may be shaped and sized for injection. In some embodiments, the insert is sized and shaped to pass through a cannula or needle of gauge 20 or smaller. This means that the insert can be injected through a cannula or needle of the indicated gauge without an unusual amount of force. The phrase "or smaller" in this context means having a smaller outer diameter. A smaller outer diameter will correspond to a larger gauge number, for example, a 25-gauge needle has a smaller outer diameter than a 22-gauge needle.

[0184] In some embodiments, the insert is sized and shaped to pass through a needle or cannula of gauge 20 to 27, a needle or cannula of gauge 21 to 27, a needle or cannula of gauge 22 to 27, a needle or cannula of gauge 23 to 27, a needle or cannula of gauge 24 to 27, a needle or cannula of gauge 25 to 27, or a needle or cannula of gauge 25.5 to 27.

[0185] In other embodiments, the insert is sized and shaped to pass through a cannula or needle of gauge 20 or smaller, gauge 22 or smaller, gauge 23 or smaller, gauge 24 or smaller, gauge 25 or smaller, gauge 25.5 or smaller, gauge 26 or smaller, or gauge 26.5 or smaller. Preferably, the insert is sized and shaped to pass through a cannula or needle smaller than gauge 25, or smaller than gauge 26, or smaller than gauge 27. In some embodiments, the insert is sized and shaped to pass through a cannula or needle of approximately gauge 29 to approximately gauge 25.5, such as approximately gauge 28 to approximately gauge 25.5, or approximately gauge 28 to approximately gauge 26. In some embodiments, the needle or cannula is approximately gauge 22, 22s, 23, 24 Petition 870260060402, dated 06 / 19 / 2026, page 50 / 113 42 / 80 or 25, however, preferably it is of approximately caliber 25.5, 26, 26.5, 26s, 27, 27.5, 28, 28.5, 29, 29.5, 30 or 30.5.

[0186] 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.

[0187] In some embodiments, the insert may be rod-shaped or cylindrical in shape and does not exceed 8 mm in length and 3 mm in diameter.

[0188] In some embodiments, the insert has a length of approximately 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 1mm, about 1.5mm, about 2mm, about 2.5mm, about 3mm, about 3.5mm, about 4mm, about 4.5mm, about 5mm, about 5.5mm, about 6mm, about 6.5mm, about 7mm, about 7.5mm, about 8mm, about 8.5mm, 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.

[0189] In some embodiments, the insert has a diameter of 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 0.57mm, about 0.50mm, about 0.41mm, about 0.42mm, about 0.37mm, about 0.34mm, about 0.31mm, about 0.26mm or about 0.15mm. d. Insert Manufacturing

[0190] The insert can be manufactured by mixing the API with a matrix polymer. In some embodiments, the matrix polymer is a polymer solution. Petition 870260060402, dated 06 / 19 / 2026, p. 51 / 113 43 / 80 in a solvent, for example, in water or ethanol. API, matrix polymer solution, and any other matrix ingredients are mixed to form a paste suitable for extrusion through a dispensing tip. The paste can be extruded through an 18-25 gauge cannula or dispensing tip. In some embodiments, a 21-23 gauge cannula or dispensing tip is used. For example, the gauge of the cannula or dispensing tip can be 20, 21, 22, or 23. The extruded paste is referred to in this document as an extrudate, an elongated die, or a rod. Rods can be about 4-5 inches (about 10-13 cm) long. The extrudate is a solid at room temperature. The extrudate can 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.

[0191] In an extrusion process, extrusion parameters can be controlled, such as fluid pressure, flow rate, and temperature of the material being extruded. Suitable extruders can be selected for their ability to deliver the coextruded materials at sufficient pressures and flow rates to form the product into die head and outlet port or dispensing tip sizes that will produce a product which, when segmented, can be injected through a needle or cannula as described in this document.

[0192] If a polymer solution was used and the extrudates are to be coated, the extruded API-polymer mixture is allowed to dry before coating. For example, the extrudate may be allowed to dry for about 30 minutes to about 48 hours at room temperature before coating.

[0193] The extrudate may be coated with one or more layers, although in some embodiments no coating is applied. Preferably, the coating is applied before segmentation to the desired insert length. Petition 870260060402, dated 06 / 19 / 2026, page 52 / 113 44 / 80 The 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 coating layers. Alternatively, the coating can be sprayed onto the extrudate.

[0194] In other embodiments, the outer coating / layer may be pre-formed, for example, in a tube shape, and the API-polymer paste may be extruded into the tube.

[0195] Depending on the polymer used for the matrix, the extruded rods may be cured. Curing can be done, for example, by oven heating, microwave heating or chemical treatment.

[0196] In some embodiments, the die rod is uncured or is cured by heating at a temperature lower than 80 °C. In other embodiments, the die rod is cured for about 15 minutes to about 4 hours at a temperature of about 80 °C to about 160 °C. In some embodiments, the die rod is cured for about 15 minutes to about 4 hours at about 120 °C to about 160 °C. In still other embodiments, the die rod is cured for about 10 minutes to about 4 hours at about 130 °C to about 150 °C, for example, about 130 °C to about 140 °C or about 140 °C to about 150 °C. In still other methods, the die stem is cured for about 30 minutes to about 4 hours at about 130°C to about 150°C.For example, the curing time can be approximately 15 minutes, approximately 30 minutes, approximately 45 minutes, approximately 60 minutes, approximately 75 minutes, approximately 90 minutes, approximately 105 minutes, or approximately 120 minutes, and the curing temperature can be 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 rods can be allowed to cool to room temperature before other manufacturing steps are performed. If the insert is coated, the... Petition 870260060402, dated 06 / 19 / 2026, p. 53 / 113 45 / 80 coating can be applied before or after curing.

[0197] The drug release rate was evaluated for uncoated and PVA-coated PVA matrix inserts. The inventors found, in general, that the higher the curing temperature and the longer the curing period, the slower the drug release rate, but also the slower the erosion.

[0198] When all curing, cooling and / or coating and drying steps are completed, the rods are segmented into inserts of about 1 mm to about 15 mm in length, for example, inserts of about 1 mm to about 10 mm or about 2 mm to about 6 mm. For example, the rods can be segmented into inserts of 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.

[0199] The rods can be segmented or cut into a series of shorter products, by any technique suitable for cutting the rods, which may vary depending on whether the product is cured, uncured, or partially cured. For example, the segmenting station may employ tweezers, scissors, cutting blades, or any other technique. The technique applied may vary according to the desired configuration for each cut portion of the product. For example, when open ends are desired, a shearing action may be suitable. However, when it is desired to seal each end as the cut is made, tweezers may be used.

[0200] In some embodiments, the extrudates are coated by immersion in a PVA solution in water with a PVA concentration of approximately 1%. Petition 870260060402, dated 06 / 19 / 2026, page 54 / 113 46 / 80 in w / w about 15% in w / w, about 1% in w / w about 10% in w / w, about 2% in w / w about 10% in w / w, about 2% in w / w about 8% in w / w, about 2% in w / w about 6% in w / w, about 3% in w / w about 6% in w / w, about 2% in w / w, about 2.5% in w / w, about 3% in w / w, about 3.5% in w / w, about 4% in w / w, about 4.5% in w / w, about 5% in w / w, about 5.5% in w / w, about 6% in w / w, about 6.5 % in w / w, around 7% in p / p, approximately 7.5% p / p, approximately 8% p / p, approximately 8.5% p / p, approximately 9% p / p, approximately 9.5% p / p, or approximately 10% p / p.

[0201] The coated extrudates can then be air-dried. The immersion coating process can be repeated 1-10 more times, preferably 1-6 or 1-5 more times, and air-dried between each coating. The coated extrudates can then be cured as described above. After cooling, the extrudates are then cut into inserts.

[0202] e. Insert Properties

[0203] Some eye diseases, including those described above, may require treatment for the rest of the patient's life. Currently available therapies require repeated therapeutic treatments. However, repetitive therapy by implanting a drug delivery device in the eye is limited for devices containing non-biodegradable materials, as non-biodegradable device debris accumulates in the eye. Thus, it would be very beneficial for patients to be provided with an implantable drug delivery device that erodes completely at or shortly after the next device needs to be implanted.

[0204] However, it is extremely challenging to design a drug delivery device that provides controlled release of therapeutic levels of a drug over a significant period of time that is also capable of completely eroding out in, for example, a matter of months or about a year. Many Petition 870260060402, dated 06 / 19 / 2026, page 55 / 113 47 / 80 materials that are effective in controlling drug release for significant periods are either not biodegradable or erode very slowly.

