Bioerodible ocular drug delivery inserts 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

[0001] This application is a divisional application with application number 202180019407.7, application date September 13, 2021, and invention name “Bioerodegradable ocular drug delivery insert and treatment method”. Technical Field

[0002] The present invention relates to implantable bioerodible inserts for delivering active pharmaceutical agents to the eye. The present invention also relates to methods of using such inserts to treat patients in need of therapeutic relief, and methods of making such inserts. Background Art

[0003] Implantable drug delivery inserts have certain advantages over conventional drug delivery methods, such as oral administration or intravenous injection. For example, in conventional drug delivery methods, the concentration of the drug (active pharmaceutical ingredient) may vary greatly, reaching a maximum concentration (C max ), followed by a sharp decline. To maintain therapeutic levels, the drug may need to be administered at high doses, which may result in temporarily high, potentially toxic drug concentrations. As the drug is metabolized or cleared by the body, drug concentrations may decrease to safe and therapeutic levels. When drug levels drop to subtherapeutic levels, another dose must be administered, and the cycle is thus repeated. Therefore, a problem with conventional dosing is that for some types of drugs, the patient may be exposed to undesirably high levels of the drug for a long time from the repeated dosing cycles required for treatment. In addition, frequent dosing may be required, reducing patient compliance.

[0004] Implantable drug delivery inserts can reduce the need for frequent dosing and avoid high systemic concentrations of drugs. However, achieving a constant drug delivery rate (so-called zero-order release) over an acceptable duration is challenging.

[0005] In addition, many implantable drug delivery inserts 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, particularly for delivering drugs to anatomical locations with small volumes. Repeated therapeutic treatments via implantation can be limited due to undesirable accumulation of non-biodegradable portions of the implantable drug delivery device.

[0006] Furthermore, it is extremely challenging to provide an implantable drug delivery device that is small enough to be implanted in a patient with minimal discomfort, yet large enough to contain sufficient drug to provide sustained release of therapeutic levels of the drug.

[0007] In view of these factors, there remains a need in the art for improved designs and methods for preparing implantable drug delivery devices that can provide controlled and sustained release of a drug to a patient to achieve a desired local or systemic physiological or pharmacological effect.

[0008] One ophthalmic disease for which improved drug delivery is needed 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 by AMD. AMD causes progressive loss of central vision due to changes in the degeneration and new blood vessels of the macula (a special area in the center of the retina). In general, macular degeneration can lead to slow or sudden loss of vision.

[0009] There are two forms of AMD: dry AMD and wet AMD. Typically, AMD begins with dry AMD, which is characterized by the formation of drusen, yellow plaque-like deposits, in the macula between the retinal pigment epithelium and the underlying choroid. About 15% of dry AMD patients develop wet AMD, which is characterized by the formation of new blood vessels (choroidal neovascularization) and vision loss in the choroid.

[0010] Dry macular degeneration is more common than wet AMD, with about 90% of people with AMD being diagnosed with dry AMD. The dry form of AMD can be caused by aging and thinning of macular tissue, macular pigmentation, or a combination of these two processes. The wet form of the disease usually causes more severe vision loss. With wet AMD, new blood vessels grow beneath the retina and leak blood and fluid. This leakage causes retinal cells to die and forms blind spots in central vision.

[0011] While there is currently no cure for AMD, a number of treatments for wet AMD exist, but many of them are inconvenient or have significant adverse effects. Summary of the invention

[0012] According to various embodiments of the present invention, after extensive experiments, the inventors have invented a novel bioerodible drug delivery insert comprising an active pharmaceutical ingredient (API) and a bioerodible polymer. This insert is particularly useful for delivering an effective amount of API topically to the eye. In addition, the insert provides a sustained release of the API. In some aspects, the insert provides a sustained release for a period of time that is almost synchronized with the time required for the insert to completely erode in the eye.

[0013] These inserts can be administered intraocularly (e.g., intravitreally, suprachoroidally, and intracamerally) or subconjunctivally. For example, the insert can be placed by a needle or cannula, such as by intravitreal injection. Thus, in some aspects, the invention relates to a drug delivery insert that can deliver effective intraocular concentrations of an API while delivering low systemic concentrations of the API, for example, to reduce the risk of toxicity or other adverse side effects.

[0014] In some aspects, the invention relates to methods of treating or preventing ocular diseases by topical (eg, intraocular) administration of an API or a pharmaceutically acceptable salt thereof.

[0015] In one embodiment, the present invention is directed to an ocular drug delivery insert comprising a solid matrix core comprising a matrix polymer and vorolanib or a pharmaceutically acceptable salt thereof, wherein the amount of vorolanib or a pharmaceutically acceptable salt thereof in the insert is from about 10% w / w to about 98% w / w, wherein the drug release rate of the insert is from about 0.01 μg / day to about 100 μg / day for at least 14 days, and wherein the insert is capable of at least 20% erosion within 95 days. In another embodiment, the amount of vorolanib or a pharmaceutically acceptable salt thereof in the insert is from about 60% w / w to about 98% w / w.

[0016] In another embodiment, the insert further comprises a coating substantially surrounding the core. In some embodiments, the amount of coating is about 5% w / w to about 20% w / w of the insert. In further embodiments, the insert further comprises a delivery port.

[0017] In another embodiment, the insert is sized and shaped to pass through a 20G (gauge) to 27G needle or cannula, and the insert has a length of about 1 mm to about 10 mm. In another embodiment, the insert is sized and shaped to pass through a needle or cannula less than 25G. In another embodiment, the insert has a length of about 1 mm to about 6 mm.

[0018] 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.

[0019] In some aspects, the coating comprises a different grade of PVA than the matrix polymer. In some embodiments, the coating comprises more than one layer of coating comprising PVA, and the DH of the PVA in at least one layer of coating is different from the DH of the matrix polymer PVA. In some embodiments, the MW of the PVA in the coating is different from the MW of the matrix polymer PVA. In another embodiment, the coating comprises at least two layers of coating comprising PVA, and at least one of the layers of the coating comprises a different grade of PVA than at least one other layer of coating. In other aspects, the DH of the PVA in at least two layers of coating comprising PVA is different. In some embodiments of the insert, the MW of the PVA in at least two layers of coating comprising PVA is different.

[0020] In another embodiment, the insert is capable of at least 90% erosion within 440 days.

[0021] In one aspect of the insert, the drug release rate is about 0.1 μg / day to about 20 μg / day. In another aspect of the insert, the drug release rate is about 0.1 μg / day to about 10 μg / day. In another aspect of the insert, the drug release rate is about 0.1 μg / day to about 2 μg / day.

[0022] In one embodiment, the core comprises from about 200 μg to about 2000 μg of voronib or a pharmaceutically acceptable salt thereof.

[0023] In another embodiment, the duration of release of voronib is at least about 90 days. In another embodiment, the duration of release of voronib is about 60 days to about 270 days.

[0024] In one aspect of the invention, the core comprises from about 1% w / w to about 15% w / w PVA.

[0025] In another aspect of the invention, the intercalant is cured at about 130°C to about 150°C for about 30 minutes to about 4 hours.

[0026] In another aspect of the invention, the insert has approximately zero order release rate kinetics.

[0027] In one embodiment, the insert is cylindrical. In another embodiment, at least one end of the insert forms a delivery port.

[0028] In another embodiment, the insert is made by dissolving PVA in an aqueous solution to form a PVA solution, mixing the PVA solution with voronib or a pharmaceutically acceptable salt thereof to form a matrix mixture, extruding the mixture through a dispensing tip to form a matrix in an elongated shape, curing the matrix in the elongated shape at a temperature of about 140° C. to about 160° C. for about 30 minutes to about 2 hours, and dividing the matrix in the elongated shape.

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

[0030] The present invention also relates to a method of treating or preventing an ocular disease in a subject in need thereof, comprising injecting one or more inserts into the vitreous of the subject's eye.

[0031] In addition, the present invention relates to a method of treating macular degeneration in a subject in need thereof, comprising injecting one or more inserts into the vitreous of the subject's eye. In some embodiments, the macular degeneration treated is age-related macular degeneration.

[0032] In another aspect, the present invention provides a method for preparing an ocular drug delivery insert, comprising dissolving PVA in an aqueous solution to form a PVA solution, mixing the PVA solution with voronib or a pharmaceutically acceptable salt thereof to form a matrix mixture, extruding the mixture through a dispensing tip to form a matrix in an elongated shape, curing the matrix in the elongated shape at a temperature of about 140° C. to about 160° C. for about 30 minutes to about 6 hours, and dividing the matrix in the elongated shape.

[0033] In another aspect, the elongated shaped matrix is ​​covered with a coating comprising PVA prior to solidification of the matrix.

[0034] Furthermore, the present invention relates to a method of treating a disease in a subject in need thereof, wherein the disease is selected from the group consisting of macular degeneration, retinal vein occlusion, and diabetic retinopathy, the method comprising administering about 0.01 μg / day to about 100 μg / day of voronib directly to the eye of the subject.

[0035] In one embodiment, voronib or a pharmaceutically acceptable salt thereof is delivered by injecting one or more ocular drug delivery inserts containing voronib or a pharmaceutically acceptable salt thereof into the eye.

[0036] In another embodiment, the insert is administered by intravitreal injection.

[0037] In some embodiments, the insert is injected through a needle or cannula of less than 25G. In some embodiments, the injection does not require an incision.

[0038] In some aspects, 1-6 insertions are injected.

[0039] In some aspects, each insert contains about 200 μg to about 2000 μg.

[0040] In some aspects, the total amount of voronib in all injected inserts is from about 600 μg to about 6000 μg.

[0041] In some embodiments, each of the one or more ocular drug delivery inserts has a drug release rate of about 0.1 μg / day to about 100 μg / day for at least 60 days.

[0042] In some embodiments, one or more ocular drug delivery inserts deliver a total average daily dose of voronib of about 1 μg / day to about 50 μg / day for at least 30 days.

[0043] In other embodiments, one or more ocular drug delivery inserts deliver a total average daily dose of voronib from about 1 μg / day to about 20 μg / day for at least 30 days.

[0044] The present invention also provides an ocular drug delivery insert comprised of a solid matrix core comprising an API and at least two different grades of PVA, wherein the insert has a drug release rate of from about 0.0001 μg / day to about 200 μg / day for at least 30 days, wherein the insert is capable of at least 20% erosion within 95 days, and wherein the insert is sized and shaped to pass through a 20G to 27G needle or cannula. In some embodiments of the insert, the two different grades of PVA are a mixture selected from the following list, including: a mixture of MW 78000, 88% hydrolyzed and MW 78000, 98% hydrolyzed; a mixture of MW78000, 88% hydrolyzed and MW 78000, 99+% hydrolyzed; a mixture of MW 6000, 80% hydrolyzed and MW 78000, 98% hydrolyzed; a mixture of MW 6000, 80% hydrolyzed and MW 78000, 99+% hydrolyzed; a mixture of MW 78000, 88% hydrolyzed and MW125000, 88% hydrolyzed; and a mixture of MW 6000, 80% hydrolyzed and MW 125000, 88% hydrolyzed.

[0045] In addition, the present invention provides an ocular drug delivery insert comprising (a) a solid matrix core comprising PVA and an API, and (b) a coating comprising PVA substantially surrounding the core; wherein the insert comprises at least two different grades of PVA, wherein the insert is capable of at least 20% erosion within 95 days, and wherein the size and shape of the insert is suitable for passage through a 20G to 27G needle or cannula.

[0046] In some embodiments of the insert, the coating comprises a different grade of PVA than the core PVA. In some embodiments, the DH of the PVA in the coating is different from the DH of the core PVA. In other embodiments, the MW of the PVA in the coating is different from the MW of the core PVA. In other embodiments, the coating comprises at least two layers of coatings comprising PVA, and at least one layer of coating comprises a different grade of PVA than at least one other layer of coating. In further embodiments, the DH of the PVA in at least two layers of coating is different. In some embodiments, the MW of the PVA in at least two layers of coating is different.

[0047] In other aspects of the insert, the amount of API in the insert is about 60% w / w to about 98% w / w. In other aspects, the core comprises about 20% w / w to about 60% w / w PVA. In further embodiments, the amount of coating is about 5% w / w to about 20% w / w of the insert. In other embodiments, the insert is capable of at least 90% erosion within 440 days.

[0048] In some embodiments, the insert has approximately zero-order release rate kinetics, and the drug release rate of the insert is about 0.0001 μg / day to about 200 μg / day for at least 30 days. In other embodiments, the drug release rate is about 0.001 μg / day to about 100 μg / day for at least 30 days. In other embodiments, the release duration of the API is at least about 90 days. In other embodiments, the release duration of the API is about 60 days to about 270 days.

[0049] In some aspects of the intercalant, the intercalant is cured at about 130°C to about 150°C for about 30 minutes to about 4 hours.

[0050] In other aspects, the insert is cylindrical. In another embodiment, at least one end of the insert forms a delivery port. In another embodiment, the insert has a length of about 1 mm to about 10 mm, or a size and shape suitable for passing through a needle or cannula of less than 25G.

[0051] The present invention also provides an ocular drug delivery insert, comprising:

[0052] (a) a solid matrix core comprising PVA and an API, wherein the PVA is selected from the group consisting of: MW 6000, 80% hydrolyzed, MW 9000-10000, 80% hydrolyzed, MW 25000, 88% hydrolyzed, MW 25000, 98% hydrolyzed, MW 30000-70000, 87-90% hydrolyzed, MW 78000, 88% hydrolyzed, MW 78000, 98% hydrolyzed, MW 78000, 99+% hydrolyzed, MW 89000-98000, 99+% hydrolyzed, MW 85000-124000, 87-89% hydrolyzed, MW 108000, 99 + % hydrolyzed, MW 125,000, 88% hydrolyzed, MW 133,000, 99% hydrolyzed, MW 146,000-186,000, 99+% hydrolyzed, and mixtures thereof; and

[0053] (b) at least one coating comprising PVA substantially surrounding the core, wherein the PVA in the coating is selected from the group consisting of: MW 6000, 80% hydrolyzed, MW 9000-10000, 80% hydrolyzed, MW 25000, 88% hydrolyzed, MW 25000, 98% hydrolyzed, MW 30000-70000, 87-90% hydrolyzed, MW 78000, 88% hydrolyzed, MW 78000, 98% hydrolyzed, MW 78000, 99+% hydrolyzed, MW 89000-98000, 99+% hydrolyzed, MW 85000-124000, 87-89% hydrolyzed, MW 108000-99 + % hydrolyzed, MW 125000, 88% hydrolyzed, MW 133000, 99% hydrolyzed, MW 146000-186000, 99+% hydrolyzed, and mixtures thereof;

[0054] The PVA in the core and the PVA in the at least one coating are different grades of PVA.

[0055] In some embodiments, the intercalant includes at least 2 layers of PVA, and the DH of the outermost layer of PVA is lower than the DH of any of the other layers of PVA.

[0056] In other embodiments of the inserts of the present invention, the API has a molecular weight of 1000 AMU or less and a water solubility of less than about 200 μg / mL at 25°C. In other embodiments, the API is a VEGF inhibitor. In other embodiments, the API is a TKI inhibitor. In other embodiments, the API is voronib or a pharmaceutically acceptable salt thereof. In further embodiments, the API is axitinib or a pharmaceutically acceptable salt thereof. In other embodiments, the API is a Tie-2 activator. In some embodiments, the API is razuprotafib or a pharmaceutically acceptable salt or zwitterion thereof.

[0057] In some aspects of the methods described herein, the subject has geographic atrophy, the subject is at risk for developing geographic atrophy, the subject has vision loss, the subject is at risk for developing vision loss, the subject has ischemic retinal vein occlusion, or the subject has non-ischemic retinal vein occlusion.

