Methods for preventing age-related macular degeneration by administering an ocular drug delivery insert - Patents.com

Abstract

The present invention relates to a method of preventing, stabilizing, or slowing the progression of AMD in the eye of a human subject, the method comprising administering to the eye an ocular drug delivery insert.

Description

[Background technology]

[0001] background

[0002] Age-related macular degeneration ("AMD") is the leading cause of blindness worldwide. AMD causes progressive loss of central vision due to degenerative and / or neovascular changes in the macula, a specialized area in the center of the retina. Generally, macular degeneration can result in delayed or sudden vision loss. AMD is estimated to affect nearly 200 million people worldwide, with late-stage AMD affecting nearly 11 million people.

[0003] There are two forms of AMD: dry AMD and wet AMD. AMD usually begins as dry AMD, characterized by the formation of yellow spot-like deposits called drusen in the macula, between the retinal pigment epithelium and the underlying choroid. Dry AMD can progress to wet AMD.

[0004] Dry macular degeneration is more common than wet AMD, with approximately 90% of AMD patients diagnosed with dry AMD. The dry form of AMD can result from aging and thinning of macular tissue, deposition of pigment within the macula, or a combination of the two processes.

[0005] The wet form of the disease usually leads to more severe vision loss. Wet AMD is characterized by the formation of new blood vessels in the choroid (choroidal neovascularization), macular atrophy (geographic atrophy), and vision loss. In wet AMD, new blood vessels grow underneath the retina, leaking blood and fluid. This leakage causes retinal cells to die, resulting in blind spots in central vision.

[0006] A person may have AMD in one eye or both eyes, but it may be at a different stage in each eye. Wet AMD usually develops first in one eye, which is referred to as unilateral wet AMD. Patients with wet AMD in one eye have a significant risk of developing choroidal neovascularization in the fellow eye. A retrospective study involving patients with unilateral wet AMD treated with anti-vascular endothelial growth factor (VEGF) therapy and with at least 3 years of follow-up after the start of treatment found that 38% of these patients had conversion in the fellow eye within 3 years after the onset of wet AMD in the first eye.

[0007] Although there are several treatments for wet AMD, existing treatments are inconvenient or have significant adverse effects, and they do not cure wet AMD. Additionally, there are currently no drugs to prevent wet AMD. Summary of the Invention

[0008] According to various embodiments of the present invention and after extensive experimentation, the inventors have invented a novel bioerodible drug delivery insert comprising an active pharmaceutical ingredient (API) and a bioerodible polymer, as well as a method of using the insert. The insert is particularly useful for locally delivering an effective amount of the API to the eye. In addition, the insert provides sustained release of the API. In some aspects, the insert provides sustained release of the API for a period of time approximately synchronized with the period required for complete erosion of the insert in the eye.

[0009] These inserts may be administered intraocularly, for example, intravitreally, suprachoroidally, intracamerally, or subconjunctivally. For example, the inserts may be placed through a needle or cannula for intravitreal injection. Thus, in some embodiments, the present invention relates to drug delivery inserts that can deliver effective intraocular concentrations of API while delivering low systemic concentrations of API to reduce the risk of toxicity or other undesirable side effects.

[0010] Thus, in some embodiments, the present invention relates to the use of the insert to treat or prevent an ocular disease as described herein by local (e.g., intraocular) administration of an API or a pharma-ceutically acceptable salt thereof.

[0011] In some embodiments, the invention provides a method of preventing wet AMD in the eye of a human subject, the method comprising administering to the eye an ocular drug delivery insert comprising borolanib, or a pharma- ceutically acceptable salt thereof, wherein the insert releases about 0.1 μg / day to about 60 μg / day of borolanib for at least 90 days, and wherein the insert permits at least 20% erosion within 95 days.

[0012] In another aspect, the invention provides a method of preventing choroidal neovascularization in an eye of a human subject, the method comprising administering to the eye an ocular drug delivery insert comprising borolanib, or a pharma- ceutically acceptable salt thereof, wherein the insert releases about 0.1 μg / day to about 60 μg / day of borolanib for at least 90 days, and wherein the insert allows for at least 20% erosion within 95 days.

[0013] In yet another embodiment, the invention provides a method for preventing conversion of class 3 AMD to class 4 AMD in an eye of a human subject, the method comprising administering to the eye an ocular drug delivery insert comprising borolanib, or a pharma- ceutical acceptable salt thereof, wherein the insert releases about 0.1 μg / day to about 60 μg / day of borolanib for at least 90 days, wherein the insert permits at least 20% erosion within 95 days, and wherein the eye has class 3 AMD at baseline.

[0014] In another aspect, the invention provides a method of slowing the progression of AMD in an eye of a human subject, the method comprising administering to the eye an ocular drug delivery insert comprising borolanib, or a pharma- ceutically acceptable salt thereof, wherein the insert releases about 0.1 μg / day to about 60 μg / day of borolanib for at least 90 days, wherein the insert permits at least 20% erosion within 95 days, and wherein the eye has class 2, class 3, or class 4 AMD at baseline.

[0015] In some embodiments, a method for preventing wet AMD in an eye of a human subject includes administering to the eye an ocular drug delivery insert comprising borolanib, or a pharma- ceutically acceptable salt thereof, wherein the insert has an average drug release rate over a 30 day period of about 0.1 μg / day to about 40 μg / day of borolanib, and wherein the insert permits at least 20% erosion within 95 days.

[0016] In another aspect, a method of preventing choroidal neovascularization in an eye of a human subject includes administering to the eye an ocular drug delivery insert comprising borolanib, or a pharma- ceutically acceptable salt thereof, wherein the insert has an average drug release rate over a 30 day period of about 0.1 μg / day to about 40 μg / day of borolanib, and wherein the insert is capable of eroding by at least 20% within 95 days.

[0017] In another embodiment, a method for preventing conversion of class 3 AMD to class 4 AMD in an eye of a human subject comprises administering to the eye an ocular drug delivery insert comprising borolanib, or a pharma- ceutical acceptable salt thereof, wherein the average drug release rate of the insert over a 30 day period is from about 0.1 μg / day to about 40 μg / day of borolanib, and wherein the insert permits at least 20% erosion within 95 days, and wherein the eye has class 3 AMD at baseline.

[0018] In some embodiments, a method of slowing the progression of AMD in an eye of a human subject includes administering to the eye an ocular drug delivery insert comprising borolanib, or a pharma- ceutically acceptable salt thereof, wherein the insert has an average drug release rate over a 30 day period of about 0.1 μg / day to about 40 μg / day of borolanib, and wherein the insert permits at least 20% erosion within 95 days, and wherein the eye has class 2, class 3, or class 4 AMD at baseline.

[0019] In certain aspects of these methods, the subject has unilateral wet AMD in the subject's fellow eye at baseline.

[0020] In other aspects of the method, at baseline, the eye is class 1 or has class 2 AMD. In some embodiments, the subject has class 3 AMD in the other eye of the subject at baseline. In other embodiments, the subject has class 3 AMD in both eyes at baseline. In still other embodiments, at baseline, the eye has class 3 AMD and the other eye of the subject has class 4 AMD. In some aspects of the method, at baseline, the eye has class 2 AMD and the other eye of the subject has class 4 AMD. In other aspects, at baseline, the eye is class 1 and the other eye of the subject has class 4 AMD.

[0021] In some embodiments of the method, an ocular drug delivery insert containing borolanib, or a pharma- ceutically acceptable salt thereof, that releases about 0.1 μg / day to about 40 μg / day of borolanib for at least 90 days and allows for at least 20% erosion within 95 days is administered to both eyes of the subject.

[0022] Additionally, the present invention includes a method of providing neuroprotection to ocular tissue in the eye of a human subject, the method comprising administering to the eye an ocular drug delivery insert comprising borolanib, or a pharma- ceutically acceptable salt thereof, wherein the insert releases from about 0.1 μg / day to about 60 μg / day of borolanib for at least 90 days, and wherein the insert allows for at least 20% erosion within 95 days.

[0023] The invention also provides a method of preventing loss of vision due to damage or loss of retinal cells, such as retinal neurons, in the eye of a human subject, the method comprising administering to the eye an ocular drug delivery insert comprising borolanib, or a pharma- ceutically acceptable salt thereof, the insert releasing about 0.1 μg / day to about 60 μg / day of borolanib for at least 90 days, and the insert allowing for at least 20% erosion within 95 days. The invention further provides a method of reducing the incidence of loss of vision due to damage or loss of retinal cells, such as retinal neurons, in the eye of a human subject, the method comprising administering to the eye an ocular drug delivery insert comprising borolanib, or a pharma- ceutically acceptable salt thereof, the insert releasing about 0.1 μg / day to about 60 μg / day of borolanib for at least 90 days, and the insert allowing for at least 20% erosion within 95 days. In some embodiments of these methods, administration of the ocular drug delivery insert reduces retinal thinning in the eye. In other embodiments, administration of the ophthalmic drug delivery insert protects against photoreceptor degeneration in the eye. The retinal cells may be photoreceptors, bipolar cells, ganglion cells, horizontal cells, or amacrine cells.

[0024] In some embodiments, the present invention provides a method for treating or preventing an ocular disease, the method comprising administering to an eye an ocular drug delivery insert comprising borolanib, or a pharma- ceutically acceptable salt thereof, the insert releasing about 0.1 μg / day to about 60 μg / day of borolanib for at least 90 days, the insert allowing at least 20% erosion within 95 days, and the ocular disease being characterized by retinal neuronal damage. In some aspects of the method, the retinal neuronal damage affects photoreceptors. In other aspects of the method, the ocular disease is geographic atrophy, wAMD, glaucoma, diabetic macular edema, or retinal detachment.

[0025] In some embodiments of the method, there is no change from baseline in the BCVA of the eye for 180 days from the date the insert is administered.In other embodiments, the change from baseline in the BCVA of the eye for 180 days from the date the insert is administered is a loss of 5 or less ETDRS letters.In yet other embodiments, the CST of the eye does not increase by more than 75 μm for 180 days from the date the insert is administered.

[0026] In other embodiments, the CST of the eye is not increased above baseline.

[0027] In certain aspects of the method, there is no detectable choroidal neovascularization in the eye for 180 days from the date the insert is administered.

[0028] In other embodiments, the eye does not progress to a higher AMD classification than the baseline eye for at least 180 days from the date the insert is administered.

[0029] In some embodiments of the method, the subject's IVI questionnaire composite score does not increase significantly from baseline for at least 180 days after the day the insert is administered.

[0030] Additional embodiments of inserts that may be used in the methods of the invention are described herein. Thus, the methods described above are not limited to administration of inserts having only the characteristics described above, such as drug release rate and insert erosion rate.

[0031] For example, in some embodiments, the insert comprises a solid matrix core comprising borolanib, or a pharma- ceutically acceptable salt thereof, and a matrix polymer. In some aspects, the matrix polymer is polyvinyl alcohol (PVA). In some embodiments, the amount of matrix polymer in the insert is about 1 w / w% to about 15 w / w%.

[0032] In some embodiments, the amount of borolanib, or a pharma- ceutically acceptable salt thereof, in the insert is about 60% to about 98% w / w. In other embodiments, the amount of borolanib, or a pharma- ceutically acceptable salt thereof, in the insert is about 85% to about 99% w / w.

[0033] In yet other embodiments, the insert allows for at least 90% erosion within 440 days.

[0034] In some embodiments, the insert comprises about 200 μg to about 2000 μg of borolanib or a pharma- ceutically acceptable salt thereof.

[0035] In yet other embodiments, the insert releases about 0.5 μg / day to about 30 μg / day of borolanib for at least 120 days.

[0036] In some embodiments of the method, the insert is administered by intravitreal injection via a 20-27 gauge needle or cannula.

[0037] In some embodiments, the insert has a length of about 1 mm to about 10 mm.

[0038] In some embodiments, the insert further comprises a coating substantially surrounding the core. In yet other embodiments, the coating comprises PVA. In other embodiments, the insert further comprises a delivery port.

[0039] In some embodiments, the insert matrix polymer is PVA and the coating comprises a different grade of PVA than the matrix polymer.

[0040] In yet another embodiment, the coating comprises at least two coats comprising PVA, where at least one of the coats comprises a different grade of PVA than at least one other coat.

[0041] In some embodiments, the coating comprises two or more coatings comprising PVA, the matrix polymer is PVA, and the DH of the PVA in at least one coating is different from the DH of the matrix polymer PVA.

[0042] In yet other embodiments, the matrix polymer is PVA and the MW of the PVA in the coating is different from the MW of the matrix polymer.

[0043] In some embodiments of the method, 1 to 6 inserts are inserted. In certain embodiments, the total amount of borolanib in all of the inserts is about 600 μg to about 6000 μg.

[0044] In some embodiments, the one or more ocular drug delivery inserts deliver a total average daily dose of borolanib of about 1 μg / day to about 50 μg / day for at least 30 days. In some embodiments of the method, the insert comprises about 60 O C~about 120 O In yet another embodiment, the insert is cured at about 200 minutes to about 1440 minutes at 400° C. In yet another embodiment, the insert is cured at about 400° C. at 400° C. for ... O C ~ approx. 160 O C for about 15 minutes to about 4 hours, and then dividing the elongated matrix.

[0045] In some embodiments of the method, the ocular drug delivery insert comprises a solid matrix core comprising a matrix polymer and borolanib or a pharma- ceutically acceptable salt thereof, wherein the amount of borolanib or a pharma- ceutically acceptable salt thereof in the insert is about 10% to about 98% w / w, the drug release rate of the insert is about 0.01 μg / day to about 100 μg / day for at least 14 days, and the insert allows for at least 20% erosion within 95 days. In another embodiment, the amount of borolanib or a pharma- ceutically acceptable salt thereof in the insert is about 60% to about 98% w / w.

[0046] In other embodiments, the insert further comprises a coating substantially surrounding the core. In some embodiments, the amount of coating is about 5% to about 20% w / w of the insert. In additional embodiments, the insert further comprises a delivery port.

[0047] In some embodiments of the method, the ocular drug delivery insert comprises a solid matrix core comprising the API and at least two different grades of PVA, the drug release rate of the insert is from about 0.0001 μg / day to about 200 μg / day for at least 30 days, the insert allows for at least 20% erosion within 95 days, and the insert is sized and molded to fit through a 20-27 gauge needle or cannula. In some embodiments, the two different grades of PVA are a mixture selected from the list including a mixture of an 88% hydrolysate of MW 78,000 and a 98% hydrolysate of MW 78,000, a mixture of an 88% hydrolysate of MW 78,000 and a 99+% hydrolysate of MW 78,000, a mixture of an 80% hydrolysate of MW 6,000 and a 98% hydrolysate of MW 78,000, a mixture of an 80% hydrolysate of MW 6,000 and a 99+% hydrolysate of MW 78,000, a mixture of an 88% hydrolysate of MW 78,000 and an 88% hydrolysate of MW 125,000, and a mixture of an 80% hydrolysate of MW 6,000 and an 88% hydrolysate of MW 125,000.

[0048] In another embodiment of the method, an ocular drug delivery insert comprises (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 allows for at least 20% erosion within 95 days, and wherein the insert is sized and molded to fit through a 20-27 gauge needle or cannula.

[0049] In some embodiments of the method, the ocular drug delivery insert comprises: (a) 80% hydrolysate of MW 6,000, 80% hydrolysate of MW 9,000-10,000, 88% hydrolysate of MW 25,000, 98% hydrolysate of MW 25,000, 87-90% hydrolysate of MW 30,000-70,000, 88% hydrolysate of MW 78,000, 98% hydrolysate of MW 78.000, 99+% hydrolysate of MW 78,000, 99+% hydrolysate of MW 89,000-98,000, 87-89% hydrolysate of MW 85,000-124,000, 99% hydrolysate of MW 108,000 + % hydrolysate of MW 125,000, 88% hydrolysate of MW 125,000, 99% hydrolysate of MW 133,000, 99+% hydrolysate of MW 146,000-186,000, and mixtures thereof; and a solid matrix core comprising the API; and (b) at least one coating comprising PVA substantially surrounding the core, wherein the PVA in the coating is an 80% hydrolysate of MW 6,000, an 80% hydrolysate of MW 9,000-10,000, an 88% hydrolysate of MW 25,000, a 98% hydrolysate of MW 25,000, an 87-90% hydrolysate of MW 30,000-70,000, an 88% hydrolysate of MW 78,000, a 98% hydrolysate of MW 78.000, a 99+% hydrolysate of MW 78,000, a 99+% hydrolysate of MW 89,000-98,000, an 87-89% hydrolysate of MW 85,000-124,000, or a 99% hydrolysate of MW 108,000; +% hydrolyzate of MW 125,000, 88% hydrolyzate of MW 125,000, 99% hydrolyzate of MW 133,000, 99+% hydrolyzate of MW 146,000-186,000, and mixtures thereof; The PVA in the core and the PVA in the at least one coating are different grades of PVA.

[0050] In some embodiments of the method, 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 some embodiments, the coating comprises at least two coatings comprising PVA, at least one of the coatings comprising a different grade of PVA than at least one other coating. In some embodiments, the PVA in at least two coatings has a different DH. In some embodiments, the PVA in at least two coatings has a different MW.

