Bio-erosive eye drug delivery implants and treatment methods

Abstract

The present invention relates to implantable, bioerodible inserts for delivering active pharmaceutical ingredients to the eye. The present invention also relates to methods of treatment using such inserts and methods of making such inserts.

Description

[Technical Field]

[0001]

[0001]

[0002] The present invention relates to an implantable bioerosive implant for delivering active pharmaceuticals to the eye. The present invention also relates to a method for treating patients requiring therapeutic relief using such an implant, and a method for manufacturing such an implant. [Background technology]

[0002]

[0003]

[0004] Implantable drug delivery devices offer certain advantages over conventional drug delivery methods such as oral administration or intravenous injection. For example, with conventional drug delivery methods, the concentration of the drug (active pharmaceutical ingredient) can fluctuate considerably, and the maximum concentration (C) can be reached immediately after administration. max The drug reaches a certain level and then drops sharply. Maintaining a therapeutic level may require administering the drug at a high dose, which can temporarily result in high drug concentrations that are potentially toxic. As the drug is metabolized or eliminated by the body, the drug concentration may decrease to safe and therapeutic levels. If the drug level falls below the therapeutic level, another dose must be administered, and thus the cycle is repeated. Thus, a problem with conventional medication is that, for certain types of drugs, patients may be chronically exposed to unnecessarily high levels of the drug from the repeated dosing cycles required for treatment. In addition, frequent dosing may be required, leading to decreased patient adherence to medication.

[0003]

[0005] Implantable drug delivery devices can reduce the need for frequent medication and avoid high systemic drug concentrations. However, achieving a consistent drug delivery rate (so-called zero-order release) within an acceptable duration is challenging.

[0004]

[0006] In addition, many implantable drug delivery implants contain non-biodegradable materials that remain permanently in the patient's body even after all of the drug has been administered. This can be problematic, especially for drug delivery to anatomical locations with small volumes. Repeated therapeutic procedures using implants may be limited due to the undesirable accumulation of non-biodegradable portions of implantable drug delivery devices.

[0005]

[0007] Furthermore, providing an implantable drug delivery device that is small enough to be implanted in a patient with minimal discomfort, yet large enough to contain enough drug to provide sustained delivery at therapeutic levels, is extremely challenging.

[0006]

[0008] Considering these factors, there remains a need in the field of technology to improve the design and preparation methods of implantable drug delivery devices that provide controlled and sustained drug release to patients in order to obtain desired local or systemic physiological or pharmacological effects.

[0007]

[0009] One ophthalmic condition that necessitates improved drug delivery is age-related macular degeneration ("AMD"). AMD is the leading cause of blindness worldwide, with the World Health Organization estimating that approximately 14 million people are blind or severely impaired due to AMD. AMD causes progressive loss of central vision due to degeneration and neovascularization in the macula, a special region at the center of the retina. Generally, macular degeneration can result in slow or sudden vision loss.

[0008]

[0010] There are two types of AMD: dry AMD and wet AMD. Typically, AMD begins as dry AMD, characterized by the formation of drusen, which are yellow, spot-like deposits in the macula between the retinal pigment epithelium and the underlying choroid. Approximately 15% of patients with dry AMD develop wet AMD, which is characterized by the formation of new blood vessels in the choroid (choroidal neovascularization) and vision loss.

[0009]

[0011] Dry macular degeneration is more common than wet AMD, and about 90% of AMD patients are diagnosed with dry AMD. Dry AMD can result from aging and thinning of macular tissue, pigment deposits in the macula, or a combination of the two processes. The wet form of the disease usually leads to more severe vision loss. In wet AMD, new blood vessels grow under the retina, and blood and fluid leak out. This leakage kills retinal cells and creates a blind spot in central vision.

[0010]

[0012] Although there is no cure for AMD, there are several treatments for wet AMD, but many of them are inconvenient or have significant adverse effects.

Summary of the Invention

[0011]

[0013] In accordance with various embodiments of the present invention and after extensive experimentation, the inventors have invented a novel biodegradable drug delivery insert comprising an active pharmaceutical ingredient (API) and a biodegradable polymer. This insert is particularly useful for the topical delivery of an effective amount of API to the eye. In addition, the insert provides sustained release of the API. In some embodiments, the insert provides sustained release for a period that substantially matches the period required for complete erosion of the insert in the eye.

[0012]

[0014] These inserts may be administered into the eye, such as intravitreally, suprachoroidally, and into the anterior chamber, or subconjunctivally. For example, the insert may be placed by a needle or cannula, such as by intravitreal injection. Thus, in some embodiments, the present invention relates to a drug delivery insert that can deliver an effective intraocular concentration of API while delivering a low systemic concentration of API to reduce, for example, the risk of toxicity or other undesirable side effects.

[0013]

[0015] In some embodiments, the present invention relates to a method for treating or preventing an eye disease by topical (e.g., intraocular) administration of an API or a pharmaceutically acceptable salt thereof.

[0014]

[0016] In one embodiment, the present invention relates to an ophthalmic delivery insert comprising a solid matrix core containing a matrix polymer and brolanib or a pharmaceutically acceptable salt thereof, wherein the amount of brolanib or a pharmaceutically acceptable salt thereof in the insert is from about 10% w / w to about 98% w / w, the drug release rate of the insert is from about 0.01 μg / day to about 100 μg / day for at least 14 days, and the insert is capable of at least 20% erosion within 95 days. In another embodiment, the amount of brolanib or a pharmaceutically acceptable salt thereof in the insert is from about 60% w / w to about 98% w / w.

[0015]

[0017] In another embodiment, the insert further comprises a coating substantially surrounding the core. In some embodiments, the amount of the coating is from about 5% w / w to about 20% w / w of the insert. In additional embodiments, the insert further comprises a delivery port.

[0016]

[0018] In another embodiment, the insert is sized and shaped to pass through a 20-27 gauge needle or cannula, and the insert has a length of from about 1 mm to about 10 mm. In yet another embodiment, the insert is sized and shaped to pass through a needle or cannula smaller than 25 gauge. In a further embodiment, the insert has a length of from about 1 mm to about 6 mm.

[0017]

[0019] 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.

[0018]

[0020] In some embodiments, the coating includes a different grade of PVA than the matrix polymer. In some embodiments, the coating includes one or more films containing PVA, and the DH of the PVA in at least one film is different from the DH of the PVA in the matrix polymer. In some embodiments, the MW of the PVA in the coating is different from the MW of the PVA in the matrix polymer. In further embodiments, the coating includes at least two films containing PVA, and at least one of the films contains a different grade of PVA than at least one other film. In yet another embodiment, the PVA in at least two films containing PVA is different in DH. In some embodiments of the insert, the PVA in at least two films containing PVA is different in MW.

[0019]

[0021] In yet another embodiment, the insert can be eroded by at least 90% within 440 days.

[0020]

[0022] In one embodiment of the insert, the drug release rate is approximately 0.1 μg / day to approximately 20 μg / day. In another embodiment of the insert, the drug release rate is approximately 0.1 μg / day to approximately 10 μg / day. In yet another embodiment of the insert, the drug release rate is approximately 0.1 μg / day to approximately 2 μg / day.

[0021]

[0023] In one embodiment, the core contains approximately 200 μg to approximately 2000 μg of borolanib or a pharmaceutically acceptable salt thereof.

[0022]

[0024] In another embodiment, the duration of borolanib release is at least about 90 days. In yet another embodiment, the duration of borolanib release is about 60 days to about 270 days.

[0023]

[0025] In one aspect of the present invention, the core contains approximately 1% w / w to approximately 15% w / w of PVA.

[0024]

[0026] In another aspect of the present invention, the insert was cured at approximately 130°C to approximately 150°C for approximately 30 minutes to approximately 4 hours.

[0025]

[0027] In yet another aspect of the present invention, the insert has approximately zero-order emission velocity dynamics.

[0026]

[0028] In one embodiment, the insert is cylindrical in shape. In a further embodiment, at least one end of the insert forms a delivery port.

[0027]

[0029] In another embodiment, the insert is prepared by dissolving PVA in an aqueous solution to form a PVA solution, mixing the PVA solution with borolanib or a pharmaceutically acceptable salt thereof to form a matrix mixture, extruding the mixture through a dispensing tip to form an elongated matrix, curing the elongated matrix at a temperature of about 140°C to about 160°C for about 30 minutes to about 2 hours, and then dividing the elongated matrix.

[0028]

[0030] In other embodiments, the insert is prepared by dissolving PVA in an aqueous solution to form a PVA solution, mixing the PVA solution with borolanib or a pharmaceutically acceptable salt thereof to form a matrix mixture, extruding the mixture through a dispensing tip to form an elongated matrix, coating the elongated matrix with the PVA solution, curing the elongated matrix at a temperature of approximately 140°C to 160°C for approximately 30 minutes to 2 hours, and then dividing the elongated matrix.

[0029]

[0031] The present invention also relates to a method for treating or preventing an eye condition in a subject requiring such treatment, comprising the step of injecting one or more implants into the vitreous humor of the subject's eye.

[0030]

[0032] In addition, the present invention relates to a method for treating macular degeneration in a subject requiring such treatment, comprising the step of injecting one or more implants into the vitreous humor of the subject's eye. In some embodiments, the macular degeneration being treated is age-related macular degeneration.

[0031]

[0033] In another embodiment, the present invention provides a method for producing an eye drop delivery insert, comprising the steps of: dissolving PVA in an aqueous solution to form a PVA solution; mixing the PVA solution with borolanib or a pharmaceutically acceptable salt thereof to form a matrix mixture; extruding the mixture through a dispensing tip to form an elongated matrix; curing the elongated matrix at a temperature of about 140°C to about 160°C for about 30 minutes to about 6 hours; and dividing the elongated matrix.

[0032]

[0034] In another embodiment, an elongated matrix is ​​covered with a PVA-containing coating before the matrix is ​​cured.

[0033]

[0035] In addition, the present invention relates to a method for treating a condition selected from the group consisting of macular degeneration, retinal vein occlusion, and diabetic retinopathy in a subject requiring such treatment, the method comprising the step of directly administering bororanib at a dose of about 0.01 μg / day to about 100 μg / day to the eye of the subject.

[0034]

[0036] In one embodiment, bororanib or a pharmaceutically acceptable salt thereof is delivered by injecting one or more eye drop delivery inserts containing bororanib or a pharmaceutically acceptable salt thereof into the eye.

[0035]

[0037] In another embodiment, the insert is administered by intravitreal injection.

[0036]

[0038] In some embodiments, the insert is injected through a needle or cannula smaller than 25 gauge. In some embodiments, an incision is not required for injection.

[0037]

[0039] In some embodiments, one to six inserts are injected.

[0038]

[0040] In some embodiments, each of the inserts contains approximately 200 μg to approximately 2000 μg.

[0039]

[0041] In some embodiments, the total amount of borolanib in all implants injected is approximately 600 μg to 6000 μg.

[0040]

[0042] In some embodiments, each of one or more eye drop delivery inserts has a drug release rate of about 0.1 μg / day to about 100 μg / day for at least 60 days.

[0041]

[0043] In some embodiments, one or more eye drop delivery inserts deliver a total average daily dose of bororanib ranging from approximately 1 μg / day to approximately 50 μg / day for at least 30 days.

[0042]

[0044] In other embodiments, one or more eye drop delivery inserts deliver a total average daily dose of bororanib of approximately 1 μg / day to approximately 20 μg / day for at least 30 days.

[0043]

[0045] The present invention also provides an ophthalmic drug delivery implant comprising a solid matrix core containing API and at least two different grades of PVA, wherein the drug release rate of the implant is about 0.0001 μg / day to about 200 μg / day for at least 30 days, the implant is capable of at least 20% erosion within 95 days, and the implant is sized and molded to pass through a 20-27 gauge needle or cannula. In some embodiments of this insert, the two different grades of PVA are mixtures selected from a list including: a mixture of MW78,000, 88% hydrolyzed and MW78,000, 98% hydrolyzed; a mixture of MW78,000, 88% hydrolyzed and MW78,000, 99+% hydrolyzed; a mixture of MW6,000, 80% hydrolyzed and MW78,000, 98% hydrolyzed; a mixture of MW6,000, 80% hydrolyzed and MW78,000, 99+% hydrolyzed; a mixture of MW78,000, 88% hydrolyzed and MW125,000, 88% hydrolyzed; and a mixture of MW6,000, 80% hydrolyzed and MW125,000, 88% hydrolyzed.

[0044]

[0046] In addition, the present invention provides an ophthalmic drug delivery implant comprising (a) a solid matrix core comprising PVA and API, and (b) a coating comprising PVA substantially surrounding the core, comprising at least two different grades of PVA, capable of at least 20% erosion within 95 days, and sized and molded to pass through a 20-27 gauge needle or cannula.

[0045]

[0047] In some embodiments of the insert, the coating contains a different grade of PVA than the PVA of the core. In some embodiments, the DH of the PVA in the coating is different from the DH of the PVA in the core. In other embodiments, the MW of the PVA in the coating is different from the MW of the PVA in the core. In yet another embodiment, the coating contains at least two films containing PVA, at least one of which contains a different grade of PVA than at least one other film. In yet another embodiment, the PVA in at least two films is different in DH. In some embodiments, the PVA in at least two films is different in MW.

[0046]

[0048] In other embodiments of the insert, the amount of API in the insert is approximately 60% w / w to approximately 98% w / w. In yet another embodiment, the core contains approximately 20% w / w to approximately 60% w / w of PVA. In yet another embodiment, the amount of coating is approximately 5% w / w to approximately 20% w / w of the insert. In yet another embodiment, the insert is capable of at least 90% erosion within 440 days.

[0047]

[0049] In some embodiments, the insert has approximately zero-order release rate dynamics, and the drug release rate of the insert is at least about 0.0001 μg / day to about 200 μg / day over 30 days. In yet other embodiments, the drug release rate is at least about 0.001 μg / day to about 100 μg / day over 30 days. In further embodiments, the duration of API release is at least about 90 days. In additional embodiments, the duration of API release is at least about 60 days to about 270 days.

[0048]

[0050] In some embodiments of the inserts, the inserts were cured at approximately 130°C to 150°C for approximately 30 minutes to 4 hours.

[0049]

[0051] In other embodiments, the insert is cylindrical in shape. In another embodiment, at least one end of the insert forms a delivery port. In a further embodiment, the insert is sized and shaped to pass through a needle or cannula smaller than 25 gauge, having a length of about 1 mm to about 10 mm.

[0050]

[0052] The present invention (a) MW6,000, 80% hydrolysis, MW9,000~10,000, 80% hydrolysis, MW25,000, 88% hydrolysis, MW25,000, 98% hydrolysis, MW30,000~70,000, 87~90% hydrolysis, MW78,00 0, 88% hydrolysis, MW78,000, 98% hydrolysis, MW78,000, 99+% hydrolysis, MW89,000~98,000, 99+% hydrolysis, MW85,000~124,000, 87~89% hydrolysis, MW108,000, 99 + A solid matrix core containing an API, and PVA selected from the group consisting of % hydrolysis, MW125,000, 88% hydrolysis, MW133,000, 99% hydrolysis, MW146,000-186,000, 99+% hydrolysis, and mixtures thereof, and (b) At least one coating comprising PVA substantially surrounding the core, wherein the PVA in the coating is MW6,000, 80% hydrolyzed; MW9,000-10,000, 80% hydrolyzed; MW25,000, 88% hydrolyzed; MW25,000, 98% hydrolyzed; MW30,000-70,000, 87-90% hydrolyzed; MW78,000, 88% hydrolyzed; MW78,000, 98% hydrolyzed; MW78,000, 99+% hydrolyzed; MW89,000-98,000, 99+% hydrolyzed; MW85,000-124,000, 87-89% hydrolyzed; MW108,000, 99 +Coating selected from PVA selected from the group consisting of % hydrolysis, MW125,000, 88% hydrolysis, MW133,000, 99% hydrolysis, MW146,000-186,000, 99+% hydrolysis, and mixtures thereof. An eye drug delivery insert containing, We also provide eye drop delivery inserts in which the PVA in the core and the PVA in at least one coating are of different grades.

[0051]

[0053] In some embodiments, the insert comprises at least two coatings of PVA, where the DH of the PVA in the outermost coating is lower than the DH of any of the PVA in the other coatings.

[0052]

[0054] In other embodiments of the inserts of the present invention, the API has a molecular weight of 1000 AMU or less and water solubility of less than about 200 μg / mL at 25°C. In other embodiments, the API is a VEGF inhibitor. In other embodiments, the API is a TKI inhibitor. In yet another embodiment, the API is borolanib or a pharmaceutically acceptable salt thereof. In yet another embodiment, the API is axitinib or a pharmaceutically acceptable salt thereof. In yet another embodiment, the API is a Tie-2 activator. In some embodiments, the API is razprotafib or a pharmaceutically acceptable salt or zwitterion thereof.

[0053]

[0055] In some aspects of the method of the present invention, the subject has geographic atrophy, is at risk of developing geographic atrophy, has visual impairment, is at risk of developing visual impairment, has ischemic retinal vein occlusion, or has non-ischemic retinal vein occlusion.

[0054]

[0056] The present invention also provides a method for inhibiting angiogenesis in the eye of a subject requiring it, comprising the step of implanting one or more ophthalmic drug delivery implants in the vitreous humor of the subject's eye, wherein the number of implants administered during the administration procedure is 1 to 6 implants, and each of the one or more implants has a drug release rate of bororanib of about 0.01 μg / day to about 100 μg / day for at least 30 days.

[0055]

[0057] The present invention also provides a method for inhibiting VEGFR and PDGFR in the eye of a subject requiring such inhibition, comprising the step of implanting one or more ophthalmic drug delivery implants in the vitreous humor of the eye of the subject, wherein the number of implants administered during the administration procedure is 1 to 6 implants, and each of the one or more implants has a drug release rate of approximately 0.01 μg / day to approximately 100 μg / day of vorolanib for at least 30 days.

[0056]

[0058] In addition, the present invention provides a method for treating macular degeneration in a subject requiring it, comprising the step of implanting one or more ophthalmic drug delivery implants in the vitreous humor of the subject's eye, wherein the number of implants administered during the administration procedure is 1 to 6 implants, and each of the one or more implants has a drug release rate of bororanib of about 0.01 μg / day to about 100 μg / day for at least 30 days. In some embodiments, the macular degeneration to be treated is age-related macular degeneration.