[0058] The present invention also provides a method of inhibiting ocular angiogenesis in a subject in need thereof, comprising implanting one or more ocular drug delivery inserts in the vitreous of an eye of the subject, wherein the number of inserts administered during administration is 1 to 6, and wherein each of the one or more inserts has a voronib drug release rate of about 0.01 μg / day to about 100 μg / day for at least 30 days.

[0059] It also provides a method of inhibiting VEGFR and PDGFR in an eye of a subject in need thereof, comprising implanting one or more ocular drug delivery inserts in the vitreous of the subject's eye, wherein the number of inserts administered during administration is 1 to 6, and wherein each of the one or more inserts has a voronib drug release rate of about 0.01 μg / day to about 100 μg / day for at least 30 days.

[0060] In addition, the present invention provides a method of treating macular degeneration in a subject in need thereof, comprising implanting one or more ocular drug delivery inserts in the vitreous of an eye of the subject, wherein the number of inserts administered during administration is 1 to 6, and wherein each of the one or more inserts has a voronib drug release rate of about 0.01 μg / day to about 100 μg / day for at least 30 days. In some embodiments, the macular degeneration treated is age-related macular degeneration.

[0061] In some embodiments, the method of treatment or administration further comprises administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of a Tie-2 activator. In another embodiment, the Tie-2 activator is ralostadil or a pharmaceutically acceptable salt or zwitterion thereof. In other embodiments, the method of treatment further comprises administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of a steroidal anti-inflammatory agent.

[0062] In addition, the present invention provides a method for inhibiting VE-PTP in the eye of a subject in need thereof, comprising injecting one or more inserts into the vitreous of the subject's eye. In other aspects, the present invention provides a method for treating glaucoma in a subject in need thereof, comprising injecting one or more inserts into the vitreous of the subject's eye. In other embodiments, the present invention provides a method for treating elevated IOP in a subject in need thereof, comprising injecting one or more inserts into the vitreous of the subject's eye. In another embodiment, the present invention provides a method for lowering IOP in a subject in need thereof, comprising injecting one or more inserts into the vitreous of the subject's eye. In some embodiments, the method further comprises administering a VEGF inhibitor.

[0063] In some aspects, the invention provides an insert for treating or preventing an ocular disease in a subject in need thereof.

[0064] In other aspects, the invention provides an insert for inhibiting angiogenesis in an eye of a subject in need thereof.

[0065] In other aspects, the invention provides an insert for inhibiting VEGFR and PDGFR in an eye of a subject in need thereof.

[0066] In some aspects, the invention provides an insert for treating age-related macular degeneration in a subject in need thereof.

[0067] In some aspects, the invention provides an insert for treating retinal vein occlusion in an eye of a subject in need thereof.

[0068] In some aspects, the invention provides an insert for treating diabetic retinopathy in an eye of a subject in need thereof.

[0069] In some embodiments, the invention provides an insert for inhibiting VE-PTP in an eye of a subject in need thereof.

[0070] In some embodiments, the invention provides an insert for treating glaucoma in an eye of a subject in need thereof.

[0071] In other embodiments, the invention provides an insert for treating elevated IOP in an eye of a subject in need thereof.

[0072] In other embodiments, the invention provides an insert for lowering IOP in an eye of a subject in need thereof.

[0073] In other embodiments, the invention provides an insert for treating uveitis in an eye of a subject in need thereof.

[0074] In a further embodiment, the invention provides an insert for treating chronic non-infectious uveitis affecting the posterior segment of the eye in an eye of a subject in need thereof.

[0075] In some embodiments, the insert is injected through a needle or cannula of less than 25G. In some embodiments, the injection does not require an incision. BRIEF DESCRIPTION OF THE DRAWINGS

[0076] Figure 1 Exemplary ocular drug delivery inserts of the present invention are described.

[0077] Figure 2 : Figure 2 Depicted are the average weight changes of different grades of PVA membranes after immersion in PBS for 24 h.

[0078] Figure 3 A scale showing the relative film strength of the films evaluated is depicted.

[0079] Figure 4A An in vitro drug release profile is depicted showing the cumulative percentage of drug released from Formulation A implants, which were coated formulations cured at 140°C for 4 hours.

[0080] Figure 4B The in vitro drug release profile is depicted, showing the cumulative amount of drug (μg) released from Formulation A implants.

[0081] Figure 5 Photographs of eroded Formulation A implants taken after 314 and 447 days of immersion in dissolution medium are shown, with the photo of the 447 day implant including the intact implant for comparison.

[0082] Figure 6 Depicted is the in vitro drug release profile of the uncoated Formulation A implant, which is identical to Formulation A but without the coating.

[0083] Figure 7Photographs of eroded uncoated Formulation A implants taken after 287 and 352 days of immersion in dissolution medium are shown, with the photo of the 352 day implant including the intact implant for comparison.

[0084] Fig. 8A Depicted is an in vitro drug release profile showing the cumulative percentage of drug released from Formulation B implants, which were coated formulations cured at 140°C for 30 minutes.

[0085] Figure 8B The in vitro drug release profile is depicted, showing the cumulative amount of drug (μg) released from Formulation B implants.

[0086] Fig. 9 Photographs of eroded Formulation B implants taken after 59, 88 and 155 days of immersion in dissolution medium are shown.

[0087] Fig.10 The in vitro drug release profile of Formulation C (uncured coated formulation) is described.

[0088] Fig.11 Shown are photographs of two samples of eroded Formulation C implants that were immersed in dissolution medium at 37°C for 98 days and then immersed at room temperature for 113 days.

[0089] Fig.12 A comparison of the in vitro drug release profiles of Formulations A, B and C is described.

[0090] Fig.13A Depicted is the average amount of drug remaining in the insert versus time for an in vivo study in which inserts were implanted in rabbit eyes at various time points and analyzed to determine the amount of voronib (μg) remaining in the insert. One curve shows the levels of the insert in eyes with 3 inserts and the other curve shows the levels of the insert in eyes with 6 inserts.

[0091] Fig. 13B Cumulative percent drug release versus time for inserts implanted in the same in vivo study is depicted. One curve shows the levels of inserts for eyes implanted with 3 inserts and the other curve shows the levels of inserts for eyes implanted with 6 inserts. DETAILED DESCRIPTION

[0092] 1. Active Pharmaceutical Ingredients (API)

[0093] The insert of the present invention comprises an active pharmaceutical ingredient (API). The API is sometimes referred to herein as a "drug".

[0094] In certain embodiments, the API used in the inserts and methods of the present invention has a molecular weight of 1000 AMU or less and a water solubility of less than about 200 μg / mL at 25° C. In other embodiments, the API has a water solubility of 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 API has an aqueous solubility of about 0.1 μg / mL to about 200 μg / mL, about 0.1 μg / mL to about 150 μg / mL, about 0.1 μg / mL to about 100 μg / mL, about 0.1 μg / mL to about 75 μg / mL, about 0.1 μg / mL to about 50 μg / mL, about 0.1 μg / mL to about 20 μg / mL, about 0.1 μg / mL to about 10 μg / mL, or about 0.5 μg / mL to about 50 μg / mL at 25°C.

[0095] The ocular inserts of the present invention can be used to deliver various types of APIs. Examples of such APIs and specific APIs include:

[0096] In some embodiments, the API is a vascular endothelial growth factor (VEGF) inhibitor (sometimes also referred to as anti-VEGF), a kinase inhibitor (such as 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. The API has one or more of the following actives, including altiratinib, rebastinib, afatinib, alectinib, apatinib, ASP-3026, axitinib, bafetinib, baricitinib, binimetinib, bosutinib, brigatinib, cabozanib, abozantinib), canertinib, cediranib, CEP-11981, CEP-37440, ceritinib, cobimetinib, copanlisib, crenolanib, crizotinib, CYT387, dabrafenib, damnacanthal, dasatinib, dorama doramapimod, enterctinib, erlotinib, everolimus, filgotinib, foretinib, fostamatinib, gefitinib, grandinin, ibrutinib, icotinib, idelalisib, imatinib, I PI-145, JSI-124, lapatinib, lenvatinib, lestaurtinib, linifanib, masitinib, motesanib, mubritinib, neratinib, nilotinib, nintedanib, pacritinib, palbociclib,pazopanib, pegaptanib, perifosine, pexmetinib, PF-06463922, ponatinib, PX-866, quizartinib, radotinib, razuprotafib (AKB-9778), regorafenib, ruxolitinib, selumetinib, semaxanib, sirolimus, sorafenib, sorafenib tosylate, staurosporine, sunitinib, sunitinib malate malate), SU6656, temsirolimus, TG101348, tivozanib, toceranib, tofacitinib, trametinib, TSR-011, vandetanib, vatalanib, vemurafenib, vorolanib, and X-396.

[0097] In some embodiments, the API can be a steroidal anti-inflammatory agent, such as a steroid or corticosteroid, non-limiting examples of which are fluocinolone acetonide, hydrocortisone, hydrocortisone acetate, triamcinolone acetonide, methylprednisolone, dexamethasone, medrysone, methylprednisolone, prednisolone 21-phosphate, prednisolone acetate, fluoromethalone, and betamethasone.

[0098] In other embodiments, the API is a prostaglandin or a prostaglandin analog or agonist, such as bimatoprost, latanoprost, latanoprost nitrate, tafluprost, or travoprost.

[0099] In other embodiments, the API is an alpha-2 adrenergic receptor agonist, such as brimonidine, brimonidine tartrate, or brimonidine pamoate.

[0100] In certain aspects, the API is a beta blocker, such as timolol.

[0101] In other aspects, the API is a carbonic anhydrase inhibitor (CAI), such as acetazolamide, brinzolamide, doxolamide, or methazolamide.

[0102] In other aspects, the API is a rho-khinase inhibitor, such as natadil.

[0103] Also consider the use of nonsteroidal anti-inflammatory drugs (NSAIDs). NSAIDs include diclofenac, etoldolac, fenoprofen, floctafenine, flurbiprofen, ibuprofen, indoprofen, ketoprofen, ketorolac, lomoxicam, morazone, naproxen, perisoxal, pirprofen, pranoprofen, suprofen, suxibuzone, tropesin, ximoprofen, zaltoprofen, zileuton, and zomepirac. COX-2 inhibitors such as valdecoxib, rofecoxib, and celecoxib are also contemplated.

[0104] In some embodiments, the API is a neuroprotectant, such as nimodipine; an antibiotic, such as tetracycline, chlortetracycline, corynin, neomycin, polymyxin, corynin, oxytetracycline, chloramphenicol, gentamicin, or erythromycin; or an antibacterial agent, such as sulfonamide, sulfamethoxazole, sulfamethoxazole, sulfamethoxazole, furacillin, or sodium propionate.

[0105] In another embodiment, the API is a complementary inhibitor, such as a C3 inhibitor, such as APL-2 (pegcetacoplan) or a C5 inhibitor.

[0106] Anesthetics and analgesics, such as lidocaine and related compounds, are also considered.

[0107] In some embodiments, the insert comprises multiple APIs.

[0108] In addition, the present invention also contemplates analogs, derivatives, pharmaceutically acceptable salts, esters, prodrugs, codrugs, and protected forms thereof of the API.

[0109] The term "pharmaceutically acceptable salt" of a given compound refers to salts that retain the biological effectiveness and properties of the given compound and are biologically or otherwise suitable.

[0110] Pharmaceutically acceptable salts include salts with inorganic or organic acids and salts with inorganic or organic bases. Those skilled in the art will recognize various synthetic methods that can be used to prepare non-toxic pharmaceutically acceptable salts.

[0111] Salts can be derived from inorganic acids including hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc. Salts can be derived from organic acids including acetic acid, propionic acid, glycolic acid, gluconic acid, pamoic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, lactic acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc.

[0112] In some embodiments, the salt is an acetonide salt.

[0113] Pharmaceutically acceptable base addition salts can be prepared from inorganic bases 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.

[0114] In addition, pharmaceutically acceptable salts include organic salts such as choline, glucosamine, tris, meglumine, lysine, arginine, tributylamine and benzathine penicillin salts.

[0115] In some embodiments, the API is in an amorphous form, a crystalline form, a polymorph, a hydrate, or a solvate.

[0116] Unless otherwise specified, the doses described in this application (e.g., 100 μg) refer to the weight of the pharmacologically active portion, not the weight of a given API salt or API ester. Thus, for example, when an insert contains a pharmaceutically acceptable salt or ester of an API (e.g., rerotafil sodium), the weight must be adjusted to provide an amount of API salt equal to the amount of API described herein. For example, an insert referred to herein as containing 100 μg of rerotafil sodium means that the insert contains an amount of salt equivalent to 100 μg of the rerotafil molecule. 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., voronib).

[0117] In some embodiments of the invention, the API is voronib or a pharmaceutically acceptable salt thereof.

[0118] The chemical name of voronib is (S,Z)-N-(1-(dimethylcarbamoyl)pyrrolidin-3-yl)-5-(5-fluoro-2-oxoindole-3-ylidene)methyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide. Synonyms include the term "X-82". The molecular formula is C 23 H 26 FN5O3. The solubility of voronib in water is less than 0.1 μg / mL. Voronib has the following structure:

[0119]

[0120] As used herein, "voronib or a pharmaceutically acceptable salt thereof" includes amorphous and crystalline forms, polymorphs, hydrates, and solvates of voronib or a pharmaceutically acceptable salt thereof.

[0121] Voronib is an orally active multikinase inhibitor that inhibits activation of vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR).

[0122] For example, methods of making voronib are described in U.S. Patents 7,683,057, 8,524,709, 8,039,470, and U.S. Published Application 2019 / 0233403; each of which is incorporated by reference in its entirety.

[0123] In some embodiments, the API is rerotafil (AKB-9778) or a pharmaceutically acceptable salt or zwitterion thereof, for example, rerotafil sodium, rerotafil choline, rerotafil glucosamine, rerotafil trishydroxymethylaminomethane (razuprotafib tris), rerotafil meglumine, rerotafil lysine, rerotafil arginine, rerotafil tributylamine, rerotafil benzathine penicillin. Rerotafil is a potent and selective inhibitor of VE-PTP (vascular endothelial protein tyrosine phosphatase) catalytic activity. Rerotafil promotes TIE2 activation, enhances ANG1-induced TIE2 activation, and stimulates phosphorylation of signaling molecules in the TIE2 pathway, including protein kinase (AKT), nitric oxide synthase (eNOS), and extracellular regulated protein kinase (ERK).

[0124] The chemical name of ralostadyl is [4-[(2S)-2-[[(2S)-2-(methoxycarbonylamino)-3-phenylpropyl]amino]-2-(2-thiophen-2-yl-1,3-thiazol-4-yl)ethyl]phenyl]aminosulfonic acid. The molecular formula is C 26 H 26 N4O6S3. Its CAS registration number is 1008510-37-9. Its chemical structure is:

[0125]

[0126] The method for making lerotafil is described in US Pat. No. 7,622,593, the entire contents of which are incorporated herein by reference.

[0127] In some embodiments of the invention, the API is axitinib or a pharmaceutically acceptable salt or ester thereof.

[0128] The chemical name of Axitinib is N-methyl-2-[3-((E)-2-pyridin-2-yl-vinyl)-1H-indazol-6-ylsulfonyl]-benzamide. The molecular formula is C 22 H 18 N4OS, molecular weight is 386.47 Daltons. Chemical structure:

[0129]

[0130] The pKa of axitinib is 4.8. The solubility of axitinib in aqueous media exceeds 0.2 μg / mL in the range of pH 1.1 to pH 7.8.

[0131] For example, methods of preparing axitinib are described in U.S. Patents 6,891,044 and 8,791,140, ​​each of which is incorporated by reference in its entirety.