[0051] Additional embodiments of inserts that may be used in the methods of the present invention are described below. [Brief description of the drawings]

[0052] [Figure 1] 1 illustrates an exemplary ocular drug delivery insert for use in the present invention. [Diagram 2] 1 depicts a graph showing the average weight change of different grades of PVA films after immersion in PBS for 24 hours. [Diagram 3] A scale is provided to indicate the relative film strength of the films evaluated. [Figure 4A] 1 shows an in vitro drug release profile showing the cumulative percent drug release from Formulation A inserts, a coating formulation cured at 140° C. for 4 hours. [Figure 4B] 1 shows an in vitro drug release profile showing the cumulative amount of drug (μg) released from Formulation A inserts. [Diagram 5] Photographs of eroded Formulation A inserts taken after immersion in dissolution medium for 314 and 447 days are shown, with the photograph of the 447 day insert including an intact insert for comparison. [Figure 6] FIG. 1 shows the in vitro drug release profile of an uncoated Formulation A insert, which is the same as Formulation A but does not have the coating. [Figure 7] Photographs of uncoated eroded Formulation A inserts taken after immersion in dissolution medium for 287 and 352 days are shown, with the photograph of the 352 day insert including an intact insert for comparison. [Figure 8A] 1 shows an in vitro drug release profile showing the cumulative drug release percentage from Formulation B inserts, a coating formulation cured at 140° C. for 30 minutes. [Figure 8B] 1 shows an in vitro drug release profile showing the cumulative drug released (μg) for Formulation B insert. [Figure 9] Photographs of eroded Formulation B inserts taken after immersion in dissolution medium for 59, 88 and 155 days are shown. [Figure 10] FIG. 1 shows the in vitro drug release profile of Formulation C insert, an uncured coating formulation. [Figure 11] Photographs of two samples of eroded Formulation C inserts taken after immersion in dissolution medium for 98 days at 37° C., then 113 days at room temperature are shown. [Figure 12] 1 shows a comparison of the in vitro drug release profiles of Formulations A, B and C. [Figure 13A] 1 shows the average amount of drug remaining in the insert versus time in an in vivo study in which inserts implanted in rabbit eyes were removed at various time points and assayed to determine the amount of borolanib (μg) remaining in the insert. One curve shows the levels of inserts from eyes implanted with 3 inserts, and the other curve shows the levels of inserts from eyes implanted with 6 inserts. [Figure 13B]1 shows cumulative percent drug released versus time for excised inserts from the same in vivo study, with one curve showing insert levels from an eye implanted with 3 inserts and the other curve showing insert levels from an eye implanted with 6 inserts. [Figure 14] 1 is a bar graph comparing the change in Corrected Total Lesion Fluorescence (CTFL) percentage over time for different drug doses in a porcine model of laser-induced choroidal neovascularization. [Figure 15] 1 is a graph showing the mean change in best BCVA from the screening visit for subjects in a Phase 1 clinical trial. [Figure 16] 1 is a graph showing the mean change in CST from the screening visit for subjects in a Phase 1 clinical trial. [Figure 17] 1 is a graph showing supplemental therapy-free rates for each visit for subjects in a Phase 1 clinical trial. [Figure 18] Results of visual acuity measurements are shown: Visual acuity was measured using the OKT. Solid vertical bars represent the mean spatial frequency thresholds, and dots indicate the spread of individual values ​​within each group. Data were analyzed for significance using one-way ANOVA with Sidak's multiple comparison post-hoc test for pairwise comparisons indicated. [Figure 19] Results of contrast threshold measurements are shown: Using the OKT, thresholds were measured in mice capable of discriminating the minimum contrast between a light and a dark vertical bar presented as a rotating visual stimulus. In the figure, the solid vertical bars represent the mean contrast thresholds, and the dots indicate the spread of individual values ​​within each group. Data were analyzed for significance using one-way ANOVA with Sidak's multiple comparison post-hoc test for the pairwise comparisons indicated. [Figure 20]Figure 1 shows retinal thickness measured by vertical optical coherence tomography (OCT) scan: OCT was used to obtain cross-sectional images of the retina in the vertical axis. Images were used to quantify total retinal thickness in individual eyes. A) Vertical bars represent the mean within each study group, and dots indicate the spread of individual values ​​within each group. Data were analyzed for significance using one-way ANOVA with Sidak's multiple comparison post-hoc test for pairwise comparisons indicated. B) Measurements taken at approximately 3 μm increments across the scan, from the inferior to superior retina, are plotted on a line graph. [Figure 21] Retinal thickness measured by horizontal OCT scans is shown: OCT was used to obtain cross-sectional images of the retina on the horizontal axis. Images were used to quantify total retinal thickness in individual eyes. A) Vertical bars represent the mean within each study group, and dots indicate the spread of individual values ​​within each group. Data were analyzed for significance using one-way ANOVA with Sidak's multiple comparison post-hoc test for pairwise comparisons indicated. B) Measurements taken at approximately 3 μm increments across the scan, from the nasal to the temporal retina, are plotted on a line graph. [Figure 22] Shown is outer nuclear layer (ONL) thickness measured by vertical OCT scan: OCT was used to obtain cross-sectional images of the retina in the vertical axis. Images were used to quantify ONL thickness in individual eyes. A) Vertical bars represent the mean within each study group, and dots indicate the spread of individual values ​​within each group. Data were analyzed for significance using one-way ANOVA with Sidak's multiple comparison post-hoc test for pairwise comparisons indicated. B) Measurements taken at approximately 3 μm increments across the scan, from the inferior to superior retina, are plotted on a line graph. [Figure 23] Shown is ONL thickness measured by horizontal OCT scan: OCT was used to obtain cross-sectional images of the retina in the horizontal axis. Images were used to quantify ONL thickness in individual eyes. A) Vertical bars represent the mean within each study group, and dots indicate the spread of individual values ​​within each group. Data were analyzed for significance using one-way ANOVA with Sidak's multiple comparison post-hoc test for pairwise comparisons indicated. B) Measurements taken at approximately 3 μm increments across the scan, from the nasal to the temporal retina, are plotted on a line graph. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0053] 1. Active Pharmaceutical Ingredients (API) The insert of the present invention comprises an active pharmaceutical ingredient (API), borolanib. The API may also be referred to herein as a "drug." In some embodiments of the present invention, the API is a pharma- ceutically acceptable salt of borolanib.

[0054] Borolanib has the chemical name (S,Z)-N-(1-(dimethylcarbamoyl)pyrrolidin-3-yl)-5-((5-fluoro-2-oxoindolin-3-ylidene)methyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide. Synonyms include the term "X-82". The molecular formula is C 23 H 26 FN5O3. The aqueous solubility of borolanib is less than 10 μg / mL. Borolanib has the following structure: [ka] has.

[0055] Borolanib is an orally active multikinase inhibitor that can inhibit the activation of vascular endothelial growth factor receptors (VEGFR) and platelet-derived growth factor receptors (PDGFR).

[0056] Methods for making borolanib are described, for example, in U.S. Pat. Nos. 7,683,057, 8,524,709, 8,039,470, and U.S. Published Application No. 2019 / 0233403, each of which is incorporated by reference in its entirety.

[0057] As used herein, "borolanib or a pharma- ceutically acceptable salt thereof" includes amorphous and crystalline forms, polymorphs, hydrates, and solvates of borolanib or a pharma- ceutically acceptable salt thereof.

[0058] Additionally, the present invention contemplates the use of analogs, derivatives, pharma- ceutically acceptable salts, esters, prodrugs, codrugs, and protected forms thereof of the API.

[0059] The term "pharmaceutically acceptable salt" refers to salts that retain the biological effectiveness and properties of a given compound and which are not biologically or otherwise undesirable.

[0060] Pharmaceutically acceptable salts include salts with inorganic or organic acids and inorganic or organic bases. Those skilled in the art will recognize various synthetic techniques that may be used to prepare non-toxic pharma- ceutically acceptable salts.

[0061] Salts may be derived from inorganic acids, including hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc. Salts may be derived from organic acids, including acetic acid, propionic acid, glycolic acid, gluconic acid, pamoic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, lactic acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluene-sulfonic acid, salicylic acid, etc.

[0062] Pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Salts derived from inorganic bases include sodium, potassium, lithium, ammonium, calcium and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines.

[0063] Additionally, pharma- ceutically acceptable salts include organic salts, such as choline salts, glucosamine salts, tris salts, meglumine salts, lysine salts, arginine salts, tributylamine salts, and benzathine salts.

[0064] In some embodiments, the API is in an amorphous form, a crystalline form, a polymorph, a hydrate, or a solvate.

[0065] Unless otherwise specified, the doses (e.g., 100 μg) described in this application refer to the weight of the pharmacologically active moiety, not the weight of a given API salt or API ester. Thus, for example, if the insert contains a pharma- ceutically acceptable salt or ester of borolinib, the weight must be adjusted to provide an amount of API salt equivalent to the amount of API described herein. In another example, a drug release rate of 100 μg / day means that the insert releases 100 μg / day of the pharmacologically active moiety (e.g., borolinib).

[0066] Prior to formulation of the insert, the API may be milled to a fine particle size. In some embodiments, the D of the API for use in manufacturing the insert may be 90 is less than 200 μm, less than 100 μm, less than 50 μm, less than 40 μm, less than 30 μm, less than 20 μm, or less than 15 μm. 90 is about 0.01 μm to about 100 μm, about 0.01 μm to about 80 μm, about 0.1 μm to about 50 μm, about 0.1 μm to about 20 μm, about 0.1 μm to about 15 μm, about 0.1 μm to about 12 μm, about 1 μm to about 50 μm, about 1 μm to about 30 μm, about 1 μm to about 25 μm, about 1 μm to about 20 μm, about 1 μm to about 15 μm, about 1 μm to about 12 μm, about 5 μm to about 10 μm, about 7 μm, about 8 μm, about 9 μm, about 10 μm, about 11 μm, or about 12 μm.

[0067] 2. Ocular Drug Delivery Inserts An "ocular drug delivery insert" is a device that can be implanted in the eye, contain a drug, and release the drug in the eye after implantation. "Ocular drug delivery insert" includes all of the inserts described herein.

[0068] The ocular drug delivery insert comprises a core that includes an API dispersed within a solid matrix. In some embodiments, the core is at least partially covered by a coating. In other embodiments, the insert consists of only the core. It is not surrounded by a coating or any kind of barrier surrounding the core. The insert is bioerodible.

[0069] In some embodiments, the insert includes both a core and a coating. The coating is a layer that partially or completely surrounds the core. The coating is an outer layer, which may be preformed into the desired shape (e.g., a tube) before being placed around the core, or the coating may be formed, for example, by co-extrusion of the core and coating, spraying the coating onto the core, or dipping the core into the coating material one or more times (e.g., 1-10 coats). If the core is coated, the coating may completely surround the core or may only partially surround the core.

[0070] The insert may be a variety of different shapes, for example, a cylinder, a rod, a sphere, or a disk. In some embodiments, the insert is cylindrical, and the coating covers the entire surface of the cylinder except for the ends of the rod or cylinder. The ends of the rod may function as a delivery port. In some embodiments, one end of the cylinder is covered by the coating and the other is not. In some embodiments, one of the ends is covered by a drug-impermeable cap, such as a silicone cap.

[0071] A rod is a solid geometric shape with parallel sides, the length of the side is greater than the diameter of the cross-sectional shape or its longest side. The cross-sectional shape may be a polygon, such as a circle, an ellipse, a square, a rectangle, a triangle, or a hexagon. A person skilled in the art will recognize that the shape of the insert may not be exact due to the manufacturing process, e.g., the exterior may not be smooth and perfectly uniform. For example, the sides of a cylinder or rod may not be perfectly straight or perfectly parallel. The cross-section of a cylinder or rod may not be perfectly circular or elliptical. Cross-sections of other shapes may not exactly meet the definition of their shapes. For example, a square cross-section may not have perfectly straight sides and corner angles may not be exactly 90 degrees. A sphere or pellet may not be perfectly spherical.

[0072] A matrix In some embodiments, the core is a solid matrix that includes a matrix polymer and the API, which may be in a solid form such as a powder, particles, or granules dispersed throughout the matrix. The matrix components and the API form a homogenous mixture in which the API is dispersed. The matrix is ​​solid at room temperature and is bioerodible. The matrix helps to control the release rate of the API, thus modifying the release rate of the API when compared to the unformulated API. In some embodiments, the matrix slows down the drug release rate, resulting in sustained delivery of the drug and less frequent dosing.

[0073] In some embodiments, the matrix also includes other pharma- ceutically acceptable ingredients, hi other embodiments, the only material used to form the matrix is ​​one or more matrix polymers.

[0074] 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 copolymers thereof.

[0075] In certain embodiments, the matrix polymer comprises PVA, hi some embodiments, the only non-active pharmaceutical ingredient in the matrix is ​​PVA.

[0076] Various grades of PVA may be used. The degree of hydrolysis (DH) of PVA ranges from about 70% to about 99%. + % and the molecular weight (MW) may be from about 6000 to 200,000, i.e., the matrix polymer may be from about 70 mol % to about 99 mol % having a molecular weight of from about 6,000 to 200,000.+ For example, the DH is about 70% to about 80%, about 80% to about 90%, about 80% to about 85%, about 88% to about 90%, about 90% to about 99%, or about 100% to about 109%. + %, about 98 to about 99 + %, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99%. +%, and the MW may be about 5000, about 6000, about 7000, about 8000, about 9000, about 10,000, about 15,000, about 18,000, about 20,000, about 25,000, about 30,000, about 40,000, about 50,000, about 60,000, about 70,000, about 75,000, about 78,000, about 80,000, about 85,000, 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 is about 5000-10,000, about 6000-10,000, about 9000-10,000, about 10,000-30,000, about 10,000-25,000, about 25,000-50,000, about 30,000-70,000, about 60,000-80,000, about 70 ,000 to 80,000, about 75,000 to 80,000, about 75,000 to 100,000, about 89,000 to 98,000, about 85,000 to 124,000, about 100,000 to 150,000, about 146,000 to 186,000, or about 150,000 to 200,000. In certain embodiments, the PVA is an 80% hydrolysate of MW 6,000, an 80% hydrolysate of MW 9,000-10,000, an 88% hydrolysate of MW 25,000, a 98% hydrolysate of MW 25,000, an 87-90% hydrolysate of MW 30,000-70,000, an 88% hydrolysate of MW 78,000, a 98% hydrolysate of MW 78,000, a 99+% hydrolysate of MW 78,000, a 99+% hydrolysate of MW 89,000-98,000, an 87-89% hydrolysate of MW 85,000-124,000, a 99% hydrolysate of MW 108,000, or a combination thereof. + % hydrolysate, 88% hydrolysate of MW 125,000, 99% hydrolysate of MW 133,000, or 99+% hydrolysate of MW 146,000-186,000.

[0077] In other embodiments, the matrix polymer comprises a mixture of two, three or four different grades of PVA. In some embodiments, the PVA is a mixture of two different grades of PVA. In some embodiments, the ratio of the two grades in the mixture is 1:1 to 1:15. In some embodiments, the ratio of the two grades is 1:6, 1:7, 1:8, 1:9, 1:10, 1:11 or 1:12 of slow eroding PVA to fast eroding PVA. The erosion rate of PVA may be measured as described in Example 1. For example, in some embodiments, the mixture of PVA has a ratio of 6000 MW 80% DH to 125,000 MW 88% DH of 1:9. In other embodiments, the ratio of the two grades in the mixture is 1:1 to 1:15, for example, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11 or 1:12 of fast eroding PVA to slow eroding PVA.

[0078] Examples of PVA mixtures include a mixture of 80% hydrolyzate of MW 6,000 and 98% hydrolyzate of MW 78,000; + % hydrolyzate of MW 78,000 and 99% hydrolyzate of MW 78,000. + % hydrolysate, and a mixture of an 80% hydrolysate of MW 6,000 and an 88% hydrolysate of MW 125,000.

[0079] The MW and DH must be selected to provide the desired drug release rate, the desired drug release duration, and the desired erosion rate for the particular drug, indication for which the ocular drug delivery insert is to be used.

[0080] The polymer solution used to form the core matrix may be dissolved in a solvent, such as water or ethanol, at 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 5 w / w% to about 20 w / w%, about 5 w / w% to about 15 w / w%, about 10 w / w% to about 20 w / w%, about 5 w / w% to about 8 w / w%, about 5 w / w% to about 7 w / w%, about 6 w / w%, or about 7 w / w%. The composition may contain about 8 w / w%, about 6 w / w% to about 7 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%, 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% of a polymer, such as PVA.

[0081] The polymer solution and API may be combined, for example, in a ratio of API:polymer solution 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.

[0082] In some embodiments, the core comprises borolanib or a pharma- ceutically acceptable salt thereof and PVA.In some embodiments, the core consists of borolanib or a pharma- ceutically acceptable salt thereof and PVA.

[0083] In a further embodiment, the PVA solution and the API are combined in a ratio of about 1:1 w / w API:PVA solution.

[0084] In some embodiments, the PVA solution and the API are combined in a ratio of about 1:2 w / w API:PVA solution.

[0085] In some embodiments, the core is 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%~about 15w / w%, about 0.1w / w%~about 10w / w%, about 1w / w%~about 20%, about 1w / w%~about 15%, about 1w / w%~about 10w / w%, about 1w / w%~about 9w / w%, about 1w / w% ~ approx. 8w / w%, approx. 1w / w% ~ approx. 7w / w%, approx. 1w / w% ~ approx. 6w / w%, approx. 2w / w% ~ approx. 10w / w%, approx. 2w / w% ~ approx. 8w / w%, approx. 2w / w% ~ approx. 6w / w%, approx. 3w / w% ~90w / w%, approximately 3w / w%~75w / w%, approximately 3w / w%~60w / w%, approximately 3w / w%~40w / w%, approximately 3w / w%~20w / w%, approximately 3w / w%~15w / w%, approximately 3w / w%~about 10w / w%, about 3w / w%~about 8w / w%, about 3w / w%~about 7, about 3w / w%~about 5w / w%, about 4w / w%~about 60w / w%, about 4w / w%~about 50w / w%, about 4w / w%~ About 40 w / w%, about 4 w / w% to about 25 w / w%, about 4 w / w% to about 20 w / w%, about 4 w / w% to about 15 w / w%, about 4 w / w% to about 10 w / w%, about 4 w / w% to about 8 w / w%, about 4 w / w% to about 7 w / w%, about 5 w / w% to about 10 w / w%, about 5 w / w% to about 8 w / w%, or about 5 w / w% to about 7 w / w% of non-active (non-API) ingredients, such as matrix polymers. These weight percentages are based on the dry weight of the core (i.e., after any drying steps in processing).

[0086] In some embodiments, the amount of matrix polymer in the core is 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 1 w / w% to about 20%, or about 1 w / w% ~15%, approx. 1w / w% ~ approx. 10w / w%, approx. 1w / w% ~ approx. 9w / w%, approx. 1w / w% ~ approx. 8w / w%, approx. 1w / w% ~ approx. 7w / w%, about 1w / w% to about 6w / w%, about 2w / w% to about 10w / w%, about 2w / w% to about 8w / w%, about 2w / w% to about 6w / w %, about 3w / w% to about 90w / w%, about 3w / w% to about 75w / w%, about 3w / w% to about 60w / w%, about 3w / w% to about 40w / w%, about 3w / w% to about 20w / w%, about 3w / w% to about 15w / w%, about 3w / w% to about 10w / w%, about 3w / w% to about 8w / w%, about 3 w / w% to about 7, about 3 w / w% to about 5 w / w%, about 4 w / w% to about 60 w / w%, about 4 w / w% to about 50 w / w%, about 4 w / w% to about 40 w / w%, about 4 w / w% to about 25 w / w%, about 4 w / w% to about 20 w / w%, about 4 w / w% to about 15 w / w%, about 4 w / w% to about 10 w / w%, about 4 w / w% to about 8 w / w%, about 4 w / w% to about 7 w / w%, about 5 w / w% to about 10 w / w%, about 5 w / w% to about 8 w / w%, or about 5 w / w% to about 7 w / w%, or about 1 w / w%, 1.5 w / w%, 2 w / w%, 2.5w / w%, 3w / w%, 3.5w / w%, 4w / w%, 4.5w / w%, 5w / w%, 5.5w / w%, 6w / w%, 6.5 w / w%, 7w / w%, 7.5w / w%, 8w / w%, 8.5w / w%, 9w / w%, 9.5w / w%, 10w / w%, 10.5w / w%, 11w / w%, 11.5w / w%, 12w / w%, 15w / w%, 18w / w%, 20w / w%, 25w / w%, 30w / w%, 35w / w%, 40w / w%, 50w / w%, 55w / w%, 60w / w%, 65w / w%, or 70w / w%. These weight percentages are based on the dry weight of the core (ie, after any drying step in processing).

[0087] The term "the insert consists of" a core that includes 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 components, but the insert does not have a shell, coating, cap, cover or tube or other outer layer, and therefore, when immersed in a fluid environment, such as the vitreous humor of the eye or an in vitro drug release medium, the exterior of the core is in direct contact with the fluid.

[0088] b. Coating 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, hi other embodiments, the insert does not comprise a coating.

[0089] 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 may modify the API release rate of the matrix. The diffusion membrane may function, for example, by modifying the flux into the matrix and / or restricting the passage of the API out of the matrix. In other embodiments, the coating increases the durability of the insert when compared to an uncoated core, for example, during processing, packaging, and / or delivery of the dose. In certain embodiments, the coating both modifies the API release rate and increases the durability of the insert.

[0090] The coating may completely surround the core or may only partially surround the core. In some embodiments, the coating substantially covers the core, meaning that the coating 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%, or at least 95% 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 95%, about 70% to about 98%, about 70% to about 100%, about 80% to about 95%, about 80% to about 96%, about 80% to about 98%, about 80% to about 99%, about 90% to about 99%, or about 90% to about 98% of the surface area of ​​the core. For cylindrical inserts, the surface area A is calculated as A=2πrL+2πr2, where r is the radius of the insert and L is the length of the insert. In some embodiments, a region of the core is left uncovered by the coating to form a delivery port. In some embodiments, more than one region is left uncovered to form more than one delivery port.