[0057]

[0059] In some embodiments, the treatment or administration method further includes the step of administering a pharmaceutical composition containing a therapeutically effective amount of a Tie-2 activator to a target. In further embodiments, the Tie-2 activator is razprotafib, or a pharmaceutically acceptable salt or zwitterion thereof. In yet other embodiments, the treatment method further includes the step of administering a pharmaceutical composition containing a therapeutically effective amount of a steroidal anti-inflammatory agent to a target.

[0058]

[0060] In addition, the present invention provides a method for inhibiting VE-PTP in the eye of a subject requiring it, comprising the step of injecting one or more implants into the vitreous humor of the subject's eye. In another embodiment, the present invention provides a method for treating glaucoma in a subject requiring it, comprising the step of injecting one or more implants into the vitreous humor of the subject's eye. In yet another embodiment, the present invention provides a method for treating elevated IOP in a subject requiring it, comprising the step of injecting one or more implants into the vitreous humor of the subject's eye. In yet another embodiment, the present invention provides a method for reducing IOP in a subject requiring it, comprising the step of injecting one or more implants into the vitreous humor of the subject's eye. In some embodiments, the method further comprises the step of administering a VEGF inhibitor.

[0059]

[0061] In some embodiments, the present invention provides an insert for use in treating or preventing eye conditions in subjects where such treatment is required.

[0060]

[0062] In another embodiment, the present invention provides an implant for use in inhibiting angiogenesis in the eye in subjects requiring it.

[0061]

[0063] In yet another embodiment, the present invention provides an implant for use in inhibiting VEGFR and PDGFR in the eye of a target that requires it.

[0062]

[0064] In some embodiments, the present invention provides an implant for use in treating age-related macular degeneration in subjects requiring it.

[0063]

[0065] In some embodiments, the present invention provides an insert for use in treating retinal vein occlusion in the eye of a subject requiring such treatment.

[0064]

[0066] In some embodiments, the present invention provides an implant for use in treating diabetic retinopathy in the eye of a person requiring it.

[0065]

[0067] In some embodiments, the present invention provides an insert for use in inhibiting VE-PTP in the eye of a target requiring it.

[0066]

[0068] In some embodiments, the present invention provides an implant for use in treating glaucoma in the eye of a subject requiring it.

[0067]

[0069] In other embodiments, the present invention provides an insert for use in treating elevated IOP in the eye of a subject requiring it.

[0068]

[0070] In yet another embodiment, the present invention provides an insert for use in reducing IOP in the eye of a subject requiring it.

[0069]

[0071] In additional embodiments, the present invention provides an insert for use in treating uveitis in the eye of a subject requiring it.

[0070]

[0072] In a further embodiment, the present invention provides an insert for use in treating chronic non-infectious uveitis affecting the posterior segment of the eye in a subject requiring such treatment.

[0071]

[0073] In some embodiments, the insert is injected through a needle or cannula smaller than 25 gauge. In some embodiments, an incision is not required for injection. [Brief explanation of the drawing]

[0072] [Figure 1] This figure shows an exemplary eye drop delivery insert of the present invention. [Figure 2] This graph shows the average weight change of PVA films of different grades after 24 hours of immersion in PBS. [Figure 3] This diagram shows a scale indicating the relative film strength of the evaluated films. [Figure 4A] This figure shows the in vitro drug release profile, representing the cumulative drug release percentage from formulation A implant, a coated formulation cured at 140°C for 4 hours. [Figure 4B] This figure shows the in vitro drug release profile, representing the cumulative amount (μg) of drug released from the formulation A implant. [Figure 5] These are photographs of eroded Formulation A implants removed after immersion in a dissolving medium for 314 and 447 days. The photograph of the 447-day implant includes an intact implant for comparison. [Figure 6] This figure shows the in vitro drug release profile of an uncoated formulation A implant, which is identical to formulation A except for the absence of a coating. [Figure 7] These are photographs of eroded, uncoated Formulation A implants removed after immersion in a dissolving medium for 287 and 352 days, with the 352-day implant photograph including an intact implant for comparison. [Figure 8A] This figure shows the in vitro drug release profile, representing the cumulative drug release percentage from formulation B implants, which are coated formulations cured at 140°C for 30 minutes. [Figure 8B] This figure shows the in vitro drug release profile, illustrating the cumulative drug release amount (μg) from the formulation B implant. [Figure 9] These are photographs of eroded Formulation B implants removed after immersion in the dissolving medium for 59, 88, and 155 days. [Figure 10] This figure shows the in vitro drug release profile of formulation C, which is an uncured, coated formulation. [Figure 11]These are photographs of two samples of eroded formulation C implants, removed after immersion in a dissolving medium at 37°C for 98 days, followed by 113 days at room temperature. [Figure 12] This figure shows a comparison of the in vitro drug release profiles of formulations A, B, and C. [Figure 13A] This graph shows the average amount of residual drug in an implant over time for in vivo studies in which implants embedded in rabbit eyes were removed at various time points and assayed to determine the amount (μg) of borolanib remaining in the implant. One curve shows the levels for implants from eyes with three implants, and the other shows the levels for implants from eyes with six implants. [Figure 13B] This graph shows the cumulative percentage of drug released over time for implants removed from the same in vivo study. One curve shows the level for implants from eyes with three implants, and the other shows the level for implants from eyes with six implants. [Modes for carrying out the invention]

[0073] 1. Active pharmaceutical ingredients (APIs)

[0090] The insert of the present invention contains an active pharmaceutical ingredient (API). The API may be referred to as "drug" in this specification.

[0074]

[0091] In some embodiments, the API for the inserts and methods of the present invention is an API having a molecular weight of 1000 AMU or less and 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 approximately 0.1 μg / mL to 200 μg / mL, approximately 0.1 μg / mL to 150 μg / mL, approximately 0.1 μg / mL to 100 μg / mL, approximately 0.1 μg / mL to 75 μg / mL, approximately 0.1 μg / mL to 50 μg / mL, approximately 0.1 μg / mL to 20 μg / mL, approximately 0.1 μg / mL to 10 μg / mL, or approximately 0.5 μg / mL to 50 μg / mL.

[0075]

[0092] The eye implants of the present invention can be used to deliver various classes of APIs. Examples of these classes of APIs and specific APIs include:

[0076]

[0093] In some embodiments, the API is a kinase inhibitor such as a vascular endothelial growth factor (VEGF) inhibitor (sometimes referred to as anti-VEGF), a tyrosine kinase (TKI) inhibitor, 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 having one or more of these activities include artiratinib, levatinib, afatinib, alectinib, apatinib, ASP-3026, axitinib, bafetinib, baricitinib, binimetinib, bosutinib, brigatinib, cabozantinib, canertinib, sediranib, CEP-11981, CEP-37440, ceritinib, cobimetinib, and copa Nlisib, clenolanib, crizotinib, CYT387, dabrafenib, damnacanthal, dasatinib, dramapimod, entrectinib, erlotinib, everolimus, filgotinib, foretinib, fostamatinib, gefitinib, grandinin, ibrutinib, icotinib, idelalisib, imatinib, IPI-145, JSI-124, lapatinib, len Vatinib, Restaurtinib, Linifanib, Masitinib, Motesanib, Mublitinib, Neratinib, Nilotinib, Nintedanib, Pacritinib, Palbociclib, Pazopanib, Pegaptanib, Perifosine, Pexmetinib, PF-06463922, Ponatinib, PX-866, Quizartinib, Radotinib, Lazprotafib (AKB-9778), Regorafenib, Ru This includes xolitinib, selumetinib, semacanib, sirolimus, sorafenib, sorafenib tosylate, staurosporine, sunitinib, sunitinib malate, SU6656, temsirolimus, TG101348, tivozanib, toceranib, tofacitinib, trametinib, TSR-011, vandetanib, batalanib, vemurafenib, bororanib, and X-396.

[0077]

[0094] In some embodiments, the API may be a steroidal anti-inflammatory agent such as a steroid or corticosteroid, and non-limiting examples of steroidal anti-inflammatory agents include fluocinolone acetonide, hydrocortisone, hydrocortisone acetate, triamcinolone acetonide, methylprednisolone, dexamethasone, medrisone, methylprednisolone, prednisolone 21-phosphate, prednisolone acetate, fluorometholone, and betamethasone.

[0078]

[0095] In other embodiments, the API is a prostaglandin or a prostaglandin analog or agonist such as bimatoprost, latanoprost, latanoprostenbunod, tafluprost, or travoprost.

[0079]

[0096] In yet another embodiment, the API is an alpha-2 adrenergic receptor agonist such as brimonidine, brimonidine tartrate, or brimonidine pamoate.

[0080]

[0097] In some embodiments, the API is a beta-blocker such as timolol.

[0081]

[0098] In other embodiments, the API is a carbonic anhydrase inhibitor (CAI) such as acetazolamide, brinzolamide, dorzolamide, or metazolamide.

[0082]

[0099] In other embodiments, the API is a rho kinase inhibitor such as netalusdil.

[0083]

[0100] Nonsteroidal anti-inflammatory drugs (NSAIDs) should also be considered. NSAIDs include diclofenac, etodolac, fenoprofen, phloctafenin, flurbiprofen, ibuprofen, indoprofen, ketoprofen, ketorolac, lornoxicam, morazon, naproxen, perisoxal, pirprofen, pranoprofen, suprofen, suxibzon, tropesin, ximoprofen, zaltoprofen, ziroiton, and zomepirac. COX-2 inhibitors such as vardecoxib, rofecoxib, and celecoxib should also be considered.

[0084]

[0101] In some embodiments, the API is a neuroprotective agent such as nimodipine; an antibiotic such as tetracycline, chlortetracycline, bacitracin, neomycin, polymyxin, gramicidin, oxytetracycline, chloramphenicol, gentamicin, or erythromycin; or an antibacterial agent such as sulfonamide, sulfacetamide, sulfamethizol, sulfisoxazole, nitrofurazone, or sodium propionate.

[0085]

[0102] In another embodiment, the API is a complement inhibitor such as a C3 inhibitor, for example, APL-2 (pegcetacoplan), or a C5 inhibitor.

[0086]

[0103] Anesthetics and analgesics such as lidocaine and related compounds are also possible.

[0087]

[0104] In some embodiments, the insert includes more than one API.

[0088]

[0105] In addition, the present invention also considers the use of analogues, derivatives, pharmaceutically acceptable salts, esters, prodrugs, codrugs, and protected forms thereof of the API.

[0089]

[0106] The term "pharmaceutically acceptable salt" of a given compound refers to a salt that retains the biological efficacy and properties of the given compound and is free from any biological or other undesirable characteristics.

[0090]

[0107] Pharmaceutically acceptable salts include salts with inorganic or organic acids, and salts with inorganic or organic bases. Those skilled in the art will be aware of the various synthetic methods that can be used to prepare non-toxic, pharmaceutically acceptable salts.

[0091]

[0108] Salts can be derived from inorganic acids, including hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. Salts can also 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, and salicylic acid.

[0092]

[0109] In some embodiments, the salt is an acetonide salt.

[0093]

[0110] 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.

[0094]

[0111] In addition, pharmaceutically acceptable salts include organic salts such as choline, glucosamine, tris, meglumine, lysine, arginine, tributylamine, and benzathine salts.

[0095]

[0112] In some embodiments, the API is in amorphous, crystalline, polymorphous, hydrated, or solvated form.

[0096]

[0113] Unless otherwise specified, the doses described herein (e.g., 100 μg) refer to the weight of the pharmacologically active portion, not the weight of a given API salt or API ester. Therefore, for example, if an insert contains a pharmaceutically acceptable salt or ester of an API, such as razprotafib sodium, the weight must be adjusted to provide an amount of API salt equal to the amount of API described herein. For example, a reference herein to an insert containing 100 μg of razprotafib sodium means that the insert contains an amount of salt equal to 100 μg of razprotafib molecules. In another example, a drug release rate of 100 μg / day means that the insert releases 100 μg / day of the pharmacologically active portion (e.g., borolanib).

[0097]

[0114] In some embodiments of the present invention, the API is borolanib or a pharmaceutically acceptable salt thereof.

[0098]

[0115] Bororanib has the chemical name (S,Z)-N-(1-(dimethylcarbamoyl)pyrrolinidine-3-yl)-5-((5-fluoro-2-oxoindoline-3-ylidene)methyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide. Synonyms include the term "X-82". The molecular formula is C 23 H 26 It is FN5O3. The solubility of borolanib in water is less than 0.1 μg / mL. Borolanib has the following structure.

[0099] [ka]

[0100]

[0116] As used herein, “borolanib or a pharmaceutically acceptable salt thereof” includes amorphous and crystalline forms, polymorphs, hydrates, and solvates of borolanib or a pharmaceutically acceptable salt thereof.

[0101]

[0117] Bororanib is an orally active multi-kinase inhibitor that can inhibit the activation of vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR).

[0102]

[0118] Methods for manufacturing borolanib are described, for example, in U.S. Patent Nos. 7,683,057, 8,524,709, 8,039,470, and U.S. Publication No. 2019 / 0233403, each of which is incorporated by reference in whole.

[0103]

[0119] In some embodiments, the API is razprotafib (AKB-9778) or a pharmaceutically acceptable salt or zwitterion thereof, such as razprotafib sodium, razprotafibcholine, razprotafibglucosamine, razprotafibtris, razprotafibmeglumine, razprotafibridine, razprotafibarginine, razprotafibtributylamine, or razprotafibbenzathine. Razprotafib is a potent and selective inhibitor of the catalytic activity of VE-PTP (vascular endothelial protein tyrosine phosphatase). Razprotafib promotes TIE2 activation, enhances ANG1-induced TIE2 activation, and stimulates phosphorylation of signaling molecules in the TIE2 pathway, including AKT, eNOS, and ERK.

[0104]

[0120] Lazprotafib has the chemical name [4-[(2S)-2-[[(2S)-2-(methoxycarbonylamino)-3-phenylpropanoyl]amino]-2-(2-thiophen-2-yl-1,3-thiazole-4-yl)ethyl]phenyl]sulfamic acid. Its molecular formula is C 26 H 26 It is N4O6S3. The CAS registry number for razprotafib is 1008510-37-9. The chemical structure is:

[0105] [ka] That is the case.

[0106]

[0121] Methods for manufacturing laprotafinib are described, for example, in U.S. Patent No. 7,622,593, which is incorporated by reference in its entirety.

[0107]

[0122] In some embodiments of the present invention, the API is axitinib or a pharmaceutically acceptable salt or ester thereof.

[0108]

[0123] Axitinib has the chemical name N-methyl-2-[3-((E)-2-pyridin-2-yl-vinyl)-1H-indazole-6-ylsulfanyl]-benzamide. The molecular formula is C 22 H 18 N4OS and the molecular weight is 386.47 daltons. The chemical structure is

[0109]

Chemical formula

[0110] Axitinib has a pKa of 4.8. The solubility of axitinib in an aqueous medium over the range of pH 1.1 to pH 7.8 exceeds 0.2 μg / mL.

[0111] Methods for manufacturing axitinib are described, for example, in U.S. Patent Nos. 6,891,044 and 8,791,140, each of which is incorporated by reference in its entirety.

[0112]

[0124] Prior to formulating the insert, the API can be milled to produce a fine particle size. In some embodiments, the D 90 of the API used to manufacture the insert 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 D 90These are approximately 0.01 μm to 100 μm, approximately 0.01 μm to 80 μm, approximately 0.1 μm to 50 μm, approximately 0.1 μm to 20 μm, approximately 0.1 μm to 15 μm, approximately 0.1 μm to 12 μm, approximately 1 μm to 50 μm, approximately 1 μm to 30 μm, approximately 1 μm to 25 μm, approximately 1 μm to 20 μm, approximately 1 μm to 15 μm, approximately 1 μm to 12 μm, approximately 5 μm to 10 μm, approximately 7 μm, approximately 8 μm, approximately 9 μm, approximately 10 μm, approximately 11 μm, or approximately 12 μm.

[0113] 2. Eye drop delivery insert

[0125] An "ophthalmic drug delivery implant" is a device that can be implanted in the eye, contains a drug, and can release the drug within the eye after implantation. An "ophthalmic drug delivery implant" encompasses all implants described herein.

[0114]

[0126] The eye drop delivery implant comprises a core containing an API dispersed in a solid matrix. In some embodiments, the core is at least partially covered by a coating. The implant is biocompatible.

[0115]

[0127] In other embodiments, the insert consists only of a core. The core is not surrounded by a coating or any kind of barrier surrounding the core.

[0116]

[0128] In some embodiments, the insert includes both a core and a coating. The coating is a layer that partially or completely surrounds the core. The coating may be an outer layer that is pre-formed into a desired shape (for example, the desired shape may be a tube) before being placed around the core, or the coating may be formed by, for example, co-extrusion of the core and coating, spraying the coating onto the core, or dipping the core into the coating material once or multiple times (for example, 1 to 10 coatings). If the core is coated, the coating may completely surround the core or only partially surround it.

[0117]

[0129] The insert may be of various different shapes, such as a cylinder, rod, sphere, or disc. In some embodiments, the insert is cylindrical, and the coating covers the entire surface of the cylinder except for the 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, while the other is not. In some embodiments, one of the ends is covered by a drug-impermeable cap, such as a silicone cap. A rod is a solid geometric shape with parallel sides, the length of which is greater than the diameter or the longest side of the cross-sectional shape. The cross-sectional shape may be a polygon, such as a circle, ellipse, square, rectangle, triangle, or hexagon. Those skilled in the art will recognize that, due to the manufacturing process, the shape of the insert may not be precise; for example, the outside may not be smooth or perfectly uniform. For example, the sides of a cylinder or rod may not be perfectly straight or perfectly parallel. The cross-section of a cylinder may not be perfectly circular or elliptical. The cross-sections of other shapes may not precisely meet the definition of their shape. For example, a square cross-section may not have perfectly straight sides, and the angles of its corners may not be exactly 90 degrees. A sphere or pellet may not be perfectly spherical.

[0118] a. matrix

[0130] In some embodiments, the core is a solid matrix comprising a matrix polymer and an API, which may exist in solid form such as powder, particles, or granules dispersed throughout the matrix. The matrix components and API form a homogeneous mixture in which the API is dispersed. The matrix is ​​solid at room temperature and bio-erosive. The matrix controls the release rate of the API and therefore modulates the API release rate compared to an unformulated API. In some embodiments, the matrix slows the drug release rate, providing longer-term drug delivery and less frequent dosing.