[0132] Prior to preparation of the insert, the API may be ground to produce a fine particle size. In some embodiments, the API used to make the insert has a particle size of about 0.05 g / cm2. 90 In some embodiments, D 90 It is about 0.01 μm to about 100 μm, about 0.01 μm to about 80 μm, about 0.1 μm to about 50 μm, about 0.1 μm to about 20, about 0.1 μm to about 15 μm, about 0.1 μm to 12 μm, about 1 μm to about 50 μm, about 1 μm to about 30 μm, about 1 μm to about 25 μm, about 1 μm to about 20 μm, about 1 μm to about 15 μm, about 1 μm to about 12 μm, about 5 μm to about 10, about 7 μm, about 8 μm, about 9 μm, about 10 μm, about 11 μm or about 12 μm.

[0133] 2. Ocular Drug Delivery Inserts

[0134] An "ocular drug delivery insert" is a device that can be implanted into the eye, contains a drug, and releases the drug in the eye after implantation. An "ocular drug delivery insert" includes all inserts described herein.

[0135] The ocular drug delivery insert comprises a core comprising an API dispersed in a solid matrix. In some embodiments, the core is at least partially covered by a coating. The insert is bioerodible.

[0136] In other embodiments, the insert consists of the core alone. It is not surrounded by a coating or any type of barrier around the core.

[0137] In some embodiments, the insert comprises a core and a coating. The coating is a layer that partially or completely surrounds the core. The coating is an outer layer that can be preformed into a desired shape (e.g., it can be a tube) before being placed around the core, or the coating can be formed by, for example, coextrusion of the core and the coating, spraying the coating onto the core, or dipping the core into the coating material one or more times (e.g., 1-10 layers). If the core is coated, the coating can completely surround the core, or it can only partially surround the core.

[0138] The insert can be in various shapes, such as a cylinder, a rod, a sphere or a disc. In certain embodiments, the insert is cylindrical in shape, and the coating covers the entire surface of the cylinder except the end of the rod or cylinder. The end of the rod can be used as a delivery port. In certain embodiments, one end of the cylinder is covered with a coating, while the other end is not covered with a coating. In certain embodiments, one end is covered with a drug-impermeable cap (such as a silicone cap). The rod is a solid geometric figure with parallel edges, wherein the length of one side is greater than the diameter or the longest side of the cross-sectional shape. The cross-sectional shape can be circular, oval, square, rectangular, triangular or polygonal (such as a hexagon). Those skilled in the art will recognize that due to the manufacturing process, the insert shape may be imprecise, for example, the outside may not be smooth and completely uniform. For example, the edge of a cylinder or rod may not be completely straight or completely parallel. The cross section of a cylinder may not be a perfect circle or oval. The cross sections of other shapes may not fully conform to the limitations of these shapes. For example, a square cross section may not have a completely straight edge, and the angle of the angle may not be exactly 90 degrees. The sphere or ball may not be perfectly spherical.

[0139] a. Matrix

[0140] In certain embodiments, the core is a solid matrix, including a matrix polymer and an API, and the API can exist in a solid form, such as a powder, microparticle or granule dispersed throughout the matrix. The matrix component and the API form a uniform mixture, and the API is dispersed therein. The matrix is ​​solid at room temperature and is bioerodible. The matrix controls the release rate of the API, thereby changing the API release rate compared to the unprepared API. In certain embodiments, the matrix slows down the drug release rate and provides extended delivery of the drug and less frequent administration.

[0141] In some embodiments, the matrix further comprises other pharmaceutically acceptable ingredients. In other embodiments, the only material used to form the matrix is ​​one or more matrix polymers.

[0142] The polymer used to form the matrix ("matrix polymer") may include one or more of the following: polyvinyl alcohol (PVA), poly(caprolactone) (PCL), polyethylene glycol (PEG), poly(dl-lactide-co-glycolide) (PLGA), polyvinyl alcohol (PVA), poly(lactic acid) (PLA), poly(glycolic acid) (PGA), polyalkyl cyanoacrylate, or a copolymer thereof.

[0143] In some embodiments, the matrix polymer comprises PVA. In some embodiments, the only inactive pharmaceutical ingredient in the matrix is ​​PVA.

[0144] Different grades of PVA can be used. The degree of hydrolysis (DH) of PVA can be from about 70% to about 99%. +%, and the molecular weight (MW) may be about 6000-200000, that is, the matrix polymer is about 70 mol% to about 99 + mol % hydrolyzed PVA has a molecular weight of about 6000-200000. For example, DH can be about 80% to about 90%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 88% to about 90%, about 90% to about 99 + %, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99 + % or about 98 to about 99 + %; and the MW can be about 5000, about 6000, about 7000, about 8000, about 9000, about 10000, about 15000, about 18000, about 20000, about 25000, about 30000, about 40000, about 50000, about 60000, about 70000, about 75000, about 78000, about 80000, about 85000 , about 90,000, about 100,000, about 108,000, about 110,000, about 120,000, about 125,000, about 130,000, about 133,000, about 140,000, about 146,000, about 150,000, about 160,000, about 170,000, about 180,000, about 186,000, about 190,000 or about 200,000. In some embodiments, the MW can be about 5000-10000, about 6000-10000, about 9000-10000, about 10000-25000, about 25000-50000, about 30000-70000, about 60000-80000, about 70000-80000, about 75000-80000, about 75000-100000, about 89000-98000, about 85000-124000, or about 146000-186000. In some embodiments, the PVA is MW 6000, 80% hydrolyzed, MW 9000-10000, 80% hydrolyzed, MW 25000, 88% hydrolyzed, MW 25000, 98% hydrolyzed, MW 30000-70000, 87-90% hydrolyzed, MW 78000, 88% hydrolyzed, MW 78000, 98% hydrolyzed, MW 78000, 99+% hydrolyzed, MW 89000-98000, 99+% hydrolyzed, MW 85000-124000, 87-89% hydrolyzed, MW 108000, 99 + % hydrolyzed, MW 125,000, 88% hydrolyzed, MW 133,000, 99% hydrolyzed, or MW 146,000-186,000, 99+% hydrolyzed.

[0145] In other embodiments, the matrix polymer includes 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 of the slower eroding PVA to the faster eroding PVA is 1:6, 1:7, 1:8, 1:9, 1:10, 1:11 or 1:12. The PVA erosion rate can be measured as described in Example 1. For example, in some embodiments, the ratio of 6000MW, 80%DH to 125000MW, 88%DH of the PVA mixture is 1:9. In other embodiments, the ratio of the two grades in the mixture of the faster eroding PVA to the slower eroding PVA is 1:1 to 1:15, for example, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11 or 1:12.

[0146] Examples of PVA blends include a blend of MW 6000, 80% hydrolyzed and MW 78000, 98% hydrolyzed; a blend of MW 6000, 80% hydrolyzed and MW 78000, 99 + % hydrolyzed mixture; MW 78000, 98% hydrolyzed and MW 78000, 99 + % hydrolyzed; and a mixture of MW 6000, 80% hydrolyzed and MW 125000, 88% hydrolyzed.

[0147] The MW and DH are selected to provide the desired drug release rate for a particular drug, an indication of the ocular drug delivery insert being used, the desired duration of drug release, and the desired erosion rate.

[0148] The polymer solution used to form the matrix may contain about 1% w / w to about 20% w / w, about 1% w / w to about 15% w / w, about 2% w / w to about 15% w / w, about 2% w / w to about 12% w / w, about 2% w / w to about 10% w / w, about 3% w / w to about 10% w / w, about 3% w / w to about 8% w / w, about 3% w / w to about 6% w / w, about 2% w / w, about 2.5% w / w, about 3% w / w, about 3.5% w / w, about 10 ... w / w, about 4% w / w, about 4.5% w / w, about 5% w / w, about 5.5% w / w, about 6% w / w, about 6.5% w / w, about 7% w / w, about 7.5% w / w, about 8% w / w, about 8.5% w / w, about 9% w / w, about 9.5% w / w, about 10% w / w, about 10.5% w / w, about 11% w / w, about 11.5% w / w, about 12% w / w, about 13% w / w, about 14% w / w or about 15% w / w polymer (such as PVA).

[0149] The polymer solution and API can be combined, for example, in a ratio of 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 API:polymer solution.

[0150] In some embodiments, the core comprises voronib or a pharmaceutically acceptable salt thereof and PVA. In some embodiments, the core consists of voronib or a pharmaceutically acceptable salt thereof and PVA.

[0151] 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.

[0152] In further embodiments, the PVA solution and the API are combined in a ratio of about 1:1 w / w API:PVA solution.

[0153] In some embodiments, the PVA solution and the API are combined in a ratio of about 1:2 w / w API:PVA solution.

[0154] In certain embodiments, the core contains from about 0.1% w / w to about 90% w / w, from about 0.1% w / w to about 80% w / w, from about 0.1% w / w to about 70% w / w, from about 0.1% w / w to about 60% w / w, from about 0.1% w / w to about 50% w / w, from about 0.1% w / w to about 40% w / w, from about 0.1% w / w to about 30% w / w, from about 0.1% w / w to about 25% w / w, from about 0.1% w / w to about 20% w / w, from about 0.1% w / w to about 15% w / w, from about 0.1% w / w to about 10% w / w, from about 3% w / w to about 90% w / w. w / w, about 3% w / w to about 75% w / w, about 4% w / w to about 60% w / w, about 4% w / w to about 50% w / w, about 4% w / w to about 40% w / w, about 4% w / w to about 25% w / w, about 1% w / w to about 10% w / w, about 1% w / w to about 9% w / w, about 1% w / w to about 8% w / w, about 1% w / w to about 7% w / w, about 1% w / w to about 6% w / w, about 2% w / w to about 8% w / w, about 2% w / w to about 6% w / w, or about 3% w / w to about 5% w / w of inactive (non-API) ingredients, such as a matrix polymer. These weight percentages are based on the dry weight of the core (i.e., after any drying step in processing).

[0155] In some embodiments, the amount of matrix polymer in the core is from about 0.1% to about 90% w / w, from about 0.1% w / w to about 80% w / w, from about 0.1% w / w to about 70% w / w, from about 0.1% w / w to about 60% w / w, from about 0.1% w / w to about 50% w / w, from about 0.1% w / w to about 40% w / w, from about 0.1% w / w to about 30% w / w, from about 0.1% w / w to about 25% w / w, from about 0.1% w / w to about 20% w / w. w / w, about 0.1% w / w to about 15% w / w, about 0.1% w / w to about 10% w / w, about 3% w / w to about 90% w / w, about 3% w / w to about 75% w / w, about 4% w / w to about 60% w / w, about 4% w / w to about 50% w / w, about 4% w / w to about 40% w / w, about 4% w / w to about 25% w / w, about 1% w / w to about 10% w / w, about 1% w / w to about 9% w / w, about 1% w / w to about about 8% w / w, about 1% w / w to about 7% w / w, about 1% w / w to about 6% w / w, about 2% w / w to about 8% w / w, about 2% w / w to about 6% w / w, or about 3% w / w to about 5% w / w; or about 1% w / w, 1.5% w / w, 2% w / w, 2.5% w / w, 3% w / w, 3.5% w / w, 4% w / w, 4.5% w / w, 5% w / w, 5.5% w / w, 6% w / w, 6.5% w / w, % w / w, 7% w / w, 7.5% w / w, 8% w / w, 8.5% w / w, 9% w / w, 9.5% w / w, 10% w / w, 10.5% w / w, 11% w / w, 11.5% w / w, 12% w / w, 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 in processing).

[0156] The term "insert consists of a core comprising a solid matrix and an API" means that the entire insert is in the form of a solid matrix and an API. The matrix may also include additional ingredients, but the insert does not have a shell, coating, cap, cover or tube or other outer layer, so that when immersed in a fluid environment (e.g., the vitreous humor of the eye or an in vitro drug release medium), the outside of the core is in direct contact with the fluid.

[0157] b. Coating

[0158] In some embodiments of the invention, the insert comprises or consists of (a) a core comprising the API and a solid matrix and (b) a coating. In other embodiments, the insert does not comprise a coating.

[0159] In some embodiments, the coating is permeable to the passage of the API and acts as a diffusion membrane for the active pharmaceutical ingredient. The diffusion membrane can change the API release rate of the matrix. The diffusion membrane can work by, for example, changing the fluid flowing into the matrix and / or limiting the API from flowing out of the matrix. In other embodiments, compared to the uncoated core, the coating increases the durability of the insert, for example during processing, packaging and / or delivery of the medicament. In some embodiments, the coating changes the API release rate and increases the durability of the insert.

[0160] The coating may completely surround the core, or only partially surround the core. In some embodiments, the coating substantially covers the core, meaning that it covers at least 70% of the surface area of ​​the core. 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 surface area of ​​the core. In other embodiments, the coating surrounds about 40% to about 98%, about 50% to about 98%, about 60% to about 98%, about 70% to about 98%, or about 80% to about 98% of the surface area of ​​the core. For cylindrical inserts, the surface area A is calculated with A=2πrL+2πr2, where r is the radius of the insert and L is the length of the insert. In some embodiments, one face of the core is covered with a coating to form a delivery port. In some embodiments, more than one face is left uncovered to form more than one delivery port.

[0161] The delivery port is permeable to the API.

[0162] In some embodiments, the insert is in the shape of a rod, such as a cylinder, and only the two ends of the rod / cylinder are uncoated.

[0163] To illustrate one embodiment of the ocular drug delivery insert of the present invention, Figure 1 A longitudinal cross-sectional view of an ocular drug delivery insert 100 according to one embodiment of the present invention is shown. Insert 100 includes a solid matrix core 105. Insert 100 also includes a coating 110 substantially surrounding core 105. Insert 100 also has two delivery ports 115 located at opposite ends of insert 100. In this particular embodiment, at least one of the delivery ports 115 includes a membrane permeable to the API contained in core 105 to allow the API to be released from delivery port 115.

[0164] In some embodiments, the coating, like the matrix, is bioerodible.

[0165] The coating may comprise polymeric and / or non-polymeric components. In some embodiments, the coating comprises one or more polymers, such as polyvinyl alcohol (PVA), poly(caprolactone) (PCL), polyethylene glycol (PEG), poly(dl-lactide-co-glycolide) (PLGA), polyvinyl alcohol (PVA), poly(lactic acid) (PLA), polyglycolic acid (PGA), polyalkyl cyanoacrylate, or a copolymer thereof.

[0166] In embodiments where the core is coated, the coating may be formed from 1-10 layers of polymer. For example, the core may have 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 layers of coating. In certain embodiments, each layer of coating comprises the same polymer as the other coatings. In specific embodiments, each layer of coating is composed of the same polymer as the other coatings. In other embodiments, where the coating is formed from more than one layer of coating, at least two layers of coating comprise different polymers.

[0167] In certain embodiments, the coating comprises PVA. In other embodiments, the coating consists of PVA. In some embodiments, the only inactive pharmaceutical ingredient in the coating is PVA. In other embodiments, the matrix polymer comprises PVA and the coating comprises PVA.

