Drug delivery to the posterior eye segment

Abstract

The present invention relates to means and methods to non-invasive ocular drug delivery technologies, particularly aimed at delivering pharmaceutically active ingredients (APIs) to the posterior segment of the eye.

Description

[0001] DRUG DELIVERY TO THE POSTERIOR EYE SEGMENT

[0002] RELATED APPLICATION / S

[0003] This application claims the benefit of priority of U.S. Provisional Patent Application No. 63 / 713,704 filed on 30 October 2024, the contents of which are incorporated herein by reference in their entirety.

[0004] FIELD AND BACKGROUND OF THE INVENTION

[0005] The present invention, in some embodiments thereof, relates to means and methods to non- invasive ocular drug delivery technologies, particularly aimed at delivering pharmaceutically active ingredients (APIs) to the posterior segment of the eye. The terms “drug” and “API” are used herein interchangeably. As used herein, “non-invasive” means not penetrating the surface of the eye. Examples of non-invasive drug delivery technologies include eyedrops, drug eluting contact lenses, conjunctival inserts, and other means for delivering drugs that may touch the eye surface but do not penetrate it.

[0006] Conditions such as diabetic macular edema, cystoid macular edema, retinal vein occlusion, and age-related macular degeneration represent considerable therapeutic challenges due to their location in the posterior segment of the eye, which complicates effective medication delivery.

[0007] Existing technologies face substantial drawbacks, primarily centered around the invasive nature of current treatments. Intravitreal injections, while effective at delivering drugs directly to the posterior segment, pose risks including infection, retinal detachment, and patient discomfort. Additionally, repeated injections may be required to maintain therapeutic drug levels, leading to increased cumulative risk and patient burden.

[0008] The prior art also includes topical ophthalmic solutions and systemic administration, both of which exhibit poor bioavailability at the posterior segment due to the eye's anatomical barriers including the cornea, conjunctiva, sclera, and blood-retinal barrier.

[0009] Additional background art includes an article by Ross A. et al; titled “Topical sustained drug delivery to the retina with a drug-eluting contact lens” (Biomaterials 217 (2019) 119285), disclosing contact lens-based dexamethasone delivery system (Dex-DS) that achieved sustained drug delivery to the retina at therapeutic levels. Dex-DS consists of a dexamethasone-polymer film encapsulated inside a contact lens.

[0010] An article by Gabai, A. et al; titled “Innovative Strategies for Drug Delivery to the Ocular Posterior Segment” (Pharmaceutics 2023, 15, 1862. www(dot)doi(dot)org / 10.3390 / pharmaceuticsl5071862), disclosing drug delivery systems (DDSs) to vehicle treatments and drugs to the ocular posterior segment and the retina.

[0011] An article by Ldscher M, et al; titled: “Topical Drug Delivery to the Posterior Segment of the Eye.” (Pharmaceutics. 2022 Jan 6; 14(1): 134. doi: 10.3390 / pharmaceutics 14010134. PMID: 35057030; PMCID: PMC8779621.), disclosing drug characteristics for delivering topical drug to the posterior segment of the eye.

[0012] An article by Samoila, L.; et al; titled “Topical Treatment for Retinal Degenerative Pathologies: A Systematic Review.” (Int. J. Mol. Sci. 2023, 24, 8045. www(dot)doi(dot)org / 10.3390 / ijms24098045), disclosing a systematic review of the scientific literature in recent years, focusing on the latest developments of topical treatment intended for retinal degenerative diseases.

[0013] International Patent Application Publication No. W02007012974A2 disclosing an ophthalmic composition which is an aqueous suspension comprising drug, cyclodextrin and water, the composition having an aqueous phase of from about 0.1% (w / v) to about 90% (w / v) of the drug in solution, as dissolved free drug and as dissolved drug / cyclodextrin complex(es), and a solid phase of from about 10% (w / v) to about 99.9% (w / v) of the drug as solid drug / cyclodextrin particles, suspended in the aqueous phase; the size of the solid particles being from about 10 nm to about 1 mm, the drug / cyclodextrin particles being capable of dissolving in aqueous tear fluid within 24 hours of application to the eye surface. The aqueous eye suspension can be in the form of eye drops, eye gel or eye mist. Nasal compositions and ophthalmic and nasal compositions in powder form are also disclosed.

[0014] International Patent Application Publication No. W02018100434A1 disclosing ophthalmic compositions containing solid complexes of active pharmaceutical ingredient and cyclodextrin, to their method of preparation and their uses. The compositions can include an active agent drug / cyclodextrin complex substantially dissolved in an aqueous eye drop vehicle. The ophthalmic composition is generally in the form of a microsuspension including an active agent complex having a diameter of less than about 100 pm.

[0015] International Patent Application Publication No. W02021001366A1 disclosing a method for stabilizing the pH of an aqueous composition comprising a drug which is prone to oxidation, the method comprising the addition of an additive to prevent oxidation of the drug which is prone to oxidation. In particular, the present disclosure relates to a method for stabilizing the pH of an aqueous composition comprising a corticosteroid, the method comprising the addition of an additive to prevent oxidation of the corticosteroid. The present disclosure also relates to a composition comprising a corticosteroid and an additive to prevent oxidation of the corticosteroid. U.S. patent No. US7767223B2 disclosing methods for reducing or preventing transplant rejection in the eye of an individual are described, comprising: a) performing an ocular transplant procedure; and b) implanting in the eye a bioerodible drug delivery system comprising an immunosuppressive agent and a bioerodible polymer.

[0016] International Patent Application Publication No. W02004062649A2 disclosing biodegradable implants sized for implantation in an ocular region and methods for treating medical conditions of the eye. The implants are formed from a mixture of hydrophilic end and hydrophobic end PLGA, and deliver active agents into an ocular region without a high burst release.

[0017] U.S. patent No. US3960150A disclosing an ocular insert for the continuous controlled administration of a predetermined therapeutically effective dosage of drug to the eye over a prolonged period of time. The device meters the flow of drug by means of a drug release rate controlling material. The insert bioerodes in the environment of the eye concurrently with the dispensing or at a point in time after the dispensing of the therapeutically desired amount of drug.

[0018] Applicants’ earlier patent applications published as WO2021 / 214761, W02023 / 073706, W02023 / 073707, WO2024224394, and WO2024224395 described ophthalmic drug delivery devices for insertion under the eyelid.

[0019] SUMMARY OF THE INVENTION

[0020] Following is a non-exclusive list including some examples of embodiments of the invention. The invention also includes embodiments which include fewer than all the features in an example and embodiments using features from multiple examples, also if not expressly listed below.

[0021] Example 1. A method for delivering a pharmaceutically active ingredient (API) to the posterior segment of an eye, comprising: a. placing an elastomeric matrix with API on a bulbar conjunctiva under an eyelid; b. allowing said API to be released from said elastomeric matrix composition to the bulbar conjunctiva.

[0022] Example 2. The method according to example 1, wherein the elastomeric matrix comprises dispersed or suspended particles of said API within said matrix.

[0023] Example 3. The method according to example 1 or example 2, wherein said allowing comprises allowing for at least one hour.

[0024] Example 4. The method according to any one of examples 1-3, wherein said elastomeric matrix comprises at least 30% by weight of ophthalmic demulcents. Example 5. The method according to any one of examples 1-4, wherein the API comprises particles having a size range of 0.01 to 20 micrometers.

[0025] Example 6. The method according to any one of examples 1-5, wherein a solubility of the API in water at 25 °C and neutral pH is less than Img / ml,

[0026] Example 7. The method according to any one of examples 1-6, wherein a solubility of the API in water at 25°C and neutral pH is between 0.05 mg / ml and 0.5 mg / ml.

[0027] Example 8. The method according to any one of examples 1-7, wherein the API comprises a steroid selected from the group consisting of dexamethasone and fluocinolone acetonide.

[0028] Example 9. The method according to any one of examples 1-8, wherein the API comprises one or more of: Dexamethasone, Triamcinolone acetonide, Fluocinolone acetonide, Difluprednate, Pazopanib, Regorafenib, Axitinib, Sunitinib, or PAN-90806.

[0029] Example 10. The method according to any one of examples 1-9, wherein the API comprises one or more of: Bevacizumab, Ranibizumab, Aflibercept, Brolucizumab, Faricimab, Pegaptanib, Conbercept, Prednisolone sodium phosphate, FluoromethoIone, Sirolimus (Rapamycin), Squalamine lactate, Isopropyl unoprostone, Nepafenac, Lifitegrast, Volociximab, Abicipar pegol, Risuteganib, Nesvategrast, Eplerenone, Acrizanib, OTT166 (SF0166).

[0030] Example 11. The method according to any one of examples 1-10, wherein the elastomeric matrix does not comprise cyclodextrins and / or other non-plasticizing solubilizing agents.

[0031] Example 12. The method according to any one of claims 1-11, wherein the elastomeric matrix is free of native cyclodextrins.

[0032] Example 13. The method according to any one of examples 1-12, wherein the ophthalmic demulcents include polyvinyl alcohol (PVOH).

[0033] Example 14. The method according to any one of examples 1-13, further comprising maintaining the API in the tear fluid for at least 6 hours after the placing.

[0034] Example 15. The method according to any one of examples 1-14, wherein a peak concentration of the API is observed in the tear fluid at 6 hours after the placing.

[0035] Example 16. The method according to any one of examples 1-15, wherein a peak concentration of the API is observed in the tear fluid at 1 hour after the placing.

[0036] Example 17. The method according to any one of examples 1-16, wherein the elastomeric matrix remains stable after exposure to tear fluid.

[0037] Example 18. The method according to any one of claims 1-17, wherein the elastomeric matrix retains structural integrity for at least 2 hours in simulated tear fluid. Example 19. The method according to any one of examples 1-18, wherein the placing is at a frequency lower than three times daily.

[0038] Example 20. The method according to any one of examples 1-19, wherein the insert has a shape with an ascent greater than 45°.

[0039] Example 21. The method according to any one of examples 1-20, wherein the elastomeric matrix is according to any one of examples 62-78.

[0040] Example 22. The method according to any one of examples 1-21, wherein the API is water insoluble or very slightly water soluble.

[0041] Example 23. The method according to any one of examples 1-22, wherein the API has water solubility of less than Ig / L at 25 °C and neutral pH.

[0042] Example 24. The method according to any one of examples 1-23, wherein the API has a molecular weight of less than 1000 Da and a log P value between 1 and 5.

[0043] Example 25. The method according to any one of examples 1-24, wherein the API has a scleral permeability coefficient of at least 1 x 107cm / s.

[0044] Example 26. The method according to any one of examples 1-25, wherein the API comprises particles having a size from 0.01 micrometer to 20 micrometers.

[0045] Example 27. The method according to any one of examples 1-26, wherein the API is selected from the group consisting of fluocinolone acetonide, triamcinolone acetonide, difluprednate, regorafenib, pazopanib, axitinib, sunitinib, PAN-90806, and dexamethasone.

[0046] Example 28. The method according to any one of examples 1-27, wherein the posterior segment condition is selected from diabetic macular edema, posterior uveitis, age-related macular degeneration, geographic atrophy or retinal vein occlusion.

[0047] Example 29. The method according to any one of examples 1-28, wherein the treatment is initiated in a subject diagnosed with a posterior segment condition in a mild form characterized by one or more of: (a) CMT < 300 pm on OCT using the device’s normative database; (b) BCVA > 20 / 40; (c) no intraretinal or subretinal fluid on OCT; (d) no choroidal neovascular membrane on OCT-A or fluorescein angiography; or (e) SUN vitreous haze < 1+.

[0048] Example 30. The method according to any one of examples 1-29, wherein the elastomeric matrix is placed and retained under the eyelid by the subject without clinical assistance.

[0049] Example 31. The method according to any one of examples 1-30, wherein the elastomeric matrix comprises two types of PVOH that differ in chain length and / or degree of hydrolysis.

[0050] Example 32. The method according to any one of examples 1-31, wherein the two types are LCFH and SCPH. Example 33. The method according to any one of examples 1-32, wherein a ratio between the two types is about 1: 1.

[0051] Example 34. The method according to any one of examples 1-33, wherein the matrix is substantially free of cyclodextrin.

[0052] Example 35. The method according to any one of examples 1-34, wherein the matrix is substantially free of API non-plasticizing solubilizing agents.

[0053] Example 36. The method according to any one of examples 1-35, wherein the matrix comprises API non-plasticizing solubilizing agents.

[0054] Example 37. The method according to any one of examples 1-36, wherein the eye is permitted to blink normally during use of the insert.

[0055] Example 38. The method according to any one of examples 1-37, wherein placing the elastomeric matrix on the bulbar conjunctiva is in a manner allowing the eye to blink normally during the release of the API from the matrix.

[0056] Example 39. The method according to any one of examples 1-38, further comprising blinking normally with the eyelid during the release of the API from the matrix.

[0057] Example 40. The method according to any one of examples 1-39, wherein the lower eyelid completely covers the insert.

[0058] Example 41. The method according to any one of examples 1-40, wherein the elastomeric matrix has tensile strength of between 0.01 MPa and 2 MPa, Young’s modulus of between 0.01 MPa and 2 MPa, elongation at break of between 100% and 1000%, or any combination thereof.

[0059] Example 42. A method for delivering a pharmaceutically active ingredient (API) to the posterior segment of an eye, comprising: a. placing an elastomeric matrix comprising micrometric solid API particles on a bulbar conjunctiva under an eyelid; and b. allowing the API particles to dissolve in tear fluid on the bulbar conjunctiva for a period of at least 4 hours.

[0060] Example 43. An insert for use in the treatment of a condition of the posterior segment of an eye, comprising an elastomeric matrix comprising dispersed or suspended particles of an API suitable for treating the condition, the insert being sized and shaped to be placed on a bulbar conjunctiva under an eyelid.

[0061] Example 44. The insert according to example 43, wherein the elastomeric matrix comprises at least 30% by weight of ophthalmic demulcents.

[0062] Example 45. The insert according to example 43 or example 44, wherein the API particles have a size range of 0.01 to 20 micrometers. Example 46. The insert according to any one of examples 43-45, wherein the elastomeric matrix comprises polyvinyl alcohol (PVOH) and one or more plasticizers.

[0063] Example 47. The insert according to any one of examples 43-46, wherein the combined mass ratio of the plasticizers to PVOH is at least 2:1, and the total weight of PVOH and plasticizers is at least 70% by weight of the elastomeric matrix, excluding water.

[0064] Example 48. The insert according to any one of examples 43-47, wherein the matrix comprises one or more mucoadhesive materials.

[0065] Example 49. The insert according to any one of examples 43-48, wherein the matrix is substantially free of cyclodextrins.

[0066] Example 50. The insert according to any one of examples 43-49, wherein the mechanical properties of the elastomeric matrix include a tensile strength ranging from 0.05 to 2 MPa and an elongation at break between 100% to 900%.

[0067] Example 51. The insert according to any one of examples 43-50, wherein the API is insoluble in water.

[0068] Example 52. The insert according to any one of examples 43-51, wherein the API comprises a water solubility at 25°C of less than Ig / L.

[0069] Example 53. The insert according to any one of examples 43-52, wherein the API comprises particles having a size from 0.01 micrometer to 20 micrometers.

[0070] Example 54. The insert according to any one of examples 43-53, wherein the elastomeric matrix comprises two types of PVOH that differ in chain length and / or degree of hydrolysis.

[0071] Example 55. The insert according to any one of examples 43-54, wherein the two types being LCFH and SCPH.

[0072] Example 56. The insert according to any one of examples 43-55, wherein a ratio between the two types is about 1: 1.

[0073] Example 57. The insert according to any one of examples 43-56, wherein the matrix is substantially free of cyclodextrin.

[0074] Example 58. The insert according to any one of examples 43-57, wherein the matrix is substantially free of non-plasticizing solubilizing agents.

[0075] Example 59. The insert according to any one of examples 43-58, wherein the matrix comprises API non-plasticizing solubilizing agents.

[0076] Example 60. The insert according to any one of examples 43-59, wherein the lower eyelid completely covers the insert. Example 61. The insert according to any one of examples 43-60, wherein the elastomeric matrix has tensile strength of between 0.01 MPa and 2 MPa, Young’s modulus of between 0.01 MPa and 2 MPa, elongation at break of between 100% and 1000%, or any combination thereof.

[0077] Example 62. An ophthalmic composition for delivering a pharmaceutically active ingredient (API) to the posterior segment of an eye, comprising: an elastomeric matrix comprising dispersed or suspended particles of the API within the composition; wherein the elastomeric matrix comprises at least 30% by weight of ophthalmic demulcents; and wherein the API particles have a size range of 0.01 to 20 micrometers; and wherein the elastomeric matrix composition comprises polyvinyl alcohol (PVOH).

[0078] Example 63. The ophthalmic composition according to example 62, wherein at least 90% of the API particles have diameters of 10 microns or less.

[0079] Example 64. The ophthalmic composition according to example 62 or example 63, wherein at least 50% of the API particles have diameters of 5 microns or less.

[0080] Example 65. The ophthalmic composition according to any one of examples 62-64, wherein a mass of the demulcents makes at least 50% of the mass of the composition.

[0081] Example 66. The ophthalmic composition according to any one of examples 62-65, wherein the ophthalmic demulcents include PVOH, glycerin and polyethylene glycol.

[0082] Example 67. The ophthalmic composition according to any one of examples 62-66, wherein a mass of the PVOH is less than half the mass of all the other demulcents in the composition together.

[0083] Example 68. The ophthalmic composition according to any one of examples 62-67, wherein the API is water insoluble.

[0084] Example 69. The ophthalmic composition according to any one of examples 62-68, wherein the API comprises a water solubility at 25°C of less than Ig / L.

[0085] Example 70. The ophthalmic composition according to any one of examples 62-69, wherein the API comprises particles having a size from 0.01 micrometer to 20 micrometers.

[0086] Example 71. The ophthalmic composition according to any one of examples 62-70, wherein the elastomeric matrix comprises two types of PVOH that differ in chain length and / or degree of hydrolysis.

[0087] Example 72. The ophthalmic composition according to any one of examples 62-71, wherein the two types are LCFH and SCPH. Example 73. The ophthalmic composition according to any one of examples 62-72, wherein a ratio between the two types is about 1: 1.

[0088] Example 74. The ophthalmic composition according to any one of examples 62-73, wherein the matrix is substantially free of cyclodextrin.

[0089] Example 75. The ophthalmic composition according to any one of examples 62-74, wherein the matrix is substantially free of API non-plasticizing solubilizing agents.

[0090] Example 76. The ophthalmic composition according to any one of examples 62-75, wherein the matrix comprises API non-plasticizing solubilizing agents.

[0091] Example 77. The ophthalmic composition according to any one of examples 62-76 when formed as an insert, wherein the lower eyelid completely covers the insert.

[0092] Example 78. The ophthalmic composition according to any one of examples 62-77, wherein the elastomeric matrix has tensile strength of between 0.01 MPa and 2 MPa, Young’s modulus of between 0.01 MPa and 2 MPa, elongation at break of between 100% and 1000%, or any combination thereof.

[0093] Example 79. A method for delivering a pharmaceutically active ingredient (API) to the posterior segment of an eye, comprising: a. placing an elastomeric matrix under an eyelid; wherein particles of the API are dispersed or suspended within the elastomeric matrix; b. allowing the API to be released from the elastomeric matrix into a conjunctival sac of the eye.

[0094] Example 80. A method of local non-invasive delivery of a pharmaceutically active ingredient (API) to the posterior segment of an eye, the method comprising topically applying an elastomeric matrix on a bulbar conjunctiva under an eyelid of the eye; wherein the elastomeric matrix comprises particles of the API.

[0095] Example 81. The method according to example 80, wherein the particles are suspended in a suspending medium that contains at least 30% w / w ophthalmic demulcents.

[0096] Example 82. The method according to example 80 or example 81, further comprising maintaining the matrix in the eye for a period of between 1 hour and 1 week.

[0097] Example 83. A method of treating a condition of the posterior segment of the eye, the method comprising: a. suspending or dispersing in an elastomeric matrix micrometric particles of a pharmaceutically active ingredient (API) suitable for treating the condition; the elastomeric matrix comprising at least 50% ophthalmic demulcents other than water; wherein the elastomeric matrix is configured to lengthen a drug availability of the API after administration; b. administering the elastomeric matrix comprising the API on a bulbar conjunctiva in the conjunctival sac of an eye affected by the condition.

[0098] Example 84. A method of delivering a pharmaceutically active ingredient (API) to a posterior segment of the eye, comprising: a. administering an elastomeric matrix to a bulbar conjunctiva in the conjunctival sac of an eye affected by a condition treatable by the delivering; wherein the elastomeric matrix is formulated to lengthen the drug availability of the API at the anterior surface of the eye by being composed of at least 50% ophthalmic demulcents other than water dispersing therein micrometric particles of the API; and b. utilizing the lengthened drug availability of the drug at the anterior segment of the eye to facilitate targeted delivery of the drug to the posterior segment of the eye, thereby delivering the drug to the posterior segment of the eye.

[0099] Example 85. A method of treating a condition of the posterior segment of the eye, the method comprising: a. generating in the tear fluid of the eye a drug concentration of at least 10 pg / ml for a continuous period of at least 1 hour, preferably at least 2 hours, the drug being suitable for treating the condition, wherein the generating comprises: i. placing on a bulbar conjunctiva under the eyelid of the eye an ocular insert comprising the drug at a concentration of at least 1% w / w, and ii. keeping the ocular insert under the eyelid for at least 2 hours, preferably at least 4 hours.

