WO2023173093A1 - Continuous dosing regimen for treatment of a condition of the eye - Google Patents

Continuous dosing regimen for treatment of a condition of the eye Download PDF

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Publication number
WO2023173093A1
WO2023173093A1 PCT/US2023/064148 US2023064148W WO2023173093A1 WO 2023173093 A1 WO2023173093 A1 WO 2023173093A1 US 2023064148 W US2023064148 W US 2023064148W WO 2023173093 A1 WO2023173093 A1 WO 2023173093A1
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WO
WIPO (PCT)
Prior art keywords
drug delivery
day
vorolanib
insert
days
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2023/064148
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English (en)
French (fr)
Other versions
WO2023173093A9 (en
Inventor
Said Saim
Dario PAGGIARINO
Owen N. DURHAM
Nancy LURKER
Jay S. DUKER
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Eyepoint Pharmaceuticals Inc
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Eyepoint Pharmaceuticals Inc
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Filing date
Publication date
Application filed by Eyepoint Pharmaceuticals Inc filed Critical Eyepoint Pharmaceuticals Inc
Priority to JP2024553782A priority Critical patent/JP2025507154A/ja
Priority to IL315333A priority patent/IL315333A/en
Priority to US18/843,571 priority patent/US20250186398A1/en
Priority to KR1020247033492A priority patent/KR20240156416A/ko
Priority to CN202380027037.0A priority patent/CN118871107A/zh
Priority to CA3245209A priority patent/CA3245209A1/en
Priority to AU2023230976A priority patent/AU2023230976A1/en
Priority to EP23715702.9A priority patent/EP4489750A1/en
Publication of WO2023173093A1 publication Critical patent/WO2023173093A1/en
Publication of WO2023173093A9 publication Critical patent/WO2023173093A9/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • A61K9/0051—Ocular inserts or implants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents

Definitions

  • AMD Age-related macular degeneration
  • AMD causes the progressive loss of central vision attributable to degenerative and/or neovascular changes in the macula, a specialized area in the center of the retina.
  • macular degeneration can produce a slow or sudden loss of vision.
  • AMD is estimated to affect almost 200 million people around the world, with late-stage AMD affecting almost 11 million people.
  • AMD begins as dry AMD, which is characterized by the formation of drusen, yellow plaque-like deposits in the macula between the retinal pigment epithelium and the underlying choroid. Dry AMD may progress to wet AMD.
  • Dry macular degeneration is more common than wet AMD, with about 90% of AMD patients being diagnosed with dry AMD.
  • the dry form of AMD may result from the aging and thinning of macular tissues, depositing of pigment in the macula, or a combination of the two processes.
  • the wet form of the disease usually leads to more serious 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.
  • a person may have AMD in one eye, or may have it in both eyes, but may be at different stages of AMD in each eye.
  • Wet AMD typically occurs first in one eye, referred to as unilateral wet AMD. Patients having wet AMD in one eye have a significant risk of developing choroidal neovascularization in their fellow eye.
  • the inventors have invented a novel bioerodible drug delivery insert comprising an active pharmaceutical ingredient (API) and a bioerodible polymer, and methods of using this insert.
  • This insert is particularly useful for local delivery of an effective amount of the API to the eye.
  • the insert provides sustained release of the API.
  • the insert provides sustained release of API for a period that is nearly synchronized with the period required for complete erosion of the insert in an eye.
  • These inserts may be administered intraocularly, e.g., intravitreally, suprachoroidally, intracamerally, or subconjunctivally.
  • the inserts may be placed through a needle or cannula for an intravitreal injection.
  • the invention relates to a drug delivery insert that can deliver effective intraocular concentrations of the API while delivering low systemic concentrations of the API to reduce the risk of toxicity or other undesirable side effects.
  • the invention provides a method for preventing or treating an ocular condition by administering one or more ocular drug delivery inserts.
  • the invention provides a method of treating a posterior ocular condition, comprising: injecting into an eye of a human subject, wherein the eye has the posterior ocular condition, a loading dose of one or more initial ocular drug delivery inserts, each insert comprising a solid matrix core comprising a matrix polymer and vorolanib or a pharmaceutically acceptable salt thereof, wherein the release rate for each initial ocular drug delivery insert is about 0.1 ⁇ g/day to about 150 ⁇ g/day of vorolanib for at least 30 days, and each initial ocular drug delivery insert is capable of at least 20% erosion within 95 days; following release of about 30%, but before release of about 100%, of the vorolanib from the loading dose, injecting into the eye a maintenance dose of one or more additional ocular drug delivery inserts, each insert comprising a solid matrix core comprising a matrix polymer and vorolanib or the pharmaceutically acceptable salt thereof, wherein the release rate for each additional ocular drug delivery insert is about
  • a method of treating a posterior ocular condition comprising injecting into an eye of a human subject, wherein the eye has the posterior ocular condition, a loading dose of one or more initial ocular drug delivery inserts, each insert comprising a solid matrix core comprising a matrix polymer and vorolanib or a pharmaceutically acceptable salt thereof, wherein the release rate for each initial ocular drug delivery insert is about 0.1 ⁇ g/day to about 150 ⁇ g/day of vorolanib for at least 30 days and each initial ocular drug delivery insert is capable of at least 20% erosion within 95 days; about 15 days to about 365 days after the injecting of the loading dose, injecting into the eye a maintenance dose of one or more additional ocular drug delivery inserts comprising a solid matrix core comprising a matrix polymer and vorolanib or a pharmaceutically acceptable salt thereof, wherein the release rate for each additional ocular drug delivery insert is about 0.1 ⁇ g/day to about 100
  • a method of treating a posterior ocular condition comprising injecting into an eye of a human subject, wherein the eye has the posterior ocular condition, a maintenance dose of one or more additional ocular drug delivery inserts, each insert comprising a solid matrix core comprising a matrix polymer and vorolanib or a pharmaceutically acceptable salt thereof, wherein the release rate for each additional ocular drug delivery insert is about 0.1 ⁇ g/day to about 100 ⁇ g/day of vorolanib for at least 30 days, and each additional ocular drug delivery insert is capable of at least 20% erosion within 95 days, wherein the eye has previously received a dose of one or more previous ocular drug delivery inserts comprising a solid matrix core comprising a matrix polymer and vorolanib or a pharmaceutically acceptable salt thereof, wherein the release rate for the previous ocular drug delivery insert is about 0.1 ⁇ g/day to about 150 ⁇ g/day of vorolanib for at least 30
  • a method of treating a posterior ocular condition comprising injecting into an eye of a human subject, wherein the eye has the posterior ocular condition, a maintenance dose of one or more additional ocular drug delivery inserts, each insert comprising a solid matrix core comprising a matrix polymer and vorolanib or a pharmaceutically acceptable salt thereof, wherein the release rate for each additional ocular drug delivery insert is about 0.1 ⁇ g/day to about 100 ⁇ g/day of vorolanib for at least 30 days and each additional ocular drug delivery insert is capable of at least 20% erosion within 95 days, wherein the eye has previously received a dose of one or more previous ocular drug delivery inserts comprising a solid matrix core comprising a matrix polymer and vorolanib or a pharmaceutically acceptable salt thereof, wherein the release rate for the previous ocular drug delivery insert is about 0.1 ⁇ g/day to about 150 ⁇ g/day of vorolanib for at least 30 days and
  • a method of treating a posterior ocular condition comprising: injecting into an eye of a human subject, wherein the eye has the posterior ocular condition, a loading dose of one or more initial ocular drug delivery inserts, each insert comprising a solid matrix core comprising a matrix polymer and vorolanib or a pharmaceutically acceptable salt thereof, wherein the average drug release rate over a 30 day period for each initial ocular drug delivery insert is about 0.1 ⁇ g/day to about 150 ⁇ g/day of vorolanib, and each initial ocular drug delivery insert is capable of at least 20% erosion within 95 days, following release of about 30%, but before release of about 100%, of the vorolanib from the loading dose, injecting into the eye a maintenance dose of one or more additional ocular drug delivery inserts, each insert comprising a solid matrix core comprising a matrix polymer and vorolanib or the pharmaceutically acceptable salt thereof, wherein the average drug release rate over a 30 day period for each additional
  • a method of treating a posterior ocular condition comprising: injecting into an eye of a human subject, wherein the eye has the posterior ocular condition, a loading dose of one or more initial ocular drug delivery inserts, each insert comprising a solid matrix core comprising a matrix polymer and vorolanib or a pharmaceutically acceptable salt thereof, wherein the average drug release rate over a 30 day period for each initial ocular drug delivery insert is about 0.1 ⁇ g/day to about 150 ⁇ g/day of vorolanib and each initial ocular drug delivery insert is capable of at least 20% erosion within 95 days, about 15 days to about 365 days after the injecting of the loading dose, injecting into the eye a maintenance dose of one or more additional ocular drug delivery inserts comprising a solid matrix core comprising a matrix polymer and vorolanib or a pharmaceutically acceptable salt thereof, wherein the average drug release rate over a 30 day period for each additional ocular drug delivery insert
  • a method of treating a posterior ocular condition comprising: injecting into an eye of a human subject, wherein the eye has the posterior ocular condition, a maintenance dose of one or more additional ocular drug delivery inserts, each insert comprising a solid matrix core comprising a matrix polymer and vorolanib or a pharmaceutically acceptable salt thereof, wherein the average drug release rate over a 30 day period for each additional ocular drug delivery insert is about 0.1 ⁇ g/day to about 100 ⁇ g/day of vorolanib, and each additional ocular drug delivery insert is capable of at least 20% erosion within 95 days, wherein the eye has previously received a dose of one or more previous ocular drug delivery inserts comprising a solid matrix core comprising a matrix polymer and vorolanib or a pharmaceutically acceptable salt thereof, wherein the average drug release rate over a 30 day period for the previous ocular drug delivery insert is about 0.1 ⁇ g/day to about 150 ⁇ g/
  • a method of treating a posterior ocular condition comprising: injecting into an eye of a human subject, wherein the eye has the posterior ocular condition, a maintenance dose of one or more additional ocular drug delivery inserts, each insert comprising a solid matrix core comprising a matrix polymer and vorolanib or a pharmaceutically acceptable salt thereof, wherein the average drug release rate over a 30 day period for each additional ocular drug delivery insert is about 0.1 ⁇ g/day to about 100 ⁇ g/day of vorolanib and each additional ocular drug delivery insert is capable of at least 20% erosion within 95 days, wherein the eye has previously received a dose of one or more previous ocular drug delivery inserts comprising a solid matrix core comprising a matrix polymer and vorolanib or a pharmaceutically acceptable salt thereof, wherein the average drug release rate over a 30 day period for the previous ocular drug delivery insert is about 0.1 ⁇ g/day to about 150 ⁇ g/
  • the invention also provides a method of treating a posterior ocular condition, comprising the steps of: (a) injecting into an eye of a human subject, wherein the eye has the posterior ocular condition, a first loading dose of one or more initial ocular drug delivery inserts, each insert comprising a solid matrix core comprising a matrix polymer and vorolanib or a pharmaceutically acceptable salt thereof, wherein each initial ocular drug delivery insert has a release rate of about 0.1 ⁇ g/day to about 150 ⁇ g/day of vorolanib for at least 30 days, or has an average drug release rate over a 30 day period of about 0.1 ⁇ g/day to about 150 ⁇ g/day of vorolanib; (b) about 15 days to about 60 days after injection of the first loading dose, injecting into the eye a second loading dose of one or more initial ocular drug delivery inserts, each insert comprising a solid matrix core comprising a matrix polymer and vorolanib or a pharmaceutically acceptable salt thereof,
  • the invention provides a method of treating a posterior ocular condition, comprising the steps of: (a) injecting into an eye of a human subject, wherein the eye has the posterior ocular condition, a first loading dose of one or more initial ocular drug delivery inserts, each insert comprising a solid matrix core comprising a matrix polymer and vorolanib or a pharmaceutically acceptable salt thereof, wherein each initial ocular drug delivery insert has a release rate of about 0.1 ⁇ g/day to about 150 ⁇ g/day of vorolanib for at least 30 days, or has an average drug release rate over a 30 day period of about 0.1 ⁇ g/day to about 150 ⁇ g/day of vorolanib; (b) about 15 days to about 60 days after injection of the first loading dose, injecting into the eye a second loading dose of one or more initial ocular drug delivery inserts, each insert comprising a solid matrix core comprising a matrix polymer and vorolanib or a pharmaceutically acceptable
  • each initial ocular drug delivery insert is capable of at least 20% erosion within 95 days and/or each additional ocular drug delivery insert is capable of at least 20% erosion within 95 days.
  • the posterior ocular condition is selected from wet AMD, diabetic retinopathy (DR), retinal vein occlusion (RVO), and diabetic macular edema (DME).
  • the DR is nonproliferative diabetic retinopathy (NPDR).
  • the ocular drug delivery insert is administered to an eye in which CST is less than 500 ⁇ m, 400 ⁇ m, 350 ⁇ m, 300 ⁇ m, 250 ⁇ m, or 200 ⁇ m at baseline.
  • the ocular drug delivery insert is administered to an eye in which CST is less than 500 ⁇ m, 400 ⁇ m, 350 ⁇ m, 300 ⁇ m, 250 ⁇ m, or 200 ⁇ m on the day the insert is administered. [0024] In other embodiments, the ocular drug delivery insert is administered to an eye in which CST is 500 ⁇ m or less, 400 ⁇ m or less, 350 ⁇ m or less, 300 ⁇ m or less, 250 ⁇ m or less, or 200 ⁇ m or less at baseline.
  • the ocular drug delivery insert is administered to an eye in which CST is 500 ⁇ m or less, 400 ⁇ m or less, 350 ⁇ m or less, 300 ⁇ m or less, 250 ⁇ m or less, or 200 ⁇ m or less on the day of administration.
  • CST in the eye is 350 ⁇ m or less at baseline in the eye to which the ocular drug delivery insert is administered.
  • CST in the eye is 350 ⁇ m or less on the day of administration in the eye to which the ocular drug delivery insert is administered.
  • the invention also provides a method of treating a posterior ocular condition in an eye in need thereof, comprising, at a first timepoint, administering to the eye an agent that inhibits activation of VEGF receptors, such as a VEGF ligand, VEGF inhibitor or anti-VEGF (an induction treatment), and, at a second timepoint, administering to the eye an ocular drug delivery insert comprising vorolanib or a pharmaceutically acceptable salt thereof (a maintenance treatment to maintain the induction treatment).
  • 1-6 inserts are injected at a given timepoint.
  • the total amount of vorolanib in all of the inserts is about 600 ⁇ g to about 6000 ⁇ g.
  • the one or more ocular drug delivery inserts deliver a total average daily dose of vorolanib of about 1 ⁇ g/day to about 50 ⁇ g/day for at least 30 days.
  • additional embodiments of the 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.
  • the insert comprises a solid matrix core comprising vorolanib, or a pharmaceutically acceptable salt thereof, and a matrix polymer.
  • the matrix polymer is polyvinyl alcohol (PVA).
  • the amount of matrix polymer in the insert is about 1% w/w to about 15% w/w.
  • the amount of vorolanib, or pharmaceutically acceptable salt thereof, in the insert is about 60% w/w to about 98% w/w. In other embodiments, the amount of vorolanib, or pharmaceutically acceptable salt thereof, in the insert is about 85% w/w to about 99% w/w.
  • the insert is capable of at least 90% erosion within 440 days.
  • the insert comprises about 200 ⁇ g to about 2000 ⁇ g of vorolanib or a pharmaceutically acceptable salt thereof.
  • the insert releases about 0.5 ⁇ g/day to about 30 ⁇ g/day of vorolanib for at least 120 days.
  • the insert is administered by intravitreal injection through a 20 to 27 gauge needle or cannula.
  • the insert has a length of about 1 mm to about 10 mm.
  • the insert does not comprise a coating.
  • the matrix polymer is PVA.
  • the insert comprises a coating substantially surrounding the core.
  • the coating comprises PVA.
  • the insert further comprises a delivery port.
  • the insert matrix polymer is PVA
  • the coating comprises a different grade of PVA than the matrix polymer.
  • the coating comprises at least two coats comprising PVA, and wherein at least one of the coats comprises a different grade of PVA from at least one other coat.
  • the coating comprises more than one coat comprising PVA
  • the matrix polymer is PVA
  • the DH of the PVA in at least one coat differs from the DH of the matrix polymer PVA.
  • the matrix polymer is PVA and the MW of the PVA in the coating differs from the MW of the matrix polymer.
  • the insert was cured for about 200 minutes to about 1440 minutes at about 60 oC to about 120 oC.
  • the insert is made by dissolving PVA in an aqueous solution to form a PVA solution, mixing the PVA solution with vorolanib or a pharmaceutically acceptable salt thereof to form a matrix mixture, extruding the mixture through a dispensing tip to form an elongated shaped matrix, curing the elongated shaped matrix at a temperature of about 80 oC to about 160 oC for about 15 minutes to about 4 hours, and segmenting the elongated shaped matrix.