[0168] Different grades of PVA can be used. The degree of hydrolysis (DH) of PVA can be from about 70% to about 99%. + %, and the molecular weight (MW) may be about 6000-200000, that is, the matrix polymer is about 70 mol% to about 99+ mol% hydrolyzed PVA, and its molecular weight is about 6000-200000. For example, DH can be about 80% to about 90%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 88% to about 90%, about 90% to about 99 + %, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99 + % or about 98% to about 99 +%, and MW can be about 5000, about 6000, about 7000, about 8000, about 9000, about 10000, about 15000, about 18000, about 20000, about 25000, about 30000, about 40000, about 50000, about 60000, about 70000, about 75000, about 78000, about 80000, about 8500 about 140,000, about 146,000, about 150,000, about 160,000, about 170,000, about 180,000, about 186,000, about 190,000, or about 200,000. In some embodiments, the MW can be about 5000-10000, about 6000-10000, about 9000-10000, about 10000-25000, about 25000-50000, about 30000-70000, about 60000-80000, about 70000-80000, about 75000-80000, about 75000-100000, about 89000-98000, about 85000-124000, or about 146000-186000. In some embodiments, the PVA is MW 6000, 80% hydrolyzed, MW 9000-10000, 80% hydrolyzed, MW 25000, 88% hydrolyzed, MW 25000, 98% hydrolyzed, MW 30000-70000, 87-90% hydrolyzed, MW 78000, 88% hydrolyzed, MW 78000, 98% hydrolyzed, MW 78000, 99+% hydrolyzed, MW 89000-98000, 99+% hydrolyzed, MW 85000-124000, 87-89% hydrolyzed, MW 108000, 99 + % hydrolyzed, MW 125,000, 88% hydrolyzed, MW 133,000, 99% hydrolyzed, or MW 146,000-186,000, 99+% hydrolyzed.

[0169] 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 of the slower eroding PVA to the faster eroding PVA is 1:6, 1:7, 1:8, 1:9, 1:10, 1:11 or 1:12. The PVA erosion rate can be measured as described in Example 1. For example, in some embodiments, the ratio of 6000MW, 80%DH to 125000MW, 88%DH of the PVA mixture is 1:9. In other embodiments, the ratio of the two grades in the mixture of the faster eroding PVA to the slower eroding PVA is 1:1 to 1:15, for example, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11 or 1:12.

[0170] Examples of PVA blends include a blend of MW 6000, 80% hydrolyzed and MW 78,000, 98% hydrolyzed; a blend of MW 6000, 80% hydrolyzed and MW 78,000, 88% hydrolyzed; a blend of MW 6000, 80% hydrolyzed and MW 78,000, 99% hydrolyzed. + % hydrolyzed mixture; MW 78000, 88% hydrolyzed and MW 78000, 98% hydrolyzed mixture; MW 78000, 98% hydrolyzed and MW 78000, 99 + % hydrolyzed; and a mixture of MW 6000, 80% hydrolyzed and MW 125000, 88% hydrolyzed.

[0171] 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 other embodiments, both the core and the coating comprise a mixture of two different grades of PVA. When the coating comprises more than one layer of PVA, one or more layers of the coating may comprise a mixture of two different grades of PVA.

[0172] In embodiments where both the core and the coating comprise PVA, the core PVA and the coating PVA may be the same or different grades of PVA. The term "different grades of PVA" as used herein refers to PVAs that differ in molecular weight (MW), degree of hydrolysis (DH), or both MW and DH. In addition, as used herein, if the PVA being compared to the mixture is not a mixture of exactly the same PVA grades (e.g., a mixture of 6000, 80% hydrolyzed PVA with MW 78000, 98% hydrolyzed PVA), then a PVA grade mixture that is "a different grade of PVA" will be considered to have a different grade of PVA than a PVA composition containing only MW 78000, 98% hydrolyzed PVA, or a mixture containing MW 6000, 80% hydrolyzed PVA with MW 125000, 88% hydrolyzed PVA.

[0173] Thus, the core PVA and the coating PVA may have the same MW and DH, or may differ in MW or DH, or may differ in both MW and DH. In some embodiments, the core comprises PVA, and the insert comprises a coating comprising PVA, wherein the MW of the coating PVA is the same as the MW of the core PVA, and the DH of the coating PVA is lower than the DH of the core PVA. In some embodiments, the MW and DH of the coating PVA are both lower than the MW and DH of the core PVA.

[0174] In some embodiments, the coating is formed by more than one layer. When the insert coating includes more than one layer of PVA, a PVA with the same MW and DH can be used for the core and at least one of the layers. In other embodiments, the core includes a PVA that is different in MW and / or DH from the PVA in at least one layer. In some embodiments, the core includes a PVA that is different in MW and DH from the PVA in at least one layer. In other embodiments, the PVA in the core and the PVA in at least one layer of coating have the same MW but different in DH. In some embodiments, the DH of the PVA in at least one layer of coating is lower than the DH of the PVA in the core. In other embodiments, the PVA in the core and the PVB in at least one layer of coating are different in MW but have the same DH. In some embodiments, the MW of the PVA in at least one layer of coating is lower than the MW of the PVA in the core.

[0175] In some embodiments, the insert coating comprises a single coating comprising PVA. In other embodiments, the insert coating comprises more than one coating comprising PVA, and the PVA in each coating has the same MW and DH. In some embodiments, at least one coating comprises a PVA that is different in MW and / or DH from the PVA in at least one other coating. In some embodiments, at least one coating comprises a PVA that is different in MW and DH from the PVA in at least one other coating. In some embodiments, no two coatings comprise the same grade of PVA, i.e., the PVA in each coating is different in MW and / or DH from each other coating.

[0176] In embodiments where the insert coating comprises more than one coating comprising PVA, the PVA in the outermost coating is more soluble (in PBS) than the PVA in any other coating. In some embodiments, the PVA in at least one of the coatings is more soluble than the core PVA.

[0177] In certain embodiments, the insert comprises (a) a solid matrix core comprising PVA and an API, and (b) a coating comprising PVA substantially surrounding the core; and the DH of the PVA in the coating is lower than the DH of the PVA in the core. In one embodiment of the insert, the insert comprises 2 layers of coating comprising PVA. In other embodiments, the insert comprises 3 layers of coating comprising PVA. In other embodiments, the insert comprises 4 layers of coating comprising PVA. In further embodiments, the insert comprises 5 layers of coating comprising PVA. In other embodiments, the insert comprises 6 layers of coating comprising PVA.

[0178] In embodiments having more than one coating, the first coating applied to the core is the innermost coating and the last coating applied is the outermost coating. In some embodiments of these inserts having more than one coating of PVA, 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 more than one coating of PVA, 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 other coating.

[0179] In some aspects, the insert comprises (a) a solid matrix core comprising PVA and an API, wherein the PVA is selected from the group consisting of: MW 6000, 80% hydrolyzed, MW 9000-10000, 80% hydrolyzed, MW 25000, 88% hydrolyzed, MW 25000, 98% hydrolyzed, MW 30000-70000, 87-90% hydrolyzed, MW 78000, 88% hydrolyzed, MW 78000, 98% hydrolyzed, MW 78000, 99+% hydrolyzed, MW 89000-98000, 99+% hydrolyzed, MW 85000-124000, 87-89% hydrolyzed, MW 108000-99 + % hydrolyzed, MW 125000, 88% hydrolyzed, MW 133000, 99% hydrolyzed, MW 146000-186000, 99+% hydrolyzed, and mixtures thereof; and (b) at least one coating comprising PVA substantially surrounding the core, wherein the PVA in the coating is selected from the group consisting of PVA of MW 6000, 80% hydrolyzed, MW 9000-10000, 80% hydrolyzed, MW 25000, 88% hydrolyzed, MW 25000, 98% hydrolyzed, MW 30000-70000, 87-90% hydrolyzed, MW 78000, 88% hydrolyzed, MW 78000, 98% hydrolyzed, MW 78000, 99+% hydrolyzed, MW 89000-98000, 99+% hydrolyzed, MW 85000-124000, 87-89% hydrolyzed, MW 108000, 99 + % hydrolyzed, MW 125000, 88% hydrolyzed, MW 133000, 99% hydrolyzed, MW 146000-186000, 99+% hydrolyzed and mixtures thereof; and wherein the PVA in the core and the PVA in the at least one coating are different grades of PVA. In other aspects, if such inertness, the insert comprises at least 2 layers of PVA, and the DH of the outermost layer of PVA is lower than the DH of any PVA in each of the other layers.

[0180] The present invention provides the ability to customize the grade of PVA used to make ocular inserts. The MW and DH of the core and coating PVA are selected to provide the desired drug release rate for a particular drug, an indication for the ocular drug delivery insert being used, the desired duration of drug release, and the desired erosion rate. Different durations of drug release may be required for different ocular diseases or disorders. For example, for the treatment of diabetic retinopathy, a 12 month duration of drug release (as provided by Formulation A) may be ideal, while for an insert used to inhibit ocular inflammation caused by injury or surgery, a duration of less than one month may be ideal.

[0181] The polymer solution used to form the coating may contain about 1% w / w to about 20% w / w, about 1% w / w to about 15% w / w, about 2% w / w to about 15% w / w, about 2% w / w to about 12% w / w, about 2% w / w to about 10% w / w, about 3% w / w to about 10% w / w, about 3% w / w to about 8% w / w, about 3% w / w to about 6% w / w, about 2% w / w, about 2.5% w / w, about 3% w / w, about 3.5% w / w, or about 5% w / w. w / w, about 4% w / w, about 4.5% w / w, about 5% w / w, about 5.5% w / w, about 6% w / w, about 6.5% w / w, about 7% w / w, about 7.5% w / w, about 8% w / w, about 8.5% w / w, about 9% w / w, about 9.5% w / w, about 10% w / w, about 10.5% w / w, about 11% w / w, about 11.5% w / w, about 12% w / w, about 13% w / w, about 14% w / w or about 15% w / w polymer (such as PVA).

[0182] For inserts comprising a PVA coating, 1-10 layers of PVA solution may be used to cover, i.e., the insert may comprise 1-10 layers of PVA coating. For example, the insert may comprise 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 layers of PVA.

[0183] In some embodiments, the weight of the insert coating is from about 0.1% w / w to about 60% w / w, from about 0.1% w / w to about 40% w / w, from about 0.1% w / w to about 20% w / w, from about 1% w / w to about 40% w / w, from about 1% w / w to about 30% w / w, from about 1% w / w to about 20% w / w, from about 1% w / w to about 10% w / w, from about 5% w / w to about 30% w / w, from about 5% w / w to about 25% w / w, from about 5% w / w to about 20% w / w, from about 5% w / w to about 15% w / w, from about 10% w / w to about 25% w / w, from about 10% w / w to about 20% w / w, from about 10% w / w to about 18% w / w, or from about 12% w / w to about 18% w / w of the insert. These weight percentages are based on the dry weight of the intercalant (ie, after any drying steps in processing).

[0184] In some embodiments, the total amount of inactive ingredients in the insert is from about 1% w / w to about 70% w / w, from about 1% w / w to about 50% w / w, from about 3% w / w to about 90% w / w, from about 3% w / w to about 75% w / w, from about 4% w / w to about 60% w / w, from about 4% w / w to about 50% w / w, from about 4% w / w to about 40% w / w, from about 4% w / w to about 25% w / w, from about 5 ... About 40% w / w, about 5% w / w to about 30% w / w, about 5% w / w to about 25% w / w, about 5% w / w to about 20% w / w, about 5% w / w to about 15% w / w, about 10% w / w to about 25% w / w, about 10% w / w to about 22% w / w, about 15% w / w to about 25% w / w, about 15% w / w to about 22% w / w, or about 18% w / w to about 22% w / w. These weight percentages are based on the dry weight of the intercalant (i.e., after any drying step in processing).

[0185] In some embodiments, the amount of PVA in the insert is about 1% w / w to 80% w / w, about 1% w / w to 75% w / w, about 3% w / w to 80% w / w, about 3% w / w to 70% w / w, about 4% w / w to 60% w / w, about 4% w / w to 50% w / w, about 4% w / w to 40% w / w, about 4% w / w to 25% w / w, about 5% w / w to 40% w / w, about 5% w / w to 45% w / w, about 6% w / w to 80 ... 0% w / w, about 5% w / w to 30% w / w, about 5% w / w to 25% w / w, about 5% w / w to 20% w / w, about 5% w / w to 15% w / w, about 10% w / w to about 25% w / w, about 10% w / w to about 22% w / w, about 15% w / w to about 25% w / w, about 15% w / w to about 22% w / w, or about 18% w / w to about 22% w / w. These weight percentages are based on the dry weight of the intercalant (i.e., after any drying step in processing).

[0186] In some embodiments, the present invention provides an insert having a very high drug content relative to the inactive ingredients in the insert, which is surprising given the ability of the insert to provide drug release over an extended period of time. In some embodiments, the amount of API in the insert is about 5% w / w to about 98%, about 10% w / w to about 98%, about 15% w / w to about 98%, about 20% w / w to about 98%, about 30% w / w to about 98%, about 40% w / w to about 98%, about 50% w / w to about 98%, about 60% w / w to about 98% w / w, about 65% w / w to about 98% w / w, about 70% w / w to about 98% w / w, about 75% w / w to about 98% w / w, about 65% w / w to about 90% w / w, about 70% w / w to about 90% w / w, about 75% w / w to about 90% w / w, or about 80% w / w to about 90% w / w. These weight percentages are based on the dry weight of the insert (i.e., after any drying step in processing).

[0187] In some embodiments, the only inactive ingredient in the insert is a polymer, such as PVA.

[0188] The coating thickness around the core may be about 20 μm to 400 μm, about 20 μm to 300 μm, about 20 μm to about 200 μm, about 20 μm to about 100 μm, about 5 μm to about 75 μm, about 5 μm to about 50 μm, or about 5 μm to about 25 μm.

[0189] c. Insert shape and size

[0190] In some embodiments, when the insert is prepared for implantation within the vitreous of an eye, the insert is no larger than about 15 mm, or preferably no larger than about 10 mm in any direction, so that the insert can be inserted through an incision of 15 mm or less.

[0191] In some embodiments, the shape and size of the insert can be used for injection. In some embodiments, the size and shape of the insert is suitable for passing through a 20G or smaller cannula or needle. This means that the insert can be injected through a cannula or needle with the gauge without requiring abnormal force. In this article, the term "or smaller" means having a smaller outer diameter. A smaller outer diameter will correspond to a larger gauge size number, for example, a 25G needle has a smaller outer diameter than a 22G needle.

[0192] In some embodiments, the insert is sized and shaped to pass through a 20 to 27G needle or cannula, a 21 to 27G needle or cannula, a 22 to 27G needle or cannula, a 23 to 27G needle or cannula, a 24 to 27G needle or cannula, a 25 to 27G needle or cannula, or a 25.5 to 27G needle or cannula.

[0193] In other embodiments, the insert is sized and shaped to pass through a cannula or needle of 20G or less, 22G or less, 23G or less, 24G or less, 25G or less, 25.5G or less, 26G or less, or 26.5G or less. Preferably, the insert is sized and shaped to pass through a cannula or needle of less than 25G, less than 26G, or less than 27G. In some embodiments, the insert is sized and shaped to pass through a cannula or needle of about 29G to about 25.5G, such as from about 28G to about 25.5G, or from about 28G to about 26G. In some embodiments, the needle or cannula is about 22, 22s, 23, 24, or 25G, but preferably about 25.5, 26, 26.5, 26s, 27, 27.5, 28, 28.5, 29, 29.5, 30, or 30.5G.

[0194] In some embodiments, the insert is in the shape of a rod, cylinder, or sphere and may be less than about 12 mm in length and less than about 1 mm in diameter.

[0195] In some embodiments, the insert may be rod-shaped or cylindrical and may be no longer than 8 mm and no larger than 3 mm in diameter.

[0196] In some embodiments, the length of the insert is about 1 mm to 10 mm, 2 mm to 10 mm, 1 mm to 4 mm, 4 mm to 8 mm, 6 mm to 10 mm, 8 mm to 10 mm, 1 mm to 12 mm, 2 mm to 12 mm, or 4 mm to 12 mm; about 1 mm, about 1.5 mm, about 2 mm, about 2.5 mm, about 3 mm, about 3.5 mm, about 4 mm, about 4.5 mm, about 5 mm, about 5.5 mm, about 6 mm, about 6.5 mm, about 7 mm, about 7.5 mm, about 8 mm, about 8.5 mm, about 9 mm, about 9.5 mm, about 10 mm, about 10.5 mm, about 11 mm, about 11.5 mm, about 12 mm, about 12.5 mm, about 13 mm, about 13.5 mm, about 14 mm, about 14.5 mm, or about 15 mm.