[0100] Example 86. A method of delivering a drug to the posterior segment of an eye, comprising: a. providing a supply of the drug to a bulbar conjunctiva in the conjunctival sac of the eye; and b. maintaining the supply of the drug to the bulbar conjunctiva in the conjunctival sac for a drug supply period of at least 1 hour.

[0101] Example 87. A method of treating a condition of the posterior segment of an eye, comprising delivering a drug to the posterior segment of the eye in a method according to any one of the methods claimed herein.

[0102] Example 88. The method according to example 87, wherein the condition is selected from the group consisting of diabetic macular edema, cystoid macular edema, age related macular degeneration, diabetic retinopathy, geographic atrophy, retinitis pigmentosa, chronic central serous.

[0103] Example 89. The method according to example 87 or example 88, wherein the drug is dexamethasone.

[0104] Example 90. A method of delivering a drug to the posterior segment of the eye, the method comprising: delivering the drug in the trans-scleral route without using any penetration enhancer, nor an injection.

[0105] Example 91. A drug product sized and shaped so that when inserted into the cul-de-sac the drug product contacts the lower bulbar conjunctiva across a contact area larger than 25mm2, optionally from 25mm2 to 50mm2.

[0106] Example 92. The drug product according to example 91, wherein the API is water insoluble or very slightly soluble in water at 25 °C and neutral pH.

[0107] Example 93. The drug product according to example 91 or example 92, wherein the API comprises particles having a size from 0.01 micrometer to 20 micrometers.

[0108] Example 94. The drug product according to any one of examples 91-93, wherein the elastomeric matrix comprises two types of PVOH that differ in chain length and / or degree of hydrolysis.

[0109] Example 95. The drug product according to any one of examples 91-94, wherein the two types being LCFH and SCPH.

[0110] Example 96. The drug product according to any one of examples 91-95, wherein a ratio between the two types is about 1: 1.

[0111] Example 97. The drug product according to any one of examples 91-96, wherein the matrix is substantially free of cyclodextrin.

[0112] Example 98. The drug product according to any one of examples 91-97, wherein the matrix is substantially free of API non-plasticizing solubilizing agents.

[0113] Example 99. The drug product according to any one of examples 91-98, wherein the matrix comprises API non-plasticizing solubilizing agents.

[0114] Example 100. The drug product according to any one of examples 91-99, wherein the lower eyelid completely covers the insert.

[0115] Example 101. A method of treating an eye inflicted by one or more of the following conditions: diabetic macular edema, cystoid macular edema, age related macular degeneration, diabetic retinopathy, geographic atrophy, retinitis pigmentosa, chronic central serous chorioretinopathy, the method comprising: a. placing an elastomeric matrix on a bulbar conjunctiva under an eyelid of the eye; wherein the elastomeric matrix comprises dispersed or suspended micrometric particles of the API within the composition; b. allowing the API to be released from the elastomeric matrix into the bulbar conjunctiva in a conjunctival sac of the eye.

[0116] Example 102. The method according to example 101, wherein the API is water insoluble or very slightly water soluble.

[0117] Example 103. The method according to example 101 or example 102, wherein the API has water solubility of less than Ig / L at 25 °C and neutral pH.

[0118] Example 104. The method according to any one of examples 101-103, wherein the API comprises particles having a size from 0.01 micrometer to 20 micrometers.

[0119] Example 105. The method according to any one of examples 101-104, wherein the elastomeric matrix comprises two types of PVOH that differ in chain length and / or degree of hydrolysis.

[0120] Example 106. The method according to any one of examples 101-105, wherein the two types being LCFH and SCPH.

[0121] Example 107. The method according to any one of examples 101-106, wherein a ratio between the two types is about 1: 1.

[0122] Example 108. The method according to any one of examples 101-407, wherein the matrix is substantially free of cyclodextrin.

[0123] Example 109. The method according to any one of examples 101-108, wherein the matrix is substantially free of API non-plasticizing solubilizing agents.

[0124] Example 110. The method according to any one of examples 101-109, wherein the matrix comprises API non-plasticizing solubilizing agents.

[0125] Example 111. The method according to any one of examples 101-110, wherein the eye is allowed to blink.

[0126] Example 112. The method according to any one of examples 101-111, wherein the lower eyelid completely covers the insert.

[0127] Example 113. The method according to any one of examples 101-112, wherein the elastomeric matrix has tensile strength of between 0.01 MPa and 2 MPa,

[0128] Young’s modulus of between 0.01 MPa and 2 MPa, elongation at break of between 100% and 1000%, or any combination thereof. Example 114. A method of treating a condition of the posterior segment of an eye, comprising: a. placing an elastomeric matrix under an eyelid of the eye; wherein micrometric particles of an API suitable for treating the condition are dispersed or suspended within the elastomeric matrix; and b. allowing the elastomeric matrix to stay in the eye until the API concentration in the tear fluid of the eye is higher than 20nmol / ml for at least 1 hour.

[0129] Example 115. The method according to example 114, wherein the allowing is until the API concentration in the tear fluid of the eye is higher than 20nmol / ml for at least 4 hours.

[0130] Example 116. The method according to example 114 or example 115, wherein the allowing is until the API concentration in the tear fluid of the eye is higher than 40nmol / ml for at least 1 hour.

[0131] Example 117. The method according to any one of examples 114-116, wherein the allowing is until the API concentration in the tear fluid of the eye is higher than 40nmol / ml for at least 4 hours.

[0132] Example 118. A method of treating a condition of the posterior segment of an eye, comprising: a. placing an elastomeric matrix under an eyelid of the eye; wherein micrometric particles of an API for treating the condition are dispersed or suspended within the elastomeric matrix; and b. allowing the elastomeric matrix to stay in the eye until the API concentration in the tear fluid of the eye is higher than lOpg / ml for at least 1 hour.

[0133] Example 119. The method according to example 118, wherein the allowing is until the API concentration in the tear fluid of the eye is higher than lOpg / ml for at least 4 hours.

[0134] Example 120. The method according to example 118 or example 119, wherein the allowing is until the API concentration in the tear fluid of the eye is higher than 20pg / ml for at least 1 hour.

[0135] Example 121. The method according to any one of examples 118-120, wherein the allowing is until the API concentration in the tear fluid of the eye is higher than 20pg / ml for at least 4 hours.

[0136] Example 122. The method according to any one of examples 118-121, wherein the API is dexamethasone.

[0137] Example 123. A method of delivering a drug to the posterior segment of an eye, the method comprising: contacting a portion of an elastomeric matrix with the bulbar conjunctiva of the eye and maintaining the contact for a time period of at least 10 minutes, optionally 30 min, optionally 1 hour, optionally 2 hours; wherein the matrix comprises microparticles of the drug dispersed in an elastic dispersing medium; the drug being effective in treating a condition of the posterior eye segment; and the contacting and maintaining are together effective in delivering the drug to the posterior segment of the eye.

[0138] Example 124. A method of delivering a drug to the posterior segment of an eye, the method comprising: contacting a portion of an elastomeric matrix with the bulbar conjunctiva of the eye and maintaining the contact for a time period of at least 10 minutes, optionally 30 min, optionally 1 hour, optionally 2 hours; wherein the matrix comprises the drug, water, one or more polymers with hydrogen bondforming repeating units, and one or more plasticizers other than water in a combined mass at least double the combined mass of the one or more polymers; the drug being effective in treating a condition of the posterior eye segment, and the contacting and maintaining are together effective in delivering the drug to the posterior segment of the eye.

[0139] Example 125. A method of delivering a drug to the posterior segment of an eye, the method comprising: contacting a portion of an elastomeric matrix with the bulbar conjunctiva of the eye and maintaining the contact for a time period of at least 10 minutes, optionally 30 min, optionally 1 hour, optionally 2 hours; wherein the matrix comprises the drug, water, one or more polymers with hydrogen bond-forming repeating units, and one or more plasticizers other than water in a combined mass at least double the combined mass of the one or more polymers; the drug being effective in treating a condition of the posterior eye segment, and the contacting and maintaining are together effective in delivering the drug to the posterior segment of the eye.

[0140] Example 126. A method of delivering a drug to the posterior segment of an eye, the method comprising: contacting a portion of an elastomeric matrix with the bulbar conjunctiva of the eye and maintaining the contact for a time period of at least two hours; wherein volume of the matrix increases by no more than 100% after being immersed in water for 15 minutes at 25°C, and a dog-bone shaped flat piece of elastomer made of the same composition as the elastomeric matrix, except for not including the drug, elongates by at least 100% without breaking when pulled at a rate of 40mm / min; the drug being effective in treating a condition of the posterior eye segment; and the contacting and maintaining are together effective in delivering the drug to the posterior segment of the eye.

[0141] Example 127. A method of delivering a drug to the posterior segment of an eye, the method comprising: contacting a portion of an elastomeric matrix with the bulbar conjunctiva under an eyelid of the eye and maintaining the contact for a time period of at least 2 hours; wherein the matrix comprises the drug and configured to stay under the eyelid when the eyeball moves in relation to the eyelid, the drug being effective in treating a condition of the posterior eye segment, and the contacting and maintaining are together effective in delivering the drug to the posterior segment of the eye.

[0142] Example 128. A method for delivering a pharmaceutically active ingredient (API) to the posterior segment of an eye via a trans-scleral route, comprising: a. placing an elastomeric matrix with API on a bulbar conjunctiva under an eyelid; b. allowing the API to be released from the elastomeric matrix composition to the bulbar conjunctiva.

[0143] Example 129. A method for delivering a pharmaceutically active ingredient (API) to the posterior segment of an eye, comprising: a. placing an elastomeric matrix with API on a bulbar conjunctiva under an eyelid; b. allowing the API to be released from the elastomeric matrix composition to the bulbar conjunctiva and reach the posterior segment of an eye via a trans-scleral route.

[0144] Example 130. The method, insert, ophthalmic composition, drug product according to any of the preceding examples, wherein the matrix is a porous matrix.

[0145] Example 131. A composition for use in the treatment of a disease of the posterior segment of the eye, the composition comprising an elastomeric matrix containing a pharmaceutically active ingredient (API), and adapted to be placed on a bulbar conjunctiva under an eyelid and to release the API to the bulbar conjunctiva.

[0146] Example 132. The composition for use according to example 131, wherein the posterior segment disease is diabetic macular edema, posterior uveitis, age-related macular degeneration, geographic atrophy, or retinal vein occlusion. Example 133. The composition for use according to example 131 or 132, wherein the API is dexamethasone.

[0147] Example 134. The composition for use according to any one of examples 131-133, wherein the API is selected from the group consisting of fluocinolone acetonide, triamcinolone acetonide, difluprednate, regorafenib, pazopanib, axitinib, sunitinib, and PAN-90806.

[0148] Example 135. The composition for use according to any one of examples 131-134, wherein the API has a molecular weight of less than 1000 Da and a log P value between 1 and 5.

[0149] Example 136. The composition for use according to any one of examples 131-135, wherein the elastomeric matrix comprises a film-forming polymer, a plasticizer, and water. Example 137. The composition for use according to any one of examples 131-136, wherein the composition is indicated for early intervention in patients diagnosed with a mild form of a posterior segment condition, characterized by one or more of (a) CMT < 300 pm on OCT using the device’s normative database; (b) BCVA > 20 / 40; (c) no intraretinal or subretinal fluid on OCT; (d) no choroidal neovascular membrane on OCT-A or fluorescein angiography; or (e) SUN vitreous haze < 1+.

[0150] Example 138. A method of treating a posterior segment condition of the eye in a human subject, comprising topically applying to the bulbar conjunctiva under the eyelid an ophthalmic composition comprising an elastomeric matrix that releases a pharmaceutically active ingredient, wherein the condition is at an early stage of disease progression characterized by one or more of:

[0151] (a) a central macular thickness (CMT) less than about 300 pm on optical coherence tomography (OCT), relative to the device’s normative database;

[0152] (b) a best-corrected visual acuity (BCVA) of 20 / 40 or better;

[0153] (c) absence of intraretinal or subretinal fluid on OCT;

[0154] (d) absence of a choroidal neovascular membrane as assessed by OCT angiography (OCT- A) or fluorescein angiography; or

[0155] (e) vitreous haze graded as < 1+ on the Standardization of Uveitis Nomenclature (SUN) scale.

[0156] Example 139. The method according to example 138, wherein the condition is diabetic macular edema, and the early- stage condition is characterized by: (a) leakage on fluorescein angiography graded as mild according to Early Treatment Diabetic Retinopathy Study (ETDRS) or equivalent clinical guidelines.

[0157] (b) central macular thickness (CMT) less than 300 pm as measured by optical coherence tomography (OCT) using the device’s normative database; and

[0158] (c) visual acuity of 20 / 40 or better. Example 140. The method according to any one of examples 138-139, wherein the condition is early-stage retinal vein occlusion characterized by: (a) mild cystoid changes on OCT without center-involving macular edema; (b) a central macular thickness (CMT) less than 300 pm on OCT relative to the device’s normative database; and (c) best corrected visual acuity of 20 / 40 or better.

[0159] Example 141. The method according to any one of examples 138-140, wherein the condition is early-stage non-infectious posterior uveitis characterized by: (a) mild vitreous haze or cells graded as <1+ on the Standardization of Uveitis Nomenclature (SUN) scale; (b) absence of macular edema on OCT; and c) inflammation limited to a level that is controllable with local corticosteroids.

[0160] Example 142. The method according to any one of examples 438-141, wherein the condition is early-stage geographic atrophy, characterized by: (a) one or more small, well- demarcated atrophic lesions not involving the foveal center, as confirmed by fundus autofluorescence (FAF) or near-infrared imaging; and (b) absence of choroidal neovascularization as confirmed by optical coherence tomography angiography (OCT-A) or fluorescein angiography.

[0161] Example 143. The method according to any one of examples 138-142, wherein the API is selected from the group consisting of: corticosteroids (e.g. dexamethasone, triamcinolone acetonide, fluocinolone acetonide); anti-VEGF agents (e.g. ranibizumab, aflibercept, bevacizumab); nonsteroidal anti-inflammatory agents (e.g. nepafenac, bromfenac).

[0162] Example 144. The method according to any one of examples 138-143, wherein the API is selected from the group consisting of: complement inhibitors (e.g. pegcetacoplan, avacincaptad pegol); anti-inflammatory agents (e.g. corticosteroids); neuroprotective agents (e.g. brimonidine).

[0163] Example 145. The method according to any one of examples 138-144, wherein the API is selected from the group consisting of: corticosteroids (e.g. dexamethasone); anti-VEGF agents (e.g. ranibizumab, aflibercept, bevacizumab).

[0164] Example 146. The method according to any one of examples 138-145, wherein the API is selected from the group consisting of: corticosteroids (e.g. dexamethasone, fluocinolone acetonide); immunomodulatory agents (e.g. methotrexate, cyclosporine); anti-VEGF agents (e.g. ranibizumab, aflibercept).

[0165] Example 147. The method according to any one of examples 138-146, wherein the API is selected from the group consisting of: complement inhibitors (e.g. pegcetacoplan, avacincaptad pegol); anti-VEGF agents (e.g. ranibizumab, aflibercept, bevacizumab).

[0166] Example 148. An elastomeric matrix comprising a pharmaceutically active ingredient (API) for use in delivering the API to the posterior segment of an eye by a method comprising placing the elastomeric matrix on a bulbar conjunctiva under an eyelid and allowing the API to be released from the elastomeric matrix to the bulbar conjunctiva.

[0167] Example 149. The elastomeric matrix for use according to example 148, wherein the API reaches therapeutically effective levels in at least one of the retina, choroid, or optic nerve.

[0168] Example 150. The elastomeric matrix for use according to example 148 or 149, wherein the elastomeric matrix comprises dispersed or suspended particles of the API within the matrix.

[0169] Example 151. The elastomeric matrix for use according to any one of examples 148-150, wherein the allowing comprises allowing for at least one hour.

[0170] Example 152. The elastomeric matrix for use according to any one of examples 148-151, wherein allowing the API to be released comprises allowing micrometric solid particles of the API to dissolve in tear fluid on the bulbar conjunctiva for a period of at least 4 hours.

[0171] Example 153. The elastomeric matrix for use according to any one of examples 148-152, wherein the elastomeric matrix comprises at least 30% by weight of ophthalmic demulcents.

[0172] Example 154. The elastomeric matrix for use according to any one of examples 148-153, wherein a solubility of the API in water at 25 °C and neutral pH is less than Img / ml.

[0173] Example 155. The elastomeric matrix for use according to any one of examples 148-154, wherein the API comprises one or more of: Dexamethasone, Triamcinolone acetonide, Fluocinolone acetonide, Difluprednate, Pazopanib, Regorafenib, Axitinib, Sunitinib, or PAN- 90806.

[0174] Example 156. The elastomeric matrix for use according to any one of examples 148-155, wherein the API comprises a steroid selected from the group consisting of dexamethasone and fluocinolone acetonide.

[0175] Example 157. The elastomeric matrix for use according to any one of examples 148-156, wherein the API comprises one or more of: Bevacizumab, Ranibizumab, Aflibercept, Brolucizumab, Faricimab, Pegaptanib, Conbercept, Prednisolone sodium phosphate, FluoromethoIone, Sirolimus (Rapamycin), Squalamine lactate, Isopropyl unoprostone, Nepafenac, Lifitegrast, Volociximab, Abicipar pegol, Risuteganib, Nesvategrast, Eplerenone, Acrizanib, OTT166 (SF0166).

[0176] Example 158. The elastomeric matrix for use according to any one of examples 148-157, wherein the elastomeric matrix is free of native cyclodextrins.

[0177] Example 159. The elastomeric matrix for use according to any one of examples 148-158, wherein the ophthalmic demulcents include polyvinyl alcohol (PVOH).

[0178] Example 160. The elastomeric matrix for use according to any one of examples 148-159, further comprising maintaining the API in the tear fluid for at least 6 hours after the placing. Example 161. The elastomeric matrix for use according to any one of examples 148-160, wherein a peak concentration of the API is observed in the tear fluid at 1 hour after the placing.

[0179] Example 162. The elastomeric matrix for use according to any one of examples 148-161, wherein the placing is at a frequency lower than three times daily.

[0180] Example 163. The elastomeric matrix for use according to any one of examples 148-162, wherein the elastomeric matrix is formed as an insert having a shape with an ascent greater than 45°, and the placing is with the ascent intersecting the opening of the eyelid.

[0181] Example 164. The elastomeric matrix for use according to any one of examples 148-163, wherein the API is water insoluble or very slightly water insoluble.

[0182] Example 165. The elastomeric matrix for use according to any one of examples 148-164, wherein the API has water solubility of less than Ig / L at 25°C and neutral pH.

[0183] Example 166. The elastomeric matrix for use according to any one of examples 148-165, wherein the API has a molecular weight of less than 1000 Da and a log P value between 1 and 5.

[0184] Example 167. The elastomeric matrix for use according to any one of examples 148-166, wherein the API has a scleral permeability coefficient of at least 1 x 107cm / s.

[0185] Example 168. The elastomeric matrix for use according to any one of examples 148-167, wherein the use comprises treatment of a condition of the posterior segment of an eye by a method comprising placing the elastomeric matrix on a bulbar conjunctiva under an eyelid and allowing the API to be released from the elastomeric matrix to the bulbar conjunctiva.

[0186] Example 169. The elastomeric matrix for use according to any one of examples 148-168, wherein the API is selected from the group consisting of fluocinolone acetonide, triamcinolone acetonide, difluprednate, regorafenib, pazopanib, axitinib, sunitinib, PAN-90806, and dexamethasone.

[0187] Example 170. The elastomeric matrix for use according to any one of examples 148-169, wherein the posterior segment condition is selected from diabetic macular edema, posterior uveitis, age-related macular degeneration, geographic atrophy or retinal vein occlusion.

[0188] Example 171. The elastomeric matrix for use according to any one of examples 148-170, wherein the use is for treating a subject diagnosed with a posterior segment condition in a mild form characterized by one or more of: (a) CMT < 300 pm on OCT using the device’s normative database; (b) BCVA > 20 / 40; (c) no intraretinal or subretinal fluid on OCT; (d) no choroidal neovascular membrane on OCT-A or fluorescein angiography; or (e) SUN vitreous haze < 1+.

[0189] Example 172. The elastomeric matrix for use according to any one of examples 148-171, wherein the elastomeric matrix is placed and retained under the eyelid by the subject without clinical assistance. Example 173. The elastomeric matrix for use according to any one of examples 148-172, wherein the elastomeric matrix comprises two types of PVOH that differ in chain length and / or degree of hydrolysis.

[0190] Example 174. The elastomeric matrix for use according to any one of examples 148-173, wherein the two types being long chain fully hydrolyzed (LCFH) and short chain partially hydrolyzed (SCPH).

[0191] Example 175. The elastomeric matrix for use according to any one of examples 148-174, wherein a ratio between the two types is about 1: 1.

[0192] Example 176. The elastomeric matrix for use according to any one of examples 148-175, wherein the matrix is substantially free of cyclodextrin.

[0193] Example 177. The elastomeric matrix for use according to any one of examples 148-176, wherein the matrix is substantially free of solubilizing agents.

[0194] Example 178. The elastomeric matrix for use according to any one of examples 148-177, wherein the eye is permitted to blink normally during the use of the insert.

[0195] Example 179. The elastomeric matrix for use according to any one of examples 148-178, wherein the lower eyelid completely covers the insert.

[0196] Example 180. The elastomeric matrix for use according to any one of examples 148-179, wherein the elastomeric matrix has tensile strength of between 0.01 MPa and 2 MPa, Young’s modulus of between 0.01 MPa and 2 MPa, elongation at break of between 100% and 1000%, or any combination thereof.

[0197] Example 181. The elastomeric matrix for use according to any one of examples 148-179, wherein the use is for treating diabetic macular edema at an early stage of disease progression.