  • the ocular drug delivery insert comprises a solid matrix core comprising a matrix polymer and vorolanib or a pharmaceutically acceptable salt thereof, wherein the amount of the vorolanib or pharmaceutically acceptable salt thereof in the insert is about 10% w/w to about 98% w/w, wherein the drug release rate for the insert is about 0.01 ⁇ g/day to about 100 ⁇ g/day for at least 14 days and wherein the insert is capable of at least 20% erosion within 95 days.
  • the amount of the vorolanib or pharmaceutically acceptable salt thereof in the insert is about 60% w/w to about 98% w/w.
  • the insert further comprises a coating substantially surrounding the core.
  • the amount of coating is about 5% w/w to about 20% w/w of the insert.
  • the insert further comprises a delivery port.
  • the ocular drug delivery insert consists of a solid matrix core comprising an API and at least two different grades of PVA, wherein the drug release rate for the insert is about 0.0001 ⁇ g/day to about 200 ⁇ g/day for at least 30 days, wherein the insert is capable of at least 20% erosion within 95 days, and wherein the insert is sized and shaped to fit through a 20 to 27 gauge needle or cannula.
  • the two different grades of PVA is a mixture selected from the list comprising: a mixture of MW 78,000, 88% hydrolyzed and MW 78,000, 98% hydrolyzed; a mixture of MW 78,000, 88% hydrolyzed and MW 78,000, 99+% hydrolyzed; a mixture of MW 6,000, 80% hydrolyzed and MW 78,000, 98% hydrolyzed; a mixture of MW 6,000, 80% hydrolyzed and MW 78,000, 99+% hydrolyzed; a mixture of MW 78,000, 88% hydrolyzed and MW 125,000, 88% hydrolyzed; and a mixture of MW 6,000, 80% hydrolyzed and MW 125,000, 88% hydrolyzed.
  • the 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 is capable of at least 20% erosion within 95 days, and wherein the insert is sized and shaped to fit through a 20 to 27 gauge needle or cannula.
  • the ocular drug delivery insert comprises: (a) a solid matrix core comprising a PVA selected from the group consisting of MW 6,000, 80% hydrolyzed, MW 9,000-10,000, 80% hydrolyzed, MW 25,000, 88% hydrolyzed, MW 25,000, 98% hydrolyzed, MW 30,000-70,000, 87-90% hydrolyzed, MW 78,000, 88% hydrolyzed, MW 78,000, 98% hydrolyzed, MW 78,000, 99+% hydrolyzed, MW 89,000-98,000, 99+% hydrolyzed, MW 85,000-124,000, 87-89% hydrolyzed, MW 108,000, 99 + % hydrolyzed, MW 125,000, 88% hydrolyzed, MW 133,000, 99% hydrolyzed, MW 146,000-186,000, 99+% hydrolyzed, and mixtures thereof; and an API; and (b) at least one coating comprising PVA substantially surrounding the core, wherein
  • the coating comprises a different grade of PVA than the core PVA.
  • the DH of the PVA in the coating differs from the DH of the core PVA.
  • the MW of the PVA in the coating differs from the MW of the core PVA.
  • the coating comprises at least two coats comprising PVA, and wherein at least one of the coats comprises a different grade of PVA from at least one other coat.
  • the PVA in at least two coats differ in DH.
  • the PVA in at least two coats differ in MW.
  • FIG.1 depicts an exemplary ocular drug delivery insert for use in the invention.
  • FIG.2 Figure 2 depicts graphs showing the average weight change of films of different grades of PVA after 24 h immersion in PBS.
  • FIG.3 depicts a scale showing the relative film strengths of the films evaluated.
  • FIG.4A depicts the in vitro drug release profile showing cumulative percent drug release from a Formulation A insert, which is a coated formulation cured at 140°C for 4 hours.
  • FIG.4B depicts the in vitro drug release profile showing cumulative amount ( ⁇ g) of drug released from a Formulation A insert.
  • FIG.5 shows photographs of eroded Formulation A inserts taken after immersion in dissolution medium for 314 and 447 days, and the photo of the 447 day insert includes an intact insert for comparison.
  • FIG.6 depicts the in vitro drug release profile for an Uncoated Formulation A insert, which is the same as Formulation A but without a coating.
  • FIG.7 shows photographs of eroded Uncoated Formulation A inserts taken after immersion in dissolution medium for 287 and 352 days, and the photo of the 352 day insert includes an intact insert for comparison.
  • FIG.8A depicts the in vitro drug release profile showing cumulative percent drug release from a Formulation B insert, which is a coated formulation cured at 140°C/30 minutes.
  • FIG.8B depicts the in vitro drug release profile showing cumulative amount ( ⁇ g) drug release from a Formulation B insert.
  • FIG.9 shows photographs of eroded Formulation B inserts taken after immersion in dissolution medium for 59, 88 and 155 days.
  • FIG.10 depicts the in vitro drug release profile for a Formulation C insert, an uncured coated formulation.
  • FIG.11 shows photographs of two samples of eroded Formulation C inserts taken after immersion in dissolution medium for 98 days at 37 oC then 113 days at room temperature.
  • FIG. 12 depicts a comparison of the in vitro drug release profiles for Formulations A, B and C.
  • FIG. 13A depicts average amount of drug remaining in an insert versus time for an in vivo study in which inserts that had been implanted in rabbit eyes were explanted at various time points and assayed to determine the amount ( ⁇ g) of vorolanib remaining in the insert.
  • One curve shows levels for inserts from eyes in which 3 inserts were implanted, and the other shows levels for inserts from eyes in which 6 inserts were implanted.
  • FIG. 13B depicts cumulative percent of drag released versus time for explanted inserts from the same in vivo study.
  • One curve shows levels for inserts from eyes in which 3 inserts were implanted, and the other shows levels for inserts from eyes in which 6 inserts were implanted.
  • FIG. 14 is a bar graph comparing the Corrected Total Lesion Fluorescence (CTFL) percentage change over time for different drug doses in a swine model of laser-induced choroidal neovascularization.
  • CTFL Corrected Total Lesion Fluorescence
  • FIG. 15 is a graph showing the average change in best BCVA from the screening visit for the subjects in a Phase 1 clinical trial.
  • FIG. 16 is a graph showing the average change in CST from the screening visit for the subjects in a Phase 1 clinical trial.
  • FIG. 17 is a graph showing the supplemental-free rate for each visit for the subjects in a Phase 1 clinical trial.
  • FIGS. 18A-18B are graphs showing in vitro/in vivo correlation of drag release for Formulation A 630 ⁇ g of vorolanib.
  • FIG. 19A is a simulation (based on in vitro release) for Formula A of repeat injection every 6 months with 2 insert loading dose.
  • FIG. 19B is a simulation (based on in vitro release) for Formula A of repeat injection every 6 months without 2 insert loading dose.
  • FIG. 20 is a simulation (based on in vitro release) for Formula B4 of repeat injection every 6 months with 2 insert loading dose.
  • FIG.21 is a simulation (based on in vitro release) for Formula E60 of repeat injection every 6 months.
  • FIG.22 is a simulation (based on in vitro release) for Formula E60 of repeat injection every 6 months following loading with 2 inserts at T0.
  • FIG.23 is a simulation (based on in vitro release) for Formula E4 of repeat injection every 6 months following loading with 2 inserts at T0.
  • FIG.24 is a simulation (based on in vitro release) for Formula E4 of repeat injection every 6 months following loading with 1 insert at T0 and 1 insert at week 1.
  • FIG.25 is a simulation (based on in vitro release) for Formula E4 of repeat injection every 6 months following loading with 1 insert at T0 and 1 insert at 2 months.
  • FIG.26A is a graph of a simulation plotting the amount of vorolanib remaining (residual drug) in a single 8 mm Formulation A explant (implant removed from an eye) versus the day on which the implant was explanted. Day 0 is the date on which the implant was injected.
  • Fig.26B is a graph of a simulation plotting the amount of vorolanib remaining (residual drug) in a single 8 mm Formulation B30 explant (implant removed from an eye) versus the day on which the implant was explanted. Day 0 is the date on which the implant was injected.
  • Fig.26C is a graph of a simulation plotting the amount of vorolanib remaining (residual drug) in a single 8 mm Formulation C explant (implant removed from an eye) versus the day on which the implant was explanted. Day 0 is the date on which the implant was injected.
  • Fig.27A is a graph of a simulation plotting the release rate ( ⁇ g vorolanib/day) over time for a single 8 mm Formulation A explant.
  • Fig.27B is a graph of a simulation plotting the release rate ( ⁇ g vorolanib/day) over time for a single 8 mm Formulation B30 explant.
  • Fig.27C is a graph of a simulation plotting the release rate ( ⁇ g vorolanib/day) over time for a single 8 mm Formulation C explant.
  • Fig.28A is a graph of a simulation plotting the residual vorolanib versus the day on which the implant is explanted for Formulation A for a loading dose of 2 implants on day 0 and a maintenance dose of 1 implant administered every 120 days.
  • Fig.28B is a graph of a simulation plotting the residual vorolanib versus the day on which the implant is explanted for Formulation B30 for a loading dose of 2 implants on day 0 and a maintenance dose of 1 implant administered every 120 days.
  • Fig.28C is a graph of a simulation plotting the residual vorolanib versus the day on which the implant is explanted for Formulation C for a loading dose of 2 implants on day 0 and a maintenance dose of 1 implant administered every 120 days.
  • Fig.29A is a graph of a simulation plotting the release rate ( ⁇ g vorolanib/day) over time for Formulation A for a loading dose of 2 implants on day 0 and a maintenance dose of 1 insert administered every 120 days.
  • Fig.29B is a graph of a simulation plotting the release rate ( ⁇ g vorolanib/day) over time for Formulation B30 for a loading dose of 2 implants on day 0 and a maintenance dose of 1 insert administered every 120 days.
  • Fig.29C is a graph of a simulation plotting the release rate ( ⁇ g vorolanib/day) over time for Formulation C for a loading dose of 2 implants on day 0 and a maintenance dose of 1 insert administered every 120 days.
  • Fig.30A is a graph of a simulation plotting the residual vorolanib versus the day on which the implant is explanted for Formulation A for a loading dose of 1 implant and a maintenance dose of 1 implant administered every 120 days.
  • Fig.30B is a graph of a simulation plotting the residual vorolanib versus the day on which the implant is explanted for Formulation B30 for a loading dose of 1 implant and a maintenance dose of 1 implant administered every 120 days.
  • Fig.30C is a graph of a simulation plotting the residual vorolanib versus the day on which the implant is explanted for Formulation C for a loading dose of 1 implant and a maintenance dose of 1 implant administered every 120 days.
  • Fig.31A is a graph of a simulation plotting the release rate ( ⁇ g vorolanib/day) over time for Formulation A for a loading dose of 1 implant on day 0 and a maintenance dose of 1 insert administered every 120 days.
  • Fig.31B is a graph of a simulation plotting the release rate ( ⁇ g vorolanib/day) over time for Formulation B30 for a loading dose of 1 implant on day 0 and a maintenance dose of 1 insert administered every 120 days.
  • Fig.31C is a graph of a simulation plotting the release rate ( ⁇ g vorolanib/day) over time for Formulation C for a loading dose of 1 implant on day 0 and a maintenance dose of 1 insert administered every 120 days.
  • Fig.32A is a graph of a simulation plotting the residual vorolanib versus the day on which the implant is explanted for Formulation A for a loading dose of 2 implants on day 0 and a maintenance dose of 1 implant administered every 180 days.
  • Fig.32B is a graph of a simulation plotting the residual vorolanib versus the day on which the implant is explanted for Formulation B30 for a loading dose of 2 implants on day 0 and a maintenance dose of 1 implant administered every 180 days.
  • Fig.32C is a graph of a simulation plotting the residual vorolanib versus the day on which the implant is explanted for Formulation C for a loading dose of 2 implants on day 0 and a maintenance dose of 1 implant administered every 180 days.
  • Fig.33A is a graph of a simulation plotting the residual vorolanib versus the day on which the implant is explanted for Formulation A for a loading dose of 2 implants on day 0 and a maintenance dose of 1 implant administered every 240 days.
  • Fig.33B is a graph of a simulation plotting the residual vorolanib versus the day on which the implant is explanted for Formulation B30 for a loading dose of 2 implants on day 0 and a maintenance dose of 1 implant administered every 240 days.
  • FIG.33C is a graph of a simulation plotting the residual vorolanib versus the day on which the implant is explanted for Formulation C for a loading dose of 2 implants on day 0 and a maintenance dose of 1 implant administered every 240 days.
  • FIG.34 shows the line fit used to determine a drug release rate from in vivo data.
  • the insert of the invention comprises the active pharmaceutical ingredient (API) vorolanib.
  • An API is sometimes referred to as a “drug” herein.
  • the API is a pharmaceutically acceptable salt of vorolanib.
  • Vorolanib has the chemical designation (S,Z)-N-(1-(Dimethylcarbamoyl)pyrrolidin-3- yl)-5-((5-fluoro-2-oxoindolin-3-ylidene)methyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide. Synonyms include the term “X-82”.
  • Vorolanib has the following structure: [00109] Vorolanib is an orally active multikinase inhibitor and can inhibit activation of vascular endothelial growth factor receptors (VEGFR) and platelet-derived growth factor receptors (PDGFR). [00110] Methods for manufacturing vorolanib are described, e.g., in US Patent No.7,683,057; 8,524,709; 8,039,470; and US Publ. Appl. No.2019/0233403; each of which is incorporated by reference in its entirety.
  • VEGFR vascular endothelial growth factor receptors
  • PDGFR platelet-derived growth factor receptors
  • vorolanib or a pharmaceutically acceptable salt thereof includes amorphous and crystalline forms, polymorphs, hydrates and solvates of vorolanib or its pharmaceutically acceptable salts.
  • the invention contemplates the use of analogs, derivatives, pharmaceutically acceptable salts, esters, prodrugs, codrugs, and protected forms thereof of the API.
  • pharmaceutically acceptable salt refers to salts that retain the biological effectiveness and properties of the given compound, and which are not biologically or otherwise undesirable.
  • Pharmaceutically acceptable salts include salts with inorganic acids or organic acids, and salts with inorganic bases or organic bases.
  • Salts may be derived from inorganic acids, including hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
  • Salts may be derived from organic acids, including acetic acid, propionic acid, glycolic acid, gluconic acid, pamoic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, lactic acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluene-sulfonic acid, salicylic acid, and the like.
  • 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.
  • pharmaceutically acceptable salts include organic salts such as choline, glucosamine, tris, meglumine, lysine, arginine, tributylamine, and benzathine salts.
  • the API is an amorphous form, a crystalline form, a polymorph, a hydrate, or a solvate.
  • the doses described in this application e.g., 100 ⁇ g refer to the weight of the pharmacologically active moiety, rather than the weight of a given API salt or API ester.
  • the weight when the insert contains a pharmaceutically acceptable salt or ester of vorolanib, the weight must be adjusted to provide an amount of the API salt that is equivalent to the amount of the API described herein.
  • a Drug Release Rate of 100 ⁇ g/day means that the insert releases 100 ⁇ g/day of the pharmacologically active moiety (e.g., vorolanib).
  • the API Before formulation of the insert, the API may be milled to produce a fine particle size.
  • the D90 for the API for use in manufacturing the insert is less than 200 ⁇ m, less than 100 ⁇ m, less than 50 ⁇ m, less than 40 ⁇ m, less than 30 ⁇ m, less than 20 ⁇ m, or less than 15 ⁇ m.
  • the D90 is about 0.01 ⁇ m to about 100 ⁇ m, about 0.01 ⁇ m to about 80 ⁇ m, about 0.1 ⁇ m to about 50 ⁇ m, about 0.1 ⁇ m to about 20, about 0.1 ⁇ m to about 15 ⁇ m, about 0.1 ⁇ m to about 12 ⁇ m, about 1 ⁇ m to about 50 ⁇ m, about 1 ⁇ m to about 30 ⁇ m, about 1 ⁇ m to about 25 ⁇ m, about 1 ⁇ m to about 20 ⁇ m, about 1 ⁇ m to about 15 ⁇ m, about 1 ⁇ m to about 12 ⁇ m, about 5 ⁇ m to about 10, about 7 ⁇ m, about 8 ⁇ m, about 9 ⁇ m, about 10 ⁇ m, about 11 ⁇ m, or about 12 ⁇ m.
  • Ocular Drug Delivery Insert is a device that can be implanted in an eye, contains a drug, and can release the drug in the eye after implantation. “Ocular drug delivery insert” encompasses all of the inserts described herein. [00122]
  • the ocular drug delivery insert comprises a core comprising an API dispersed in a solid matrix. In some embodiments, the core is at least partially covered by a coating. In other embodiments, the insert consists only of the core. It is not surrounded by a coating or any kind of barrier surrounding the core. The insert is bioerodible.
  • the insert comprises both a core and a coating. The coating is a layer that partially or fully surrounds the core.
  • the coating is an outer layer, which may be preformed into the desired shape (e.g., it may be a tube) before it is placed around the core, or the coating may be formed, e.g., by coextrusion of core and coating, spraying the coating onto the core, or dipping the core into the coating material once or multiple 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.