[0119]

[0131] In some embodiments, the matrix also includes other pharmaceutically acceptable components. In other embodiments, the sole material used to form the matrix is ​​one or more matrix polymers.

[0120]

[0132] The polymers used to form the matrix ("matrix polymer") may include one or more of the following: polyvinyl alcohol (PVA), poly(caprolactone) (PCL), polyethylene glycol (PEG), poly(dl-lactide-co-glycolide) (PLGA), polyvinyl alcohol (PVA), poly(lactic acid) (PLA), poly(glycolic acid) (PGA), polyalkyl cyanoacrylate, or copolymers thereof.

[0121]

[0133] In certain embodiments, the matrix polymer includes PVA. In some embodiments, the only inactive pharmaceutical component in the matrix is ​​PVA.

[0122]

[0134] Various grades of PVA can be used. The degree of hydrolysis (DH) of PVA is approximately 70% to 99%. + It may be %, and the molecular weight (MW) may be approximately 6,000 to 200,000, that is, the matrix polymer has a molecular weight of approximately 6,000 to 200,000, and is approximately 70 mol% to approximately 99 + This is molar percentage of hydrolyzed PVA. For example, DH is approximately 80% to 90%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 88% to 90%, and 90% to 99%. + %, approximately 91%, approximately 92%, approximately 93%, approximately 94%, approximately 95%, approximately 96%, approximately 97%, approximately 98%, approximately 99 + %, or approximately 98 to 99 +It can also be a percentage, and MW is approximately 5000, 6000, 7000, 8000, 9000, 10,000, 15,000, 18,000, 20,000, 25,000, 30,000, 40,000, 50,000, 60,000, 70,000, 75,000, 78,000, 80,000, 85,000, and 90 It may be 1,000, approximately 100,000, approximately 108,000, approximately 110,000, approximately 120,000, approximately 125,000, approximately 130,000, approximately 133,000, approximately 140,000, approximately 146,000, approximately 150,000, approximately 160,000, approximately 170,000, approximately 180,000, approximately 186,000, approximately 190,000, or approximately 200,000. In some embodiments, MW may be approximately 5,000 to 10,000, approximately 6,000 to 10,000, approximately 9,000 to 10,000, approximately 10,000 to 25,000, approximately 25,000 to 50,000, approximately 30,000 to 70,000, approximately 60,000 to 80,000, approximately 70,000 to 80,000, approximately 75,000 to 80,000, approximately 75,000 to 100,000, approximately 89,000 to 98,000, approximately 85,000 to 124,000, or approximately 146,000 to 186,000. In a particular embodiment, PVA is hydrolyzed in the following ways: MW6,000, 80% hydrolyzed; MW9,000-10,000, 80% hydrolyzed; MW25,000, 88% hydrolyzed; MW25,000, 98% hydrolyzed; MW30,000-70,000, 87-90% hydrolyzed; MW78,000, 88% hydrolyzed; MW78,000, 98% hydrolyzed; MW78,000, 99+% hydrolyzed; MW89,000-98,000, 99+% hydrolyzed; MW85,000-124,000, 87-89% hydrolyzed; MW108,000, 99 + % hydrolysis, MW125,000; 88% hydrolysis, MW133,000; 99% hydrolysis; or MW146,000-186,000; 99+% hydrolysis.

[0123]

[0135] 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 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, where the slower-eroding PVA is paired with 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 6,000 MW, 80% DH in a 1:9 ratio to 125,000 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, where the faster-eroding PVA is paired with the slower-eroding PVA.

[0124]

[0136] Examples of PVA mixtures include a mixture of MW6,000, 80% hydrolyzed and MW78,000, 98% hydrolyzed; and a mixture of MW6,000, 80% hydrolyzed and MW78,000, 99% hydrolyzed. + Mixture of % hydrolysis; MW78,000, 98% hydrolysis and MW78,000, 99 + A mixture of % hydrolyzed compounds; and a mixture of MW6,000, 80% hydrolyzed compounds and MW125,000, 88% hydrolyzed compounds.

[0125]

[0137] The MW and DH should be selected to provide the desired drug release rate for a particular drug, the indications for which the ophthalmic delivery insert is used, the desired duration of drug release, and the desired erosion rate.

[0126]

[0138] The polymer solution used to form the matrix is ​​composed of approximately 1% w / w to 20% w / w, 1% w / w to 15% w / w, 2% w / w to 15% w / w, 2% w / w to 12% w / w, 2% w / w to 10% w / w, 3% w / w to 10% w / w, 3% w / w to 8% w / w, 3% w / w to 6% w / w, 2% w / w, 2.5% w / w, 3% w / w, and 3.5% w / w in a solvent such as water or ethanol. It may also contain polymers such as PVA in amounts of %w / w, approximately 4%w / w, approximately 4.5%w / w, approximately 5%w / w, approximately 5.5%w / w, approximately 6%w / w, approximately 6.5%w / w, approximately 7%w / w, approximately 7.5%w / w, approximately 8%w / w, approximately 8.5%w / w, approximately 9%w / w, approximately 9.5%w / w, approximately 10%w / w, approximately 10.5%w / w, approximately 11%w / w, approximately 11.5%w / w, approximately 12%w / w, approximately 13%w / w, approximately 14%w / w, or approximately 15%w / w.

[0127]

[0139] The polymer solution and API may be combined in API:polymer solution ratios 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.

[0128]

[0140] In some embodiments, the core comprises borolanib or a pharmaceutically acceptable salt thereof and PVA. In some embodiments, the core consists of borolanib or a pharmaceutically acceptable salt thereof and PVA.

[0129]

[0141] 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.

[0130]

[0142] In further embodiments, the PVA solution and the API are combined in an API:PVA solution ratio of approximately 1:1 w / w.

[0131]

[0143] In some embodiments, the PVA solution and API are combined in an API:PVA solution ratio of approximately 1:2 w / w.

[0132]

[0144] In some configurations, the core is approximately 0.1% w / w to 90% w / w, approximately 0.1% w / w to 80% w / w, approximately 0.1% w / w to 70% w / w, approximately 0.1% w / w to 60% w / w, approximately 0.1% w / w to 50% w / w, approximately 0.1% w / w to 40% w / w, approximately 0.1% w / w to 30% w / w, approximately 0.1% w / w to 25% w / w, approximately 0.1% w / w to 20% w / w, approximately 0.1% w / w to 15% w / w, approximately 0.1% w / w to 10% w / w, approximately 3% w / w to 90% w / w, approximately Contains inert (non-API) components such as matrix polymers in amounts of approximately 3% w / w to 75% w / w, approximately 4% w / w to 60% w / w, approximately 4% w / w to 50% w / w, approximately 4% w / w to 40% w / w, approximately 4% w / w to 25% w / w, approximately 1% w / w to 10% w / w, approximately 1% w / w to 9% w / w, approximately 1% w / w to 8% w / w, approximately 1% w / w to 7% w / w, approximately 1% w / w to 6% w / w, approximately 2% w / w to 8% w / w, approximately 2% w / w to 6% w / w, or approximately 3% w / w to 5% w / w. These weight percentages are based on the dry weight of the core (i.e., after any drying step during processing).

[0133]

[0145] In some configurations, the amount of matrix polymer in the core is approximately 0.1% to 90% w / w, approximately 0.1% w / w to 80% w / w, approximately 0.1% w / w to 70% w / w, approximately 0.1% w / w to 60% w / w, approximately 0.1% w / w to 50% w / w, approximately 0.1% w / w to 40% w / w, approximately 0.1% w / w to 30% w / w, approximately 0.1% w / w to 25% w / w, and approximately 0.1% w / w. ~20% w / w, 0.1% w / w~15% w / w, 0.1% w / w~10% w / w, 3% w / w~90% w / w, 3% w / w~75% w / w, 4% w / w~60% w / w, 4% w / w~50% w / w, 4% w / w~40% w / w, 4% w / w~25% w / w, 1% w / w~10% w / w, 1% w / w~9% w / w, 1% w / w~ 8% w / w, approximately 1% w / w to approximately 7% w / w, approximately 1% w / w to approximately 6% w / w, approximately 2% w / w to approximately 8% w / w, approximately 2% w / w to approximately 6% w / w, or approximately 3% w / w to approximately 5% w / w, or approximately 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% w / w, 7% These percentages are w / w, 7.5% w / w, 8% w / w, 8.5% w / w, 9% w / w, 9.5% w / w, 10% w / w, 10.5% w / w, 11% w / w, 11.5% w / w, 12% w / w, 15% w / w, 18% w / w, 20% w / w, 25% w / w, 30% w / w, 35% w / w, 40% w / w, 50% w / w, 55% w / w, 60% w / w, 65% w / w, or 70% w / w. These weight percentages are based on the dry weight of the core (i.e., after any drying step during processing).

[0134]

[0146] The term "the insert consists of a core containing a solid matrix and API" means that the entire insert is in the form of a solid matrix and API. The matrix may also contain additional components, but the insert has no shell, coating, cap, cover, or tube or other outer layer, and therefore, when immersed in a fluid environment such as the vitreous fluid of the eye or an in vitro drug release medium, the outside of the core is in direct contact with this fluid.

[0135] b. coating

[0147] In some embodiments of the present invention, the insert comprises or consists of (a) a core containing an API and a solid matrix, and (b) a coating. In other embodiments, the insert does not include a coating.

[0136]

[0148] In some embodiments, the coating is permeable to the movement of the API and acts as a diffusion membrane for the active pharmaceutical ingredient. The diffusion membrane can regulate the API release rate through the matrix. The diffusion membrane can operate, for example, by regulating the flow of fluid into the matrix and / or restricting the movement 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 the processing, packaging, and / or transport of the dose. In certain embodiments, the coating regulates the API release rate and increases the durability of the insert.

[0137]

[0149] The coating may completely enclose the core or partially enclose it. In some embodiments, the coating substantially covers the core, meaning that the coating covers at least 70% of the core's surface area. In some embodiments, the coating covers at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, about 70% to about 100%, about 70% to about 95%, about 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's surface area. In other embodiments, the coating encloses 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's 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 embodiments, certain areas of the core are left uncovered to form delivery ports. In some embodiments, one or more areas are left uncovered to form one or more delivery ports.

[0138]

[0150] The delivery port is transparent to the API.

[0139]

[0151] In some embodiments, the insert is rod-shaped, for example, cylindrical, with only the two ends of the rod / cylinder being uncoated.

[0140]

[0152] To provide an example of an embodiment of the eye drop delivery insert of the present invention, Figure 1 shows a longitudinal cross-sectional view of an eye drop delivery insert 100 according to one embodiment of the present invention. The insert 100 includes a solid matrix core 105. The insert 100 further includes a coating 110 that substantially surrounds the core 105. The insert 100 also features two delivery ports 115 located at opposite ends of the insert 100. In this particular embodiment, at least one of the delivery ports 115 includes a membrane permeable to an API contained in the core 105, allowing the API to be released from the delivery port(s) 115.

[0141]

[0153] In some embodiments, the coating is bio-erosive, like a matrix.

[0142]

[0154] The coating may contain polymer and / or non-polymer components. In some embodiments, the coating contains one or more polymers such as polyvinyl alcohol (PVA), poly(caprolactone) (PCL), polyethylene glycol (PEG), poly(dl-lactide-co-glycolide) (PLGA), poly(lactic acid) (PLA), poly(glycolic acid) (PGA), polyalkyl cyanoacrylate, or copolymers thereof.

[0143]

[0155] In embodiments where the core is coated, the coating may be formed from 1 to 10 films of polymer. For example, the core may be coated with 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 films. In some embodiments, each film contains the same polymer as the other films. In certain embodiments, each film consists of the same polymer as the other films. In other embodiments where the coating is formed from more than one film, at least two of the films contain different polymers.

[0144]

[0156] In certain embodiments, the coating contains PVA. In other embodiments, the coating consists of PVA. In some embodiments, the only inactive pharmaceutical component in the coating is PVA. In other embodiments, the matrix polymer contains PVA, and the coating contains PVA.

[0145]

[0157] Various grades of PVA can be used. The degree of hydrolysis (DH) of PVA is approximately 70% to 99%. + It may be %, and the molecular weight (MW) may be approximately 6,000 to 200,000, that is, the matrix polymer has a molecular weight of approximately 6,000 to 200,000 and is approximately 70 mol% to approximately 99% + This is molar percentage of hydrolyzed PVA. For example, DH is approximately 80% to 90%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 88% to 90%, and 90% to 99%. + %, approximately 91%, approximately 92%, approximately 93%, approximately 94%, approximately 95%, approximately 96%, approximately 97%, approximately 98%, approximately 99 + %, or approximately 98 to 99 +It can also be a percentage, and MW is approximately 5000, 6000, 7000, 8000, 9000, 10,000, 15,000, 18,000, 20,000, 25,000, 30,000, 40,000, 50,000, 60,000, 70,000, 75,000, 78,000, 80,000, 85,000, and 90 It may be 1,000, approximately 100,000, approximately 108,000, approximately 110,000, approximately 120,000, approximately 125,000, approximately 130,000, approximately 133,000, approximately 140,000, approximately 146,000, approximately 150,000, approximately 160,000, approximately 170,000, approximately 180,000, approximately 186,000, approximately 190,000, or approximately 200,000. In some embodiments, MW may be approximately 5,000 to 10,000, approximately 6,000 to 10,000, approximately 9,000 to 10,000, approximately 10,000 to 25,000, approximately 25,000 to 50,000, approximately 30,000 to 70,000, approximately 60,000 to 80,000, approximately 70,000 to 80,000, approximately 75,000 to 80,000, approximately 75,000 to 100,000, approximately 89,000 to 98,000, approximately 85,000 to 124,000, or approximately 146,000 to 186,000. In a particular embodiment, PVA is hydrolyzed in the following ways: MW6,000, 80% hydrolyzed; MW9,000-10,000, 80% hydrolyzed; MW25,000, 88% hydrolyzed; MW25,000, 98% hydrolyzed; MW30,000-70,000, 87-90% hydrolyzed; MW78,000, 88% hydrolyzed; MW78,000, 98% hydrolyzed; MW78,000, 99+% hydrolyzed; MW89,000-98,000, 99+% hydrolyzed; MW85,000-124,000, 87-89% hydrolyzed; MW108,000, 99 + % hydrolysis, MW125,000; 88% hydrolysis, MW133,000; 99% hydrolysis; or MW146,000-186,000; 99+% hydrolysis.

[0146]

[0158] In other embodiments, the PVA is a mixture of two, three, or four different grades of PVA. In some embodiments, the PVA is a mixture of two different grades of PVA. In some embodiments, the ratio of the two grades in the mixture is 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, with slower-eroding PVA versus 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 6,000 MW, 80% DH to 125,000 MW, 88% DH at 1:9. 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, where the faster-eroding PVA is more slowly-eroding than the faster-eroding PVA.

[0147]

[0159] Examples of PVA mixtures include a mixture of MW6,000, 80% hydrolyzed and MW78,000, 98% hydrolyzed; a mixture of MW6,000, 80% hydrolyzed and MW78,000, 88% hydrolyzed; and a mixture of MW6,000, 80% hydrolyzed and MW78,000, 99% hydrolyzed. + Mixture of % hydrolysis; MW78,000, 88% hydrolysis and MW78,000, 98% hydrolysis; MW78,000, 98% hydrolysis and MW78,000, 99 + A mixture of % hydrolyzed compounds; and a mixture of MW6,000, 80% hydrolyzed compounds and MW125,000, 88% hydrolyzed compounds.

[0148]

[0160] 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 yet other embodiments, both the core and the coating comprises a mixture of two different grades of PVA. If the coating comprises more than one film of PVA, one or more of the films may comprise a mixture of two different grades of PVA.

[0149]

[0161] In embodiments in which both the core and the coating contain PVA, the PVA of the core and the PVA of the coating may be the same or different grades of PVA. As used herein, the term “different grades of PVA” means that the PVA differs in molecular weight (MW), degree of hydrolysis (DH), or both MW and DH. In addition, as used herein, if a mixture of PVAs being compared is not a mixture of exactly the same PVA grades, then a mixture of PVA grades is “different grades of PVA,” for example, a mixture of 6,000, 80% hydrolyzed PVA and MW78,000, 98% hydrolyzed PVA is considered to be a different grade of PVA than a PVA composition containing only MW78,000, 98% hydrolyzed PVA, or a PVA composition containing a mixture of MW6,000, 80% hydrolyzed PVA and MW125,000, 88% hydrolyzed PVA.

[0150]

[0162] Therefore, the PVA of the core and the PVA of the coating 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 includes PVA and the insert includes a PVA-containing coating, where the MW of the PVA of the coating is the same as the MW of the PVA of the core, and the DH of the PVA of the coating is lower than the DH of the PVA of the core. In some embodiments, the MW and DH of the PVA of the coating are each lower than the MW and DH of the PVA of the core.

[0151]

[0163] In some embodiments, the coating is formed from more than one film. If the insert coating includes more than one film of PVA, PVA having the same MW and DH may be used in at least one of the core and film(s). In other embodiments, the core includes PVA in at least one film and PVA that differs in MW and / or DH. In some embodiments, the core includes PVA in at least one film and PVA that differs in both MW and DH. In other embodiments, the PVA in the core and the PVA in at least one film have the same MW but differ in DH. In some embodiments, the DH of the PVA in at least one film is lower than the DH of the PVA in the core. In other embodiments, the PVA in the core and the PVA in at least one film have the same DH but differ in MW. In some embodiments, the MW of the PVA in at least one film is lower than the MW of the PVA in the core.

[0152]

[0164] In some embodiments, the insert coating comprises a single film containing PVA. In other embodiments, the insert coating comprises one or more films containing PVA, where the PVA in each coating has the same MW and DH. In some embodiments, at least one film contains a different PVA in MW and / or DH than the PVA in at least one other film. In some embodiments, at least one film contains a different PVA in both MW and DH than the PVA in at least one other film. In some embodiments, the two films do not contain the same grade of PVA, i.e., the PVA in each film is different in MW and / or DH from each of the other films.

[0153]

[0165] In embodiments where the insert coating comprises one or more coatings containing PVA, the PVA in the outermost coating is more soluble than the PVA in any of the other coatings (in PBS). In some embodiments, the PVA in at least one of the coatings is more soluble than the PVA in the core.