[0198] Example 182. The elastomeric matrix for use according to claim 181, wherein the diabetic macular edema at an early stage of disease progression is characterized by one or more of the following criteria: (a) leakage on fluorescein angiography graded as mild according to the Early Treatment Diabetic Retinopathy Study (ETDRS) or equivalent clinical guidelines and central macular thickness (CMT) less than 300 pm as measured by optical coherence tomography (OCT) using a normative database; and (b) leakage on fluorescein angiography graded as mild according to the Early Treatment Diabetic Retinopathy Study (ETDRS) or equivalent clinical guidelines and visual acuity of 20 / 40 or better.

[0199] Example 183. The elastomeric matrix for use according to example 181, wherein the API for treating diabetic macular edema is selected from the group consisting of: corticosteroids, anti- VEGF agents, and nonsteroidal anti-inflammatory agents. Example 184. The elastomeric matrix for use according to any one of examples 148-179, wherein the use is for treating age related macular degeneration (AMD) at an early stage of disease progression.

[0200] Example 185. The elastomeric matrix for use according to example 192, wherein the AMD at an early stage of disease progression is characterized by one or more of the following criteria:

[0201] (a) small or intermediate drusen (<125 pm) with no pigment epithelial detachment or hemorrhage;

[0202] (b) absence of subretinal or intraretinal fluid confirmed by OCT; (c) absence of neovascular membrane as assessed by OCT- A or fluorescein angiography; and (d) pigment alteration of the retinal pigment epithelium with or without atrophy.

[0203] Example 186. The elastomeric matrix for use according to example 184, wherein the API for treating age related macular degeneration is selected from the group consisting of complement inhibitors, anti-inflammatory agents, neuroprotective agents.

[0204] Example 187. The elastomeric matrix for use according to any one of examples 148-179, wherein the use is for treating early-stage retinal vein occlusion.

[0205] Example 188. The elastomeric matrix for use according to example 187, wherein the early- stage retinal vein occlusion is characterized by one or both of the following criteria: (a) mild cystoid changes on OCT without center- involving macular edema and a central macular thickness (CMT) less than 300 pm on OCT relative to the device’s normative database; and (b) mild cystoid changes on OCT without center- involving macular edema and best corrected visual acuity of 20 / 40 or better.

[0206] Example 189. The elastomeric matrix for use according to example 187, wherein the API for treating early-stage retinal vein occlusion is selected from the group consisting of corticosteroids, immunomodulatory agents and anti-VEGF agents.

[0207] Example 190. The elastomeric matrix for use according to any one of examples 148-179, wherein the use is for treating early-stage non-infectious posterior uveitis.

[0208] Example 191. The elastomeric matrix for use according to example 190, wherein the early- stage non-infectious posterior uveitis is characterized by any two or more of the following criteria: (a) mild vitreous haze or cells graded as <1+ on the Standardization of Uveitis Nomenclature (SUN) scale; (b) absence of macular edema on OCT ; (c) inflammation limited to a level that is controllable with local corticosteroids; and (d) anterior segment inflammation.

[0209] Example 192. The elastomeric matrix for use according to example 190, wherein the API for treating early-stage non-infectious posterior uveitis is selected from the group consisting of complement inhibitors and anti-VEGF agents.

[0210] Example 193. The elastomeric matrix for use according to any one of examples 148-179, wherein the use is for treating geographic atrophy at an early stage of disease progression. Example 194. The elastomeric matrix for use according to example 193, wherein the geographic atrophy at an early stage of disease progression is characterized by one or more of the following criteria: (a) one or more small, well-demarcated atrophic lesions not involving the foveal center, as confirmed by fundus autofluorescence (FAF) or near-infrared imaging; and (b) absence of choroidal neovascularization as confirmed by optical coherence tomography angiography (OCT- A) or fluorescein angiography; and (c) OCT finding of atrophy at the level of the retinal pigment epithelium.

[0211] Example 195. The elastomeric matrix for use according to example 193, wherein the API for treating geographic atrophy is a complement inhibitor.

[0212] Unless otherwise defined, all technical and / or scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention pertains. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of embodiments of the invention, exemplary methods and / or materials are described below. In case of conflict, the patent specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and are not intended to be necessarily limiting.

[0213] BRIEF DESCRIPTION OF THE DRAWINGS

[0214] Some embodiments of the invention are herein described, by way of example only, with reference to the accompanying drawings. With specific reference now to the drawings in detail, it is stressed that the particulars shown are by way of example and for purposes of illustrative discussion of embodiments of the invention. In this regard, the description taken with the drawings makes apparent to those skilled in the art how embodiments of the invention may be practiced.

[0215] In the drawings:

[0216] Figures la-c are SEM images of exemplary porous matrices, according to some embodiments of the invention;

[0217] Figures 2a-e are schematic representations of positions of inserts in the eye, according to some embodiments of the invention;

[0218] Figure 3 is a flowchart of an exemplary method for delivering a pharmaceutically active ingredient (API) to the posterior segment of an eye, according to some embodiments of the invention;

[0219] Figure 4 is a flowchart of an exemplary method for treating a condition of the posterior segment of the eye, according to some embodiments of the invention; Figure 5 is a flowchart of an exemplary method for delivering a pharmaceutically active ingredient (API) to a posterior segment of the eye, according to some embodiments of the invention; and

[0220] Figure 6a-d are results of a pharmacokinetic study that investigated the delivery of dexamethasone to tissues in the eye;

[0221] Figures 7a-c are clinical results obtained from three distinct patients (Patient 1, 2 and 3);

[0222] Figures 8a-c are results of examinations performed on patients 1, 2 and 3 at the baseline, 3 weeks and 4 weeks; and

[0223] Figure 9a-b are pre-clinical results, showing the relationship between matrix weight and drug concentration.

[0224] DESCRIPTION OF SPECIFIC EMBODIMENTS OF THE INVENTION

[0225] The present invention, in some embodiments thereof, relates to means and methods to non- invasive ocular drug delivery technologies, particularly aimed at delivering pharmaceutically active ingredients (APIs) to the posterior segment of the eye.

[0226] Overview

[0227] An aspect of some embodiments of the invention relates to delivering pharmaceutically active ingredients (APIs) to the posterior segment of the eye. In some embodiments, the APIs are delivered through a hydrophilic layer. In some embodiments, the hydrophilic layer is located in the eye. In some embodiments, the hydrophilic layer is located under an eyelid. In some embodiments, the API is delivered by positioning an insert comprising the API either on top of or adjacent to the hydrophilic layer, for example by positioning the insert in a hydrophilic environment that is adjacent to the hydrophilic layer. In some embodiments, the API is released in the hydrophilic environment and then allowed to pass through the hydrophilic layer. In some embodiments, the API is released directly within the hydrophilic layer. In some embodiments, the API is water insoluble or very slightly soluble in water, for example have water solubility, at 25 °C and neutral pH, lower than O.lmg / ml or lower than Img / ml. In some embodiments, water solubility from 0.05 to 0.5 mg / ml is preferred. In some embodiments, the API is provided in a degradable insert. In some embodiments, the insert is considered degradable when its macroscopic structure degrades, even if only inter-molecular bonds are broken. Degradability may be graded according to degradation time. As used herein, a non-degradable insert or matrix can stay in the eye for days or longer. Degradable inserts or matrices stay in the eye for shorter periods, e.g., 6, 12, or 24 hours, before they degrade or erode to parts small enough to be secreted from the eye. In some embodiments, the API is provided in a non-degradable insert or an insert with a very long degradation time (weeks to months after placing in the eye).

[0228] The term “elastomeric matrix”, as used herein, refers to a crosslinked polymeric structure form that displays rubber-like elasticity and can undergo deformation under the influence of a force and regain its original shape once the force has been removed. In the context of some embodiments of the present invention, the elastomeric matrix is a form of physically crosslinked polymeric structure having an open-cell porous micro structure that can incorporate sequestered and releasable substances within its interconnected voids.

[0229] In some embodiments, the combination of water, film-forming polymer, and high concentration of plasticizer(s) in the elastomeric matrix composition enables the formation of a physically cross-linked structure (e.g., through hydrogen bonding or polymer chain entanglement) that enhances the matrix’s structural integrity and allows sustained contact with the conjunctiva.

[0230] According to some embodiments of the present invention, the elastomeric matrix is a network of hydrogen-bonded polymers and plasticizers. According to some embodiments of the present invention, the elastomeric matrix is a network of hydrogen-bonded polymers, plasticizers and water. In some embodiments, the elastomeric matrix provided herein is essentially devoid of covalent crosslinking.

[0231] In some embodiments, the insert (degradable or non-degradable) does not comprise enhancers, for example cyclodextrins or other solubilizing / enhancer agents (e.g., non-plasticizing solubilizing agents). In some embodiments, the degradable or non-degradable insert comprises at least one enhancer or other solubilizing / enhancer agents, e.g. non-plasticizing solubilizing agents. Cyclodextrin helps hydrophobic molecules to dissolve in water. According to available theory, hydrophobic molecules of appropriate size are entrapped by cyclodextrin, which is hydrophilic on the outside and hydrophobic on the inside, and the cyclodextrin-molecule complex is dissolved in the water. In some embodiments, this solubility shortens the time it takes for the API to be released from the matrix, which may be counterproductive in embodiments that seek to prolong the release. It is noted that substituted cyclodextrins are more soluble than native ones. Thus, in some embodiments, native cyclodextrin may be used to increase the solubility of the API to a limited degree. In some embodiments, mixtures of native and substituted cyclodextrins may be used.

[0232] As used herein, “non-plasticizing solubilizing agents” refers to excipients or additives that are included in the formulation primarily to enhance the aqueous solubility of the API by forming inclusion complexes, micelles, or solubilized solutions, without contributing significantly to the mechanical properties of the elastomeric matrix (e.g. flexibility, tensile strength, or film-forming characteristics). Examples of non-plasticizing solubilizing agents include, but are not limited to, cyclodextrins, surfactants, and co-solvents such as ethanol or DMSO. Excipients that have both solubilizing and plasticizing properties, such as PEG, propylene glycol, or glycerol are considered plasticizing agents.

[0233] An aspect of some embodiments of the invention relate to matrices, inserts, devices, drug products, which may be related collectively as a drug delivery platform.

[0234] Unless otherwise specified, any of the embodiments described herein may, in some embodiments, be practiced with the matrix, insert, or composition being substantially free of solubilizing agents, substantially free of non-plasticizing solubilizing agents, substantially free of cyclodextrins, or substantially free of native cyclodextrins, consistent with the definitions and descriptions provided herein.

[0235] In some embodiments, delivery of the API from the insert extends for a period of at least an hour, for example, 1, 2, 4, 6, 8, 12, or 24 hours, or even longer. In some embodiments, delivery of the API from the insert extends for a period of from about a day to about several days or weeks after placing the insert in place. In some embodiments, the release of the API is purposely delayed from the moment the insert is applied, for example, by making the insert with outer layers empty of the API. In some embodiments, a layer of wet formulation (e.g., comprising water, PVOH, and plasticizers and no API) is first cast and dried, and then, a similar layer, but with API is cast on the first, dried, and then a third layer, similar to the first is cast on the second dry layer, and dried to obtain a tri-layer structure, with API only in the middle layer, and possibly in the vicinity of an interface between an API free layer and the API-containing layer, due to some mixing between the layers. In such embodiments, the API does not release until it diffuses through the empty layer (i.e., the layer with no API). Erosion of the empty layer may shorten such a diffusion time. In some embodiments, the delay is from about an hour to about 6 hours. In some embodiments, optionally a peak release of the API from the insert is at about 1 hour after placing the insert in place, optionally after 3 hours, optionally after 6 hours. In some embodiments, peak release is kept after reaching the peak for the rest of the time that the insert is in place. In some embodiments, the peak release is reduced with time, but stays significant as to keep enabling API delivery to the posterior segment, possibly at rates lower than the peak rate. In some embodiments, API is provided without causing any adverse effect, like irritation and / or discomfort.

[0236] In some embodiments, a potential advantage of the insert is that it potentially combines the advantages of not causing foreign body feeling, is convenient in the eye, allows itself to insertion by the user / patient, does not interfere with vision, and stays under the eyelid for long periods. In some embodiments, the elastomeric matrix (insert) is placed and retained under the eyelid by the subject without clinical assistance. This may be achieved by shaping and / or formulating the insert as disclosed for example in Applicants’ patent application WO2021214761A1 and WO2024224394A1, both being incorporated herein by reference. .

[0237] In some embodiments, another potential advantage of the present invention is that the matrix / insert allows for sustained contact with the conjunctiva, preferably with the bulbar conjunctiva.

[0238] The terms “matrix”, “elastomeric matrix” and “insert” are interchangeable.

[0239] Before explaining at least one embodiment of the invention in detail, it is to be understood that the invention is not necessarily limited in its application to the details of construction and the arrangement of the components and / or methods set forth in the following description and / or illustrated in the drawings and / or the Examples. The invention is capable of other embodiments or of being practiced or carried out in various ways.

[0240] Introduction

[0241] In some embodiments, the technology disclosed herein encompasses a method of delivering pharmaceutically active ingredients (APIs) to the posterior segment of the eye through non- invasive means. In some embodiments, the technology encompasses compositions, by which such delivery may take place. In some embodiments, the technology encompasses methods of treating a condition of the posterior segment of the eye, by delivering an API to the posterior segment by the provided delivery method. In some embodiments, a primary aspect of the technology involves the topical application of an elastomeric matrix under the eyelid, where the matrix contains API particles, optionally suspended within a medium rich in ophthalmic demulcents, and particularly in non-water ophthalmic demulcents. The term “suspension” and “dispersion” (and derivatives thereof) are interchangeable. In some embodiments, the API particles are suspended in an elastic dispersing medium. As used herein, the term "elastic dispersing medium" refers to a substance that can (or does) distribute or disperse particles, droplets, or the like, while also being able to deform under stretch, and return towards its original shape once the stress is removed. In some embodiments, the elastic dispersing medium is an elastomer that allows particles to be spread throughout it while maintaining structural integrity and at least some degree of elasticity. Elastomeric matrices described in W02023073707A1 are examples of elastic dispersing mediums, for example, when they are prepared as described therein under “Example 1” in W02023073707A1, which is incorporated herein by reference. In some embodiments, the water content is smaller than 50%, for example, between 20 and 30%, while other demulcents may be present at higher concentrations. For example, in some embodiments, non-water ophthalmic demulcents make at least 30% or at least 50% of the matrix making the insert. In some embodiments, this high concentration of ophthalmic demulcents facilitates the residence of the matrix on the bulbar conjunctiva by reducing rapid washout by tear fluid. Alternatively or additionally, the high concentration of demulcents may facilitate the residence of the matrix on the bulbar conjunctiva, for example, by forming weak hydrogen bonds with mucins on the ocular surface, by increasing the local viscosity and forming a hydration shell that reduces tear clearance, or by enhancing the wetting and contact area of the matrix on the ocular surface.

[0242] As used herein, the term ‘ophthalmic composition’ encompasses compositions formed as sustained-release devices such as inserts or matrices configured for placement on the bulbar conjunctiva.

[0243] In some embodiments, the shape of the elastomeric matrix, including features such as a steep ascent from the edge towards the center (e.g., an angle larger than 45° relative to a reference surface), enhances the device’s ability to remain in place under the eyelid during blinking and eye movements. In some embodiments, the placing is with the ascent intersecting the opening of the eyelid. A potential advantage of this is that this potentially allows the eyelid to grab the device via the ascended part.

[0244] As used herein, “ascent” refers to the steepness of a retention portion at the leading edge of the ophthalmic device, the steepness defined between two points on the anterior surface of the device that are horizontally separated by at most about 1 mm and vertically different in height by at least 1 mm relative to a reference plane, for example, the posterior surface plane, the eye surface, or a flat surface, on which the device rests with the posterior surface facing the plane and adjacent to it, thereby forming an angle of 45° or greater. Such a steep ascent increases the grabbing force exerted by the eyelid edge on the device, enhancing moving of the device with the eyelid, thereby decreasing dislodgements and increasing retention beneath the eyelid.

[0245] In some embodiments, the steep ascent described above is defined by a retention portion of the insert having a vertical height difference at least equal to a horizontal distance from the edge of the body, when both the height difference and the horizontal distance are measured in a relaxed state of the insert lying on a horizontal plane.

[0246] In some embodiments, the steep ascent described above comprises posterior and anterior surfaces of the insert that join at an edge. A portion of this edge that lies nearest to an opening of the eyelid, when the insert is properly placed in the eye, is referred to as a leading edge. The body of the insert defines an imaginary central vertical cross-sectional plane that intersects the leading edge and is perpendicular to a horizontal plane on which the insert rests in a relaxed state. In some such embodiments, the steep ascent has a height difference of at least 1 mm over at most a 1 mm horizontal distance, measured parallel to the horizontal plane between two lines, with the difference between their vertical distances from the horizontal plane defining the height difference. Each of those two lines is perpendicular to the horizontal plane, lies within the central vertical cross- sectional plane, and is measured vertically from the horizontal plane to the anterior surface.

[0247] In some embodiments, the steep ascent is defined by a curve on the anterior surface within the central vertical cross-sectional plane that has a slope of at least 45° along all tangents to the curve within a horizontal distance, measured parallel to the horizontal plane, of 1 mm between two points on the curve.

[0248] Steep ascents like those may balance the attaching forces between the insert and the ocular surface with the sliding forces exerted by the eyelid during blinking and eye movements, which tend to move the matrix along with the eyelid. This balance may help prevent dislodgement of the matrix from the eye and reduce the risk of unintended movement out from under the eyelid onto the corneal surface, which could cause irritation or interfere with vision.

[0249] In some embodiments, the elastomeric matrix achieves sustained tear fluid concentrations of the API at levels of at least about 10 pg / mL (or at least about 20 nmol / mL) for a period of at least one hour following administration. This sustained concentration is achieved, in some such embodiments, through the combination of hydrophobic API particles embedded in the matrix and the formulation of the matrix with ophthalmic demulcents and plasticizers that modulate the matrix’s erosion and dissolution rate.

[0250] An aspect of some embodiments of the invention includes a method for delivering a pharmaceutically active ingredient (API) to the posterior segment of an eye, that results in therapeutically effective levels in at least one of the retina, choroid, or optic nerve. The method may include placing an elastomeric matrix with the API on a bulbar conjunctiva under an eyelid; and allowing the API to be released from the elastomeric matrix to the bulbar conjunctiva.

[0251] As used herein, the requirement that a pharmaceutically active ingredient (API) reaches and maintains a therapeutically effective level in at least one of the retina, choroid, or optic nerve of a human subject is satisfied when the treatment produces a clinical or biomarker response consistent with pharmacological activity in those tissues. Because direct sampling of posterior ocular tissues in humans is not always feasible, in some embodiments, the presence of therapeutically effective levels is inferred from responses in the subject, including, by way of example, improvement or stabilization in signs or symptoms of the condition. In some embodiments, such improvement may be observed by imaging, for example, reduction or stabilization of central macular thickness on OCT, reduction in vascular leakage on fluorescein angiography or OCT-angiography, or reduction in vitreous haze or cell scores. In some embodiments, an improvement or stabilization indicative for achieving and maintaining therapeutically effective levels of the API in the retina, choroid, and / or optic nerve may be observed by biomarkers quantifications. For example, decrease in tearfluid cytokine levels (e.g., VEGF, IL-6, TNF-a), chemokines (e.g., IL8, CCL3), or other molecular markers known to correlate, positively or negatively, with therapeutic effect on the condition being treated.

[0252] In some embodiments, the methodology involves the topical application of an elastomeric matrix under the eyelid in a hydrophilic environment that is adjacent to a hydrophilic layer under the eyelid. In some embodiments, the API is released into the hydrophilic environment and allowed to go through the hydrophilic layer into the eye, and more specifically to the posterior segment of the eye. In some embodiments, the API is released directly into the hydrophilic layer by allowing direct contact between the insert and the hydrophilic layer.

[0253] In some embodiments, the composition is formulated to facilitate sustained drug release and enhance the period for which drug is available at the eye surface, e.g., in the tear fluid. This period, referred to herein as drug availability period, may be enhanced, in some embodiments, from minutes to hours, or even days. Enhanced drug availability periods may be particularly advantageous for targeting conditions of the posterior segment of the eye, for example, diabetic macular edema, cystoid macular edema, retinal vein occlusion, and age-related macular degeneration. Such targeting may require the API to reach hard to access locations, for example, the posterior segment of the eye, while avoiding adverse effects that may be caused, for example, by administering high doses of a drug via the systemic route, or injecting the drug directly to the posterior segment.

[0254] In some embodiments, the composition is configured to provide sustained API release sufficient to require administration of less than three times daily. Such administration rates, for example, of once or twice daily, or even once or twice weekly, allow tailoring the treatment to the therapeutic and / or undesired effect the individual patient experiences with the treatment. Such tailoring may be much more flexible than is allowed when intraocular injections are used, each 4, 8, or 12 weeks. On the other hand, administration frequency of less than three times daily is much more convenient than instilling eyedrops 6 times daily, as may be required by several prior art therapies.