[0205] Furthermore, providing a drug delivery device small enough to implant in a patient's eye with minimal discomfort, yet capable of holding a sufficient drug load to provide sustained drug delivery, significantly increases the challenges described above. The difficulty of handling and processing such devices without significant breakage also adds to the challenges.

[0206] The inventors overcame these challenges to provide a drug delivery device small enough to be implanted in the eye with minimal discomfort, capable of providing sustained drug delivery for months, while also fully eroding sometime after the end of the drug delivery period of the device. Furthermore, the inventors found a way to provide devices with different drug delivery periods / durations and delivery rates. Additionally, these devices provide an essentially linear release of the drug after an initial burst of drug delivery. Moreover, the insert has a very high drug content relative to the inactive ingredients in the insert, which is surprising given the insert's ability to provide drug release over extended periods. Insert Erosion:

[0207] In some embodiments, the insert is capable of eroding completely within 365 days. The ability of an insert to erode within a given period of time can be assessed using the following Erosion Assessment Protocol. A sample insert is placed in a 10 ml glass vial with 5 ml of phosphate-buffered saline (PBS) solution, the vial is incubated at 37 °C, the PBS in the vial is replaced once every 24 hours for each day of the Petition 870260060402, dated 06 / 19 / 2026, page 56 / 113 48 / 80 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 relative to the original weight is calculated as follows: Final Weight x 100 = Remaining % Starting Weight

[0208] For example, if an insert originally weighs 500 μg and weighs 200 μg after incubation in PBS for 200 days according to the Erosion Assessment Protocol, the insert weighs 40% of its original weight and has lost 60% of its weight. It has undergone 60% erosion in 200 days. An insert is considered completely eroded when less than 10% of the insert's original weight remains. In some applications, the insert is capable of at least 20% erosion within 95 days, at least 25% erosion within 95 days, at least 30% erosion within 95 days, at least 30% erosion within 110 days, at least 40% erosion within 110 days, at least 30% erosion within 180 days, at least 40% erosion within 180 days, at least 50% erosion within 180 days, at least 60% erosion within 180 days, at least 40% erosion within 220 days, at least 50% erosion within 220 days, at least 60% erosion within 220 days.at least 70% erosion within 220 days, at least 60% erosion within 280 days, at least 70% erosion within 280 days, at least 80% erosion within 280 days, at least 60% erosion within 365 days, at least 70% erosion within 365 days, at least 80% erosion within 365 days, at least 90% erosion within 365 days, at least 70% erosion within 400 days, at least 80% erosion within 400 days, at least 90% erosion within 400 days, at least 70% erosion within 440 days, at least 80% erosion within 440 days, or at least 90% erosion within, Petition 870260060402, dated 06 / 19 / 2026, page 57 / 113 49 / 80 440 days measured using the Erosion Assessment Protocol. Drug Release Rate

[0209] The inventors found that the curing temperature, curing duration, and insert surface area affect the release rate. An increase in diameter with length held constant increased the release rate. When the diameter was held constant, increasing the length increased the release rate.

[0210] In some embodiments, the insert has a Drug Release Rate of 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, 0.01 μg / day to about 50 μg / day, 0.01 μg / day to about 20 μg / day, 0.01 μg / day to about 10 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 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 or about 1 μg / day to about 10 μg / day. In some embodiments, this is the release rate after steady-state release is achieved.In some modalities, this is the release rate after 2 days, 3 days, 5 days, 8 days, 10 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 of drug release.

[0211] In some forms, the insert has this release rate 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 Petition 870260060402, dated 06 / 19 / 2026, page 58 / 113 50 / 80 or at least 365 days, as measured by the in vitro Drug Release Method.

[0212] The following in vitro Drug Delivery Method is used to evaluate the amount of drug released: an insert is placed in a 10 ml glass tube and 5 ml of PBS is added to the tube. The tube is incubated in a water bath at 37 °C. A sample of the medium is collected each day of the established period and the delivery medium is replaced with fresh PBS. The amount of API released can be measured quantitatively by HPLC as described in Example 2B.

[0213] The duration (total time period) during which the insert releases the API may be between about 90 days to about 365 days, about 90 days to about 260 days, about 90 days to about 200 days, or is 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. The in vitro drug release test described above may be used to determine whether an insert releases drug during this time period.

[0214] In some embodiments, the insert of the invention provides an initial or immediate rapid release of the drug in vivo for a period of time before reaching a steady-state rate. In preferred embodiments of the invention, the initial rapid release period is much shorter than the total API release duration (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 Petition 870260060402, dated 06 / 19 / 2026, p. 59 / 113 51 / 80 days, 80 days, 90 days, 100 days, 105 days, 110 days. In an in vitro study conducted on rabbit eyes, the inventors found a surprisingly high initial burst of drug release, meaning that the initial API release from the insert was faster than expected before leveling off to a steady state. This burst may be beneficial as it allows Cmax and equilibrium to be reached quickly, thus delivering therapeutically effective amounts locally to the eye rapidly. After this burst, the API release rate levels off to deliver a therapeutically effective amount of API each day.

[0215] In preferred embodiments, the insert of the invention releases the API at a substantially constant rate (i.e., zero-order drug release kinetics, R2 is 0.7-1) during a predetermined period after implantation, for example, during 14 days, 28 days, 42 days, 56 days, 168 days, 180 days, 224 days, 300 days or 365 days.

[0216] The substantially constant API release duration of the insert may 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 embodiments, this 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. 3. Therapeutic Method a. Administration of the ocular insert for medication delivery

[0217] An “ocular drug delivery insert” is an implantable device. “Ocular drug delivery insert” encompasses all inserts described in this document. Petition 870260060402, dated 06 / 19 / 2026, pp. 60 / 113 52 / 80

[0218] The ocular drug delivery insert can be administered to prevent or treat an eye condition or disease in an individual who needs it. In some embodiments, the ocular drug delivery insert is administered to treat an anterior eye condition. In other embodiments, it can be administered to treat a posterior eye condition. In some embodiments, the ocular drug delivery insert is administered to prevent an anterior eye condition. In other embodiments, it can be administered to prevent a posterior eye condition.

[0219] An anterior eye condition is a disease, illness, or condition that affects or involves an anterior region or structure of the eye (i.e., the front of the eye, also called the anterior segment), such as a periocular muscle or eyelid, or fluid located anterior to the posterior wall of the lens capsule or ciliary muscles. Thus, an anterior eye condition may affect or involve the conjunctiva, cornea, anterior chamber, iris, posterior chamber (located between the iris and the lens), lens or lens capsule, and blood vessels and nerves that vascularize or innervate an anterior ocular region or site.

[0220] An anterior eye condition may include a disease, illness or condition such as, but not limited to, glaucoma.

[0221] A posterior ocular condition is a disease, illness, or condition that primarily affects or involves a posterior ocular region or structure (i.e., the back of the eye, also called the posterior segment), such as the choroid or sclera (in a position posterior to a plane through the posterior wall of the lens capsule), vitreous, vitreous chamber, retina, optic nerve or optic disc, and blood vessels and nerves that vascularize or innervate a posterior ocular region or site.

[0222] A posterior eye condition may include a disease, illness Petition 870260060402, dated 06 / 19 / 2026, pp. 61 / 113 53 / 80 or conditions such as, but not limited to, acute macular neuroretinopathy; Behçet's disease; geographic atrophy; choroidal neovascularization; diabetic uveitis; histoplasmosis; infections, such as infections caused by fungi, bacteria, or viruses; macular degeneration, such as neovascular macular degeneration, acute macular degeneration, non-exudative age-related macular degeneration, and exudative age-related macular degeneration; edema, such as macular edema, cystoid macular edema, and diabetic macular edema; multifocal choroiditis; ocular trauma affecting a posterior ocular site or location; ocular tumors;Retinal disorders, such as retinal vein occlusion, central retinal vein occlusion, diabetic retinopathy (including proliferative diabetic retinopathy), proliferative vitreoretinopathy (PVR), hypertensive retinopathy, occlusive retinal artery disease such as central retinal artery occlusion (CRAO) and branch retinal artery occlusion (BRAO), retinal detachment, uveitic retinal disease; sympathetic ophthalmia; Vogt Koyanagi-Harada (VKH) syndrome; uveal diffusion; a posterior ocular condition caused or influenced by laser eye treatment;or posterior ocular conditions caused or influenced by photodynamic therapy, photocoagulation, radiation retinotherapy, epiretinal membrane disorders, retinal vein branch occlusion, anterior ischemic optic neuropathy, non-retinopathic diabetic retinal dysfunction, and retinitis pigmentosa. Glaucoma can also be considered a posterior ocular condition, as the therapeutic goal is to prevent loss or reduce the occurrence of vision loss due to damage to or loss of retinal cells or optic nerve cells (e.g., via neuroprotection).