[0091] The delivery port is transparent to the API.

[0092] In some embodiments, the insert is rod-shaped, eg, cylindrical, and only the two ends of the rod / cylinder are uncoated.

[0093] To provide an illustration of an embodiment of an ocular drug delivery insert of the present invention, Figure 1 shows a longitudinal cross-sectional view of an ocular drug delivery insert 100 according to one embodiment of the present invention. The insert 100 includes a solid matrix core 105. The insert 100 further includes a coating 110 that substantially surrounds the core 105. The insert 100 also features two delivery ports 115 located at opposite ends of the insert 100. In this particular embodiment, at least one of the delivery ports 115 includes a membrane that is permeable to an API contained within the core 105, thereby allowing the API to be released from the delivery port(s) 115.

[0094] In some embodiments, the coating, like the matrix, is bioerodible.

[0095] 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), poly(lactic acid) (PLA), poly(glycolic acid) (PGA), polyalkylcyanoacrylate, or copolymers thereof.

[0096] In embodiments where the core is coated, the coating may be formed from 1-10 coats of polymer. For example, the core may be coated with 1 coat, 2 coats, 3 coats, 4 coats, 5 coats, 6 coats, 7 coats, 8 coats, 9 coats, or 10 coats. In some embodiments, each of the coats comprises the same polymer as the other coats. In certain embodiments, each of the coats comprises the same polymer as the other coats. In other embodiments where the coating is formed from two or more coats, at least two of the coats comprise different polymers.

[0097] In certain embodiments, the coating comprises PVA. In other embodiments, the coating consists of PVA. In some embodiments, the only non-active pharmaceutical ingredient in the coating is PVA. In other embodiments, the matrix polymer comprises PVA, the coating also comprises PVA, or both. In yet other embodiments, the matrix polymer consists of PVA, and the coating also consists of PVA, or both.

[0098] Various grades of PVA may be used. The degree of hydrolysis (DH) of PVA ranges from about 70% to about 99%. +% and the molecular weight (MW) may be from about 6000 to 200,000, i.e., the matrix polymer may be from about 70 mol % to about 99 mol % having a molecular weight of from about 6,000 to 200,000. + For example, the DH is about 70% to about 80%, about 80% to about 90%, about 80% to about 85%, about 88% to about 90%, about 90% to about 99%, or about 100% to about 109%. + %, about 98 to about 99 + %, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99%. +%, and the MW may be about 5000, about 6000, about 7000, about 8000, about 9000, about 10,000, about 15,000, about 18,000, about 20,000, about 25,000, about 30,000, about 40,000, about 50,000, about 60,000, about 70,000, about 75,000, about 78,000, about 80,000, about 85,000, 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 is about 5000-10,000, about 6000-10,000, about 9000-10,000, about 10,000-30,000, about 10,000-25,000, about 25,000-50,000, about 30,000-70,000, about 60,000-80,000, about 70 ,000 to 80,000, about 75,000 to 80,000, about 75,000 to 100,000, about 89,000 to 98,000, about 85,000 to 124,000, about 100,000 to 150,000, about 146,000 to 186,000, or about 150,000 to 200,000. In certain embodiments, the PVA is an 80% hydrolysate of MW 6,000, an 80% hydrolysate of MW 9,000-10,000, an 88% hydrolysate of MW 25,000, a 98% hydrolysate of MW 25,000, an 87-90% hydrolysate of MW 30,000-70,000, an 88% hydrolysate of MW 78,000, a 98% hydrolysate of MW 78,000, a 99+% hydrolysate of MW 78,000, a 99+% hydrolysate of MW 89,000-98,000, an 87-89% hydrolysate of MW 85,000-124,000, a 99% hydrolysate of MW 108,000, or a combination thereof. + % hydrolysate, 88% hydrolysate of MW 125,000, 99% hydrolysate of MW 133,000, or 99+% hydrolysate of MW 146,000-186,000.

[0099] In other embodiments, the PVA comprises a mixture of two, three or four different grades of PVA. In some embodiments, the PVA is a mixture of two different grades of PVA. In some embodiments, the ratio of the two grades in the mixture is 1:1 to 1:15. In some embodiments, the ratio of the two grades is 1:6, 1:7, 1:8, 1:9, 1:10, 1:11 or 1:12 of slow eroding PVA to fast eroding PVA. The erosion rate of PVA may be measured as described in Example 1. For example, in some embodiments, the mixture of PVA has a ratio of 6000 MW 80% DH to 125,000 MW 88% DH of 1:9. In other embodiments, the ratio of the two grades in the mixture is 1:1 to 1:15, for example, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11 or 1:12 of fast eroding PVA to slow eroding PVA.

[0100] Examples of PVA mixtures include a mixture of an 80% hydrolysate of MW 6,000 and a 98% hydrolysate of MW 78,000, a mixture of an 80% hydrolysate of MW 6,000 and an 88% hydrolysate of MW 78,000, a mixture of an 80% hydrolysate of MW 6,000 and a 99% hydrolysate of MW 78,000, and a mixture of an 80% hydrolysate of MW 6,000 and a 99% hydrolysate of MW 78,000. + % hydrolysate of MW78,000, a mixture of 88% hydrolysate of MW78,000 and 98% hydrolysate of MW78,000, a mixture of 98% hydrolysate of MW78,000 and 99% hydrolysate of MW78,000 + % hydrolysate, and a mixture of an 80% hydrolysate of MW 6,000 and an 88% hydrolysate of MW 125,000.

[0101] In certain embodiments, the core comprises a mixture of two different grades of PVA. In some embodiments, the coating comprises a mixture of two different grades of PVA. In yet other embodiments, both the core and the coating comprise a mixture of two different grades of PVA. When the coating comprises more than one coat of PVA, one or more of the coats may comprise a mixture of two different grades of PVA.

[0102] In embodiments in which both the core and the coating comprise PVA, the core PVA and the coating PVA may be the same or different grades of PVA. As used herein, the term "different grades of PVA" means that the PVA has different molecular weight (MW), degree of hydrolysis (DH), or both MW and DH. In addition, as used herein, a mixture of grades of PVA is a "different grade of PVA" when the PVA to which it is compared is not a mixture of exactly the same PVA grades, for example, a mixture of 80% hydrolyzed PVA of 6,000 and 98% hydrolyzed PVA of MW 78,000 is considered to be a different grade of PVA than a PVA composition that contains only 98% hydrolyzed PVA of MW 78,000 or a mixture of 80% hydrolyzed PVA of MW 6,000 and 88% hydrolyzed PVA of MW 125,000.

[0103] Thus, the core PVA and the coating PVA may have the same MW and DH, or the MW or DH may be different, or both the MW and DH may be different. In some embodiments, the core comprises PVA and the insert comprises a coating comprising PVA, and the MW of the coating PVA is the same as the MW of the core PVA and the DH of the coating PVA is lower than the DH of the core PVA. In some embodiments, the MW and DH of the coating PVA are each lower than the MW and DH of the core PVA.

[0104] In some embodiments, the coating is formed from two or more coatings. When the insert coating includes two or more coatings of PVA, PVA with the same MW and DH may be used for at least one of the core and coating(s). In other embodiments, the core includes PVA with a different MW and / or DH from the PVA in at least one coating. In some embodiments, the core includes PVA with both a different MW and DH from the PVA in at least one coating. In other embodiments, the PVA in the core and the PVA in at least one coating have the same MW but different DH. In some embodiments, the DH of the PVA in at least one coating is lower than the DH of the PVA in the core. In other embodiments, the PVA in the core and the PVA in at least one coating have different MW but the same DH. In some embodiments, the MW of the PVA in at least one coating is lower than the MW of the PVA in the core.

[0105] In some embodiments, the insert coating comprises a single coating comprising PVA. In other embodiments, the insert coating comprises two or more coatings comprising PVA, the PVA in each coating having the same MW and DH. In some embodiments, at least one coating comprises a PVA that differs 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 differs in both MW and DH from the PVA in at least one other coating. In some embodiments, the two coatings do not comprise the same grade of PVA, i.e., the PVA in each coating differs in MW and / or DH from each of the other coatings.

[0106] In some embodiments where the insert coating includes two or more coats that include PVA, the PVA in the outermost coat is more soluble (in PBS) than the PVA in any of the other coats, hi some embodiments, the PVA in at least one of the coats is more soluble than the core PVA.

[0107] 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, wherein 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 two coatings comprising PVA. In another embodiment, the insert comprises three coatings comprising PVA. In yet another embodiment, the insert comprises four coatings comprising PVA. In a further embodiment, the insert comprises five coatings comprising PVA. In yet another embodiment, the insert comprises six coatings comprising PVA.

[0108] In embodiments with two or more coatings, the first coating applied to the core is the innermost coating and the last coating applied is the outermost coating. In some embodiments of these inserts having two or more coatings 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 two or more coatings 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 is lower than the MW and DH of the PVA in any of the other coatings.

[0109] In some embodiments, the insert comprises: (a) an 80% hydrolysate of MW 6,000; an 80% hydrolysate of MW 9,000-10,000; an 88% hydrolysate of MW 25,000; a 98% hydrolysate of MW 25,000; an 87-90% hydrolysate of MW 30,000-70,000; an 88% hydrolysate of MW 78,000; a 98% hydrolysate of MW 78.000; a 99+% hydrolysate of MW 78,000; a 99+% hydrolysate of MW 89,000-98,000; an 87-89% hydrolysate of MW 85,000-124,000; a 99% hydrolysate of MW 108,000; +a solid matrix core comprising a PVA selected from the group consisting of an 80% hydrolysate of MW 6,000, an 88% hydrolysate of MW 125,000, a 99% hydrolysate of MW 133,000, a 99+% hydrolysate of MW 146,000-186,000, and mixtures thereof, and the API; and (b) at least one coating comprising PVA substantially surrounding the core, wherein the PVA in the coating is an 80% hydrolysate of MW 6,000, an 88% hydrolysate of MW 125,000, a 99% hydrolysate of MW 133,000, a 99+% hydrolysate of MW 146,000-186,000, and mixtures thereof. 80% hydrolysate of MW 25,000, 88% hydrolysate of MW 25,000, 98% hydrolysate of MW 25,000, 87-90% hydrolysate of MW 30,000-70,000, 88% hydrolysate of MW 78,000, 98% hydrolysate of MW 78.000, 99+% hydrolysate of MW 78,000, 99+% hydrolysate of MW 89,000-98,000, 87-89% hydrolysate of MW 85,000-124,000, 99% hydrolysate of MW 108,000 + % hydrolysate of MW 125,000, 88% hydrolysate of MW 133,000, 99% hydrolysate of MW 146,000-186,000, and mixtures thereof), where the PVA in the core and the PVA in the at least one coating are different grades of PVA. In another embodiment, where it is inert, the insert comprises at least two coatings of PVA, where the DH of the PVA in the outermost coating is lower than the DH of either of the PVA in each of the other coatings.

[0110] The present invention provides the ability to tailor the PVA grade used to manufacture the ocular insert. The MW and DH of the core and coating PVA must be selected to provide the desired drug release rate, the desired drug release duration, and the desired erosion rate for the particular drug, indication for which the ocular insert will be used. Different periods of drug release may be desirable for different ocular diseases or conditions. For example, a 12-month period of drug release (such as that provided by Formulation A) may be desirable for the treatment of diabetic retinopathy, whereas a period of less than one month may be desirable for an insert to inhibit ocular inflammation caused by injury or surgery.

[0111] The polymer solution used to form the coating may be in a solvent, such as water or ethanol, at a concentration of about 1 w / w% to about 20 w / w%, about 1 w / w% to about 15 w / w%, about 1 w / w% to about 10 w / w%, about 2 w / w% to about 15 w / w%, about 2 w / w% to about 12 w / w%, about 2 w / w% to about 10 w / w%, about 2 w / w% to about 8 w / w%, about 2 w / w% to about 6 w / w%, about 3 w / w% to about 10 w / w%, about 3 w / w% to about 8 w / w%, about 3 w / w% to about 6 w / w%, about 2 ...2 w / w% to about 20 w / w%, about 2 w / w% to about 20 w / w%, about 2 w / w% to about 20 w / w%, about 2 w / w% to about 20 w / w%, about 2 w / w% to about 20 w / w%, about 2 w / w% to about 20 w / w%, about 2 w / w% to about 20 w / w%, about 2 w / w% to about 20 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%, 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% of a polymer, such as PVA.

[0112] In the case of inserts that include a PVA coating, the core may be covered with 1 to 10 coats of the PVA solution, i.e., the insert may include 1 to 10 coats of PVA. For example, the insert may include 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 coats of PVA.

[0113] 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 1 w / w% to about 6 w / w%, from about 3 w / w% to about 20 w / w%, or about 3 w / w% about 10 w / w%, about 3 w / w% to about 6 w / w%, about 5 w / w% to about 30 w / w%, about 5 w / w% to about 25 w / w%, about 5 w / w% to about 20 w / w%, about 5 w / w% to about 15 w / w%, about 5 w / w% to about 10 w / w%, about 10 w / w% to about 25 w / w%, about 10 w / w% to about 20 w / w%, about 10 w / w% to about 18 w / w%, or about 12 w / w% to about 18 w / w% of the insert. These weight percentages are based on the dry weight of the insert (i.e., after any drying steps in processing).

[0114] In some embodiments, the total amount of non-active ingredients in the insert is 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 ...0 w / w%, from Approximately 10w / w%, approximately 1w / w% to approximately 70w / w%, approximately 1w / w% to approximately 50w / w%, approximately 1w / w% to approximately 20%, approximately 1w / w% to approximately 15%, approximately 1w / w% to approximately 10w / w%, approximately 1w / w% to approximately 9w / w%, approximately 1w / w% to approximately 8w / w% , about 1w / w% to about 7w / w%, about 1w / w% to about 6w / w%, about 2w / w% to about 10w / w%, about 2w / w% to about 8w / w%, about 2w / w% to about 6w / w%, about 3w / w% to about 90w / w%, about 3w / w% to about 75w / w%, about 3w / w% ~ approx. 60w / w%, approx. 3w / w% ~ approx. 40w / w%, approx. 3w / w% ~ approx. 20w / w%, approx. 3w / w% ~ approx. 15w / w%, approx. 3w / w% ~ approx. 10w / w%, approx. 3w / w% ~ approx. 8w / w%, approx. 3w / w% ~ approx. 7, approx. 5w / w%, approximately 4w / w% to approximately 60w / w%, approximately 4w / w% to approximately 50w / w%, approximately 4w / w% to approximately 40w / w%, approximately 4w / w% to approximately 25w / w%, approximately 4w / w% to approximately 20w / w%, approximately 4w / w% to approximately 15w / w%, approximately 4w / w% to approximately 1 0 w / w%, about 4 w / w% to about 8 w / w%, about 4 w / w% to about 7 w / w%, about 5 w / w% to about 40 w / w%, about 5 w / w% to about 30 w / w%, about 5 w / w% to about 25 w / w%, about 5 w / w% to about 20 w / w%, about 5 w / w% to about 15 w / w%, about 5 w / w% to about 7 w / w%, about 10 w / w% to about 25 w / w%, about 10 w / w% to about 22 w / w%, about 15 w / w% to about 25 w / w%, about 15 w / w% to about 22 w / w%, or about 18 w / w% to about 22 w / w%. These weight percentages are based on the dry weight of the insert (i.e., after any drying steps in processing).

[0115] In some embodiments, the amount of PVA in the insert is 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 1 w / w% to about 80 w / w%, from about 1 w / w% to about 75 w / w%, from about 1 w / w% to about 60 w / w%, from about 1 w / w% to about 30 w / w%, from about 1 w / w% to about 20%, from about 1 w / w% to about 15%, or about 1 w / w% ~10w / w%, 1w / w%~9w / w%, 1w / w%~8w / w%, 1w / w%~7w / w%, 1w / w%~6w / w%, 2w / w%~10w / w%, 2w / w%~8w / w%, 2w / w% ~6w / w%, 3w / w%~90w / w%, 3w / w%~80w / w%, 3w / w%~75w / w%, 3w / w%~70w / w%, 3w / w%~60w / w%, 3w / w%~40w / w%, 3w / w%~about 20w / w%, about 3w / w%~about 15w / w%, about 3w / w%~about 10w / w%, about 3w / w%~about 8w / w%, about 3w / w%~about 7, about 3w / w%~about 5w / w%, about 4w / w%~about 60w / w%, about 4w / w %~about 50w / w%, about 4w / w%~about 40w / w%, about 4w / w%~about 25w / w%, about 4w / w%~about 20w / w%, about 4w / w%~about 15w / w%, about 4w / w%~about 10w / w%, about 4w / w%~about 8w / w%, about 4 % to about 7 w / w%, about 5 w / w% to about 40 w / w%, about 5 w / w% to about 30 w / w%, about 5 w / w% to about 25 w / w%, about 5 w / w% to about 20 w / w%, about 5 w / w% to about 15 w / w%, about 5 w / w% to about 10 w / w%, about 5 w / w% to about 7 w / w%, about 10 w / w% to about 25 w / w%, about 10 w / w% to about 22 w / w%, about 15 w / w% to about 25 w / w%, about 15 w / w% to about 22 w / w%, or about 18 w / w% to about 22 w / w%. These weight percentages are based on the dry weight of the insert (i.e., after any drying steps in processing).

[0116] In some embodiments, the present invention provides inserts having a very high drug loading compared to non-active 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 w / w%, about 10 w / w% to about 98 w / w%, about 15 w / w% to about 98 w / w%, about 20 w / w% to about 98 w / w%, about 30 w / w% to about 98 w / w%, about 40 w / w% to about 98 w / w%, about 50 w / w% to about 98 w / w%, about 60 w / w% to about 98 w / w%, about 65 w / w% to about 98 w / w%, about 70 w / w% to about 98 w / w%, about 80 w / w% to about 98 w / w%, about 90 w / w% to about 98 w / w%, about 100 w / w% to about 98 w / w%, about 150 w / w% to about 98 w / w%, about 20 w / w% to about 98 w / w%, about 30 w / w% to about 98 w / w%, about 40 w / w% to about 98 w / w%, about 50 w / w% to about 98 w / w%, about 60 w / w% to about 98 w / w%, about 65 w / w% to about 98 w / w%, about 70 w / w% to about 98 w / w%, about 100 w / w% to about 98 w / w%, about 15 ... % 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%, about 80 w / w% to about 90 w / w%, about 80 w / w% to about 99 w / w%, about 85 w / w% to about 98 w / w%, about 85 w / w% to about 99 w / w%, about 90 w / w% to about 99 w / w%, or about 90 w / w% to about 98 w / w%. These weight percentages are based on the dry weight of the insert (i.e., after any drying steps in processing).

[0117] In some embodiments, the only non-active ingredient in the insert is a polymer, such as PVA.

[0118] The thickness of the coating around the core may be, for example, about 20 μm to about 400 μm, about 20 μm to about 300 μm, about 20 μm to about 200 μm, about 20 μm to about 100 μm, about 5 μm to about 75 μm, about 5 μm to about 50 μm, or about 5 μm to about 25 μm.

[0119] c. Shape and dimensions of insert In some embodiments, when the insert is prepared for implantation within the vitreous of the eye, the insert does not exceed about 15 mm in any direction, or preferably does not exceed about 10 mm, so that the insert can be inserted through an incision of 15 mm or less.

[0120] In some embodiments, the insert may be molded and sized for insertion. In some embodiments, the insert is sized and molded to fit through a cannula or needle of 20 gauge or less. This means that the insert can be inserted through any cannula or needle having the listed gauge without requiring an extraordinary amount of force. The phrase "or less" in this context means having a smaller outer diameter. A smaller outer diameter will correspond to a larger gauge size number, for example, a 25 gauge needle has a smaller outer diameter than a 22 gauge needle.