[0197] In some embodiments, the diameter of the insert is about 0.1 mm to about 2 mm, about 0.1 mm to about 1 mm, about 0.1 mm to about 0.8 mm, about 0.1 mm to about 0.6 mm, about 0.1 mm to about 0.5 mm, about 0.3 mm to about 0.5 mm, about 0.3 mm to about 0.4 mm, about 0.2 mm to 0.4 mm, about 0.1 mm to 0.2 mm, or about 0.4 mm to about 0.6 mm; about 0.57 mm, about 0.50 mm, about 0.41 mm, about 0.42 mm, about 0.37 mm, about 0.34 mm, about 0.31 mm, about 0.26 mm, or about 0.15 mm.

[0198] d. Intercalant Manufacturing

[0199] Inserts can be made by mixing the API with a matrix polymer. In some embodiments, the matrix polymer is a solution of a polymer in a solvent (e.g., water or ethanol). The API, 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 18-25G cannula or a dispensing tip. In some embodiments, a 21-23G cannula or a dispensing tip is used. For example, the specification of the cannula or the dispensing tip can be 20, 21, 22, or 23. The extruded paste is referred to herein as an extrudate, an elongated matrix, or a rod. The length of the rod can be about 4-5 inches (about 10-13 cm). The extrudate is solid at room temperature. The extrudate can have one or more additional layers for coating. In some embodiments, the extrudate is dried at room temperature for at least 24 hours before coating.

[0200] During the extrusion process, extrusion parameters such as fluid pressure, flow rate, and temperature of the extruded material can be controlled. An appropriate extruder can be selected to deliver the coextruded material at sufficient pressure and flow rate to form a product with a die and exit port or dispensing tip of a certain size to produce a product that can be injected through a needle or cannula as described herein.

[0201] If a polymer solution is used and the extrudate is to be coated, the extruded API-polymer mixture is allowed to dry prior to coating. For example, the extrudate may be dried at room temperature for about 30 minutes to about 48 hours prior to coating.

[0202] The extrudate may be coated with one or more layers, although in some embodiments no coating is applied. Preferably, the coating is applied prior to segmentation into the desired insertion lengths. The coating may be applied by dipping the extrudate into a liquid coating material and allowing it to dry or harden. The process may be repeated to add additional layers of coating. Alternatively, the coating may be sprayed onto the extrudate.

[0203] In other embodiments, the coating / outer layer may be preformed, for example into a tube, and the API-polymer paste may be extruded into the tube.

[0204] Depending on the polymer used for the matrix, the extruded rods can be cured. Curing can be performed, for example, by heating in an oven, microwave heating or chemical treatment.

[0205] In certain embodiments, matrix rod is uncured or heat-cured at a temperature lower than 80 ℃.In other embodiments, matrix rod is cured for about 15 minutes to about 4 hours at a temperature of about 80 ℃ to about 160 ℃.In certain embodiments, matrix rod is cured for about 15 minutes to about 4 hours at a temperature of about 120 ℃ to about 160 ℃.In other embodiments, matrix rod is cured for about 10 minutes to about 4 hours at about 130 ℃ to about 150 ℃ (for example, about 130 ℃ to about 140 ℃ or about 140 ℃ to about 150 ℃).In other embodiments, matrix rod is cured for about 30 minutes to about 4 hours at about 130 ℃ to about 150 ℃. For example, the curing time can be about 15 minutes, about 30 minutes, about 45 minutes, about 60 minutes, about 75 minutes, about 90 minutes, about 105 minutes, or about 120 minutes, and the curing temperature can be about 120° C., about 125° C., about 130° C., about 135° C., about 140° C., about 145° C., about 150° C., about 155° C., or about 160° C. After curing, the rod can be allowed to cool to room temperature before performing other manufacturing steps. If the insert is to be coated, the coating can be applied before or after curing.

[0206] The drug release rates of uncoated and PVA coated PVA matrix inserts were evaluated. The inventors found that, in general, the higher the curing temperature and the longer the curing time, the slower the drug release rate, but also the slower the erosion.

[0207] When all curing, cooling and / or coating and drying steps are complete, the rod is divided into inserts of about 1 mm to about 15 mm in length, such as about 1 mm to about 10 mm or about 2 mm to about 6 mm in length. For example, the rod can be divided into inserts of about 1 mm, about 1.5 mm, about 2 mm, about 2.5 mm, about 3 mm, about 3.5 mm, about 4 mm, about 4.5 mm, about 5 mm, about 5.5 mm, about 6 mm, about 6.5 mm, about 7 mm, about 7.5 mm, about 8 mm, about 8.5 mm, about 9 mm, about 9.5 mm, about 10 mm, about 10.5 mm, about 11 mm, about 11.5 mm, about 12 mm, about 12.5 mm, about 13 mm, about 13.5 mm, about 14 mm, about 14.5 mm, or about 15 mm.

[0208] The rod may be segmented or cut into a series of shorter products by any suitable technique for segmenting the rod, which may vary depending on whether the product is cured, uncured, or partially cured. For example, the segmentation station may employ pliers, scissors, a slicing blade, or any other technique. The technique applied may vary depending on the configuration desired for each segmented portion of the product. For example, when open ends are desired, a shearing action may be appropriate. However, if it is desired to seal each end when cutting, pliers may be used.

[0209] In some embodiments, the extrudate is dip coated in an aqueous PVA solution wherein the PVA concentration is about 1% w / w to about 15% w / w, about 1% w / w to about 10% w / w, about 2% w / w to about 10% w / w, about 2% w / w to about 8% w / w, about 2% w / w to about 6% w / w, about 3% w / w to about 6% w / w, about 2% w / w, about 2.5% w / w, about 3% w / w, about 3.5% w / w, about 4% w / w, about 4.5% w / w, about 5% w / w, about 5.5% w / w, about 6% w / w, about 6.5% w / w, about 7% w / w, about 7.5% w / w, about 8% w / w, about 8.5% w / w, about 9% w / w, about 9.5% w / w, or about 10% w / w.

[0210] The coated extrudate may then be air dried. The dip coating process may be repeated 1-10 times, preferably 1-6 times or 1-5 times, with air drying between each coating process. The coated extrudate may then be cured as described above. After cooling, the extrudate is then divided into inserts.

[0211] e. Intercalant Characteristics

[0212] Some ocular diseases, including those described above, may require treatment for the remainder of a patient's life. Currently available treatments require repeated treatments. However, repeated treatments by implanting a drug delivery device into the eye are limited for devices containing non-biodegradable materials because non-biodegradable residues of the device accumulate in the eye. Therefore, it would be highly beneficial to the patient to provide an implantable drug delivery device that would completely erode when or shortly after the next device needs to be implanted.

[0213] However, it is extremely challenging to design a drug release device that provides controlled release of therapeutic levels of a drug over a considerable period of time, which can also completely erode within, for example, a few months or about a year. Many materials that effectively control drug release over a considerable period of time are not bioerodible or erode too slowly.

[0214] Additionally, providing a drug delivery device that is small enough to be implanted in a patient's eye with minimal discomfort, yet is able to contain sufficient drug load to provide sustained release of the drug, adds significantly to the above challenges. The difficulty in handling and processing such devices without significant damage also adds to the challenges.

[0215] The inventors have overcome these challenges and provided a drug delivery device that is small enough to be implanted in the eye with minimal discomfort, capable of providing sustained release of drug for months while completely eroding sometime after the device's drug delivery period has ended. In addition, the inventors have discovered a method of providing devices with varying drug delivery periods / durations and delivery rates. In addition, these devices provide a substantially linear release of drug after an initial burst of drug delivery. Furthermore, the insert has a very high drug content relative to the inactive ingredients in the insert, which is surprising given the insert's ability to provide drug release over an extended period of time.

[0216] i. Intercalant Erosion:

[0217] In some embodiments, the insert is capable of completely eroding within 365 days. The erosion ability of the insert over a given time period can be evaluated using the following erosion assessment protocol. The sample insert is placed in a 10 mL glass vial containing 5 mL of phosphate buffered saline (PBS) and incubated at 37°C, with the PBS in the bottle replaced every 24 hours each day for the time period of interest (e.g., 365 days, 200 days, 110 days). At the end of this time period, the insert is removed from the vial, allowed to dry, then visually inspected and weighed. The weight loss compared to the original weight is calculated as follows:

[0218]

[0219] For example, if an insert that originally weighed 500 μg weighs 200 μg after 200 days of incubation in PBS, the insert weighs 40% of its original weight and has lost 60% of its weight according to the Erosion Evaluation Protocol. It has experienced 60% erosion in 200 days. An insert is considered fully eroded when less than 10% of its original weight remains. In some embodiments, the insert is capable of at least 20% erosion within 95 days, at least 25% erosion within 95 days, at least 30% erosion within 110 days, at least 30% erosion within 110 days, at least 40% erosion within 180 days, at least 30% erosion within 180 days, at least 40% erosion within 180 days, at least 50% erosion within 180 days, at least 60% erosion within 180 days, at least 40% erosion within 220 days, at least 50% erosion within 220 days, at least 60% erosion within 220 days, at least 70% erosion within 280 days. At least 60% erosion within 280 days, at least 70% erosion within 280 days, at least 80% erosion within 280 days, at least 60% erosion within 365 days, at least 70% erosion within 365 days, at least 80% erosion within 365 days, at least 90% erosion within 365 days, at least 70% erosion within 400 days, at least 80% erosion within 400 days, at least 90% erosion within 400 days, at least 70% erosion within 440 days, at least 80% erosion within 440 days, or at least 90% erosion within 440 days as measured using the Erosion Assessment Program.

[0220] ii. Drug release rate

[0221] The inventors have found that the curing temperature, curing duration and insert surface area all affect the release rate. The release rate increases as the diameter remains constant with increasing length. When the diameter remains constant, increasing the length can increase the release rate.

[0222] In some embodiments, the drug release rate of the insert is about 0.01 μg / day to about 100 μg / day, about 0.01 μg / day to about 90 μg / day, about 0.01 μg / day to about 80 μg / day, about 0.01 μg / day to about 70 μg / day, about 0.01 μg / day to about 50 μg / day, about 0.01 μg / day to about 20 μg / day, about 0.01 μg / day to about 10 μg / day, about 0.1 μg / day to about 60 μg / day, about 0.1 μg / day to about 50 μg / day. In some embodiments, the release rate is about 0.1 μg / day to about 40 μg / day, about 0.1 μg / day to about 30 μg / day, about 0.1 μg / day to about 20 μg / day, about 0.1 μg / day to about 10 μg / day, about 0.1 μg / day to about 5 μg / day, about 0.1 μg / day to about 2 μg / day, about 0.1 μg / day to about 1 μg / day, about 1 μg / day to about 40 μg / day, about 1 μg / day to about 30 μg / day, about 1 μg / day to about 20 μg / day, or about 1 μg / day to about 10 μg / day. In some embodiments, this is the release rate after steady-state release is reached. In some embodiments, this is the release rate after 2 days, 3 days, 5 days, 8 days, 10 days, 15 days, 20 days, 25 days, 30 days, 40 days, 50 days, 60 days, 70 days, 80 days, 90 days, 100 days, 105 days, or 110 days of drug release.

[0223] In some embodiments, the insert has a release rate of 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 as measured by an in vitro Drug Release Method.

[0224] The following in vitro drug release method was used to evaluate the amount of drug released: The insert was placed in a 10 mL glass tube and 5 mL of PBS was added to the tube. The tube was incubated in a water bath at 37°C. The medium samples were collected every day during the period and the release medium was replaced with fresh PBS. The amount of API released can be quantitatively measured by HPLC as described in Example 2B.

[0225] The duration (total length of time) during which the insert releases the API can be between about 90 days to about 365 days, about 90 days to about 260 days, about 90 days to about 200 days, or at least about 8 weeks, at least about 10 weeks, at least about 12 weeks, at least about 18 weeks, at least about 22 weeks, at least about 28 weeks, at least about 30 weeks, at least about 36 weeks, at least about 40 weeks, at least about 44 weeks, or at least about 52 weeks. The above in vitro drug release assay can be used to determine whether the insert releases the drug over this duration.

[0226] In some embodiments, the inserts of the present invention provide an initial rapid release or burst of drug in vivo over a period of time before a steady-state rate is reached. In preferred embodiments of the present invention, the initial period of rapid release is much less than the total duration of API release (e.g., less than 10%). In some embodiments, the initial period is, for example, 1 to 120 days, 20 to 120 days, 80 to 120 days, 1 to 20 days, 2 to 50 days, 3 to 40 days, 5 to 60 days, 1 day, 2 days, 3 days, 4 days, 5 days, 8 days, 10 days, 12 days, 15 days, 20 days, 25 days, 30 days, 40 days, 50 days, 60 days, 70 days, 80 days, 90 days, 100 days, 105 days, 110 days. In in vitro studies conducted on rabbit eyes, the inventors found that the initial burst of drug release was unexpectedly high, meaning that the initial release of API from the insert was faster than expected before settling to a steady state. This burst may be beneficial because it allows rapid achievement of C max and balance, thereby quickly providing a therapeutically effective amount to the eye. After this burst, the API release rate tends to stabilize to provide a therapeutically effective amount of API every day.

[0227] In preferred embodiments, the insert of the invention releases the drug at a substantially constant rate (i.e., zero-order drug release kinetics, R) for a predetermined duration of time after implantation, such as 14 days, 28 days, 42 days, 56 days, 168 days, 180 days, 224 days, 300 days, or 365 days. 2 Release API for 0.7-1).

[0228] The duration of substantially constant release of the API from the insert may be from 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 30 weeks, at least 32 weeks, at least 36 weeks, at least 40 weeks, at least 44 weeks, at least 48 weeks, or at least 52 weeks.

[0229] 3. Treatment

[0230] a. Administration of Ocular Drug Delivery Inserts

[0231] An ocular drug delivery insert is an implantable device. An "ocular drug delivery insert" includes all inserts described herein.

[0232] The ocular drug delivery insert may be administered in the eye of a subject in need thereof to prevent or treat an ocular disease or condition. In some embodiments, the ocular drug delivery insert is administered to treat anterior ocular diseases. In other embodiments, it may be administered to treat posterior ocular diseases. In some embodiments, the ocular drug delivery insert is administered to prevent anterior ocular diseases. In other embodiments, it may be administered to prevent posterior ocular diseases.

[0233] "Anterior ocular disease" refers to a disease, ailment, or disorder that affects or involves the anterior ocular region (i.e., the front part of the eye, also called the anterior segment of the eye) or structures, such as the periocular muscles or eyelids, or the fluid located in front of the posterior wall of the lens capsule or the ciliary muscle. Thus, an anterior ocular disease may affect or involve the conjunctiva, cornea, anterior chamber, iris, posterior chamber (located between the iris and lens), lens or lens capsule, and blood vessels and nerves in vascularized or neurotized anterior ocular regions or areas.

[0234] Anterior ocular disease may include diseases, ailments, or diseases such as, but not limited to, glaucoma.

[0235] A "posterior ocular disease" is a disease, ailment, or disorder that primarily affects or involves the posterior ocular region or structures (i.e., the back of the eyeball, also known as the posterior segment), such as the choroid or sclera (located posteriorly through the plane of the posterior wall of the lens capsule), the vitreous body, the vitreous chamber, the retina, the optic nerve or optic disc, and the blood vessels and nerves of the vascularized or neurotized posterior ocular region or area.