[0154]

[0166] In a particular embodiment, the insert comprises (a) a solid matrix core containing PVA and API, and (b) a coating substantially surrounding the core, wherein the DH of the PVA in the coating is lower than the DH of the PVA in the core. In one embodiment of this insert, the insert comprises two coatings containing PVA. In another embodiment, the insert comprises three coatings containing PVA. In yet another embodiment, the insert comprises four coatings containing PVA. In yet another embodiment, the insert comprises five coatings containing PVA. In yet another embodiment, the insert comprises six coatings containing PVA.

[0155]

[0167] In embodiments having one or more coatings, the first coating applied to the core is the innermost coating, and the last coating applied is the outermost coating. In some embodiments of these inserts having one or more PVA coatings, the DH of the PVA in the innermost coating is higher than the DH of the PVA in the outermost coating. In other embodiments of these inserts having one or more PVA coatings, the MW of the PVA in the innermost coating is higher than the MW of the PVA in the outermost coating. In some embodiments, the DH of the PVA in the outermost coating is lower than the DH of the PVA in each of the other coatings. In other embodiments, the MW and DH of the PVA in the outermost coating are lower than the MW and DH of the PVA in any of the other coatings.

[0156]

[0168] In some embodiments, the inserts are (a) MW6,000, 80% hydrolyzed; MW9,000-10,000, 80% hydrolyzed; MW25,000, 88% hydrolyzed; MW25,000, 98% hydrolyzed; MW30,000-70,000, 87-90% hydrolyzed; MW78,000, 88% hydrolyzed; MW78,000, 98% hydrolyzed; MW78,000, 99+% hydrolyzed; MW89,000-98,000, 99+% hydrolyzed; MW85,000-124,000, 87-89% hydrolyzed; MW108,000, 99 +(b) A solid matrix core comprising (b) at least one coating comprising PVA substantially surrounding the core, wherein the PVA in the coating comprises PVA of MW6,000, 80% hydrolysis, MW133,000, 99% hydrolysis, MW146,000-186,000, 99+% hydrolysis, and mixtures thereof, and API, and (b) at least one coating comprising PVA substantially surrounding the core, wherein the PVA in the coating comprises PVA of MW6,000, 80% hydrolysis, MW9,000-1 0,000, 80% hydrolysis, MW25,000, 88% hydrolysis, MW25,000, 98% hydrolysis, MW30,000~70,000, 87~90% hydrolysis, MW78,000, 88% hydrolysis, MW78 ,000, 98% hydrolysis, MW78,000, 99+% hydrolysis, MW89,000~98,000, 99+% hydrolysis, MW85,000~124,000, 87~89% hydrolysis, MW108,000, 99 + The PVA is selected from the group consisting of % hydrolysis, MW125,000, 88% hydrolysis, MW133,000, 99% hydrolysis, MW146,000-186,000, 99+% hydrolysis, and mixtures thereof, wherein the PVA in the core and the PVA in at least one coating are of different grades. In another embodiment of this insert, the insert comprises at least two coatings of PVA, where the DH of the PVA in the outermost coating is lower than the DH of any of the PVA in each of the other coatings.

[0157]

[0169] The present invention provides the ability to match PVA grades used in the manufacture of ocular implants. The MW and DH grades of the core and coating PVA should be selected to provide the desired drug release rate for a particular drug, the indication in which the ocular implant is used, the desired duration of drug release, and the desired erosion rate. Different durations of drug release may be desired for different eye diseases or conditions. For example, a 12-month duration of drug release (as provided by Formulation A) may be desirable for the treatment of diabetic retinopathy, while a duration of less than one month may be desirable for implants to inhibit inflammation of the eye caused by injury or surgery.

[0158]

[0170] The polymer solution used to form the coating is composed of approximately 1% w / w to 20% w / w, 1% w / w to 15% w / w, 2% w / w to 15% w / w, 2% w / w to 12% w / w, 2% w / w to 10% w / w, 3% w / w to 10% w / w, 3% w / w to 8% w / w, 3% w / w to 6% w / w, 2% w / w, 2.5% w / w, 3% w / w, and 3.5% w / w in a solvent such as water or ethanol. It may also contain polymers such as PVA in amounts of %w / w, approximately 4%w / w, approximately 4.5%w / w, approximately 5%w / w, approximately 5.5%w / w, approximately 6%w / w, approximately 6.5%w / w, approximately 7%w / w, approximately 7.5%w / w, approximately 8%w / w, approximately 8.5%w / w, approximately 9%w / w, approximately 9.5%w / w, approximately 10%w / w, approximately 10.5%w / w, approximately 11%w / w, approximately 11.5%w / w, approximately 12%w / w, approximately 13%w / w, approximately 14%w / w, or approximately 15%w / w.

[0159]

[0171] With respect to an insert containing a PVA coating, the insert may be covered with 1 to 10 coatings of PVA solution, i.e., the insert may contain 1 to 10 PVA coatings. For example, the insert may contain 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 PVA coatings.

[0160]

[0172] In some configurations, the weight of the insert coating is approximately 0.1% w / w to 60% w / w of the insert, approximately 0.1% w / w to 40% w / w, approximately 0.1% w / w to 20% w / w, approximately 1% w / w to 40% w / w, approximately 1% w / w to 30% w / w, approximately 1% w / w to 20% w / w, and approximately 1% w / w to 10% w / w. These percentages are %w / w, approximately 5%w / w to 30%w / w, approximately 5%w / w to 25%w / w, approximately 5%w / w to 20%w / w, approximately 5%w / w to 15%w / w, approximately 10%w / w to 25%w / w, approximately 10%w / w to 20%w / w, approximately 10%w / w to 18%w / w, or approximately 12%w / w to 18%w / w. These weight percentages are based on the dry weight of the insert (i.e., after any drying step during processing).

[0161]

[0173] In some embodiments, the total amount of inert components in the insert is approximately 1% w / w to 70% w / w, approximately 1% w / w to 50% w / w, approximately 3% w / w to 90% w / w, approximately 3% w / w to 75% w / w, approximately 4% w / w to 60% w / w, approximately 4% w / w to 50% w / w, approximately 4% w / w to 40% w / w, approximately 4% w / w to 25% w / w, approximately 5% w / w These percentages are approximately 40% w / w, 5% w / w to 30% w / w, 5% w / w to 25% w / w, 5% w / w to 20% w / w, 5% w / w to 15% w / w, 10% w / w to 25% w / w, 10% w / w to 22% w / w, 15% w / w to 25% w / w, 15% w / w to 22% w / w, or 18% w / w to 22% w / w. These weight percentages are based on the dry weight of the insert (i.e., after any drying step during processing).

[0162]

[0174] In some configurations, the amount of PVA in the insert is approximately 1% w / w to 80% w / w, 1% w / w to 75% w / w, 3% w / w to 80% w / w, 3% w / w to 70% w / w, 4% w / w to 60% w / w, 4% w / w to 50% w / w, 4% w / w to 40% w / w, 4% w / w to 25% w / w, and 5% w / w to 4% These percentages are 0% w / w, approximately 5% w / w to 30% w / w, approximately 5% w / w to 25% w / w, approximately 5% w / w to 20% w / w, approximately 5% w / w to 15% w / w, approximately 10% w / w to 25% w / w, approximately 10% w / w to 22% w / w, approximately 15% w / w to 25% w / w, approximately 15% w / w to 22% w / w, or approximately 18% w / w to 22% w / w. These weight percentages are based on the dry weight of the insert (i.e., after any drying step during processing).

[0163]

[0175] In some embodiments, the present invention provides an insert having a very high drug content compared to the inert components in the insert, which is remarkable considering the insert's ability to provide drug release over a long period of time. In some embodiments, the amount of API in the insert is approximately 5% w / w to 98%, 10% w / w to 98%, 15% w / w to 98%, 20% w / w to 98%, 30% w / w to 98%, 40% w / w to 98%, 50% w / w to 98%, 60% w / w to 98% w / w, 65% w / w to 98% w / w, 70% w / w to 98% w / w, 75% w / w to 98% w / w, 65% w / w to 90% w / w, 70% w / w to 90% w / w, 75% w / w to 90% w / w, or 80% w / w to 90% w / w. These weight percentages are based on the dry weight of the insert (i.e., after any drying step during processing).

[0164]

[0176] In some embodiments, the only inert component in the insert is a polymer such as PVA.

[0165]

[0177] The thickness of the coating around the core may be, for example, approximately 20 μm to 400 μm, approximately 20 μm to 300 μm, approximately 20 μm to 200 μm, approximately 20 μm to 100 μm, approximately 5 μm to 75 μm, approximately 5 μm to 50 μm, or approximately 5 μm to 25 μm.

[0166] c. Shape and dimensions of the insert

[0178] In some embodiments, when the implant is prepared for implantation into the vitreous humor of the eye, the implant does not exceed about 15 mm in any direction, or preferably about 10 mm, and therefore the implant can be inserted through an incision of 15 mm or less.

[0167]

[0179] In some embodiments, the insert may be molded and sized for injection. In some embodiments, the insert is sized and molded to pass through a cannula or needle of 20 gauge or less. This means that the insert can be injected through any of the cannulas or needles having the gauges described without an abnormal amount of force. In this context, the phrase “less than” means having a smaller outer diameter. A smaller outer diameter corresponds to a larger gauge size number; for example, a 25 gauge needle has a smaller outer diameter than a 22 gauge needle.

[0168]

[0180] In some embodiments, the insert is sized and shaped to pass through a 20-27 gauge needle or cannula, a 21-27 gauge needle or cannula, a 22-27 gauge needle or cannula, a 23-27 gauge needle or cannula, a 24-27 gauge needle or cannula, a 25-27 gauge needle or cannula, or a 25.5-27 gauge needle or cannula.

[0169]

[0181] In other embodiments, the insert is sized and molded to pass through cannulas or needles of 20 gauge or less, 22 gauge or less, 23 gauge or less, 24 gauge or less, 25 gauge or less, 25.5 gauge or less, 26 gauge or less, or 26.5 gauge or less. Preferably, the insert is sized and molded to pass through cannulas or needles smaller than 25 gauge, smaller than 26 gauge, or smaller than 27 gauge. In some embodiments, the insert is sized and molded to pass through cannulas or needles of about 29 gauge to about 25.5 gauge, for example, about 28 gauge to about 25.5 gauge, or about 28 gauge to about 26 gauge. In some embodiments, the needle or cannula is about 22, 22s, 23, 24, or 25 gauge, but preferably about 25.5, 26, 26.5, 26s, 27, 27.5, 28, 28.5, 29, 29.5, 30, or 30.5 gauge.

[0170]

[0182] In some embodiments, the insert may be rod-shaped, cylindrical, or spherical, with a length of less than approximately 12 mm and a diameter of less than approximately 1 mm.

[0171]

[0183] In some embodiments, the insert may be rod-shaped or cylindrical, and its length and diameter shall not exceed 8 mm and 3 mm.

[0172]

[0184] In some embodiments, the insert has a length of approximately 1mm to 10mm, 2mm to 10mm, 1mm to 4mm, 4mm to 8mm, 6mm to 10mm, 8mm to 10mm, 1mm to 12mm, 2mm to 12mm, or 4mm to 12mm, approximately 1mm, approximately 1.5mm, approximately 2mm, approximately 2.5mm, approximately 3mm, approximately 3.5mm, approximately 4mm, approximately 4.5mm, approximately 5mm, approximately 5.5mm, approximately 6mm, approximately 6.5mm, approximately 7mm, approximately 7.5mm, approximately 8mm, approximately 8.5mm, approximately 9mm, approximately 9.5mm, approximately 10mm, approximately 10.5mm, approximately 11mm, approximately 11.5mm, approximately 12mm, approximately 12.5mm, approximately 13mm, approximately 13.5mm, approximately 14mm, approximately 14.5mm, or approximately 15mm.

[0173]

[0185] In some embodiments, the insert has a diameter of approximately 0.1 mm to 2 mm, approximately 0.1 mm to 1 mm, approximately 0.1 mm to 0.8 mm, approximately 0.1 mm to 0.6 mm, approximately 0.1 mm to 0.5 mm, approximately 0.3 mm to 0.5 mm, approximately 0.3 mm to 0.4 mm, approximately 0.2 mm to 0.4 mm, approximately 0.1 mm to 0.2 mm, or approximately 0.4 mm to 0.6 mm, approximately 0.57 mm, approximately 0.50 mm, approximately 0.41 mm, approximately 0.42 mm, approximately 0.37 mm, approximately 0.34 mm, approximately 0.31 mm, approximately 0.26 mm, or approximately 0.15 mm.

[0174] d. Manufacturing of inserts

[0186] The inserts can be manufactured by mixing the API with a matrix polymer. In some embodiments, the matrix polymer is a solution of the polymer in a solvent, e.g., water or ethanol. The API, the matrix polymer solution, and any other matrix components are mixed to form a paste suitable for extrusion through a dispensing tip. The paste can be extruded through an 18–25 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 may be 20, 21, 22, or 23. The extruded paste is referred to herein as an extruded product, an elongated matrix, or a rod. The rod may be about 4–5 inches (about 10–13 cm) in length. The extruded product is solid at room temperature. The extruded product may be coated with one or more additional layers. In some embodiments, the extruded product is dried at room temperature for at least 24 hours before coating.

[0175]

[0187] In the extrusion process, extrusion parameters such as fluid pressure, flow rate, and temperature of the extruded material can be controlled. A suitable extruder can be selected for its ability to deliver the co-extruded material with sufficient pressure and flow rate to form a product with a die head and outlet port or dispensing tip size that, when divided, can be injected through a needle or cannula as described herein.

[0176]

[0188] When a polymer solution is used and the extruded material is to be coated, the extruded API-polymer mixture is dried before coating. For example, the extruded material may be dried at room temperature for about 30 minutes to about 48 hours before coating.

[0177]

[0189] The extruded material may be coated with one or more layers, but in some embodiments, no coating is applied. Preferably, the coating is applied before dividing the material into the desired insert length. The coating may be applied by dipping the extruded material into a liquid coating material and allowing it to dry or harden. This process can be repeated to add additional coating layers. Alternatively, the coating may be sprayed onto the extruded material.

[0178]

[0190] In other embodiments, the coating / outer layer may be pre-formed, for example, into a tubular shape, and the API-polymer paste may be extruded into the tube.

[0179]

[0191] Depending on the polymer used in the matrix, the extruded rod may be cured. Curing may be carried out, for example, by heating in an oven, microwave heating, or chemical treatment.

[0180]

[0192] In some embodiments, the matrix rod is not cured or is cured by heating at a temperature below 80°C. In other embodiments, the matrix rod is cured at a temperature of about 80°C to about 160°C for about 15 minutes to about 4 hours. In some embodiments, the matrix rod is cured at about 120°C to about 160°C for about 15 minutes to about 4 hours. In yet another embodiment, the matrix rod is cured 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 for about 10 minutes to about 4 hours. In yet another embodiment, the matrix rod is cured at about 130°C to about 150°C for about 30 minutes to about 4 hours. For example, the curing time may be approximately 15 minutes, 30 minutes, 45 minutes, 60 minutes, 75 minutes, 90 minutes, 105 minutes, or 120 minutes, and the curing temperature may be approximately 120°C, 125°C, 130°C, 135°C, 140°C, 145°C, 150°C, 155°C, or 160°C. After curing, the rod may be cooled to room temperature before other manufacturing steps are performed. If the insert is to be coated, the coating may be applied before or after curing.

[0181]

[0193] The drug release rate was evaluated for both uncoated inserts and PVA-coated PVA matrix inserts. The inventors found that, generally, higher curing temperatures and longer curing periods resulted in slower drug release rates as well as slower erosion.

[0182]

[0194] Once all curing, cooling, and / or coating and drying steps are complete, the rod is divided into inserts of approximately 1 mm to 15 mm in length, for example, 1 mm to 10 mm or 2 mm to 6 mm. For example, the rod may be divided into inserts of approximately 1 mm, 1.5 mm, 2 mm, 2.5 mm, 3 mm, 3.5 mm, 4 mm, 4.5 mm, 5 mm, 5.5 mm, 6 mm, 6.5 mm, 7 mm, 7.5 mm, 8 mm, 8.5 mm, 9 mm, 9.5 mm, 10 mm, 10.5 mm, 11 mm, 11.5 mm, 12 mm, 12.5 mm, 13 mm, 13.5 mm, 14 mm, 14.5 mm, or 15 mm.

[0183]

[0195] The rod may be divided or otherwise cut into a series of shorter products by any suitable technique for cutting the rod, which may vary depending on whether the product is hardened, unhardened, or partially hardened. For example, the dividing station may be tweezers, shears, slicing blades, or any other technique. The technique applied may vary depending on the desired contour of each cut portion of the product. For example, if open ends are desired, shearing may be appropriate. However, if it is desired that each end be closed when the cutting is made, tweezers may be used.

[0184]

[0196] In some configurations, the extruded material has a composition of approximately 1% w / w to 15% w / w, approximately 1% w / w to 10% w / w, approximately 2% w / w to 10% w / w, approximately 2% w / w to 8% w / w, approximately 2% w / w to 6% w / w, approximately 3% w / w to 6% w / w, approximately 2% w / w, approximately 2.5% w / w, approximately 3% w / w, approximately 3.5% w / w, and approximately The material is immersion coated in a PVA solution in water having a PVA concentration of 4% w / w, approximately 4.5% w / w, approximately 5% w / w, approximately 5.5% w / w, approximately 6% w / w, approximately 6.5% w / w, approximately 7% w / w, approximately 7.5% w / w, approximately 8% w / w, approximately 8.5% w / w, approximately 9% w / w, approximately 9.5% w / w, or approximately 10% w / w.

[0185]

[0197] The coated extruded material can then be air-dried. The dipping coating process may be repeated 1 to 10 times, preferably 1 to 6 or 1 to 5 times, with air-drying between each coating. The coated extruded material can then be cured as described above. After cooling, the extruded material is then cut into inserts.

[0186] e. Insertion characteristics

[0198] Some eye diseases, including those mentioned above, may require lifelong treatment for patients. Currently available therapies require repeated treatment. However, repeated therapy with intraocular drug delivery devices is limited for devices containing non-biodegradable materials, as non-biodegradable residues of the device accumulate in the eye. Therefore, providing implantable drug delivery devices that are completely eroded before, during, or immediately after the time when a subsequent device needs to be implanted would be highly beneficial for patients.