[0121] In some embodiments, the insert is sized and shaped to fit through a 20-27 gauge needle or cannula, a 21-27 gauge needle or cannula, a 22-27 gauge needle or cannula, a 23-27 gauge needle or cannula, a 24-27 gauge needle or cannula, a 25-27 gauge needle or cannula, or a 25.5-27 gauge needle or cannula.

[0122] In other embodiments, the insert is sized and molded to fit through a cannula or needle that is 20 gauge or less, 22 gauge or less, 23 gauge or less, 24 gauge or less, 25 gauge or less, 25.5 gauge or less, 26 gauge or less, or 26.5 gauge or less. Preferably, the insert is sized and molded to fit through a cannula or needle that is smaller than 25 gauge, smaller than 26 gauge, or smaller than 27 gauge. In some embodiments, the insert is sized and molded to fit through a cannula or needle that is about 29 gauge to about 25.5 gauge, such as about 28 gauge to about 25.5 gauge, or about 28 gauge to about 26 gauge. In some embodiments, the needle or cannula is about 22, 22s, 23, 24 or 25 gauge, but preferably about 25.5, 26, 26.5, 26s, 27, 27.5, 28, 28.5, 29, 29.5, 30 or 30.5 gauge.

[0123] In some embodiments, the insert may be rod-shaped, cylindrical or spherical, less than about 12 mm in length and less than about 1 mm in diameter.

[0124] In some embodiments, the insert may be rod-shaped or cylindrical, not exceeding 8 mm in length and 3 mm in diameter.

[0125] In some embodiments, the insert has a length of 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.

[0126] In some embodiments, the insert has a diameter of about 0.1 mm to about 2 mm, about 0.1 mm to about 1 mm, about 0.1 mm to about 0.8 mm, about 0.1 mm to about 0.6 mm, about 0.1 mm to about 0.5 mm, about 0.3 mm to about 0.5 mm, about 0.3 mm to about 0.4 mm, about 0.2 mm to 0.4 mm, about 0.1 mm to 0.2 mm, or about 0.4 mm to about 0.6 mm, about 0.57 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.

[0127] d. Manufacturing of inserts The insert may be manufactured by mixing the API with a matrix polymer. In some embodiments, the matrix polymer is one or more polymer solutions 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 may be extruded through an 18-25 gauge cannula or dispensing tip. In some embodiments, a 21-23 or 23-26 gauge cannula or dispensing tip is used. For example, the gauge of the cannula or dispensing tip may be 20, 21, 22, 23, 24, 25, or 26. The extruded paste is referred to herein as an extrudate, an elongated shaped matrix, or a rod. The rod may be about 4-5 inches (about 10-13 cm) in length. The extrudate is solid at room temperature. The extrudate may be coated with one or more additional layers. In some embodiments, the extrudate is dried at room temperature for at least 24 hours before coating.

[0128] In the extrusion process, extrusion parameters may be controlled, such as flow pressure, flow rate, and temperature of the extruded material, etc. A suitable extruder may be selected for its ability to deliver the coextruded material at sufficient pressure and flow rate to form a product at the size of the die head and exit port or dispensing tip that, when portioned and dried, will produce a product that can be inserted through a needle or cannula as described herein.

[0129] If a polymer solution is used and the extrudate is coated, the extruded API-polymer mixture is dried before coating. For example, the extrudate may be dried at room temperature for about 30 minutes to about 48 hours before coating.

[0130] The extrudate may be coated with one or more layers, although in some embodiments, no coating is applied. The coating may be applied prior to dividing into the desired insert lengths. The coating may be applied by dipping the extrudate in a liquid coating material and allowing it to dry or harden. This process may be repeated to add additional coating layers. Alternatively, the coating may be sprayed onto the extrudate.

[0131] In other embodiments, the coating / outer layer may be preformed, for example, into a tubular shape, and the API-polymer paste may be extruded into the tube.

[0132] Depending on the polymer used in the matrix, the matrix may be cured. Curing may be accomplished, for example, by heating in an oven, microwave heating, or chemical treatment. In other embodiments, the matrix may not be cured. Instead, the matrix may be dried at ambient temperature or at temperatures of about 80 O It may be dried at a temperature of not more than C.

[0133] In some embodiments, the matrix is ​​uncured or cured for 80 O In another embodiment, the matrix is ​​cured by heating at a temperature below about 80° C. O C ~ approx. 160 O C for about 10 minutes to about 300 minutes (5 hours), about 80 O C ~ approx. 160 O C for about 15 minutes to about 4 hours, about 120 O C ~ approx. 160 O C: 15 minutes to 4 hours, 130 minutes O C~about 150 O C: 10 minutes to 4 hours, 140 O C ~ approx. 160 O C: 10 to 30 minutes, 130 minutes O C~about 150 O C: 30 minutes to 4 hours, 60 minutes O C~about 120 O C: 200 minutes to 1440 minutes, 60 minutes O C ~ about 100O C: 300 to 600 minutes, 80 O C~about 90 O C: 400 to 500 minutes, 80 O C~about 120 O C: 600 minutes to 1440 minutes, 80 minutes O C ~ approx. 110 O C for about 800 to 1,440 minutes.

[0134] In a further embodiment, the matrix is ​​about 90 O C: 200 minutes to 1600 minutes, 90 minutes O C: 200 to 500 minutes, 90 O C: 500 minutes to 1600 minutes, 90 minutes O C for about 240 minutes, about 90 C 480 minutes, or 90 minutes O C for approximately 1440 minutes.

[0135] In some embodiments, the matrix is ​​about 100 O C: 200 minutes to 1600 minutes, 100 minutes O C: 200 to 500 minutes, 100 O C: 500 minutes to 1600 minutes, 100 minutes O C: approx. 240 minutes, approx. 100 O C for about 480 minutes, or about 100 O C for approximately 1440 minutes.

[0136] In some embodiments, the matrix is ​​about 110 O C: 30 minutes to 1600 minutes, 110 minutes O C: 30 minutes to 200 minutes, 110 minutes O C: 200 minutes to 1600 minutes, 110 minutes O C for about 30 minutes, about 110 O C for about 60 minutes, and about 110 O C for about 240 minutes or about 110 minutes O C for approximately 1440 minutes.

[0137] In yet other embodiments, the matrix is ​​cured for about 10 minutes to about 4 hours at about 140°C, about 10 minutes to about 1 hour at about 140°C, about 15 minutes to about 30 minutes at about 140°C, about 30 minutes to about 1 hour at about 140°C, about 1 hour to about 4 hours at about 140°C, about 1 hour to about 3 hours at about 140°C, about 10 minutes to about 400 minutes at about 140°C, about 30 minutes to about 400 minutes at about 140°C, about 60 minutes to about 380 minutes at about 140°C, about 60 minutes to about 300 minutes at about 140°C, about 180 minutes to about 300 minutes at about 140°C, about 220 minutes to about 280 minutes at about 140°C, about 230 minutes to about 300 minutes at about 140°C, or about 30 minutes to about 90 minutes at about 140°C.

[0138] Examples of the curing temperature include about 60°C to about 100°C, about 60°C to about 80°C, about 80°C to about 100°C, about 80°C to about 110°C, about 80°C to about 120°C, about 85°C to about 115°C, about 90°C to about 100°C, about 90°C to about 110°C, about 90°C to about 120°C, about 90°C to about 130°C, about 120°C to about 140°C, about 130°C to about 150°C, about 140°C to about 160°C, about 135°C to about 145°C, or about 140°C to about 150°C.

[0139] Examples of curing times include about 20 minutes to about 400 minutes, about 30 minutes to about 400 minutes, about 60 minutes to about 400 minutes, about 90 minutes to about 400 minutes, about 120 minutes to about 400 minutes, about 180 minutes to about 360 minutes, about 200 minutes to about 320 minutes, about 200 minutes to about 300 minutes, about 20 minutes to about 240 minutes, about 20 minutes to about 200 minutes, about 20 minutes to about 180 minutes, about 20 minutes to about 120 minutes, about 20 minutes to about 90 minutes, about 20 minutes to about 60 minutes, about 30 minutes to about 120 minutes, and about 60 minutes to about 180 minutes.

[0140] Additionally, examples of cure times include about 10 minutes, about 15 minutes, about 20 minutes, about 30 minutes, about 45 minutes, about 60 minutes, about 75 minutes, about 90 minutes, about 105 minutes, about 120 minutes, about 150 minutes, about 180 minutes, about 210 minutes, about 240 minutes, about 270 minutes, about 300 minutes, about 330 minutes, about 360 minutes, about 390 minutes, about 420 minutes, about 450 minutes, about 480 minutes, about 510 minutes, about 540 minutes, about 570 minutes, about 600 minutes, about 630 minutes, about 660 minutes, about 690 minutes, about 720 minutes, or about 1440 minutes. The curing temperature can be, for example, room temperature, about 60°C, about 65°C, about 70°C, about 75°C, about 80°C, about 85°C, about 90°C, about 95°C, about 100°C, about 105°C, about 110°C, 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.

[0141] After curing, the rod may be allowed to cool to room temperature before other manufacturing steps are performed. If the insert is to be coated, the coating may be applied before or after curing.

[0142] Drug release rates were evaluated for both uncoated and PVA coated-PVA matrix inserts. We found that, in general, higher cure temperatures and longer cure times resulted in slower drug release rates but also slower erosion.

[0143] 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 length, e.g., about 1 mm to about 10 mm, or about 2 mm to about 6 mm. For example, the rod may 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.

[0144] The rod may be split or otherwise cut into a series of shorter products by any suitable technique for cutting the rod, which may vary depending on whether the product is cured, uncured, or partially cured. For example, at the splitting station, pliers, scissors, a slicing blade, or any other technique may be used. The technique applied may vary depending on the desired placement of each cut portion of the product. For example, if an open end is desired, a shearing operation may be appropriate. However, if it is desired to seal each end as the cut is made, pliers may be used.

[0145] In some embodiments, the extrudate comprises from about 1 w / w% to about 20 w / w%, from about 1 w / w% to about 15 w / w%, from about 1 w / w% to about 10 w / w%, from about 2 w / w% to about 10 w / w%, from about 2 w / w% to about 8 w / w%, from about 2 w / w% to about 6 w / w%, from about 3 w / w% to about 6 w / w%, about 2 w / w%, about 2.5 w / w%, about 3 w / w%, about 3 The substrate is dip coated in an aqueous PVA solution at a PVA concentration of about 0.5 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%.

[0146] The coated extrudate may then be air-dried. The process of dip-coating may be repeated 1-10 additional times, preferably 1-6 or 1-5 additional times, with air-drying between each coat. The coated extrudate may then be cured as described above. After cooling, the extrudate is then cut into inserts.

[0147] e. Insert characteristics Some eye diseases, including those described herein, may require treatment for the rest of a patient's life. Currently available therapies require repeated therapeutic treatments. However, repeated therapy by implanting a drug delivery device in the eye is limited by devices that contain non-biodegradable materials, because non-biodegradable residues of the device accumulate in the eye. Therefore, it would be highly beneficial for patients to provide an implantable drug delivery device that completely erodes before or after the next device needs to be implanted.

[0148] However, it is extremely difficult to design a drug delivery device that provides controlled release of a drug at therapeutic levels over a significant period of time and that can also be completely eroded, for example, within a few months or within about a year. Many of the materials that are effective in controlling drug release over a significant period of time are not bioerodible or erode too slowly.

[0149] In addition, providing a drug delivery device small enough to be implanted within a patient's eye that can contain a sufficient drug load to provide sustained delivery of the drug while minimizing discomfort greatly increases the challenges described above, as does the difficulty of handling and disposing of such devices without significant breakage.

[0150] The present inventors have overcome these challenges and provide a drug delivery device that is small enough to be implanted in the eye with minimal discomfort, which can provide sustained delivery of drug for months, while also being completely eroded at some point after the device's drug delivery period ends.In addition, the present inventors have found a way to provide devices with different drug delivery periods / durations and delivery rates.Furthermore, these devices provide essentially linear release of drug after an initial burst of drug delivery.In addition, the inserts have a very high drug loading compared to the non-active ingredients in the inserts, which is surprising considering the inserts' ability to provide drug release over an extended period of time.

[0151] i. Insert Erosion: In some embodiments, the insert allows complete erosion within 365 days. The ability of the insert to erode within a given period of time may be evaluated using the following erosion evaluation protocol: A sample insert is placed in a 10 mL glass vial containing 5 mL of phosphate buffered saline (PBS), the vial is incubated at 37° C., and the PBS in the vial is replaced once every 24 hours daily for the desired period (e.g., 365 days, 200 days, 110 days). At the end of this period, the insert is removed from the vial and dried, then visually inspected and weighed. The weight loss compared to the original weight is calculated as follows:

number

[0152] For example, if an insert weighs 500 μg and weighs 200 μg after 200 days of incubation in PBS according to the erosion evaluation protocol, the weight of the insert is 40% of the original weight, and its weight is reduced by 60%. This means that the insert has been eroded by 60% in 200 days. If less than 10% of the original weight of the insert remains, the insert is considered to be completely eroded. In some embodiments, the insert is completely eroded within 760 days, 730 days, 700 days, 660 days, 630 days, 600 days, 570 days, 540 days, 400 days, 365 days, 300 days, 280 days, 240 days, 210 days, 200 days, 180 days, 160 days, or 140 days.In other embodiments, the insert exhibits at least 5% erosion within 60 days, at least 10% erosion within 60 days, at least 15% erosion within 60 days, at least 20% erosion within 60 days, at least 25% erosion within 60 days, at least 5% erosion within 75 days, at least 10% erosion within 75 days, at least 15% erosion within 75 days, at least 20% erosion within 75 days, at least 10% erosion within 95 days, at least 15% erosion within 95 days, at least 20 ... erosion, at least 25% erosion within 95 days, at least 30% erosion within 95 days, at least 35% erosion within 95 days, at least 40% erosion within 95 days, at least 15% erosion within 100 days, at least 20% erosion within 100 days, at least 25% erosion within 100 days, at least 30% erosion within 100 days, at least 35% erosion within 100 days, at least 20% erosion within 110 days, at least 30% erosion within 110 days, at least 40% erosion within 110 days, at least 30% erosion within 180 days, at least 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 30% erosion within 220 days, at least 40% erosion within 220 days, at least 50% erosion within 220 days, at least 60% erosion within 220 days, at least 70% erosion within 220 days, at least 40% erosion within 280 days, at least 50% erosion within 280 days, at least 50% erosion within 280 days, at least 60% erosion within 280 days, at least 70% erosion within 280 days at least 80% erosion within 365 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 60% erosion within 400 days, at least 70% erosion within 400 days, at least 80% erosion within 400 days, at least 90% erosion within 400 days, at least 60% erosion within 440 days, at least 70% erosion within 440 days, at least 80% erosion within 440 days, or at least 90% erosion within 440 days.

[0153] ii. Drug release rate: We found that cure temperature, cure time and insert surface area all affected the release rate. Increasing the diameter while keeping the length constant increased the release rate. Increasing the length increased the release rate when the diameter was kept constant.

[0154] In some embodiments, the insert is administered in a dose range of about 0.01 μg / day to about 100 μg / day, about 0.01 μg / day to about 90 μg / day, about 0.01 μg / day to about 80 μg / day, about 0.01 μg / day to about 70 μg / day, about 0.01 μg / day to about 50 μg / day, about 0.01 μg / day to about 20 μg / day, ... ~about 10μg / day, about 0.1μg / day to about 100μg / day, about 0.1μg / day to about 150μg / day, about 0.1μg / day to about 60μg / day, about 0.1μg / day ~50μg / day, approx. 0.1μg / day ~ approx. 40μg / day, approx. 0.1μg / day ~ approx. 30μg / day, approx. 0.1μg / day ~ approx. 20μg / day, approx. 0.1μg / day ~about 10μg / day, about 0.1μg / day to about 5μg / day, about 0.1μg / day to about 2μg / day, about 0.1μg / day to about 1μg / day, about 0.5μg / day to about 1 5μg / day, about 0.5μg / day to about 10μg / day, about 0.5μg / day to about 20μg / day, about 0.5μg / day to about 30μg / day, about 1μg / day to about 50μg / day, about 1 μg / day to about 40 μg / day, about 1 μg / day to about 30 μg / day, about 1 μg / day to about 20 μg / day, about 1 μg / day to about 15 μg / day, about 1 μg / day to about 10 μg / day, about 5 μg / day to about 30 μg / day, about 5 μg / day to about 20 μg / day, or about 10 μg / day to about 30 μg / day. In some embodiments, this is the release rate after steady state release is achieved. In some embodiments, this is the release rate after 2, 3, 5, 8, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, 100, 105, or 110 days of drug release. In some embodiments, the drug release rate is the average drug release rate measured by in vitro drug release method (described below) over a certain period, for example, 30 days, 60 days, 90 days, 120 days or 180 days.As used herein, the term "average release rate" refers to the sum of the release rates of the ocular drug delivery insert over a period (for example, 30 days) divided by the total number of days to arrive at the average release rate.The average release rate is easily calculated by measuring the daily release rate over a period using the method described herein.

[0155] Thus, for example, in some embodiments, the ocular drug delivery insert has an average drug release rate over a 30 day period of about 0.1 μg / day to about 150 μg / day.

[0156] In some embodiments, the insert has this release rate for at least 14 days, at least 30 days, at least 60 days, at least 90 days, at least 100 days, at least 120 days, at least 180 days, at least 200 days, at least 240 days, at least 270 days, at least 300 days, or at least 365 days as measured by in vitro drug release methods.

[0157] The following in vitro drug release method is used to evaluate the amount of drug released: inserts are placed in 10 mL glass tubes and 5 mL of PBS is added into the tubes. The tubes are incubated in a water bath at 37° C. Samples of the medium are taken and the release medium is replaced with fresh PBS every day for a specified period of time. The amount of API released may be quantitatively measured by HPLC as described in Example 2C.

[0158] The duration (total length of time) during which the insert releases API may be up to about 365 days, about 260 days, or about 200 days, or the duration may be at least about 8 weeks, at least about 10 weeks, at least about 12 weeks, at least about 18 weeks, at least about 22 weeks, at least about 28 weeks, at least about 30 weeks, at least about 36 weeks, at least about 40 weeks, at least about 44 weeks, or at least about 52 weeks. Alternatively, the duration of API release may be at least about 28 days, at least about 42 days, at least about 56 days, at least about 120 days, at least about 168 days, at least about 180 days, at least about 200 days, at least about 224 days, at least about 270 days, at least about 300 days, at least about 365 days, or at least about 730 days. The in vitro drug release methods described above may be used to determine whether the insert releases drug during this period.

[0159] In some embodiments, the inserts of the present invention provide an initial rapid release, or burst, of drug in vivo for a period of time before a steady state rate is reached. In preferred embodiments of the present invention, the initial rapid release period is much shorter (e.g., less than 10%) than the total duration of API release. In some embodiments, this initial period is, for example, 1-120 days, 20-120 days, 80-120 days, 1-20 days, 2-50 days, 3-40 days, 5-60 days, 1 day, 2 days, 3 days, 4 days, 5 days, 8 days, 10 days, 12 days, 15 days, 20 days, 25 days, 30 days, 40 days, 50 days, 60 days, 70 days, 80 days, 90 days, 100 days, 105 days, 110 days. In in vitro studies carried out in rabbit eyes, the inventors found a surprisingly high initial burst of drug release, meaning that the initial release of API from the insert was faster than expected, i.e., before leveling off and reaching a steady state. max This may be beneficial in allowing equilibrium to be achieved rapidly, thus providing a therapeutically effective amount locally to the eye quickly. After this burst, the API release rate levels off, providing a therapeutically effective amount of the API daily.