[0223] Thus, the invention provides methods for preventing or treating various eye conditions by administering the ocular insert for drug delivery to an eye of an individual who needs it.

[0224] The API in the insert to be administered for a specific eye condition or disease is selected based on the suitability of the API for that condition. Petition 870260060402, dated 06 / 19 / 2026, page 62 / 113 54 / 80 ocular. Thus, for example, an insert to be administered to reduce intraocular pressure will contain an API effective in reducing intraocular pressure.

[0225] In certain modalities, inserts are administered to prevent or treat macular degeneration in an individual who needs it, for example, age-related macular degeneration (AMD), such as dry AMD and wet AMD. The insert may be administered to prevent the death of retinal pigment epithelial cells. The insert may be administered to inhibit angiogenesis. In some modalities, inserts are administered to prevent or treat vision loss in an individual, such as vision loss associated with macular degeneration. Additionally, the insert may be administered to prevent or slow the progression of dry AMD or wet AMD. In some modalities, the insert is administered to prevent or treat retinal vein occlusion in an individual who needs it, for example, central retinal vein occlusion (CRVO) or branch retinal vein occlusion (BRVO).In other embodiments, the inserts may be administered to prevent or treat non-ischemic retinal vein occlusion or ischemic retinal vein occlusion. In still other embodiments, the insert is administered to treat diabetic retinopathy in one eye of an individual who needs it. In some embodiments of these methods, the insert comprises a VEGF inhibitor, a kinase inhibitor such as a TKI inhibitor, a VE-PTP inhibitor, an Ang-1 inhibitor, an Ang2 inhibitor, and / or a Tie-2 activator. In some embodiments, the insert comprises vorolanib or a pharmaceutically acceptable salt thereof. In other embodiments, the insert comprises axitinib or a pharmaceutically acceptable salt thereof. In still other embodiments, the insert comprises razuprotafib or a pharmaceutically acceptable salt or zwitterion thereof.

[0226] In some cases, the insert is administered to inhibit VEGFR and / or PDGFR in an eye of an individual who needs it. In some Petition 870260060402, dated 06 / 19 / 2026, pp. 63 / 113 In the 55 / 80 embodiments, the insert administered to inhibit VEGFR and / or PDGFR comprises vorolanib or a pharmaceutically acceptable salt thereof. In other embodiments, the insert comprises axitinib,

[0227] In other embodiments, the insert is administered to activate Tie-2. In some embodiments of this method, the insert comprises a Tie-2 activator. In a further embodiment, the Tie-2 activator is razuprotafib or a pharmaceutically acceptable salt or zwitterion thereof.

[0228] The invention also provides a method for treating glaucoma in an individual in need thereof, comprising administering a drug delivery insert. In some embodiments, the insert is administered to treat elevated intraocular pressure (IOP) in one eye of an individual in need thereof. In other embodiments, the insert is administered to reduce intraocular pressure in one eye of an individual in need thereof. In a further embodiment, the individual has elevated intraocular pressure. In another embodiment, the individual has ocular hypertension. In yet another embodiment, the individual has glaucoma. A reduction in IOP can be assessed by determining the difference in the individual's IOP (in millimeters of mercury (mmHg)) 60 days after implantation of the insert relative to the individual's IOP at a pre-treatment baseline. In some embodiments of these methods, the insert comprises a Tie-2 activator.In an additional embodiment, the Tie-2 activator is razuprotafib or a pharmaceutically acceptable salt or zwitterion thereof. In other embodiments of these methods, the insert comprises an alpha2-adrenergic receptor. In a further embodiment, the alpha2-adrenergic receptor is brimonidine or a pharmaceutically acceptable salt thereof.

[0229] In still other embodiments, the insert is administered to treat uveitis. In an additional embodiment, the insert is administered to treat chronic non-infectious uveitis affecting the posterior segment of the eye. In some Petition 870260060402, dated 06 / 19 / 2026, pp. 64 / 113 In 56 / 80 modalities, the insert is administered to treat postoperative inflammation in the eye. In some modalities of these methods, the insert comprises a steroidal anti-inflammatory agent.

[0230] In some embodiments, the invention provides a treatment method comprising administering an ocular insert for drug delivery of the invention comprising a VEGF inhibitor. In some embodiments of these methods, the VEGF inhibitor is vorolanib or a pharmaceutically acceptable salt thereof. The invention also encompasses combination treatments such as treating an individual with a VEGF inhibitor and a Tie-2 activator or treating an individual with a VEGF inhibitor and a steroidal anti-inflammatory agent.

[0231] Thus, in some embodiments of the method in which a VEGF inhibitor is administered, the method further comprises administering a Tie-2 activator, such as razuprotafib or a pharmaceutically acceptable salt or zwitterion thereof. In some embodiments of this method, the Tie-2 activator is administered in an ocular drug delivery insert of the invention.

[0232] In other embodiments of the method in which a VEGF inhibitor is administered, the method further comprises administering a steroidal anti-inflammatory agent, such as fluocinolone acetonide. In some embodiments of this method, the steroidal anti-inflammatory agent is administered in an ocular drug delivery insert of the invention.

[0233] In still other embodiments, the invention provides treatment methods comprising administering an ocular insert for drug delivery of the invention comprising a Tie-2 activator. In other embodiments of this method, the method further comprises administering a VEGF inhibitor. In some embodiments of this method, the Tie-2 activator is razuprotafib or a pharmaceutically acceptable salt or zwitterion thereof. In further embodiments Petition 870260060402, dated 06 / 19 / 2026, pp. 65 / 113 In the 57 / 80 embodiment of this method, the VEGF inhibitor is vorolanib or a pharmaceutically acceptable salt thereof. In additional embodiments, the VEGF inhibitor is aflibercept, bevacizumab, or ranibizumab.

[0234] In the combination treatments of the invention, i.e., in methods where more than one API is administered to the individual being treated, the different APIs administered may be administered in the same ocular drug delivery insert, in separate inserts, or one API may be delivered in one ocular drug delivery insert of the invention, and the other API(s) may be administered in a different pharmaceutical formulation, which may be a different type of dosage form. For example, the dosage form may be a different type of ocular implant, an eye drop, a solution for injection, or a suspension for injection. Furthermore, the different APIs may be administered simultaneously in the same injection or in separate injections during the same procedure or at different times.When different APIs are administered at different times, it is assumed that the dosing form or insert used to deliver the first API is still releasing / delivering the first API when the dosing form or insert containing the other API is administered.

[0235] The various embodiments of the invention are generally provided for delivering a therapeutically effective concentration of an API locally, for example, to an individual's eye. In certain embodiments, the method for treating an eye condition comprises placing the insert on the surface of an eye or within an eye, such as in the vitreous or aqueous humor of an eye. In certain embodiments, the inserts of the invention may be delivered to any site within or on an eye, for example, the anterior segment or the posterior segment.

[0236] Insert administration may involve inserting the insert into an individual's eye, such as inserting the insert into the aqueous humor or, preferably, into the vitreous humor of an eye. Insert administration may involve implanting Petition 870260060402, dated 06 / 19 / 2026, page 66 / 113 58 / 80 surgically inserting an insert into or on an eye, such as a scleral implant, subconjunctival implant, suprachoroidal implant, suprascleral implant, or intravitreal implant. The insert can be surgically implanted into an individual's eye, for example, in the vitreous humor of an eye, under the retina, or in the sclera. In some modalities, the insert can be placed by injection through a needle or cannula. The insert can gradually release an API into the eye, thus avoiding frequent painful administrations of the drug.

[0237] In certain embodiments, the insert is injected into an individual's eye, preferably without requiring an incision. In certain embodiments, the insert is injected into the vitreous humor of an eye. In preferred embodiments, the administration of the insert comprises intravitreal injection.

[0238] In some embodiments, a needle or cannula with a gauge of 20-27 is used for the injection. In other embodiments, a needle or cannula with a gauge of 25 to 27 is used. In preferred embodiments, a needle with a gauge smaller than 25 is used for the injection, for example, a needle with a gauge of 25.5, 26, 26.5 or 27.