[0236] Posterior ocular disease may include the following diseases, ailments or diseases, for example, including but not limited to: acute macular neuroretinopathy; Behcet's disease; geographic atrophy; choroidal neovascularization; diabetic uveitis; histoplasmosis; infections, such as those caused by fungi, bacteria or viruses; macular degeneration, such as neovascular macular degeneration, acute macular degeneration, non-exudative age-related macular degeneration and exudative age-related macular degeneration; edema, such as macular edema, cystoid macular edema and diabetic macular edema; multifocal choroiditis; ocular trauma involving the posterior ocular site or location; ocular tumors; retinal diseases, such as retinal vein occlusion, central retinal vein occlusion, diabetic retinopathy (including proliferative diabetic retinopathy), proliferative Proliferative vitreoretinopathy (PVR), hypertensive retinopathy, retinal artery occlusive disease such as central retinal artery occlusion (CRAO) and branch retinal artery occlusion (BRAO), retinal detachment, uveitic retinal disease; sympathetic ophthalmia; uveal-meningeal (Vogt-Koyanagi-Harada) (VKH) syndrome; uveal diffusion; posterior ocular disease caused by or affected by ocular laser therapy; or caused by or affected by photodynamic therapy, photocoagulation, radioretinopathy, epiretinal membrane disease, branch retinal vein occlusion, anterior ischemic optic neuropathy, non-retinopathy diabetic retinopathy, and retinitis pigmentosa. Glaucoma may also be considered a posterior ocular disease because the goal of treatment is to prevent or reduce the occurrence of vision loss due to damage or loss of retinal cells or optic nerve cells (e.g., through neuroprotection).

[0237] Thus, the present invention provides methods for preventing or treating various ocular diseases by administering an ocular drug delivery insert into the eye of a subject in need thereof.

[0238] The API in an insert administered for a particular ocular disease or condition is selected based on the suitability of the API for that particular ocular disease. Thus, for example, an insert administered to reduce intraocular pressure would contain an API effective to reduce intraocular pressure.

[0239] In some embodiments, the insert is administered to a subject in need for the prevention or treatment of macular degeneration, such as age-related macular degeneration ("AMD"), such as dry AMD and wet AMD. The insert may be administered to prevent the death of retinal pigment epithelial cells. The insert may be administered to inhibit angiogenesis. In some embodiments, the insert is administered to a subject to prevent or treat vision loss, such as vision loss associated with macular degeneration. In addition, the insert may be administered to prevent or delay the progression of dry AMD to wet AMD. In some embodiments, the insert is administered to a subject in need to prevent or treat retinal vein occlusion, such as central retinal vein occlusion ("CRVO") or branch retinal vein occlusion ("BRVO"). In other embodiments, the insert may be administered to prevent or treat non-ischemic retinal vein occlusion or ischemic retinal vein occlusion. In other embodiments, the insert is administered to treat diabetic retinopathy in the eye of a subject in need. In some embodiments of these methods, the insert includes a VEGF inhibitor, a kinase inhibitor (such as 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 intercalating agent comprises voronib or a pharmaceutically acceptable salt thereof. In other embodiments, the intercalating agent comprises axitinib or a pharmaceutically acceptable salt thereof. In other embodiments, the intercalating agent comprises ralostadil or a pharmaceutically acceptable salt thereof or a zwitterion.

[0240] In some aspects, an insert is administered in the eye of a subject in need thereof to inhibit VEGFR and / or PDGFR. In some embodiments, the insert administered for inhibiting VEGFR and / or PDGFR comprises voronib or a pharmaceutically acceptable salt thereof. In other embodiments, the insert comprises axitinib.

[0241] In other embodiments, the intercalant is administered to activate Tie-2. In some embodiments of the method, the intercalant comprises a Tie-2 activator. In another embodiment, the Tie-2 activator is rerotafil or a pharmaceutically acceptable salt or zwitterion thereof.

[0242] The present invention also provides a method for treating glaucoma in a subject in need thereof, comprising administering a drug delivery insert. In some embodiments, the insert is administered in the eye of a subject in need thereof to treat elevated intraocular pressure (IOP). In other embodiments, the insert is administered in the eye of a subject in need thereof to reduce intraocular pressure. In another embodiment, the subject has elevated intraocular pressure. In another embodiment, the subject suffers from high intraocular pressure. In another embodiment, the subject suffers from glaucoma. The reduction in IOP can be assessed by determining the difference in the subject's IOP (in millimeters of mercury (mmHg)) 60 days after implantation of the insert relative to the baseline subject's IOP before treatment. In some embodiments of these methods, the insert comprises a Tie-2 activator. In another embodiment, the Tie-2 activator is ralostadil or a pharmaceutically acceptable salt or zwitterion thereof. In other embodiments of these methods, the insert comprises an α2-adrenergic receptor. In another embodiment, the α2-adrenergic receptor is brimonidine or a pharmaceutically acceptable salt thereof.

[0243] In other embodiments, the insert is administered to treat uveitis. In another embodiment, the insert is administered to treat chronic non-infectious uveitis affecting the posterior segment of the eye. In some embodiments, the insert is administered to treat post-operative inflammation of the eye. In some embodiments of these methods, the insert comprises a steroidal anti-inflammatory agent.

[0244] In some embodiments, the present invention provides a method of treatment comprising administering an ocular drug delivery insert of the present invention comprising a VEGF inhibitor. In some embodiments of these methods, the VEGF inhibitor is voronib or a pharmaceutically acceptable salt thereof. The present invention also includes combination therapy, such as treating a subject with a VEGF inhibitor and a Tie-2 activator or treating a subject with a VEGF inhibitor and a steroidal anti-inflammatory agent.

[0245] Thus, in some embodiments of the method of administering a VEGF inhibitor, the method further comprises administering a Tie-2 activator, such as ralostadil or a pharmaceutically acceptable salt or zwitterion thereof. In some embodiments of the method, the Tie-2 activator is administered in an ocular drug delivery insert of the present invention.

[0246] In other embodiments of the method of administering a VEGF inhibitor, the method further comprises administering a steroidal anti-inflammatory agent, such as fluocinolone acetonide. In some embodiments of the method, the steroidal anti-inflammatory agent is administered in an ocular drug delivery insert of the present invention.

[0247] In other embodiments, the present invention provides a method of treatment comprising administering an ocular drug delivery insert of the present invention comprising a Tie-2 activator. In other embodiments of the method, the method further comprises administering a VEGF inhibitor. In some embodiments of the method, the Tie-2 activator is ralostadil or a pharmaceutically acceptable salt or zwitterion thereof. In other embodiments of the method, the VEGF inhibitor is voronib or a pharmaceutically acceptable salt thereof. In further embodiments, the VEGF inhibitor is aflibercept, bevacizumab, or ralostadil.

[0248] In the combination therapy of the present invention, i.e., in methods of administering more than one API to a subject being treated, the different APIs administered may be administered in the same ocular drug delivery insert, in separate inserts, or one API may be delivered in an ocular drug delivery insert of the present invention, while the other APIs may be administered in another pharmaceutical formulation, which may be a different type of dosage form. For example, the dosage form may be a different type of ocular implant, eye drops, solution for injection, or suspension for injection. In addition, the different APIs administered may be administered simultaneously in the same injection, or administered as separate injections during the same procedure, or administered at different times. When different APIs are administered at different times, it is contemplated that the dosage form or insert for delivering the first API is still releasing / delivering the first API when the dosage form or insert containing the other API is administered.

[0249] Various embodiments of the present invention are generally used to deliver therapeutically effective concentrations of an API topically (e.g., to the eye of a subject). In some embodiments, methods for treating an ocular disease include placing an insert on the surface of or in the eye, such as on the vitreous or aqueous humor of the eye. In some embodiments, the insert of the present invention can be delivered to any site in or on the eye, for example, the anterior or posterior.

[0250] Administration of the insert may include inserting the insert into the eye of the subject, such as inserting the insert into the aqueous humor, or preferably inserting the vitreous body of the eye. Administration of the insert may include surgical implantation of the insert into or on the eye, such as a scleral implant, a subconjunctival implant, an implant on the choroid, an implant on the sclera, or an intravitreal implant. The insert may be surgically implanted into the eye of the subject, such as implanted in the vitreous body of the eye, under the retina, or on the sclera. In certain embodiments, the insert may be placed by needle or cannula injection. The insert may gradually release the API into the eye, thereby avoiding the pain of frequent administration.

[0251] In some embodiments, the insert is injected into the eye of the subject, preferably without the need for an incision. In some aspects, the insert is injected into the vitreous of the eye. In preferred embodiments, administering the insert comprises intravitreal injection.

[0252] In some embodiments, a needle or cannula having a gauge size of 20-27G is used for injection. In other embodiments, a needle or cannula having a gauge size of 25 to 27G is used. In a preferred embodiment, a needle less than 25G is used for injection, for example, a needle having a gauge of 25.5, 26, 26.5 or 27G.

[0253] In some embodiments of the method of administration of the present invention, topical and / or subconjunctival anesthesia may be administered at the injection site prior to injection of the insert. In addition, a broad-spectrum antiseptic may be administered to the inferior fornix. The insert may be placed below the optic disc and behind the equator of the eye. The conjunctiva may be displaced so that after the needle is removed, the conjunctival and scleral needle entry sites will not be aligned. The needle for injecting the insert may be inserted through the conjunctiva and sclera, up to the front stop of the applicator, and the plunger depressed to deliver the insert to the back of the eye.

[0254] b. Subjects

[0255] The subject can be selected from rodents, lagomorphs, sheep, pigs, dogs, cats, horses, cattle and primates. In preferred embodiments, the subject is a human. In some embodiments of the methods of treatment provided herein, the subject is in need of the treatment because the subject has the disease being treated. In some embodiments of the methods of prevention provided herein, the subject is in need of prevention of the disease because the subject is at risk of the disease.

[0256] c. Dosage

[0257] In some embodiments, the total API dose delivered is about 0.0001 μg / day to about 200 μg / day, about 0.0001 μg / day to about 150 μg / day, about 0.0001 μg / day to about 100 μg / day, about 0.0001 μg / day to about 80 μg / day, about 0.0001 μg / day to about 50 μg / day, about 0.0001 μg / day to about 30 μg / day, about 0.0001 μg / day to about 10 μg / day, about 0.0001 μg / day to about 5 μg / day, about 0.0001 μg / day to about 200 μg / day, about 0.0001 μg / day to about 1 In some embodiments, the dosage is from about 0.001 μg / day to about 100 μg / day, from about 0.001 μg / day to about 80 μg / day, from about 0.001 μg / day to about 60 μg / day, from about 0.001 μg / day to about 40 μg / day, from about 0.001 μg / day to about 30 μg / day, from about 1 μg / day to about 25 μg / day, from about 0.001 μg / day to about 20 μg / day, from about 0.001 μg / day to about 15 μg / day, from about 0.001 μg / day to about 10 μg / day, from about 0.001 μg / day to about 8 μg / day, from about 0.0005 μg / day to about 15 μg / day, or from about 0.005 μg / day to about 10 μg / day. In some embodiments, this is the dose delivered after steady state is reached.

[0258] In some embodiments, the API is voronib and the total dose of voronib delivered is about 0.1 μg / day to about 100 μg / day, about 0.5 μg / day to about 80 μg / day, about 1 μg / day to about 50 μg / day, about 1 μg / day to about 40 μg / day, about 1 μg / day to about 30 μg / day, about 1 μg / day to about 25 μg / day, about 1 μg / day to about 20 μg / day, about 1 μg / day to about 15 μg / day, about 1 μg / day to about 10 μg / day, about 1 μg / day to about 8 μg / day, about 4 μg / day to about 15 μg / day, or about 5 μg / day to about 10 μg / day. In some embodiments, this is the dose delivered after steady state is achieved.

[0259] In some embodiments, the API is axitinib and the total dose of axitinib delivered is about 0.0001 μg / day to about 100 μg / day, about 0.0001 μg / day to about 80 μg / day, about 0.0001 μg / day to about 50 μg / day, about 0.0001 μg / day to about 40 μg / day, about 0.0001 μg / day to about 30 μg / day, about 0.001 μg / day to about 25 μg / day, about 0.0001 μg / day to about 20 μg / day, about 0.0001 μg / day to about 15 μg / day, about 0.001 μg / day to about 10 μg / day, about 0.001 μg / day to about 8 μg / day, about 0.001 μg / day to about 15 μg / day, or about 0.005 μg / day to about 10 μg / day. In some embodiments, this is the dose delivered after steady state is achieved.

[0260] This dosage (e.g., 1-6 inserts) can be achieved by a single administration (i.e., a single treatment in one eye). Therefore, a treatment may require a single administration of 1 insert, 2 inserts, 3 inserts, 4 inserts, 5 inserts, or 6 inserts in each eye of the subject. In some embodiments, the subject may receive treatment for only one eye or both eyes. If more than one insert is to be injected for a single treatment, the inserts may be injected separately in separate injections, or several inserts may be injected in a single injection. For example, 1, 2, or 3 inserts may be injected in a single injection. If multiple inserts need to be injected for a single treatment, they may be divided into several injections. For example, if 4-6 inserts are to be injected for a single treatment, they may be divided into 2 or 3 injections, with 2-3 inserts injected each time.

[0261] Each insert may contain about 1 μg to about 3000 μg, about 10 μg to about 2000 μg, about 10 μg to about 1000 μg, about 100 μg to about 500 μg, about 10 μg to about 800 μg, about 50 μg to about 600 μg, about 200 μg to about 2000 μg, about 600 μg to about 2000 μg, about 800 μg to about 2000 μg, about 800 μg to about 1500 μg, about 100 μg to about 500 μg, about 100 μg to about 300 μg, or about 300 μg to about 550 μg of voronib. For example, each insert may contain about 400 μg, about 420 μg, about 440 μg, about 480 μg, about 500 μg, about 520 μg, about 540 μg, about 560 μg, about 580 μg, about 600 μg, about 620 μg, about 640 μg, about 660 μg, about 680 μg, about 700 μg, about 720 μg, about 740 μg, about 780 μg. , about 800 μg, about 820 μg, about 840 μg, about 860 μg, about 880 μg, about 900 μg, about 920 μg, about 940 μg, about 960 μg, about 980 μg, about 1000 μg, about 1020 μg, about 1040 μg, about 1045 μg, about 1060 μg, about 1080 μg or about 2000 μg of an API, such as voronib.

[0262] The total amount of API (e.g., voronib) in all inserts (total payload) is about 200 μg to about 6000 μg, about 600 μg to about 6000 μg, about 800 μg to about 6000 μg, about 600 μg to about 5040 μg, about 600 μg to about 4500 μg, about 1000 μg to about 5400 μg, about 1000 μg to about 3000 μg, or about 2000 μg to about 4000 μg. For example, the total API amount of all inserts is about 1400 μg, about 1420 μg, about 1500 μg, about 1600 μg, about 1800 μg, about 1900 μg, about 1980 μg, about 2000 μg, about 2040 μg, about 2080 μg, about 3000 μg, about 3120 μg, about 3180 μg, about 3240 μg, about 3400 μg, about 3600 μg, about 3800 μg, about 4000 μg, about 4140 μg, about 4160 μg, about 4180 μg, about 4200 μg, about 4400 μg, about 4600 μg, about 5000 μg or about 5040 μg.

[0263] 4. definition

[0264]

[0026] The following words and phrases used in the specification and claims generally have the meanings described below, unless the context of their use dictates otherwise.

[0265] Unless the context clearly dictates otherwise, the singular forms "a," "an," and "the" include plural references. For example, "a matrix polymer" refers to one or more matrix polymers.

[0266] As used herein, the terms "bioerode," "bioerosion," "biodegrade," and "biodegradation" refer to the gradual disintegration, dissolution, or breakdown of an intercalant in a biological system over a period of time, such as 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).