  • the insert may be a variety of different shapes, e.g., a cylinder, rod, sphere, or disk. In some embodiments, the insert is cylindrical in shape, and the coating covers the entire surface of the cylinder except the ends of the rod or cylinder. The ends of the rod may act as delivery ports.
  • a rod is a solid geometrical figure with parallel sides, wherein the length of a side is longer than the diameter or longest side of the shape of the cross section.
  • the cross-section shape may be a circle, oval, square, rectangle, triangle, or polygon such as a hexagon.
  • the insert shape may not be precise, e.g., the exterior may not be smooth and perfectly even.
  • the sides of the cylinder or rod may not be perfectly straight or perfectly parallel.
  • the core is a solid matrix comprising a matrix polymer and an API, which may be present in a solid form, such as a powder, particles, or granules, dispersed throughout the matrix.
  • the matrix ingredients and 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 rate of release of the API, thus modifying the rate of API release as compared to unformulated API.
  • the matrix slows the rate of drug release and provides for prolonged delivery of the drug, and less frequent dosing.
  • the matrix also comprises other pharmaceutically acceptable ingredients.
  • the only material used to form the matrix is one or more matrix polymers.
  • the polymer used to form the matrix may comprise one or more of the following: polyvinyl alcohol (PVA), poly(caprolactone) (PCL), polyethylene glycol (PEG), poly(dl-lactide-co-glycolide) (PLGA), polyvinyl alcohol (PVA), poly(lactic acid) (PLA), poly(glycolic acid) (PGA), polyalkyl cyanoacrylate, or a copolymer thereof.
  • the matrix polymer comprises PVA.
  • the only inactive pharmaceutical ingredient in the matrix is PVA.
  • Various grades of PVA may be used.
  • the degree of hydrolysis (DH) of the PVA may be about 70% to about 99 + %, and the molecular weight (MW) may be about 6000-200,000, i.e., the matrix polymer is about 70 mole % to about 99 + mole % hydrolyzed PVA having a molecular weight of about 6,000-200,000.
  • the DH may be 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 + %, 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
  • the MW may be 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 70,000-80,000, about 75,000-80,000, about 75,000-100,000, about 89,000-98,000, about 85,000-124,000, about 100,000-150,000, about 146,000-186,000, or about 150,000-200,000.
  • the PVA is MW 6,000, 80% hydrolyzed, MW 9,000-10,000, 80% hydrolyzed, MW 25,000, 88% hydrolyzed, MW 25,000, 98% hydrolyzed, MW 30,000-70,000, 87-90% hydrolyzed, MW 78,000, 88% hydrolyzed, MW 78,000, 98% hydrolyzed, MW 78,000, 99+% hydrolyzed, MW 89,000-98,000, 99+% hydrolyzed, MW 85,000-124,000, 87-89% hydrolyzed, MW 108,000, 99 + % hydrolyzed, MW 125,000, 88% hydrolyzed, MW 133,000, 99% hydrolyzed, or MW 146,000-186,000, 99+% hydrolyzed.
  • the matrix polymer comprises a mixture of two, three or four different grades of PVA.
  • the PVA is a mixture of two different grades of PVA.
  • the ratio of the two grades in the mixture is from 1:1 to 1:15.
  • the ratio of the two grades is 1:6, 1:7, 1:8, 1:9, 1:10, 1:11 or 1:12 of the slower eroding PVA to the faster eroding PVA.
  • the PVA erosion rate may be measured as described in Example 1.
  • the mixture of PVA has a ratio of 1:96000 MW, 80% DH to 125,000 MW, 88% DH.
  • the ratio of the two grades in the mixture is from 1:1 to 1:15, e.g., 1:6, 1:7, 1:8, 1:9, 1:10, 1:11 or 1:12, of the faster eroding PVA to the slower eroding PVA.
  • Examples of PVA mixtures include a mixture of MW 6,000, 80% hydrolyzed with MW 78,000, 98% hydrolyzed; a mixture of MW 6,000, 80% hydrolyzed with MW 78,000, 99 + % hydrolyzed; a mixture of MW 78,000, 98% hydrolyzed with MW 78,000, 99 + % hydrolyzed; and a mixture of MW 6,000, 80% hydrolyzed with MW 125,000, 88% hydrolyzed.
  • the MW and DH should be selected to provide the rate of drug release desired for the particular drug, the indication for which the ocular drug delivery insert will be used, the duration of drug release desired and the rate of erosion desired.
  • the polymer solution used to form the core matrix may comprise 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 to about 8% w/w, about 6% w/w to about 7% w/w, about 2% w/w to about
  • the polymer solution and the API may be combined in a ratio of, e.g., about 0.5:1, about 1:1, about 1:1.2, about 1:1.5, about 1:1.7, or about 1:2 w/w API:polymer solution.
  • the core comprises vorolanib or a pharmaceutically acceptable salt thereof and PVA.
  • the core consists of vorolanib or a pharmaceutically acceptable salt thereof and PVA.
  • the PVA solution and API are combined in a ratio of about 1:1 w/w API:PVA solution.
  • the PVA solution and API are combined in a ratio of about 1:2 w/w API:PVA solution.
  • the core comprises about 0.1% w/w to about 90% w/w, about 0.1% w/w to about 80% w/w, about 0.1% w/w to about 70% w/w, about 0.1% w/w to about 60% w/w, about 0.1% w/w to about 50% w/w, about 0.1% w/w to about 40% w/w, about 0.1% w/w to about 30% w/w, about 0.1% w/w to about 25% w/w, about 0.1% w/w to about 20% w/w, about 0.1% w/w to about 15% w/w, about 0.1% w/w to about 10% w/w, about 1% w/w to about 20%, about 1% w/w to about 15%, about 1% w/w to about 10% w/w, about 1% w/w to about 20%, about 1% w/w to about 15%, about 1% w/w to about 10% w/w, about 1% w/w to about 20%,
  • the amount of matrix polymer in the core is about 0.1% w/w to about 90% w/w, about 0.1% w/w to about 80% w/w, about 0.1% w/w to about 70% w/w, about 0.1% w/w to about 60% w/w, about 0.1% w/w to about 50% w/w, about 0.1% w/w to about 40% w/w, about 0.1% w/w to about 30% w/w, about 0.1% w/w to about 25% w/w, about 0.1% w/w to about 20% w/w, about 0.1% w/w to about 15% w/w, about 0.1% w/w to about 10% w/w, about 1% w/w to about 20%, about 1% w/w to about 15%, about 1% w/w to about 10% w/w, about 1% w/w to about 20%, about 1% w/w to about 15%, about 1% w/w to about 10% w/w, about 1%
  • the insert consists of” a core comprising a solid matrix and API means that the entire insert is in the form of a solid matrix and API.
  • the matrix may also include additional ingredients, but the insert does not have a shell, coating, cap, covering or tube or other outer layer, so that when immersed in a fluid environment, such as the vitreous humor of the eye or an in vitro drug release medium, the exterior of the core is in direct contact with this fluid.
  • the insert comprises or consists of (a) a core comprising an API and a solid matrix, and (b) a coating.
  • the insert does not comprise a coating.
  • the coating is permeable to the passage of the API, and acts as a diffusion membrane for the active pharmaceutical ingredient.
  • a diffusion membrane may modify the API release rate of the matrix.
  • the diffusion membrane may operate by, for example, modifying fluid flow into the matrix and/or limiting the passage of the API out of the matrix.
  • the coating increases the durability of the insert, as compared to an uncoated core, e.g., during processing, packaging, and/or delivering the dose.
  • the coating both modifies the API release rate and increases the durability of the insert.
  • the coating may completely surround the core or may only partially surround the core.
  • the coating substantially covers the core, which means that it covers at least 70% of the surface area of the core. In some embodiments, the coating covers at least 75%, at least 80%, at least 85%, at least 90%, 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.
  • an area of the core is left uncovered by a coating to form a delivery port.
  • more than one area is left uncovered to form more than one delivery port.
  • the delivery port is permeable to the API.
  • the insert is rod-shaped, e.g., cylindrical, and only the two ends of the rod/cylinder are uncoated.
  • figure 1 shows a longitudinal cross-sectional view of an ocular drug delivery insert 100 according to one embodiment of the invention.
  • Insert 100 comprises solid matrix core 105. Insert 100 further comprises a coating 110, substantially surrounding the core 105. Insert 100 also features two delivery ports 115 which are located at opposite ends of insert 100. In this particular embodiment, at least one of the delivery ports 115 comprises a membrane permeable to the API contained in core 105 to allow the API to be released from the delivery port/s 115. [00148] In some embodiments, like the matrix, the coating is bioerodible. [00149] The coating may comprise polymeric and/or nonpolymeric ingredients.
  • 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), polyalkyl cyanoacrylate, or a copolymer thereof.
  • PVA polyvinyl alcohol
  • PCL poly(caprolactone)
  • PEG polyethylene glycol
  • PLGA poly(dl-lactide-co-glycolide)
  • PLA poly(lactic acid)
  • PGA poly(glycolic acid)
  • the coating may be formed from 1-10 coats of polymer.
  • 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.
  • each of the coats comprise the same polymer as the other coats. In certain embodiments, each of the coats consists of the same polymer as the other coats. In other embodiments in which the coating is formed from more than one coat, at least two of the coats comprise different polymers.
  • the coating comprises PVA. In other embodiments, the coating consists of PVA. In some embodiments, the only inactive pharmaceutical ingredient in the coating is PVA. In other embodiments, both the matrix polymer comprises PVA and the coating comprises PVA. In yet other embodiments, both the matrix polymer consists of PVA and the coating consists of PVA. [00152] Various grades of PVA may be used.
  • the degree of hydrolysis (DH) of the PVA may be about 70% to about 99 + %, and the molecular weight (MW) may be about 6000-200,000, i.e., the matrix polymer is about 70 mole % to about 99 + mole % hydrolyzed PVA having a molecular weight of about 6,000-200,000.
  • the DH may be 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 + %, 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 1
  • the MW may be 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 70,000-80,000, about 75,000-80,000, about 75,000-100,000, about 89,000-98,000, about 85,000-124,000, about 100,000-150,000, about 146,000-186,000, or about 150,000-200,000.
  • the PVA is MW 6,000, 80% hydrolyzed, MW 9,000-10,000, 80% hydrolyzed, MW 25,000, 88% hydrolyzed, MW 25,000, 98% hydrolyzed, MW 30,000-70,000, 87-90% hydrolyzed, MW 78,000, 88% hydrolyzed, MW 78,000, 98% hydrolyzed, MW 78,000, 99+% hydrolyzed, MW 89,000-98,000, 99+% hydrolyzed, MW 85,000-124,000, 87-89% hydrolyzed, MW 108,000, 99 + % hydrolyzed, MW 125,000, 88% hydrolyzed, MW 133,000, 99% hydrolyzed, or MW 146,000-186,000, 99+% hydrolyzed.
  • the PVA is a mixture of two, three or four different grades of PVA. In some embodiments the PVA is a mixture of two different grades of PVA. In some embodiments, the ratio of the two grades in the mixture is from 1:1 to 1:15. In some embodiments, the ratio of the two grades is 1:6, 1:7, 1:8, 1:9, 1:10, 1:11 or 1:12 of the slower eroding PVA to the faster eroding PVA.
  • the PVA erosion rate may be measured as described in Example 1. For example, in some embodiments the mixture of PVA has a ratio of 1:96000 MW, 80% DH to 125,000 MW, 88% DH.
  • the ratio of the two grades in the mixture is from 1:1 to 1:15, e.g., 1:6, 1:7, 1:8, 1:9, 1:10, 1:11 or 1:12, of the faster eroding PVA to the slower eroding PVA.
  • Examples of PVA mixtures include a mixture of MW 6,000, 80% hydrolyzed with MW 78,000, 98% hydrolyzed; a mixture of MW 6,000, 80% hydrolyzed with MW 78,000, 88% hydrolyzed; a mixture of MW 6,000, 80% hydrolyzed with MW 78,000, 99 + % hydrolyzed; a mixture of MW 78,000, 88% hydrolyzed with MW 78,000, 98% hydrolyzed; a mixture of MW 78,000, 98% hydrolyzed with MW 78,000, 99 + % hydrolyzed; and a mixture of MW 6,000, 80% hydrolyzed with MW 125,000, 88% hydrolyzed.
  • the core comprises a mixture of two different grades of PVA.
  • the coating comprises a mixture of two different grades of PVA.
  • both the core and coating comprise a mixture of two different grades of PVA.
  • 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.
  • the core PVA and the coating PVA may be the same or different grades of PVA. Used herein, the term “different grade of PVA” means the PVA differs in molecular weight (MW), degree of hydrolysis (DH) or both MW and DH.
  • a mixture of grades of PVA is a “different grade of PVA” if the PVA to which the mixture is compared is not a mixture of the same exact PVA grades, e.g., a mixture of 6,000, 80% hydrolyzed PVA with MW 78,000, 98% hydrolyzed PVA, would be considered a different grade of PVA from a PVA composition that contains only MW 78,000, 98% hydrolyzed PVA, or that contains a mixture of MW 6,000, 80% hydrolyzed PVA with MW 125,000, 88% hydrolyzed PVA.
  • the core PVA and the coating PVA may have the same MW and DH, or may differ in MW or DH, or may differ in both MW and DH.
  • the core comprises PVA
  • the insert comprises a coating comprising PVA, wherein the MW of the coating PVA is the same as the MW of the core PVA, and the DH of the coating PVA is lower than the DH of the core PVA.
  • the MW and the DH of the coating PVA are each lower than the MW and DH of the core PVA.
  • the coating is formed from more than one coat.
  • the insert coating comprises more than one coat of PVA
  • PVA having the same MW and DH may be used for the core and at least one of the coat/s.
  • the core comprises a PVA that differs in MW and/or DH from the PVA in at least one coat.
  • the core comprises a PVA that differs in both MW and DH from the PVA in at least one coat.
  • the PVA in the core and the PVA in at least one coat have the same MW but differ in DH.
  • the DH of the PVA in at least one coat is lower than the DH of the PVA in the core.
  • the PVA in the core and the PVA in at least one coat differ in MW but have the same DH. In some embodiments the MW of the PVA in at least one coat is lower than the MW of the PVA in the core [00159] In some embodiments, the insert coating comprises a single coat comprising PVA. In other embodiments, the insert coating comprises more than one coat comprising PVA, and the PVA in each coating has the same MW and DH. In some embodiments, at least one coat comprises PVA that differs in MW and/or DH from the PVA in at least one other coat. In some embodiments, at least one coat comprises PVA that differs in both MW and DH from the PVA in at least one other coat.
  • no two coats comprise the same grade PVA, i.e., the PVA in each coat differs in MW and/or DH from each of the other coats.
  • the insert coating comprises more than one coat comprising PVA
  • the PVA in the outermost coat is more soluble (in PBS) than the PVA in any of the other coats.
  • the PVA in at least one of the coats is more soluble than the core PVA.
  • the insert comprises (a) a solid matrix core comprising PVA and an API, and (b) a coating comprising PVA substantially surrounding the core; and the DH of the PVA in the coating is lower than the DH of the PVA in the core.
  • the insert comprises 2 coats comprising PVA.
  • the insert comprises 3 coats comprising PVA.
  • the insert comprises 4 coats comprising PVA.
  • the insert comprises 5 coats comprising PVA.
  • the insert comprises 6 coats comprising PVA.
  • the first coat applied to the core is the innermost coat, and the last coat applied is the outermost coat.
  • the DH of the PVA in the innermost coat is higher than the DH of the PVA in the outermost coat.
  • the MW of the PVA in the innermost coat is higher than the MW of the PVA in the outermost coat.
  • the DH of the PVA in the outermost coat is lower than the DH of the PVA in each of the other coats.
  • the MW and DH of the PVA in the outermost coat is lower than the MW and DH of the PVA in any of the other coats.
  • the insert comprises (a) a solid matrix core comprising a PVA selected from the group consisting of MW 6,000, 80% hydrolyzed, MW 9,000-10,000, 80% hydrolyzed, MW 25,000, 88% hydrolyzed, MW 25,000, 98% hydrolyzed, MW 30,000-70,000, 87-90% hydrolyzed, MW 78,000, 88% hydrolyzed, MW 78,000, 98% hydrolyzed, MW 78,000, 99+% hydrolyzed, MW 89,000-98,000, 99+% hydrolyzed, MW 85,000-124,000, 87-89% hydrolyzed, MW 108,000, 99 + % hydrolyzed, MW 125,000, 88% hydrolyzed, MW 133,000, 99% hydrolyzed, MW 146,000-186,000, 99+% hydrolyzed, and mixtures thereof; and an API, and (b) at least one coating comprising PVA substantially surrounding the core, wherein the PVA in the coating is selected from
  • the insert comprises at least 2 coats of PVA and the DH of the PVA in the outermost coat is lower than the DH of any of the PVA in each of the other coats.
  • the invention provides the ability to tailor the PVA grades used to manufacture the ocular insert.
  • the PVA MW and DH of core and coating should be selected to provide the rate of drug release desired for the particular drug, the indication for which the ocular insert will be used, the duration of drug release desired, and the rate of erosion desired. Different durations of drug release may be desired for different ocular diseases or conditions.