[0160] In a preferred embodiment, the inserts of the present invention release API at a substantially constant rate over a predetermined period of time after implantation (i.e., zero order drug release kinetics, R 2 is between 0.7 and 1). For example, the insert may release the API at a substantially constant rate for about 14 days, about 28 days, about 42 days, about 56 days, about 168 days, about 180 days, about 224 days, about 270 days, about 300 days, or about 365 days. In some embodiments, the insert releases the API at a substantially constant rate for at least 14 days, at least 28 days, at least 42 days, at least 56 days, at least 120 days, at least 168 days, at least 180 days, at least 224 days, at least 270 days, at least 300 days, at least 365 days, at least 540 days, at least 600 days, or at least 730 days.

[0161] The duration of substantially constant API release from the insert may be within a period of about 1 to about 48 months, about 2 to about 36 months, about 2 to about 24 months, about 2 to about 12 months, or about 3 to about 9 months. In some embodiments, the duration of substantially constant API release is about 60 days to about 730 days, about 60 days to about 540 days, about 60 days to about 365 days, about 60 days to about 300 days, about 60 days to about 270 days, about 90 days to about 365 days, about 90 days to about 270 days, about 180 days to about 365 days, or about 365 days to about 730 days. In some embodiments, it is at least about 12 weeks, at least about 18 weeks, at least about 22 weeks, at least about 24 weeks, at least about 30 weeks, at least about 32 weeks, at least about 36 weeks, at least about 40 weeks, at least about 44 weeks, at least about 48 weeks, or at least about 52 weeks. The in vitro drug release tests described above may be used to determine whether the insert releases drug during this period.

[0162] 3.Treatment method In some embodiments, the insert is administered intraocularly to a subject in need thereof to inhibit VEGFR and / or PDGFR, hi other embodiments, the insert is administered intraocularly to a subject in need thereof to inhibit angiogenesis.

[0163] In other aspects, the ocular drug delivery insert is administered to a subject in need thereof to prevent or treat a particular ocular condition or disease of the eye, e.g., to treat an anterior ocular condition, to prevent an anterior ocular condition, to treat a posterior ocular condition, or to prevent a posterior ocular condition.

[0164] An "anterior ocular condition" is a disease, illness, or condition that affects or involves the anterior (i.e., the front of the eye, also referred to as the anterior segment) ocular region or structure, 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 condition may affect or involve the conjunctiva, cornea, anterior chamber, iris, posterior chamber (located between the iris and the lens), lens or lens capsule, as well as blood vessels and nerves that vascularize or innervate anterior ocular regions or sites. Anterior ocular conditions may include diseases, illnesses, or conditions, such as, but not limited to, glaucoma.

[0165] A "posterior ocular condition" is a disease, illness or condition that primarily affects or involves posterior (i.e., the back of the eye, also referred to as the posterior segment) ocular regions or structures, such as the choroid or sclera (which lie in a plane posterior to the posterior wall of the lens capsule), vitreous body, vitreous cavity, retina, optic nerve or optic nerve head, and blood vessels and nerves that vascularize or innervate in the posterior ocular region or site.

[0166] Posterior ocular conditions include diseases, illnesses, or conditions such as, but not limited to, acute macular neuroretinopathy, Behcet's disease, geographic atrophy, choroidal neovascularization, diabetic uveitis, histoplasmosis, infections such as fungal, bacterial, or viral infections, macular degeneration such as neovascular macular degeneration, acute macular degeneration, age-related macular degeneration (AMD) (such as non-exudative (dry) AMD, or exudative (wet) AMD (also known as advanced neovascular AMD)), edema such as macular edema, cystoid macular edema, or diabetic macular edema (DME), multifocal choroiditis, ocular trauma affecting a posterior ocular site or location, ocular tumors, retinal disorders such as retinal vein occlusion, central retinal vein occlusion, diabetic retinopathy (including proliferative and non-proliferative diabetic retinopathy), proliferative vitreoretinopathy (PVR), hypertensive retinopathy, retinal artery occlusion disease such as central retinal artery occlusion (CRAO) and branch retinal artery occlusion (BRAO), retinal detachment, uveitis retinal disease, sympathetic ophthalmia, Vogt-Koyanagi-Harada (VKH) syndrome, uveal diffusion, posterior segment conditions caused or affected by ocular laser treatment, or posterior segment conditions caused or affected by photodynamic therapy, photocoagulation, radioretinal therapy, preretinal membrane disorders, branch retinal vein occlusion, anterior ischemic optic neuropathy, non-retinopathy diabetic retinal dysfunction, and retinitis pigmentosa. Glaucoma may also be considered a posterior segment condition, since the treatment goal is to prevent or reduce the occurrence of vision loss due to damage or loss of retinal cells or optic nerve cells (e.g., by neuroprotective drugs).

[0167] Thus, the present invention provides methods of preventing or treating various ocular conditions by administering an ocular drug delivery insert into the eye of a subject in need thereof.

[0168] For example, the present invention provides a method for treating or preventing an ocular disease by administering an ocular drug delivery insert into the eye of a subject in need thereof, the ocular disease being characterized by damage to retinal neurons and / or the optic nerve. In some embodiments, the disease may be geographic atrophy, glaucoma, diabetic macular edema, wet AMD, and retinal detachment. In some embodiments, the ocular disease is characterized by damage to photoreceptors.

[0169] In addition, the present invention provides a method for providing neuroprotection to ocular tissue by administering ocular drug delivery insert into the eye of a subject who needs it.For example, the present invention provides a method for providing neuroprotection to the posterior part of the eye, particularly to the retina.For example, the present invention provides a method for providing neuroprotection to the retina to prevent retinal disease, such as dry AMD or wet AMD, or to slow down retinal disease progression, such as slowing down the progression from dry AMD to wet AMD, or slowing down the progression through the stages of AMD.

[0170] In some embodiments, the ocular condition is diabetic macular edema (DME). In other embodiments, the ocular condition is retinal vein occlusion, such as central retinal vein occlusion ("CRVO") or branch retinal vein occlusion ("BRVO"). In still other embodiments, the ocular condition is non-ischemic retinal vein occlusion or ischemic retinal vein occlusion. In other embodiments, the condition is diabetic retinopathy. In other embodiments, the condition is non-proliferative diabetic retinopathy.

[0171] In some embodiments, the insert is administered to prevent or treat vision loss in a subject in need thereof, for example, vision loss associated with macular degeneration.

[0172] In other embodiments of the method of preventing or treating various ocular conditions by administering an ocular drug delivery insert into the eye of a subject in need thereof, the ocular condition is AMD.

[0173] The present invention also provides methods for preventing vision loss due to damage or loss of retinal cells, such as retinal neurons. The present invention further provides methods for reducing the incidence of vision loss due to damage or loss of retinal cells, such as retinal neurons. In some embodiments of these methods, administration of the ocular drug delivery insert reduces retinal thinning in the eye. In other embodiments, administration of the ocular drug delivery insert protects against photoreceptor degeneration in the eye. The retinal cells may be photoreceptors, bipolar cells, ganglion cells, horizontal cells, or amacrine cells.

[0174] 4. Age-related macular degeneration Age-related macular degeneration (AMD) is one of the most common causes of vision loss and is predicted to affect nearly 200 million people worldwide (Wong WL, Su X, Li X, et al. Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: a systematic review and meta-analysis. Lancet Glob. Health. 2014;2:e106-116). Late-stage AMD, characterized by macular atrophy (known as geographic atrophy) and choroidal neovascularization (CNV), affects nearly 11 million people (ibid.). Approximately two-thirds of late-stage AMD cases involve CNV, which is manifested by the exudation of fluid and blood and, if untreated, often leads to vision loss and fibrotic scarring.

[0175] Age-related macular degeneration (AMD) can be divided into three stages, based in part on the number and size of drusen found under the retina during a retinal examination. Dry AMD can be classified into early, intermediate, and advanced stages, while wet AMD is always considered to be an advanced form of AMD. Wet AMD includes neovascular age-related macular degeneration, which is also an advanced form of AMD.

[0176] The following table describes the four classifications or stages of AMD as defined by the National Eye Institute AREDS study, depending on the presence of certain markers of AMD. See https: / / www.nei.nih.gov / research / clinical-trials / age-related-eye-disease-studies-aredsareds2 / about-areds-and-areds2. [Table 1]

[0177] An individual may have AMD in only one eye (unilateral) or in both eyes (bilateral), but each eye may be at a different stage of AMD.

[0178] When a subject has unilateral disease or is in a more advanced stage of disease, the other eye of the subject is referred to herein as "fellow eye". The fellow eye does not meet the diagnostic criteria for the disease (e.g., wet AMD) that the other eye is diagnosed with. For example, a subject with unilateral wet AMD may not have evidence of choroidal neovascularization in the fellow eye.

[0179] Typically, early AMD causes no vision loss and only small or a few medium-sized drusen. Individuals with early AMD have a low risk of progressing to advanced AMD within five years.

[0180] Individuals with intermediate AMD are at significant risk for developing advanced AMD. Intermediate AMD is characterized by the presence of either multiple medium-sized drusen or at least one large drusen in one or both eyes, as well as changes in the retinal pigment epithelium (RPE). Individuals may have some or no vision loss in the affected eye(s).

[0181] There are two types of advanced AMD: dry (non-neovascular or non-exudative) AMD and wet (neovascular or exudative) AMD. If an individual has large drusen in both eyes, rather than just one, the individual is more likely to progress to advanced AMD within five years. Individuals with advanced AMD may have vision loss in the affected eye(s) due to macular damage. Having advanced AMD in one eye significantly increases the risk of developing advanced AMD in the other eye.

[0182] In dry AMD, photoreceptors (light-sensitive retinal cells) die gradually, impeding the eye's ability to sense light. This destruction, along with degeneration of the retinal pigment epithelium (RPE), the underlying tissue that supports the retina, leads to vision loss. Complete loss of RPE cells in an area is called geographic atrophy.

[0183] In advanced wet AMD, abnormal blood vessels develop under the retina, which is called choroidal neovascularization. These blood vessels may leak fluid or blood, causing damage to the surrounding tissues, including the photoreceptors. Dry AMD may progress relatively slowly from early to advanced stages, or may not progress at all. However, wet AMD tends to progress rapidly, and sudden vision loss may occur from leakage or bleeding under or into the retina. The same eye may have characteristics of both wet and dry AMD.

[0184] Drusen deposits seen in intermediate or advanced dry AMD may expand and physically affect photoreceptors and / or RPE. Larger drusen may lead to progressive tissue hypoxia and release of factors such as VEGF and PLGF, which in turn stimulate increased vascular permeability, macular edema, exudation and choroidal neovascularization (CNV) seen in wet AMD. These new blood vessels are initially fragile and may break, causing subretinal hemorrhage and photoreceptor toxicity. Progression of choroidal neovascularization may lead to discoid scar formation, also known as end-stage wet AMD. At this stage, drug or surgical treatment may not be effective.

[0185] Intravitreal injection of VEGF inhibitors can reduce the degree of exudation resulting from CNV. Ranibizumab (Genentech, USA), bevacizumab (Genentech, USA) and aflibercept (Regeneron Pharmaceuticals, USA) are used worldwide to treat CNV secondary to AMD. However, these treatments carry the risk of rare but serious adverse events due to the intravitreal procedures and require monthly visits to a retina specialist, which represents a significant burden.

[0186] The present invention provides a method for preventing or treating AMD by administering an ocular drug delivery insert into the eye of a subject. As described above, the ocular drug delivery insert of the present invention can provide long-term drug release, which may result in fewer injections, fewer visits to a retina specialist, and potentially better visual outcome.

[0187] In certain embodiments, the insert is administered to prevent wet AMD in the eye of the subject. In other embodiments, the insert is administered to prevent choroidal neovascularization in the eye of the subject. In yet other embodiments, the insert is administered to prevent the conversion of class 3 AMD to class 4 AMD in the eye of the subject. In some embodiments, the insert is administered to slow the progression of AMD from early to late AMD in the eye of the subject. In other embodiments, the insert is administered to stabilize the eye within the stage of AMD. In some embodiments, the insert is administered to protect retinal pigment epithelial cells in the eye.

[0188] In certain embodiments of the method, the subject has unilateral wet AMD in the other eye of the subject at baseline. In some embodiments, the eye is class 1 or has class 2 AMD at baseline. In other embodiments of the method, the subject has class 3 AMD in the other eye of the subject at baseline. In still other embodiments, the subject has class 3 AMD in both eyes at baseline. In some embodiments of the method, the eye has class 3 AMD and the other eye of the subject has class 4 AMD at baseline. In other embodiments, the eye has class 2 AMD and the other eye of the subject has class 4 AMD at baseline. In still other embodiments of the method, the eye is class 1 and the other eye of the subject has class 4 AMD at baseline. In some embodiments of the method, an ocular drug delivery insert comprising borolanib, or a pharma- ceutically acceptable salt thereof, that releases about 0.1 μg / day to about 40 μg / day of borolanib for at least 90 days and allows for at least 20% erosion within 95 days is administered to both eyes of the subject.

[0189] A variety of methods may be used to diagnose AMD, determine the stage of AMD, or monitor the progression of the eye through the stages of AMD. Some of these diagnostic tools can detect choroidal neovascularization or changes in existing neovascularization.

[0190] For example, evaluation of best corrected visual acuity (BCVA) may be used to evaluate and monitor visual acuity changes as AMD progresses. In subjects with markers for AMD or at risk for AMD, visual acuity changes may be monitored by evaluating BCVA at different time points. In addition, evaluating BCVA before administering a particular AMD therapy and at various time points during therapy may help determine whether the therapy is effective in improving the adverse effects of AMD on visual acuity, slowing the progression of AMD, or stabilizing AMD. For example, an increase in BCVA of at least 5 ETDRS letters compared to baseline may indicate that a particular therapy reduces the effects of AMD. For example, an increase in ETDRS letters of at least 10 letters, or at least 15 letters, indicates a more significant improvement. Stabilization of visual acuity in subjects with intermediate or advanced AMD, for example, loss of 15 or fewer ETDRS letters during treatment, indicates that the therapy stabilizes or slows the progression of AMD. A loss of 10 or fewer ETDRS letters or a loss of 5 or fewer ETDRS letters during treatment indicates a more significant effect on stabilizing or slowing AMD progression.

[0191] People with early stage AMD may suffer from vision loss in low light, low contrast and / or changing light conditions, which affects their vision-related quality of life. The Impact of Vision Impairment (IVI) questionnaire can be used to measure the impact of vision impairment on certain aspects of quality of life and has been found to be reliable. See Weih, LM, Hassell, JB & Keeffe, J. Assessment of the impact of vision impairment. Investigative ophthalmology & visual science 43, 927-935 (2002). The IVI has three vision-specific subscales: reading and accessing information, mobility and independence, and mental well-being. The composite score is the sum of the scores of all three subscales. In some embodiments of the present invention, the subject's IVI questionnaire composite score does not increase significantly from baseline for at least 180 days, at least 365 days, or at least 545 days.

[0192] A dilated eye examination using an ophthalmoscope may be used to detect the presence of drusen in the eye and to quantify the number of drusen.

[0193] Fluorescein angiography (FA) or optical coherence tomography (OCT) may be used to detect choroidal neovascularization and monitor neovascular and exudative changes in AMD, such as an increase in lesion size. OCT may be either spectral domain OCT (SD-OCT) or OCT-angiography (OCT-A).

[0194] In some embodiments of the invention, no new choroidal neovascular lesions appear within 6 months from the date of administration when compared to baseline. In other embodiments, existing choroidal neovascular lesions remain less than 5 mm in diameter as measured by OCT for at least 6 months after administration of the ocular drug delivery insert.

[0195] In some embodiments of the present invention, administration of the ocular drug delivery insert prevents significant loss of vision. For example, in some embodiments, there is no change from baseline in the BCVA of the eye to which the insert is administered for a period of time, the period being measured from the day the ocular drug delivery insert is administered. In other embodiments, there is a loss of 5 or fewer ETDRS letters. In yet other embodiments, there is a loss of 10 or fewer ETDRS letters. In yet other embodiments, there is a loss of 15 or fewer ETDRS letters. In some embodiments, there is a gain of 5 or more ETDRS letters. This period may be at least 90 days, at least 180 days, at least 270 days, or at least 365 days.

[0196] In some embodiments of the present invention, administration of the ocular drug delivery insert prevents an increase in central zone retinal thickness (CST) (average thickness of the macula in a central ETDRS grid of 1 mm), also known as central retinal thickness. For example, in some embodiments, the CST of the eye to which the insert is administered does not increase above baseline for a period of time, the period being measured from the day the ocular drug delivery insert is administered. In other embodiments, the CST does not increase by more than 100 μm, more than 75 μm, more than 50 μm, more than 25 μm, or more than 15 μm during the period. In some embodiments of the present invention, the subject's IVI questionnaire composite score does not increase significantly from baseline during a period of time.

[0197] In some embodiments of the method, there is no detectable choroidal neovascularization in the eye into which the insert is administered for a period of time, the period being measured from the day the ocular drug delivery insert is administered. In other embodiments, the eye into which the insert is administered does not progress to a higher AMD classification than the baseline eye for a period of time.

[0198] This period may be 90, 180, 270, 365, or 545 days. At the end of this period, specific test or evaluation method results are compared to the baseline.

[0199] As used herein, the "baseline" eye may be evaluated immediately prior to administration of the ocular drug delivery insert, such as on day 0 (day of treatment) or 7 days prior to the day of administration (days -7 to -1).

[0200] In some embodiments of the invention, the eye is evaluated for evidence of AMD (e.g., drusen, BCVA, CST, or neovascularization) at baseline and then at one or more time points, such as, for example, 30, 60, 90, 120, 150, 180, 210, 270, 300, 330, and / or 365 days after administration (administration occurs on day 0). The eye may also be evaluated at additional time points.

[0201] The term "preventing," when used in reference to a condition, refers to the administration of a drug to prevent or delay the onset of an ocular condition in a subject, as compared to a subject not receiving the drug. The term "slowing the progression" of a particular ocular condition means preventing the worsening of that condition in a subject, as compared to a subject at the same disease stage who is not receiving the drug.

[0202] The term "treatment" means reducing, ameliorating, or stabilizing an existing undesirable condition.

[0203] a. Administration of Ocular Drug Delivery Insert The administration of the insert may include inserting the insert into the subject's eye, such as inserting the insert into the aqueous humor of the eye or preferably into the vitreous humor. The administration of the insert may include surgically implanting the insert into or on the eye, such as scleral implantation, subconjunctival implantation, suprachoroidal implantation, suprascleral implantation, or intravitreal implantation. The insert may be surgically implanted into the subject's eye, such as intravitreal, subretinal, or suprascleral of the eye. In some embodiments, the insert may be placed by insertion through a needle or cannula. The insert may slowly release the API in the eye, thus avoiding painful and frequent drug administration.

[0204] In certain embodiments, the insert is inserted into the subject's eye, preferably without the need for an incision. In certain aspects, the insert is inserted into the vitreous of the eye. In preferred embodiments, administration of the insert comprises an intravitreal injection.

[0205] In some embodiments, a needle or cannula having a gauge size of 20 to 27 is used for insertion. In other embodiments, a needle or cannula having a gauge size of 25 to 27 is used. In preferred embodiments, a needle smaller than 25 gauge is used for insertion, for example, a needle having a gauge of 25.5, 26, 26.5, or 27.