[0239] In some embodiments of the method of administration of the invention, prior to injection of the insert, a topical and / or subconjunctival anesthetic may be administered at the injection site. In addition, a broad-spectrum microbicide may be administered into the inferior fornix. The insert may be placed below the optic disc and posterior to the equator of the eye. The conjunctiva may be displaced so that, after withdrawal of the needle, the conjunctival and scleral needle entry sites do not align. The needle used to inject the insert may be inserted through the conjunctiva and sclera until the positive stop of the applicator, and the plunger pressed to deliver the insert to the back of the eye. b. Individuals

[0240] The subject can be selected from rodents, lagomorphs, sheep, Petition 870260060402, dated 06 / 19 / 2026, p. 67 / 113 59 / 80 swine, canines, felines, equines, bovines, and primates. In preferred modalities, the individual is a human being. In some modalities of the treatment methods provided in this document, the individual needs the described treatment because the individual has the condition being treated. In some modalities of the prevention methods provided in this document, the individual needs prophylaxis for the described condition because the individual is at risk of developing the condition. c. Dose

[0241] In some embodiments, the total dose of API delivers from 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, from about 0.0001 pg / day to about 1 μg / day, from about 0.001 μg / day to about 200 μg / day, from about 0.001 μg / day to about 150 μg / day, from about 0.001 μg / day to about 100 μg / day, from about 0.001 μg / day to about 80 μg / day, from about 0.001 μg / day to about 60 μg / day, from about 0.001 μg / day to about 40 μg / day, from about 0.001 μg / day to about 30 μg / day, from about 1 μg / day to about 25 pg / day, from about from 0.001 μg / day to about 20 μg / day, from about 0.001 pg / day to about 15 pg / day, from about 0.001 μg / day to about 10 μg / day, from about 0.001 μg / day to about 8 μg / day,From approximately 0.0005 μg / day to approximately 15 μg / day or from approximately 0.005 μg / day to approximately 10 μg / day. In some embodiments, this is the dose delivered after steady state is reached.

[0242] In some embodiments, the API is vorolanib and the total vorolanib dose delivered is about 0.1 μg / day to about 100 μg / day, about 0.5 μg / day to about 80 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 Petition 870260060402, dated 06 / 19 / 2026, pp. 68 / 113 60 / 80 μg / day to approximately 25 μg / day, approximately 1 μg / day to approximately 20 μg / day, approximately 1 μg / day to approximately 15 μg / day, approximately 1 μg / day to approximately 10 μg / day, approximately 1 μg / day to approximately 8 μg / day, approximately 4 μg / day to approximately 15 μg / day, or approximately 5 μg / day to approximately 10 μg / day. In some embodiments, this is the dose delivered after steady state is achieved.

[0243] In some embodiments, the API is axitinib and the total dose of axitinib delivered is from 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 40 μg / day, about 0.0001 μg / day to about 30 μg / day, about 0.001 μg / day to about 25 μg / day, about 0.0001 μg / day to about 20 μg / day, about 0.0001 μg / day to about 15 μg / day, approximately 0.001 μg / day to approximately 10 μg / day, approximately 0.001 μg / day to approximately 8 μg / day, approximately 0.001 μg / day to approximately 15 μg / day, or approximately 0.005 μg / day to approximately 10 pg / day. In some embodiments, this is the dose delivered after steady state is reached.

[0244] This dose can be achieved by administering, for example, 1-6 inserts at once, i.e., for a single treatment in one eye. Thus, a treatment may require the administration of 1 insert, 2 inserts, 3 inserts, 4 inserts, 5 inserts, or 6 inserts at once per eye of an individual. In some modalities, a subject may receive treatment in only one eye or in both eyes. When more than one insert is injected for a single treatment, the inserts may be injected individually in separate injections or some inserts may be injected in one injection. For example, 1, 2, or 3 inserts may be injected in a single injection. When more than one insert is injected for a single treatment, they may be divided into several injections. For example, if 4-6 inserts are injected for a single treatment, they may be divided to be administered in 2 or 3 injections of 2-3 inserts / injection. Petition 870260060402, dated 06 / 19 / 2026, p. 69 / 113 61 / 80

[0245] Each insert can comprise from approximately 1 µg to approximately 3000 µg, from approximately 10 µg to approximately 2000 µg, from approximately 10 µg to approximately 1000 µg, from approximately 100 µg to approximately 500 µg, from approximately 10 µg to approximately 800 µg, from approximately 50 µg to approximately 600 µg, from approximately 200 µg to approximately 2000 µg, from approximately 600 µg to approximately 2000 µg, from approximately 800 µg to approximately 2000 µg, from approximately 800 µg to approximately 1500 μρ, about 100 μρ to about 500 μρ, about 100 μρ to about 300 μρ or about 300 μρ to about 550 μρ of vorolanibe.For example, each insert may comprise about 400 μηι, about 420 μηι, about 440 μηι, about 480 μηι, about 500 μηι, about 520 μηι, about 540 μηι, about 560 μηι, about 580 μηι, about 600 μηι, about 620 μηι, about 640 μηι, about 660 μηι, about 680 μηι, about 700 μηι, about 720 μηι, about 740 μηι, about 780 μηι, about 800 μηι, about 820 μηι, about 840 μηι, about 860 μηι, about 880 μηι, about 900 μηι, about 920 μηι, about 940 μηι, about 960 μm, about 980 μm, about 1000 μm, about 1020 μm, about 1040 μm, about 1045 μm, about 1060 μm, about 1080 μm or about 2000 μm of API, for example, vorolanibe.

[0246] The total amount of API, por exemplo, vorolanibe, em todos os insertos (carρα útil total) pode ser de cerca de 200 µr a cerca de 6000 µr, cerca de 600 µr a cerca de 6000 µr, cerca de 800 µr a cerca de 6000 µr, cerca de 600 µr a cerca de 5040 µr, cerca de 600 mr a cerca de 4500 mr, cerca de 1000 mr a cerca de 5400 mr, cerca de 1000 mr a cerca de 3000 mr or cerca de 2000 mr a cerca de 4000 mr. For example, the total amount of API for all inserts can be about 1400 μr, about 1420 μr, about 1500 μr, about 1600 μr, about 1800 μr, about 1900 μr, about 1980 μr, about 2000 μr, about 2040 μr, about 2080 μr, about de 3000 mfr, cerca de 3120 mfr, cerca de 3180 mfr, cerca de 3240 mfr, cerca de 3400 mfr, cerca de 3600 mfr, cerca de 3800 mfr, cerca de 4000 mfr, cerca de 4140 mfr, cerca de 4160 mfr, cerca de 4180 mfr, cerca de 4200 mr, cerca de 4400 m, about 4600 m, about 5000 m or about 5040 m. Petition 870260060402, dated 06 / 19 / 2026, pp. 70-113 62 / 80 4. Definitions

[0247] As used in the descriptive report and claims, the following words and phrases are generally intended to have the meanings set forth below, except to the extent that the context in which they are used indicates otherwise.

[0248] The singular forms “um”, “uma” and “o” include plural references unless the context clearly indicates otherwise. For example, “um polymer matricial” means one or more matrix polymers.

[0249] The terms “bioerode”, “bioerosion”, “biodegrade” and “biodegradation” as used in this document, refer to the gradual disintegration, dissolution or breakdown of the insert over a period of time in a biological system, for example, by one or more physical or chemical degrading processes, for example, enzymatic action, hydrolysis, ion exchange or dissolution by solubilization, emulsion formation or micelle formation.

[0250] The term prevention, when used in relation to a condition, refers to the administration of a drug to reduce the frequency or delay the onset of symptoms of a medical condition in an individual compared to an individual who does not receive the drug. Thus, prevention of macular degeneration includes, for example, reducing the number of diagnoses of macular degeneration in a treated population versus an untreated control population and / or delaying the onset of symptoms of macular degeneration in a treated population versus an untreated control population.Prevention of dry macular degeneration includes, for example, reducing the number of detectable drusen in a population of individuals receiving prophylactic treatment compared to an untreated control population, and / or delaying the appearance of detectable drusen in a treated population versus an untreated control population, for example, by a statistically and / or clinically significant amount. Prevention of vision loss includes, for example, reducing the magnitude. Petition 870260060402, dated 06 / 19 / 2026, pp. 71 / 113 63 / 80, or alternatively, to delay, the vision loss experienced by individuals in a treated population versus an untreated control population.

[0251] The term “treatment” means to reduce, improve or stabilize the existing unwanted condition.

[0252] The term “room temperature” means 22 °C. “Solid at room temperature” means solid at a temperature of 22 °C.

[0253] When the term about is used in conjunction with a numerical value or range, it modifies that value or range by extending the limits above and below the numerical values ​​presented. In general, the term about is used in this document to modify a numerical value above and below the established value by a variance of 10 percent of the value, upwards or downwards (higher or lower), i.e., ±10%, unless a different variation is indicated (e.g., ±30%, ±20%, ±5%, ±1%, ±0.5%, etc.).

[0254] The term and / or refers to and encompasses each of the items mentioned individually, as well as any and all possible combinations of one or more of the items mentioned.