[0187]

[0199] However, designing a drug delivery device that provides controlled release of therapeutic-level drugs over a considerable period, and that can be completely eroded, for example, within a few months or about a year, is extremely difficult. Many materials that are effective in controlling drug release over a considerable period are either not bioerosive or erode too slowly.

[0188]

[0200] Furthermore, providing a drug delivery device that is small enough to be implanted in a patient's eye with minimal discomfort, yet can contain a sufficient drug load to provide sustained drug delivery, significantly increases the aforementioned difficulties. The difficulty of handling and fabricating such devices without significant damage also adds to the challenges.

[0189]

[0201] The inventors have overcome these difficulties and provided a drug delivery device small enough to be implanted in the eye with minimal discomfort, which can provide sustained drug delivery for several months while also being completely eroded some time after the device's drug delivery period has ended. In addition, the inventors have found a way to provide devices with different drug delivery periods / durations and delivery rates. Furthermore, these devices provide an essentially linear release of the drug after an initial burst of drug delivery. Moreover, the implants have a very high drug content compared to the inactive components in the implant, which is remarkable considering the implant's ability to provide drug release over a long period.

[0190] i. Erosion of the insert:

[0202] In some embodiments, the insert can be completely eroded within 365 days. The ability of the insert to be eroded within a given period can be evaluated using the following erosion evaluation protocol. The sample insert is placed in a 10 mL glass vial containing 5 mL of phosphate-buffered saline (PBS), the vial is incubated at 37°C, and the PBS in the vial is changed once every 24 hours for each day of the period in question (e.g., 365 days, 200 days, 110 days). At the end of this period, the insert is removed from the vial, dried, then visually inspected and weighed. The weight loss compared to the original weight is calculated as follows:

[0191]

number

[0192]

[0203] For example, if an implant originally weighed 500 μg and weighed 200 μg after 200 days of incubation in PBS according to the erosion assessment protocol, the implant weighed 40% of its original weight and lost 60% of its weight. The implant underwent 60% erosion in 200 days. If less than 10% of the implant's original weight remains, the implant is considered to have been completely eroded. In some embodiments, the insert is measured using an erosion assessment protocol and exhibits 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, and within 220 days. It is possible for at least 70% erosion to occur, 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 440 days.

[0193] ii. Drug release rate:

[0204] The inventors found that curing temperature, curing time, and insert surface area all affect the discharge rate. Increasing the diameter while keeping the length constant increased the discharge rate. When the diameter was kept constant, increasing the length increased the discharge rate.

[0194]

[0205] In some embodiments, the inserts are approximately 0.01 μg / day to 100 μg / day, approximately 0.01 μg / day to 90 μg / day, approximately 0.01 μg / day to 80 μg / day, approximately 0.01 μg / day to 70 μg / day, 0.01 μg / day to 50 μg / day, 0.01 μg / day to 20 μg / day, 0.01 μg / day to 10 μg / day, approximately 0.1 μg / day to 60 μg / day, approximately 0.1 μg / day to 50 μg / day, and approximately 0.1 μg / day. The drug release rates are approximately 40 μg / day, 0.1 μg / day to 30 μg / day, 0.1 μg / day to 20 μg / day, 0.1 μg / day to 10 μg / day, 0.1 μg / day to 5 μg / day, 0.1 μg / day to 2 μg / day, 0.1 μg / day to 1 μg / day, 1 μg / day to 40 μg / day, 1 μg / day to 30 μg / day, 1 μg / day to 20 μg / day, or 1 μg / day to 10 μg / day. In some embodiments, this drug release rate is the release rate after steady-state release has been achieved. In some embodiments, this drug release rate is the release rate after drug release on 2, 3, 5, 8, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, 100, 105, or 110 days.

[0195]

[0206] In some embodiments, the insert has a release rate measured by an in vitro drug release method for at least 14 days, at least 30 days, at least 60 days, at least 90 days, at least 100 days, at least 120 days, at least 180 days, at least 200 days, at least 240 days, at least 270 days, at least 300 days, or at least 365 days.

[0196]

[0207] The following in vitro drug release method is used to evaluate the amount of drug released: The 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 37°C water bath. A sample of the medium is removed each day of the specified period, and the release medium is replaced with fresh PBS. The amount of API released can be quantitatively measured by HPLC as described in Example 2B.

[0197]

[0208] The duration (total time) during which the implant releases the API may be approximately 90 to 365 days, approximately 90 to 260 days, approximately 90 to 200 days, or at least approximately 8 weeks, at least approximately 10 weeks, at least approximately 12 weeks, at least approximately 18 weeks, at least approximately 22 weeks, at least approximately 28 weeks, at least approximately 30 weeks, at least approximately 36 weeks, at least approximately 40 weeks, at least approximately 44 weeks, or at least approximately 52 weeks. The above in vitro drug release test can be used to determine whether the implant releases the drug during this duration.

[0198]

[0209] In some embodiments, the inserts of the present invention provide an initial rapid release or burst of drug in vivo during the period before a steady-state rate is achieved. In preferred embodiments of the present invention, the initial period of rapid release is much shorter than the total duration of API release (e.g., less than 10%). In some embodiments, this initial period is, for example, 1-120 days, 20-120 days, 80-120 days, 1-20 days, 2-50 days, 3-40 days, 5-60 days, 1 day, 2 days, 3 days, 4 days, 5 days, 8 days, 10 days, 12 days, 15 days, 20 days, 25 days, 30 days, 40 days, 50 days, 60 days, 70 days, 80 days, 90 days, 100 days, 105 days, or 110 days. In in vitro studies performed in rabbit eyes, the inventors found a surprisingly high initial burst of drug release, meaning that the initial release of the API from the insert was earlier than expected before stabilizing to a steady state. This burst is C max This may be beneficial because it allows for rapid equilibrium to be achieved, and therefore, a therapeutically effective amount to be delivered locally and rapidly to the eye. After this burst, the API release rate stabilizes, delivering a therapeutically effective amount of API each day.

[0199]

[0210] In preferred embodiments, the insert of the present invention releases the API at a substantially constant rate (i.e., zero-order drug release kinetics, R) 2 (The ratio is 0.7 to 1), and the release occurs over a specified duration after implantation, for example, 14 days, 28 days, 42 days, 56 days, 168 days, 180 days, 224 days, 300 days, or 365 days.

[0200]

[0211] The duration of substantially constant API release from the implant 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, the duration 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.

[0201] 3. Treatment method a. Administration of eye drop delivery inserts

[0212] An "ophthalmic drug delivery insert" is an implantable device. The term "ophthalmic drug delivery insert" encompasses all inserts described herein.

[0202]

[0213] Eye drop delivery implants may be administered to prevent or treat eye conditions or diseases in subjects requiring them. In some embodiments, eye drop delivery implants are administered to treat anterior eye conditions. In other embodiments, eye drop delivery implants may be administered to treat posterior eye conditions. In some embodiments, eye drop delivery implants are administered to prevent anterior eye conditions. In other embodiments, eye drop delivery implants may be administered to prevent posterior eye conditions.

[0203]

[0214] An anterior eye condition is a disease, illness, or condition that affects or involves the anterior (i.e., anterior, also called the anterior part of the eye) region or structure of the eye, such as the periorbital muscles, eyelids, or fluids located anterior to the posterior wall of the lens capsule or the ciliary muscle. Therefore, anterior eye conditions may affect or involve the conjunctiva, cornea, anterior chamber, iris, posterior chamber (located between the iris and the lens), lens, lens capsule, and the blood vessels and nerves that angiogenesis or innervate the anterior eye region or area.

[0204]

[0215] The condition of the anterior eye may include, but is not limited to, diseases, illnesses, or conditions such as glaucoma.

[0205]

[0216] "Posterior eye conditions" primarily refer to diseases, illnesses, or conditions that affect or involve the posterior (i.e., posterior) eye region or structures, including the choroid or sclera (located posterior to the entire posterior wall of the lens capsule), the vitreous humor, the vitreous chamber, the retina, the optic nerve or optic disc, and the blood vessels and nerves that angiogenically or nervely innervate the posterior eye region or area.

[0206]

[0217] Conditions of the posterior eye include, but are not limited to, acute macular neuroretinopathy; Behçet's disease; geographic atrophy; choroidal neovascularization; diabetic uveitis; histoplasmosis; infections such as those caused by fungi, bacteria, or viruses; macular degeneration such as neovascular macular degeneration, acute macular degeneration, 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; eye trauma affecting the posterior eye site or position; eye tumors; retinal vein occlusion, central retinal vein occlusion, diabetic retinopathy (including proliferative diabetic retinopathy), and proliferative vitreous retina. This may include retinal artery occlusive diseases such as peritubular retinal retinopathy (PVR), hypertensive retinopathy, central retinal artery occlusion (CRAO), and branch retinal artery occlusion (BRAO); retinal disorders such as retinal detachment and uveitis; sympathetic ophthalmia; Vogt-Koyanagi-Harada (VKH) syndrome; uveal diffusion; posterior eye conditions caused or affected by laser treatment of the eye; or posterior eye conditions caused or affected by photodynamic therapy, photocoagulation, or radiation retinatherapy; epiretinal membrane disorders, branch retinal vein occlusion, anterior ischemic optic neuropathy, non-retinopathy, diabetic retinal dysfunction, and retinitis pigmentosa. Since the treatment goal is to prevent or reduce the incidence of vision loss resulting from damage to or loss of retinal cells or optic nerve cells (e.g., by neuroprotection), glaucoma can also be considered a posterior eye condition.

[0207]

[0218] Therefore, the present invention provides a method for preventing or treating various eye conditions by administering an eye drug delivery insert to the eye in need.

[0208]

[0219] The API in an implant administered for a specific eye condition or disease is selected based on the API's suitability for that eye condition. Therefore, for example, an implant administered to lower intraocular pressure will contain an API effective in lowering intraocular pressure.

[0209]

[0220] In certain embodiments, the implant is administered to prevent or treat age-related macular degeneration ("AMD"), such as dry AMD and wet AMD, in subjects requiring it. The implant may be administered to prevent the death of retinal pigment epithelial cells. The implant may be administered to inhibit angiogenesis. In some embodiments, the implant is administered to prevent or treat vision loss, such as vision loss associated with macular degeneration, in subjects. In addition, the implant may be administered to prevent or slow the progression of dry AMD to wet AMD. In some embodiments, the implant is administered to prevent or treat retinal vein occlusion, such as central retinal vein occlusion ("CRVO") or branch retinal vein occlusion ("BRVO"), in subjects requiring it. In other embodiments, the implant may be administered to prevent or treat non-ischemic or ischemic retinal vein occlusion. In yet another embodiment, the implant is administered to treat diabetic retinopathy in the eye of a subject requiring it. In some embodiments of these methods, the insert comprises a kinase inhibitor such as a VEGF inhibitor or a TKI inhibitor, a VE-PTP inhibitor, an Ang-1 inhibitor, an Ang-2 inhibitor, and / or a Tie-2 activator. In some embodiments, the insert comprises borolanib or a pharmaceutically acceptable salt thereof. In other embodiments, the insert comprises axitinib or a pharmaceutically acceptable salt thereof. In yet another embodiment, the insert comprises razprotafib or a pharmaceutically acceptable salt thereof or a zwitterion.

[0210]

[0221] In some embodiments, the implant is administered to inhibit VEGFR and / or PDGFR in the eye of the target person requiring it. In some embodiments, the implant administered to inhibit VEGFR and / or PDGFR contains bororanib or a pharmaceutically acceptable salt thereof. In other embodiments, the implant contains axitinib.

[0211]

[0222] In other embodiments, the insert is administered to activate Tie-2. In some embodiments of this method, the insert contains a Tie-2 activator. In further embodiments, the Tie-2 activator is razprotafib or a pharmaceutically acceptable salt or zwitterion thereof.

[0212]

[0223] The present invention also provides a method for treating glaucoma in a subject requiring the use of a drug delivery implant, comprising the step of administering a drug delivery implant. In some embodiments, the implant is administered in the eye of a subject requiring the use of the implant to treat elevated intraocular pressure (IOP). In other embodiments, the implant is administered in the eye of a subject requiring the use of the implant to reduce intraocular pressure. In further embodiments, the subject has elevated intraocular pressure. In another embodiment, the subject has high intraocular pressure. In yet another embodiment, the subject has glaucoma. The reduction in IOP can be assessed by determining the difference in the subject's IOP (in millimeters of mercury (mmHg)) at 60 days after implantation of the implant compared to the subject's IOP at baseline before treatment. In some embodiments of these methods, the implant contains a Tie-2 activator. In further embodiments, the Tie-2 activator is razprotafib or a pharmaceutically acceptable salt or zwitterion thereof. In other embodiments of these methods, the implant contains an alpha-2 adrenergic receptor. In further embodiments, the alpha-2 adrenergic receptor is brimonidine or a pharmaceutically acceptable salt thereof.

[0213]

[0224] In further embodiments, the implant is administered to treat uveitis. In even further embodiments, the implant is administered to treat chronic non-infectious uveitis affecting the posterior segment of the eye. In some embodiments, the implant is administered to treat postoperative inflammation in the eye. In some embodiments of these methods, the implant contains a steroidal anti-inflammatory agent.

[0214]

[0225] In some embodiments, the present invention provides a treatment method comprising the step of administering an ophthalmic drug delivery insert of the present invention containing a VEGF inhibitor. In some embodiments of these methods, the VEGF inhibitor is bororanib or a pharmaceutically acceptable salt thereof. The present invention also encompasses combination treatments such as treatment of a target with a VEGF inhibitor and a Tie-2 activator, or treatment of a target with a VEGF inhibitor and a steroidal anti-inflammatory agent.

[0215]

[0226] Accordingly, in some embodiments of the method of administering a VEGF inhibitor, the method further includes the step of administering a Tie-2 activator such as razprotafib or a pharmaceutically acceptable salt or zwitterion thereof. In some embodiments of this method, the Tie-2 activator is administered by the ophthalmic delivery insert of the present invention.

[0216]

[0227] In other embodiments of the method in which a VEGF inhibitor is administered, the method further includes the step of administering a steroidal anti-inflammatory agent such as fluocinolone acetonide. In some embodiments of this method, the steroidal anti-inflammatory agent is administered by the eye drug delivery insert of the present invention.

[0217]

[0228] In further embodiments, the present invention provides a method of treatment comprising the step of administering an ophthalmic delivery insert of the present invention comprising a Tie-2 activator. In other embodiments of this method, the method further comprises the step of administering a VEGF inhibitor. In some embodiments of this method, the Tie-2 activator is razprotafib or a pharmaceutically acceptable salt or zwitterion thereof. In additional embodiments of this method, the VEGF inhibitor is bororanib or a pharmaceutically acceptable salt thereof. In further embodiments, the VEGF inhibitor is aflibercept, bevacizumab, or ranibizumab.

[0218]

[0229] In the combined treatment of the present invention, that is, in a method in which more than one API is administered to the subject being treated, the different APIs to be administered may be administered in the same ophthalmic delivery insert or in separate inserts, or one API may be delivered in the ophthalmic delivery insert of the present invention and the other APIs(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 ophthalmic implant, eye drops, injectable solution, or injectable suspension. In addition, the different APIs to be administered may be administered simultaneously in the same injection, or in separate injections during the same procedure or at different times. If the different APIs are administered at different times, the dosage form or insert used to deliver the first API may still be releasing / delivering the first API when the dosage form or insert containing the other APIs is administered.

[0219]

[0230] Various embodiments of the present invention are generally provided for delivering therapeutically effective concentrations of APIs topically, for example, to the eye of a target. In certain embodiments, a method for treating an eye condition includes the step of placing an implant on the surface of the eye or inside the eye, for example, in the vitreous humor or aqueous humor of the eye. In certain embodiments, the implant of the present invention may be delivered to any site inside or over the eye, for example, the anterior or posterior part.

[0220]

[0231] The step of administering the implant may include inserting the implant into the target eye, for example, into the aqueous humor, or preferably into the vitreous fluid of the eye. The step of administering the implant may also include surgically implanting the implant into or over the eye, such as a scleral implant, subconjunctival implant, suprachoroidal implant, suprascleral implant, or intravitreal implant. The implant may be surgically implanted into the target eye, for example, within the vitreous humor, subretinal, or scleral. In some embodiments, the implant may be placed by injection through a needle or cannula. The implant gradually releases the API within the eye, thus avoiding painful and frequent administration of the drug.

[0221]

[0232] In certain embodiments, the implant is injected into the target eye, preferably without requiring an incision. In certain embodiments, the implant is injected into the vitreous humor of the eye. In preferred embodiments, the step of administering the implant includes intravitreous injection.

[0222]

[0233] In some embodiments, needles or cannulas having gauge sizes of 20 to 27 are used for injection. In other embodiments, needles or cannulas having gauge sizes of 25 to 27 are used. In preferred embodiments, needles smaller than 25 gauge, for example, needles having gauges of 25.5, 26, 26.5, or 27, are used for injection.

[0223]

[0234] In some embodiments of the administration method of the present invention, local and / or subconjunctival anesthesia may be administered to the injection site before the injection of the implant. In addition, a broad-spectrum bactericide may be administered into the inferior fornix. The implant may be placed below the optic disc and behind the occipital equator. The conjunctiva may be moved so that the needle entry sites of the conjunctiva and sclera do not align after the needle is withdrawn. The needle used to inject the implant can be inserted through the conjunctiva and sclera to the positive stop of the applicator, and the plunger is pushed down to deliver the implant behind the eye.

[0224] b. subject

[0235] The subject may be selected from rodents, rabbits, sheep, pigs, dogs, cats, horses, cattle, and primates. In a preferred embodiment, the subject is human. In some embodiments of the treatment methods provided herein, the subject has a condition to be treated and therefore requires the treatment described. In some embodiments of the prevention methods provided herein, the subject is at risk of a condition and therefore requires prevention of the condition described.