[0255] In some embodiments, prolonged drug availability times are achieved by a combination of drug particle size and chemical composition of the elastomeric matrix embedding it. One such combination is micrometric particles of a water insoluble or very slightly soluble drug (e.g., dexamethasone) dispersed or suspended in matrix composition that includes even proportions of PVOH of two types and non- water plasticizers in amount at least double that of the two types of PVOH together. The two types of PVOH may be, for example, one with long chains and full hydrolysis (LCFH), and the other with short chains and partial hydrolysis (SCPH). As used herein, micrometric particles are particles that have size distribution with less than 0.5% of the particles being 20pm or larger, and the median being between 2pm and 10pm. Another such combination may be of much smaller particles (e.g., with at least half of them smaller than 1 micrometer), combined with a matrix having a larger proportion of the PVOH with short chains and partial hydrolysis. Without being bound to theory, it is assumed that the smaller particles accelerate the drug dissolution, while the excess of short chain partially hydrolyzed PVOH accelerates the erosion of the insert, allowing for compatibility between the drug dissolution rate and the insert erosion rate, so the insert is not intact much longer after it cease releasing drug. The first combination may be more suitable for cases in which longer supply of the drug is desired, and the second combination may be more suitable for cases in which shorter and stronger bursts of the drug are desired.

[0256] In some embodiments, short chains are of 200 to 2000 monomeric units; long chains are of 2200 to 5000 monomeric units; fully hydrolyzed PVOH is of hydrolysis degree of 97% or more; and partially hydrolyzed is of hydrolysis degree of 95% or less.

[0257] Known alternatives that claim delivery of API to the posterior segment of the eye show several disadvantages. For example, the API in eye drops wash away within minutes (short drug availability period) and cannot guarantee long stable provision of treatment, and in some cases the drug might be completely washed away from the eye before a therapeutic effect is achieved. In the case of intraocular injections, while it has been shown that sustained release is possible, the treatment is invasive and many times traumatic and prone to complications. Lastly, loading contact lenses with drugs is challenging in manufacture, storage, and usage.

[0258] Exemplary pathways of delivery of the API

[0259] In some embodiments, the pathway of delivery of the API particles is via a trans-scleral path and / or a trans-corneal path. In some embodiments, more specifically, the pathway of delivery of the API is by being released into a hydrophilic environment and then allowed to go through a hydrophilic layer in a trans-scleral path and / or a trans-comeal path. In some embodiments, the pathway of delivery of the API is by being released directly into hydrophilic layer. In some embodiments, when pathway of delivery is trans-corneal, the pathway of delivery of the API includes going through one or more hydrophobic layers.

[0260] In some embodiments, the API is delivered via either path without the need to provide further penetration enhancing techniques, for example injections, iontophoresis, or chemical enhancers (for example cyclodextrins, chitosans, peptides, liposomes, benzalkonium chloride (BAC)). In some embodiments, the elastomeric matrix is substantially free of cyclodextrin, for example, native cyclodextrin. In some embodiments, the elastomeric matrix is substantially free of non-plasticizing solubilizing agents.

[0261] In some embodiments, optionally, the API particles are delivered via either path with the assistance of at least one enhancer.

[0262] Without being bound to theory, penetration enhancers are compounds that help drugs overcome the barriers protecting the eye from penetration of foreign bodies or materials, to facilitate the drug reaching therapeutic levels at eye tissue lying behind such barriers.

[0263] In some embodiments, avoiding penetration enhancers may be advantageous, especially in matrices that are free of covalent cross-linking. Such matrices, held together by hydrogen (and not covalent) bonds, are more easily disturbed than chemically cross-linked polymeric matrices, because the hydrogen bonds holding together the physically cross-linked matrices may be more easily replaced by hydrogen bonds with penetration enhancers, than chemical bonds in chemically cross-linked matrices can be replaced by chemical bonds with penetration enhancers.

[0264] Thus, avoiding penetration enhancers may be advantageous in enhancing shelf life of the physically cross-linked drug products disclosed herein, thanks to avoidance of materials that may interact non-favorably with other ingredients of the drug products, e.g., during storage. Penetration enhancers might interact non-favorably with the excipients (e.g., PVOH, water, or plasticizers) or with the pharmaceutically active ingredients (e.g., dexamethasone).

[0265] Furthermore, many penetration enhancers pose safety problems because they may damage the corneal epithelium or other ocular tissue, particularly if used for prolonged time.

[0266] Some common types of penetration enhancers, which inserts optionally avoid, include: Surfactants, such as benzalkonium chloride (BAK) and Tween 80 or other polysorbates. BAK is a cationic surfactant, sometimes used as preservative in eye drops, that acts as a penetration enhancer by disrupting the corneal epithelium, thereby increasing drug permeability through the cornea. BAK, however, is not advisable for repeated use as it might damage the cornea. This is one reason, for which being preservative-free is considered an advantage for ophthalmic compositions. Polysorbates, such as Tween 80, are non-ionic surfactants, that can improve drug solubility and enhance corneal permeability.

[0267] Cyclodextrins are molecules that can form inclusion complexes with hydrophobic drugs, increasing their solubility in aqueous media and carry them across aqueous barriers, such as the aqueous layer of the tear fluid. This way they enhance the penetration of hydrophobic drugs into ocular tissue lying behind such aqueous barriers.

[0268] Chelating agents, such as EDTA, GPTA, BAPTA, or EDDS, are sometimes used as penetration enhancers, as they are able to disrupt the tight junctions between epithelial cells by chelating ions essential for maintaining the integrity of such tight junctions. Chelating agent may similarly disrupt the mucin layer of the tear film. Thus, in some embodiments, chelating agents are avoided to increase drug product safety.

[0269] Fatty acid and lipid-based enhancers, such as oleic acid and sodium caprate.

[0270] Oleic acid is a fatty acid that can fluidize cell membranes, thereby increasing drug permeability through ocular barriers.

[0271] Sodium caprate medium-chain fatty acid that can enhance paracellular transport by opening tight junctions in the corneal epithelium.

[0272] Cell-penetrating peptides (CPPs)

[0273] CPPs are short-chain peptides, usually composed of 30 or less amino acid residues, capable of trespassing membranes with no need for chiral interactions with surface receptors.

[0274] Iontophoresis is not a component of any drug product; but means for transporting drugs across ocular membranes by electrical currents. Our preferred products deliver the drug to the posterior segment without iontophoresis, and without electrifying the eye to any extent.

[0275] Nevertheless, some embodiments do include penetration enhancers. For example, the insert may include some highly mucoadhesive polymers that prolong the contact time of the drug with the ocular surface, such as hyaluronic acid and chitosan, which may be considered penetration enhancers.

[0276] On the other hand, thiolated polymers, which are also known as penetration enhancers that prolong contact time of the drug with the ocular surface thanks to their muco-adhesiveness, are avoided, due to safety concerns associated with them, such as their potential toxicity to ocular tissues.

[0277] While in the paragraphs above avoidance of use of penetration enhancers is mentioned, it should be noted that, in some embodiments, penetration enhancers are included, and their disadvantageous are mitigated with careful formulation of the insert as a whole. Therefore, in some embodiments, the API is delivered via either path in the presence of penetration enhancers within the matrix, for example chemical enhancers (for example cyclodextrins, chitosans, peptides, liposomes, benzalkonium chloride (BAC), surfactants, chelating agents, fatty acid, lipid-based enhancers, and / or cell penetrating peptides).

[0278] Exemplary Compositions and Properties of Elastomeric Matrices

[0279] In some embodiments, the elastomeric matrix is formulated with polyvinyl alcohol (PVOH) and various plasticizers. In some embodiments, PVOH, a water-soluble synthetic polymer obtained via the hydrolysis of polyvinyl acetate, serves as the structural backbone of the matrix. In some embodiments, the elastomeric matrix comprises a polymer with hydrogen bondforming repeating unit. As used herein a "polymer with hydrogen bond-forming repeating units" is a polymer whose repeating units (i.e., the individual structural units that make up the polymer chain) have functional groups capable of forming hydrogen bonds with each other or with other molecules. Examples of such functional groups include hydroxyl (-OH), amino (-NH2), carboxyl (-COOH), carbonyl (C=O), amide (-CONH2), and thiol (-SH). Examples of such polymers include PVOH, polyacrylic acid (a / k / a carbomer), alginic acid, gelatine, guar gum, methyl cellulose, hyaluronic acid, polyvinylpyrrolidone (PVP), chitosan, and hydroxypropyl cellulose (HPC). While some polymers may be very short (e.g., contain as little as 10-20 repeating units), in the context of this application, a polymer preferably has more than 100 repeating units, and usually between about 500 and about 5000.

[0280] In some embodiments, the composition avoids covalent crosslinking. The reliance on physical cross-linking allows for the degradability (erodibility) of the matrix and inserts made thereof, and allows it to soften in the eye. Physical crosslinking also allows manufacturing the matrix without the use of aggressive chemicals, required for chemical cross-linking, which must be totally removed before the matrix can be used on an eye (or, to that matter, any other medical use). . Furthermore, the physical crosslinking allows for flexibility in formulation design, for example, as described herein. Such flexibility is not available in designing chemically crosslinked matrices, as the chemical bonds are much less flexible, and may be replaced or broken much less easily than the physical crosslinking.

[0281] In some embodiments, the matrix further includes plasticizers, such as polyols (such as, propylene glycol and / or glycerin), polyprotic organic acids (such as citric acid), and polyamines (such as spermidine). In some embodiments, these plasticizers increase the elasticity and pliability of the matrix, ensuring it adheres comfortably under the eyelid and sustains its mechanical properties, including tensile strength and elongation at break, for example, in storage under dry conditions. In the eye (or in vitro, after immersion in simulated tear fluid, for example, for 5, 10, or 15 minutes), some or the matrices tend to become softer and stickier, and in some embodiments, slimy. The simulated tear fluid referred to herein is an aqueous solution containing about 0.67 % sodium chloride, about 0.2 % sodium bicarbonate and about 0.008 % calcium chloride.

[0282] In some embodiments, the combined mass ratio of plasticizers to PVOH is at least 2: 1, (for example, 2.5: 1, 3: 1, 4: 1, 5: 1. 6: 1, or any ratio up to 20: 1) with the mass content of PVOH and plasticizers constituting at least 70% (for example 75%, 80%, 90%, or 95%) by weight of the matrix, excluding water. In some embodiments, in general, the insert can be manufactured using one or more types of matrices. For example, three types of matrices which differ from each other by a level of rigidity. For example, a first matrix that is “soft”, a second matrix that is “medium” and a third matrix that is “hard”. It is noted that the terms hard and soft are used relatively, and the hard matrix, while less soft than the medium matrices, would still be considered soft to touch. The term “hard” is used for simplicity, to refer to the softness degree of the less soft of the matrices.

[0283] In some embodiments, the different levels of rigidness translate in different time lengths of degradation and / or release of API. For example, the “soft” matrix will release the API over a period of time of 6 hours, while the “medium” matrix will release the API over a period of time of 24 hours, while the “hard” matrix will release the API over a period of time of more than 24 hours to over a week (or more).

[0284] The table below, summarizes some mechanical properties measured under dry conditions with matrices that all had the same composition (less than 50% water and PVOH less than half of the plasticizers), but differed in the types of PVOH, which resulted in differing in softness, as indicated in the table.

[0285] The measurements were made with PVOH of the Emprove® Essential series, with LCFH being 28-99, SCPH1 being 4-88 and SCPH2 being 5-88.

[0286] The values are presented as average ± standard deviation among three repetitions. The compressive module was measured only once, so standard deviation is not presented. These results exemplify that increasing the amount of short chain partially hydrolyzed PVOH may lower elastic module, tensile strength, and elongation at break. In these examples, the difference between PVOH of the same hydrolysis degree (88%) and slightly different chain length (750 and 630) was reflected in modest changes in mechanical properties.

[0287] Mechanical measurements presented herein were performed using computer-controlled Mark 10 model Fl 05 tension / compression test frame, equipped with 10N or 100N force sensor equipped with standard grips and head. Software: “IntelliMESUR®”.

[0288] Wet measurements were performed in Simulated tear fluid (STF) with pH adjusted to ~7.2.

[0289] Tensile measurements done using “Dog bone” model. Dog bone dimensions: total length 6 cm. Grip width 2 cm, neck width 0.8 cm, thickness 0.5-3.5 mm. Measurement speed 40mm / min.

[0290] Press measurements performed using 12.7mm flat head and cylinder- shaped samples. Sample dimensions: 4mm diameter, height 2.5-3.0 mm. Measurement speed 20 mm / min.

[0291] Tensile measurements of wet sample may be performed after soaking a “dog bone” sample in 5 ml STF. After designated time in the STF, the doe bone may be taken out of the liquid, mounted on the grips, and measured immediately.

[0292] Press measurements of wet samples may be performed by soaking individual samples separately in small containers and measuring each sample after a designated time by pressing the sample inside the liquid without touching or moving the sample from the container before measurement.

[0293] An exemplary elastomeric matrix, the dry material of which was composed of 20% PVOH, all of which 28-99, 20% polyethylene glycol, and 60% glycerol, was measured to have Young’s Modulus of 0.41 MPa, tensile strength of 0.51 MPa, and elongation at break of 456%.

[0294] In some embodiments, the level of “softness” may be manipulated by hydrophobic additives like hydrophobic polymers (for example, of the Eudragit® series) or fluorinated or semifluorinated alkanes. However, care should be given not to get the matrix too soft, because too soft matrixes may be hard to handle. For handling reasons, tensile strength of an insert is preferably at least 0.01 MPa measured as described herein under dry conditions.

[0295] In some embodiments, the nature of the API affects the level of rigidity of the matrix. For example, hydrophobic APIs may reduce the level of rigidity of the matrix, e.g., after staying for some time in the eye, as a function of their concentration in the matrix. The higher is the concentration of the API, the higher is the likelihood that the rigidity would decrease. Therefore, in some embodiments, the type of matrix is designed or selected according to the needs of the treatment and the nature and concentration of the API. For example, when using an API that is hydrophobic, depending on the desired drug availability period, a different type of matrix can be used. For long drug availability periods, e.g., when the matrix should remain on the eye and retain a portion of its API for more than one day a “hard” matrix will be used, while for shorter drug availability periods, a softer matrix can be used. It should be noted that this flexibility in design is not limiting, in the sense that inserts can be taken out of the eye according to needs. Thus, inserts may be manufactured with matrices that stay in the eye for longer than it takes to release the API.

[0296] In some embodiments, softness is correlated with erosion time, so that softer inserts erode faster than harder inserts. Accordingly, in some embodiments, different matrices of different softness degrees are designed or selected based on a relationship between the period they remain in the eye before being completely eroded, and the desired drug availability period. For example, for an API to be released to the eye for 6 hours, the insert may be made of a matrix designed to erode shortly after drug availability is less desired, for example, by about 6 to 8 hours.

[0297] Without being bound by theory, the following model may help understanding the way the matrices described herein may be manipulated as necessary for getting different APIs to the posterior segment for various periods. According to the model, particles of hydrophobic APIs are homogeneously dispersed in the insert, in microscopic pores defined by PVOH. These particles slowly dissolve in the fluid filling the pores, be it water-plasticizer mixture with which the insert is manufactured, or tear fluid replacing it after sitting in the eye for long enough. Therefore, the matrix should keep its porous structure for as long as further API is to be dissolved and supplied to the eye.

[0298] Considering the softening effect hydrophobic drugs may have on the inserts, a formulation that in absence of drug provides medium softness and erodes within 24 hours may be used with adequate amounts of a hydrophobic drug for eroding at a short time, e.g., 6 to 8 hours.

[0299] In some embodiments, a general advantage of inserts over implants or injections is that inserts can be used to tailor the treatment to the patient. For example, if a patient develops adverse reaction to something injected into his eye, it is very complicated, if at all possible, to stop the treatment. An insert may simply be taken out.

[0300] In some embodiments, the matrix is designed to provide a controlled release of the API. For example, the matrix is designed to address a specific technical need, for example, how much API to be released at a certain time, or how much API is to be released in total over a period, or when the API will begin to be delivered after the insert has been applied. In some embodiments, this is done by amending the configuration of the matrix, for example by changing the rigidity of the matrix, by adding delaying layers to the insert matrix, or by adding delaying coating to the API, and other. Delaying layers may be outer layer, attached to the anterior and posterior surfaces of the insert, and not including an API, so that API starts releasing only after the delaying layers are eroded to an extent allowing API going through them. In some embodiments, the formulation of the delaying layers is the same as the formulation of the drug-carrying layer, but this is not necessarily so. The outer layer may be formulated to obtain a required delay, while the drugcarrying layer may be designed according to the required drug availability period.

[0301] In some embodiments, the matrix is characterized by having a porous structure. For example, the matrix comprises pores having a diameter from about 0.5pm to about 50pm. In some embodiments, without being bound to theory, during the manufacturing process, the hydrophobic API allocates itself within the pores when the matrix is generated. In some embodiments, different sizes of pores are generated, and particles of corresponding sizes fill them. It is assumed that some pores may remain empty, and some pores may host more than one particle.

[0302] Thus, in some embodiments, the particle size distribution of the API is selected to fit the dissolution time required in order to have the desired drug availability period. For example, for shorter drug availability periods, finer API particles may be used.

[0303] In some embodiments, the insert is a matrix made of Polyvinyl Alcohol (PVOH) and water- soluble plasticizers. Preferably, each of the plasticizers by itself is a liquid at room temperature. In some embodiments, the insert is made of a matrix having a sponge-like structure, made of a porous PVOH skeleton with pores filled with plasticizers. Laboratory experiments proved that upon contact with water, the plasticizers are released and replaced with water, leading to a wet PVOH skeleton.

[0304] In some embodiments, the insert comprises mucoadhesive materials, optionally, as part of the formulation of the suspending medium, in which the API is suspended or dispersed. Alternatively, the insert may include an outer mucoadhesive layer, optionally, devoid of API particles. In some embodiments, the mucoadhesive layer is added to the matrix, e.g., by dipping the matrix in mucoadhesive material, spraying and / or spreading on the matrix bio-adhesive material, or in any other method known in the art.

[0305] Preferably, the mucoadhesive layer is at the posterior surface of the insert, i.e., the surface that faces the eyeball, rather than the eyelid.

[0306] Some of the mucoadhesive materials that are useful for obtaining a mucoadhesive insert include PVOH, preactivated thiomers, hyaluronic acid, chitosan, and carbapol. The mucoadhesive material may comprise, in some embodiments, Carbopol polymer [e.g., Carbopol 934 (BF Goodrich Co., Cleveland, Ohio)], carbomer, polycarbophil, pectin, a modified cellulose (e.g., caboxymethyl cellulose, sodium carboxymethylcellulose, hydroxymethyl propyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, and the like), polyanhydrides, polymers and copolymers of acrylic acid, methacrylic acid, and their lower alkyl esters [e.g., polyacrylic acid, poly(methyl methacrylates), poly(ethyl methacrylates), polybutylmethacrylate), polyisobutyl methacrylate), poly(hexylmethacrylate), poly(isodecyl methacrylate), poly(lauryl methacrylate), polyphenyl methacrylate), and poly(methyl acrylate).

[0307] Exemplary porous structure of matrices making inserts for use in delivering drugs to the posterior eve segment

[0308] Referring now to Figures la-c, showing SEM images of exemplary porous matrices, according to some embodiments of the invention.

[0309] In order to get a dry structure suitable for SEM imaging (Scanning Electron Microscopy) the plasticizers-free wet PVOH skeleton were dried by freeze drying (Lyophilization). Two types of matrices were tested, matrix that allows release within 24 hours and more than 24 hours.

[0310] As shown in Figure la, the top surface is different than the sub-layer (shown in Figure lb). On the surface of the matrix that allows release within 24h (la), pore number per unit area is small (estimated to be 0.8- 1 pore / pm2). This may lead to limited water diffusion in and out an insert made of such a matrix, thus allowing slow diffusion and controlled release of soluble drugs while dispersed solid drug particles are trapped inside.

[0311] As mentioned above, the sub layer of the same matrix (Fig. lb) is very homogeneous, with pore size in the few microns range. This liquid phase can hold dissolved drug while the tightly packed scaffold can lock dispersed drug particles.

[0312] On the other hand, the sub-layer of the matrix that allows release more than 24h, shown in Figure 1c, shows two different types of pores. The main pores are larger, and the walls of the main pores are porous. The secondary pores are 0.2-0.5 microns wide.

[0313] Exemplary chemical composition of matrices for use in methods according to embodiments of the invention

[0314] In some embodiments, an insert used to deliver drugs to the posterior surface of the eye is made of an elastomeric matrix comprising water, PVOH, and one or more plasticizers other than water. The combined mass of the one or more plasticizers is at least double that of the PVOH.

[0315] In some embodiments, the PVOH is of two (or more) types that differ from one another in hydrolysis degree (HD), degree of polymerization, or both. In some embodiments, the two types of the PVOH differ in chain length, for example, by at least 1000, and have similar degrees of hydrolysis, both between 97% and 100%. In some embodiments, a first type of the two or more types has a hydrolysis degree from 97 % to 100 %. In some embodiments, a second type of the two or more types has a hydrolysis degree is lower than 93%. In some embodiments, a second type of the two or more types has a hydrolysis degree from 80 % to 93%. In some embodiments, a first type of the two or more types has chains with more than 2500 units. In some embodiments, a second type of the two or more types has chains with less than 1500 units.

[0316] In some embodiments, a mass ratio between a first type of PVOH and a second type of PVOH of the two or more types is from about 3: 1 to about 1:3.

[0317] In some embodiments, a first type of the two or more types has chains with more than 2500 units and hydrolysis degree of 97% to 100%, and a second type of the two or more types has chains with less than 1000 units and hydrolysis degree of 80% to 93%. In some embodiments, the second type of PVOH makes more than 50% of the PVOH.

[0318] In some embodiments, the at least two types of PVOH determine a degradation time of degradation of the elastomeric matrix making the insert. In some embodiments, the degradation comprises change in mechanical properties under wet conditions. In some embodiments, the degradation comprises change in shape under wet conditions. In some embodiments, the at least two types of PVOH determine a time development of mechanical properties of the elastomeric matrix under wet conditions.