[0255] The terms comprising, consisting of, and consisting essentially of have their meanings usually accepted under patent law. When the term includes or including is used in the descriptive report or claims, it is intended to be inclusive in a manner similar to the term comprising, as that term is interpreted when used as a transitional word in a claim.

[0256] The terms “optional” and “optionally” mean that the circumstance subsequently described may or may not occur, so that the description includes instances in which the circumstance occurs and instances in which it does not occur.

[0257] When features or aspects of the disclosure or claims are described in terms of Markush groups, the group described includes any Petition 870260060402, dated 06 / 19 / 2026, pp. 72 / 113 64 / 80 individual member, as well as subgroups of members of the Markush group.

[0258] As will be understood by those skilled in the art, all terms such as “up to”, “at least”, “greater than”, “less than” include the cited number and refer to ranges that can be subsequently divided into subranges. Finally, as will be understood by those skilled in the art, a range includes each individual member and includes the endpoints of the range. For example, a group with 1-3 members refers to groups with 1, 2, or 3 members. Similarly, a group that has 1-5 members refers to groups that have 1, 2, 3, 4, or 5 members, and so forth.

[0259] The term substantially all as used herein refers to the majority of the total quantity, for example, at least 80%, at least 85%, at least 90%, at least 95% or at least 99% of a total quantity.

[0260] The term % w / w means the proportion of a given substance within a mixture, measured by weight or mass. Thus, for example, for an insert where the core comprises at least about 8% w / w of inactive ingredients, the total weight of inactive ingredients in the core is at least about 8% of the total weight of the core. For example, if the total weight of the core is 100 mg, the inactive ingredients in this core would weigh at least 8 mg.

[0261] The term % w / v means the percentage by weight of the ingredient (such as a solute) in the total volume of 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 for 100 mg of solution.

[0262] All cited patents, published applications, scientific publications and books are incorporated herein by reference in their entirety.

[0263] Although several aspects and modalities have been revealed in Petition 870260060402, dated 06 / 19 / 2026, pp. 73 / 113 65 / 80 of this document, other aspects and modalities will be evident to those skilled in the art. EXAMPLES Example 1

[0264] The PVA grades mentioned in the table below were transformed into films, which were then evaluated for erosion rate and resistance.

[0265] To form films, a 4.5% PVA solution in water was melted by pouring it into a tray and air-drying it at room temperature. Once dry, the films were cut into 1x1 square samples. Six samples of each film 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 the sample film squares were cured, they were weighed and imaged. Then, each sample was immersed in PBS for 24 hours at room temperature. The samples were then removed from the PBS, and 4 of each PVA grade were oven-dried at 50 °C for 2 hours, and 2 of each PVA grade were air-dried at room temperature on paper towels, as described in the table below. The samples were then weighed and imaged again. Table 1 MW / DH of PVA 100 C / 3 h 140 C / 30 min 140 C / 4 h Oven dried at 50 C / 2 h Air dried at RT 6000 / 80 % n=6 n=6 n=6 n=4 n=2 25000 / 88 % n=6 n=6 n=6 n=4 n=2 78000 / 98 % n=6 n=6 n=6 n=4 n=2 125000 / 88 % n=6 n=6 n=6 n=4 n=2 1:9 mixture of 6000 / 80 % and 78000 / 98 % n=6 n=6 n=6 n=4 n=2 1:9 mixture of 6000 / 80 % and 125000 / 88% n=6 n=6 n=6 n=4 n=2

[0266] The average weight change after 24 hours of immersion in PBS was calculated and is shown in the graphs in Figure 2. The degree of hydrolysis (DH) and the molecular weight (MW) of PVA determine the solubility of the films. Each film of PVA mixture 6000 / 80%, 25000 / 88%, 125000 / 88% and 6000 / 80%-125000 / 88% was dissolved at the end of day 1 under all curing conditions tested. The film of Petition 870260060402, dated 06 / 19 / 2026, pp. 74 / 113 66 / 80 78000 / 98% lasted longer. The relative resistances of the tested films are shown in Figure 3. Example 2A

[0267] The inserts were produced according to the parameters in the following table: Table 2 API:PVA Ratio 1:1 1:1 1:1 1:1 1:1 1:1 1:1 1:1 1:1 1:1 Core PVA Solution 4% 4% 4% 4% 4.5% 4.5% 4.5% 4.5% 4.5% 4.5% 5% Topcoat PVA Solution 4% 4% 4% 4% 4.5% 4.5% 4.5% 4.5% 4.5% 4.5% 5% Number of Coatings 2, 4 4 1-4 1-4 4 4 2-4 2-4 2-4 0, 2-4 4 Curing 140 °C 1 h 140 °C 2 h 140 °C 4 h 100 °C 3 h none 140 °C 30 min 140 °C 1 h 140 °C 2 h 140 °C 3 h 100 °C 4 h 140 °C 4 h Table 3 API:PVA Ratio 1:1 w / w 1:1 w / w 1:1 w / w 1:1.3 5 w / w 1:1 w / w 1:1 w / w 1:1 w / w 1:1 w / w 1:1.3 5 w / w 1:1 w / w 1:1 w / w 1:1 w / w 1:1 w / w 1:1.3 5 w / w Core PVA Solution 4.5% 6.5% 9% 9% 4.5% 6.5% 9% 9% 4.5% 6.5% 9% 9% No Coating s No coating Curing 140 °C 30 min 140 °C 30 min 140 °C 30 min 140 °C 30 min 140 °C 1h 140 °C 1h 140 °C 1h 140 °C 1h 140 °C 4h 140 °C 4h 140 °C 4h 140 °C 4h

[0268] The inserts were manufactured by mixing vorolanib with a 78000 / 98% PVA solution in water at the vorolanib:PVA solution ratio (w / w) specified in the tables above. The mixture was then extruded from a 20, 21, or 23 gauge dispensing tip and dried at room temperature.

[0269] For inserts that were coated, the extrudate was then dip-coated in a 78000 / 98% PVA solution and air-dried. The dip-coating process was repeated to achieve the number of coatings specified in the table above. The coating process involved immersing the extrudates in the PVA solution with 5 min of drying at room temperature between Petition 870260060402, dated 06 / 19 / 2026, pp. 75 / 113 67 / 80 for the first layers and then at least 10 min of drying time before immersion to form the final layer / coating. The coated extrudates were then cured as described in the table. After cooling to room temperature, the extrudates were cut into inserts of 2 mm, 3.5 mm, 5 mm, 6 mm or 8 mm in length. Example 2B

[0270] 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 water bath at 37 °C. Samples of the delivery medium were collected at 12- to 24-hour intervals, and the delivery medium was replaced with fresh PBS. The amount of vorolanib released was quantitatively measured by HPLC according to the method described in Example 2B. The in vitro release rate was tested, and the average release rate was determined from the cumulative release versus time. Example 2C

[0271] The insert samples were analyzed for API content. The inserts tested for content were cut into 4 pieces and all 4 pieces were placed in a labeled scintillation vial. 3.0 ml of methanol were pipetted into the vial and the vial was placed under a cabinet. This procedure was repeated for all samples. The sample vials were placed in a sonicator, an appropriate amount of water was added, and the samples were sonicated for 30 minutes. Sonication was repeated 5 more times, with the sonicator cooled between each sonication. Extra sonication can be done as needed to ensure that the API is completely dissolved. HPLC was performed with the following parameters: Column: ZORBAX Eclipse XDB-C18; 4.6X150 mm; 5 microns; Mobile Phase A: Water + 0.1% phosphoric acid; Mobile Phase B: Acetonitrile + 0.1% phosphoric acid; Gradient Method; Stopping time of Petition 870260060402, dated 06 / 19 / 2026, pp. 76 / 113 68 / 80 min; UV: 214 nm. 2D Example

[0272] Erosion of sample inserts was evaluated. A sample insert was placed in a 10 ml glass vial with 5 ml of phosphate-buffered saline (PBS), and the vial was incubated at 37 °C without agitation. The PBS in the vial was replaced once every 24 hours for each day of the period of interest. At the end of the period, the sample was removed from the vial, weighed, and photographed.

[0273] The drug release rate curves for a 4.5% PVA coated formulation cured at 140°C for 4 hours, called Formulation A, are shown in Figures 4A (% cumulative drug release) and 4B (cumulative drug release (μg)). The drug release rate curve for an Uncoated Formulation A implant is shown in Figure 6. Photographs of eroded Formulation A implants taken after immersion in dissolution medium for 314 and 447 days are shown in Figure 5. An intact implant is included in the 447-day photograph for comparison. Photographs of eroded Uncoated Formulation A implants taken after immersion in dissolution medium for 287 and 352 days are shown in Figure 7. An intact implant is included in the 352-day photograph for comparison.