[0225] c. dose

[0236] In some embodiments, the total dose of API delivered is approximately 0.0001 μg / day to approximately 200 μg / day, approximately 0.0001 μg / day to approximately 150 μg / day, approximately 0.0001 μg / day to approximately 100 μg / day, approximately 0.0001 μg / day to approximately 80 μg / day, approximately 0.0001 μg / day to approximately 50 μg / day, approximately 0.0001 μg / day to approximately 30 μg / day, approximately 0.0001 μg / day to approximately 10 μg / day, approximately 0.0001 μg / day to approximately 5 μg / day, approximately 0.0001 μg / day to approximately 1 μg / day, approximately 0.001 μg / day to approximately 200 μg / day, and approximately 0.001 μg / day to approximately The recommended daily intake is 150 μg / day, approximately 0.001 μg / day to 100 μg / day, approximately 0.001 μg / day to 80 μg / day, approximately 0.001 μg / day to 60 μg / day, approximately 0.001 μg / day to 40 μg / day, approximately 0.001 μg / day to 30 μg / day, approximately 1 μg / day to 25 μg / day, approximately 0.001 μg / day to 20 μg / day, approximately 0.001 μg / day to 15 μg / day, approximately 0.001 μg / day to 10 μg / day, approximately 0.001 μg / day to 8 μg / day, approximately 0.0005 μg / day to 15 μg / day, or approximately 0.005 μg / day to 10 μg / day. In some embodiments, this is a dose delivered after a steady state has been achieved.

[0226]

[0237] In some embodiments, the API is bororanib, and the total dose of bororanib delivered is approximately 0.1 μg / day to approximately 100 μg / day, approximately 0.5 μg / day to approximately 80 μg / day, approximately 1 μg / day to approximately 50 μg / day, approximately 1 μg / day to approximately 40 μg / day, approximately 1 μg / day to approximately 30 μg / day, approximately 1 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 a steady state has been achieved.

[0227]

[0238] In some embodiments, the API is axitinib, and the total dose of axitinib delivered is approximately 0.0001 μg / day to approximately 100 μg / day, approximately 0.0001 μg / day to approximately 80 μg / day, approximately 0.0001 μg / day to approximately 50 μg / day, approximately 0.0001 μg / day to approximately 40 μg / day, approximately 0.0001 μg / day to approximately 30 μg / day The daily doses are approximately 0.001 μg / day to 25 μg / day, 0.0001 μg / day to 20 μg / day, 0.0001 μg / day to 15 μg / day, 0.001 μg / day to 10 μg / day, 0.001 μg / day to 8 μg / day, 0.001 μg / day to 15 μg / day, or 0.005 μg / day to 10 μg / day. In some embodiments, this is the dose delivered after a steady state has been achieved.

[0228]

[0239] This dosage can be achieved, for example, by administering 1 to 6 implants in one eye in a single dose, i.e., as a single treatment. Thus, a single treatment may require the administration of 1, 2, 3, 4, 5, or 6 implants per eye in a single dose. In some embodiments, the subject may receive treatment in only one eye or both eyes. If more than one implant is injected as a single treatment, the implants may be injected individually in separate injections, or several implants may be injected in a single injection. For example, 1, 2, or 3 implants may be injected in a single injection. If more than one implant is injected as a single treatment, the implants may be divided into several injections. For example, if 4 to 6 implants are injected as a single treatment, the implants may be divided into 2 or 3 injections of 2 to 3 implants / injection.

[0229]

[0240] Each insert may contain approximately 1 μg to 3000 μg, 10 μg to 2000 μg, 10 μg to 1000 μg, 100 μg to 500 μg, 10 μg to 800 μg, 50 μg to 600 μg, 200 μg to 2000 μg, 600 μg to 2000 μg, 800 μg to 2000 μg, 800 μg to 1500 μg, 100 μg to 500 μg, 100 μg to 300 μg, or 300 μg to 550 μg of borolanib. For example, each insert contains approximately 400 μg, 420 μg, 440 μg, 480 μg, 500 μg, 520 μg, 540 μg, 560 μg, 580 μg, 600 μg, 620 μg, 640 μg, 660 μg, 680 μg, 700 μg, 720 μg, 740 μg, 780 μg, and 800 μg. It may also contain approximately 820 μg, 840 μg, 860 μg, 880 μg, 900 μg, 920 μg, 940 μg, 960 μg, 980 μg, 1000 μg, 1020 μg, 1040 μg, 1045 μg, 1060 μg, 1080 μg, or 2000 μg of API, such as borolanib.

[0230]

[0241] The total amount of API in all insertions, for example, borolanib (total payload), may be approximately 200 μg to 6000 μg, 600 μg to 6000 μg, 800 μg to 6000 μg, 600 μg to 5040 μg, 600 μg to 4500 μg, 1000 μg to 5400 μg, 1000 μg to 3000 μg, or 2000 μg to 4000 μg. For example, the total amount of API in all inserts may be approximately 1400 μg, 1420 μg, 1500 μg, 1600 μg, 1800 μg, 1900 μg, 1980 μg, 2000 μg, 2040 μg, 2080 μg, 3000 μg, 3120 μg, 3180 μg, 3240 μg, 3400 μg, 3600 μg, 3800 μg, 4000 μg, 4140 μg, 4160 μg, 4180 μg, 4200 μg, 4400 μg, 4600 μg, 5000 μg, or 5040 μg.

[0231] 4. definition

[0242] When used herein and in the claims, the following words and phrases are generally intended to have the meanings set forth below, unless the context in which they are used indicates otherwise.

[0232]

[0243] The singular forms "a," "an," and "the" refer to multiple things unless the context clearly indicates otherwise. For example, "matrix polymer" refers to one or more matrix polymers.

[0233]

[0244] The terms “biodegradable,” “biodegradation,” “biodegradation,” and “biodegradation,” as used herein, refer to the gradual breakdown, dissolution, or degradation of an insert over a period of time in a biological system, for example, by one or more physical or chemical degradation processes, such as enzymatic action, hydrolysis, ion exchange, or dissolution by solubilization, emulsion formation, or micelle formation.

[0234]

[0245] The term "prevention," when used in relation to a condition, refers to the administration of a drug to reduce the frequency of symptoms of a medical condition or delay their onset in a subject compared to a subject that does not receive the drug. Thus, prevention of macular degeneration includes, for example, reducing the number of macular degeneration diagnoses in the treated population compared to an untreated control population, and / or delaying the onset of symptoms of macular degeneration in the treated population compared to an untreated control population. Prevention of dry macular degeneration includes, for example, reducing the number of detectable drusen in the population of subjects receiving prophylactic treatment compared to an untreated control population, and / or delaying the appearance of detectable drusen in the treated population compared to an untreated control population, by a statistically and / or clinically significant amount. Prevention of visual loss includes, for example, reducing the magnitude of visual loss experienced by a subject in the treated population compared to an untreated control population, or alternatively delaying visual loss.

[0235]

[0246] The term "treatment" means reducing, improving, or stabilizing an existing undesirable condition.

[0236]

[0247] The term "room temperature" means 22°C. "Solid at room temperature" means a solid at a temperature of 22°C.

[0237]

[0248] The term "about" when used with a number or range modifies that value or range by extending the boundary above and below the stated number. Generally, the term "about" is used herein to modify a number above and below a given value by a variation of 10 percent above or below (higher or lower), i.e., ±10%, unless different variations are indicated (e.g., ±30%, ±20%, ±5%, ±1%, ±0.5%, etc.).

[0238]

[0249] The terms "and / or" refer to and encompass each of the listed items individually, and to every possible combination of one or more of the listed items.

[0239]

[0250] The terms “comprising,” “consisting of,” and “essentially consisting of” have their usual permissible meanings under patent law. When used herein and in the claims, the terms “includes” or “including” are intended to be inclusive in the same manner as the term “comprising” is interpreted when used as a transitional term in a claim.

[0240]

[0251] The terms "optional" and "optionally" mean that the situation described thereafter may or may not occur, and therefore the description includes both cases in which the situation occurs and cases in which it does not occur.

[0241]

[0252] Where any feature or aspect of the present disclosure or claims is described in terms of a Markush group, the group described includes any individual member and subgroups of members of the Markush group.

[0242]

[0253] As will be understood by those skilled in the art, all terms such as “maximum,” “minimum,” “greater than,” and “less than” include the stated number and refer to a range that may later be divided into subranges. Finally, as will be understood by those skilled in the art, a range includes each individual member and includes the endpoint of the range. For example, a group having 1 to 3 members refers to a group having 1, 2, or 3 members. Similarly, a group having 1 to 5 members refers to a group having 1, 2, 3, 4, or 5 members, and so on.

[0243]

[0254] As used herein, the term “substantially all” means most of the total amount, for example, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% of the total amount.

[0244]

[0255] The term %w / w means the proportion of a particular substance within a mixture as measured by weight or mass. Thus, for example, for an insert where the core contains at least about 8% w / w of an inert component, the total weight of the inert component in the core is at least about 8% of the total weight of the core. For example, if the total core weight is 100 mg, the inert component in this core is at least 8 mg in weight.

[0245]

[0256] The term %w / v means the percentage of the weight of a component (such as a solute) in the total volume of a solution. A 2% w / v PVA solution means 2 grams of PVA in 100 mL of solution. A 2% w / w PVA solution means 2 grams of PVA for 100 mg of solution.

[0246]

[0257] All cited patents, published applications, scientific publications, and books are hereby incorporated by reference in their entirety.

[0247]