[0206] In some embodiments of the administration method of the present invention, topical and / or subconjunctival anesthesia may be administered to the insertion site prior to insertion of the insert. Additionally, a broad-spectrum bactericide may be administered to the lower fornix. The insert may be placed below the optic nerve head and posterior to the equator of the eye. After the needle is withdrawn, the conjunctiva may be shifted so that the needle entry site in the conjunctiva and sclera is not in a straight line. The needle used to insert the insert may be inserted through the conjunctiva and sclera to the positive stop of the applicator, and the plunger is depressed to deliver the insert to the rear of the eye.

[0207] In some embodiments, the (one or more) inserts are administered once every 90 to 270 days, once every 90 to 180 days, once every 120 to 720 days, once every 270 to 720 days, once every 270 to 540 days, once every 360 to 720 days, once every 360 to 540 days, or once every 540 to 720 days.

[0208] b. Target In some embodiments, the ocular drug delivery insert is administered to the eye of a subject. In certain embodiments, the subject is a mammal. In further embodiments, the subject is a human.

[0209] c.Dose In some embodiments, the total dose of borolanib delivered is from about 0.0001 μg / day to about 200 μg / day, from about 0.0001 μg / day to about 150 μg / day, from about 0.0001 μg / day to about 100 μg / day, from about 0.0001 μg / day to about 80 μg / day, from about 0.0001 μg / day to about 50 μg / day, from about 0.0001 μg / day to about 30 μg / day, from about 0.0001 μg / day to about 10 μg / day, from about 0.0001 μg / day to about 5 μg / day, from about 0.0001 μg / day to about 1 μg / day, g / day, about 0.001μg / day to about 200μg / day, about 0.001μg / day to about 150μg / day, about 0.001μg / day to about 100μg / day, about 0.001μg / day to about 80μg / day, about 0.001μg / day to about 60μg / day, Approximately 0.001μg / day to approximately 40μg / day, approximately 0.001μg / day to approximately 30μg / day, approximately 1μg / day to approximately 25μg / day, approximately 0.001μg / day to approximately 20μg / day, approximately 0.001μg / day to approximately 15μg / day, approximately 0.001μg / day to approximately 10μg / day, about 0.001μg / day to about 8μg / day, about 0.005μg / day to about 15μg / day, about 0.005μg / day to about 10μg / day, about 0.01μg / day to about 100μg / day, about 0.01μg / day to about 90μg / day, about 0.01μg / day to about 80μg / day, about 0.01μg / day to about 70μg / day, 0.01μg / day to about 50μg / day, 0.01μg / day to about 20μg / day, 0.01μg / day to about 10μg / day, about 0.1μg / day to about 150μg / day, Approximately 0.1μg / day to approximately 100μg / day, approximately 0.1μg / day to approximately 80μg / day, approximately 0.1μg / day to approximately 60μg / day, approximately 0.1μg / day to approximately 50μg / day, approximately 0.1μg / day to approximately 40μg / day, approximately 0.1μg / day to approximately 30μg / day , about 0.1μg / day to about 20μg / day, about 0.1μg / day to about 10μg / day, about 0.1μg / day to about 5μg / day, about 0.1μg / day to about 2μg / day, about 0.1μg / day to about 1μg / day, about 0.5μg / day to about 15μg / day, about 0.5 μg / day to about 10 μg / day, about 1 μg / day to about 50 μg / day, about 1 μg / day to about 40 μg / day, about 1 μg / day to about 30 μg / day, about 1 μg / day to about 20 μg / day, about 1 μg / day to about 15 μg / day, about 1 μg / day to about 10 μg / day, about 1 μg / day to about 5 μg / day, about 1 μg / day to about 10 μg / day, about 5 μg / day to about 30 μg / day, about 5 μg / day to about 20 μg / day, or about 10 μg / day to about 30 μg / day. In some embodiments, this is the release rate after steady state release is achieved. In some embodiments, this is the release rate after 2, 3, 5, 8, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, 100, 105 or 110 days of drug release.

[0210] This dosage may be achieved, for example, by administering 1-6 inserts at a time, i.e., for a single treatment of one eye. Thus, one treatment may require administering 1 insert, 2 inserts, 3 inserts, 4 inserts, 5 inserts, or 6 inserts per eye of the subject at a time. In some embodiments, the subject may receive treatment of only one eye or both eyes. If more than one insert is inserted for a single treatment, the inserts may be inserted separately in separate insertions, or some inserts may be inserted in one insertion. For example, one, two, or three inserts may be inserted in one insertion. If more than three inserts are inserted for a single treatment, they may be split into several insertions. For example, if 4-6 inserts are inserted for a single treatment, they may be split and administered in two or three insertions of 2-3 inserts / insertion.

[0211] Each insert may contain about 1 μg to about 3000 μg, about 1 μg to about 1000 μg, about 1 μg to about 500 μg, about 10 μg to about 2000 μg, about 10 μg to about 1000 μg, about 100 μg to about 500 μg, about 10 μg to about 800 μg, about 50 μg to about 600 μg, about 200 μg to about 2000 μg, about 600 μg to about 2000 μg, about 800 μg to about 2000 μg, about 800 μg to about 1500 μg, about 100 μg to about 500 μg, about 100 μg to about 300 μg, or about 300 μg to about 550 μg of borolanib. For example, each insert may be 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, g, 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 API, e.g., borolanib.

[0212] The total amount of borolanib including all inserts (total payload) may be about 50 μg to about 1000 μg, about 200 μg to about 6000 μg, about 600 μg to about 6000 μg, about 800 μg to about 6000 μg, about 600 μg to about 5040 μg, about 600 μg to about 4500 μg, about 1000 μg to about 5400 μg, about 1000 μg to about 3000 μg, or about 2000 μg to about 4000 μg. For example, the total API amount of all inserts can be 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.

[0213] 5. Combination - induction and maintenance treatment The present invention also provides a method of treating a posterior ocular condition of an eye in need of treatment, the method comprising administering to the eye, at a first time point, an agent that inhibits activation of a VEGF receptor, such as a VEGF ligand, a VEGF inhibitor, or an anti-VEGF, and, at a second time point, administering to the eye an ocular drug delivery insert comprising borolanib or a pharma- ceutical acceptable salt thereof to maintain the induction treatment (maintenance treatment).

[0214] In some embodiments, the posterior ocular condition is selected from wet AMD, diabetic retinopathy (DR), macular edema following retinal vein occlusion (RVO), and diabetic macular edema (DME). In some embodiments, the posterior ocular condition is neovascular age-related macular degeneration.

[0215] The first and second time points are preferably on different days. For example, the second time point may be at least about 1 week, at least about 2 weeks, at least about 4 weeks, at least about 8 weeks, or at least about 24 weeks after the first time point, preferably at least 1 week, at least 2 weeks, at least 4 weeks, at least 8 weeks, or at least 24 weeks after the first time point.

[0216] Generally, the drug used for induction therapy (induction therapy agent) is any standard of care VEGF inhibitor (sometimes referred to as anti-VEGF). In some embodiments, the drug is a VEGF inhibitor selected from ranibizumab, bevacizumab, and aflibercept. In some embodiments, the VEGF inhibitor is administered by injection, for example, by intravitreal injection. In some embodiments, the VEGF inhibitor is an aflibercept injection for intravitreal use.

[0217] In some embodiments for treating wet AMD, the dose of aflibercept is about 2 mg or 2 mg (0.05 mL) administered by intravitreal injection every 4 weeks (approximately every 28 days, monthly). In some embodiments, monthly injections administered for the first 12 weeks (3 months) are followed by intravitreal injections of about 2 mg or 2 mg (0.05 mL) once every 8 weeks (2 months) or once every 12 weeks.

[0218] In some embodiments for treating macular edema, the dose of aflibercept is about 2 mg or 2 mg (0.05 mL) administered once every 4 weeks (approximately every 25 days, every month) by intravitreal injection.

[0219] In some embodiments for treating diabetic macular edema (DME) or diabetic retinopathy (DR), the dose of aflibercept is about 2 mg or 2 mg (0.05 mL) administered by intravitreal injection every 4 weeks (approximately every 28 days, monthly) for the first 5 injections, followed by about 2 mg or 2 mg (0.05 mL) by intravitreal injection once every 8 weeks (2 months). In some embodiments, aflibercept is administered in a dosage every 4 weeks (monthly) after the first 20 weeks (5 months).

[0220] In some embodiments, VEGF inhibitor is administered to eye once a month until eye is dry or no further visual or anatomical improvement is observed against baseline.Eye can then be evaluated periodically, for example, once every 2, 3, 4, 5, 6, 7 or 8 weeks.If fluid recurs, VEGF inhibitor is administered to eye again and evaluation continues.In some embodiments, VEGF inhibitor treatment interval can be extended from once a month (every 4 weeks or once every 28 days) to once every 5 weeks or once every 6 weeks.If eye remains fluid-free for a given interval, the period during which eye remains fluid-free is assigned as VEGF inhibitor treatment interval (for example, once treatment every 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 weeks). Ocular evaluation for fluid and / or vision would continue periodically, for example, once every 2, 3, 4, 5, 6, 7 or 8 weeks, with treatment intervals adjusted to be the same as non-fluid intervals.

[0221] In some embodiments, the ocular drug delivery insert administered at the second time point (i.e., to an eye that has previously undergone induction treatment) comprises a solid matrix core comprising a matrix polymer and borolanib or a pharma- ceutically acceptable salt thereof, wherein the amount of borolanib or a pharma- ceutically acceptable salt thereof in the insert is from about 10% w / w to about 98% w / w, the drug release rate of the insert is from about 0.01 μg / day to about 100 μg / day for at least 14 days, and the insert permits at least 20% erosion within 95 days.

[0222] In a further embodiment, the first dose of the ocular drug delivery insert is a loading dose and subsequent doses are maintenance doses, as described herein.

[0223] Thus, the present invention provides a method that may be described as "maintenance therapy" for posterior ocular conditions. In most eyes, this treatment may result in a less intensive treatment regimen than treatment with a VEGF inhibitor alone, and may maintain the visual and anatomical stability of most eyes for more than six months. In some embodiments, the eye is treated with one or more supplemental doses of a VEGF inhibitor after one or more doses of an ocular drug delivery insert are administered. In some embodiments of the present invention, a VEGF inhibitor is administered to the eye being treated simultaneously with the ocular insert of the present invention. As used herein, combination treatment means that the eye to which the VEGF inhibitor is administered still contains an ocular insert that releases borolanib.

[0224] In some embodiments, the VEGF inhibitor is administered as a loading dose prior to administration of the first dose of the ocular drug delivery insert as described herein. In some embodiments, the first dose of the ocular drug delivery insert is administered within about 1 week, at least about 2 weeks, at least about 4 weeks, at least about 8 weeks, at least about 12 weeks, or at least about 24 weeks of the eye being treated with the VEGF inhibitor.

[0225] In some embodiments, the first dose of the ocular drug delivery insert is administered to an eye that has previously responded to at least 2, 3, 4, 5, 6, 7, or 8 intravitreal injections of a VEGF inhibitor.

[0226] In some embodiments, replacement therapy is administered after administration of a loading dose of an ocular drug delivery insert described herein, for example while the loading dose of the ocular drug delivery insert is present in the eye.

[0227] In some embodiments, replacement therapy is administered after administration of a maintenance dose of an ocular drug delivery insert described herein, for example while the maintenance dose of the ocular drug delivery insert is present in the eye.

[0228] In some embodiments, aflibercept is administered as induction treatment as described herein on day 1, week 4, and week 8. In some embodiments, the first dose of the ocular drug delivery insert is administered to the eye that previously received induction treatment on day 1, week 4, and week 8, 30 minutes after the induction treatment on week 8.

[0229] In some embodiments, aflibercept supplemental treatment is administered beginning at week 12 to an eye that previously received aflibercept induction treatment on days 1, 4, and 8, and a first dose of the ocular drug delivery insert 30 minutes after induction treatment at week 8. In some embodiments, aflibercept supplemental treatment is administered to an eye at week 12, and there is a BCVA loss of 5 or more letters from the test peak due to wet AMD, and a CST increase of 75 microns or more on SD-OCT from the test nadir, a BCVA loss of 10 or more letters from the test peak due to wet AMD, a CST increase of 100 microns or more on SD-OCT from the test nadir for two consecutive visits, or new or worsening vision-threatening bleeding due to wet AMD.

[0230] In some embodiments, the first ocular drug delivery insert is administered to an eye where the CST is less than 500 μm, 400 μm, 350 μm, 300 μm, 250 μm, or 200 μm. In some embodiments, the ocular drug delivery insert is administered to an eye where the CST is less than 500 μm, 400 μm, 350 μm, 300 μm, 250 μm, or 200 μm.

[0231] 6.Definition As used in this specification and the claims, the following words and phrases are generally intended to have the meanings set forth below, unless the context in which they are used indicates otherwise.

[0232] The singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. For example, "a matrix polymer" means one or more matrix polymers.

[0233] The terms "bioerode," "bioerosion," "biodegrade," and "biodegradation," as used herein, refer to the gradual breakdown, dissolution, or destruction of an insert over a period of time within a biological system, for example, by one or more physical or chemical degradation processes, such as enzymatic action, hydrolysis, ion exchange, or dissolution by solubilization, emulsion formation, or micelle formation.

[0234] The term "room temperature" is used in O C. "Solid at room temperature" means 22 O At a temperature of 100°C it means a solid.

[0235] When the term "about" is used in connection with a numerical value or range, it modifies the value or range by expanding the boundaries above and below the numerical values ​​set forth. In general, the term "about" is used herein to modify a numerical value above and below the set forth value by a 10 percent variation above or below (higher or lower) the value, i.e., by a variance of ±10%, unless a different variation is indicated (e.g., ±30%, ±20%, ±5%, ±1%, ±0.5%, etc.).

[0236] The term "and / or" refers to and includes each listed item individually, as well as any and all possible combinations of one or more of the listed items.

[0237] The terms "comprising," "consisting of," and "consisting essentially of" have the meanings given them in accordance with patent law. When the term "includes" or "including" is used in this specification or in the claims, it is intended to be inclusive in a manner similar to the term "comprising" when that term is used as a transitional term in the claims.

[0238] The terms "optional" and "optionally" mean that the subsequently described circumstance may or may not occur, so that the description includes cases where the circumstance occurs and cases where it does not occur.

[0239] When features or aspects of the disclosure or claims are described in terms of a Markush group, the described group includes any individual members as well as subgroups of members of the Markush group.

[0240] As will be understood by those of skill in the art, all language such as "up to," "at least," "greater than," "less than," and the like, includes the recited numbers and refers to ranges that may then be broken down into subranges. Finally, as will be understood by those of skill in the art, ranges include individual members and include the end points 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 on.

[0241] The term "substantially all," as used herein, refers to a majority of the total, for example, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% of the total.

[0242] The term w / w% refers to the percentage of a particular substance in a mixture when measured by weight or mass. Thus, for example, if the core is an insert containing at least about 8 w / w% non-active ingredients, the total weight of the non-active 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 non-active ingredients in the core will be at least 8 mg.

[0243] The term w / v% refers to the weight percent of a component (such as a solute) in the total volume of the solution. A 2 w / v% PVA solution would mean 2 grams of PVA in 100 mL of solution. A 2 w / w% PVA solution would mean 2 grams of PVA for 100 mg of solution.

[0244] All cited patents, patent applications, scientific publications and books are incorporated herein by reference in their entirety.

[0245] While various aspects and embodiments have been disclosed herein, other aspects and embodiments will be apparent to those skilled in the art. EXAMPLES

[0246] Example 1 The grades of PVA listed in the table below were processed into films and the films were then evaluated for erosion rate and strength.

[0247] To form the films, 4.5% PVA in water was cast by pouring into a tray and air drying at room temperature. Once the films were dry, they were cut into 1×1 square specimens. Six specimens of each film were then cured at 100° C. for 3 hours, 140° C. for 30 minutes, or 140° C. for 4 hours as listed in the table below. After the square specimen films were cured, they were weighed and imaged. Each specimen was then immersed in PBS at room temperature for 24 hours. The specimens were then removed from the PBS and four of each grade of PVA were oven dried at 50° C. for 2 hours and two of each grade of PVA were air dried on a paper towel at room temperature as listed in the table below. The specimens were then weighed and imaged again. [Table 2]

[0248] The average weight change after 24 hours of immersion in PBS was calculated and is shown in the graph in Figure 2. The degree of hydrolysis (DH) and molecular weight (MW) of the PVA determines the solubility of the film. The 6000 / 80%, 25,000 / 88%, 125,000 / 88%, and 6000 / 80% to 125,000 / 88% mixed PVA films each dissolved by the end of the first day at all cure conditions tested. The 78,000 / 98% film lasted the longest. The relative film strength of the films tested is shown in Figure 3.

[0249] Example 2A Inserts were made according to the parameters in the table below: [Table 3] [Table 4]

[0250] Inserts were prepared by mixing borolanib with a 78,000 / 98% PVA aqueous solution at the w / w ratio of borolanib:PVA solution specified in the table above. The mixture was then extruded through a 20, 21 or 23 gauge dispensing tip and allowed to dry at room temperature.

[0251] For coated inserts, the extrudates were then dip coated in a 78,000 / 98% PVA solution and air dried. The dip coating process was repeated to achieve the number of coats specified in the table above. The coating process involved immersing the extrudates in the PVA solution with 5 minutes room temperature drying between the first layers, followed by at least 10 minutes of drying time before immersion to form the final layer / coating. The coated extrudates were then cured as specified in the table. After cooling to ambient temperature, the extrudates were cut into 2mm, 3.5mm, 5mm or 6mm or 8mm long inserts.

[0252] Example 2B The drug release rate of the inserts was tested in vitro. Each insert sample was placed in a 10 mL glass tube and 5 mL of PBS was added to the main tube. The tubes were incubated in a water bath at 37 °C. Samples of the release medium were taken at 12-24 hour intervals and the release medium was replaced with fresh PBS. The amount of released borolanib was quantitatively measured by HPLC according to the method described in Example 2C. The in vitro release rate was tested and the average release rate was determined from the cumulative release versus time.

[0253] Example 2C A sample of the insert was assayed for API content. The insert tested for content was cut into four strips and all four strips were placed in a labeled scintillation vial. 3.0 mL of methanol was pipetted into the vial and the vial was placed under the cabinet. This procedure was repeated for all samples. The sample vial was placed in a sonicator and an appropriate amount of water was added and the sample was sonicated for 30 minutes. The sonication was repeated five more times, cooling the sonicator between each sonication. Additional sonication can be performed as needed to ensure complete dissolution of the API. HPLC was performed with the following parameters: Column: ZORBAX Eclipse XDB-C18, 4.6×150 mm, 5 micron, Mobile Phase A: Water + 0.1% phosphoric acid, Mobile Phase B: Acetonitrile + 0.1% phosphoric acid, Gradient method, Stop time 30 minutes, UV: 214 nm.

[0254] Example 2D Erosion of the sample inserts was evaluated. The sample inserts were placed in 10 mL glass vials containing 5 mL of phosphate buffered saline (PBS) and the vials were incubated at 37° C. without agitation. The PBS in the vials was replaced once every 24 hours for each day of interest. At the end of the period, the samples were removed from the vials, weighed and photographed.

[0255] The drug release kinetics curves for the coated 4.5% PVA formulation (designated Formulation A) cured at 140° C. for 4 hours are shown in FIG. 4A (cumulative % drug release) and 4B (cumulative drug release (μg)). The drug release kinetics curve for the uncoated Formulation A insert is shown in FIG. 6. Photographs of the eroded Formulation A insert taken after immersion in dissolution medium for 314 and 447 days are shown in FIG. 5. For comparison, the 447 day photograph includes an intact insert. Photographs of the uncoated eroded Formulation A insert taken after immersion in dissolution medium for 287 and 352 days are shown in FIG. 7. For comparison, the 352 day photograph includes an intact insert.