[0267] The term "prevention," when used in relation to a disease, refers to the administration of an agent to reduce the frequency or delay the onset of symptoms of a medical disease in a subject relative to a subject not receiving the agent. Thus, prevention of macular degeneration includes, for example, reducing the number of diagnoses of macular degeneration in a treated population compared to an untreated control population, and / or delaying the onset of symptoms of macular degeneration in a treated population compared to an untreated control population. Prevention of dry macular degeneration includes, for example, reducing the number of detectable drusen in a population of subjects receiving preventive treatment compared to an untreated control population, and / or delaying the onset of detectable drusen in a treated population compared to an untreated control population, e.g., by a statistically and / or clinically significant amount. Prevention of vision loss includes, for example, reducing or delaying the extent to which a subject experiences vision loss in a treated population compared to an untreated control population.

[0268] The term "treat" refers to the reduction, improvement or stabilization of an existing undesirable condition.

[0269] The term "room temperature" refers to 22°C. "Solid at room temperature" refers to a solid at a temperature of 22°C.

[0270] When the term "about" is used in conjunction with a numerical value or range, it modifies the numerical value or range by extending the boundaries above and below the stated numerical value. Generally speaking, the term "about" is used herein to modify a numerical value above or below the stated value by a variance of 10%, up or down (higher or lower), i.e., ±10%, unless a different variance (variance) is indicated (e.g., ±30%, ±20%, ±5%, ±1%, ±0.5%, etc.).

[0271] The term "and / or" refers to and includes each listed item individually and any and all possible combinations of one or more of the listed items.

[0272] The terms "comprising," "consisting of," and "consisting essentially of" have their generally accepted meanings under patent law. When the term "includes" or "including" is used in the specification or claims, it is intended to be inclusive in a manner similar to the term "comprising" in that the term is interpreted as comprising when used as a transitional word in a claim.

[0273] The terms "optional" and "optionally" mean that the subsequently described event may or may not occur, and that the description includes instances where the event occurs and instances where it does not.

[0274] Where features or aspects of the disclosure or claims are described in terms of Markush groups, the described group includes any individual member and subgroup of members of the Markush group.

[0275] As will be understood by those skilled in the art, all language (e.g., "up to," "at least," "greater than," "less than") includes the stated numbers and refers to ranges that can be subsequently subdivided into subranges. Finally, as will be understood by those skilled in the art, ranges include each individual member and include the endpoints of the range. For example, a group having 1-3 members refers to groups having 1, 2, or 3 members. Similarly, a group having 1-5 members refers to groups having 1, 2, 3, 4, or 5 members, and so forth.

[0276] As used herein, the term "substantially all" refers to a majority 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.

[0277] The term "% w / w" refers to the proportion of a particular substance in a mixture, measured by weight or mass. Thus, for example, for an insert whose core comprises at least about 8% w / w inactive ingredients, the total weight of the inactive ingredients in the core is at least about 8% of the total weight of the core. For example, if the total weight of the core is 100 mg, the weight of the inactive ingredients in the core is at least 8 mg.

[0278] The term "% w / v" refers to the weight percentage of an ingredient (eg, a solute) in the total volume of a solution. A 2% w / v PVA solution means there are 2 grams of PVA in 100 mL of solution. A 2% w / w PVA solution means there are 2 grams of PVA in 100 mg of solution.

[0279] All cited patents, published applications, scientific publications, and books are incorporated herein by reference in their entirety.

[0280] While various aspects and embodiments have been disclosed herein, other aspects and embodiments will be apparent to those skilled in the art.

[0281] Example

[0282] Example 1

[0283] The PVA grades listed in the table below were made into films and then evaluated for erosion rate and strength.

[0284] To form the membranes, a 4.5% aqueous solution of PVA was poured into a tray and air dried at room temperature. While the membranes were drying, the membranes were cut into 1x1 square samples. Six samples of each membrane were then cured at 100°C for 3 hours, 140°C for 30 minutes, or 140°C for 4 hours, as described in the table below. After the sample membrane squares were cured, they were weighed and imaged. Each sample was then immersed in PBS for 24 hours at room temperature. The samples were then removed from the PBS, and 4 of each grade of PVA were dried at 50°C for 2 hours, and 2 of each grade of PVA were air dried on a paper towel at room temperature, as described in the table below. The samples were then weighed and imaged again.

[0285]

[0286] Calculate the average weight change after immersion in PBS for 24 hours and Figure 2 The PVA degree of hydrolysis (DH) and molecular weight (MW) determine the solubility of the film. Under all curing conditions tested, the 6000 / 80%, 25000 / 88%, 125000 / 88% and 6000 / 80%-125000 / 88% mixed PVA films dissolved at the end of the first day. The 78000 / 98% film lasted the longest. The relative film strength of the tested films is shown in Figure 1. Figure 3 shown.

[0287] Example 2A

[0288] Make the insert according to the parameters in the table below:

[0289]

[0290]

[0291] Inserts were made by mixing voronib with a 78000 / 98% PVA solution in water at the w / w voronib:PVA solution ratios specified in the table above. The mixture was then extruded from a 20, 21 or 23G dispensing tip and dried at room temperature.

[0292] For coated inserts, the extrudates were then dipped in a 78000 / 98% PVA solution and air dried. The dipping process was repeated to achieve the number of coats specified in the table above. The coating process consisted of dipping the extrudates in the PVA solution with 5 minutes of room temperature drying between the first layers and then a minimum of 10 minutes of drying time before dipping to form the final layer / coating. The coated extrudates were then cured as per the table. After cooling to ambient temperature, the extrudates were cut into 2 mm, 3.5 mm, 5 mm or 6 mm or 8 mm long inserts.

[0293] Example 2B

[0294] 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 water bath at 37°C. Samples of the release medium were collected at intervals of 12 to 24 hours and replaced with fresh PBS. The amount of voronib 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 based on the cumulative release time.

[0295] Example 2C

[0296] The insert samples were analyzed for API content. Cut the insert of the test content into 4 pieces and place all 4 pieces in a labeled scintillation vial. Use a pipette to transfer 3.0 mL of methanol to the vial and place the vial under the cabinet. Repeat this step for all samples. Place the sample vial in a sonicator, add an appropriate amount of water, and sonicate the sample for 30 minutes. Repeat the sonication for 5 more times, cooling the sonicator between each sonication. Perform additional sonication as needed to ensure complete dissolution of the API. HPLC was performed using the following parameters: Column: ZORBAX Eclipse XDB-C18; 4.6X150mm; 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: 214nm.

[0297] Example 2D

[0298] The 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 stirring. The PBS in the vial was replaced every 24 hours on each day of the period of interest. At the end of the period, the sample was removed from the vial, weighed and photographed.

[0299] The drug release rate curve of the 4.5% PVA coating formulation (referred to as formulation A) cured at 140°C for 4 hours is shown in FIG. Figure 4A (Cumulative drug release percentage) and Figure 4B (Cumulative drug release (μg)) is shown in the figure. The drug release rate curve of the uncoated formulation A implant is shown in Figure 6 shown. Figure 5 Shown are photographs of eroded Formulation A implants taken after immersion in dissolution medium for 314 and 447 days. The 447 day photograph includes the intact implant for comparison. Figure 7 Shown are photographs of eroded uncoated Formulation A implants taken after immersion in dissolution medium for 287 and 352 days. The 352 day photograph includes the intact implant for comparison.

[0300] The drug release rate curves of the 4.5% PVA coating formulation (referred to as Formulation B) cured at 140°C for 30 minutes are shown in Figure 8 (cumulative drug release percentage) and Figure 8B (Cumulative drug release (μg)) is shown. Fig. 9 Shown are photographs of eroded Formulation B implants taken after immersion in dissolution medium for 59, 88 and 155 days.

[0301] The drug release rate curve of the uncured coated 4.5% PVA formulation (referred to as formulation C) is shown in Fig.10 shown. Fig.11 Shown are two photographs of different samples of eroded Formulation C implants immersed in dissolution medium at 37°C for 98 days and then at room temperature for 113 days, respectively.

[0302] Comparison of drug release profiles of formulations A, B and C Fig.12 shown.

[0303] Formulation A releases drug more slowly and erodes more slowly than formulations B and C. Formulation C releases drug more quickly and erodes more quickly than formulations A and B.

[0304] Example 3

[0305] Intercalants containing more than one PVA grade were prepared according to the parameters in the following table:

[0306]

[0307] The insert was made by mixing voronib with an aqueous PVA solution at a 1:1 ratio of voronib:PVA solution w / w to form a paste. The mixture was then extruded from a 21G dispensing tip to form a rod approximately 4-5 inches long and dried at room temperature. The extrudate rods were cured as described in the table above.

[0308] The extrudates were dip coated in an aqueous PVA solution and dried at room temperature. For inserts with more than one coating, the coating process involved dipping the extrudates in a PVA solution with 5 minutes of room temperature drying between the first layers, followed by at least 10 minutes of drying time before dipping to form the final layer / coating.

[0309] After the final coat, the coated rods were cured according to the conditions described in the table above. After cooling to ambient temperature, the coated rods were cut into 8 mm long inserts using a razor blade.

[0310] API release was measured according to the method described in Example 2B.

[0311] The API content was measured according to the method described in Example 2C.

[0312] The erosion of the implant was evaluated according to the method described in Example 2D.

[0313] Intercalants containing more than one PVA grade were prepared according to the parameters in the following table:

[0314]

[0315]

[0316] The insert was made by mixing vorprotanab with an aqueous PVA solution at a 1:1 ratio of vorprotanab:PVA solution w / w to form a paste. The mixture was then extruded from a 21G dispensing tip to form a rod approximately 4-5 inches long and dried at room temperature. The extruded rods were cured as described in the table above.

[0317] The extrudates were dip coated in an aqueous PVA solution and dried at room temperature. For inserts with more than one coating, the coating process consisted of dipping the extrudates in a PVA solution with 5 minutes of room temperature drying between the first layers, followed by at least 10 minutes of drying time before dipping to form the final layer / coating.

[0318] After the final coat, the coated rods were cured according to the conditions described in the table above. After cooling to ambient temperature, the coated rods were cut into 8 mm long inserts using a razor blade.

[0319] API release was measured according to the method described in Example 2B.

[0320] The API content was measured according to the method described in Example 2C.

[0321] The erosion of the implant was evaluated according to the method described in Example 2D.

[0322] Example 4

[0323] Make the insert according to the parameters in the table below:

[0324]

[0325]

[0326]

[0327]

[0328] API and PVA aqueous solution were mixed in the API:PVA solution ratio specified in the table to form a paste. The paste was extruded through a dispensing tip with a 20-23G gauge to form a rod about 4-5 inches long and dried at room temperature. The extruded rods were cured before or after coating as described in the table above.

[0329] The extrudates were dip coated in an aqueous PVA solution. The coating process consisted of dipping the extrudates in the PVA solution with 5 minutes of room temperature drying between the first layers and then at least 10 minutes of drying time before dipping to form the final layer / coating. After the final coating, the coated bars were cured according to the table above or dried at room temperature for 24 hours.

[0330] The coated rods were cut into inserts of 2 mm, 3.5 mm, 5 mm or 6 mm length using a razor blade.

[0331] API release was measured according to the method described in Example 2B.

[0332] The API content was measured according to the method described in Example 2C.

[0333] The erosion of the implant was evaluated according to the method described in Example 2D.

[0334] Example 5 - Pharmacokinetic Study

[0335] Intravitreal pharmacokinetic studies were conducted in male Belted Rabbits. The purpose of this study was to characterize the plasma and ocular tissue pharmacokinetics of voronib inserts following bilateral intravitreal injections on day 1. Animals were evaluated up to 24 months after placement of the intravitreal inserts.

[0336] The following table describes the grouped dose levels and treatments.

[0337]

[0338] After administration of anesthesia, voronib inserts with a diameter of 0.37 mm and a length of 3.5 mm, designed to release the drug for at least 6 months, were injected intravitreally into each eye of 52 male Dutch-striped rabbits using a syringe. The low-dose group (1) received 3 inserts per eye for a total dose of 630 μg per eye. The high-dose group (2) animals received 6 inserts per eye, prescribed 2 separate injections (3 inserts per injection) for a total dose of 1260 μg per eye.

[0339] Prior to each scheduled sacrifice point, one whole blood sample was collected from two animals per group by marginal ear vein puncture. Samples were tested for levels of voronib and its metabolites. Two animals per group were euthanized at 6, 12, 24, and 48 hours on day 1, at days 7 and 14, and at 1, 2, 4, 6, 8, 16, and 24 months. Vitreous and ocular tissues were collected from both eyes for analysis of ocular tissue drug distribution, inserts were collected, and liver and kidney samples were collected for assessment of tissue distribution.

[0340] result: At steady state, vitreous levels of voronib were 56 ng / mL at a low dose of 630 μg and 97 ng / mL at a high dose of 1260 μg (~dose proportional). Retinal / choroidal levels were 49 ng / g and 89 ng / g, respectively. There was a burst of drug release during the first 90 days, followed by steady state. Steady state was reached on day 105. Maximum concentrations observed in the vitreous and retina / choroid appeared to be nearly dose proportional. After 99 days, no significant changes in plasma levels were found. By day 180, vitreous C levels at a 630 μg dose were 56 ng / mL and 97 ng / mL (~dose proportional). Retinal / choroidal levels were 49 ng / g and 89 ng / g, respectively. max 232 ng / mL, T max AUC last By day 180, a 1260 μg dose of vitreous C max 1697ng / mL, T max For 720h, AUC last It is 1583.2μg·h / mL.

[0341] Fig.13A The relationship between the average amount of drug remaining in the insert and time at which the insert was removed at various time points was described, and an analysis was performed to determine the amount of voronib remaining in the insert. Fig. 13B The cumulative percentage of drug released after removal of the insert is described as a function of time.

[0342] Example 6 - Toxicology and Pharmacokinetic Studies

[0343] The insert was also studied in 80 Holland's Holland rabbits (40 males and 40 females) for 18 months intravitreal toxicity. The animals were evaluated at 6 and 18 months after placement of the intravitreal insert. The objectives were to characterize the ocular toxicity, plasma pharmacokinetics, and biodegradation of the voronib insert following bilateral intravitreal injections.

[0344] The following table describes the grouping and dose levels. For the toxicology group, animals were sacrificed at 6 and 18 months. For plasma pharmacokinetic analysis, blood samples were collected on days 1, 3, and 7 and at 1, 2, 3, 4, 5, 6, 12, 14, 16, and 18 months.

[0345]

[0346] After administration of anesthesia, a voronib insert with a diameter of 0.37 mm and a length of 3.5 mm, designed to release the drug for at least 6 months, was intravitreally injected into each eye of each Dutch rabbit using a syringe. Animals in the placebo group (1) received two placebos by injection in each eye. Animals in the low-dose group (2) received 2 inserts in each eye. Animals in the medium-dose group (3) received 3 inserts in each eye, divided into two separate injections. Animals in the high-dose group (4) received 4 inserts in each eye, divided into two separate injections (2 inserts / injection). Animals in the highest-dose group (5) received 6 inserts in each eye, divided into two separate injections (3 inserts / injection).

[0347] At each scheduled time point, whole blood was collected by auricular vein puncture. Samples were analyzed for clinical pathology and plasma pharmacokinetics. Animals were euthanized according to the above schedule. A full gross necropsy was performed on all animals sacrificed or found dead during the study. Organs were weighed and tissues were collected. Ocular tissues were collected for histopathological examination only.

[0348] in conclusion: Plasma pharmacokinetic and toxicology studies provided vitreous C max Furthermore, voronib levels in the vitreous and retina / choroid remained significantly above the IC for VEGFR at the time points tested. 50 .

[0349] There were no adverse findings with voronib, and there were no adverse findings with up to 6 insertions. The no observed adverse effect level (NOAEL) for insertions was established as 6 insertions / eye (1260 μg / eye).