[0319] In some embodiments, degradation does not include cleavage of covalent bonds.

[0320] In some embodiments, a combined mass content of the PVOH and the one or more plasticizers is at least 70 %wt of the total weight of the matrix excluding water, for example, 70%, 80%, 90%, or 95%.

[0321] In some embodiments, the combined mass ratio of the one or more plasticizers to the PVOH is between 2: 1 and 20: 1.

[0322] In some embodiments, the elastomeric matrix is characterized by substantially isotropic swelling when immersed in excess of simulated tear fluid for about 10 minutes. The swelling is considered isotropic, if the length, width, and thickness of a slab of the matrix changes length by the same ratio ± 20%. For example, each dimension changes by 15%±3%, i.e., by between 12% and 18%.

[0323] In some embodiments, the elastomeric matrix swells by less than 50 % by volume under wet conditions. Here also, the swelling is measured by comparing the initial volume (e.g., the product of length, width, and thickness, each measured with a caliber) of a slab of the matrix, before insertion to simulated tear fluid, to the final volume of the same slab of matrix measured after the matrix is being soaked for 10 minutes in excess of simulated tear fluid. The swelling (expressed in percentages) is defined as . 100 In some embodiments, each of the one or more plasticizers has a molar mass of no more than l,000g / mol.

[0324] In some embodiments, each of the one or more plasticizers is independently selected from the group consisting of a polyol, a polyprotic organic acid, a polyamine, an alkyl gluceth, an aliphatic polyalkylene glycol, an ethanolamine, a saccharide, an oligosaccharide, an amino acid, a polyphenol, tromethamine, urea, tannic acid, and any salt thereof and / or combinations thereof. In some embodiments, the polyol is selected from the group consisting of ethylene glycol, diethylene glycol, triethylene glycol, tetraethylene glycol, propylene glycol, triacetin erythritol, a poly-glycol, , a poloxamer, and a co-polymer thereof, and glycerol and esters thereof. In some embodiments, the polyprotic organic acid is selected from the group consisting of oxalic acid, maleic acid, citric acid, and any salt thereof. In some embodiments, the polyamine is selected from the group consisting of spermine, spermidine, diethylenetriamine, triethylenetetramine, tris(2- aminoethyl)amine, a polyethylenimine, and any salt thereof. In some embodiments, the aliphatic polyalkylene glycol is selected from the group consisting of a polyethylene glycol, a polypropylene glycol, a poly-glycol a poloxamer, and a polysorbate. In some embodiments, the aliphatic polyalkylene glycol is polyethylene glycol. In some embodiments, a mass content of the PVOH is substantially equal to a mass content of the aliphatic polyalkylene glycol. In some embodiments, the aliphatic polyalkylene glycol is selected from the group consisting of polyethylene glycol, polypropylene glycol, and any mixture thereof.

[0325] In some embodiments, the water constitutes less than 50 %wt of the total mass content of the matrix. The relatively small amounts of water in the insert may allow longer shelf-life, as many degradation processes of APIs occur in water, so the smaller the amount of water, the better in this respect.

[0326] In some embodiments, the mass content of the PVOH is less than 25 %wt of the total weight of non- water ingredients of the matrix. In some embodiments, the mass content of the PVOH is less than a third of the total weight of the one or more plasticizers. In some embodiments, the elastomeric matrix is essentially devoid of covalent crosslinking.

[0327] In some embodiments, the matrix making the insert is characterized by tensile strength of between 0.01 MPa and 2 MPa. Other preferred ranges include 0.01 MPa to 1 MPa, 0.05MPa to 1 MPa, and 0.05MPa to 2MPa.

[0328] In some embodiments, the matrix making the insert is characterized by Elastic module (Young’s Module) of between 0.01 MPa and 2 MPa. Other preferred ranges include 0.01 MPa to 1 MPa, 0.05MPa to 1 MPa, and 0.05MPa to 2MPa. In some embodiments, the matrix is characterized by this Young’s Modulus, and by tensile strength as recited above. In some embodiments, the matrix making the insert is characterized by elongation at break of between 100% and 1000%, for example, more than 150%, 200%, 300%, 500%, 700% or 900%. In some embodiments, the matrix is characterized by this elongation at break, and by tensile strength and / or Young’s Modulus as recited above.

[0329] In some embodiments, the one or more plasticizers constitutes at least 30 %wt, 40 %wt, 50 %wt, 60 %wt, 70 %wt, 80 %wt of the total weight of the matrix. In some embodiments, the plasticizer constitutes 30-80 %wt of the weight of the matrix and any sub-range therebetween.

[0330] In some embodiments, the plasticizer is selected from polyols (e.g. ethylene glycol, diethylene glycol (DEG), triethylene glycol (TEG), and tetraethylene glycol), propylene glycols, glycerol, esters of glycerol (e.g. triacetin), polyprotic organic acids, e.g., oxalic acid, maleic acid, citric acid, etc.), polyamines (e.g., spermine, spermidine, diethylenetriamine, triethylenetetramine, tris(2-aminoethyl)amine, a polyethylenimine (PEI; polyaziridine, etc.), alkyl gluceths, aliphatic polyether glycos (e.g., polyethylene glycol, polypropylene glycol,), ethanolamines, erythritols, tromethamine, urea, saccharides, amino acids (e.g., glycine, aspartate / aspartic acid etc.), polyphenols (e.g. tannic acid) and any combinations thereof.

[0331] In some embodiments, the plasticizer is an ophthalmic demulcent, as described by the FDA in 21 CFR 349.12.

[0332] Examples of demulcents that may be used as plasticizers include dextran, gelatin, povidone, hyaluronic acid or pharmaceutically acceptable salt thereof, polyols, cellulose and cellulose derivatives. PVOH is also a demulcent, but is not used as a plasticizer.

[0333] Examples of polyols include glycerol, polyethylene glycol (e.g., PEG 300 or PEG 400), propylene glycol, and polysorbate (e.g., polysorbate 80).

[0334] Examples of cellulose derivatives include carboxymethyl cellulose sodium, hydroxyethyl cellulose, methylcellulose, and hydroxypropyl methylcellulose (HPMC).

[0335] Thus, according to some embodiments of the present invention, the plasticizers are ophthalmic demulcents selected from the group consisting of cellulose derivatives, carboxymethylcellulose sodium, hydroxyethyl cellulose, hypromellose, hydroxypropyl cellulose, methylcellulose, hemicellulose, dextran, gelatin, liquid polyols, glycerin, polyethylene glycol 300, polyethylene glycol 400, polysorbate 80, propylene glycol, povidone, and any combination thereof.

[0336] In some embodiments, the matrix comprises glycerol as a single plasticizer. In some embodiments, the matrix comprises propylene glycol as a single plasticizer. In some embodiments, the matrix comprises glycerol and propylene glycol as plasticizers. In some embodiments, the matrix comprises glycerol and propylene glycol, each alone or a mixture thereof mixed with PEG, as plasticizers. In some of embodiments, the amount of PEG and the amount of PVOH are substantially the same.

[0337] In some embodiments, the insert is configured to reside on the bulbar conjunctiva of an eye, covered by an eyelid, preferably in a hydrophilic environment adjacent to a hydrophilic layer, whether the eye is open or close. In some embodiments, the insert is preferably small enough not to cover the cornea when residing on the bulbar conjunctiva. It is noted that the cornea may be irritated more easily than the bulbar conjunctiva, and therefore, it is preferable that the insert is shaped and sized not to cover the cornea. Furthermore, covering the cornea may hinder sight, and require very high transparency, which may be obviated by omitting any contact with the cornea. Being completely covered by the eyelid is a considerable advantage, for example, over devices that circumvent the cornea, but has one portion under the lower eyelid and another portion under the upper eyelid. In some embodiments, even the compositions described herein, which are exceptionally soft and comfortable for long stay under an eyelid, are not comfortable when they are so huge. Additionally, such prior art devices require application by a medical professional and sometimes also the use of a dedicated applicator. Some embodiments of the present invention are suitable for self-administration by most patients, optionally, without a need for an applicator or clinical assistance. In some embodiments, the eye is permitted to blink normally during the use of the insert. In some embodiments, the lower eyelid completely covers the insert. In some embodiments, the insert is small enough to be fully covered by the eyelid underneath which it is placed. In some embodiments, preferably, the insert is configured to reside under a lower eyelid, where there is more space for the drug product, and it may cause less irritation to the eye, and may be held in the eye for longer periods without disturbing the patient.

[0338] In some embodiments, the preparation of an elastomeric matrix from a mother solution (comprising the suspending medium and API) may start with the preparation of a PVOH solution.

[0339] Briefly, 420 ml of purified water are added into 500 ml round bottom flask equipped with an overhead stirrer. The flask is placed into a heating mantle, and 80 gr of PVOH are added in portions while stirring and heating until all the PVOH dissolved. In some embodiments, these 80 g or PVOH include PVOH of different types, having different chain lengths, degrees of hydrolyzation, or both.

[0340] The PVOH solution is left to stir and heat for additional 1-2 hours, and thereafter the solution is left to cool to room temperature while stirring.

[0341] Plasticizers and 80 gr of the PVOH solution are added in a 500 ml glass beaker to obtain a mother solution. Optionally purified water is added to dilute concentrations of solutes. The suspending medium is heated with magnetic stirring until all the components are fully dissolved, and thereafter heating is turned off and the mixture is left to cool.

[0342] In some embodiments, the API is added to the suspending medium, preferably as powder of micrometric particles. In some embodiments, the API is added when the suspending medium is at about room temperature, as not to encourage reactions between the API and ingredients of the suspending medium. This also allows using APIs that are heat sensitive. In some embodiments, the API is homogenized into the suspending medium by vigorous homogenization, to provide a mother solution that upon drying provides an elastomeric matrix with the API homogeneously suspended therein.

[0343] The mother solution is poured into an open mold and left to dry. In some embodiments, the dried mother solution is taken out of the mold to provide the insert.

[0344] Exemplary shapes

[0345] In some embodiments, the insert is configured to reside on the bulbar conjunctiva of the eye and includes a shaped body having two distinct surfaces: a posterior surface, configured to conform to the sclera, and an anterior surface, configured to minimize disturbance to the eyelid when the posterior surface resides on the sclera at the bulbar conjunctiva. In some embodiments, preferably, both surfaces are smooth, to minimize irritation to the eye and to the eyelid.

[0346] In some embodiments, a retention portion may be defined between a portion of the posterior surface and a corresponding portion of the anterior surface. In some embodiments, the entire insert may serve as a retention portion. In some embodiments, the retention portion is only a portion of the insert. In some embodiments, an insert may have two (or more) retention portions.

[0347] In some embodiments, the retention portion is shaped with a sharp ascent, for example, from the edge of the insert towards its center. In some embodiments, the ascent may be referred to as sharp if an angle between a reference surface and the insert is larger than 45°. In some embodiments, the elastomeric matrix is formed as an insert having a shape with an ascent greater than 45°, and the placing of the insert is with the ascent intersecting the opening of the eyelid. In some embodiments, the reference surface may be the eye surface on which the insert rests. Alternatively, the reference surface may be any surface, flat or convex, on which the insert rests. In some embodiments, the sharp ascent is not from an edge of the insert but between two inner points of the insert. In some embodiments, the sharp ascent is from a leading edge of the insert inwards. An edge may be referred to as leading, if it is disposed adjacent to an opening of an eyelid when the insert is underneath that eyelid. In some embodiments, the retention portion may be defined by heights between the posterior surface and the anterior surface, or by heights between the posterior surface and the reference surface. In some embodiments, each such height may be measured from a point on the posterior surface (hereinafter the posterior point) to a corresponding point on the anterior (or reference) surface (hereinafter the anterior (or reference) point. The sharp ascent may be expressed in two such heights that differ from each other by at least 1mm and distanced from each other by at most 1mm.

[0348] In some embodiments, an insert with a sharp ascent is manufactured by casting a mother solution as described herein into a mold, having an inner surface with a sharp ascent. In some embodiments, when the mother solution is dried, the surface that faced the mold becomes the anterior surface of the insert, and the surface that faced the air becomes the posterior surface of the insert. Mother solutions as described herein ensure that under such circumstances the shape of the two surfaces together define between them a retention portion as described herein.

[0349] Exemplary Drug Particle Size Distribution

[0350] In some embodiments, API particles incorporated into the elastomeric matrix have a specific size range of from about 0.01 to 20 micrometers. Particles having sizes only within this range are referred to herein as micrometric particles.

[0351] As particles of less than 1 micrometer in size dissolve much faster than larger micrometric particles, in some embodiments, the percentage of particles smaller than 1 micrometer is kept low, to avoid too fast dissolution of the API. In some embodiments, the dissolution of particles larger than 1 micrometer is slower than required for effective drug delivery to the posterior eye segment, and their percentage in the size distribution is kept high. In some embodiments, the median diameter of the particles is between 3 and 7 micrometers. Large particles, of 20 micrometers or more are preferably avoided to avoid scratching the eye surface, and their proportion in the particle size distribution is 0.5% or less. In some embodiments, 90% of the particles are smaller than 10 micrometers.

[0352] In some embodiments, a potential advantage of such size distribution of API particles is that it allows for dissolution rate that optimized for providing dissolved API under the required time scale. The size distribution of the drug particles is determined during the manufacture of the drug, and retained during the preparation of the inserts by the vigorous homogenization of the mother solution (i.e., the suspending medium with the API particles).

[0353] In some embodiments, exemplary APIs include one or more of steroids such as dexamethasone and fluocinolone acetonide, non-steroidal anti-inflammatory drugs (NSAIDs), antibiotics, integrin inhibitors (such as lifitegrast (Xiidra) - volociximab (M200), and abicipar pegol). and antioxidants. For instance, a specific application may involve API particles with an average size of 5 micrometers, which potentially ensures effective distribution and release.

[0354] In some embodiments, the various ingredients of the suspending medium contribute to the dissolution of the API within the matrix. In some embodiments, the solubility of the API in different ingredients of the plasticizers may be different than its water solubility. In some embodiments this may make an insoluble drug to dissolve, even if only very slightly. In some embodiments, such dissolution may ease the transfer of the drug from the matrix to the eye, and thus, the API dissolution nature and amounts of the various plasticizers may be selected, in some embodiments, considering their ability to dissolve the API One such example is dexamethasone, whose solubility in glycerol is much higher than in water. Thus, in some embodiments, a dexamethasone-containing matrix may have more glycerol than used in matrices to dissolve, for example, water soluble APIs. Accordingly, in some embodiments, the solubility of the API in various plasticizers may be considered in designing the exact composition of the matrix, for example, plasticizers or demulcents that dissolve the API better than water may be preferred as ingredients of the suspending medium.

[0355] Exemplary Ophthalmic Demulcents and Suspending Medium

[0356] In some embodiments, the suspending medium within which API particles are suspended in the elastomeric matrix making the insert predominantly comprises ophthalmic demulcents, accounting for at least 30% by weight of the insert. In some embodiments, these demulcents, including for example glycerin and polyethylene glycol, enhance the residence time of the API within the tear film, maintaining prolonged contact with the ocular surface, thereby lengthening the drug availability period, and ensuring steady drug release.

[0357] In some embodiments, this demulcent-rich medium avoids the use of cyclodextrins or other solubilizing / penetration enhancer agents, which could rapidly decrease drug residence times. For example, an insert may comprise 40% by weight glycerin and 20% by weight polyethylene glycol as the primary demulcents, and not include any cyclodextrin, and provide meaningful concentrations of dexamethasone to the posterior segment of the eye for at least 1, 2, 4, 6, 12, or 24 hours.

[0358] Nevertheless, in some embodiments, the demulcent-rich medium comprises penetration enhancers, for example cyclodextrins or other solubilizing / enhancer agents, including, in some embodiments, non-plasticizing solubilizing agents. Exemplary Pharmacokinetic Findings

[0359] In some embodiments, the insert and drug delivery method aim to deliver a quantity of API to the retina. In some embodiments, the quantity is a therapeutic efficient quantity. In some embodiments, the therapeutic efficient quantity of the drug is maintained in the retina for extended period of time, from hours to days. In some embodiments, post-administration, the API demonstrates therapeutic efficient levels at the posterior segment of the eye from up to 24 hours to up to a week or more, with peak concentrations typically observed around one hour, optionally at 3 hours, optionally at 6 hours.

[0360] For example, upon applying an elastomeric matrix containing 0.6 mg of dexamethasone, therapeutic levels in the retina can be sustained for up to 24 hours or more with a peak concentration around 6 hours. See also Examples below.

[0361] Exemplary Application and Mechanism of Delivery

[0362] In some embodiments, the elastomeric matrix is designed for placement under the eyelid, and to be pressed by the eyelid into proximity to the ocular surface. More specifically, the elastomeric matrix is designed for placement in a hydrophilic environment adjacent to or in direct contact with a hydrophilic layer under the eyelid, for example in the bulbar conjunctiva. In some embodiments, the insert is pressed against the bulbar conjunctiva, to provide direct contact between the insert and the mucin layer of the tear fluid. Without being bound to theory, it may be assumed that liquid from the mucin layer penetrates the insert’s matrix, and replaces some of the waterplasticizers mixture filling the pores of the matrix. In some embodiments, this placement strategy promotes extended drug retention within the tear film and supports effective therapeutic delivery to the posterior segment via trans-corneal and / or trans-scleral pathways. In some embodiments, the matrix remains in place under tear fluid exposure and is configured for maintaining consistent drug release profiles and ensuring sustained therapeutic action. Optionally, the insert dimensions maximize the contact area with the bulbar conjunctiva, under constraints of good comfortability. For example, a matrix designed with specific dimensions of 10 mm x 5 mm x 0.5 mm may be employed for ease of placement and comfort while maximizing contact area with the bulbar conjunctiva under the eyelid. For example, the matrix is designed having a thickness between 0.2mm and 2mm (for example 0.2mm, 0.5mm, 1mm, 2mm), and for the other dimensions: 6mm x 4mm, 8mm x 2mm.

[0363] Referring now to Figures 2a-e, showing schematic representations of positions of inserts in the eye, according to some embodiments of the invention. In Figures 2a-e, a schematic representation of the area between the bulbar conjunctiva epithelial layer 202 and the palpebral conjunctiva epithelial layer 204 is shown, comprising the mucin layer 206 and the aqueous layer 208 in between, including exemplary inserts 210.

[0364] In some embodiments, the insert is configured to attach itself to the surface of the tissue to which is being positioned, for example to attach itself to the surface of the bulbar conjunctiva, as schematically shown in Figures 2c-d. In some embodiments, inserts that do not attach to surfaces, but leave space between them and the conjunctival epithelium, as schematically shown by arrow D in Figures 2a-b, are less preferable.

[0365] In some embodiments, there are no natural materials separating between the insert and the surface of the tissue, for example, there is no water or liquids or tear fluid between the insert and the surface of the tissue.

[0366] In some embodiments, a potential advantage of designing an insert to attach itself to the surface of the bulbar conjunctiva is that it allows a hydrophobic drug to go directly from the insert into the hydrophobic environment of the conjunctival epithelium, without having to cross the hydrophilic barrier of the tear fluid. This way, increased contact area of the insert with the tissue, increases the efficiency of delivery of the hydrophobic API to the conjunctiva, and from there, into deeper tissues of the eye, like the sclera and the choroid-retina. Additionally, inserts designed for residing under the lower eyelid are limited in size, for example, to up to 50mm2, and in some embodiments are more comfortable if their size is limited to no more than 40 mm2. Thus, in some embodiments, the contact area is from about 10mm2to about 50mm2, preferably between 25mm2and 50mm2. In some embodiments, when the API is hydrophobic, the hydrophilic layer of the tear fluid is a barrier, in which the solubility of the API is very low. On the other hand, the epithelial cells of the conjunctiva are more prone to accept hydrophobic materials. In some embodiments, the inserts are designed to provide the API with a direct route into the cells of the conjunctiva, shortening or avoiding completely, the drug journey through the tear film. In some embodiments, placing more than one insert in an eye at the same time may be useful because two (or more) inserts have larger contact area with the conjunctiva than a single insert. In some embodiments, the contact area affects the drug delivery rate, and the final concentrations achieved in the retina.

[0367] In some embodiments, diagrammatically illustrated in Fig. 2e, the insert is thick enough to push the palpebral conjunctiva, which, in turn, bulbs, and wraps the insert, maximizing contact area between the insert and conjunctival epithelium.

[0368] In some embodiments, one insert is placed in the eye, for example in a hydrophilic environment adjacent to or in contact with a hydrophilic layer in the conjunctival sac, or cul-de- sac, at a certain time. In some embodiments, more than one insert can be positioned at a same time. Using one insert at a time may be more convenient than placing two inserts under the same eyelid at the same time. Nevertheless, in some embodiments, more than one insert is placed at a same time under a same eyelid, for example, one near the other along the cul-de-sac. In some embodiments, one insert is placed per day. In some embodiments, by the time a second insert is to be placed under the eyelid, the insert placed the day before is already eroded to minor remains or has completely disappeared from under the eye.

[0369] In some embodiments, inserts are placed twice, or three (or more) times per day, for example every 8 hours, or every 6 hours, as needed. In some embodiments, an insert is placed once, twice, or three times a week or at lower frequencies, e.g., once per month, according to the needs. Preferably, the frequency at which a patient places inserts under his or her eyelid is tailored to the patients and the administration frequency that they can follow most easily, which is usually, once daily. Other preferred administration frequencies are twice daily, or once every other day, or less frequently.

[0370] Exemplary conditions treatable by methods disclosed herein

[0371] In some embodiments, one or more of the following conditions can be treated: diabetic macular edema; cystoid macular edema; age related macular degeneration; diabetic retinopathy; geographic atrophy; retinitis pigmentosa; chronic central serous chorioretinopathy.