  • a 12 month duration (such as is provided by Formulation A) of drug release may be desirable for the treatment of diabetic retinopathy, whereas a duration of less than a month may be desirable for an insert for inhibiting ocular inflammation caused by injury or surgery.
  • the polymer solution used to form the coating may comprise about 1% w/w to about 20% w/w, about 1% w/w to about 15% w/w, about 1% w/w to about 10% w/w, about 2% w/w to about 15% w/w, about 2% w/w to about 12% w/w, about 2% w/w to about 10% w/w, about 2% w/w to about 8% w/w, about 2% w/w to about 6% w/w, about 3% w/w to about 10% w/w, about 3% w/w to about 8% w/w, about 3% w/w to about 6% w/w, about 2% w/w, about 2.5% w/w, about 3% 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
  • the core may be covered with 1-10 coats of a solution of PVA, i.e., the insert may comprise 1-10 PVA coatings.
  • the insert may comprise 1 coat, 2 coats, 3 coats, 4 coats, 5 coats, 6 coats, 7 coats, 8 coats, 9 coats, or 10 coats of PVA.
  • the weight of the insert coating is about 0.1% w/w to about 60% w/w, about 0.1% w/w to about 40% w/w, about 0.1% w/w to about 20% w/w, about 1% w/w to about 40% w/w, about 1% w/w to about 30% w/w, about 1% w/w to about 20% w/w, about 1% w/w to about 10% w/w, about 1% w/w to about 6% w/w, about 3% w/w to about 20% w/w, about 3% w/w to about 10% w/w, about 3% w/w to about 6% w/w, about 5% w/w to about 30% w/w, about 5% w/w to about 25% w/w, about 5% w/w to about 20% w/w, about 5% w/w to about 15% w/w, about 5% w/w to about 10% w
  • the total amount of inactive ingredients in the insert is about 0.1% w/w to about 90% w/w, about 0.1% w/w to about 80% w/w, about 0.1% w/w to about 70% w/w, about 0.1% w/w to about 60% w/w, about 0.1% w/w to about 50% w/w, about 0.1% w/w to about 40% w/w, about 0.1% w/w to about 30% w/w, about 0.1% w/w to about 25% w/w, about 0.1% w/w to about 20% w/w, about 0.1% w/w to about 15% w/w, about 0.1% w/w to about 10% w/w, about 1% w/w to about 70% w/w, about 1% w/w to about 50% w/w, about 1% w/w to about 20%, about 0.1% w/w to about 20%, about 0.1% w/w to about 15% w/w, about 0.1% w/w to about 10%
  • the amount of PVA in the insert is about 0.1% w/w to about 30% w/w, about 0.1% w/w to about 25% w/w, about 0.1% w/w to about 20% w/w, about 0.1% w/w to about 15% w/w, about 0.1% w/w to about 10% w/w, about 1% w/w to about 80% w/w, about 1% w/w to about 75% w/w, about 1% w/w to about 60% w/w, about 1% w/w to about 30% w/w, about 1% w/w to about 20%, about 1% w/w to about 15%, about 1% w/w to about 10% w/w, about 1% w/w to about 9% w/w, about 1% w/w to about 8% w/w, about 1% w/w to about 30% w/w, about 0.1% w/w to about 25% w/w, about 0.1% w/w to about
  • the invention provides an insert having a very high drug content, relative to the inactive ingredients in the insert, which is surprising given the ability of the insert to provide release of the drug over extended periods.
  • 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 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/w, about
  • the only inactive ingredient in the insert is a polymer such as PVA.
  • the thickness of the coat around the core may be e.g., about 20 ⁇ m to about 400 ⁇ m, about 20 ⁇ m to about 300 ⁇ m, about 20 ⁇ m to about 200 ⁇ m, about 20 ⁇ m to about 100 ⁇ m, about 5 ⁇ m to about 75 ⁇ m, about 5 ⁇ m to about 50 ⁇ m, or about 5 ⁇ m to about 25 ⁇ m.
  • the insert when the insert is prepared for implantation within the vitreous of the eye, the insert does not exceed about 15 mm, or preferably does not exceed about 10 mm, in any direction, so that the insert can be inserted through an incision of 15 mm or smaller.
  • the insert may be shaped and sized for injection.
  • the insert is sized and shaped to fit through a cannula or needle of 20 gauge or smaller. This means that the insert can be injected through either a cannula or a needle having the recited gauge without an unusual amount of force.
  • the phrase “or smaller” in this context means having a smaller outer diameter.
  • the insert is sized and shaped to fit through a 20 to 27 gauge needle or cannula, a 21 to 27 gauge needle or cannula, a 22 to 27 gauge needle or cannula, a 23 to 27 gauge needle or cannula, a 24 to 27 gauge needle or cannula, a 25 to 27 gauge needle or cannula, or a 25.5 to 27 gauge needle or cannula.
  • the insert is sized and shaped to fit through a cannula or needle of 20 gauge or smaller, 22 gauge or smaller, 23 gauge or smaller, 24 gauge or smaller, 25 gauge or smaller, 25.5 gauge or smaller, 26 gauge or smaller, or 26.5 gauge or smaller.
  • the insert is sized and shaped to fit through a cannula or needle smaller than 25 gauge, smaller than 26 gauge, or smaller than 27 gauge.
  • the insert is sized and shaped to fit through a cannula or needle of about 29 gauge to about 25.5 gauge, such as from about 28 gauge to about 25.5 gauge, or from about 28 gauge to about 26 gauge.
  • the needle or canula is about 22, 22s, 23, 24 or 25 gauge, but preferably is about 25.5, 26, 26.5, 26s, 27, 27.5, 28, 28.5, 29, 29.5, 30 or 30.5 gauge.
  • the insert is rod-shaped, cylindrical or spherical, and may be less than about 12 mm long and less than about 1 mm in diameter.
  • the insert may be rod shaped or cylindrical and does not exceed 8 mm in length and 3 mm in diameter.
  • 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.
  • 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. d.
  • the insert may be manufactured by mixing the API with a matrix polymer.
  • the matrix polymer is a solution of 1 or more polymers in a solvent, e.g., in water or ethanol.
  • the API, matrix polymer solution, and any other matrix ingredients are mixed to form a paste suitable for extrusion through a dispensing tip.
  • the paste may be extruded through an 18-25 gauge canula or dispensing tip.
  • a 21-23 or a 23-26 gauge canula or dispensing tip is used.
  • 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 rods 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.
  • extrusion parameters may be controlled, such as fluid pressure, flow rate, and temperature of the material being extruded.
  • Suitable extruders may be selected for the ability to deliver the co-extruded materials at pressures and flow rates sufficient to form the product at sizes of the die head and exit port or dispensing tip that will produce a product which, when segmented and dried, can be injected through a needle or cannula as described herein.
  • the extruded API- polymer mixture is allowed to dry before coating.
  • the extrudate may be allowed to dry for about 30 minutes to about 48 hours at room temperature before coating.
  • the extrudate may be coated with one or more layers, although in some embodiments no coating is applied. The coating may be applied before segmenting into the desired insert length.
  • the coating may be applied by dipping the extrudate into 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. [00185] In other embodiments, the coating/outer layer may be pre-formed in, e.g., a tube shape, and the API-polymer paste may be extruded into the tube. [00186] Depending on the polymer used for the matrix, the matrix may be cured. Curing may be done, for example, by heating in an oven, microwave heating or chemical treatment. In other embodiments the matrix may not be cured. Instead it may be allowed to dry at air temperature or dried at a temperature of about 80 oC or lower.
  • the matrix is uncured or is cured by heating at a temperature less than 80 oC. In other embodiments the matrix is cured for about 10 minutes to about 300 minutes (5 hours) at a temperature of about 80 oC to about 160 oC, about 15 minutes to about 4 hours at a temperature of about 80 oC to about 160 oC, about 15 minutes to about 4 hours at about 120 oC to about 160 oC, about 10 minutes to about 4 hours at about 130 oC to about 150 oC, about 10 minutes to about 30 minutes at about 140 oC to about 160 oC, about 30 minutes to about 4 hours at about 130 oC to about 150 oC, about 200 minutes to about 1440 minutes at about 60 oC to about 120 oC, about 300 minutes to about 600 minutes at about 60 oC to about 100 oC, about 400 minutes to about 500 minutes at about 80 oC to about 90 oC, about 600 minutes to about 1440 minutes at about 80 oC to about 120 oC, about
  • the matrix is cured for about 200 minutes to about 1600 minutes at about 90 oC, about 200 minutes to about 500 minutes at about 90 oC, about 500 minutes to about 1600 minutes at about 90 oC, about 240 minutes at about 90 oC, about 480 minutes at about 90 oC, or about 1440 minutes at about 90 oC.
  • the matrix is cured for about 200 minutes to about 1600 minutes at about 100 oC, about 200 minutes to about 500 minutes at about 100 oC, about 500 minutes to about 1600 minutes at about 100 oC, about 240 minutes at about 100 oC, about 480 minutes at about 100 oC, or about 1440 minutes at about 100 oC.
  • the matrix is cured for about 30 minutes to about 1600 minutes at about 110 oC, about 30 minutes to about 200 minutes at about 110 oC, about 200 minutes to about 1600 minutes at about 110 oC, about 30 minutes at about 110 oC, about 60 minutes at about 110 oC, about 240 minutes at about 110 oC or about 1440 minutes at about 110 oC.
  • the matrix is cured for about 10 minutes to about 4 hours at about 140 oC, about 10 minutes to about 1 hour at about 140 oC, about 15 minutes to about 30 minutes at about 140 oC, about 30 minutes to about 1 hour at about 140 oC, about 1 hour to about 4 hours at about 140 oC, or about 1 hour to about 3 hours at about 140 oC, about 10 minutes to about 400 minutes at about 140 oC, about 30 minutes to about 400 minutes at about 140 oC, about 60 minutes to about 380 minutes at about 140 oC, about 60 minutes to about 300 minutes at about 140 oC, about 180 minutes to about 300 minutes at about 140 oC, about 220 minutes to about 280 minutes at about 140 oC, about 230 minutes to about 300 minutes at about 140 oC, or about 30 minutes to about 90 minutes at about 140 oC.
  • Examples of curing temperatures include about 60 oC to about 100 oC, about 60oC to about 80 oC, about 80oC to about 100oC, about 80oC to about 110oC, about 80oC to about 120 oC, about 85oC to about 115 oC, about 90oC to about 100 oC, about 90oC to about 110oC, about 90oC to about 120oC , about 90oC to about 130oC, about 120oC to about 140oC, about 130oC to about 150oC, about 140oC to about 160oC, about 135oC to about 145oC, about 140oC to about 150oC.
  • 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.
  • examples of curing time 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 may be, for example, room temperature, about 60 oC, about 65 oC, about 70oC, about 75 oC, about 80oC, about 85oC, about 90oC, about 95 oC, about 100oC, about 105 oC, about 110oC, about 120 oC, about 125 oC, about 130 oC, about 135 oC, about 140 oC, about 145 oC, about 150 oC, about 155 oC or about 160 oC.
  • the rods may be allowed to cool to room temperature before other manufacturing steps are performed. If the insert will be coated, the coating may be applied before or after curing.
  • the rods are segmented into about 1 mm to about 15 mm long inserts, e.g., about 1 mm to about 10 mm, or about 2 mm to about 6 mm inserts.
  • the rods may be segmented into 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 inserts.
  • the rods may be segmented, or otherwise cut into a series of shorter products, by any suitable technique for cutting the rods, which may vary according to whether the product is cured, uncured, or partially cured.
  • the segmenting station may employ pincers, shears, slicing blades, or any other technique.
  • the technique applied may vary according to a configuration desired for each cut portion of the product. For example, where open ends are desired, a shearing action may be appropriate. However, where it is desired to seal each end as the cut is made, a pincer may be used.
  • the extrudates are dip coated in a solution of PVA in water with a concentration of PVA 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 10% w/w, about 2% w/w to about 8% w/w, about 2% w/w to about 6% w/w, about 3% w/w to about 6% w/w, about 2% w/w, about 2.5% w/w, about 3% w/w, about 3.5% w/w, about 4% w/w, about 4.5% w/w, about 5% w/w, about 5.5% w/w, about 6% w/w, about 6.5% w/w, about 7% w/w, about 7.5% w/w, about 8% w/w, about 8.5% w/w, about a concentration of PVA of about
  • the coated extrudates may then be air dried.
  • the process of dip-coating may be repeated 1-10 more times, preferably 1-6 or 1-5 more times, and air dried between each coating.
  • the coated extrudates may then be cured, as described above. After cooling, the extrudates are then cut into inserts. e. Insert Properties [00200]
  • the difficulty of handling and processing such devices without significant breakage also adds to the challenges.
  • the inventors have overcome these challenges to provide a drug delivery device small enough to be implanted into the eye with minimal discomfort that is able to provide sustained delivery of the drug for months while also fully eroding sometime after the drug delivery period of the device has ended.
  • the inventors have found a way to provide devices having different drug delivery periods/durations and rates of delivery.
  • these devices provide an essentially linear release of the drug after an initial burst of drug delivery.
  • the insert has a very high drug content, relative to the inactive ingredients in the insert, which is surprising given the ability of the insert to provide release of the drug over extended periods. i.
  • the insert is capable of completely eroding within 365 days.
  • the ability of an 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 with 5 mL phosphate buffered saline (PBS), the vial is incubated at 37°C, the PBS in the vial is replaced once every 24 hours for each day of the time period of interest (e.g., 365 days, 200 days, 110 days). At the end of this period, the insert is removed from the vial, allowed to dry, and then visually inspected and weighed.
  • PBS phosphate buffered saline
  • the reduction in weight as compared to the original weight is calculated as follows: [00205] For example, if an insert that originally weighs 500 ⁇ g, and weighs 200 ⁇ g after incubating in PBS for 200 days according to the Erosion Evaluation Protocol, the insert weighs 40% of its original weight, and has lost 60% of its weight. It has undergone 60% erosion in 200 days. An insert is considered to be completely eroded when less than 10% of the original weight of the insert remains.
  • the insert completely erodes within 760 days, within 730 days, within 700 days, within 660 days, within 630 days, within 600 days, within 570 days, within 540 days, within 400 days, within 365 days, within 300 days, within 280 days, within 240 days, within 210 days, within 200 days, within 180 days, within 160 days, or within 140 days.
  • the insert is capable of 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 within 95 days, 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 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
  • the insert has a Drug Release Rate of about 0.01 ⁇ g/day to about 100 ⁇ g/day, about 0.01 ⁇ g/day to about 90 ⁇ g/day, about 0.01 ⁇ g/day to about 80 ⁇ g/day, about 0.01 ⁇ g/day to about 70 ⁇ g/day, about 0.01 ⁇ g/day to about 50 ⁇ g/day, about 0.01 ⁇ g/day to about 20 ⁇ g/day, about 0.01 ⁇ g/day to about 10 ⁇ g/day, about 0.1 ⁇ g/day to about 100 ⁇ g/day, about 0.1 ⁇ g/day to about 150 ⁇ g/day, about 0.1 ⁇ g/day to about 60 ⁇ g/day, about 0.1 ⁇ g
  • this is the release rate after steady-state release is achieved. In some embodiments, this is the release rate after 2 days, 3 days, 5 days, 8 days, 10 days, 15 days, 20 days, 25 days, 30 days, 40 days, 50 days, 60 days, 70 days, 80 days, 90 days, 100 days, 105 days or 110 days of drug release. In some embodiments, the drug release rate is the average drug release rate, measured by the in vitro Drug Release Method (described below) over a specified period, e.g., 30 days, 60 days, 90 days, 120 days or 180 days.
  • the term “average release rate” refers to the sum total of the release rates of an ocular drug delivery insert over a period (e.g., 30 days) divided by the total number of days, to arrive at an average release rate. Average release rates are readily calculated by measuring the release rate for each day of the period using the methods described herein. [00208] 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 ⁇ g/day to about 150 ⁇ g/day.
  • 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 the in vitro Drug Release Method.
  • the following in vitro Drug Release Method is used to evaluate the amount of drug released: an insert is placed in a 10 mL glass tube, and 5 mL PBS is added to the tube. The tube is incubated in a water bath at 37°C. A sample of the medium is taken on each day of the stated period, and the release medium replaced with fresh PBS.
  • the amount of API released may be measured quantitatively by HPLC as described in Example 2B.
  • 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.
  • 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 method described above may be used to determine whether an insert releases drug for this duration.
  • the insert of the invention provides an initial rapid release, or burst, of drug in vivo, for a period of time before achieving a steady state rate. In preferred embodiments of the invention, the initial period of rapid release is much less than total duration of API release (e.g., less than 10%).
  • this initial period is, e.g., 1 to 120 days, 20 to 120 days, 80 to 120 days, 1 to 20 days, 2 to 50 days, 3 to 40 days, 5 to 60 days, 1 day, 2 days, 3 days, 4 days, 5 days, 8 days, 10 days, 12 days, 15 days, 20 days, 25 days, 30 days, 40 days, 50 days, 60 days, 70 days, 80 days, 90 days, 100 days, 105 days, 110 days.