[0350] The highest event observed was yellow discoloration of the lens, which appeared to be dose and API color related. There were no histopathological / microscopic findings associated with lens discoloration. The second highest event observed was focal, punctate, or linear lens opacities, which appeared to be primarily related to the number of injections and, to a lesser extent, the number of inserts.

[0351] Mild inflammation (<2+ aqueous humor or vitreous cells) was initially observed in all groups. After 3 months, all inflammatory cells gradually resolved and cleared. The highest inflammatory events observed were seen in the placebo group (2 inserts, no drug).

[0352] Intraocular pressure (IOP) did not change from baseline, but some transient changes were observed.

[0353] Plasma levels of voronib were in the low pg / mL range.

[0354] Example 7 - Safety and effectiveness

[0355] To evaluate the safety and efficacy of voronib inserts in a porcine (minipig) 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 using voronib inserts in a porcine model of laser-induced choroidal neovascularization (CNV).

[0356] The following table describes the experimental design:

[0357]

[0358]

[0359] On the day of laser treatment (Groups 1-4), animals were treated with an 810 nm diode laser delivered through an indirect ophthalmoscope. Approximately 6 single laser spots were placed between the retinal veins. Both eyes received laser treatment according to the schedule in the table above.

[0360] On the day of intravitreal injection, animals were anesthetized and the eyes were prepared aseptically. The conjunctiva was gently grasped with conjunctival forceps (colibriforcep) and the injection (25G injection needle) was performed 2-3 mm posterior to the superior limbus (through the pars plana), with the needle directed slightly posterior to avoid contact with the lens. Animals were allowed to recover normally from the surgery. After 4-6 hours, pigs were given topical antibiotic eye drops and then BID for another 2 days, with at least 6 hours between doses. Animals were dosed on day 0 immediately after laser CNV induction or 7 days before laser CNV induction according to the schedule in the table above. Animals in groups 5-6 did not undergo laser CNV surgery and were implanted on day 0.

[0361] During the acclimatization period and the study, the animals were evaluated for mortality and morbidity and for general health, with particular attention to the eyes. Body weight was measured before treatment and before necropsy, and animals in groups 5 and 6 were weighed monthly.

[0362] Complete ocular examinations (OE) were performed by a veterinary ophthalmologist at the time points indicated in the experimental design table using a slit-lamp biomicroscope and indirect ophthalmoscopy (modified Hackett and McDonald) to assess ocular surface morphology, anterior and posterior segment inflammation, cataract formation, and retinal changes. Mydriasis ocular examinations were performed using topical 1% tropicamide HCL.

[0363] Fluorescein angiography was performed on both eyes of anesthetized animals at the time points indicated in the experimental design table.

[0364] Full-field electroretinography (ERG) was performed on both eyes of the animals at baseline and 3 months after administration (Group 5-6 only). On the day of ERG measurement, the animals were anesthetized after dark adaptation. A mini-ganzfeld light stimulator was used to deliver a brief flash of 0.33Hz at maximum intensity to induce ERG. 20 responses for each animal were amplified, filtered and averaged. Standard ERG measurements were performed on animals according to ISCEV standard regulations, including scotopic (0.01 candela), scotopic (3 candela) and photopic (25 candela) measurements.

[0365] At the time points indicated in the experimental design table, after final data collection, animals were euthanized. Eyes from Groups 5-6 were evaluated histologically.

[0366] result: Overall, a dose-related efficacy was found, and no toxicity was observed clinically. 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 the greatest decrease in CTLF values ​​in animals treated with aflibercept followed by the high dose, and similar decreases in CTLF values ​​in the remaining groups. In both groups that underwent ERG, ERG b-wave amplitude decreased from baseline to day 84; however, this could be attributed to difficulties in ERG acquisition.

[0367] Eyes that underwent histological examination showed some inflammation, which may have been more severe in animals given the higher-dose implant. The implant surgery may have contributed to the increased inflammation observed in the higher-dose group.

[0368] The aflibercept and placebo implants performed as expected, with aflibercept having normal therapeutic doses and the placebo implant being well tolerated in this model.

[0369] in conclusion:

[0370] In PK studies, plasma levels of voronib were in the low pg / mL range. Dose-related efficacy was found, and no clinically observed toxicity. Thus, the insert of the present invention is capable of locally releasing safe and therapeutically effective steady-state levels of voronib over a sustained period of time, while producing only negligible systemic levels of voronib. In addition, the insert is completely bioerodible.

Claims

1. An ocular drug delivery insert comprising a solid matrix core comprising PVA and about 200 μg to about 2000 μg of voronib or a pharmaceutically acceptable salt thereof, wherein the amount of voronib or a pharmaceutically acceptable salt thereof in the insert is about 70% w / w to about 98% w / w, and wherein the insert has a drug release rate of about 0.1 μg / day to about 60 μg / day for at least 60 days, wherein the insert is capable of at least 30% erosion within 180 days.

2. The insert of claim 1, wherein the insert further comprises a coating composed of PVA, the coating substantially surrounding the core.

3. The insert of claim 1, wherein the insert is capable of at least 90% erosion within 440 days.

4. The insert of claim 1, wherein the drug release rate is from about 0.1 μg / day to about 20 μg / day.

5. The insert of claim 1, wherein the drug release rate is about 0.1 μg / day to about 10 μg / day.

6. The insert of claim 1, wherein the drug release rate is about 0.1 μg / day to about 2 μg / day.

7. The insert of claim 1, wherein the duration of release of the voronib is at least about 90 days.

8. The insert of claim 1, wherein the duration of release of the voronib is from about 60 days to about 270 days.

9. The insert of claim 1, wherein the core comprises about 1% w / w to about 15% w / w PVA.

10. The intercalant of claim 8, wherein the intercalant is cured at about 80°C to about 160°C for about 15 minutes to about 4 hours.

11. The insert of claim 1, wherein the insert has approximately zero-order release rate kinetics.

12. The insert of claim 1, wherein the insert is sized and shaped to pass through a 20G to 27G needle or cannula.

13. The interposer of claim 1, wherein the interposer is cylindrical.

14. The insert of claim 1, wherein the insert has a length of about 1 mm to about 10 mm.

15. The insert of claim 1, wherein the insert has a length of about 6 mm to about 10 mm.

16. The insert of claim 1 further comprising a delivery port.

17. The insert of claim 1, wherein the insert is made by dissolving PVA in an aqueous solution to form a PVA solution, mixing the PVA solution with voronib or a pharmaceutically acceptable salt thereof to form a matrix mixture, extruding the mixture through a dispensing tip to form a matrix in an elongated shape, curing the matrix in an elongated shape at a temperature of about 80° C. to about 160° C. for about 15 minutes to about 4 hours, and dividing the matrix in an elongated shape.

18. The insert of claim 1, wherein the insert consists of a core consisting of PVA and voronib.

19. An ocular drug delivery insert comprising (a) a solid matrix core comprising PVA and about 200 µg to about 2000 µg of voronib or a pharmaceutically acceptable salt thereof, and (b) a coating comprising PVA substantially surrounding the core; wherein the amount of voronib or a pharmaceutically acceptable salt thereof in the insert is about 70% w / w to about 98% w / w, wherein the insert has a drug release rate of about 0.1 µg / day to about 60 µg / day for at least 60 days, and wherein the insert is capable of at least 30% erosion within 180 days.

20. The insert of claim 19, wherein the insert is capable of at least 90% erosion within 440 days.

21. The insert of claim 19, wherein the drug release rate is about 0.1 μg / day to about 20 μg / day.

22. The insert of claim 19, wherein the drug release rate is about 0.1 μg / day to about 10 μg / day.

23. The insert of claim 19, wherein the drug release rate is about 0.1 μg / day to about 2 μg / day.

24. The insert of claim 19, wherein the duration of release of the voronib is at least about 90 days.

25. The insert of claim 19, wherein the coating comprises a different grade of PVA than the core PVA.

26. The insert of claim 19, wherein the coating comprises more than one coating comprising PVA, and the DH of the PVA in the coating is different from the DH of the core PVA.

27. The insert of claim 19, wherein the MW of the PVA in the coating is different from the MW of the core PVA.

28. The insert of claim 19, wherein the coating comprises at least two coatings comprising PVA, and wherein at least one of the coatings further comprises a different grade of PVA than at least one other coating.

29. The insert of claim 28, wherein the PVA in at least two coatings differs in DH.

30. The insert of claim 28, wherein the PVA in at least two coatings differ in MW.

31. The intercalant of claim 19, wherein the intercalant is cured at about 80°C to about 160°C for about 15 minutes to about 4 hours.

32. The insert of claim 19, wherein the insert has approximately zero order release rate kinetics.

33. The insert of claim 19, wherein the insert is cylindrical.

34. The insert of claim 19, wherein the insert is sized and shaped to pass through a 20G to 27G needle or cannula.

35. The insert of claim 19, wherein the insert has a length of about 1 mm to about 10 mm.

36. The insert of claim 19, wherein the amount of the coating is from about 5% w / w to about 25% w / w of the insert.

37. The insert of claim 19, wherein at least one end of the insert is covered with a coating.

38. The insert of claim 19, wherein the insert is made by dissolving PVA in an aqueous solution to form a PVA solution, mixing the PVA solution with voronib or a pharmaceutically acceptable salt thereof to form a matrix mixture, extruding the mixture through a dispensing tip to form a matrix in an elongated shape, coating the matrix in an elongated shape with the PVA solution, curing the matrix in an elongated shape at a temperature of about 80° C. to about 160° C. for about 15 minutes to about 2 hours, and dividing the matrix in an elongated shape.

39. The insert of claim 19, wherein the PVA is a mixture selected from the group consisting of: A mixture of MW 78,000, 88% hydrolyzed and MW 78,000, 98% hydrolyzed; a mixture of MW 78,000, 88% hydrolyzed and MW 78,000, 99+% hydrolyzed; a mixture of MW 6,000, 80% hydrolyzed and MW 78,000, 98% hydrolyzed; a mixture of MW 6,000, 80% hydrolyzed and MW 78,000, 99+% hydrolyzed; a mixture of MW 78,000, 88% hydrolyzed and MW 125,000, 88% hydrolyzed; and a mixture of MW 6,000, 80% hydrolyzed and MW 125,000, 88% hydrolyzed.

40. The insert of claim 19, wherein the core consists of PVA and voronib.

41. An ocular drug delivery insert comprising a solid matrix core comprising PVA and voronib or a pharmaceutically acceptable salt thereof, wherein the insert comprises at least two different grades of PVA, wherein the amount of voronib or a pharmaceutically acceptable salt thereof in the insert is from about 70% w / w to about 98% w / w, wherein the insert has a drug release rate of from about 0.1 μg / day to about 60 μg / day for at least 60 days, and wherein the insert is capable of at least 30% erosion within 180 days.

42. The insert of claim 41, wherein the insert is capable of at least 90% erosion within 440 days.

43. The insert of claim 41, wherein the core comprises about 200 μg to about 2000 μg of voronib or a pharmaceutically acceptable salt thereof.

44. The insert of claim 41, wherein the drug release rate is from about 0.1 μg / day to about 20 μg / day.

45. The insert of claim 41, wherein the drug release rate is about 0.1 μg / day to about 10 μg / day.

46. ​​The insert of claim 41, wherein the drug release rate is about 0.1 μg / day to about 2 μg / day.

47. The insert of claim 41, wherein the duration of release of the voronib is at least about 90 days.

48. The insert of claim 41, wherein the insert comprises a coating comprising PVA substantially surrounding the core.

49. The insert of claim 48, wherein the coating comprises a different grade of PVA than the core PVA.

50. The insert of claim 48, wherein the MW of the PVA in the coating is different from the MW of the core PVA.

51. The insert of claim 48, wherein the coating comprises at least two coatings comprising PVA, and wherein at least one of the coatings further comprises a different grade of PVA than at least one other coating.

52. The insert of claim 51, wherein the PVA in at least two coatings differs in DH.

53. The insert of claim 51 , wherein the PVA in at least two coatings differ in MW.

54. The intercalant of claim 41, wherein the intercalant is cured at about 80°C to about 160°C for about 15 minutes to about 4 hours.

55. The insert of claim 41, wherein the insert has approximately zero order release rate kinetics.

56. The insert of claim 41, wherein the insert is cylindrical.

57. The insert of claim 41, wherein the insert is sized and shaped to pass through a 20G to 27G needle or cannula.

58. The insert of claim 41, wherein the insert has a length of about 1 mm to about 10 mm.

59. The insert of claim 48, wherein the coating is present in an amount of about 5% w / w to about 25% w / w of the insert.

60. The insert of claim 48, wherein at least one end of the insert is covered with a coating.

61. The insert of claim 48, wherein the insert is made by dissolving PVA in an aqueous solution to form a PVA solution, mixing the PVA solution with voronib or a pharmaceutically acceptable salt thereof to form a matrix mixture, extruding the mixture through a dispensing tip to form a matrix in an elongated shape, coating the matrix in an elongated shape with the PVA solution, curing the matrix in an elongated shape at a temperature of about 80° C. to about 160° C. for about 15 minutes to about 4 hours, and dividing the matrix in an elongated shape.

62. The insert of claim 41, wherein the two different grades of PVA are a mixture selected from the group consisting of: A mixture of MW 78,000, 88% hydrolyzed and MW 78,000, 98% hydrolyzed; a mixture of MW 78,000, 88% hydrolyzed and MW 78,000, 99+% hydrolyzed; a mixture of MW 6,000, 80% hydrolyzed and MW 78,000, 98% hydrolyzed; a mixture of MW 6,000, 80% hydrolyzed and MW 78,000, 99+% hydrolyzed; a mixture of MW 78,000, 88% hydrolyzed and MW 125,000, 88% hydrolyzed; and a mixture of MW 6,000, 80% hydrolyzed and MW 125,000, 88% hydrolyzed.

63. The insert of claim 41 , wherein the core consists of PVA and voronib.

64. A method of making an ocular drug delivery insert comprising dissolving PVA in an aqueous solution to form a PVA solution, mixing the PVA solution with voronib or a pharmaceutically acceptable salt thereof to form a matrix mixture, extruding the mixture through a dispensing tip to form a matrix in an elongated shape, curing the matrix in the elongated shape at a temperature of about 80° C. to about 160° C. for about 15 minutes to about 4 hours, and dividing the matrix in the elongated shape to form an insert comprising about 70% w / w to about 98% w / w voronib or a pharmaceutically acceptable salt thereof.

65. The method of claim 64, wherein: Prior to solidifying the matrix of elongated shapes, the matrix of elongated shapes is covered with a coating comprising PVA.

66. An ocular drug delivery insert comprising a solid matrix core comprised of polyvinyl alcohol and voronib or a pharmaceutically acceptable salt thereof, wherein the amount of voronib or a pharmaceutically acceptable salt thereof in the insert is from about 75% w / w to about 98% w / w, wherein the insert has a drug release rate of from about 0.1 μg / day to about 20 μg / day substantially for at least about 14 days, wherein the duration of drug release is at least 12 weeks.

67. The ocular drug delivery insert of claim 66, wherein the amount of voronib or a pharmaceutically acceptable salt thereof in the insert is from about 800 μg to about 2000 μg.

68. The ocular drug delivery insert of claim 66, wherein the insert is sized and shaped to pass through a 20G or smaller cannula or needle.

69. The ocular drug delivery insert of claim 68, wherein the insert is in the shape of a rod having a length of about 6 mm to about 10 mm.

70. The ocular drug delivery insert of claim 66, wherein the content of matrix polymer in the core is from about 4% w / w to about 25% w / w.

71. The ocular drug delivery insert of claim 66, wherein the content of matrix polymer in the core is from about 1% w / w to about 10% w / w.

72. The ocular drug delivery insert of claim 66, wherein the duration of drug release is at least 18 weeks.

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