[0372] For example, drugs for treating conditions of the posterior segment may include analgesics, antibiotics, corticosteroids, immunosuppressants, carbonic anhydrase inhibitors, antibodies, vitamins, Chemotherapeutic s, folic acid analogs, antidiabetics, anti-VEGF, and agents for photodynamic therapy. Exemplary analgesics may include Paracetamol and NSAIDs (e.g., Flurbiprofen, Ketorolac, Diclofenac, Bromfenac and Nepafenac). Exemplary antibiotics may include Doxycycline, Tetracycline, Erythromycin, Minocycline, Penicillin, Gentamicin, Ceftazidime, Amikacin. Exemplary corticosteroids may include Dexamethasone and Triamcinolone acetonide.

[0373] Exemplary immunosuppressants may include Cyclosporine. Exemplary carbonic anhydrase inhibitors may include Acetazolamide (Diamox sequel®) and Etoxolamide.

[0374] Exemplary antibodies may include Secukinumab, Tocilizumab, Ustekinumab, Abatacept, and Rituximab. Exemplary vitamins may include Vitamin B12. Exemplary Chemotherapeutic s may include Carboplatin and Topotecan. Exemplary folic acid analogs may include Methotrexate. Exemplary antidiabetics may include insulin. Exemplary anti-VEGF may include Aflibercept, Ranibizumab, Bevacizumab, Brolucizumab, and Faricimab. Exemplary agent for photodynamic therapy is Verteporfin. Exemplary targets in the posterior segment may include Pain receptors (e.g., COX enzymes), Bacterial ribosomes, Glucocorticoid receptors, T-cell activation pathways, Carbonic anhydrase, cytokines (e.g., IL-17A, IL-6, IL- 12, IL-23), costimulatory molecules (e.g., CD80 / CD86), B-cells cluster of differentiation (e.g., CD20), Folate receptors, Bacterial ribosomes, DNA, Topoisomerase I, Dihydrofolate reductase, Retinal Ganglion Cells, Retinal Pigment Epithelium, Endothelial Cell, growth factors (e.g., VEGF-A, VEGF-B, PGF, VEGFand Angiopoietin-2), Abnormal blood vessels. Exemplary indications include: Ocular trauma, treatment-associated pain, Neovascularization, Ocular rosacea, Orbital cellulitis, Giant cell arteritis, Uveitis, AMD (Age-related macular degeneration), DME (Diabetic Macular Edema), Idiopathic or rclatcd-to-Bchcct’s disease uveitis, Glaucoma, Deficiency optic neuropathy, Scleritis, Pseudoscleritis, Endophthalmitis, Choroidal Neovascularization (CNV), diabetic retinopathy (DR), retinal vein occlusion (RVO), retinal vein occlusion.

[0375] Examples of drugs and their related targets and conditions are provided below: Pharmacologic Agents for Ocular Posterior Conditions

[0376] • Pharmacologic Group: Analgesics o Drug: Paracetamol o Indication: Ocular trauma treatment-associated pain o Administration Route: Oral o Affected Part of the Eye: General ocular pain o Biological Target: Pain receptors (e.g., COX enzymes) o Reference: Varela-Fernandez et al. (2020).

[0377] • Pharmacologic Group: NSAIDs o Drug: Flurbiprofen, Ketorolac, Diclofenac, Bromfenac, Nepafenac o Indication: Ocular trauma treatment-associated pain o Administration Route: Oral, Intravitreal o Affected Part of the Eye: General ocular pain o Biological Target: Pain receptors (e.g., COX enzymes) o Reference: Varela-Fernandez et al. (2020); Baranano et al. (2009).

[0378] • Pharmacologic Group: Antibiotics o Drug: Doxycycline o Indication: Neovascularization o Administration Route: Oral o Affected Part of the Eye: Retina o Biological Target: Bacterial ribosomes (inhibition of protein synthesis) o Reference: Samtani et al. (2009).

[0379] Pharmacologic Group: Antibiotics o Drug: Tetracycline o Indication: Ocular rosacea o Administration Route: Oral o Affected Part of the Eye: Eyelids / skin around the eye o Biological Target: Bacterial ribosomes (inhibition of protein synthesis) o Reference: Shen et al. (2010).

[0380] • Pharmacologic Group: Antibiotics o Drug: Erythromycin o Indication: Orbital cellulitis o Administration Route: Oral o Affected Part of the Eye: Orbit o Biological Target: Bacterial ribosomes (inhibition of protein synthesis) o Reference: Shen et al. (2010).

[0381] • Pharmacologic Group: Corticosteroids o Drug: Dexamethasone o Indication: Giant cell arteritis, Uveitis, AMD, DME o Administration Route: Oral, Subconjunctival, Intravitreal o Affected Part of the Eye: Retina, Uvea, Vitreous o Biological Target: Glucocorticoid receptors (anti-inflammatory effects) o Reference: Varela-Fernandez et al. (2020); Wong et al. (2018); Kwak and D’Amico (1992).

[0382] • Pharmacologic Group: Immunosuppressants o Drug: Cyclosporine o Indication: Idiopathic or rclatcd-to-Bchcct’s disease uveitis o Administration Route: Oral o Affected Part of the Eye: Uvea (iris, ciliary body) o Biological Target: T-cell activation pathways (inhibition) o Reference: Garcia (2011).

[0383] • Pharmacologic Group: Carbonic Anhydrase Inhibitors o Drug: Acetazolamide (Diamox sequel®) o Indication: Glaucoma o Administration Route: Oral o Affected Part of the Eye: Anterior segment (aqueous humor) o Biological Target: Carbonic anhydrase (reduction of aqueous humor production) o Reference: Ramsay et al. (2018); Kaur et al. (2002). Pharmacologic Group: Anti-VEGF o Drug: Aflibercept o Indication: AMD, DME, DR, RVO o Administration Route: Intravitreal o Affected Part of the Eye: Retina o Biological Target: VEGF-A, VEGF-B, PGF o Reference: Peynshaert et al. (2018); Bakri et al. (2007).

[0384] • Pharmacologic Group: Anti-VEGF o Drug: Ranibizumab o Indication: AMD, DME, DR, RVO o Administration Route: Intravitreal o Affected Part of the Eye: Retina o Biological Target: VEGF-A o Reference: Bakri et al. (2007).

[0385] • Pharmacologic Group: Anti-VEGF o Drug: Bevacizumab o Indication: AMD, DME, DR, RVO o Administration Route: Intravitreal o Affected Part of the Eye: Retina o Biological Target: VEGF-A o Reference: Bakri et al. (2007).

[0386] • Pharmacologic Group: Anti-VEGF o Drug: Brolucizumab o Indication: AMD, DME o Administration Route: Intravitreal o Affected Part of the Eye: Retina o Biological Target: VEGF-A o Reference: Maronas et al. (2019).

[0387] • Pharmacologic Group: Anti-VEGF o Drug: Faricimab o Indication: AMD, DME o Administration Route: Intravitreal o Affected Part of the Eye: Retina o Biological Target: VEGF and Angiopoietin-2 o Reference: Maronas et al. (2019).

[0388] • Pharmacologic Group: Photodynamic Therapy o Drug: Verteporfin o Indication: AMD, Choroidal Neovascularization (CNV) o Administration Route: Intravenous infusion o Affected Part of the Eye: Choroid, Retina o Biological Target: Abnormal blood vessels o Reference: Maronas et al. (2019).

[0389] • Examples for targets for retinal (or posterior segment treatments) are as follows: o Integrins receptors targets such as: avP3, avP5, a5pi, a5p3, avP6, avP8. o VEGF targets such as: VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-A, PDGFR-B, and FGFR o Wnt signaling pathway through the FZD4 and LRP5 / 6 receptors, as well as TSPAN12 o Exemplary drugs:

[0390] ■ Risuteganib targets integrins avP3, avP5, a5pi, and a5p3. It is indicated for diabetic macular edema (DME) and dry age-related macular degeneration (AMD) with geographic atrophy (GA).

[0391] ■ SF-0166, nesvategrast, targets integrins avP3, avP6, and avP8. It is indicated for age-related macular degeneration (AMD) and diabetic macular edema (DME).

[0392] ■ Volociximab, targets integrin a5pi and is indicated for subfoveal choroidal neovascularization (CNV) secondary to AMD .

[0393] • Additional anti-VEGFs: o Conbercept (KH902) 165 anti (VEGF- A, VEGF-B, PGF) o Pazopanib eye drops Tyrosine Kinase Inhibitor (TKI) o Sirolimus (Rapamycin) mTor Inhibitor o Pegaptanib anti (VEGF-A)

[0394] • Additional drugs: regorafenib, restoret, and axitinib implarv APIs

[0395] In some embodiments, the APIs are either hydrophobic or hydrophilic in nature. In some embodiments, the API may include one or more of Dexamethasone, bevacizumab (Avastin®), ranibizumab, (Lucentis®), aflibercept (EYLEA®), brolucizumab (Beovu®), faricimab (Vabysmo®).

[0396] In general, one or more of the following APIs can be used in embodiments of the present invention:

[0397] Steroids, such as dexamethasone, triamcinolone acetonide, and fluocinolone acetonide; NSAIDs, such as Nepafenac;

[0398] Antibiotics, such as the ones mentioned here: www(dot)sci-hub(dot)se / 10.1007 / 978- 981-10-5260-6_21;

[0399] Antioxidants, such as vitamin E, lutein, zeaxanthin, and methylprednisolone;

[0400] Exemplary drugs in trials for topical application to the posterior segment, such as squalamine lactate, pazopanib (Votrient), acrizanib, OTT166 (=SF0166), regorafenib, isopropyl unoprostone (Rescula).

[0401] Additional potential APIs are one or more of:

[0402] Acetylcholine chloride. Apraclonidine hydrochloride. Atropine sulfate. Azelastine hydrochloride. Bacitracin. Bacitracin zinc. Benoxinate hydrochloride. Bepotastine besilate. Besifloxacin hydrochloride. Betaxolol hydrochloride. Brimonidine tartrate. Bromfenac sodium. Carteolol hydrochloride. Cetirizine hydrochloride. Chloroprocaine hydrochloride. Ciprofloxacin hydrochloride. Cromolyn sodium. Cyclopentolate hydrochloride. Cysteamine hydrochloride. Dexamethasone sodium phosphate. Diclofenac sodium. Difluprednate. Dorzolamide hydrochloride. Epinastine hydrochloride. Fluorescein sodium. Flurbiprofen sodium. Ganciclovir. Gatifloxacin. Gentamicin sulfate. Ketorolac tromethamine. Levobunolol hydrochloride Levofloxacin. Lidocaine hydrochloride. Lodoxamide tromethamine. Moxifloxacin hydrochloride. Natamycin. Nepafenac. Ofloxacin. Oxymetazoline hydrochloride. Phenylephrine hydrochloride. Pilocarpine hydrochloride. Prednisolone sodium phosphate. Proparacaine hydrochloride. Sulfacetamide sodium. Tetracaine hydrochloride. Timolol maleate. Trimethoprim sulfate. Tropicamide. Chlortetracycline hydrochloride. Dapiprazole hydrochloride. Demecarium bromide. Dipivefrin hydrochloride. Emedastine difumarate. Gentamicin sulfate. Hydroxyamphetamine hydrobromide. Idoxuridine. Levobetaxolol hydrochloride. Levocabastine hydrochloride Metipranolol hydrochloride. Nedocromil sodium. Norfloxacin. Oxytetracycline hydrochloride. Pemirolast potassium. Pheniramine maleate. Pyrilamine maleate. Sulfacetamide sodium. Sulfisoxazole diolamine. Technetium tc-99m sodium pertechnetate generator. Tetracycline hydrochloride. Phenylephrine hydrochloride. Hydroxypropyl cellulose. Avacincaptad pegol sodium. Pegaptanib sodium.

[0403] Azithromycin. Bimatoprost. Brilliant blue G. Brinzolamide. Cyclosporine. Dexamethasone. Echothiophate iodide. Epinephrine. Erythromycin. FluoromethoIone

[0404] FluoromethoIone acetate / Gramicidin. Hydrocortisone. Hydrocortisone acetate. Latanoprost. Latanoprostene bunod. Loteprednol etabonate. Lotilaner. Medrysone. Methylprednisolone. Netarsudil dimesylate. Netarsudil mesylate. Omidenepag isopropyl. Perfluorohexyloctane. Prednisolone acetate. Rimexolone. Suprofen. Tafluprost. Timolol. Travoprost. Trifluridine. Triamcinolone acetonide. Trypan blue. Unoprostone isopropyl. Vidarabine.

[0405] Antibiotics: Azithromycin. Erythromycin. Gramicidin. Besifloxacin hydrochloride. Ciprofloxacin hydrochloride. Gatifloxacin. Gentamicin sulfate. Levofloxacin. Norfloxacin. Ofloxacin. Sulfacetamide sodium. Trimethoprim sulfate. Chlortetracycline hydrochloride. Oxytetracycline hydrochloride. Tetracycline hydrochloride. Tobramycin.

[0406] Steroids: Dexamethasone. FluoromethoIone. FluoromethoIone acetate. Hydrocortisone. Hydrocortisone acetate. Loteprednol etabonate. Methylprednisolone. Prednisolone acetate. Rimexolone. Triamcinolone acetonide. Medrysone. Dexamethasone sodium phosphate. Prednisolone sodium phosphate.

[0407] Prostaglandin Analogues (for Glaucoma): Bimatoprost. Latanoprost. Latanoprostene bunod. Tafluprost. Travoprost. Unoprostone isopropyl.

[0408] NSAIDs (Non-Steroidal Anti-Inflammatory Drugs): Suprofen. Bromfenac sodium. Diclofenac sodium. Difluprednate. Flurbiprofen sodium. Ketorolac tromethamine. Nepafenac.

[0409] Immunosuppressants: Cyclosporine.

[0410] Carbonic Anhydrase Inhibitors (for Glaucoma): Brinzolamide

[0411] Dyes: Brilliant blue G. Trypan blue.

[0412] Beta Blockers (for Glaucoma): Timolol. Betaxolol hydrochloride. Carteolol hydrochloride. Levobunolol hydrochloride. Timolol maleate. Metipranolol hydrochloride. Levobetaxolol hydrochloride.

[0413] Alpha-2 Adrenergic Agonists (for Glaucoma): Apraclonidine hydrochloride. Brimonidine tartrate. Carbonic Anhydrase Inhibitors (for Glaucoma): Dorzolamide hydrochloride.

[0414] Mast Cell Stabilizers / Antihistamines (for Allergy): Azelastine hydrochloride. Bepotastine besilate. Cetirizine hydrochloride. Epinastine hydrochloride. Lodoxamide tromethamine. Nedocromil sodium. Pemirolast potassium. Emedastine difumarate.

[0415] Prostaglandin Analogs (for Glaucoma): Tafluprost

[0416] Rho Kinase Inhibitors (for Glaucoma): Netarsudil dimesylate. Netarsudil mesylate. Cholinergics (for Glaucoma): Pilocarpine hydrochloride. Acetylcholine chloride.

[0417] Local Anesthetics: Benoxinate hydrochloride. Chloroprocaine hydrochloride. Lidocaine hydrochloride. Proparacaine hydrochloride. Tetracaine hydrochloride.

[0418] Mydriatics and Cycloplegics (for Pupil Dilation): Atropine sulfate. Cyclopentolate hydrochloride. Phenylephrine hydrochloride. Tropicamide. Hydroxyamphetamine hydrobromide. Dapiprazole hydrochloride.

[0419] Antivirals: Idoxuridine.

[0420] Others: Perfluorohexyloctane (used in ophthalmic surgery). Epinephrine (used in combination with local anesthetics). Omidenepag isopropyl (for Glaucoma). Vidarabine (antiviral drug). Cysteamine hydrochloride (for cystinosis). Fluorescein sodium (diagnostic dye). Hydroxypropyl cellulose (lubricant for dry eye). Technetium tc-99m sodium pertechnetate generator (radiopharmaceutical). Phenylephrine hydrochloride (decongestant and mydriatic). Pyrilamine maleate (antihistamine). Avacincaptad pegol sodium (for age-related macular degeneration). Pegaptanib sodium (for age- related macular degeneration).

[0421] Of these, preferable are water insoluble or very slightly soluble APIs, such as azithromycin, bimatoprost, brilliant blue g, brinzolamide, cyclosporine, dexamethasone, echothiophate iodide, epinephrine, erythromycin, fluorometholone, fluorometholone acetate, gramicidin, hydrocortisone, hydrocortisone acetate, latanoprost, latanoprostene bunod, loteprednol etabonate, lotilaner, medrysone, methylprednisolone, netarsudil dimesylate, netarsudil mesylate, omidenepag isopropyl, perfluorohexyloctane, prednisolone acetate, rimexolone, suprofen, tafluprost, timolol, travoprost, trifluridine, triamcinolone acetonide, trypan blue, unoprostone isopropyl, and vidarabine.

[0422] Exemplary methods of drug delivery and treatments

[0423] Referring now to Figure 3, showing a flowchart of an exemplary method for delivering a pharmaceutically active ingredient (API) to the posterior segment of an eye, according to some embodiments of the invention.

[0424] In some embodiments, the method includes one or more of the following actions:

[0425] 1. Placing an elastomeric matrix under an eyelid (302). In some embodiments, the placing comprises placing the elastomeric matrix in a hydrophilic environment adjacent to or in direct contact with a hydrophilic layer. In some embodiments, the elastomeric matrix comprises dispersed or suspended particles of the API within the composition.

[0426] 2. Allowing the API to be released from the elastomeric matrix into a conjunctival sac of the eye (304). In some embodiments, the matrix is placed and retained in place without clinical assistance. As used herein, “clinical assistance” refers to assistance provided by a healthcare professional in placing, positioning, or retaining the elastomeric matrix on the bulbar conjunctiva. In this context, healthcare professional may include physicians, nurses, optometrists, ophthalmologists, or other trained medical personnel. Clinical assistance does not include help provided by non-medical caregivers, such as family members or home care aids, nor does it include written instructions, packaging inserts, or educational materials intended to guide self-administration by the subject.

[0427] In some embodiments, the release is allowed for a period of time of at least one hour. In some embodiments, the elastomeric matrix comprises at least 30% by weight of ophthalmic demulcents. In some embodiments, the API particles have a size range of 0.01 to 20 micrometers. In some embodiments, the API is water-insoluble or very slightly soluble. In some embodiments, API comprises a steroid selected from the group consisting of dexamethasone and fluocinolone acetonide. In some embodiments, the elastomeric matrix avoids cyclodextrins or other solubilizing agents, and particularly avoids non-plasticizing solubilizing agents.

[0428] In some embodiments, the ophthalmic demulcents include polyvinyl alcohol (PVOH). In some embodiments, the drug availability of the API in the tear fluid is maintained for at least 12 hours or at least 24 hours after placing the insert in the eye. In some embodiments, the peak concentration of the API in the tear fluid depends upon the specific formulation of the elastomeric matrix. In some embodiments, a peak concentration of the API in the tear fluid is observed at 6 hours after placing the insert in the eye. In some embodiments, a peak concentration of the API is observed at 1 hour after placing the insert in the eye. In some embodiments, the elastomeric matrix remains stable after exposure to tear fluid. In some embodiments, remaining stable comprises keeping physical integrity. For example, while some of the matrix ingredients may dissolve or erode in the tear fluid, the matrix on the eye stays physically intact, rather than tearing or breaking.

[0429] Referring now to Figure 4, showing a flowchart of an exemplary method for treating a condition of the posterior segment of the eye, according to some embodiments of the invention.

[0430] In some embodiments, the method includes one or more of the following actions:

[0431] 1. Suspending or dispersing a pharmaceutically active ingredient (API) in an elastomeric matrix. In some embodiments, the elastomeric matrix comprising at least 50% ophthalmic demulcents. In some embodiments, the elastomeric matrix is configured to lengthen drug availability time in the tear fluid of the API after administration (402).

[0432] 2. Administering the elastomeric matrix comprising the API to the conjunctival sac of an eye affected by the condition (404). In some embodiments, the administering comprises placing the elastomeric matrix under the lower eyelid, for example, on the bulbar conjunctiva. Referring now to Figure 5, showing a flowchart of an exemplary method for delivering a pharmaceutically active ingredient (API) to a posterior segment of the eye, according to some embodiments of the invention.

[0433] In some embodiments, the method includes one or more of the following actions:

[0434] 1. Administering an elastomeric matrix to the conjunctival sac of an eye affected by a condition treatable by the delivering. In some embodiments, the administering comprises placing the elastomeric matrix under the lower eyelid, for example, on the bulbar conjunctiva.

[0435] In some embodiments, the elastomeric matrix is formulated to lengthen the availability of the API at the anterior surface of the eye. In some embodiments, the matrix comprising particles of the API suspended in the elastomeric matrix comprising at least 50% ophthalmic demulcents.

[0436] 2. Utilizing the lengthened bioavailability of the drug at the posterior segment of the eye to facilitate targeted delivery of the drug to the back of the eye, thereby delivering the drug to the back of the eye.

[0437] Exemplary Scleral Permeability values and Drug Selection

[0438] In some embodiments, the elastomeric matrix described herein is suitable for delivering pharmaceutically active ingredients (APIs) to the posterior segment of the eye following placement on the bulbar conjunctiva under an eyelid. In some embodiments, the matrix is formed from a composition comprising a film-forming polymer, a plasticizer, and water. In some embodiments, the polymer may be selected from pharmaceutically acceptable hydrophilic film-formers such as polyvinyl alcohol (PVA), hydroxypropyl methylcellulose (HPMC), methyl cellulose, alginic acid or a pharmaceutically acceptable salt thereof, hyaluronic acid or a pharmaceutically acceptable salt thereof, gelatine, or similar materials. In some embodiments, the plasticizer may include glycerol, propylene glycol, polyethylene glycol, sorbitol, or other compounds that modulate flexibility of the matrix and drug diffusion within and / or out of the matrix. In some embodiments, upon administration, the matrix enables sustained release of the incorporated API over a period of at least four hours. In some embodiments, this release occurs in close proximity to the scleral surface, allowing the API to reach the posterior segment (e.g., retina, choroid, or optic nerve), for example, by transscleral diffusion.