  • the insert of the invention releases the API at a substantially constant rate (i.e., zero-order drug release kinetics, R 2 is from 0.7-1) over a predetermined duration after implantation.
  • R 2 is from 0.7-1
  • it may release 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.
  • the insert releases API at a substantially constant rate for at least 14 days, at least 28 days, at least 42 days, at least 56 days, at least 120 days, at least 168 days, at least 180 days, at least 224 days, at least 270 days at least 300 days, at least 365 days, at least 540 days, at least 600 days, or at least 730 days.
  • the duration of substantially constant API release from the insert may fall 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, about 3 to about 9 months.
  • the duration of substantially constant API release is about 60 days to about 730 days, about 60 days to about 540 days, about 60 days to about 365 days, about 60 days to about 300 days, about 60 days to about 270 days, about 90 days to about 365 days, about 90 days to about 270 days, about 180 days to about 365 days, or about 365 days to about 730 days. In some embodiments it is at least about 12 weeks, at least about 18 weeks, at least about 22 weeks, at least about 24 weeks, at least about 30 weeks, at least about 32 weeks, at least about 36 weeks, at least about 40 weeks, at least about 44 weeks, at least about 48 weeks, or at least about 52 weeks.
  • the in vitro drug release test described above may be used to determine whether an insert releases drug for this duration. 3.
  • a method of treating a posterior ocular condition wherein the method utilizes a loading dose and a maintenance dose to provide the desired amount of vorolanib or a pharmaceutically acceptable salt thereof.
  • the method comprises injecting into an eye of a human subject, wherein the eye has the posterior ocular condition, a loading dose of one or more initial ocular drug delivery inserts, each insert comprising a solid matrix core comprising a matrix polymer and vorolanib or a pharmaceutically acceptable salt thereof.
  • the term “loading dose” refers to the insertion of one or more initial ocular drug delivery inserts so as to provide a first dose of vorolanib or a pharmaceutically acceptable salt thereof, to the subject.
  • the loading dose can include one ocular drug delivery insert, or can include more than on ocular drug delivery insert, including two, three, four, five, six, seven, eight, nine, ten, etc., ocular drug delivery inserts.
  • the release rate for each initial ocular drug delivery insert is, e.g., about 0.1 ⁇ g/day to about 150 ⁇ g/day of vorolanib for at least 30 days, and each initial ocular drug delivery insert is capable of, e.g., at least 20% erosion within 95 days.
  • the loading dose can include one or more initial drug delivery inserts that each have the same release rate and the same erosion rate (e.g., 20% erosion within 95 days).
  • one initial drug delivery insert of the loading dose can have a first release rate, while another initial drug delivery insert of the loading dose can have a different release rate. This can be the case for multiple initial drug delivery inserts provided as the loading dose.
  • the release rate for an initial ocular drug delivery insert can be faster than the release rate for an additional ocular drug delivery insert, and for example the release rate of the initial ocular drug delivery insert can be 1.5x, 2x, 3x, 4x, 5x, 6x, 7x, 8x, 9x, 10x, 20x, 40x, 50x, 75x, 100x, etc., higher that he release rate of an additional ocular drug delivery insert.
  • one initial drug delivery insert of the loading dose can have a first erosion rate, while another initial drug delivery insert of the loading dose can have a different erosion rate (e.g., on insert may be capable of at least 20% erosion within 95 days, while another is cable of only at least 15% erosion within 95 days).
  • the loading dose of initial drug delivery inserts can be administered in a single injection or, where the loading dose comprises more than one insert, e.g, 2, 3, 4, 5 or 6 inserts, the inserts may be divided into more than one loading injection, and e.g., 1, 2, 3, 4 or 5, inserts may be given at the first loading injection and the remaining loading dose inserts in one or more other injections. Where there is more than one loading dose injection, the injections may be administered at about the same time, meaning within a 60 minute period, or at different times on the same day, or even on different days.
  • the second loading dose injection may be administered about 15 days to about 60 days, about 15 days to about 45 days, or about 45 days to about 60 days, after the first loading dose injection.
  • the second loading dose may be administered about 30 days after the first loading dose injection. If there are multiple loading dose injections, generally all of the loading injections are administered within a 60 day period. Where more than one loading injection is administered, the period starting on the day on which the first loading injection is administered and ending on the day the last loading injection is administered is called the loading period.
  • the methods of treatment further include, following release of a certain percentage of drug (e.g., following release of about 30%, but before release of about 100%) from the loading dose (or last administered loading dose if the loading dose is divided into more than one injection), or following a certain number of days after the loading dose (e.g., about 15 to about 365 days after injection of the loading dose, or last administered loading dose if the loading dose is divided into more than one injection) of the vorolanib from the loading dose, injecting into the eye a maintenance dose of one or more additional ocular drug delivery inserts.
  • the loading dose and maintenance dose inserts comprise a solid matrix core comprising a matrix polymer and vorolanib or the pharmaceutically acceptable salt thereof.
  • the term “maintenance dose” refers to the insertion of one or more additional ocular drug delivery inserts so as to provide a continued dosage of vorolanib or a pharmaceutically acceptable salt thereof, to the subject, for a desired period.
  • the maintenance dose can include one ocular drug delivery insert, or can include more than on ocular drug delivery insert, including two, three, four, five, six, seven, eight, nine, ten, etc., ocular drug delivery inserts.
  • the release rate for each additional ocular drug delivery insert is, e.g., about 0.1 ⁇ g/day to about 100 ⁇ g/day of vorolanib for at least 90 days, and each additional ocular drug delivery insert is capable of at least 20% erosion within 95 days.
  • the release rate and/or erosion rate of each additional ocular drug delivery insert can be in the same range as each initial drug delivery insert of the loading dose.
  • both the initial drug delivery insert/s and additional ocular drug delivery insert/s can have a release rate of about 0.1 ⁇ g/day to about 150 ⁇ g/day of vorolanib for at least 30 days, and an erosion rate of at least 20% erosion within 95 days.
  • the additional ocular drug delivery insert/s and initial drug delivery insert/s can differ in release rate and/or erosion rate.
  • the release rates for each initial ocular drug delivery device of the loading dose, as well as the release rates for each additional ocular drug delivery device of the maintenance dose can be any rate described herein.
  • the release rates for each initial drug delivery device and each additional drug delivery device are within about 0.1 ⁇ g/day to about 150 ⁇ g/day of vorolanib.
  • the release rate of each initial ocular drug delivery insert and/or each additional ocular drug delivery insert is about 0.1 ⁇ g/day to about 60 ⁇ g/day, about 0.1 ⁇ g/day to about 30 ⁇ g/day, or about 0.1 ⁇ g/day to about 10 ⁇ g/day.
  • the release rates can have values within these ranges as well, and as described herein, the loading dose and/or the maintenance dose can include multiple different ocular drug delivery devices that each have different release rates that provide the desired loading dose and/or maintenance dose.
  • each initial and/or additional ocular drug delivery insert may have, e.g., an average drug release rate over a 30 day period of about 0.1 ⁇ g/day to about 150 ⁇ g/day.
  • each initial and/or additional ocular drug delivery insert has an average drug release rate over a 30-day period of about 0.1 ⁇ g/day to about 30 ⁇ g/day.
  • the insert average drug release rate over a 30-day period is about 0.1 ⁇ g/day to about 150 ⁇ g/day.
  • the drug release rate is the average drug release rate, measured by the in vitro Drug Release Method (described herein) over a specified period, e.g., 30 days, 60 days, 90 days, 120 days or 180 days.
  • the term “average drug release rate” refers to the sum total of the release rates of an ocular drug delivery insert over a period (e.g., 30 days, 60 days, 90 days, 120 days or 180 days or longer) divided by the total number of days, to arrive at an average drug release rate. Average drug release rates are readily calculated by measuring the release rate for each day using the method described herein. [00227] The drug release rate is further described elsewhere herein.
  • the amount of the vorolanib or pharmaceutically acceptable salt thereof in each initial ocular drug delivery insert, and/or each additional ocular drug delivery insert is about 60% w/w to about 98% w/w. In other embodiments, the amount of the vorolanib or pharmaceutically acceptable salt thereof in each initial ocular drug delivery insert, and/or each additional ocular drug delivery insert, is 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 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 30% w/w to about 90% w/w, about 30% w/w to about 90% w/w, about 30% w/w to about 80% w/w, about 40% w/w to about 80%
  • each initial and/or additional ocular drug delivery insert comprises about 200 ⁇ g to about 2000 ⁇ g of vorolanib or a pharmaceutically acceptable salt thereof.
  • each initial ocular drug delivery insert and/or each additional ocular drug delivery insert comprises about 200 ⁇ g to about 2000 ⁇ g of vorolanib or a pharmaceutically acceptable salt thereof, or about 500 ⁇ g to about 2000 ⁇ g of vorolanib or a pharmaceutically acceptable salt thereof, about 600 ⁇ g to about 2000 ⁇ g of vorolanib or a pharmaceutically acceptable salt thereof, about 700 ⁇ g to about 2000 ⁇ g of vorolanib or a pharmaceutically acceptable salt thereof, about 800 ⁇ g to about 2000 ⁇ g of vorolanib or a pharmaceutically acceptable salt thereof, about 900 ⁇ g to about 2000 ⁇ g of vorolanib or a pharmaceutically acceptable salt thereof, about 1000 ⁇ g to about 2000 ⁇ g of vorolanib or a pharmaceutically acceptable salt thereof, about 500 ⁇ g to about 1900 ⁇ g of vorolanib or a pharmaceutically acceptable salt thereof, about 500 ⁇ g to about 1800 ⁇ g of vorolanib or a
  • the injecting of the maintenance dose occurs following release of a certain percentage of the total vorolanib in the insert/s injected previously (e.g., in the loading dose, or in the previous maintenance dose).
  • the previous dose refers to the dose that was last injected into the eye being treated.
  • the injecting of the maintenance dose occurs following release of about 40%, but before release of about 80% of the vorolanib, including following release of about 50%, but before release of about 90% of the vorolanib, or following release of about 40-60%, but before release of about 80% of the vorolanib.
  • the injecting of the maintenance dose occurs following release of about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, or about 65% of the vorolanib, but before release of about 100%, about 90%, about 80%, or about 70% of the vorolanib. In yet other embodiments, the injecting of the maintenance dose occurs following release of about 70%, about 75%, about 80%, about 85%, about 90%, about 95% of the vorolanib, but before release of about 100% of the vorolanib.
  • the injecting of the maintenance dose occurs about 10 days to about 600 days after the injecting of the last loading dose, for example, injecting of the maintenance dose occurs about 15 days to about 400 days after, about 20 days to about 365 days after, about 30 days to about 365 days after, about 30 days to about 270 days after, about 60 days to about 270 days after, about 60 days to about 180 days after, about 90 days to about 240 days after, about 90 days to about 200 days after, about 90 days to about 180 days after, about 120 days to about 270 days after, about 120 days to about 240 days after, about 120 days to about 200 days after, about 120 days to about 180 days after, about 150 days to about 210 days after, or about 150 days to about 180 days after, the injecting of the loading dose.
  • the ocular drug delivery inserts suitably include a matrix polymer that comprises PVA.
  • each initial ocular drug delivery insert and/or each additional ocular drug delivery insert comprise about 1% w/w to about 15% w/w PVA.
  • Each initial ocular drug delivery insert and/or each additional ocular drug delivery insert can both include the same amount of PVA, or can include different amounts of PVA.
  • each initial ocular drug delivery inserts of the loading dose can comprise different amounts of PVA between different initial ocular drug delivery inserts, and/or each additional ocular drug delivery inserts of the maintenance dose can comprise different amounts of PVA between different additional ocular drug delivery inserts.
  • the ocular drug delivery inserts are further described elsewhere herein.
  • each initial ocular drug delivery insert and/or each additional ocular drug delivery insert further comprises a coating substantially surrounding the core.
  • the coating suitably comprises PVA.
  • the coating can comprise a different grade of PVA than the matrix polymer. Insert coatings are further described elsewhere herein.
  • each initial ocular drug delivery insert and/or each additional ocular drug delivery insert further comprises a delivery port. Characteristics of the delivery port are described herein. The delivery report is further described elsewhere herein.
  • each initial ocular drug delivery insert and/or each additional ocular drug delivery insert is cured for about 30 minutes to about 1440 minutes at about 60 °C to about 150 °C.
  • each initial ocular drug delivery insert and/or each additional ocular drug delivery insert is injected through a 20 to 27 gauge needle or cannula and each initial ocular drug delivery insert and/or each additional ocular drug delivery insert has a length of about 1 mm to about 10 mm.
  • the needle or cannula gauge, and insert size is further described elsewhere herein.
  • the loading dose and/or the maintenance dose can include multiple different ocular drug delivery inserts have multiple different lengths, depending on the desired release profile and amount of drug to be delivery to the eye.
  • the loading dose and/or the maintenance dose is injected intravitreally. The injection is further described elsewhere herein.
  • the loading dose comprises injecting two initial ocular drug delivery inserts, three initial ocular drug delivery inserts, four initial ocular drug delivery inserts, five initial ocular drug delivery inserts, etc.
  • the maintenance dose can comprise injecting one additional ocular drug delivery insert, two additional ocular drug delivery inserts, three additional ocular drug delivery inserts, four additional ocular drug delivery inserts, five additional ocular drug delivery inserts, etc.
  • the methods comprise repeating, one or more times, injecting into the eye of the human subject, one or more maintenance doses. That is, the maintenance dose can be injected two, three, four, five, six, seven, eight, nine, ten, 15, 20, 25, 30, 35, 40, 45, 50, times etc.
  • These repeat maintenance doses may be administered at regular intervals, e.g., every 15 days, every 30 days, every 45 days, every 60 days, every 75 days, every 90 days, every 105 days, every 120 days, every 135 days, every 150 days, every 165 days, every 180 days, every 195 days, every 210 days, every 225 days, every 240 days, every 255 days, every 270 days, every 285 days, every 300 days, every 315 days, every 330 days, every 345 days, every 360 days, or every 365 days.
  • the same additional drug delivery insert characteristics e.g., composition, release rate, number of inserts
  • can be used for each maintenance dose or it can be varied between each maintenance dose, as desired.
  • various posterior ocular conditions can be treated using the methods described, including for example, wet age-related macular edema, diabetic macular edema (DME), retinal vein occlusion (RVO) and diabetic retinopathy. Ocular conditions are further described elsewhere herein.
  • Various loading doses can be provided to the subject (or previously provided to the subject) in the methods of treatment, including wherein the loading dose is about 300 ⁇ g vorolanib or a pharmaceutically acceptable salt thereof to about 1000 ⁇ g vorolanib or a pharmaceutically acceptable salt thereof, about 1000 ⁇ g vorolanib or a pharmaceutically acceptable salt thereof to about 4000 ⁇ g vorolanib or a pharmaceutically acceptable salt thereof, about 1000 ⁇ g vorolanib or a pharmaceutically acceptable salt thereof to about 3000 ⁇ g vorolanib or a pharmaceutically acceptable salt thereof, about 800 ⁇ g vorolanib or a pharmaceutically acceptable salt thereof to about 1500 ⁇ g vorolanib or a pharmaceutically acceptable salt thereof, about 1500 ⁇ g vorolanib or a pharmaceutically acceptable salt thereof to about 3500 ⁇ g vorolanib or a pharmaceutically acceptable salt thereof, about 2000 ⁇ g vorolanib or a pharmaceutically acceptable salt thereof to about 3500 ⁇ g vorolani
  • Various maintenance doses can be provided to the subject in the methods of treatment, including wherein the maintenance dose is about 300 ⁇ g vorolanib or a pharmaceutically acceptable salt thereof to about 1000 ⁇ g vorolanib or a pharmaceutically acceptable salt thereof, about 800 ⁇ g vorolanib or a pharmaceutically acceptable salt thereof to about 3800 ⁇ g vorolanib or a pharmaceutically acceptable salt thereof, about 1000 ⁇ g vorolanib or a pharmaceutically acceptable salt thereof to about 3000 ⁇ g vorolanib or a pharmaceutically acceptable salt thereof, about 900 ⁇ g vorolanib or a pharmaceutically acceptable salt thereof to about 2000 ⁇ g vorolanib or a pharmaceutically acceptable salt thereof, about 1030 ⁇ g vorolanib or a pharmaceutically acceptable salt thereof to about 1400 ⁇ g vorolanib or a pharmaceutically acceptable salt thereof, including any values and ranges within these recited ranges.
  • a method of treating a posterior ocular condition comprising injecting into an eye of a human subject, wherein the eye has the posterior ocular condition, a loading dose of one or more initial ocular drug delivery inserts, each insert comprising a solid matrix core comprising a matrix polymer and vorolanib or a pharmaceutically acceptable salt thereof, wherein the release rate for each initial ocular drug delivery insert is about 0.1 ⁇ g/day to about 150 ⁇ g/day of vorolanib for at least 30 days and each initial ocular drug delivery insert is capable of at least 20% erosion within 95 days.