[0256] The drug release kinetics curves of the coated 4.5% PVA formulation (designated Formulation B) cured at 140° C. for 30 min are shown in Figures 8 (cumulative drug release %) and 8B (cumulative drug release (μg)). Photographs of eroded Formulation B inserts taken after immersion in dissolution medium for 59, 88 and 155 days are shown in Figure 9.

[0257] The drug release rate curve for the uncured coated 4.5% PVA formulation (designated Formulation C) is shown in Figure 10. Two photographs, each showing a different sample of the eroded Formulation C insert, taken after immersion in dissolution medium at 37°C for 98 days and then at room temperature for 113 days, are shown in Figure 11.

[0258] A comparison of the drug release curves of formulations A, B and C is shown in FIG.

[0259] Formulation A releases drug more slowly and erodes more slowly than Formulations B and C. Formulation C releases drug more rapidly and erodes more rapidly than Formulations A and B.

[0260] Example 3 Inserts containing two or more grades of PVA were made according to the parameters in the following table: [Table 5]

[0261] Inserts were fabricated by mixing borolanib with an aqueous PVA solution in a 1:1 w / w ratio of borolanib:PVA solution to form a paste. The mixture was then extruded through a 21 gauge dispensing tip to form rods approximately 4-5 inches long and allowed to dry at room temperature. The extruded rods were cured as described in the table above.

[0262] The extrudate was 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 extrudate in the PVA solution with 5 minutes room temperature drying between the first layers, followed by at least 10 minutes drying time before dipping to form the final layer / coating.

[0263] After the final coat, the coated rods were cured according to the conditions listed in the table above. After cooling to ambient temperature, the coated rods were cut into 8 mm long inserts using a razor blade.

[0264] The API release rate was measured according to the method described in Example 2B.

[0265] The API content was measured according to the method described in Example 2C.

[0266] The erosion of the inserts was evaluated according to the method described in Example 2D.

[0267] Inserts containing two or more grades of PVA are made according to the parameters in the following table: [Table 6] [Table 7]

[0268] Inserts are fabricated by mixing borolanib with an aqueous PVA solution in a 1:1 w / w ratio of borolanib:PVA solution to form a paste. The mixture is then extruded through a 21 gauge dispensing tip to form an approximately 4-5 inch long rod and allowed to dry at room temperature. The extruded rod is allowed to harden as described in the table above.

[0269] The extrudate is dip coated in an aqueous PVA solution and dried at room temperature. For inserts with two or more coatings, the coating process involves dipping the extrudate in the PVA solution with 5 minutes room temperature drying between the first layers, followed by at least 10 minutes drying time before dipping to form the final layer / coating.

[0270] After the final coat, the coated rods are cured according to the conditions listed in the table above. After cooling to ambient temperature, the coated rods are cut into 8 mm long inserts using a razor blade.

[0271] The API release rate is measured according to the method described in Example 2B.

[0272] The API content is measured according to the method described in Example 2C.

[0273] Erosion of the inserts is assessed according to the method described in Example 2D.

[0274] Example 4 Prepare inserts according to the parameters in the table below: [Table 8] [Table 9]

[0275] The API is mixed with the aqueous PVA solution in the API:PVA solution ratio specified in the table to form a paste. The paste is extruded through a dispensing tip with a gauge of 20-23 to form a rod approximately 4-5 inches long and allowed to dry at room temperature. The extruded rod is cured before or after coating as specified in the table above.

[0276] The extrudate is dip coated in an aqueous PVA solution. The coating process involves immersing the extrudate in the PVA solution with 5 minutes room temperature drying between the first layers, followed by at least 10 minutes drying time before immersion to form the final layer / coating. After the final coat, the coated rods were either cured according to the table above or allowed to dry at room temperature for 24 hours.

[0277] The coated rods are cut into 2 mm, 3.5 mm, 5 mm or 6 mm long inserts using a razor blade.

[0278] The API release rate is measured according to the method described in Example 2B.

[0279] The API content is measured according to the method described in Example 2C.

[0280] Erosion of the inserts is assessed according to the method described in Example 2D.

[0281] Example 5A - Pharmacokinetic Study An intravitreal pharmacokinetic study was performed in male Dutch-belted rabbits. The objective of the study was to characterize the plasma and ocular tissue pharmacokinetics of vorolanib inserts following bilateral intravitreal injections on day 1. Animals were evaluated up to 24 months after placement of the intravitreal inserts.

[0282] The table below describes the group assignment dose levels and treatments. [Table 10]

[0283] After anesthesia administration, 0.37 mm diameter, 3.5 mm long borolanib inserts designed to release drug for at least 6 months were inserted intravitreally into each eye of 52 male Dutch-Belted rabbits using a syringe. The low-dose group (1) received three inserts per eye for a total dose of 630 μg per eye. The high-dose group (2) animals received six inserts per eye in two separate insertions (three inserts per insertion) for a total dose of 1,260 μg per eye.

[0284] One whole blood sample was taken from two target animals per group via puncture of the marginal ear vein before each scheduled sacrifice time point. Samples were tested for levels of borolanib 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 months 1, 2, 4, 6, 8, 16 and 24. Vitreous humor and ocular tissues were collected from both eyes and inserts were taken to analyze drug distribution in ocular tissues, and liver and kidney samples were taken for tissue distribution evaluation.

[0285] Results: At steady state, vitreous levels of borolanib were 56 ng / mL at the low dose of 630 μg and 97 ng / mL at the high dose of 1,260 μg (approximately dose proportional). Retina / choroid levels were 49 ng / g and 89 ng / g. There was a burst period of drug release during the first 90 days, followed by a steady state. Steady state was reached by day 105. Maximum observed concentrations in the vitreous and retina / choroid appeared to be approximately dose proportional. After 99 days, no obvious changes were seen in plasma levels. Vitreous C was significantly higher at the 630 μg dose by day 180. max was 232ng / mL, T max is 336 hours, AUC last The vitreous C value was 315.5 μg h / mL. max was 1697ng / mL, T max is 720 hours, AUC last was 1583.2 μg·h / mL.

[0286] Figure 13A shows the average amount of drug remaining in the insert versus time for inserts excised at various times and assayed to determine the amount of borolanib remaining in the insert, and Figure 13B shows the cumulative percent of released drug versus time for excised inserts.

[0287] Example 5B - Pharmacokinetic Study A second intravitreal pharmacokinetic study was conducted in Dutch-belted rabbits. The purpose of this study was to evaluate the plasma and ocular pharmacokinetics of vorolanib inserts after bilateral intravitreal injection in rabbit eyes. Animals were evaluated up to 12 months after placement of the intravitreal inserts.

[0288] Vorolanib inserts were administered by intravitreal injection into each eye of Dutch-belted rabbits. Group 1 eyes received one insert containing 643 μg of vorolanib, and Group 2 eyes received two inserts containing a total of 900 μg. Blood samples were collected on days 2, 7, 14, and 28, then monthly from months 2 to 12. Inserts were collected on days 2, 7, and 14, then at months 1, 2, 4, 6, 8, 10, and 12. Residual vorolanib levels were determined in all explants using high performance liquid chromatography. Vorolanib release rates were estimated based on residual levels in the explants. Plasma and ocular tissues were separated and analyzed for vorolanib and its metabolites using liquid chromatography-mass spectrometry.

[0289] Results: The inserts released borolanib at a mean rate of 8.1% / month in group 1 and 7.8% / month in group 2 through 12 months. Release profiles showed near zero-order kinetics through 8 months, demonstrating uniform drug release at microgram levels daily, with concentrations in target ocular tissues (choroid and retina) above the IC50 for VEGFR2. Beyond 8 months, the release rate rapidly decreased, resulting in target ocular tissue levels below the IC50 (<10 ng / mL) by 10 months. The exposure ranking of borolanib was choroid = retina = vitreous > aqueous humor > plasma. Mean borolanib concentrations in ocular tissues and plasma decreased 85%-99% between months 8 and 10.

[0290] The borolanib insert demonstrated sustained and uniform zero-order release of borolanib in rabbit eyes for up to 8 months, followed by a rapid decline by month 10. The borolanib insert is being tested in phase 2 clinical trials for wAMD and diabetic retinopathy, with trials planned in diabetic macular edema.

[0291] Example 6 - Toxicity and Pharmacokinetic Studies An 18-month intravitreal toxicity study of the inserts was also performed in 80 Dutch-belted rabbits (40 males and 40 females). Animals were evaluated for 6 to 18 months after placement of the intravitreal inserts. The objective was to characterize the ocular toxicity, plasma pharmacokinetics, and biodegradation of vorolanib inserts after bilateral intravitreal injections.

[0292] The following table describes the group assignments and dose levels. In the toxicity groups, animals were sacrificed at months 6 and 18. For plasma pharmacokinetic analysis, blood samples were collected on days 1, 3, and 7, then at months 1, 2, 3, 4, 5, 6, 12, 14, 16, and 18. [Table 11]

[0293] After administration of anesthesia, borolanib inserts measuring 0.37 mm in diameter and 3.5 mm in length, designed to release drug for at least 6 months, were inserted intravitreally in each eye of each Dutch Belted rabbit using a syringe. Animals in the placebo group (1) received two placebo inserts in each eye via insertion. Animals in the low dose group (2) received two inserts in each eye. Animals in the medium dose group (3) received three inserts in each eye via two separate insertions. Animals in the high dose group (4) received four inserts in each eye via two separate insertions (2 inserts / insertion). Animals in the highest dose group (5) received six inserts in each eye via two separate insertions (3 inserts / insertion).

[0294] Whole blood was collected at each scheduled time point by puncture of the marginal ear vein. Samples were analyzed for clinical pathology and plasma pharmacokinetics. Animals were euthanized according to the schedule described above. Complete gross necropsies were performed on all animals sacrificed or found dead during the study. Organs were weighed and tissues were harvested. Ocular tissues were harvested for histopathology only.

[0295] Conclusion: Plasma pharmacokinetic and toxicity studies showed that vitreous C max The study provides evidence of safety over 18- and 24-month exposure periods in borolanib levels in the vitreous and retina / choroid, respectively. 50 remained significantly higher than

[0296] There were no adverse findings attributable to borolanib and no adverse findings for up to six inserts. The no observed adverse effect level (NOAEL) for the inserts was determined to be six inserts / eye (1260 μg / eye).

[0297] The most common event was lens yellowing, which was dose-related and likely due to the color of the API. There were no histopathological / microscopic findings associated with the lens discoloration. The second most common event was focal, punctate, or linear lens opacities, which appeared to be primarily related to the number of insertions and, to a lesser extent, the number of inserts.

[0298] Mild inflammation (<2+ aqueous or vitreous cells) was initially observed in all groups. All inflammatory cells gradually recovered and disappeared by 3 months. Most observed inflammation events were seen in the placebo group (2 inserts without drug).

[0299] There was no change in intraocular pressure (IOP) from baseline, although some transient changes were observed.

[0300] Vorolanib plasma levels were in the low pg / mL range.

[0301] Example 7 Safety and Efficacy The safety and efficacy of borolanib inserts were evaluated 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 angiogenesis in a laser-induced model of choroidal neovascularization (CNV) using borolanib inserts in pigs.

[0302] The experimental design is described in the table below: [Table 12]

[0303] On the day of laser irradiation, animals (groups 1-4) were treated with an 810 nm diode laser delivered by indirect ophthalmoscope. Approximately six single laser spots were placed between the retinal veins. Laser treatments were performed on both eyes according to the schedule in the table above.

[0304] On the day of intravitreal injection, animals were anesthetized and eyes were prepared aseptically. The conjunctiva was gently grasped with colibri-type forceps and the injection (25G needle) was made 2-3 mm posterior to the superior limbus (through the pars plana), with the needle aimed directly and slightly posterior to avoid contact with the lens. Animals were allowed to recover normally from the procedure. After 4-6 hours, pigs received topical instillation of antibiotic eye drops, then twice daily instillations for an additional 2 days with at least 6 hours between doses. Animals were dosed according to the schedule in the table above, either on day 0 immediately after laser CNV induction or 7 days prior to laser CNV induction. Animals in groups 5-6 were implanted on day 0 without undergoing the laser CNV procedure.

[0305] During acclimation and throughout the study, animals were evaluated for mortality and morbidity as well as general health with particular attention to the eyes. Body weights were measured prior to treatment and necropsy, and animals in groups 5 and 6 were weighed monthly.

[0306] A complete ophthalmic examination (OE) using a slit-lamp biomicroscope and indirect ophthalmoscope (modified Hackett and McDonald) to assess ocular surface morphology, anterior and posterior segment inflammation, cataract formation, and retinal changes was performed by a veterinary ophthalmologist at time points as indicated in the experimental protocol. Pupil dilation for ophthalmic examination was performed using topical 1% tropicamide HCL.

[0307] Fluorescein angiography was performed on both eyes of anesthetized animals at the time points indicated in the experimental protocol.

[0308] Full-field electroretinograms (ERGs) were performed on both eyes of animals at baseline and 3 months after dosing (groups 5-6 only). On the day of ERG measurements, animals were anesthetized after dark adaptation. ERGs were elicited by brief flashes of 0.33 Hz delivered at maximal intensity from a miniganzfeld light stimulator. Twenty responses were amplified, filtered, and averaged for each animal. Animals were subjected to standard ERG measurements as defined by ISCEV standards, including dark-adapted (0.01 candela), dark-adapted (3 candela), and light-adapted (25 candela) measurements.

[0309] At the time points indicated in the protocol, animals were euthanized after final data collection. Histology was evaluated for eyes in groups 5-6.

[0310] Results: Overall, we found dose-related efficacy and no clinically observed toxicity. Fluorescein angiography analysis in all groups (1-4) showed a decrease in corrected total lesion fluorescence (CTLF) values ​​from days 7 to 28, with aflibercept-treated animals showing the greatest decrease in CTLF values, followed by the high dose, and the remaining groups showing similar decreases in CTLF values. ERG b-wave amplitude decreased from baseline to day 84 in both groups undergoing ERG, which may be due to the difficulty of ERG acquisition.

[0311] Histological examination of the eyes showed some inflammation that may have been more severe in animals dosed with the high dose inserts. The implantation procedure may have contributed to the increased inflammation observed in the high dose group.

[0312] Aflibercept and placebo inserts performed as expected, with aflibercept having a normal amount of efficacy in this model and the placebo inserts being well tolerated.

[0313] As can be seen in Figure 14, the lesions in Group 2 (medium dose) and Group 3 (high dose) animals that received inserts 7 days prior to laser CNV never reached the lesion size of the untreated eyes, indicating that the inserts prevented the lesions from reaching the size seen in the untreated eyes. Figure 14 is a bar graph comparing the percentage change in corrected total lesion fluorescence (CTFL) over time for Groups 1-4.

[0314] Conclusion:

[0315] During PK study, borolinib plasma levels were in the low pg / mL range. Dose-related efficacy was found, and no toxicity was observed clinically. Thus, the insert of the present invention can deliver safe and therapeutically effective steady-state levels of borolinib locally for a sustained period, while systemic levels of borolinib are negligible. Moreover, the insert is fully bioerodible. In addition, the insert appears to have a preventive effect against the growth of lesions.

[0316] Example 8: A Phase 1 DAVIO Multicenter, Prospective, Open-Label, Dose-Escalation Study of EYP-1901, a Tyrosine Kinase Inhibitor (TKI) Ocular Drug Delivery Insert, in Subjects with Wet AMD A Phase 1 open-label, dose-escalation clinical trial of the ocular drug delivery insert of the present invention is being conducted to evaluate the safety of the ocular drug delivery insert containing borolanib in the management of subjects with neovascular (wet) age-related macular degeneration (AMD). Six-month interim results have been evaluated and reported.

[0317] Seventeen subjects were enrolled, all of whom had previously been treated for wet AMD at the time of study initiation. Subjects in this study had been diagnosed with wet AMD in the study eye for at least 4 months prior to the screening visit. To be included, subjects had to have received anti-VEGF products, such as bevacizumab (Avastin ( 登録商標 ), Genentech), ranibizumab (Lucentis ( 登録商標 ), Genentech), or aflibercept (Eylea ( 登録商標 ), Regeneron) or other drugs had to have been administered at least three times in the past. [Table 13]

[0318] In subjects with unilateral wAMD, the affected eye was designated as the study eye, and in subjects with bilateral wAMD, the study eye was the more severely affected eye that met the inclusion / exclusion criteria, i.e., the eye with worse BCVA or, if equal, the eye that was clinically determined to be the more severely affected eye as determined by the investigator. If eyes were symmetrically affected, the study eye was the right eye.

[0319] One week after screening and standard of care anti-VEGF injection, subjects received a single dose of the study drug, i.e., ocular drug delivery insert containing borolanib and PVA. The study included four dosing cohorts: low dose, low-medium dose, medium dose, and high dose. A 25-gauge needle was used for the low-dose injection, and a 22-gauge needle was used for the other injections. [Table 14]

[0320] The release period of the active pharmaceutical ingredient (borolanib) is expected to be at least 9 months. No reinfusions of the study drug were administered during the first 6 months of the study.

[0321] After insertion on study day 0, subjects visited the clinic on study days 7, 14, and 28, and every 4 weeks thereafter until 12 months.

[0322] Assessments included BCVA by ETDRS, anterior / posterior segment examination, IOP, fluorescein angiography (FA), color fundus photography (CFP), treatment-emergent ocular and non-ocular adverse events (TEAEs), clinical laboratory evaluations (hematology, serum chemistry, coagulation, and urinalysis), vital signs measurements (see attached Schedule of Study Procedures and Assessments for details), spectral domain-optical coherence tomography (SD-OCT), and, where equipment is available, OCT-angiography (OCT-A).

[0323] The primary study endpoints are to assess safety based on treatment-emergent ocular (test and fellow) and non-ocular adverse events (TEAEs), including clinical laboratory findings, and to determine the maximum tolerated dose for the treatment of neovascular (wet) AMD, and secondary endpoints include BCVA and CST measured by OCT. Investigators are also evaluating the number of eyes free of supplemental (previously referred to as "rescue" in our study protocol) treatment at various time points, and the extent to which anti-VEGF treatment burden is reduced following EYP-1901 administration.

[0324] Following intravitreal injection of the EYP-1901 insert, FDA-approved anti-VEGF treatment for wet AMD or off-label bevacizumab may be administered at the investigator's discretion if at least one of the following criteria is met: The presence of new or worsening vision-threatening hemorrhage due to wet AMD from baseline (day 0), or Increase in CST from baseline (day 0) of more than 75 μm, or Loss of ≥10 ETDRS letters from baseline (Day 0) with intraretinal / subretinal fluid and / or hemorrhage determined to be the cause of BCVA loss. If the above criteria are not met, the Investigator may still determine the need to administer supplemental medication in the best interest of the subject's well-being.

[0325] Conclusions at 6 Months: The 6-month interim results of this study showed positive safety data with no dose-limiting toxicities (DLTs), no reported ocular serious adverse events (SAEs), and no drug-related systemic SAEs. The majority of reported ocular AEs were mild and expected. All ocular AEs were grade 2 or less, with the only grade 3 AE not drug-related. Across all dose cohorts, 76% of subjects were supplement-free for up to 4 months, and 53% of subjects were supplement-free for up to 6 months, with a median time to supplementation of 6 months for all subjects. At the 6-month visit, stable best-corrected visual acuity (BCVA) with a mean change of -2.5 letters at 6 months and central zone retinal thickness (CST) with a mean change of -2.7 μm were achieved. Three of 17 subjects required supplementation at 1 month, but these subjects were also considered suboptimal responders to standard of care anti-VEGF therapy. Overall treatment burden was reduced by 79% at 6 months across the entire cohort, with 8 of 17 subjects remaining supplemental treatment-free and 1 subject remaining supplemental treatment-free up to 9 months. The mean change in BCVA from the screening visit is shown in the graph in Figure 15. The mean change in CST from the screening visit is shown in the graph in Figure 16. The supplemental treatment freedom rates from each visit are shown in the graph in Figure 17.