[0439] In some embodiments, this delivery mechanism is particularly well-suited for APIs with physicochemical properties favorable to transscleral diffusion. In some embodiments, the drug delivery platform is positioned directly over the sclera at the bulbar conjunctiva. In some embodiments, this placement, in combination with the chemical formulation of the matrix, assisting controlled release kinetics, supports consistent diffusion of APIs to the retina and choroid, and offers a non-invasive alternative to intravitreal injection.

[0440] Exemplary early treatments

[0441] In some embodiments, because the matrix does not penetrate the eye surface, it can be administered without the need for clinical intervention, is well tolerated, and it offers means for treating posterior segment of the eye and its associated ocular conditions at an earlier stage than would typically justify intravitreal or suprachoroidal therapy. In some embodiments, the same therapeutic approaches described herein, including the use of corticosteroids, anti-VEGF agents, complement inhibitors, and other APIs listed herein, are applicable to the early-stage forms of the same conditions they treat in their later stages. Conditions that may be treated in patients with early- stage conditions include diabetic macular edema, age-related macular degeneration, retinal vein occlusion, non-infectious posterior uveitis, geographic atrophy or other posterior segment diseases in which injections into the eye, including suprachoroidal and intravitreal injections, may not yet be clinically indicated but where intervention could be beneficial.

[0442] In some embodiments, the posterior eye segment condition is diabetic macular edema (DME). A patient may be diagnosed with diabetic macular edema (DME) in an early stage if, for example, fluorescein angiography reveals mild leakage within the macular region, as graded according to the Early Treatment Diabetic Retinopathy Study (ETDRS) or equivalent clinical guidelines.

[0443] In some such cases, central macular thickness (CMT) on optical coherence tomography (OCT) typically remains within or only slightly above the normal range (e.g., below about 300 pm), and best-corrected visual acuity (BCVA) is 20 / 40 or better.

[0444] When the patient shows greater macular thickening (e.g., CMT > 300 pm) and / or reduced visual acuity (e.g., worse than 20 / 40), the condition is generally considered clinically significant or center-involved DME rather than early stage.

[0445] Thus, in some embodiments, early stage DME can be characterized by leakage on fluorescein angiography graded as mild according to Early Treatment Diabetic Retinopathy Study (ETDRS) or equivalent clinical guidelines, or central macular thickness (CMT) less than 300 pm as measured by optical coherence tomography (OCT) using the device’s normative database; and visual acuity of 20 / 40 or better.

[0446] In some embodiments, the condition treated is early-stage age-related macular degeneration (AMD). The early-stage condition may be characterized, for example, by one or more of the following clinical findings: presence of drusen without associated intraretinal or subretinal fluid as confirmed by optical coherence tomography (OCT); presence of small or intermediate drusen, defined as drusen with diameters of 125pm or less, without pigment epithelial detachment or hemorrhage; or absence of neovascular membranes as confirmed by fluorescein angiography or optical coherence tomography angiography (OCT-A). In some embodiments, treatment may be initiated in such early-stage AMD cases before intravitreal injection therapy is considered indicated by prevailing clinical guidelines, for example, prior to the development of neovascular complications or geographic atrophy.

[0447] In some embodiments, a patient may be diagnosed with age-related macular degeneration (AMD) in an early stage if, for example, fundus examination or retinal imaging reveals small or intermediate drusen (< 125 pm) within the macular region, and if imaging findings confirm the absence of advanced or neovascular changes. For example, if optical coherence tomography (OCT) shows no subretinal or intraretinal fluid and a central macular thickness (CMT) within or only slightly above the normal range (for example, below about 300 pm), and if OCT angiography (OCT-A) or fluorescein angiography shows no choroidal neovascular membrane and no pigment epithelial detachment or hemorrhage.

[0448] In such cases, best-corrected visual acuity (BCVA) is generally 20 / 40 or better. When OCT or angiographic imaging reveals retinal fluid, neovascularization, or marked macular thickening (e.g., CMT > 300 pm), or when BCVA is worse than 20 / 40, the condition is typically classified as intermediate or neovascular AMD rather than early stage. Such cases are candidates for active treatment, most commonly intravitreal anti-VEGF or corticosteroid therapy.

[0449] Thus, in some embodiments, early-stage age-related macular degeneration is characterized by:

[0450] (a) small or intermediate drusen (<125 pm) with no pigment epithelial detachment or hemorrhage;

[0451] (b) absence of subretinal or intraretinal fluid confirmed by OCT;

[0452] (c) absence of neovascular membrane as assessed by OCT-A or fluorescein angiography; and

[0453] (d) or pigment alteration of the retinal pigment epithelium with or without atrophy.

[0454] In some embodiments, the posterior segment condition is non-infectious posterior uveitis. The disease may involve inflammation affecting the retina, choroid, or vitreous. In such embodiments, the disclosed technology may be used to treat the disease topically, e.g., by delivering to the retina drugs used in clinical practice to suppress intraocular inflammation or reduce associated vascular permeability. Such drugs may include corticosteroids (e.g., dexamethasone, fluocinolone acetonide), immunomodulatory agents (e.g., methotrexate, cyclosporine), and / or anti-VEGF agents (e.g., bevacizumab, ranibizumab, aflibercept). In some embodiments, the disclosed technology enables such treatments by non-invasive topical administration that maintains drug contact with the ocular surface for a prolonged period, thereby facilitating delivery to the posterior segment.

[0455] In some embodiments, treatment is initiated at an early stage of non-infectious posterior uveitis, for example, before systemic immunosuppressive therapy or intravitreal injections are clinically indicated. Early-stage disease may be characterized by mild vitreous haze or cellular infdtrate graded as <1+ on the Standardization of Uveitis Nomenclature (SUN) scale, absence of macular edema on OCT, or inflammation controlled with topical corticosteroids. In some such early-stage cases, the currently presented technology may support localized anti-inflammatory treatment delivered non-invasively, optionally preventing progression to disease stages requiring intraocular injection or systemic immunosuppression. In some embodiments, such early-stage treatment is enabled by topical administration that provides prolonged contact between the drug and the bulbar conjunctiva, allowing therapeutic levels to reach the posterior segment.

[0456] In some embodiments, a patient may be diagnosed with non-infectious posterior uveitis in an early stage if, for example, fundus examination or imaging reveals mild vitreous haze, anterior segment inflammation is observed, or cellular infdtration graded as <1+ on the Standardization of Uveitis Nomenclature (SUN) scale, and optical coherence tomography (OCT) shows no evidence of macular edema or subretinal fluid. In such cases, inflammation is typically controllable with local corticosteroid therapy, without requiring intraocular, systemic, or biologic treatment. When inflammation exceeds this level — such as vitreous haze or cells graded above 1+, or when macular edema or other structural complications are observed, the condition is generally classified as active or advanced posterior uveitis and may require intraocular corticosteroid injection or implant, and in more severe cases, systemic therapy with corticosteroids or biologic agents.

[0457] Thus, in some embodiments, early-stage non-infectious posterior uveitis is characterized by any two or more of the following criteria:

[0458] (a) mild vitreous haze or cells graded as <1+ on the Standardization of Uveitis Nomenclature (SUN) scale;

[0459] (b) absence of macular edema on OCT; and

[0460] (c) inflammation limited to a level that is controllable with local corticosteroids.

[0461] In some embodiments, the condition is retinal vein occlusion (RVO), such as central or branch RVO. RVO is characterized by impaired venous outflow, leading to macular edema and retinal hemorrhages. Standard therapy often involves intravitreal injections of anti-VEGF agents or corticosteroids and laser therapy. In some embodiments, early-stage RVO may present with mild cystoid changes or visual acuity of 20 / 40 or better, where intravitreal therapy may not yet be indicated. The disclosed technology may enable non-invasive topical delivery of drugs such as anti-VEGF agents (e.g., bevacizumab, ranibizumab, aflibercept) or corticosteroids (e.g., dexamethasone) via prolonged conjunctival contact, for treating RVO at initial or later stages.

[0462] In some embodiments, a patient may be diagnosed with RVO in an early stage if, for example, optical coherence tomography (OCT) reveals mild cystoid or diffuse retinal thickening without center-involving macular edema. In such cases, the central macular thickness (CMT) typically remains within or only slightly above the normal range (for example, below about 300 pm) based on the device’s normative database, and best-corrected visual acuity (BCVA) is 20 / 40 or better.

[0463] When OCT shows center-involving edema, substantial cystoid spaces, or CMT > 300 pm, or when BCVA is worse than 20 / 40, the condition is generally considered clinically significant or center- involving RVO rather than early stage.

[0464] Thus, in some embodiments, early-stage retinal vein occlusion is characterized by any two or more of the following criteria:

[0465] (a) mild cystoid changes on OCT without center-involving macular edema;

[0466] (b) a central macular thickness (CMT) less than 300 pm on OCT relative to the device’s normative database; and

[0467] (c) best corrected visual acuity of 20 / 40 or better.

[0468] In some embodiments, the posterior segment condition is geographic atrophy (GA). A patient may be diagnosed with geographic atrophy (GA) in an early stage if, for example, fundus autofluorescence (FAF) or near-infrared imaging reveals one or more small atrophic lesions that do not involve the foveal center, OCT findings of atrophy at the level of the retinal pigment epithelium, and optical coherence tomography angiography (OCT- A) or fluorescein angiography confirms the absence of choroidal neovascularization. In such cases, central visual function is typically preserved, and early intervention may be directed toward delaying foveal involvement and subsequent vision loss. When foveal atrophy or neovascular conversion occurs, the condition is generally classified as advanced GA or mixed atrophic-neovascular AMD and may require intravitreal therapy.

[0469] Thus, in some embodiments, early-stage GA is characterized by the following criteria:

[0470] (a) one or more small, well-demarcated atrophic lesions not involving the foveal center, as confirmed by fundus autofluorescence (FAF) or near-infrared imaging; and (b) absence of choroidal neovascularization as confirmed by optical coherence tomography angiography (OCT- A) or fluorescein angiography.

[0471] As used herein, ‘clinical guidelines recognized by ophthalmic practitioners’ refers to professional standards or consensus statements issued by recognized bodies (e.g., AAO, EURETINA, ETDRS) that guide decision-making in retinal disease management, including criteria for initiating intravitreal injections.

[0472] In some embodiments, evaluation of retinal thickness is performed using optical coherence tomography (OCT), wherein values are interpreted relative to the device’s normative database for age-matched populations .

[0473] In some embodiments, disease severity is assessed using standardized grading systems, including the Early Treatment Diabetic Retinopathy Study (ETDRS) leakage grading and the Standardization of Uveitis Nomenclature (SUN) vitreous haze or cell scale, as commonly practiced in clinical settings.

[0474] Exemplary criteria for drug selection

[0475] The drug delivery platform has been demonstrated to deliver dexamethasone to the retina and choroid in preclinical animal models, and to achieve therapeutic effects in clinical settings such as diabetic macular edema. Given the known scleral permeability and pharmacokinetic behavior of similar compounds, the matrix is expected to be suitable for other APIs having appropriate physicochemical properties. APIs with a molecular weight of less than approximately 1000 Da and an octanol-water partition coefficient (logP) between approximately 1 and 5 are generally expected to permeate the sclera and reach posterior ocular tissues following periocular administration. This includes corticosteroids, anti- angiogenic agents, and small-molecule tyrosine kinase inhibitors, such as fluocinolone acetonide, triamcinolone acetonide, difluprednate, regorafenib, pazopanib, axitinib, sunitinib, and PAN-90806.

[0476] The logP (octanol-water partition coefficient) of an API may be determined experimentally using the shake flask method in accordance with OECD Test Guideline 107, or may be predicted computationally using software such as ACD / Labs, ChemAxon, or other industry-standard tools. In some embodiments, small molecule APIs (e.g., with molecular weight of 1000 Da or below) with logP values between 1 and 5 show favorable scleral permeability.

[0477] Scleral permeability of an API can be measured using ex vivo diffusion studies across isolated scleral tissue from animal models (e.g., rabbit, pig, or human cadaveric sclera). In some such studies, the tissue is mounted in a Franz diffusion cell or similar apparatus, and the API is applied to the donor segment. Samples from the receptor segment are collected over time and quantified, typically by HPLC or LC-MS / MS. The permeability coefficient (P_sclera) is calculated using Fick’s law of diffusion and is typically expressed in cm / s. In some embodiments, the API has P sclera value greater than approximately 1 x 107cm / s. In some embodiments, the API exhibits a scleral permeability coefficient below 5 / 106cm / s, measured as described herein. Without being bound to theory, it is suggested that in some cases, higher permeability can lead to rapid anterior loss or off-target exposure before adequate posterior levels accumulate. In some embodiments, scleral permeability from U I O7to 5 / 106cm / s provides controlled diffusion compatible with some embodiments of the disclosed drug delivery platform.

[0478] Methods of manufacturing

[0479] In some embodiments, APIs having a log P value between approximately 1 and 5, such as dexamethasone, can be homogenized to form a uniform, milky suspension at a concentration between 1% and 5% (w / w) by homogenizing API powder of micrometric particles into a solution comprising at least 50% (w / w) water and the balance comprising polyvinyl alcohol (PVOH) and one or more plasticizers such as polyethylene glycol (PEG), propylene glycol, and glycerol. For example, dexamethasone can be mixed with this aqueous solution using a high-shear homogenizer or other suitable mixing device to form a milky, visually homogeneous suspension without any agglomerates of the API. Uniformity and agglomerate absence may be tested under a microscope. The resulting suspension may be poured into a mold and allowed to set, thereby forming an elastomeric matrix in which micrometric solid particles of the API are uniformly dispersed. This stepwise process provides a reproducible method for manufacturing an ophthalmic drug product comprising micrometric solid particles of an API with a log P between 1 and 5 in an elastomeric matrix.

[0480] Thus, an aspect of some embodiments includes a method of manufacturing an ophthalmic drug product, the method comprising obtaining a uniform dispersion of an API with log P of from 1 to 5 at a concentration of from 1% to 5% (w / v or w / w) in a hydrophilic liquid, adding the dispersion to a mold, and allowing the dispersion to set in the mold, e.g., by solvent evaporation, to obtain a drug product comprising micrometric solid particles of the API in an elastomeric matrix.

[0481] In some embodiments, the ration between the mass of the PVOH and the mass of the one or more plasticizers is between 1:2 and 1:30. In some embodiments, the PVOH includes PVOH of two or more types that differ from one another in chain length, hydrolysis degree, or both. Advantages of such elastomeric matrices for use as ophthalmic devices or drug products are discussed herein elsewhere.

[0482] Exemplary methods of use

[0483] In some embodiments, the elastomeric matrix comprises a pharmaceutically active ingredient (API) for use in delivering the API to the posterior segment of an eye by a method comprising placing the elastomeric matrix on a bulbar conjunctiva under an eyelid and allowing the API to be released from the elastomeric matrix to the bulbar conjunctiva. In some embodiments, the API reaches therapeutically effective levels in at least one of the retina, choroid, or optic nerve. In some embodiments, the elastomeric matrix comprises dispersed or suspended particles of the API within the matrix. In some embodiments, the allowing comprises allowing for at least one hour. In some embodiments, allowing the API to be released comprises allowing micrometric solid particles of the API to dissolve, entirely or partially, in tear fluid on the bulbar conjunctiva for a period of at least 4 hours. In some embodiments, the elastomeric matrix comprises at least 30% by weight of ophthalmic demulcents. In some embodiments, a solubility of the API in water at 25 °C and neutral pH is less than Img / ml. In some embodiments, the API comprises one or more of: Dexamethasone, Triamcinolone acetonide, Fluocinolone acetonide, Difluprednate, Pazopanib, Regorafenib, Axitinib, Sunitinib, or PAN-90806. In some embodiments, the API comprises a steroid selected from the group consisting of dexamethasone and fluocinolone acetonide. In some embodiments, the API comprises one or more of: Bevacizumab, Ranibizumab, Aflibercept, Brolucizumab, Faricimab, Pegaptanib, Conbercept, Prednisolone sodium phosphate, FluoromethoIone, Sirolimus (Rapamycin), Squalamine lactate, Isopropyl unoprostone, Nepafenac, Eifitegrast, Volociximab, Abicipar pegol, Risuteganib, Nesvategrast, Eplerenone, Acrizanib, OTT166 (SF0166). In some embodiments, the elastomeric matrix is free of native cyclodextrins. In some embodiments, the ophthalmic demulcents include polyvinyl alcohol (PVOH). In some embodiments, the method of use further comprising maintaining the API in the tear fluid for at least 6 hours after the placing. In some embodiments, a peak concentration of the API is observed in the tear fluid at 1 hour after the placing. In some embodiments, the placing is at a frequency lower than three times daily. In some embodiments, the elastomeric matrix is formed as an insert having a shape with an ascent greater than 45°, and the placing is with the ascent intersecting the opening of the eyelid. In some embodiments, the API is water insoluble or very slightly water insoluble. In some embodiments, the API has water solubility of less than Ig / L at 25°C and neutral pH. In some embodiments, the API has a molecular weight of less than 1000 Da and a log P value between 1 and 5. In some embodiments, the API has a scleral permeability coefficient of at least 1 x 107cm / s. In some embodiments, the use comprises treatment of a condition of the posterior segment of an eye by a method comprising placing the elastomeric matrix on a bulbar conjunctiva under an eyelid and allowing the API to be released from the elastomeric matrix to the bulbar conjunctiva. In some embodiments, the API is selected from the group consisting of fluocinolone acetonide, triamcinolone acetonide, difluprednate, regorafenib, pazopanib, axitinib, sunitinib, PAN-90806, and dexamethasone. In some embodiments, the posterior segment condition is selected from diabetic macular edema, posterior uveitis, age-related macular degeneration, geographic atrophy or retinal vein occlusion. In some embodiments, the treatment is initiated in a subject diagnosed with a posterior segment condition in a mild form characterized by one or more of: (a) CMT < 300 pm on OCT using the device’s normative database; (b) BCVA > 20 / 40; (c) no intraretinal or subretinal fluid on OCT; (d) no choroidal neovascular membrane on OCT- A or fluorescein angiography; and (e) SUN vitreous haze < 1+. In some embodiments, the elastomeric matrix is placed and retained under the eyelid by the subject without clinical assistance. In some embodiments, the elastomeric matrix comprises two types of PVOH that differ in chain length and / or degree of hydrolysis. In some embodiments, the two types being long chain fully hydrolyzed (LCFH) and short chain partially hydrolyzed (SCPH). In some embodiments, a ratio between the two types is about 1: 1. In some embodiments, the matrix is substantially free of cyclodextrin. In some embodiments, the matrix is substantially free of solubilizing agents. In some embodiments, the eye is permitted to blink normally during the use of the insert. In some embodiments, the lower eyelid completely covers the insert. In some embodiments, the elastomeric matrix has tensile strength of between 0.01 MPa and 2 MPa, Young’s modulus of between 0.01 MPa and 2 MPa, elongation at break of between 100% and 1000%, or any combination thereof. In some embodiments, the elastomeric matrix for use, where the use is for treating diabetic macular edema at an early stage of disease progression. In some embodiments, the diabetic macular edema at an early stage of disease progression is characterized by one or more of the following criteria: (a) leakage on fluorescein angiography graded as mild according to the Early Treatment Diabetic Retinopathy Study (ETDRS) or equivalent clinical guidelines and central macular thickness (CMT) less than 300 pm as measured by optical coherence tomography (OCT) using a normative database; and (b) leakage on fluorescein angiography graded as mild according to the Early Treatment Diabetic Retinopathy Study (ETDRS) or equivalent clinical guidelines and visual acuity of 20 / 40 or better. In some embodiments, the API for treating diabetic macular edema is selected from the group consisting of: corticosteroids, anti-VEGF agents, and nonsteroidal anti-inflammatory agents. In some embodiments, the elastomeric matrix for use is for treating age related macular degeneration (AMD) at an early stage of disease progression. In some embodiments, the AMD at an early stage of disease progression is characterized by one or more of the following criteria: (a) small or intermediate drusen (<125 pm) with no pigment epithelial detachment or hemorrhage; (b) absence of subretinal or intraretinal fluid confirmed by OCT ; (c) absence of neovascular membrane as assessed by OCT- A or fluorescein angiography; and (d) pigment alteration of the retinal pigment epithelium with or without atrophy. In some embodiments, the API for treating age related macular degeneration (AMD) is selected from the group consisting of complement inhibitors, antiinflammatory agents, neuroprotective agents. In some embodiments, the elastomeric matrix for use is for treating early-stage retinal vein occlusion. In some embodiments, the early-stage retinal vein occlusion is characterized by one or both of the following criteria: (a) mild cystoid changes on OCT without center-involving macular edema and a central macular thickness (CMT) less than 300 pm on OCT relative to the device’s normative database; and (b) mild cystoid changes on OCT without center- involving macular edema and best corrected visual acuity of 20 / 40 or better. In some embodiments, the API for treating early-stage retinal vein occlusion is selected from the group consisting of corticosteroids, immunomodulatory agents and anti-VEGF agents. In some embodiments, the elastomeric matrix for use is for treating early-stage non-infectious posterior uveitis. In some embodiments, the early-stage non-infectious posterior uveitis is characterized by any two or more of the following criteria: (a) mild vitreous haze or cells graded as <1+ on the Standardization of Uveitis Nomenclature (SUN) scale; (b) absence of macular edema on OCT; (c) inflammation limited to a level that is controllable with local corticosteroids; and (d) anterior segment inflammation. In some embodiments, the API for treating early-stage non-infectious posterior uveitis is selected from the group consisting of complement inhibitors and anti-VEGF agents. In some embodiments, the elastomeric matrix for use is for treating geographic atrophy at an early stage of disease progression. In some embodiments, the geographic atrophy at an early stage of disease progression is characterized by one or more of the following criteria: (a) one or more small, well-demarcated atrophic lesions not involving the foveal center, as confirmed by fundus autofluorescence (FAF) or near-infrared imaging; and (b) absence of choroidal neovascularization as confirmed by optical coherence tomography angiography (OCT- A) or fluorescein angiography; and (c) OCT finding of atrophy at the level of the retinal pigment epithelium. In some embodiments, the API for treating geographic atrophy is a complement inhibitor. Exemplary methods for delivering a pharmaceutically active ingredient (API) to the posterior segment of an eye