[0274] The drug release rate curves for a 4.5% PVA coated formulation cured at 140 °C for 30 minutes, called Formulation B, are shown in Figures 8 (% cumulative drug release) and 8B (cumulative drug release (pg)). Photographs of eroded Formulation B implants taken after immersion in dissolution medium for 59, 88 and 155 days are shown in Figure 9.

[0275] The drug release rate curve for an uncured 4.5% coated PVA formulation, called Formulation C, is shown in Figure 10. Two photographs each showing a different sample of an implant. Petition 870260060402, dated 06 / 19 / 2026, pp. 77 / 113 69 / 80 eroded from Formulation C taken after immersion in dissolution medium for 98 days at 37 °C, then 113 days at room temperature are shown in Figure 11.

[0276] A comparison of the drug release curves for Formulations A, B and C is shown in Figure 12.

[0277] Formulation A releases the drug more slowly and erodes more slowly than Formulations B and C. Formulation C releases the drug more quickly and erodes more quickly than Formulations A and B. Example 3

[0278] Inserts comprising more than one degree of PVA were produced according to the parameters in the following table: Table 4 Core PVA Solution 4.5% 78K / 98% 4.5% 78K / 98% 4.5% 78K / 98% 4.5% solution mixture of 9:1 78K / 98% and 125K / 88% 4.5% solution mixture of 9:1 78K / 98% and 125K / 88% Coating PVA Solution Coating: 4.5% 78K / 88% Coating 1: 4.5% 78K / 98% Coatings 24: 4.5% 78K / 88% Coating: 4.5% 125K / 88% Coating: 4.5% 78K / 98% Coating: 4.5% 125K / 88% Cures samples of each The formulations were cured at 140 °C / 30 min. Samples of each formulation were cured at 140 °C / 1 h. Samples of each formulation were cured at 140 °C / 4 h.

[0279] The inserts were manufactured by mixing vorolanib with a PVA solution in water at a 1:1 w / w ratio of vorolanib:PVA solution to form a paste. The mixture was then extruded from a 21-gauge dispensing tip to form rods approximately 10.16–12.7 cm (4–5 inches) long and dried at room temperature. The extruded rods were cured as described in the table above.

[0280] The extrudates were coated by immersion in a PVA solution in water and allowed to dry at room temperature. For inserts with more than one coating, the coating process involved immersing the extrudates in the PVA solution with 5 min of drying at room temperature between the first coatings. Petition 870260060402, dated 06 / 19 / 2026, pp. 78 / 113 70 / 80 layers, then at least 10 minutes of drying time before immersion to form the final layer / covering.

[0281] After the final coating, the coated rods were cured according to the conditions described in the table above. After cooling to room temperature, the coated rods were cut into 8 mm long inserts using a razor blade.

[0282] API release was measured according to the method described in Example 2B.

[0283] The API content was measured according to the method described in Example 2C.

[0284] Implant erosion was assessed according to the method described in Example 2D.

[0285] Inserts comprising more than one degree of PVA are produced according to the parameters in the following tables: Table 5 Core PVA Solution 4.0% 78K / 99+% 4.5% 78K / 99+% 4.0% 89K-98K 99+% 4.0% of a 9:1 mixture of 78K / 98% and 125K / 88% 4.0% of a 9:1 mixture of 78K / 98% and 125K / 88% Coating PVA Solution Coating: 4.5% 78K / 88% Coating: 4.5% 78K / 88% Coating: 4.5% 78K / 98% Coating: 4.5% 78K / 98% Coating: 4.5% 125K / 88% Curing Samples of each formulation were cured at 140°C / 30 min Samples of each formulation were cured Samples of each formulation were cured at 140 °C for 1 hour, followed by curing at 140 °C for 4 hours. Table 6 Core PVA Solution 4.5% 78K / 98% 4.5% 78K / 99% 4.5% 78K / 88% 4.5% of 9:1 mixture solution 78K / 98% and 125K / 88% 4.5% of 9:1 mixture solution 78K / 98% and 125K / 88% Coating PVA Solution Coating 1: 5.0% 6000 / 80% Coating 13: 4.5% 78K / 98% Coating 4: 5.0% 6000 / 80% Coatings 1-5: 4.5% 78K / 98% Coating 6: 5.0% 6000 / 80% Coatings 1-2: 4.5% 78K / 98% Coverage 3: 4.5% 78K / 88% Coverage 1: 4.5% 125K / 88% Coverage 2: 4.5% 6000 / 80% Curing: Samples of each formulation were cured at 140°C / 30 min; samples of each formulation were cured at 140°C / 1h; samples of each formulation were cured at 140°C / 4h Petition 870260060402, dated 06 / 19 / 2026, pp. 79 / 113 71 / 80

[0286] The inserts are manufactured by mixing vorolanib with a PVA solution in water at a 1:1 w / w ratio of vorolanib:PVA solution to form a paste. The mixture is then extruded from a 21-gauge dispensing tip to form rods approximately 10.16–12.7 cm (4–5 inches) long and dried at room temperature. The extruded rods are cured as described in the tables above.

[0287] The extrudates are coated by immersion in a PVA solution in water and allowed to dry at room temperature. For inserts with more than one coating, the coating process involves immersing the extrudates in the PVA solution with 5 min of drying time at room temperature between the first layers and then at least 10 min of drying time before immersion to form the last layer / coating.

[0288] After the final coating, the coated rods are cured according to the conditions described in the table above. After cooling to room temperature, the coated rods are cut into 8 mm long inserts using a razor blade.

[0289] API release is measured according to the method described in Example 2B.

[0290] The API content is measured according to the method described in Example 2C.

[0291] Implant erosion is assessed according to the method described in Example 2D. Example 4

[0292] The inserts are produced according to the parameters in the following tables: Table 7 API Vorolanib API:PVA 1:1 w / w Petition 870260060402, dated 06 / 19 / 2026, pp. 80 / 113 72 / 80 PVA Core Solution 2.5% 2.5% 2.5% 2.5% 3% 3% 3% 3% 5% 5% PVA Coating Solution 4.5% 4.5% 5% 5% 5% 5% 5% 5% 5% 5% Number of Coatings 2-4 2-4 1-4 1-4 0-4 0-4 0-4 0-4 1-4 0-4 Curing after coating 140 °C 2 h after coating 140 °C 4 h after coating 140 °C 4 h before coating 140 °C 4 h after coating 150 °C 30 min after coating 140 °C 2 h after coating 140 °C 3 h after coating 140 °C 4 h after coating 150 °C 30 min after coating 140 °C 2h Table 8 API Vorolanib API:PVA 1:1 w / w Core PVA Solution 5% 5% 4% 4% 4% 5% 5% 8% 10% 12% Coating PVA Solution 6% 6% 8% 8% 10% 8% 8% 4.5% 4% 4% Number of Coatings 1-4 1-4 1-4 1-4 1-4 1-4 1-4 0-4 0-4 0-4 Curing after coating 140 °C 2 h after coating 140 °C 4 h after coating 140 °C 4 h before coating 140 °C 4 h after coating 140 °C 30 min after coating 140 °C 2 h before coating 140 °C 3 h after coating 140 °C 2 h after coating 140 °C 30 min after coating 140 °C 2 h Table 9 API Axitinib API:PVA 1:1.5 1:1.5 1:1.5 1:1.5 1:2 1:2 1:2 1:2 1:2 1:2 Core PVA Solution 3% 5% 8% 10% 3% 5% 5% 8% 10% 10% Coating PVA Solution 6% 6% 6% 6% 5% 5% 5% 5% 5% 5% Number of Coatings 0-4 0-4 0-4 0-4 0-4 0-4 0-4 0-4 0-4 0-4 Curing after coating 140 °C after coating 140 °C after coating 140 °C before coating after coating 140 °C after coating 140 °C before coating after coating 140 °C after coating 140 °C °C after coating 140 °C Petition 870260060402, dated 06 / 19 / 2026, pp. 81 / 113 73 / 80 2 h 2h 3 h 140 °C 2 h 2 h 30 min 140 °C 2h 2h 30 min 2h

[0293] The API is mixed with a PVA solution in water at the API:PVA solution ratio specified in the table to form a paste. The paste is extruded through a dispensing tip with a 20-23 gauge to form rods approximately 10.16-12.7 cm (4-5 inches) long and dried at room temperature. The extruded rods are cured before or after coating as described in the tables above.

[0294] The extrudates are coated by immersion in a PVA solution in water. The coating process involves immersing the extrudates in the PVA solution with 5 min of drying time at room temperature between the first layers and then at least 10 min of drying time before immersion to form the final layer / coating. After the final coating, the coated rods are cured according to the tables above or left to dry for 24 hours at room temperature.