[0258] Although various aspects and embodiments have been disclosed herein, other aspects and embodiments will be apparent to those skilled in the art. Further embodiments are as follows: [Embodiment 1] An ophthalmic drug delivery implant comprising a matrix polymer and a solid matrix core containing borolanib or a pharmaceutically acceptable salt thereof, wherein the amount of borolanib or a pharmaceutically acceptable salt thereof in the implant is about 10% w / w to about 98% w / w, the drug release rate of the implant is about 0.01 μg / day to about 100 μg / day for at least 14 days, and the implant is capable of at least 20% erosion within 95 days. [Embodiment 2] The eye drop delivery insert according to Embodiment 1, wherein the amount of borolanib or a pharmaceutically acceptable salt thereof in the insert is about 60% w / w to about 98% w / w. [Embodiment 3] An eye drop delivery insert according to Embodiment 1, capable of at least 90% erosion within 440 days. [Embodiment 4] An eye drop delivery insert according to Embodiment 1, wherein the drug release rate is approximately 0.1 μg / day to approximately 20 μg / day. [Embodiment 5] An eye drop delivery insert according to Embodiment 1, wherein the drug release rate is approximately 0.1 μg / day to approximately 10 μg / day. [Embodiment 6] An eye drop delivery insert according to Embodiment 1, wherein the drug release rate is approximately 0.1 μg / day to approximately 2 μg / day. [Embodiment 7] The eye drop delivery insert according to Embodiment 1, wherein the core contains approximately 200 μg to approximately 2000 μg of borolanib or a pharmaceutically acceptable salt thereof. [Embodiment 8] An ophthalmic drug delivery insert according to Embodiment 1, wherein the duration of release of bororanib is at least about 90 days. [Embodiment 9] An eye drop delivery insert according to Embodiment 1, wherein the duration of release of borolanib is approximately 60 days to approximately 270 days. [Embodiment 10] The eye drop delivery insert according to Embodiment 1, wherein the core contains approximately 1% w / w to approximately 15% w / w of PVA. [Embodiment 11] An eye drop delivery insert according to Embodiment 10, cured at approximately 130°C to approximately 150°C for approximately 30 minutes to approximately 4 hours. [Embodiment 12] An eye drop delivery insert according to Embodiment 1, having approximately zero-order release velocity dynamics. [Embodiment 13] An eye drop delivery insert according to Embodiment 1, having a cylindrical shape. [Embodiment 14] An eye drop delivery insert according to Embodiment 1, which is sized and shaped to pass through a 20-27 gauge needle or cannula, and has a length of approximately 1 mm to approximately 10 mm. [Embodiment 15] An eye drop delivery insert according to Embodiment 1, which is sized and shaped to pass through a needle or cannula smaller than 25 gauge and has a length of approximately 1 mm to approximately 6 mm. [Embodiment 16] An eye drop delivery insert according to Embodiment 1, which is produced by dissolving PVA in an aqueous solution to form a PVA solution, mixing the PVA solution with borolanib or a pharmaceutically acceptable salt thereof to form a matrix mixture, extruding the mixture through a dispensing tip to form an elongated matrix, curing the elongated matrix at a temperature of about 140°C to about 160°C for about 30 minutes to about 2 hours, and dividing the elongated matrix. [Embodiment 17] An eye drop delivery insert according to Embodiment 1 or 2, further comprising a coating substantially surrounding the core. [Embodiment 18] An eye drop delivery insert according to Embodiment 17, further comprising a delivery port. [Embodiment 19] An eye drop delivery insert according to Embodiment 17, capable of at least 90% erosion within 440 days. [Embodiment 20] The eye drop delivery insert according to Embodiment 17, wherein the core contains approximately 200 μg to approximately 2000 μg of borolanib or a pharmaceutically acceptable salt thereof. [Embodiment 21] An eye drop delivery insert according to Embodiment 17, wherein the drug release rate is approximately 0.1 μg / day to approximately 20 μg / day. [Embodiment 22] An eye drop delivery insert according to Embodiment 17, wherein the drug release rate is approximately 0.1 μg / day to approximately 10 μg / day. [Embodiment 23] An eye drop delivery insert according to Embodiment 17, wherein the drug release rate is approximately 0.1 μg / day to approximately 2 μg / day. [Embodiment 24] An ophthalmic drug delivery insert according to Embodiment 17, wherein the duration of release of borolanib is at least about 90 days. [Embodiment 25] The eye drop delivery insert according to Embodiment 17, wherein the matrix polymer contains PVA. [Embodiment 26] The eye drop delivery insert according to Embodiment 17, wherein the coating comprises PVA. [Embodiment 27] The eye drop delivery insert according to Embodiment 25, wherein the coating comprises PVA. [Embodiment 28] The eye drop delivery insert according to Embodiment 27, wherein the coating comprises a different grade of PVA than the matrix polymer. [Embodiment 29] The eye drop delivery insert according to Embodiment 27, wherein the coating comprises one or more films containing PVA, and the DH of the PVA in at least one film is different from the DH of the PVA in the matrix polymer. [Embodiment 30] The eye drop delivery insert according to Embodiment 27, wherein the MW of the PVA in the coating is different from the MW of the PVA in the matrix polymer. [Embodiment 31] The eye drop delivery insert according to Embodiment 17 or 25, wherein the coating comprises at least two films containing PVA, and at least one of the films contains a different grade of PVA than at least one of the other films. [Embodiment 32] An eye drop delivery insert according to Embodiment 31, wherein the PVA in at least two coatings containing PVA differs in DH. [Embodiment 33] An eye drop delivery insert according to Embodiment 31, wherein the PVA in at least two coatings containing PVA differs in the middle wall. [Embodiment 34] An eye drop delivery insert according to any one of embodiments 17 to 33, cured at approximately 130°C to approximately 150°C for approximately 30 minutes to approximately 4 hours. [Embodiment 35] An eye drop delivery insert according to Embodiment 17, having approximately zero-order release velocity dynamics. [Embodiment 36] An eye drop delivery insert according to Embodiment 17, having a cylindrical shape. [Embodiment 37] An eye drop delivery insert according to Embodiment 17, which is sized and shaped to pass through a 20-27 gauge needle or cannula, and has a length of approximately 1 mm to approximately 10 mm. [Embodiment 38] An eye drop delivery insert according to Embodiment 17, which is sized and shaped to pass through a needle or cannula smaller than 25 gauge. [Embodiment 39] The eye drop delivery insert according to Embodiment 17, wherein the amount of coating is approximately 5% w / w to approximately 20% w / w of the insert. [Embodiment 40] An eye drop delivery insert according to Embodiment 17, which is manufactured by dissolving PVA in an aqueous solution to form a PVA solution, mixing the PVA solution with borolanib or a pharmaceutically acceptable salt thereof to form a matrix mixture, extruding the mixture through a dispensing tip to form an elongated matrix, coating the elongated matrix with the PVA solution, curing the elongated matrix at a temperature of about 140°C to about 160°C for about 30 minutes to about 2 hours, and dividing the elongated matrix. [Embodiment 41] A method for treating or preventing an eye condition in a subject requiring such treatment, comprising the step of injecting one or more eye drug delivery inserts described in any one of Embodiments 1 to 40 into the vitreous humor of the subject's eye. [Embodiment 42] A method for inhibiting angiogenesis in the eye of a subject requiring such inhibition, comprising the step of injecting one or more eye drug delivery inserts described in any one of Embodiments 1 to 40 into the vitreous humor of the eye of the subject. [Embodiment 43] A method for inhibiting VEGFR and PDGFR in an eye requiring such inhibition, comprising the step of injecting one or more eye drug delivery inserts described in any one of Embodiments 1 to 40 into the vitreous humor of the eye. [Embodiment 44] A method for treating macular degeneration in a subject requiring such treatment, comprising the step of injecting one or more eye drug delivery inserts described in any one of Embodiments 1 to 40 into the vitreous humor of the subject's eye. [Embodiment 45] The method according to any one of Embodiments 41 to 44, further comprising the step of administering a pharmaceutical composition containing a therapeutically effective amount of a Tie-2 activator to the subject. [Embodiment 46] The method according to Embodiment 45, wherein the pharmaceutical composition comprises the eye drop delivery insert described in Embodiment 94. [Embodiment 47] The method according to Embodiment 45, wherein the Tie-2 activator is razprotafib, or a pharmaceutically acceptable salt or zwitterion thereof. [Embodiment 48] The method according to any one of embodiments 41 to 44, further comprising the step of administering a pharmaceutical composition containing a therapeutically effective amount of a steroidal anti-inflammatory agent to the subject. [Embodiment 49] A method for producing an eye drop delivery insert, comprising the steps of: dissolving PVA in an aqueous solution to form a PVA solution; mixing the PVA solution with borolanib or a pharmaceutically acceptable salt thereof to form a matrix mixture; extruding the mixture through a dispensing tip to form an elongated matrix; curing the elongated matrix at a temperature of approximately 140°C to approximately 160°C for approximately 30 minutes to approximately 6 hours; and dividing the elongated matrix. [Embodiment 50] The method according to Embodiment 49, wherein the elongated matrix is ​​covered with a coating containing PVA before the elongated matrix is ​​cured. [Embodiment 51] A method for treating a condition selected from the group consisting of macular degeneration, retinal vein occlusion, and diabetic retinopathy in a subject requiring such treatment, comprising the step of directly administering bororanib at a dose of approximately 0.01 μg / day to approximately 100 μg / day to the eye of the subject. [Embodiment 52] The method according to Embodiment 51, wherein the bororanib or a pharmaceutically acceptable salt thereof is delivered by injecting one or more ophthalmic delivery inserts containing bororanib or a pharmaceutically acceptable salt thereof into the eye. [Embodiment 53] The method according to Embodiment 52, wherein the insert is administered by intravitreal injection. [Embodiment 54] The method according to embodiment 52, wherein 1 to 6 inserts are injected. [Embodiment 55] The method according to Embodiment 52, wherein each insert contains approximately 200 μg to approximately 2000 μg. [Embodiment 56] The method according to Embodiment 52, wherein the total amount of borolanib in all the inserts is approximately 600 μg to approximately 6000 μg. [Embodiment 57] The method according to Embodiment 52, wherein each of the one or more eye drop delivery inserts has a drug release rate of about 0.1 μg / day to about 100 μg / day for at least 60 days. [Embodiment 58] The method according to Embodiment 52, wherein one or more eye drop delivery inserts deliver a total average daily dose of bororanib of about 1 μg / day to about 50 μg / day for at least 30 days. [Embodiment 59] The method according to Embodiment 52, wherein one or more eye drop delivery inserts deliver a total average daily dose of bororanib of about 1 μg / day to about 20 μg / day for at least 30 days. [Embodiment 60] The method according to Embodiment 51, wherein the subject has geographic atrophy, is at risk of developing geographic atrophy, has visual impairment, is at risk of developing visual impairment, has ischemic retinal vein occlusion, or has non-ischemic retinal vein occlusion. [Embodiment 61] A method for treating macular degeneration in a subject requiring such treatment, comprising the step of implanting one or more ophthalmic drug delivery implants into the vitreous fluid of the subject's eye, wherein the number of implants administered during the administration procedure is 1 to 6 implants, and each of the one or more implants has a drug release rate of approximately 0.01 μg / day to approximately 100 μg / day of bororanib for at least 30 days. [Embodiment 62] A method for treating diabetic retinopathy in a subject requiring the treatment thereof, comprising the step of implanting one or more ophthalmic drug delivery implants into the vitreous fluid of the eye of the subject, wherein the number of implants administered during the administration procedure is 1 to 6 implants, and each of the one or more implants has a drug release rate of approximately 0.01 μg / day to approximately 100 μg / day of bororanib for at least 30 days. [Embodiment 63] The method according to Embodiment 44 or 61, wherein the subject has age-related macular degeneration. [Embodiment 64] An ophthalmic drug delivery implant comprising a solid matrix core containing API and at least two different grades of PVA, wherein the drug release rate of the implant is approximately 0.0001 μg / day to approximately 200 μg / day for at least 30 days, the implant is capable of at least 20% erosion within 95 days, and the implant is sized and molded to pass through a 20-27 gauge needle or cannula. [Embodiment 65] The eye drop delivery insert according to Embodiment 64, wherein the two different grades of PVA are a mixture selected from the list including: a mixture of MW78,000, 88% hydrolyzed and MW78,000, 98% hydrolyzed; a mixture of MW78,000, 88% hydrolyzed and MW78,000, 99+% hydrolyzed; a mixture of MW6,000, 80% hydrolyzed and MW78,000, 98% hydrolyzed; a mixture of MW6,000, 80% hydrolyzed and MW78,000, 99+% hydrolyzed; a mixture of MW78,000, 88% hydrolyzed and MW125,000, 88% hydrolyzed; and a mixture of MW6,000, 80% hydrolyzed and MW125,000, 88% hydrolyzed. [Embodiment 66] (a) an ophthalmic drug delivery implant comprising a solid matrix core comprising PVA and API, and (b) a coating comprising PVA substantially surrounding the core, comprising at least two different grades of PVA, capable of at least 20% erosion within 95 days, and sized and molded to pass through a 20-27 gauge needle or cannula. [Embodiment 67] The eye drop delivery insert according to Embodiment 66, wherein the coating comprises a different grade of PVA than the PVA of the core. [Embodiment 68] An eye drop delivery insert according to embodiment 66 or 67, wherein the DH of the PVA in the coating is different from the DH of the PVA in the core. [Embodiment 69] The eye drop delivery insert according to Embodiment 67, wherein the MW of the PVA in the coating is different from the MW of the PVA in the core. [Embodiment 70] The eye drop delivery insert according to Embodiment 66, wherein the coating comprises at least two films containing PVA, and at least one of the films contains a different grade of PVA than at least one of the other films. [Embodiment 71] An eye drop delivery insert according to Embodiment 70, wherein the PVA in at least two coatings differs in DH. [Embodiment 72] An eye drop delivery insert according to Embodiment 70 or 71, wherein the PVA in at least two coatings differs in MW. [Embodiment 73] An eye drop delivery insert according to any one of embodiments 64 to 72, wherein the amount of API in the insert is approximately 60% w / w to approximately 98% w / w. [Embodiment 74] An eye drop delivery insert according to any one of embodiments 64 to 72, wherein the core contains approximately 20% w / w to approximately 60% w / w of PVA. [Embodiment 75] An eye drop delivery insert according to any one of embodiments 66 to 73, wherein the amount of coating is about 5% w / w to about 20% w / w of the insert. [Embodiment 76] An eye drop delivery insert according to any one of embodiments 64 to 75, which is capable of at least 90% erosion within 440 days. [Embodiment 77] An eye drop delivery insert according to any one of embodiments 64 to 75, wherein the insert has approximately zero-order release velocity dynamics, and the drug release rate of the insert is approximately 0.0001 μg / day to approximately 200 μg / day for at least 30 days. [Embodiment 78] An eye drop delivery insert according to any one of embodiments 64 to 75, wherein the drug release rate is approximately 0.001 μg / day to approximately 100 μg / day over at least 30 days. [Embodiment 79] An eye drop delivery insert according to any one of embodiments 64 to 78, wherein the duration of release of the API is at least about 90 days. [Embodiment 80] An eye drop delivery insert according to any one of embodiments 64 to 79, wherein the duration of release of the API is approximately 60 days to approximately 270 days. [Embodiment 81] An eye drop delivery insert according to any one of embodiments 64 to 79, cured at approximately 130°C to approximately 150°C for approximately 30 minutes to approximately 4 hours. [Embodiment 82] An eye drop delivery insert according to any one of embodiments 64 to 81, having a cylindrical shape. [Embodiment 83] The eye drop delivery insert according to embodiment 82, wherein at least one end of the insert forms a delivery port. [Embodiment 84] An eye drop delivery insert according to Embodiment 83, having a length of approximately 1 mm to approximately 10 mm. [Embodiment 85] An eye drop delivery insert according to any one of embodiments 64 to 84, which is sized and shaped to pass through a needle or cannula smaller than 25 gauge. [Embodiment 86] (a) MW6,000, 80% hydrolysis, MW9,000~10,000, 80% hydrolysis, MW25,000, 88% hydrolysis, MW25,000, 98% hydrolysis, MW30,000~70,000, 87~90% hydrolysis, MW78,00 0, 88% hydrolysis, MW78,000, 98% hydrolysis, MW78,000, 99+% hydrolysis, MW89,000~98,000, 99+% hydrolysis, MW85,000~124,000, 87~89% hydrolysis, MW108,000, 99 + A solid matrix core containing an API, and PVA selected from the group consisting of % hydrolysis, MW125,000, 88% hydrolysis, MW133,000, 99% hydrolysis, MW146,000-186,000, 99+% hydrolysis, and mixtures thereof, and (b) At least one coating comprising PVA substantially surrounding the core, wherein the PVA in the coating is MW6,000, 80% hydrolyzed; MW9,000~10,000, 80% hydrolyzed; MW25,000, 88% hydrolyzed; MW25,000, 98% hydrolyzed; MW30,000~70,000, 87~90% hydrolyzed; MW78,000, 88% hydrolyzed; MW78,000, 98% hydrolyzed; MW78,000, 99+% hydrolyzed; MW89,000~98,000, 99+% hydrolyzed; MW85,000~124,000, 87~89% hydrolyzed; MW108,000, 99 + Coating selected from PVA selected from the group consisting of % hydrolysis, MW125,000, 88% hydrolysis, MW133,000, 99% hydrolysis, MW146,000-186,000, 99+% hydrolysis, and mixtures thereof. An eye drug delivery insert containing, An eye drop delivery insert wherein the PVA in the core and the PVA in at least one coating are of different grades. [Embodiment 87] The eye drop delivery insert according to Embodiment 86, wherein the insert comprises at least two coatings of PVA, the DH of the PVA in the outermost coating is lower than the DH of any of the PVA in the other coatings. [Embodiment 88] An eye drop delivery insert according to any one of embodiments 64 to 86, wherein the API has a molecular weight of 1000 AMU or less and is water-soluble at 25°C with a water content of less than approximately 200 μg / mL. [Embodiment 89] An ophthalmic drug delivery insert according to any one of embodiments 64 to 86, wherein the API is a VEGF inhibitor. [Embodiment 90] An ophthalmic drug delivery insert according to any one of embodiments 64 to 86, wherein the API is a TKI inhibitor. [Embodiment 91] An ophthalmic drug delivery insert according to any one of embodiments 64 to 86, wherein the API is borolanib or a pharmaceutically acceptable salt thereof. [Embodiment 92] An ophthalmic drug delivery insert according to any one of embodiments 64 to 86, wherein the API is axitinib or a pharmaceutically acceptable salt thereof. [Embodiment 93] An ophthalmic drug delivery insert according to any one of embodiments 64 to 86, wherein the API is a Tie-2 activator. [Embodiment 94] An ophthalmic drug delivery insert according to any one of embodiments 64 to 86, wherein the API is razprotafib or a pharmaceutically acceptable salt or zwitterion thereof. [Embodiment 95] A method for treating or preventing an eye condition in a subject requiring such treatment, comprising the step of injecting one or more eye drug delivery inserts described in any one of embodiments 64 to 92 into the vitreous humor of the subject's eye. [Embodiment 96] A method for inhibiting angiogenesis in the eye of a subject requiring such inhibition, comprising the step of injecting one or more eye drug delivery inserts described in any one of embodiments 64 to 92 into the vitreous humor of the eye of the subject. [Embodiment 97] A method for inhibiting VEGFR in an eye requiring such inhibition, comprising the step of injecting one or more eye drug delivery inserts described in any one of embodiments 64 to 92 into the vitreous humor of the eye. [Embodiment 98] A method for treating macular degeneration in a subject requiring such treatment, comprising the step of injecting one or more eye drug delivery inserts described in any one of embodiments 64 to 92 into the vitreous humor of the subject's eye. [Embodiment 99] A method for treating a condition selected from the group consisting of macular degeneration, retinal vein occlusion, and diabetic retinopathy in a subject requiring such treatment, comprising the step of administering one or more ophthalmic drug delivery inserts described in any one of embodiments 64 to 92. [Embodiment 100] A method for inhibiting angiogenesis in the eye of a subject requiring such inhibition, comprising the step of injecting one or more of the eye drug delivery inserts described in Embodiment 93 or 94 into the vitreous humor of the eye of the subject. [Embodiment 101] A method for treating macular degeneration in a subject requiring such treatment, comprising the step of injecting one or more of the eye drug delivery inserts described in Embodiment 93 or 94 into the vitreous humor of the subject's eye. [Embodiment 102] A method for treating a condition selected from the group consisting of macular degeneration, retinal vein occlusion, and diabetic retinopathy in a subject requiring such treatment, the method comprising the step of administering one or more of the ophthalmic drug delivery inserts described in Embodiment 93 or 94. [Embodiment 103] The method according to any one of Embodiments 95 to 100, further comprising the step of administering a pharmaceutical composition containing a therapeutically effective amount of a Tie-2 activator to the subject. [Embodiment 104] The method according to any one of Embodiments 95 to 100, further comprising the step of administering a pharmaceutical composition containing a therapeutically effective amount of a steroidal anti-inflammatory agent to the subject. [Embodiment 105] A method for inhibiting VE-PTP in an eye requiring such inhibition, comprising the step of injecting one or more eye drug delivery inserts described in Embodiment 93 or 94 into the vitreous humor of the eye. [Embodiment 106] A method for treating glaucoma in a subject requiring such treatment, comprising the step of injecting one or more of the eye drug delivery inserts described in Embodiment 93 or 94 into the vitreous humor of the subject's eye. [Embodiment 107] A method for treating elevated IOP in a subject requiring such treatment, comprising the step of injecting one or more eye drug delivery inserts described in Embodiment 93 or 94 into the vitreous humor of the subject's eye. [Embodiment 108] A method for reducing IOP in a subject requiring such reduction, comprising the step of injecting one or more eye drop delivery inserts described in Embodiment 93 or 94 into the vitreous humor of the subject's eye. [Embodiment 109] The method according to any one of embodiments 101-102 and 105-108, further comprising the step of administering a VEGF inhibitor. [Examples]

[0248] Example 1

[0259] The grades of PVA listed in the table below were made into films, and then the films were evaluated for their erosion rate and strength.

[0249]

[0260] To form the film, a 4.5% solution of PVA in water was poured into a tray and molded by air drying at room temperature. Once the film was dry, it was cut into 1x1 square samples. Six samples from each film were then cured at 100°C for 3 hours, 140°C for 30 minutes, or 140°C for 4 hours, as shown in the table below. After curing, the squares of the sample film were weighed and imaged. Each sample was then immersed in PBS at room temperature for 24 hours. The samples were then removed from the PBS, and four grades of PVA were oven-dried at 50°C for 2 hours, and two grades of PVA were air-dried on paper towels at room temperature, as shown in the table below. The samples were then weighed and imaged again.

[0250] [Table 1]

[0251]

[0261] The weight-average weight change after 24 hours of immersion in PBS was calculated and is shown graphically in Figure 2. The degree of PVA hydrolysis (DH) and molecular weight (MW) determine the solubility of the film. The 6000 / 80%, 25,000 / 88%, 125,000 / 88%, and 6000 / 80%-125,000 / 88% mixed PVA films each dissolved by the end of day 1 under all tested curing conditions. The 78,000 / 98% film remained the longest. The relative film strength of the tested films is shown in Figure 3.

[0252] Example 2A

[0262] The inserts were fabricated according to the parameters in the table below.

[0253] [Table 2]

[0254] [Table 3]

[0255]

[0263] Inserts were prepared by mixing borolanib with a 78,000 / 98% PVA solution in water at the w / w borolanib:PVA solution ratio specified in the table above. The mixture was then extruded from a 20, 21, or 23 gauge dispensing tip and dried at room temperature.

[0256]

[0264] For coated inserts, the extruded material was then dipped and coated in a 78,000 / 98% PVA solution and air-dried. The dipping coating process was repeated to achieve the number of coatings specified in the table above. The coating process involved dipping the extruded material in the PVA solution, with a 5-minute room temperature drying time between the first layers, followed by a drying time of at least 10 minutes before dipping to form the final layer / coating. The coated extruded material was then cured as described in the table. After cooling to ambient temperature, the extruded material was cut into inserts of 2 mm, 3.5 mm, 5 mm, 6 mm, or 8 mm in length.

[0257] Example 2B

[0265] 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 tubes were incubated in a 37°C water bath. The release medium sample was removed at 12–24 hour intervals, and the release medium was replaced with fresh PBS. The amount of borolanib 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 over time.

[0258] Example 2C

[0266] The insert samples were assayed for API content. The insert to be tested was cut into four pieces, and all four pieces were placed in labeled scintillation vials. 3.0 mL of methanol was pipetteed into the vials, and the vials were placed in a cabinet. This procedure was repeated for all samples. The sample vials were placed in an sonicator, an appropriate amount of water was added, and the samples were sonicated for 30 minutes. The sonicator was cooled between each sonication, and the sonication was repeated five more times. Additional sonication may be performed as needed to ensure complete dissolution of the API. HPLC was performed with the following parameters: Column: ZORBAX Eclipse XDB-C18; 4.6 × 150 mm; 5 microns; Mobile phase A: Water + 0.1% phosphoric acid; Mobile phase B: Acetonitrile + 0.1% phosphoric acid; Gradient method; Stop time 30 minutes; UV: 214 nm.

[0259] Example 2D

[0267] Erosion of the sample insert was evaluated. The sample insert was placed in a 10 mL glass vial containing 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 each day during the period. At the end of the period, the sample was removed from the vial, weighed, and photographed.

[0260]

[0268] The drug release rate curves for a coated 4.5% PVA formulation, referred to as Formulation A, cured at 140°C for 4 hours, are shown in Figures 4A (cumulative drug release %) and 4B (cumulative drug release (μg)). The drug release rate curve for an uncoated Formulation A implant is shown in Figure 6. Photographs of eroded Formulation A implants taken after immersion in the dissolving 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 the dissolving medium for 287 and 352 days are shown in Figure 7. An intact implant is included in the 352-day photograph for comparison.

[0261]

[0269] The drug release rate curves for a coated 4.5% PVA formulation, referred to as Formulation B, cured at 140°C for 30 minutes, are shown in Figure 8 (cumulative drug release %) and 8B (cumulative drug release (μg)). Photographs of eroded Formulation B implants taken after immersion in the dissolution medium for 59, 88, and 155 days are shown in Figure 9.

[0262]

[0270] The drug release rate curve for the uncured, coated 4.5% PVA formulation, referred to as Formulation C, is shown in Figure 10. Figure 11 shows two photographs, each showing different samples of eroded Formulation C implants, taken after immersion in a dissolution medium at 37°C for 98 days, followed by 113 days at room temperature.

[0263]

[0271] Figure 12 shows a comparison of the drug release curves for formulations A, B, and C.

[0264]

[0272] Formulation A releases the drug more slowly and is eroded more slowly than formulations B and C. Formulation C releases the drug more quickly and is eroded more rapidly than formulations A and B.

[0265] Example 3

[0273] Inserts containing more than one grade of PVA were fabricated according to the parameters in the table below.

[0266] [Table 4]

[0267]

[0274] The inserts were prepared by mixing borolanib with a solution of PVA in water at a 1:1 w / w borolanib:PVA solution ratio to form a paste. The mixture was then extruded from a 21-gauge dispenser tip to form rods approximately 4-5 inches long, which were dried at room temperature. The extruded rods were cured as described in the table above.

[0268]

[0275] The extruded pieces were immersion coated in a PVA solution in water and dried at room temperature. For inserts with more than one coating, the coating process involved immersing the extruded pieces in the PVA solution, with a 5-minute room-temperature drying time between the first layers, followed by a drying time of at least 10 minutes before immersion to form the final layer / coating.

[0269]

[0276] After the final coating, the coated rods were cured according to the conditions listed in the table above. After cooling to ambient temperature, the coated rods were cut into 8mm long inserts using a razor blade.