  • the method further comprises, about 15 days to about 365 days after the injecting of the loading dose, injecting into the eye a maintenance dose of one or more additional ocular drug delivery inserts comprising a solid matrix core comprising a matrix polymer and vorolanib or a pharmaceutically acceptable salt thereof, wherein the release rate for each additional ocular drug delivery insert is about 0.1 ⁇ g/day to about 100 ⁇ g/day of vorolanib for at least 90 days and each additional ocular drug delivery insert is capable of at least 20% erosion within 95 days.
  • additional ocular drug delivery inserts comprising a solid matrix core comprising a matrix polymer and vorolanib or a pharmaceutically acceptable salt thereof, wherein the release rate for each additional ocular drug delivery insert is about 0.1 ⁇ g/day to about 100 ⁇ g/day of vorolanib for at least 90 days and each additional ocular drug delivery insert is capable of at least 20% erosion within 95 days.
  • Various posterior ocular conditions that can be treated using the methods are described herein, and suitably include wet age-related macular edema, diabetic macular edema (DME), retinal vein occlusion (RVO), and diabetic retinopathy. Ocular conditions are further described herein.
  • Exemplary dosing for use in the various methods described herein include but are not limited to, loading doses of 1-3 inserts with 1030 ⁇ g/insert, and a maintenance dose of 1-3 inserts with 1030 ug/insert.
  • a loading dose of 1 or 2 inserts with 1400 ⁇ g/insert and a maintenance dose of one insert with 1400 ⁇ g/insert include, a loading dose of 1000-4000 ⁇ g, 100- 3000 ⁇ g, 1500-3500 ⁇ g, 2000-3500 ⁇ g, or 1400-2800 ug and maintenance dose of 500-2800 ⁇ g, 800-3000 ug, or 1030-1400 ⁇ g.
  • a method of treating a posterior ocular condition comprising injecting into an eye of a human subject, wherein the eye has the posterior ocular condition, a maintenance dose of one or more additional ocular drug delivery inserts, each insert comprising a solid matrix core comprising a matrix polymer and vorolanib or a pharmaceutically acceptable salt thereof, wherein the release rate for each additional ocular drug delivery insert is about 0.1 ⁇ g/day to about 100 ⁇ g/day of vorolanib for at least 30 days, and each additional ocular drug delivery insert is capable of at least 20% erosion within 95 days, wherein the eye has previously received a dose of one or more previous ocular drug delivery inserts comprising a solid matrix core comprising a matrix polymer and vorolanib or a pharmaceutically acceptable salt thereof, wherein the release rate for the previous ocular drug delivery insert is about 0.1 ⁇ g/day to about 150 ⁇ g/day of vorolanib for at least 30
  • the human subject has received a previous ocular drug delivery insert.
  • This previous ocular drug delivery insert could have been implanted into the eye as a loading dose, as a maintenance dose, or as a part of another dosing regimen for the posterior ocular condition.
  • Other embodiments of the method and inserts used in the method are described elsewhere herein.
  • Various posterior ocular conditions that can be treated using the methods are described herein, and suitably include wet age-related macular edema, diabetic macular edema (DME), retinal vein occlusion (RVO), and diabetic retinopathy.
  • a method of treating a posterior ocular condition comprising injecting into an eye of a human subject, wherein the eye has the posterior ocular condition, a maintenance dose of one or more additional ocular drug delivery inserts, each insert comprising a solid matrix core comprising a matrix polymer and vorolanib or a pharmaceutically acceptable salt thereof, wherein the release rate for each additional ocular drug delivery insert is about 0.1 ⁇ g/day to about 10 ⁇ g/day of vorolanib for at least 30 days and each additional ocular drug delivery insert is capable of at least 20% erosion within 95 days, wherein the eye has previously received a dose of one or more previous ocular drug delivery inserts comprising a solid matrix core comprising a matrix polymer and vorolanib or a pharmaceutically acceptable salt thereof, wherein the release rate for the previous ocular drug delivery insert is about 0.1 ⁇ g/day to about 150 ⁇ g/day of vorolanib for at least 30
  • the release rates and compositions of the ocular drug delivery inserts of the previous dose and the maintenance dose can be the same, can be different from each other, and can also include different characteristics of the ocular drug delivery inserts within the previous dose and/or maintenance dose.
  • the injecting of the maintenance dose occurs about 10 days to about 600 days after the injecting of the previous dose, for example, injecting of the maintenance dose occurs about 15 days to about 400 days after, about 20 days to about 365 days after, about 30 days to about 365 days, about 30 days to about 270 days after, about 60 days to about 270 days after, about 60 days to about 180 days after, about 90 days to about 240 days after, about 90 days to about 200 days after, about 90 days to about 180 days after, [00255] about 120 days to about 270 days after, about 120 days to about 240 days after, about 120 days to about 200 days after, about 120 days to about 180 days after, about 150 days to about 210 days after, or about 150 days to about 180 days after, the injecting of the loading dose.
  • the insert is administered to inhibit VEGFR and/or PDGFR in an eye of a subject in need thereof. In other aspects, the insert is administered to inhibit angiogenesis in an eye of a subject in need thereof.
  • the ocular drug delivery insert is administered to prevent or treat a specific ocular condition or disease of the eye in a subject in need thereof, 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.
  • An "anterior ocular condition” is a disease, ailment, or condition that affects or involves an anterior (i.e., front of the eye, also referred to as the anterior segment) ocular region or structure, such as a periocular muscle or an eye lid, or a fluid located anterior to the posterior wall of the lens capsule or ciliary muscles.
  • an anterior ocular condition can affect or involve the conjunctiva, the cornea, the anterior chamber, the iris, the posterior chamber (located between the iris and lens), the lens or the lens capsule and blood vessels and nerve which vascularize or innervate an anterior ocular region or site.
  • An anterior ocular condition can include a disease, ailment or condition such as, but not limited to, glaucoma.
  • a "posterior ocular condition” is a disease, ailment or condition that primarily affects or involves a posterior (i.e., back of the eye, also referred to as the posterior segment) ocular region or structure, such as choroid or sclera (in a position posterior to a plane through the posterior wall of the lens capsule), vitreous, vitreous chamber, retina, optic nerve or optic disc, and blood vessels and nerves that vascularize or innervate a posterior ocular region or site.
  • a posterior ocular condition can include a disease, ailment or condition 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- caused 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, cystoids macular edema, or diabetic macular edema (DME); multifocal choroiditis; ocular trauma which affects a posterior ocular site or location; ocular tumors; retinal disorders, such as retinal vein occlusion, central retinal vein occlusion, diabetic
  • Glaucoma may also be considered a posterior ocular condition because the therapeutic goal is to prevent the loss of or reduce the occurrence of loss of vision due to damage to or loss of retinal cells or optic nerve cells (e.g., via neuroprotection).
  • the invention provides methods of preventing or treating various ocular conditions by administering the ocular drug delivery insert to an eye of a subject in need thereof.
  • the ocular condition is diabetic macular edema (DME).
  • the ocular condition is retinal vein occlusion, such as central retinal vein occlusion ("CRVO") or branch retinal vein occlusion ("BRVO").
  • 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 nonproliferative diabetic retinopathy.
  • the inserts are administered to prevent or treat vision loss in a subject in need thereof, e.g., vision loss associated with macular degeneration.
  • the ocular condition is AMD.
  • the invention provides a method of providing neuroprotection to an ocular tissue by administering the ocular drug delivery insert to an eye in a subject in need thereof.
  • the invention provides a method of providing neuroprotection in the posterior segment of the eye, and, in particular, of providing neuroprotection in the retina.
  • the invention provides a method of providing neuroprotection to the retina to prevent diseases of the retina, such as dry AMD or wet AMD, or to slow the progression of diseases of the retina, e.g., to slow the progression of dry AMD to wet AMD, or slow progression through the stages of AMD.
  • the invention provides a method of treatment or prophylaxis of an ocular disease, by administering the ocular drug delivery insert to an eye in a subject in need thereof, wherein the ocular disease is characterized by damage to retinal neurons.
  • the ocular disease characterized by damage to retinal neurons effects photoreceptors, such as geographic atrophy, glaucoma, diabetic macular edema, or retinal detachment.
  • Age-related macular degeneration is one of the most common causes of visual loss, projected to affect nearly 200 million people worldwide. Wong WL, Su X, Li X, et al.
  • Late-stage AMD characterized by macular atrophy (known as geographic atrophy) and choroidal neovascularization (CNV), affects nearly 11 million people. Id. Roughly two thirds of the cases of late-stage AMD involve CNV, manifest by the exudation of fluid and blood, often resulting in vision loss and a fibrotic scar if untreated.
  • Age-related macular degeneration (AMD) can be divided into three stages, in part based on the number and size of drusen seen under the retina during a retinal examination.
  • the following table describes four categories or stages of AMD, as defined in the National Eye Institute AREDS Study, according to 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.
  • An individual may have AMD in one eye only (unilateral), or have AMD in both eyes (bilateral), but may be at different stages of AMD in each eye.
  • the subject Where a subject has unilateral disease, or is at a more advanced stage of disease, the subject’s other eye is referred to herein as the “fellow eye”.
  • the fellow eye does not meet the diagnostic criteria for the disease with which the other eye has been diagnosed (e.g., wet AMD).
  • wet AMD e.g., wet AMD
  • Drusen deposits seen in intermediate or advanced dry AMD may enlarge and physically impinge on the photoreceptors and/or RPE.
  • VEGF vascular permeability
  • macular edema vascular permeability
  • CNV choroidal neovascularization
  • These new vessels are initially fragile, so they can break, leading to subretinal hemorrhage and photoreceptor toxicity.
  • the progression of choroidal neovascularization can lead to disciform scar formation, also known as end-stage wet AMD.
  • Treatment with drugs or surgery may provide no benefit.
  • Intravitreal injections of VEGF inhibitors can diminish the extent of exudation arising from CNV.
  • VEGF inhibitors are considered the standard of care. However, these treatments have a risk of rare but serious adverse events resulting from the intravitreal procedure, and require monthly visits to a retinal specialist, which is a significant burden.
  • Various methods may be used to diagnose AMD, to determine AMD stage, or to monitor the progression of an eye through the stages of AMD. Some of these diagnostic tools can detect choroidal neovascularization or changes in existing vascularization.
  • an assessment of the best corrected visual acuity may be used to assess and monitor changes in vision as AMD progresses.
  • changes in vision may be monitored by assessing BCVA at different timepoints.
  • assessing BCVA before administering a particular AMD therapy and at various time points during therapy can help determine whether the therapy is effective at improving deleterious effects of AMD on vision, slowing AMD progression or stabilizing AMD.
  • an increase of BCVA of at least 5 ETDRS letters as compared to baseline can indicate that a particular therapy is reducing the effects of AMD.
  • Increases of, e.g., at least 10 ETDRS letters, or at least 15 ETDRS letters indicate a more significant improvement.
  • Stabilization of vision e.g., a loss of ⁇ 15 ETDRS letters during treatment, in a subject with intermediate or advanced AMD, indicates that a therapy is stabilizing or slowing the progression of AMD.
  • a loss of ⁇ 10 ETDRS letters, or a loss of ⁇ 5 ETDRS letters during treatment indicates a more significant effect on stabilization or slowing of AMD progression.
  • IVI Impact of Vision Impairment
  • the IVI has three vision-specific subscales: reading and accessing information, mobility and independence, and emotional well-being.
  • a composite score is the total of the scores for all three subscales.
  • the IVI questionnaire composite score for the subject does not increase significantly from baseline for at least 180 days, at least 365 days or at least 545 days.
  • a dilated eye exam using an ophthalmoscope may be used to detect the presence of drusen in an eye and quantify and the number of drusen.
  • Fluorescein Angiography (FA) or Optical Coherence tomography (OCT) may be used to detect choroidal neovascularization, and to monitor neovascular changes and exudative changes in AMD, such as increase in lesion size.
  • OCT may be either Spectral-Domain OCT (SD-OCT) or OCT-Angiography (OCT-A).
  • SD-OCT Spectral-Domain OCT
  • OCT-A OCT-Angiography
  • no new choroidal neovascular lesions appear within 6 months from the date of administration, as compared to baseline.
  • existing choroidal neovascular lesions remain under 5 mm in diameter for at least 6 months after administration of the ocular drug delivery insert, as measured by OCT.
  • administration of the ocular drug delivery insert prevents significant loss in visual acuity. For example, in some embodiments there is no change from baseline in BCVA of the eye to which the insert is administered for a certain period of time, where the period of time is measured from the day the ocular drug delivery insert is administered. In other embodiments, there is a loss of ⁇ 5 ETDRS letters. In yet other embodiments, there is a loss of ⁇ 10 ETDRS letters. In yet other embodiments there is a loss of ⁇ 15 ETDRS letters. In some embodiments, there is a gain of ⁇ 5 ETDRS letters. The period of time may be at least 90 days, at least 180 days, at least 270 days, or at least 365 days.
  • administration of the ocular drug delivery insert prevents an increase in central subfield thickness (CST), also known as foveal thickness, (the average thickness of the macula in the central 1 mm ETDRS grid).
  • CST central subfield thickness
  • the CST of the eye to which the insert is administered does not increase over baseline for a certain period of time, where the period of time is measured from the day the ocular drug delivery insert is administered.
  • CST does not increase more than 100 ⁇ m, more than 75 ⁇ m, more than 50 ⁇ m, more than 25 ⁇ m, or more than 15 u ⁇ m during the period.
  • the period of time may be at least 90 days, at least 180 days, at least 270 days, or at least 365 days.
  • there is no detectable choroidal neovascularization in the eye to which the insert is administered for a certain period of time where the period of time is measured from the day the ocular drug delivery insert is administered.
  • the eye to which the insert was administered does not progress to an AMD category higher than the eye was at baseline for a certain period of time.
  • the period of time may be at least 90 days, at least 180 days, at least 270 days, or at least 365 days.
  • “baseline” can be evaluated just prior to administration of the first ocular drug delivery insert, such as on day 0 (treatment day) or on one of the seven days prior to the day of administration (days -7 to -1).
  • the ocular drug delivery insert is administered to an eye in which CST is less than 500 ⁇ m, 400 ⁇ m, 350 ⁇ m, 300 ⁇ m, 250 ⁇ m, or 200 ⁇ m at baseline.
  • the ocular drug delivery insert is administered to an eye in which CST is 500 ⁇ m or less, 400 ⁇ m or less, 350 ⁇ m or less, 300 ⁇ m or less, 250 ⁇ m or less, or 200 ⁇ m or less at baseline.
  • the ocular drug delivery insert is administered to an eye in which CST is less than 500 ⁇ m, 400 ⁇ m, 350 ⁇ m, 300 ⁇ m, 250 ⁇ m, or 200 ⁇ m on the day of administration. In some embodiments, the ocular drug delivery insert is administered to an eye in which the CST is 500 ⁇ m or less, 400 ⁇ m or less, 350 ⁇ m or less, 300 ⁇ m or less, 250 ⁇ m or less, or 200 ⁇ m or less on the day of administration.
  • the eye is evaluated for evidence of AMD (e.g., drusen, BCVA, CST, or neovascularization) at baseline and then at one or more timepoints, such as at 30 days, 60 days, 90 days, 120 days, 150 days, 180 days, 210 days, 270 days, 300 days, 330 days, and/or 365 days after administration, with administration occurring on day 0.
  • the eye may also be evaluated at additional timepoints.
  • the term “preventing”, when used in relation to a condition refers to administration of a drug to prevent the onset of or delay the onset of the ocular condition in a subject relative to a subject who does not receive the drug.
  • slow the progression of a particular ocular condition means to prevent the worsening of that condition in a subject relative to a subject at the same stage of disease who does not receive the drug.
  • treatment means to diminish, ameliorate, or stabilize the existing unwanted condition. 6.
  • the invention also provides a method of treating a posterior ocular condition in an eye in need thereof, comprising, at a first timepoint, administering to the eye an agent that inhibits activation of VEGF receptors, such as a VEGF ligand, VEGF inhibitor or anti-VEGF (an induction treatment), and, at a second timepoint, administering to the eye an ocular drug delivery insert comprising vorolanib or a pharmaceutically acceptable salt thereof (a maintenance treatment) to maintain the induction treatment.
  • an agent that inhibits activation of VEGF receptors such as a VEGF ligand, VEGF inhibitor or anti-VEGF
  • the posterior ocular condition is selected from wet AMD, diabetic retinopathy (DR), macular edema following retinal vein occlusion (RVO), and diabetic macular edema (DME).
  • the posterior ocular condition is Neovascular Age-related Macular Degeneration.
  • the first and second timepoints are suitably on different days.
  • 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, suitably at least 1 week, at least 2 week, at least 4 weeks, at least 8 weeks, or at least 24 weeks, after the first time point.
  • the agent used for induction treatment is any standard of care VEGF inhibitor (also sometimes referred to as an anti-VEGF).
  • the agent is a VEGF inhibitor selected from ranibizumab, bevacizumab, and aflibercept.
  • the VEGF inhibitor is administered by injection, e.g., by intravitreal injection.
  • the VEGF inhibitor is aflibercept injection for intravitreal use.
  • 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).