[0326] Example 9 - Evaluation of the effects of borolanib on visual function and structure following retinal detachment in mice method An 18-day study was performed in age-matched, experimentally naive C57Bl / 6 mice. Prior to the study, mice were randomly assigned to two separate study groups and each mouse was assigned an identification number. Before the start of dosing, a baseline study was performed in which visual acuity and contrast visual acuity were measured by optokinetic tracking (OKT), and retinal and outer nuclear layer (ONL) thickness were measured on images obtained by optical coherence tomography (OCT). Mice were orally administered vehicle (group 1) or 40 mg / kg borolanib (group 2) once daily on day 1 and continuing through day 18. On day 2, bilateral subretinal injections of sodium hyaluronate were performed to induce retinal detachment. Visual acuity and contrast visual acuity thresholds were measured on day 16, and OCT was performed to measure retinal and ONL thickness on day 17. A final collection was performed on day 18 either 30 minutes or 4 hours post-dose, whole blood was collected and processed to plasma, the left eye was collected and fixed for histology, and the right eye was collected and dissected to obtain the cornea, lens, retinal pigment epithelium (RPE) / choroid / sclera, and retina separately.

[0327] Summary and Conclusion In this mouse model, a single bilateral subretinal injection of sodium hyaluronate induces retinal detachment of the sensory retina from the retinal pigment epithelium. The model is highly reproducible across eyes and allows for evaluation of the efficacy of therapeutic interventions. In this study, borolanib was administered orally once daily for 18 days and its effect on vision loss measured by OKT recordings and retinal degeneration as measured by OCT imaging was examined.

[0328] Vorolanib was present in plasma for up to 4 hours after once-daily oral dosing for 18 consecutive days and was detectable in all ocular tissues tested, except lens tissue, for up to 4 hours after the final dose. Vorolanib appears to be detected at levels above plasma concentrations primarily in RPE / choroid / sclera tissues.

[0329] Retinal detachment induced a significant loss of both visual acuity (vehicle = 36% decrease, borolanib = 23% decrease) and contrast acuity (vehicle = 75% decrease, borolanib = 41% decrease) in both treatment groups, however the decline from baseline to the 16th day recording was less severe in borolanib-treated mice and contrast thresholds were significantly higher in borolanib-treated mice compared to vehicle (P = 0.0009).

[0330] Mice treated with borolanib did not experience a decrease in ONL thickness, suggesting a protective effect against photoreceptor degeneration. Scans taken from both the vertical and horizontal axes of the retina showed little difference in total retinal thickness measurements within each group from baseline to day 17, and there were no statistically significant differences in total retinal thickness between treatment groups. However, there was a significant loss of ONL thickness in vehicle-treated eyes (8% loss in vertical scans and 9% loss in horizontal scans) but not in borolanib-treated eyes (1% loss in vertical scans and no loss in horizontal scans). This indicates that retinal thinning occurred primarily in the photoreceptor cell bodies and that borolanib provided a protective effect specific to these cells.

[0331] In this study, borolanib administered at established therapeutic levels provided protection against loss of visual acuity and contrast vision by protecting against photoreceptor degeneration. Thus, in a mouse model of sodium hyaluronate-induced retinal detachment, borolanib administered at 40 mg / kg once daily for 18 consecutive days provides significant neuroprotection with improved visual outcomes compared to vehicle administration. These findings are supported by structural and functional improvements. Thus, the results of both optokinetic tracking and OCT of the ONL following retinal detachment in mice with subretinal injection of sodium hyaluronate suggest that borolanib has neuroprotective properties.

[0332] Experimental design Baseline: optokinetic quantification of spatial frequency threshold and contrast threshold, OCT imaging to quantify total retinal thickness and ONL thickness.

[0333] Days 1-18: Vehicle or test agent administered orally once a day (Quaque die).

[0334] Day 2: Bilateral subretinal injection of hyaluronic acid to induce detachment.

[0335] Day 16: Optokinetic quantification of spatial frequency and contrast thresholds.

[0336] Day 17: OCT imaging to quantify total retinal thickness and ONL thickness.

[0337] Day 18, 30 min ± 5 min after oral administration of vehicle or test agent: final plasma collection, eyes were enucleated and the left eye was fixed in 10% NBF, the right eye was dissected to obtain the cornea, lens, RPE / choroid / sclera, and retina, tissues were snap frozen in liquid N2, and vascular and tissue weights were recorded (n = 4 mice / group).

[0338] Day 18, 4 hours ± 15 minutes after oral administration of vehicle or test agent: Final plasma collection, eyes were enucleated and the left eye was fixed in 10% NBF, the right eye was dissected to obtain the cornea, lens, RPE / choroid / sclera, and retina, tissues were snap frozen in liquid N2, and vascular and tissue weights were recorded (n = 4 mice / group).

[0339] method anesthesia

[0340] Ketamine and xylazine were applied by intraperitoneal injection at 85 mg / kg and 14 mg / kg, respectively.

[0341] Oral gavage

[0342] Oral gavage was performed in conscious mice by trained personnel and did not require anesthesia. Standard gavage techniques were used utilizing a 22G x 1.5" and 1.25mm straight needle (Cadence Science) attached to a 1mL syringe, which was placed into the animal's mouth and passed through the esophagus to the stomach where drug was dispensed to achieve delivery. Test agent dosing was performed in accordance with the Good Practice Guide (Journal of Applied Toxicology 21:15-23) with a volume of 4mL / kg (4μl / g) of formulation administered once daily. After removal of the syringe, animals were held for an additional 30-60 seconds to observe for possible regurgitation or signs of distress.

[0343] Subretinal injection of hyaluronic acid

[0344] Hyaluronic acid (Provis Viscoelastic, Alcon Surgical, In. Catalog No. 1314033) was delivered in a 0.85 mL syringe containing 10 mg of sodium hyaluronate and was used as is. On the first day of use, an aliquot was made for future use.

[0345] Mouse eyes were dilated and animals were anesthetized according to standard operating procedures. Mice were placed on a regulated heating pad and the posterior pole was visualized under magnification. The cornea was punctured just above the limbus using a 12.7 mm 30-gauge insulin syringe, avoiding all contact with the sclera and lens. Transvitreal subretinal injections were performed using a 10 μL Hamilton syringe with a 33-gauge blunt needle inserted through the corneal puncture and through the vitreous, with the shaft directed behind the eyecup to avoid any trauma to the lens or iris. A total volume of 1 μL was delivered.

[0346] Optokinetic Tracking (OKT)

[0347] The OKT is performed using the OptoMotry (Cerebral Mechanics Inc.), which is designed for rodent use. In this non-invasive assessment, mice are placed on a platform surrounded by four LCD screens in a light-protected box. Visual stimuli are then presented to the mouse via the LCD screens, and a masked observer visualizes and scores the optokinetic pursuit reflex from a digital camcorder mounted on top of the box. The monitors display a continuous vertical sinusoidal grating that rotates between the monitors at 12 degrees / sec, which appears to the animal as a virtual three-dimensional rotating sphere. The rotation of the virtual cylinder is always centered on the animal's viewing position to ensure a constant viewing distance. Pursuit behavior is identified as a slow and steady head movement in the direction of the rotating grating. For the measurement of spatial frequency thresholds, mice were tested over a spatial frequency range of 0.064 to 0.464 cycles / degree. Using a proprietary algorithm that receives input from the masked observer, the OptoMotry device automatically adjusts the test stimuli based on whether the animal exhibited a correct or incorrect pursuit reflex. All contrast threshold measurements were performed at a spatial frequency threshold of 0.064 cycles / degree. Contrast thresholds are calculated from the luminance of the screen as the inverse of the Michelson contrast (max-min) / (max+min). The inverse of the contrast threshold is plotted.

[0348] Optical coherence tomography

[0349] Animals were anesthetized according to standard procedures and eyes were dilated. After sedation and dilation, animals were secured on a platform for imaging and presented to a Micron IV OCT module (Phoenix Research Inc.). Total retinal thickness and outer nuclear layer thickness were measured from vertical and horizontal scans within each eye, and data were plotted as the average retinal thickness across the scans.

[0350] Plasma collection

[0351] After sedation with intraperitoneal (IP) administration of ketamine / xylazine, approximately 500 μl of terminal whole blood was collected by cardiac puncture. Blood was immediately placed into K2EDTA tubes and centrifuged at 5,000×g for 10 min to obtain plasma.

[0352] Tissue collection

[0353] Animals were sedated with IP administration of ketamine / xylazine and then euthanized with intracardiac administration of Euthasol®.

[0354] For histopathology, after euthanasia at the designated time points, the upper part of the left eye was delimited with a scorch mark, and the eye was enucleated without damaging the optic nerve, placed in a screw-cap tube, and fixed in 10% neutral buffered formalin (NBF) at room temperature for 24 hours, then transferred to 70% ethanol and stored at 4°C until transport on a cold pack.

[0355] For ocular PK, right eyes were enucleated at the indicated time points and the cornea, lens, RPE / choroid / sclera, and retina were individually dissected and snap frozen in liquid N. Individual vessel and tissue weights were recorded.

[0356] Data and statistical analysis

[0357] Graphs were generated using GraphPad Prism (v.9.4.0). Statistical analysis was also performed and descriptive ones were generated for each data set using GraphPad and statistical significance was compared using one-way ANOVA for significance with Sidak's multiple comparison post-hoc test comparing the mean values ​​of: baseline vs. day 17 within each treatment group, group 1 baseline vs. group 2 baseline, and day 17 of group 1 vs. day 17 of group 2. Only changes with p-values ​​<0.05 were considered statistically significant.

[0358] Data Handling

[0359] Data collection and analysis

[0360] Statistical analysis was performed on the data using GraphPad Prism software (version 9.4.0).

[0361] result Optokinetic tracking

[0362] Optokinetic tracking (OKT) was used at baseline and on day 16 to assess visual acuity by measuring the maximum spatial frequency threshold (SFT) of a grating visual stimulus at which mice showed a consistent and verifiable optokinetic response as a measure of visual acuity, or the minimum contrast of a grating stimulus at which mice showed an optokinetic response as a function of contrast acuity.

[0363] Visual acuity was significantly reduced on day 16 compared to baseline within each treatment group (Figure 18). This loss was greater in vehicle-treated mice than in borolanib-treated mice. Although the mean SFT on day 16 was higher in borolanib mice (0.306 cycles / degree vs. 0.256 cycles / degree), the difference was not statistically significant. Similarly, mean contrast visual acuity thresholds were significantly reduced from baseline to day 16 within each treatment group (Figure 19), with borolanib treatment resulting in a statistically significant improvement in contrast thresholds compared to vehicle (***, p=0.0009, one-way ANOVA).

[0364] Thus, 40 mg / kg vorolanib administered once daily limited vision loss in this model of retinal detachment and had a significant positive effect on contrast vision loss.

[0365] OCT imaging and retinal thickness quantification OCT imaging was used to measure retinal and ONL thickness at baseline and on day 17. Scans were obtained either along the vertical axis from inferior to superior retina, or across the horizontal axis. For horizontal axis measurements, scans were obtained from temporal to nasal in the left eye and from nasal to temporal in the right eye.

[0366] The mean retinal thickness in the vertical (Figures 20A-20B) and horizontal (Figures 21A-21B) directions was approximately 222-229 μm across both groups and time points. There were no statistically significant differences between the mean values ​​compared in this study, indicating that there was minimal retinal cell death resulting from sodium hyaluronate-induced retinal detachment.

[0367] Measurements of the ONL alone in vertical scans showed a small, but non-significant, decrease in mean thickness from baseline to day 17 in vehicle-treated eyes, but not in borolanib-treated eyes (Figures 22A-22B). ONL measurements in horizontal scans also showed a loss of mean thickness from baseline to day 17 in vehicle eyes, and the difference was statistically significant (Figures 23A-23B). There was no loss of mean ONL thickness in borolanib-treated eyes. Thus, once-daily administration of borolanib significantly reduces ONL thickness loss in this mouse model of retinal detachment.

Claims

1. An ocular drug delivery insert for use in the prevention of choroidal neovascularization in the eye of human subjects, The ophthalmic drug delivery insert comprises borolanib or a pharmaceutically acceptable salt thereof. The ophthalmic drug delivery insert releases approximately 0.1 μg / day to approximately 60 μg / day of borolanib for at least 90 days. An ophthalmic drug delivery insert that allows at least 10% erosion within 95 days.

2. The ocular drug delivery insert according to claim 1, wherein the subject has unilateral wet AMD or classification 3 AMD in the other eye of the subject at baseline.

3. At the baseline, (a) The eye has classification 1 AMD or classification 2 AMD; or (b) The eye drug delivery insert according to claim 1, wherein the eye has an AMD of classification 3 and the other eye of the subject has an AMD of classification 4.

4. (a) For 180 days from the day the insert is administered, the change from baseline in the BCVA of the eye is the loss of five or fewer ETDRS characters; or (b) The ocular drug delivery insert according to claim 1, wherein the CST of the eye does not increase by more than 75 μm for 180 days from the day the insert is administered.

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

6. The ophthalmic drug delivery insert according to claim 1, wherein the insert comprises a solid matrix core containing borolanib or a pharmaceutically acceptable salt thereof, and a matrix polymer.

7. The ophthalmic drug delivery insert according to claim 6, wherein the matrix polymer is polyvinyl alcohol (PVA).

8. The ophthalmic drug delivery insert according to claim 6, wherein the amount of the matrix polymer in the insert is about 1 w / w% to about 15 w / w%.

9. The ophthalmic drug delivery insert according to claim 6, wherein the insert further comprises a coating substantially surrounding the core, the coating comprising PVA.

10. The ophthalmic drug delivery insert according to any one of claims 1 to 9, wherein the amount of bororanib or a pharmaceutically acceptable salt thereof in the insert is about 60 w / w% to about 98 w / w%.

11. The ophthalmic drug delivery insert according to any one of claims 1 to 9, wherein the amount of bororanib or a pharmaceutically acceptable salt thereof in the insert is about 85 w / w% to about 99 w / w%.

12. The ophthalmic drug delivery insert according to any one of claims 1 to 9, wherein the insert allows at least 90% erosion within 440 days.

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

14. The ophthalmic drug delivery insert according to claim 13, wherein the insert releases about 0.5 μg / day to about 30 μg / day of borolanib over at least 120 days.

15. The ophthalmic drug delivery insert according to claim 13, wherein the insert is administered by intravitreal injection via a 20-27 gauge needle or cannula, and the insert has a length of about 1 mm to about 10 mm.

16. The ophthalmic drug delivery insert according to any one of claims 1 to 9, wherein administration of the ophthalmic drug delivery insert protects the eye from photoreceptor degeneration.

17. An ocular drug delivery insert for use in the prevention of choroidal neovascularization in the eye of a human subject, The ophthalmic drug delivery insert comprises borolanib or a pharmaceutically acceptable salt thereof, and polyvinyl alcohol. The ophthalmic drug delivery insert is manufactured by dissolving PVA in an aqueous solution to form a PVA solution, mixing the PVA solution with borolanib or a pharmaceutically acceptable salt thereof to form a matrix mixture, extruding the matrix mixture through a dispensing tip to form an elongated matrix, curing the elongated matrix at a temperature of about 80°C to about 160°C for about 15 minutes to about 4 hours, and dividing the elongated matrix.

18. The ophthalmic drug delivery insert according to claim 17, wherein the amount of bororanib or a pharmaceutically acceptable salt thereof in the insert is about 60 w / w% to about 98 w / w%.

19. The ophthalmic drug delivery insert according to claim 17, wherein the amount of bororanib or a pharmaceutically acceptable salt thereof in the insert is about 85 w / w% to about 99 w / w%.

20. The ophthalmic drug delivery insert according to any one of claims 17 to 19, wherein the insert comprises about 200 μg to about 2000 μg of bororanib or a pharmaceutically acceptable salt thereof.

21. The ophthalmic drug delivery insert according to claim 20, wherein the insert releases about 0.5 μg / day to about 30 μg / day of borolanib over at least 120 days.

22. The ophthalmic drug delivery insert according to claim 20, wherein the insert allows at least 90% erosion within 440 days.

23. An ophthalmic drug delivery insert for use in providing neuroprotection to the retina in the eye of human subjects, The use described above involves administering an ophthalmic drug delivery insert containing bororanib or a pharmaceutically acceptable salt thereof to the eye. The ophthalmic drug delivery insert releases approximately 0.1 μg / day to approximately 60 μg / day of borolanib for at least 90 days. An ophthalmic drug delivery insert that allows at least 10% erosion within 95 days.

24. The ophthalmic drug delivery insert according to claim 23, wherein the insert comprises a solid matrix core comprising borolanib or a pharmaceutically acceptable salt thereof and a matrix polymer.

25. The ophthalmic drug delivery insert according to claim 24, wherein the matrix polymer is polyvinyl alcohol (PVA).

26. The ophthalmic drug delivery insert according to claim 24, wherein the amount of the matrix polymer in the insert is about 1 w / w% to about 15 w / w%.

27. ​​The ophthalmic drug delivery insert according to any one of claims 23 to 26, wherein the amount of bororanib or a pharmaceutically acceptable salt thereof in the insert is about 60 w / w% to about 98 w / w%.

28. The ophthalmic drug delivery insert according to claim 27, wherein the insert comprises about 200 μg to about 2000 μg of bororanib or a pharmaceutically acceptable salt thereof.

29. The ophthalmic drug delivery insert according to claim 27, wherein the insert is administered by intravitreal injection via a 20-27 gauge needle or cannula, and the insert has a length of about 1 mm to about 10 mm.

30. An ophthalmic drug delivery insert for use in the treatment or prevention of eye diseases, The use described above involves administering an ophthalmic drug delivery insert containing bororanib or a pharmaceutically acceptable salt thereof to the eye. The ophthalmic drug delivery insert releases approximately 0.1 μg / day to approximately 60 μg / day of borolanib for at least 90 days. The ophthalmic drug delivery insert allows for at least 10% erosion within 95 days. An ocular drug delivery insert wherein the aforementioned eye disease is geographic atrophy, glaucoma, or retinal detachment.

31. The ophthalmic drug delivery insert according to claim 30, wherein the insert comprises a solid matrix core comprising borolanib or a pharmaceutically acceptable salt thereof and a matrix polymer.

32. The ophthalmic drug delivery insert according to claim 31, wherein the matrix polymer is polyvinyl alcohol (PVA).

33. The ophthalmic drug delivery insert according to claim 31, wherein the amount of the matrix polymer in the insert is about 1 w / w% to about 15 w / w%.

34. The ophthalmic drug delivery insert according to any one of claims 30 to 33, wherein the amount of borolanib or a pharmaceutically acceptable salt thereof in the insert is about 60 w / w% to about 98 w / w%.

35. The ophthalmic drug delivery insert according to claim 34, wherein the insert comprises about 200 μg to about 2000 μg of bororanib or a pharmaceutically acceptable salt thereof.

36. The ophthalmic drug delivery insert according to claim 34, wherein the insert is administered by intravitreal injection via a 20-27 gauge needle or cannula, and the insert has a length of about 1 mm to about 10 mm.

Images