[0270]

[0277] API emissions were measured according to the method described in Example 2B.

[0271]

[0278] The API content was measured according to the method described in Example 2C.

[0272]

[0279] Implant erosion was evaluated according to the method described in Example 2D.

[0273]

[0280] An implant containing one or more grades of PVA is prepared according to the parameters in the table below.

[0274] [Table 5]

[0275] [Table 6]

[0276]

[0281] The inserts are prepared by mixing borolanib with a solution of PVA in water at a 1:1 w / w borolanib:PVA solution ratio to form a paste. The mixture is then extruded from a 21-gauge dispenser tip to form rods approximately 4-5 inches long and allowed to dry at room temperature. The extruded rods are cured as described in the table above.

[0277]

[0282] The extruded material is coated by immersion in a PVA solution in water and dried at room temperature. For inserts with more than one coating, the coating process involves immersing the extruded material in the PVA solution, with a 5-minute room-temperature drying time between the first layers, followed by a drying time of at least 10 minutes before immersion to form the final layer / coating.

[0278]

[0283] After the final coating, cure the coated rod according to the conditions listed in the table above. After cooling to ambient temperature, cut the coated rod into 8mm long inserts using a razor blade.

[0279]

[0284] API emission is measured according to the method described in Example 2B.

[0280]

[0285] The API content is measured according to the method described in Example 2C.

[0281]

[0286] Implant erosion is evaluated according to the method described in Example 2D.

[0282] Example 4

[0287] The insert is fabricated according to the parameters in the table below.

[0283] [Table 7]

[0284] [Table 8]

[0285] [Table 9]

[0286]

[0288] Mix the API with the PVA solution in water at the API:PVA solution ratio specified in the table to form a paste. Extrude the paste through a dispensing tip with a gauge of 20-23 to form rods approximately 4-5 inches long and allow to dry at room temperature. Cure the extruded rods before or after coating as described in the table above.

[0287]

[0289] The extruded material is coated by immersion in a PVA solution in water. The coating process involves immersing the extruded material in the PVA solution, with a 5-minute drying time between the first layers at room temperature, followed by a drying time of at least 10 minutes before immersion to form the final layer / coating. After the final coating, the coated rod is cured according to the table above or dried at room temperature for 24 hours.

[0288]

[0290] Using a razor blade, cut the coated rod into inserts 2mm, 3.5mm, 5mm, or 6mm in length.

[0289]

[0291] API emission is measured according to the method described in Example 2B.

[0290]

[0292] The API content is measured according to the method described in Example 2C.

[0291]

[0293] Implant erosion is evaluated according to the method described in Example 2D.

[0292] Example 5 - Pharmacokinetic Study

[0294] Intravitreal pharmacokinetic studies were conducted in male Dutch-belted rabbits. The purpose of this study was to characterize the plasma and ocular tissue pharmacokinetics of borolanib implants after bilateral intravitreal injection on day 1. Animals were evaluated up to 24 months after implantation of the intravitreal implants.

[0293]

[0295] The table below lists the assigned dose levels and treatments for each group.

[0294] [Table 10]

[0295]

[0296] After administering anesthesia, bororanib implants measuring 0.37 mm in diameter and 3.5 mm in length, designed to release the drug for at least 6 months, were injected intravitreously into the eye of each of 52 male Dutch-belted rabbits using a syringe. The low-dose group (1) received 3 implants per eye, totaling a dose of 630 μg per eye. The high-dose group (2) animals received 6 implants per eye, given in two separate injections (3 implants per injection), totaling a dose of 1,260 μg per eye.

[0296]

[0297] Prior to each scheduled slaughter point, one whole blood sample was collected from two target animals per group by puncturing the marginal aural vein. The samples were tested for levels of borolanib and its metabolites. Two animals per group were euthanized 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 fluid and ocular tissue were collected from both eyes for analysis of ocular tissue drug distribution, and the implants were recovered. Liver and kidney samples were also collected to assess tissue distribution.

[0297]

[0298] result At steady state, vitreous levels of borolanib were 56 ng / mL for the low dose of 630 μg and 97 ng / mL for the high dose of 1,260 μg (approximately dose-proportional). Retinal / choroidal levels were 49 ng / g and 89 ng / g. There was a burst period of drug release during the first 90 days, followed by a steady state. Steady state was reached by day 105. Maximum observed concentrations in the vitreous and retina / choroidal regions appeared to be approximately dose-proportional. No significant changes were observed in plasma levels after 99 days. Up to day 180, for the 630 μg dose, vitreous Cmax The concentration is 232 ng / mL, and T max The AUC is 336 hours. last The value was 315.5 μg·h / mL. Up to day 180, for a dose of 1260 μg, vitreous C max The value is 1697 ng / mL, and T max The AUC is 720 hours. last The value was 1583.2 μg·h / mL.

[0298]

[0299] Figure 13A shows the average amount of drug remaining in the insert over time for inserts that were removed at various time points and assayed to determine the amount of borolanib remaining in the insert. Figure 13B shows the cumulative percentage of drug released over time for the removed inserts.

[0299] Example 6 - Toxicological and pharmacokinetic studies

[0300] An 18-month intravitreal toxicity study of the implants was also conducted in 80 Dutch-belted rabbits (40 males and 40 females). Animals were evaluated at 6 and 18 months after implantation of the intravitreal implants. The objective was to characterize the ocular toxicity, plasma pharmacokinetics, and biodegradation of bororanib implants after bilateral intravitreal injection.

[0300]

[0301] The table below lists the group assignments and dose levels. For the toxicology group, animals were sacrificed at 6 months and 18 months. 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 for plasma pharmacokinetic analysis.

[0301] [Table 11]

[0302]

[0302] After administration of anesthesia, a 0.37 mm diameter x 3.5 mm length bororanib implant, designed to release the drug for at least 6 months, was injected intravitreously into each eye of each Dutch-belted rabbit using a syringe. Placebo group (1): Animals received two placebo implants by injection into each eye. Low-dose group (2): Animals received two implants into each eye. Medium-dose group (3): Animals received three implants into each eye, given in two separate injections. High-dose group (4): Animals received four implants into each eye, given in two separate injections (two implants / injection). Maximum-dose group (5): Animals received six implants into each eye, given in two separate injections (three implants / injection).

[0303]

[0303] Whole blood was collected by puncture of the marginal auricular vein at each scheduled time point. The samples were analyzed for clinicopathological and plasma pharmacokinetics. The animals were euthanized according to the above schedule. A complete gross autopsy was performed on all animals that were slaughtered or found dead during the study. Organs were weighed and tissues were collected. Eye tissue was collected solely for histopathological examination.

[0304]

[0304] Conclusion: Plasma pharmacokinetic and toxicological studies involved exposure to vitreous C over periods of 18 and 24 months, respectively. max It also provides evidence of safety regarding AUC. In addition, at the time tested, borolanib levels in the vitreous and retina / choroid were IC for VEGFR. 50 It remained significantly above that level.

[0305]

[0305] No adverse findings were attributed to bororanib, and no adverse findings were observed up to 6 implants. The no-observed-adverse-effect level (NOAEL) for implants was determined to be 6 implants / eye (1260 μg / eye).

[0306]

[0306] The most common observed event was yellowing of the lens, which appeared to be dose-related and attributable to the color of the API. There were no histopathological / microscopic findings associated with lens discoloration. The second most common observed event was localized, punctate, or linear lens opacity, which appeared to be mostly related to the number of injections and, to a lesser extent, the number of implants.

[0307]

[0307] Mild inflammation (<2+ aqueous humor or vitreous cells) was observed in all groups early on. All inflammatory cells gradually subsided and disappeared by 3 months. The highest observed inflammatory event was seen in the placebo group (two inserts without drug).

[0308]

[0308] There was no change in intraocular pressure (IOP) from baseline, but several transient changes were observed.

[0309]

[0309] Bororanib plasma levels were in the low pg / mL range.

[0310] Example 7 - Safety and effectiveness

[0310] The safety and efficacy of bororanib implants were evaluated in a porcine (miniature 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 laser-induced model of choroidal neovascularization (CNV) using bororanib implants in pigs.

[0311]

[0311] The experimental design is described in the table below.

[0312] [Table 12]

[0313]

[0312] On the day of laser irradiation (groups 1-4), animals were treated with an 810nm diode laser delivered through an indirect ophthalmoscope. Approximately six single laser spots were placed between the retinal veins. Both eyes were treated with laser according to the schedule in the table above.

[0314]

[0313] On the day of intravitreal injection, the animals were anesthetized and the eyes were prepared sterile. The conjunctiva was gently grasped with Colibri forceps, and the injection (25G syringe needle) was administered 2-3 mm posterior to the superior limbus (through the flattened portion), with the needle positioned just slightly posterior to avoid contact with the lens. The animals were returned to normal from the procedure. The pigs were given local antibiotic eye drops 4-6 hours later, followed by BID for a further 2 days with at least 6-hour intervals between doses. The animals were administered according to the schedule in the table above on day 0 immediately after laser CNV induction or 7 days before laser CNV induction. Animals in groups 5-6 did not undergo the laser CNV procedure and were implanted on day 0.

[0315]

[0314] During acclimatization and the study, the animals were evaluated for mortality, morbidity, and overall health, with special attention paid to the eyes. Body weight was measured before treatment and before necropsy, and animals in groups 5 and 6 were weighed monthly.

[0316]

[0315] A complete ophthalmological examination (OE) (modified Hackett and McDonald) using a slit-lamp biomicroscope and indirect ophthalmoscopic microscope was performed by a veterinary ophthalmologist at the time points indicated in the experimental design sheet to evaluate the surface morphology of the eye, anterior and posterior inflammation, cataract formation, and retinal changes. Mydriasis for the ophthalmological examination was performed using topical 1% tropicamide HCl.

[0317]

[0316] Fluorescein angiography was performed in both eyes of the anesthetized animals at the time points indicated in the experimental design sheet.

[0318]

[0317] Full-field electroretinography (ERG) was performed in both eyes of the animals at baseline and 3 months after medication (groups 5-6 only). On the day of ERG measurement, the animals were anesthetized after dark adaptation. ERG was elicited using a mini full-field light stimulator with short flashes of 0.33 Hz delivered at maximum intensity. Twenty responses were amplified, filtered, and averaged for each animal. The animals underwent standard ERG measurements as defined by the ISCEV criteria, including scotopic (0.01 candela), scotopic (3 candela), and photopic (25 candela) measurements.

[0319]

[0318] At the point indicated in the experimental design sheet, the animals were euthanized after final data collection. Histology was evaluated for the eyes from groups 5-6.

[0320]

[0319] result: Overall, dose-related efficacy was observed, and no clinically observed toxicity was noted. Fluorescein angiography analysis in all groups (1-4) showed a decrease in corrected total lesion fluorescence (CTLF) values ​​from day 7 to day 28, with aflibercept-treated animals showing the greatest decrease in CTLF values, followed by the higher dose group, and the remaining groups showing similar decreases in CTLF values. ERGb wave amplitude decreased from baseline to day 84 in both groups receiving ERG, which may be due to the difficulty of obtaining ERG.

[0321]

[0320] Eyes undergoing histological examination showed some degree of inflammation, which may have been more severe in animals administered high doses of implants. The implantation procedure may have been the cause of the increased inflammation observed in the high-dose group.

[0322]

[0321] Aflibercept and placebo implants worked as expected, aflibercept had normal efficacy in this model, and the placebo implant was well tolerated.

[0323]

[0322] Conclusion:

[0323] In PK studies, bororanib plasma levels were in the low pg / mL range. Dose-related efficacy was found, and no clinically observed toxicity. Therefore, the implant of the present invention was able to deliver safe and therapeutically effective steady-state levels of bororanib locally over a sustained period, while yielding only minimal systemic levels of bororanib. Furthermore, the implant is completely biocompatible.

Claims

1. An ophthalmic drug delivery implant comprising a matrix polymer and a solid matrix core containing borolanib or a pharmaceutically acceptable salt thereof, wherein the amount of borolanib or a pharmaceutically acceptable salt thereof in the implant is about 60% w / w to about 98% w / w, the drug release rate of the implant is about 0.01 μg / day to about 100 μg / day for at least 14 days, and the implant is capable of at least 15% erosion within 95 days.

2. The eye drop delivery insert according to claim 1, further comprising a coating substantially surrounding the core.

3. The eye drop delivery insert according to claim 2, wherein the coating comprises PVA.

4. The eye drop delivery insert according to claim 2, wherein the amount of the coating is about 5% w / w to about 20% w / w of the insert.

5. The eye drop delivery insert according to claim 1, wherein the insert is capable of at least 20% erosion within 95 days.

6. An eye drop delivery insert according to any one of claims 1 to 5, wherein the amount of bororanib or a pharmaceutically acceptable salt thereof in the insert is about 70% w / w to about 98% w / w.

7. An eye drop delivery insert according to any one of claims 1 to 5, which is capable of at least 90% erosion within 440 days.

8. An eye drug delivery insert according to any one of claims 1 to 5, wherein the drug release rate is approximately 0.1 μg / day to approximately 20 μg / day.

9. The ophthalmic drug delivery insert according to any one of claims 1 to 5, wherein the core contains about 200 μg to about 2000 μg of bororanib or a pharmaceutically acceptable salt thereof.

10. An ophthalmic drug delivery insert according to any one of claims 1 to 5, wherein the duration of release of bororanib is at least about 90 days.

11. An eye drug delivery insert according to any one of claims 1 to 5, wherein the duration of release of bororanib is approximately 60 days to approximately 270 days.

12. The eye drop delivery insert according to any one of claims 1 to 5, wherein the matrix polymer comprises PVA.

13. The eye drop delivery insert according to claim 12, wherein the core contains approximately 1% w / w to approximately 15% w / w of PVA.

14. The eye drop delivery insert according to any one of claims 2 to 4, wherein the matrix polymer comprises PVA, and the coating comprises PVA of a different grade than that of the matrix polymer.

15. An eye drop delivery insert according to any one of claims 1 to 5, having approximately zero-order release velocity dynamics.

16. An eye drop delivery insert according to any one of claims 1 to 5, having a cylindrical shape.

17. An eye drop delivery insert according to any one of claims 1 to 5, which is sized and shaped to pass through a 20 to 27 gauge needle or cannula, and has a length of about 1 mm to about 10 mm.

18. An eye drop delivery insert according to any one of claims 1 to 5, which is sized and shaped to pass through a needle or cannula smaller than 25 gauge.

19. An eye drug delivery insert for treating or preventing eye conditions in subjects who require it, The implant comprises a solid matrix core containing a matrix polymer and borolanib or a pharmaceutically acceptable salt thereof, wherein the amount of borolanib or a pharmaceutically acceptable salt thereof in the implant is about 60% w / w to about 98% w / w, the drug release rate of the implant is about 0.01 μg / day to about 100 μg / day for at least 14 days, and the implant is capable of at least 20% erosion within 95 days. The aforementioned implant is an eye drug delivery implant that is injected into the vitreous humor of the eye of the subject.

20. The eye drug delivery insert according to claim 19, wherein the aforementioned condition is selected from the group consisting of macular degeneration, retinal vein occlusion, and diabetic retinopathy.

21. An eye drug delivery insert for inhibiting angiogenesis in the eye of a subject requiring it, The implant comprises a solid matrix core containing a matrix polymer and borolanib or a pharmaceutically acceptable salt thereof, wherein the amount of borolanib or a pharmaceutically acceptable salt thereof in the implant is about 60% w / w to about 98% w / w, the drug release rate of the implant is about 0.01 μg / day to about 100 μg / day for at least 14 days, and the implant is capable of at least 20% erosion within 95 days. The aforementioned implant is an eye drug delivery implant that is injected into the vitreous humor of the eye of the subject.

22. An eye drug delivery insert for inhibiting VEGFR and PDGFR in the eye of a target requiring it, The implant comprises a solid matrix core containing a matrix polymer and borolanib or a pharmaceutically acceptable salt thereof, wherein the amount of borolanib or a pharmaceutically acceptable salt thereof in the implant is about 60% w / w to about 98% w / w, the drug release rate of the implant is about 0.01 μg / day to about 100 μg / day for at least 14 days, and the implant is capable of at least 20% erosion within 95 days. The aforementioned implant is an eye drug delivery implant that is injected into the vitreous humor of the eye of the subject.

23. An eye drug delivery insert according to any one of claims 19 to 22, further comprising a therapeutically effective amount of a steroidal anti-inflammatory agent.

24. A method for producing an eye drop delivery insert, comprising the steps of: dissolving PVA in an aqueous solution to form a PVA solution; mixing the PVA solution with borolanib or a pharmaceutically acceptable salt thereof to form a matrix mixture; extruding the mixture through a dispensing tip to form an elongated matrix; curing the elongated matrix at a temperature of approximately 140°C to approximately 160°C for approximately 30 minutes to approximately 6 hours; and dividing the elongated matrix.

25. The method according to claim 24, wherein the elongated matrix is ​​covered with a coating containing PVA before the elongated matrix is ​​cured.

26. An ophthalmic drug delivery insert comprising a matrix polymer and a solid matrix core containing borolanib or a pharmaceutically acceptable salt thereof, The amount of bororanib or a pharmaceutically acceptable salt thereof in the eye drop delivery insert is approximately 75% w / w to approximately 98% w / w. The matrix polymer is PVA, The drug release rate of the eye drop delivery insert is approximately 0.1 μg / day to approximately 20 μg / day, and the drug release rate is substantially constant for at least 14 days. An eye drop delivery insert having a drug release duration of at least approximately 12 weeks.

27. The eye drug delivery insert according to claim 26, wherein the amount of bororanib or a pharmaceutically acceptable salt thereof in the eye drug delivery insert is about 800 μg to about 2000 μg.

28. The eye drop delivery insert according to claim 26, which is sized and shaped to pass through a cannula or needle of 20 gauge or less.

29. The eye drop delivery insert according to claim 28, which is rod-shaped and has a length of approximately 6 mm to 10 mm.

30. The eye drop delivery insert according to claim 26, wherein the amount of the matrix polymer in the solid matrix core is about 4% w / w to about 25% w / w.

31. The eye drop delivery insert according to claim 30, wherein the amount of the matrix polymer in the solid matrix core is about 1% w / w to about 10% w / w.

32. The eye drop delivery insert according to claim 26, wherein the duration of drug release is at least about 18 weeks.

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