  • the dose of aflibercept is about 2 mg or 2 mg (0.05 mL) administered by intravitreal injection once every 4 weeks (approximately every 25 days, monthly).
  • 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) via intravitreal injection once every 8 weeks (2 months).
  • aflibercept is administered every 4 weeks (monthly) dosing after the first 20 weeks (5 months).
  • the VEGF inhibitor is administered to the eye once per month, until the eye is dry or until no further visual or anatomical improvement is seen over baseline.
  • the eye can then be assessed periodically, e.g., once every 2, 3, 4, 5, 6, 7 or 8 weeks. If fluid recurs, the VEGF inhibitor is administered again to the eye, and assessment continues.
  • the treatment interval for the VEGF inhibitor can be extended from once monthly (once every 4 weeks or 28 days), to once every 5 weeks or once every 6 weeks. If the eye remains fluid free for a given interval, the period over which the eye remains fluid free is assigned as the treatment interval for the VEGF inhibitor (e.g., treatment once every 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 weeks).
  • the ocular drug delivery insert administered at the second timepoint comprises a solid matrix core comprising a matrix polymer and vorolanib or a pharmaceutically acceptable salt thereof, wherein the amount of the vorolanib or pharmaceutically acceptable salt thereof in the insert is about 10% w/w to about 98% w/w, wherein the drug release rate for the insert is about 0.01 ⁇ g/day to about 100 ⁇ g/day for at least 14 days and wherein the insert is capable of at least 20% erosion within 95 days.
  • the first dose of the ocular drug delivery insert is a loading dose, and later doses are maintenance doses, as described herein.
  • the invention provides a method that may be described as “a treat to maintain therapy” for posterior ocular conditions. In a majority of eyes, this treatment may result in a less intensive treatment regimen than treatment with a VEGF inhibitor alone and may keep the majority of eyes visually and anatomically stable for six months or longer.
  • the eye is treated with one or more supplemental administrations of the VEGF inhibitor, after one or more doses of the ocular drug delivery insert have been administered.
  • the VEGF inhibitor is administered to an eye being treated concurrently with an ocular insert of the invention.
  • concurrent treatment means that the eye to which a VEGF inhibitor is administered contains an ocular insert that is still releasing vorolanib.
  • the VEGF inhibitor is administered before the first dose of the ocular drug delivery insert is administered as a loading dose, as described herein.
  • the first dose of the ocular drug delivery insert is administered to the eye that has been treated with VEGF inhibitor 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.
  • the first dose of the ocular drug delivery insert is administered to the eye that has previously responded to at least 2, 3, 4, 5, 6, 7, or 8 intravitreal injections of a VEGF inhibitor.
  • the supplemental treatment is administered after administration of the ocular drug delivery insert loading dose described herein, e.g., while the loading dose ocular drug delivery insert is present in the eye.
  • the supplemental treatment is administered after administration of the ocular drug delivery insert maintenance dose described herein, e.g., while the maintenance dose ocular drug delivery insert is present in the eye.
  • aflibercept is administered as an induction treatment, as described herein, on day 1, on week 4, and on week 8.
  • the first dose of the ocular drug delivery insert is administered to the eye that has previously received an induction treatment on day 1, on week 4, and on week 8, 30 minutes after the induction treatment on week 8.
  • the supplemental treatment of aflibercept is administered to the eye that has previously received an induction treatment of aflibercept on day 1, on week 4, and on week 8 and received the first dose of the ocular drug delivery insert 30 minutes after the induction treatment on week 8.
  • the supplemental treatment of aflibercept is administered to the eye on week 12, wherein there is BCVA reduction of ⁇ 5 letters from best on study measurement due to wet AMD and increase in CST of ⁇ 75 microns on SD-OCT from lowest on study measurement, BCVA reduction of ⁇ 10 letters from best on study measurement due to wet AMD, increase in CST of ⁇ 100 microns on SD-OCT from lowest on study measurement from two consecutive visits, or presence of new or worsening vision-threatening hemorrhage due to wet AMD.
  • the first ocular drug delivery insert is administered to an eye in which CST is less than 500 ⁇ m, 400 ⁇ m, 350 ⁇ m, 300 ⁇ m, 250 ⁇ m, or 200 ⁇ m. In some embodiments, the ocular drug delivery insert is administered to an eye in which CST is less than 500 ⁇ m, 400 ⁇ m, 350 ⁇ m, 300 ⁇ m, 250 ⁇ m, or 200 ⁇ m. 7. Administering the ocular drug delivery insert [00313] Administering the insert may comprise inserting the insert into an eye of a subject, such as inserting the insert into the aqueous humor or, preferably, into the vitreous humor of an eye.
  • Administering the insert may comprise surgically implanting the insert into or onto an eye, such as a scleral implant, subconjunctival implant, suprachoroidal implant, suprascleral implant, or intravitreal implant.
  • the insert can be surgically implanted into an eye of the subject, for example, into the vitreous of an eye, under the retina, or onto the sclera.
  • the insert may be placed by injection through a needle or cannula. The insert can gradually release an API in the eye, thus avoiding painful frequent administrations of the drug.
  • the insert is injected into an eye of the subject, preferably without requiring an incision.
  • the insert is injected into the vitreous of an eye.
  • administering the insert comprises intravitreal injection.
  • a needle or cannula having a gauge size of 20-27 is used for the injection.
  • a needle or cannula having a gauge size of 25 to 27 is used for the injection.
  • a needle smaller than 25 gauge is used for the injection, e.g., a needle with a gauge of 25.5, 26, 26.5 or 27.
  • a topical and/or subconjunctival anesthesia may be administered at the injection site.
  • a broad-spectrum microbicide may be administered into the lower fornix.
  • the insert may be place inferior to the optic disc and posterior to the equator of the eye.
  • the conjunctiva may be displaced so that after withdrawing the needle, the conjunctival and scleral needle entry sites will not align.
  • the needle used to inject the insert may be inserted through the conjunctiva and sclera up to the positive stop of the applicator, and the plunger depressed to deliver the insert into the back of the eye.
  • an (one or more) insert is administered once every 90 days to 270 days, once every 90 days 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.
  • the ocular drug delivery insert is administered to an eye of a subject. In certain embodiments, the subject is a mammal. In further embodiments, the subject is a human.
  • the total dose of vorolanib delivered is about 0.0001 ⁇ g/day to about 200 ⁇ g/day, about 0.0001 ⁇ g/day to about 150 ⁇ g/day, about 0.0001 ⁇ g/day to about 100 ⁇ g/day, about 0.0001 ⁇ g/day to about 80 ⁇ g/day, about 0.0001 ⁇ g/day to about 50 ⁇ g/day, about 0.0001 ⁇ g/day to about 30 ⁇ g/day, about 0.0001 ⁇ g/day to about 10 ⁇ g/day, about 0.0001 ⁇ g/day to about 5 ⁇ g/day, about 0.0001 ⁇ g/day to about 1 ⁇ g/day, about 0.001 ⁇ g/day to about 200 ⁇ g/day, about 0.001 ⁇ g/day to about 150 ⁇ g/day, about 0.001 ⁇ g/day to about 100 ⁇ g/day, about 0.001 ⁇ g/day to about 80 ⁇ g
  • this is the release rate after steady-state release is achieved. In some embodiments, this is the release rate after 2 days, 3 days, 5 days, 8 days, 10 days, 15 days, 20 days, 25 days, 30 days, 40 days, 50 days, 60 days, 70 days, 80 days, 90 days, 100 days, 105 days or 110 days of drug release.
  • This dose may be achieved by administering, e.g., 1-6 inserts at one time, i.e., for a single treatment in one eye.
  • one treatment may require administering 1 insert, 2 inserts, 3 inserts, 4 inserts, 5 inserts, or 6 inserts at one time per eye of a subject.
  • a subject may receive treatment of only one eye, or of both eyes.
  • the inserts may be injected individually in separate injections, or a few inserts may be injected in one injection. For example, 1, 2 or 3 inserts may be injected in a single injection. Where more than 3 inserts are to be injected for a single treatment, they may be divided into a few injections. For example, if 4-6 inserts are to be injected for a single treatment, they may be divided to be administered in 2 or 3 injections of 2-3 inserts/injection.
  • Each insert may comprise about 1 ⁇ g to about 3000 ⁇ g, about 1 ⁇ g to about 1000 ⁇ g, about 1 ⁇ g to about 500 ⁇ g, about 10 ⁇ g to about 2000 ⁇ g, about 10 ⁇ g to about 1000 ⁇ g, about 100 ⁇ g to about 500 ⁇ g, about 10 ⁇ g to about 800 ⁇ g, about 50 ⁇ g to about 600 ⁇ g, about 200 ⁇ g to about 2000 ⁇ g, about 600 ⁇ g to about 2000 ⁇ g, about 800 ⁇ g to about 2000 ⁇ g, about 800 ⁇ g to about 1500 ⁇ g, about 100 ⁇ g to about 500 ⁇ g, about 100 ⁇ g to about 300 ⁇ g, or about 300 ⁇ g to about 550 ⁇ g of vorolanib.
  • each insert may comprise about 400 ⁇ g, about 420 ⁇ g, about 440 ⁇ g, about 480 ⁇ g, about 500 ⁇ g, about 520 ⁇ g, about 540 ⁇ g, about 560 ⁇ g, about 580 ⁇ g, about 600 ⁇ g, about 620 ⁇ g, about 640 ⁇ g, about 660 ⁇ g, about 680 ⁇ g, about 700 ⁇ g, about 720 ⁇ g, about 740 ⁇ g, about 780 ⁇ g, about 800 ⁇ g, about 820 ⁇ g ⁇ about 840 ⁇ g, about 860 ⁇ g, about 880 ⁇ g, about 900 ⁇ g, about 920 ⁇ g, about 940 ⁇ g, about 960 ⁇ g, about 980 ⁇ g, about 1000 ⁇ g, about 1020 ⁇ g, about 1040 ⁇ g, about 1045 ⁇ g, about 1060 ⁇ g, about 1080 ⁇ g, or about 2000 ⁇ g of API, e.g.,
  • the total amount of vorolanib in all of the inserts together may be about 50 ⁇ g to about 1000 ⁇ g, about 200 ⁇ g to about 6000 ⁇ g, about 600 ⁇ g to about 6000 ⁇ g, about 800 ⁇ g to about 6000 ⁇ g, about 600 ⁇ g to about 5040 ⁇ g, about 600 ⁇ g to about 4500 ⁇ g, about 1000 ⁇ g to about 5400 ⁇ g, about 1000 ⁇ g to about 3000 ⁇ g, or about 2000 ⁇ g to about 4000 ⁇ g.
  • the total API amount for all inserts may be about 1400 ⁇ g, about 1420 ⁇ g, about 1500 ⁇ g, about 1600 ⁇ g, about 1800 ⁇ g, about 1900 ⁇ g, about 1980 ⁇ g, about 2000 ⁇ g, about 2040 ⁇ g, about 2080 ⁇ g, about 3000 ⁇ g, about 3120 ⁇ g, about 3180 ⁇ g, about 3240 ⁇ g, about 3400 ⁇ g, about 3600 ⁇ g, about 3800 ⁇ g, about 4000 ⁇ g, about 4140 ⁇ g, about 4160 ⁇ g, about 4180 ⁇ g, about 4200 ⁇ g, about 4400 ⁇ g, about 4600 ⁇ g, about 5000 ⁇ g, or about 5040 ⁇ g. 8.
  • a matrix polymer means one or more matrix polymers.
  • bioerode refers to the gradual disintegration, dissolution, or breakdown of the insert over a period of time in a biological system, e.g., by one or more physical or chemical degradative processes, for example, enzymatic action, hydrolysis, ion exchange, or dissolution by solubilization, emulsion formation, or micelle formation.
  • room temperature means 22 oC.
  • Solid at room temperature means that solid at a temperature of 22oC.
  • the term “substantially all” as used herein refers to most of the total amount, e.g., at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% of a total amount.
  • % w/w means the proportion of a particular substance within a mixture, as measured by weight or mass.
  • the total weight of inactive ingredients in the core is at least about 8% of the total weight of the core. For example, if the total core weight is 100 mg, the inactive ingredients in this core would weigh at least 8 mg.
  • % w/v means the percent of weight of ingredient (such as a solute) in the total volume of solution.
  • a 2% w/v PVA solution would mean 2 grams of PVA in 100 mL of solution.
  • a 2% w/w PVA solution would mean 2 grams of PVA for 100 mg of solution.
  • Inserts were made according to the parameters in the following table: [00342] Inserts were manufactured by mixing vorolanib with a solution of 78,000/98% PVA in water in the w/w vorolanib:PVA solution ratio specified in the tables above. The mixture was then extruded from a 20, 21 or 23-gauge dispensing tip and dried at room temperature. [00343] For inserts that were coated, the extrudate was then dip-coated in a 78,000/98% PVA solution and air dried. The process of dip-coating was repeated to achieve the number of coatings specified in the table above.
  • the coating process involved dipping the extrudates in the PVA solution with 5 min room temperature drying between the first layers and then at least 10 min of drying time before dipping to form the last layer/coat.
  • the coated extrudates were then cured as described in the table. After cooling to ambient temperature, the extrudates were cut into 2 mm, 3.5 mm, 5 mm or 6 mm or 8mm long inserts.
  • Example 2B [00344] 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 PBS is added to the tube. The tube was incubated in a water bath at 37°C. Samples of the release medium were taken at 12 to 24 hour intervals, and the release medium was replaced with fresh PBS.
  • Example 2C [00345] Samples of the inserts were assayed for API content. The inserts tested for content were cut into 4 pieces and all 4 pieces were placed in a labeled scintillation vial. 3.0 mL of methanol was pipetted into the vial, and the vial was placed under a cabinet. This procedure was repeated for all samples. The sample vials were placed in a sonicator, an appropriate amount of water was added, and the samples were sonicated for 30 minutes.
  • Photographs of eroded Formulation A inserts taken after immersion in dissolution medium for 314 and 447 days is shown in Figure 5. An intact insert is included in the 447 day photograph for comparison. Photographs of eroded Uncoated Formulation A inserts taken after immersion in dissolution medium for 287 and 352 days is shown in Figure 7. An intact insert is included in the 352 day photograph for comparison.
  • Drug release rate curves for a coated 4.5% PVA formulation cured at 140°C for 30 minutes, referred to as Formulation B are shown in Figures 8 (cumulative % drug release) and 8B (cumulative drug release ( ⁇ g)). Photographs of eroded Formulation B inserts taken after immersion in dissolution medium for 59, 88 and 155 days are shown in Figure 9.
  • Formulation C The drug release rate curve for an uncured coated 4.5% PVA formulation, referred to as Formulation C, is shown in Figure 10. Two photographs each showing a different sample of an eroded Formulation C insert taken after immersion in dissolution medium for 98 days at 37 oC then 113 days at room temperature are shown in Figure 11. [00350] A comparison of the drug release curves for Formulations A, B and C is shown in Figure 12. [00351] Formulation A releases drug more slowly and erodes more slowly than Formulations B and C. Formulation C releases drug more quickly and erodes more quickly than Formulations A and B.
  • Inserts comprising more than one grade of PVA were made according to the parameters in the following table: [00353] Inserts were manufactured by mixing vorolanib with a solution of PVA in water in a 1:1 w/w vorolanib:PVA solution ratio to form a paste. The mixture was then extruded from a 21 gauge dispensing tip to form approximately 4-5 inch long rods and dried at room temperature. The extrudate rods were cured as described in the table above. [00354] The extrudates were dip-coated in a solution of PVA in water and allowed to dry at room temperature.
  • the coating process involved dipping the extrudates in the PVA solution with 5 min room temperature drying between the first layers and then at least 10 min of drying time before dipping to form the last layer/coat.
  • the coated rods were cured according to the conditions described in the table above. After cooling to ambient temperature, the coated rods were cut into 8 mm long inserts using a razor blade.
  • API release was measured according to the method described in Example 2B.
  • API content was measured according to the method described in Example 2C.
  • Insert erosion was evaluated according to the method described in Example 2D.
  • Inserts comprising more than one grade of PVA are made according to the parameters in the following tables: [00360] Inserts are manufactured by mixing vorolanib with a solution of PVA in water in a 1:1 w/w vorolanib:PVA solution ratio to form a paste. The mixture is then extruded from a 21 gauge dispensing tip to form approximately 4-5 inch long rods and dried at room temperature. The extrudate rods are cured as described in the tables above. [00361] The extrudates are dip-coated in a solution of PVA in water and allowed to dry at room temperature.
  • the coating process involves dipping the extrudates in the PVA solution with 5 min room temperature drying between the first layers and then at least 10 min of drying time before dipping to form the last layer/coat.
  • the coated rods are cured according to the conditions described in the table above. After cooling to ambient temperature, the coated rods are cut into 8 mm long inserts using a razor blade.
  • API release is measured according to the method described in Example 2B.
  • API content is measured according to the method described in Example 2C.
  • Insert erosion is evaluated according to the method described in Example 2D.
  • Example 4 [00366] Inserts are made according to the parameters in the following tables:
  • the API is mixed with a solution of PVA in water 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 approximately 4-5 inch long rods and dried at room temperature.