[0295] The coated rods are cut into inserts 2 mm, 3.5 mm, 5 mm or 6 mm long using a razor blade.

[0296] API release is measured according to the method described in Example 2B.

[0297] The API content is measured according to the method described in Example 2C.

[0298] Implant erosion is assessed according to the method described in Example 2D. Example 5 - Pharmacokinetic Study

[0299] An intravitreal pharmacokinetic study was performed in male Dutch Belted rabbits. The aim of this study was to characterize the plasma and ocular tissue pharmacokinetics of a vorolanib insert after bilateral intravitreal injection on Day 1. Animals were evaluated up to 24 months after intravitreal insert placement. Petition 870260060402, dated 06 / 19 / 2026, page 82 / 113 74 / 80

[0300] The table below describes the dosage levels and treatments assigned to the group. Table 10 Treatment Group OD (Right Eye) OS (Left Eye) Group 1 Low Dose 3 inserts 3 inserts Group 2 High Dose 6 inserts 6 inserts

[0301] After administration of anesthesia, vorolanib inserts measuring 0.37 mm in diameter by 3.5 mm in length, designed to release the drug for at least 6 months, were injected, using an injector, intravitreally into each eye of 52 Dutch-belted rabbits. The low-dose group (1) received 3 inserts per eye for a total dose of 630 μg per eye. The animals in the high-dose group (2) received 6 inserts per eye administered in 2 separate injections (3 inserts per injection) for a total dose of 1260 μg per eye.

[0302] Before each scheduled sacrifice point, a whole blood sample was collected from 2 targeted animals per group by puncture of a marginal ear vein. Samples were tested for vorolanib and its metabolite levels. Two animals per group were sacrificed on day 1 at 6, 12, 24, and 48 hours, on days 7 and 14, and at 1, 2, 4, 6, 8, 16, and 24 months. Vitreous humor and ocular tissues were collected from both eyes for analysis of drug distribution in ocular tissue, inserts were collected, and liver and kidney samples were collected for tissue distribution assessment.

[0303] Results: At steady state, the vitreous level of vorolanib was 56 ng / ml for the low dose of 630 μg and 97 ng / ml for the high dose of 1260 μg. Petition 870260060402, dated 06 / 19 / 2026, pp. 83 / 113 75 / 80 (dose proportionality). Retina / choroid levels were 49 ng / g and 89 ng / g. There was a burst of drug release during the first 90 days, followed by a steady state. Steady state was reached on day 105. The maximum concentrations observed in the vitreous and retina / choroid appear to be almost dose-proportional. No apparent change was found in plasma levels after 99 days. By day 180, the vitreous Cmax was 232 ng / ml, Tmax was 336 ng / ml, and AUClast was 315.5 μg·h / ml for the 630 μg dose. Up to day 180, the vitreous Cmax was 1697 ng / ml, Tmax was 720 ng / ml, and AUClast was 1583.2 μg·h / ml for the 1260 μg dose.

[0304] Figure 13A represents the average amount of drug remaining in an insert versus time for inserts explanted at various time points and tested to determine the amount of vorolanib remaining in the insert. Figure 13B represents the cumulative percentage of drug released versus time for explanted inserts. Example 6 - Toxicology and Pharmacokinetic Study

[0305] An 18-month intravitreal toxicity study for the insert was also conducted in 80 Dutch Belted rabbits (40 males and 40 females). The animals were evaluated for a period of 6 and 18 months after placement of the intravitreal inserts. The objective was to characterize the ocular toxicity, plasma pharmacokinetics, and biodegradation of a vorolanib insert after bilateral intravitreal injection.

[0306] The tables below describe the group assignments and dosage levels. For the toxicology groups, animals were sacrificed at 6 months and 18 months. For the plasma pharmacokinetic analysis, blood samples were collected on days 1, 3, and 7, and then at 1, 2, 3, 4, 5, 6, 12, 14, 16, and 18 months. Table 11 Petition 870260060402, dated 06 / 19 / 2026, pp. 84 / 113 76 / 80 Treatment Group OD (Right Eye) OS (Left Eye) Group 1 Control 2 placebo inserts 2 placebo inserts Group 2 Low Dose 2 inserts 2 inserts Group 3 Intermediate Dose 3 inserts 3 inserts Group 4 High Dose 4 inserts 4 inserts Group 5 Highest Dose 6 inserts 6 inserts

[0307] After administration of anesthesia, vorolanib inserts measuring 0.37 mm in diameter by 3.5 mm in length, designed to release the drug for at least 6 months, were injected intravitreally into each eye of each Dutch-belted rabbit using an injector. Animals in the placebo group (1) received two placebo inserts per injection in each eye. Animals in the low-dose group (2) received 2 inserts in each eye. Animals in the medium-dose group (3) received 3 inserts in each eye administered in 2 separate injections. Animals in the high-dose group (4) received 4 inserts in each eye administered in 2 separate injections (2 inserts / injection). Animals in the highest-dose group (5) received 6 inserts in each eye administered in 2 separate injections (3 inserts / injection).

[0308] At each scheduled time point, whole blood was collected by puncture of a marginal ear vein. Samples were analyzed for clinical pathology and plasma pharmacokinetics. Animals were sacrificed according to the schemes described above. A complete macroscopic necropsy was performed on all animals that were sacrificed or found dead during the study. Organs were weighed and tissues Petition 870260060402, dated 06 / 19 / 2026, pp. 85 / 113 77 / 80 collected. Eye tissues were collected for histopathology only.

[0309] Conclusions: Plasma pharmacokinetic and toxicology studies provide evidence of safety at Cmax and vitreous AUC during an 18- and 24-month exposure period, respectively. Furthermore, at the time points tested, vorolanib levels in the vitreous and retinal / choroid remained significantly above the IC50 for VEGFR.

[0310] No adverse findings were attributed to vorolanib and there were no adverse findings for up to 6 inserts. The no-observed-adverse-effect level (NOAEL) for the inserts was determined at 6 inserts / eye (1260 μg / eye).

[0311] The most significant event observed is yellow discoloration of the lens, which appears to be dose-related and due to the color of the API. There were no histopathological / microscopic findings associated with the lens discoloration. The second most significant event observed is focal, punctate, or linear opacity of the lens and appears to be primarily related to the number of injections and, to a lesser extent, the number of inserts.

[0312] Mild inflammation (<2+ aqueous or vitreous cells) was observed in all groups initially. All inflammatory cells were gradually resolved and eliminated within 3 months. The highest observed inflammation events were seen in the placebo group (2 drug-free inserts).

[0313] There was no change in intraocular pressure (IOP) from baseline, although some transient changes were observed.

[0314] Vorolanib plasma levels were in the low pg / ml range. Example 7 - Safety and Efficacy

[0315] The safety and efficacy of a vorolanib insert were evaluated in a porcine (mini-pig) model of laser-induced choroidal neovascularization (CNV). The primary objective of this study was to evaluate the long-term safety and inhibition of vascular permeability and neovascularization in a model of Petition 870260060402, dated 06 / 19 / 2026, page 86 / 113 78 / 80 laser-induced choroidal neovascularization (CNV) using a vorolanib insert in pigs.

[0316] The experimental design is described in the following table: Table 12 Group Test Articles & Dose Volume / Laser Route CNF / Dosage Day Experimental Endpoint Euthanasia 1 Aflibercept (2mg) 50 μl / ocular IVT OR: CNV Laser (D0) • OEs: Baseline, before laser, and Days 7, 14, and 28. • Fluorescein Angiography: Days 7, 14, and 28. • Histology: Collect eyes for potential histological examination Day 28 2 Low dose 1 insert / ocular IVT 3 High dose 2 inserts / ocular IVT 4 Placebo 2 inserts / ocular IVT 5 High dose 2 inserts / ocular IVT None • OEs: Baseline, before laser, and Days 7, 14, 28, 56, and 84. • ERGs: Baseline, before necropsy • Histology: Collect eyes for histological examination Day 84 6 Placebo 2 inserts / IVT ocular

[0317] On the day of laser treatment (Groups 1-4), the animals were treated with an 810 nm diode laser administered via an indirect ophthalmoscope. Approximately 6 single laser points were placed between the retinal veins. Both eyes underwent laser treatment according to the schedule in the table above.