  • the extrudate rods are cured before or after coating as described in the tables above.
  • the extrudates are dip-coated in a solution of PVA in water.
  • the coating process involves dipping the extrudates in the PVA solution with 5 min room temperature drying between the first layers and then at least 10 min of drying time before dipping to form the last layer/coat. After the last coat, the coated rods either cured according to the tables above or allowed to dry for 24 hours at room temperature.
  • Example 5A-Pharmacokinetics Study An Intravitreal Pharmacokinetic Study was performed in Male Dutch Belted Rabbits. The objective of this study was to characterize the plasma and ocular tissue pharmacokinetics of a vorolanib insert following bilateral intravitreal injection on Day 1. Animals were evaluated up to 24 months following placement of the intravitreal insert.
  • Figure 13A depicts average amount of drug remaining in an insert versus time for inserts explanted at various time points and assayed to determine the amount of vorolanib remaining in the insert.
  • Figure 13B depicts cumulative percent of drug released versus time for explanted inserts.
  • Example 5B-Pharmacokinetics Study [00379] Another Intravitreal Pharmacokinetic Study was performed in Dutch Belted Rabbits. The objective of this study was to evaluate the plasma and ocular pharmacokinetics of a vorolanib insert following bilateral intravitreal injection in rabbit eyes. Animals were evaluated up to 12 months following placement of the intravitreal insert. [00380] Dutch Belted rabbits were administered vorolanib inserts in each eye by intravitreal injection.
  • Group 1 eyes received 1 insert containing 643 ⁇ g of vorolanib
  • Group 2 eyes received 2 inserts containing 900 ⁇ g total.
  • Blood samples were collected at 2, 7, 14, and 28 days and then once monthly for months 2-12. Inserts were recovered at 2, 7, and 14 days and then at 1, 2, 4, 6, 8, 10, and 12 months.
  • Residual vorolanib levels were determined in all explants using high-performance liquid chromatography. The vorolanib release rate was estimated based on residual levels in the explants. Plasma and ocular tissues were separated and analyzed for vorolanib and its metabolite using liquid chromatography–mass spectrometry.
  • a vorolanib insert demonstrated sustained and consistent zero-order release of vorolanib in rabbit eyes through 8 months followed by a rapid decrease through 10 months.
  • a vorolanib insert is being studied in phase 2 clinical trials in wAMD and diabetic retinopathy, and a trial in diabetic macular edema is planned.
  • Example 6-Toxicology and Pharmacokinetics Study [00383] An 18 month intravitreal toxicity study for the insert was also performed in 80 Dutch Belted rabbits (40 male and 40 female). Animals were evaluated for a period of 6 and 18 months following placement of intravitreal inserts.
  • the objective was to characterize the ocular toxicity, plasma pharmacokinetics and biodegradation of a vorolanib insert following bilateral intravitreal injection.
  • the tables below describe the group assignments and dose levels.
  • animals were sacrificed at 6 months and 18 months.
  • plasma pharmacokinetic analysis blood samples were collected at Days 1, 3, and 7 and then 1, 2, 3, 4, 5, 6, 12, 14, 16 and 18 Months.
  • vorolanib inserts measuring 0.37 mm in diameter by 3.5 mm in length designed to release drug for at least 6 months were injected, using an injector, intravitreally into each eye of each Dutch-belted rabbit.
  • the placebo group (1) animals received two placebo inserts by injection in each eye.
  • the low dose group (2) animals received 2 inserts in each eye.
  • the mid dose group (3) animals received 3 inserts in each eye given in 2 separate injections.
  • the high dose group (4) animals received 4 inserts in each eye given in 2 separate injections (2 inserts/injection).
  • the highest dose group (5) animals received 6 inserts in each eye given in 2 separate injections (3 inserts/injection).
  • whole blood was collected via puncture of a marginal ear vein. Samples were analyzed for clinical pathology and plasma pharmacokinetics. Animals were euthanized according to the schedules described above. A complete gross necropsy was performed on all animals that were sacrificed or found dead during the study. Organs were weighed and tissues collected. Ocular tissues were collected for histopathology only.
  • ERGs were elicited by brief flashes at 0.33 Hz delivered with a mini-ganzfeld photostimulator at maximal intensity. Twenty responses were amplified, filtered, and averaged for each animal. Animals underwent standard ERG measurements as dictated by ISCEV standards, including scotopic (0.01 candela), scotopic (3 candela), and photopic (25 candela) measurements. [00401] At time points indicated by the experimental design table, following final data collections, animals were euthanized. Histology was evaluated for eyes from Groups 5-6. [00402] Results: Overall, dose-related efficacy was found and there was no clinically observed toxicity.
  • Eyes undergoing histological examinations displayed some inflammation, which may have been more severe in animals dosed with high dose inserts. The implant procedure may have contributed to the increased inflammation observed in the high dose group.
  • the inserts of the invention were able to deliver safe and therapeutically effective steady state levels of vorolanib locally over a sustained period, while resulting in only negligible systemic levels of vorolanib.
  • the inserts are fully bioerodible.
  • the inserts appear to have a preventative effect on lesion growth.
  • Example 8 DAVIO, A Phase 1, Multicenter, Prospective, Open-Label, Dose Escalation Study of EYP-1901, a Tyrosine Kinase Inhibitor (TKI) Ocular Drug Delivery Insert, in Subjects with wet AMD
  • TKI Tyrosine Kinase Inhibitor
  • the subjects in this study had diagnosed wet AMD in the study eye for at least 4 months prior to the screening visit.
  • subjects had to have received at least 3 previous injections with an anti-VEGF product in the study eye, such as bevacizumab (Avastin ® , Genentech), ranibizumab, (Lucentis ® , Genentech), or aflibercept (Eylea ® , Regeneron) during the previous 6 months and a BCVA between 25 letters (20/320 Snellen equivalent) and 75 letters (20/32 Snellen equivalent).
  • an anti-VEGF product such as bevacizumab (Avastin ® , Genentech), ranibizumab, (Lucentis ® , Genentech), or aflibercept (Eylea ® , Regeneron) during the previous 6 months and a BCVA between 25 letters (20/320 Snellen equivalent) and 75 letters (20/32 Snellen equivalent).
  • the affected eye was designated as the study eye; for subjects with bilateral wAMD, the study eye was the more severely affected eye meeting the inclusion/exclusion criteria, i.e., the eye having the worse BCVA or if equal, the eye clinically judged to be the more severely affected eye as determined by the Investigator. If the eyes are symmetrically affected, the study eye was the right eye.
  • One week after screening and a standard-of-care anti-VEGF injection the subjects received 1 injection of the study drug, an ocular drug delivery insert containing vorolanib and PVA. The study included 4 dosing cohorts: low dose, low medium dose, mid dose, and high- dose.
  • a 25-gauge needle was used for the low dose injection and a 22-gauge needle was used for the other injections.
  • the duration of release of the active pharmaceutical ingredient (vorolanib) is expected to be at least 9 months. There was no reinjection of the study drug during the first 6 months of the trial. [00413] Following injection on Study Day 0, subjects were to return on Study Days 7, 14, 28, and every 4 weeks thereafter through Month 12.
  • Assessments include BCVA by ETDRS, anterior/posterior segment ocular 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 sign measurements (see details in attached Schedule of Study Procedures and Assessments), spectral-domain – optical coherence tomography (SD- OCT), and, at study sites where equipment is available, OCT-Angiography (OCT-A).
  • IOP anterior/posterior segment ocular examination
  • FTP fluorescein angiography
  • CFP color fundus photography
  • TEAEs treatment-emergent ocular and non-ocular adverse events
  • SD- OCT spectral-domain – optical coherence tomography
  • OCT-A OCT-Angiography
  • the primary study endpoint is to evaluate safety and determine the maximum tolerated dose for the treatment of neovascular (wet) AMD based on treatment -emergent ocular (study and fellow eye) and non-ocular adverse events (TEAEs), including clinical laboratory findings; the secondary endpoints include BCVA and CST measured by OCT.
  • the investigators are also evaluating the number of eyes that do not require rescue treatment (also referred to as supplemental treatment) at various time points and the degree to which the anti-VEGF treatment burden is reduced after administration of EYP-1901.
  • an 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: • Presence of new or worsening vision-threatening hemorrhage due to wet AMD from baseline (Day 0) OR • Increase in CST of >75 ⁇ m from baseline (Day 0) OR • Loss of ⁇ 10 ETDRS letters from baseline (Day 0) with intra-/sub-retinal fluid and/or hemorrhage judged to be the cause of BCVA loss.
  • BCVA visual acuity
  • CST central subfield thickness
  • the overall treatment burden was reduced by 79% at 6 months across all cohorts, and 8 out of 17 subjects remain supplemental-free with one subject supplemental-free up to 9 months.
  • the average change in BCVA from the screening visit is shown in a graph in Figure 15.
  • the average change in CST from the screening visit is shown in a graph in Figure 16.
  • the supplemental-free rate for each visit is shown in a graph in Figure 17.
  • Example 9 Simulation of repeat dosing regimens for treatment of a condition of the eye.
  • a correlation experiment was first performed in which the cumulate release from three (3) and six (6) inserts was measured in vivo (in vitreous) in an animal model, and the compared with release measured in vitro (test tube).
  • FIG.18A shows cumulate release of three inserts (210 ⁇ g each, total of 630 ⁇ g of drug), demonstrating a very close correlation between the in vivo data (large dots and best fit line) and in vitro data (small dots and best fit line). As indicated, both provided a slope of 0.002.
  • FIG.18B shows cumulate release of six inserts (total of 1260 ⁇ g of drug), again demonstrating a very close correlation between the in vivo data (large dots and best fit line) and in vitro data (small dots and best fit line). As indicated, the in vitro data had a slope of 0.0018 and the in vivo data a slope of 0.0019. [00419] Based on this finding, in vitro data was then used to generate a number of models where release rates could be simulated, and the effect of repeat dosing examined. FIGS.19A-25 show various simulations, demonstrating that repeat dosing at various intervals maintains the desired release rate and release amount of drug from the ocular drug delivery inserts.
  • FIG.19A is a simulation (based on in vitro release) for Formula A of repeat injection every 6 months with 2 insert loading dose.
  • FIG.19B is a simulation (based on in vitro release) for Formula A of repeat injection every 6 months without 2 insert loading dose.
  • FIG.20 is a simulation (based on in vitro release) for Formula B4 of repeat injection every 6 months with 2 insert loading dose.
  • FIG.21 is a simulation (based on in vitro release) for Formula E60 of repeat injection every 6 months.
  • FIG.22 is a simulation (based on in vitro release) for Formula E60 of repeat injection every 6 months following loading with 2 inserts at T0.
  • FIG.23 is a simulation (based on in vitro release) for Formula E4 of repeat injection every 6 months following loading with 2 inserts at T0.
  • FIG.24 is a simulation (based on in vitro release) for Formula E4 of repeat injection every 6 months following loading with 1 insert at T0 and 1 insert at week 1.
  • FIG.25 is a simulation (based on in vitro release) for Formula E4 of repeat injection every 6 months following loading with 1 insert at T0 and 1 insert at 2 months.
  • Example 10 In Vivo Drug Release Rates and Model [00428] A study was performed in Male Dutch Belted Rabbits.
  • Fig.26A is a graph of a simulation plotting the amount of vorolanib remaining (residual drug) in a single 8 mm Formulation A explant (implant removed from an eye) versus the day on which the implant was explanted. Day 0 is the date on which the implant was injected.
  • Fig.26B is a graph of a simulation plotting the amount of vorolanib remaining (residual drug) in a single 8 mm Formulation B30 explant (implant removed from an eye) versus the day on which the implant was explanted. Day 0 is the date on which the implant was injected.
  • Fig.26C is a graph of a simulation plotting the amount of vorolanib remaining (residual drug) in a single 8 mm Formulation C explant (implant removed from an eye) versus the day on which the implant was explanted. Day 0 is the date on which the implant was injected.
  • Fig.27A is a graph of a simulation plotting the release rate ( ⁇ g vorolanib/day) over time for a single 8 mm Formulation A explant.
  • Fig.27B is a graph of a simulation plotting the release rate ( ⁇ g vorolanib/day) over time for a single 8 mm Formulation B30 explant.
  • Fig.27C is a graph of a simulation plotting the release rate ( ⁇ g vorolanib/day) over time for a single 8 mm Formulation C explant.
  • Fig.28A is a graph of a simulation plotting the residual vorolanib versus the day on which the implant is explanted for Formulation A for a loading dose of 2 implants on day 0 and a maintenance dose of 1 implant administered every 120 days.
  • Fig.28B is a graph of a simulation plotting the residual vorolanib versus the day on which the implant is explanted for Formulation B30 for a loading dose of 2 implants on day 0 and a maintenance dose of 1 implant administered every 120 days.
  • Fig.28C is a graph of a simulation plotting the residual vorolanib versus the day on which the implant is explanted for Formulation C for a loading dose of 2 implants on day 0 and a maintenance dose of 1 implant administered every 120 days.
  • Fig.29A is a graph of a simulation plotting the release rate ( ⁇ g vorolanib/day) over time for Formulation A for a loading dose of 2 implants on day 0 and a maintenance dose of 1 insert administered every 120 days. Release rates are shown as cumulative release rates.
  • Fig.29B is a graph of a simulation plotting the release rate ( ⁇ g vorolanib/day) over time for Formulation B30 for a loading dose of 2 implants on day 0 and a maintenance dose of 1 insert administered every 120 days. Release rates are shown as cumulative release rates.
  • Fig.29C is a graph of a simulation plotting the release rate ( ⁇ g vorolanib/day) over time for Formulation C for a loading dose of 2 implants on day 0 and a maintenance dose of 1 insert administered every 120 days. Release rates are shown as cumulative release rates.
  • Fig.30A is a graph of a simulation plotting the residual vorolanib versus the day on which the implant is explanted for Formulation A for a loading dose of 1 implant and a maintenance dose of 1 implant administered every 120 days.
  • Fig.30B is a graph of a simulation plotting the residual vorolanib versus the day on which the implant is explanted for Formulation B30 for a loading dose of 1 implant and a maintenance dose of 1 implant administered every 120 days.
  • Fig.30C is a graph of a simulation plotting the residual vorolanib versus the day on which the implant is explanted for Formulation C for a loading dose of 1 implant and a maintenance dose of 1 implant administered every 120 days.
  • Fig.31A is a graph of a simulation plotting the release rate ( ⁇ g vorolanib/day) over time for Formulation A for a loading dose of 1 implant on day 0 and a maintenance dose of 1 insert administered every 120 days. Release rates are shown as cumulative release rates.
  • Fig.31B is a graph of a simulation plotting the release rate ( ⁇ g vorolanib/day) over time for Formulation B30 for a loading dose of 1 implant on day 0 and a maintenance dose of 1 insert administered every 120 days. Release rates are shown as cumulative release rates.
  • Fig.31C is a graph of a simulation plotting the release rate ( ⁇ g vorolanib/day) over time for Formulation C for a loading dose of 1 implant on day 0 and a maintenance dose of 1 insert administered every 120 days. Release rates are shown as cumulative release rates.
  • Fig.32A is a graph of a simulation plotting the residual vorolanib versus the day on which the implant is explanted for Formulation A for a loading dose of 2 implants on day 0 and a maintenance dose of 1 implant administered every 180 days.
  • Fig.32B is a graph of a simulation plotting the residual vorolanib versus the day on which the implant is explanted for Formulation B30 for a loading dose of 2 implants on day 0 and a maintenance dose of 1 implant administered every 180 days.
  • Fig.32C is a graph of a simulation plotting the residual vorolanib versus the day on which the implant is explanted for Formulation C for a loading dose of 2 implants on day 0 and a maintenance dose of 1 implant administered every 180 days.
  • Fig.33A is a graph of a simulation plotting the residual vorolanib versus the day on which the implant is explanted for Formulation A for a loading dose of 2 implants on day 0 and a maintenance dose of 1 implant administered every 240 days.
  • Fig.33B is a graph of a simulation plotting the residual vorolanib versus the day on which the implant is explanted for Formulation B30 for a loading dose of 2 implants on day 0 and a maintenance dose of 1 implant administered every 240 days.
  • Fig.33C is a graph of a simulation plotting the residual vorolanib versus the day on which the implant is explanted for Formulation C for a loading dose of 2 implants on day 0 and a maintenance dose of 1 implant administered every 240 days.

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JP2024553782A JP2025507154A (ja) 2022-03-11 2023-03-10 眼の状態の治療を目的とした連続投薬レジメン
IL315333A IL315333A (en) 2022-03-11 2023-03-10 A continuous dosing regimen to treat the condition of the eye
US18/843,571 US20250186398A1 (en) 2022-03-11 2023-03-10 Continuous dosing regimen for treatment of a condition of the eye
KR1020247033492A KR20240156416A (ko) 2022-03-11 2023-03-10 눈의 병태 치료를 위한 지속적 투여 요법
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CA3245209A CA3245209A1 (en) 2022-03-11 2023-03-10 CONTINUOUS DOSAGE REGIMEN FOR THE TREATMENT OF AN EYE CONDITION
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