[0318] On the day of intravitreal injections, the animals were anesthetized and the eyes were aseptically prepared. The conjunctiva was gently held with hummingbird forceps and the injection (25G injector needle) was made 2-3 mm posterior to the superior limbus (through pars plana), with the needle straight and slightly posterior to avoid contact with the lens. The animals were allowed to recover normally from the procedure. The pigs received a topical drop of antibiotic ophthalmic solution 4-6 hours later, and then BID for another 2 days with at least 6 hours between doses. The animals received doses on Day 0 immediately after laser CNV induction or 7 days before laser CNV induction according to the schedule in the table above. Animals in Groups 5-6 did not undergo laser CNV procedures and were implanted on Day 0. Petition 870260060402, dated 06 / 19 / 2026, p. 87 / 113 79 / 80

[0319] During acclimation and during the study, the animals were evaluated for mortality and morbidity, as well as general health, with special attention to the eyes. Body weights were measured before treatment and before necropsy; animals in Groups 5 and 6 were weighed monthly.

[0320] A complete eye examination (CEO) (Hacket and McDonald modified) using a slit-lamp biomicroscope and indirect ophthalmoscope to assess ocular surface morphology, anterior and posterior segment inflammation, cataract formation, and retinal changes was conducted by a veterinary ophthalmologist at the time points indicated in the experimental design table. Mydriasis for eye examination was performed with topical tropicamide HCl 1%.

[0321] Fluorescein angiography was performed on both eyes in anesthetized animals at the time points indicated in the experimental design table.

[0322] Full-field electroretinography (ERG) was performed on both eyes of the animals at baseline and 3 months after dosing (Group 56 only). On the day of ERG measurements, the animals were anesthetized after dark adaptation. ERGs were elicited by brief flashes at 0.33 Hz delivered with a miniganzfeld photostimulator at maximum intensity. Twenty responses were amplified, filtered, and averaged for each animal. The animals underwent standard ERG measurements as dictated by ISCEV standards, including scotopic (0.01 candela), scotopic (3 candela), and photopic (25 candela) measurements.

[0323] At the time points indicated by the experimental design table, after the final data collection, the animals were sacrificed. Histology was evaluated for the eyes of Groups 5-6.

[0324] Results: Overall, dose-related efficacy was found and Petition 870260060402, dated 06 / 19 / 2026, pp. 88 / 113 80 / 80 no clinically observed toxicity. Fluorescein angiography analysis in all groups (1-4) showed a reduced corrected total lesion fluorescence (CTLF) value from Day 7 to Day 28, with aflibercept-treated animals showing the greatest reduction in CTLF values, followed by the high dose group, with the remaining groups showing similar reductions in CTLF values. ERG b-wave amplitudes were reduced from baseline to Day 84 in both ERG-treated groups; however, this may be attributed to difficulties in ERG acquisition.

[0325] Eyes subjected to histological examination showed some inflammation, which may have been more severe in animals treated with high-dose implants. The implant procedure may have contributed to the increased inflammation observed in the high-dose group.

[0326] The aflibercept and placebo implants performed as expected, with aflibercept having normal amounts of efficacy in this model and the placebo implants being well tolerated. Conclusions:

[0327] Plasma vorolanib levels in the PK study were in the low pg / ml range. Dose-related efficacy was found and no clinically observed toxicity. Thus, the inserts of the invention were able to deliver safe and therapeutically effective steady-state levels of vorolanib locally for a sustained period, resulting in only negligible systemic levels of vorolanib. Furthermore, the inserts are completely bioerodible. Petition 870260060402, dated 06 / 19 / 2026, pp. 89 / 113

Claims

1 / 4 CLAIMS 1. Use of an ocular insert for drug delivery CHARACTERIZED in that it is in the manufacture of a medicament to treat or prevent an ocular condition in an individual in need thereof, wherein one or more of the inserts are injected into the vitreous of an eye of the individual, wherein the insert comprises a solid matrix core comprising a matrix polymer and vorolanib or a pharmaceutically acceptable salt thereof, wherein the amount of vorolanib or of a pharmaceutically acceptable salt thereof in the insert is from about 10% w / w to about 98% w / w, wherein the drug release rate to the insert is from about 0.01 μg / day to about 100 μg / day for at least 14 days, and wherein the insert is capable of at least 20% erosion within 95 days.

2. Use according to claim 1, CHARACTERIZED in that the amount of vorolanib or pharmaceutically acceptable salt thereof in the insert is about 60% w / w or about 98% w / w.

3. Use according to claim 1, CHARACTERIZED in that the drug release rate is from about 0.1 μg / day to about 20 μg / day.

4. Use according to claim 1, CHARACTERIZED in that the drug release rate is from about 0.1 μg / day to about 10 μg / day.

5. Use, according to claim 1, CHARACTERIZED in that the core comprises about 200 μg to about 2000 μg of vorolanib or of a pharmaceutically acceptable salt thereof.

6. Use, according to claim 1, CHARACTERIZED by the fact that the duration of vorolanib release is at least about 90 Petition 870260060402, dated 06 / 19 / 2026, p. 90 / 113 2 / 4 days.

7. Use, according to claim 1, CHARACTERIZED in that the core comprises about 1% w / w to about 15% w / w of PVA.

8. Use according to claim 1, CHARACTERIZED in that the insert has a cylindrical shape.

9. Use, according to claim 1, CHARACTERIZED in that the insert has dimensions and shape suitable for passing through a needle or cannula of 20 to 27 gauge, and has a length of about 1 mm to about 10 mm.

10. Use, according to claim 1, CHARACTERIZED in that the insert has dimensions and shape suitable for passing through a needle or cannula smaller than 25 gauge, and has a length of about 1 mm to about 6 mm.

11. Use according to claim 1, CHARACTERIZED in that the condition is selected from the group consisting of macular degeneration, retinal vein occlusion and diabetic retinopathy.

12. Use, according to claim 11, CHARACTERIZED in that the condition is macular degeneration.

13. Use, according to claim 12, CHARACTERIZED in that the condition is age-related macular degeneration.

14. Use, according to claim 13, CHARACTERIZED in that the condition is age-related macular degeneration in the wet form.

15. Use according to claim 1, CHARACTERIZED in that the condition is diabetic macular edema.

16. Use, according to claim 11, CHARACTERIZED Petition 870260060402, dated 06 / 19 / 2026, pp. 91 / 113 3 / 4 by the fact that the condition is retinal vein occlusion.

17. Use according to claim 11, CHARACTERIZED in that the condition is diabetic retinopathy.

18. Use of an ocular insert for drug delivery comprising vorolanib or a pharmaceutically acceptable salt thereof, CHARACTERIZED in that it is in the manufacture of a medicament to treat a condition in an individual in need thereof, wherein the condition is selected from the group consisting of macular degeneration, retinal vein occlusion, diabetic retinopathy and macular edema, wherein 1 to 6 inserts are injected by intravitreal injection, releasing from about 0.01 μg / day to about 100 μg / day of vorolanib directly into an eye of the individual.

19. Use, according to claim 18, CHARACTERIZED in that the macular edema is diabetic macular edema.

20. Use, according to claim 18, CHARACTERIZED in that each of the inserts comprises from about 200 μg to about 2000 μg of vorolanib or of a pharmaceutically acceptable salt thereof.

21. Use, according to claim 18, CHARACTERIZED in that the total amount of vorolanib or of a pharmaceutically acceptable salt thereof in all inserts is from about 600 μg to about 6000 μg.

22. Use, according to claim 18, CHARACTERIZED in that each of the one or more ocular inserts for drug delivery has a drug release rate of about 0.1 μg / day to about 100 μg / day for at least 60 days.

23. Use, according to claim 18, CHARACTERIZED in that one or more ocular drug delivery inserts provide a total average daily dose of vorolanib of about 1 μg / day to Petition 870260060402, dated 06 / 19 / 2026, page 92 / 113 4 / 4 about 50 μg / day for at least 30 days.

24. Use according to claim 18, CHARACTERIZED in that one or more ocular drug delivery inserts provide a total average daily dose of vorolanib of about 1 μg / day to about 20 μg / day for at least 30 days.

25. Use, according to claim 18, CHARACTERIZED in that the individual presents geographic atrophy, in which the individual is at risk of developing geographic atrophy, in which the individual presents vision loss, in which the individual is at risk of developing vision loss, in which the individual presents ischemic retinal vein occlusion, or in which the individual presents non-ischemic retinal vein occlusion.

26. Use, according to claim 18, CHARACTERIZED in that the condition is macular degeneration.

27. Use, according to claim 26, CHARACTERIZED in that the condition is age-related macular degeneration.

28. Use, according to claim 27, CHARACTERIZED in that the condition is age-related macular degeneration in the wet form.

29. Use according to claim 18, CHARACTERIZED in that the condition is retinal vein occlusion.

30. Use, according to claim 18, CHARACTERIZED by the fact that the condition is diabetic retinopathy. Petition 870260060402, dated 06 / 19 / 2026, pp. 93 / 113

Images