[0484] In some embodiments, a method for delivering a pharmaceutically active ingredient (API) to the posterior segment of an eye, comprises: a. placing an elastomeric matrix with API on a bulbar conjunctiva under an eyelid; b. allowing said API to be released from said elastomeric matrix composition to the bulbar conjunctiva. In some embodiments, wherein the elastomeric matrix comprises dispersed or suspended particles of said API within said matrix. In some embodiments, the allowing comprises allowing for at least one hour. In some embodiments, the elastomeric matrix comprises at least 30% by weight of ophthalmic demulcents. In some embodiments, the API comprises particles having a size range of 0.01 to 20 micrometers. In some embodiments, a solubility of the API in water at 25 °C and neutral pH is less than Img / ml. In some embodiments, a solubility of the API in water at 25°C and neutral pH is between 0.05 mg / ml and 0.5 mg / ml. In some embodiments, the API comprises a steroid selected from the group consisting of dexamethasone and fluocinolone acetonide. In some embodiments, the API comprises one or more of: Dexamethasone, Triamcinolone acetonide, Fluocinolone acetonide, Difluprednate, Pazopanib, Regorafenib, Axitinib, Sunitinib, or PAN-90806. In some embodiments, the API comprises one or more of: Bevacizumab, Ranibizumab, Aflibercept, Brolucizumab, Faricimab, Pegaptanib, Conbercept, Prednisolone sodium phosphate, FluoromethoIone, Sirolimus (Rapamycin), Squalamine lactate, Isopropyl unoprostone, Nepafenac, Eifitegrast, Volociximab, Abicipar pegol, Risuteganib, Nesvategrast, Eplerenone, Acrizanib, OTT166 (SF0166). In some embodiments, the elastomeric matrix does not comprise cyclodextrins and / or other non-plasticizing solubilizing agents. In some embodiments, the elastomeric matrix is free of native cyclodextrins. In some embodiments, the ophthalmic demulcents include polyvinyl alcohol (PVOH). In some embodiments, the method further comprises maintaining the API in the tear fluid for at least 6 hours after the placing. In some embodiments, a peak concentration of the API is observed in the tear fluid at 6 hours after the placing. In some embodiments, a peak concentration of the API is observed in the tear fluid at 1 hour after the placing. In some embodiments, the elastomeric matrix remains stable after exposure to tear fluid. In some embodiments, the elastomeric matrix retains structural integrity for at least 2 hours in simulated tear fluid. In some embodiments, the placing is at a frequency lower than three times daily. In some embodiments, the insert has a shape with an ascent greater than 45°. In some embodiments, the elastomeric matrix is according to the elastomeric matrixes disclosed herein. In some embodiments, the API is water insoluble or very slightly water soluble. In some embodiments, the API has water solubility of less than Ig / E at 25°C and neutral pH. In some embodiments, the API has a molecular weight of less than 1000 Da and a log P value between 1 and 5. In some embodiments, the API has a scleral permeability coefficient of at least 1 x 107cm / s. In some embodiments, the API comprises particles having a size from 0.01 micrometer to 20 micrometers. In some embodiments, the API is selected from the group consisting of fluocinolone acetonide, triamcinolone acetonide, difluprednate, regorafenib, pazopanib, axitinib, sunitinib, PAN-90806, and dexamethasone. In some embodiments, the posterior segment condition is selected from diabetic macular edema, posterior uveitis, age-related macular degeneration, geographic atrophy or retinal vein occlusion. In some embodiments, the treatment is initiated in a subject diagnosed with a posterior segment condition in a mild form characterized by one or more of: (a) CMT < 300 pm on OCT using the device’ s normative database; (b) BCVA > 20 / 40; (c) no intraretinal or subretinal fluid on OCT; (d) no choroidal neovascular membrane on OCT-A or fluorescein angiography; or (e) SUN vitreous haze < 1+. In some embodiments, the elastomeric matrix is placed and retained under the eyelid by the subject without clinical assistance. In some embodiments, the elastomeric matrix comprises two types of PVOH that differ in chain length and / or degree of hydrolysis. In some embodiments, the two types are LCFH and SCPH. In some embodiments, a ratio between the two types is about 1: 1. In some embodiments, the matrix is substantially free of cyclodextrin. In some embodiments, the matrix is substantially free of API non-plasticizing solubilizing agents. In some embodiments, the matrix comprises API non-plasticizing solubilizing agents. In some embodiments, the eye is permitted to blink normally during use of the insert. In some embodiments, placing the elastomeric matrix on the bulbar conjunctiva is in a manner allowing the eye to blink normally during the release of the API from the matrix. In some embodiments, the method further comprises blinking normally with the eyelid during the release of the API from the matrix. In some embodiments, the lower eyelid completely covers the insert. In some embodiments, the elastomeric matrix has tensile strength of between 0.01 MPa and 2 MPa, Young’s modulus of between 0.01 MPa and 2 MPa, elongation at break of between 100% and 1000%, or any combination thereof. In some embodiments,

[0485] In some embodiments, a method for delivering a pharmaceutically active ingredient (API) to the posterior segment of an eye, comprises: a. placing an elastomeric matrix comprising micrometric solid API particles on a bulbar conjunctiva under an eyelid; and b. allowing the API particles to dissolve in tear fluid on the bulbar conjunctiva for a period of at least 4 hours.

[0486] In some embodiments, a method for delivering a pharmaceutically active ingredient (API) to the posterior segment of an eye, comprises: a. placing an elastomeric matrix under an eyelid; wherein particles of the API are dispersed or suspended within the elastomeric matrix; b. allowing the API to be released from the elastomeric matrix into a conjunctival sac of the eye. In some embodiments, a method of local non-invasive delivery of a pharmaceutically active ingredient (API) to the posterior segment of an eye, the method comprises topically applying an elastomeric matrix on a bulbar conjunctiva under an eyelid of the eye; wherein the elastomeric matrix comprises particles of the API. In some embodiments, the particles are suspended in a suspending medium that contains at least 30% w / w ophthalmic demulcents. In some embodiments, the method further comprises maintaining the matrix in the eye for a period of between 1 hour and 1 week.

[0487] In some embodiments, a method of delivering a pharmaceutically active ingredient (API) to a posterior segment of the eye, comprises: a. administering an elastomeric matrix to a bulbar conjunctiva in the conjunctival sac of an eye affected by a condition treatable by the delivering; wherein the elastomeric matrix is formulated to lengthen the drug availability of the API at the anterior surface of the eye by being composed of at least 50% ophthalmic demulcents other than water dispersing therein micrometric particles of the API; and b. utilizing the lengthened drug availability of the drug at the anterior segment of the eye to facilitate targeted delivery of the drug to the posterior segment of the eye, thereby delivering the drug to the posterior segment of the eye.

[0488] In some embodiments, a method of delivering a drug to the posterior segment of an eye, comprises: a. providing a supply of the drug to a bulbar conjunctiva in the conjunctival sac of the eye; and b. maintaining the supply of the drug to the bulbar conjunctiva in the conjunctival sac for a drug supply period of at least 1 hour.

[0489] In some embodiments, a method of delivering a drug to the posterior segment of the eye, comprises: delivering the drug in the trans-scleral route without using any penetration enhancer, nor an injection.

[0490] In some embodiments, a method of delivering a drug to the posterior segment of an eye, the method comprises: contacting a portion of an elastomeric matrix with the bulbar conjunctiva of the eye and maintaining the contact for a time period of at least 10 minutes, optionally 30 min, optionally 1 hour, optionally 2 hours; wherein the matrix comprises microparticles of the drug dispersed in an elastic dispersing medium; the drug being effective in treating a condition of the posterior eye segment; and the contacting and maintaining are together effective in delivering the drug to the posterior segment of the eye.

[0491] In some embodiments, a method of delivering a drug to the posterior segment of an eye, the method comprises: contacting a portion of an elastomeric matrix with the bulbar conjunctiva of the eye and maintaining the contact for a time period of at least 10 minutes, optionally 30 min, optionally 1 hour, optionally 2 hours; wherein the matrix comprises the drug, water, one or more polymers with hydrogen bond-forming repeating units, and one or more plasticizers other than water in a combined mass at least double the combined mass of the one or more polymers; the drug being effective in treating a condition of the posterior eye segment, and the contacting and maintaining are together effective in delivering the drug to the posterior segment of the eye.

[0492] In some embodiments, a method of delivering a drug to the posterior segment of an eye, the method comprises: contacting a portion of an elastomeric matrix with the bulbar conjunctiva of the eye and maintaining the contact for a time period of at least 10 minutes, optionally 30 min, optionally 1 hour, optionally 2 hours; wherein the matrix comprises the drug, water, one or more polymers with hydrogen bond-forming repeating units, and one or more plasticizers other than water in a combined mass at least double the combined mass of the one or more polymers; the drug being effective in treating a condition of the posterior eye segment, and the contacting and maintaining are together effective in delivering the drug to the posterior segment of the eye.

[0493] In some embodiments, a method of delivering a drug to the posterior segment of an eye, the method comprises: contacting a portion of an elastomeric matrix with the bulbar conjunctiva of the eye and maintaining the contact for a time period of at least two hours; wherein volume of the matrix increases by no more than 100% after being immersed in water for 15 minutes at 25 °C, and a dog-bone shaped flat piece of elastomer made of the same composition as the elastomeric matrix, except for not including the drug, elongates by at least 100% without breaking when pulled at a rate of 40mm / min; the drug being effective in treating a condition of the posterior eye segment; and the contacting and maintaining are together effective in delivering the drug to the posterior segment of the eye.

[0494] In some embodiments, a method of delivering a drug to the posterior segment of an eye, the method comprises: contacting a portion of an elastomeric matrix with the bulbar conjunctiva under an eyelid of the eye and maintaining the contact for a time period of at least 2 hours; wherein the matrix comprises the drug and configured to stay under the eyelid when the eyeball moves in relation to the eyelid, the drug being effective in treating a condition of the posterior eye segment, and the contacting and maintaining are together effective in delivering the drug to the posterior segment of the eye.

[0495] In some embodiments, a method for delivering a pharmaceutically active ingredient (API) to the posterior segment of an eye via a trans-scleral route, comprises: a. placing an elastomeric matrix with API on a bulbar conjunctiva under an eyelid; b. allowing the API to be released from the elastomeric matrix composition to the bulbar conjunctiva.

[0496] In some embodiments, a method for delivering a pharmaceutically active ingredient (API) to the posterior segment of an eye, comprises: a. placing an elastomeric matrix with API on a bulbar conjunctiva under an eyelid; b. allowing the API to be released from the elastomeric matrix composition to the bulbar conjunctiva and reach the posterior segment of an eye via a trans-scleral route.

[0497] Exemplary insert

[0498] In some embodiments, an insert for use in the treatment of a condition of the posterior segment of an eye, comprises an elastomeric matrix comprises dispersed or suspended particles of an API suitable for treating the condition, the insert being sized and shaped to be placed on a bulbar conjunctiva under an eyelid. In some embodiments, the elastomeric matrix comprises at least 30% by weight of ophthalmic demulcents. In some embodiments, the API particles have a size range of 0.01 to 20 micrometers. In some embodiments, the elastomeric matrix comprises polyvinyl alcohol (PVOH) and one or more plasticizers. In some embodiments, the combined mass ratio of the plasticizers to PVOH is at least 2: 1, and the total weight of PVOH and plasticizers is at least 70% by weight of the elastomeric matrix, excluding water. In some embodiments, the matrix comprises one or more mucoadhesive materials. In some embodiments, the matrix is substantially free of cyclodextrins. In some embodiments, the mechanical properties of the elastomeric matrix include a tensile strength ranging from 0.05 to 2 MPa and an elongation at break between 100% to 900%. In some embodiments, the API is insoluble in water. In some embodiments, API comprises a water solubility at 25 °C of less than Ig / L. In some embodiments, API comprises particles having a size from 0.01 micrometer to 20 micrometers. In some embodiments, the elastomeric matrix comprises two types of PVOH that differ in chain length and / or degree of hydrolysis. In some embodiments, the two types being LCFH and SCPH. In some embodiments, a ratio between the two types is about 1: 1. In some embodiments, the matrix is substantially free of cyclodextrin. In some embodiments, matrix is substantially free of non-plasticizing solubilizing agents. In some embodiments, matrix comprises API non-plasticizing solubilizing agents. In some embodiments, lower eyelid completely covers the insert. In some embodiments, elastomeric matrix has tensile strength of between 0.01 MPa and 2 MPa, Young’s modulus of between 0.01 MPa and 2 MPa, elongation at break of between 100% and 1000%, or any combination thereof.

[0499] Exemplary ophthalmic composition

[0500] In some embodiments, an ophthalmic composition for delivering a pharmaceutically active ingredient (API) to the posterior segment of an eye, comprises: an elastomeric matrix comprising dispersed or suspended particles of the API within the composition; wherein the elastomeric matrix comprises at least 30% by weight of ophthalmic demulcents; and wherein the API particles have a size range of 0.01 to 20 micrometers; and wherein the elastomeric matrix composition comprises polyvinyl alcohol (PVOH). In some embodiments, at least 90% of the API particles have diameters of 10 microns or less. In some embodiments, at least 50% of the API particles have diameters of 5 microns or less. In some embodiments, a mass of the demulcents makes at least 50% of the mass of the composition. In some embodiments, the ophthalmic demulcents include PVOH, glycerin and polyethylene glycol. In some embodiments, a mass of the PVOH is less than half the mass of all the other demulcents in the composition together. In some embodiments, the API is water insoluble. In some embodiments, the API comprises a water solubility at 25°C of less than Ig / L. In some embodiments, the API comprises particles having a size from 0.01 micrometer to 20 micrometers. In some embodiments, the elastomeric matrix comprises two types of PVOH that differ in chain length and / or degree of hydrolysis. In some embodiments, the two types are LCFH and SCPH. In some embodiments, a ratio between the two types is about 1: 1. In some embodiments, the matrix is substantially free of cyclodextrin. In some embodiments, the matrix is substantially free of API non-plasticizing solubilizing agents. In some embodiments, the matrix comprises API nonplasticizing solubilizing agents. In some embodiments, when formed as an insert, wherein the lower eyelid completely covers the insert. In some embodiments, the elastomeric matrix has tensile strength of between 0.01 MPa and 2 MPa, Young’s modulus of between 0.01 MPa and 2 MPa, elongation at break of between 100% and 1000%, or any combination thereof.

[0501] Exemplary method of treating a condition of the posterior segment of the eye

[0502] In some embodiments, a method of treating a condition of the posterior segment of the eye, the method comprises: a. suspending or dispersing in an elastomeric matrix micrometric particles of a pharmaceutically active ingredient (API) suitable for treating the condition; the elastomeric matrix comprising at least 50% ophthalmic demulcents other than water; wherein the elastomeric matrix is configured to lengthen a drug availability of the API after administration; b. administering the elastomeric matrix comprising the API on a bulbar conjunctiva in the conjunctival sac of an eye affected by the condition.

[0503] In some embodiments, a method of treating a condition of the posterior segment of the eye, comprises: a. generating in the tear fluid of the eye a drug concentration of at least 10 pg / ml for a continuous period of at least 1 hour, preferably at least 2 hours, the drug being suitable for treating the condition, wherein the generating comprises: i. placing on a bulbar conjunctiva under the eyelid of the eye an ocular insert comprising the drug at a concentration of at least 1% w / w, and ii. keeping the ocular insert under the eyelid for at least 2 hours, preferably at least 4 hours.

[0504] In some embodiments, a method of treating a condition of the posterior segment of an eye, comprises delivering a drug to the posterior segment of the eye in a method according to any one of the methods claimed herein. In some embodiments, the condition is selected from the group consisting of diabetic macular edema, cystoid macular edema, age related macular degeneration, diabetic retinopathy, geographic atrophy, retinitis pigmentosa, chronic central serous. In some embodiments, the drug is dexamethasone.

[0505] In some embodiments, a method of treating a condition of the posterior segment of an eye, comprises: a. placing an elastomeric matrix under an eyelid of the eye; wherein micrometric particles of an API suitable for treating the condition are dispersed or suspended within the elastomeric matrix; and b. allowing the elastomeric matrix to stay in the eye until the API concentration in the tear fluid of the eye is higher than 20nmol / ml for at least 1 hour. In some embodiments, the allowing is until the API concentration in the tear fluid of the eye is higher than 20nmol / ml for at least 4 hours. In some embodiments, the allowing is until the API concentration in the tear fluid of the eye is higher than 40nmol / ml for at least 1 hour. In some embodiments, the allowing is until the API concentration in the tear fluid of the eye is higher than 40nmol / ml for at least 4 hours.

[0506] In some embodiments, a method of treating a condition of the posterior segment of an eye, comprises: a. placing an elastomeric matrix under an eyelid of the eye; wherein micrometric particles of an API for treating the condition are dispersed or suspended within the elastomeric matrix; and b. allowing the elastomeric matrix to stay in the eye until the API concentration in the tear fluid of the eye is higher than lOpg / ml for at least 1 hour. In some embodiments, the allowing is until the API concentration in the tear fluid of the eye is higher than lOpg / ml for at least 4 hours. In some embodiments, the allowing is until the API concentration in the tear fluid of the eye is higher than 20pg / ml for at least 1 hour. In some embodiments, the allowing is until the API concentration in the tear fluid of the eye is higher than 20pg / ml for at least 4 hours. In some embodiments, the API is dexamethasone.

[0507] Exemplary drug product

[0508] In some embodiments, a drug product is sized and shaped so that when inserted into the cul-de-sac the drug product contacts the lower bulbar conjunctiva across a contact area larger than 25mm2, optionally from 25mm2 to 50mm2. In some embodiments, the API is water insoluble or very slightly soluble in water at 25°C and neutral pH. In some embodiments, the API comprises particles having a size from 0.01 micrometer to 20 micrometers. In some embodiments, the elastomeric matrix comprises two types of PVOH that differ in chain length and / or degree of hydrolysis. In some embodiments, the two types being LCFH and SCPH. In some embodiments, a ratio between the two types is about 1: 1. In some embodiments, the matrix is substantially free of cyclodextrin. In some embodiments, the matrix is substantially free of API non-plasticizing solubilizing agents. In some embodiments, the matrix comprises API non-plasticizing solubilizing agents. In some embodiments, the lower eyelid completely covers the insert.

[0509] Exemplary methods of treatment

[0510] In some embodiments, a method of treating an eye inflicted by one or more of the following conditions: diabetic macular edema, cystoid macular edema, age related macular degeneration, diabetic retinopathy, geographic atrophy, retinitis pigmentosa, chronic central serous chorioretinopathy, comprises: a. placing an elastomeric matrix on a bulbar conjunctiva under an eyelid of the eye; wherein the elastomeric matrix comprises dispersed or suspended micrometric particles of the API within the composition; b. allowing the API to be released from the elastomeric matrix into the bulbar conjunctiva in a conjunctival sac of the eye. In some embodiments, the API is water insoluble or very slightly water soluble. In some embodiments, the API has water solubility of less than Ig / L at 25°C and neutral pH. In some embodiments, the API comprises particles having a size from 0.01 micrometer to 20 micrometers. In some embodiments, the elastomeric matrix comprises two types of PVOH that differ in chain length and / or degree of hydrolysis. In some embodiments, the two types being LCFH and SCPH. In some embodiments, a ratio between the two types is about 1: 1. In some embodiments, the matrix is substantially free of cyclodextrin. In some embodiments, the matrix is substantially free of API non-plasticizing solubilizing agents. In some embodiments, the matrix comprises API non-plasticizing solubilizing agents. In some embodiments, the eye is allowed to blink. In some embodiments, the lower eyelid completely covers the insert. In some embodiments, the elastomeric matrix has tensile strength of between 0.01 MPa and 2 MPa, Young’s modulus of between 0.01 MPa and 2 MPa, elongation at break of between 100% and 1000%, or any combination thereof.

[0511] General statements

[0512] As used herrein, “complement inhibitors” include pharmaceutically active substances that inhibit or modulate activation of the complement cascade, including inhibition of components of the classical, lectin, or alternative pathways, or of terminal complement complex formation. Exemplary complement inhibitors include inhibitors of C3 (for example, pegcetacoplan or POT- 4), inhibitors of C5 (for example, avacincaptad pegol, eculizumab, ravulizumab, tesidolumab), inhibitors of Factor B (for example, iptacopan) or Factor D (for example, lampalizumab, danicopan), and inhibitors of the classical pathway (for example, sutimlimab or Cl-esterase inhibitor), as well as derivatives, fragments, fusion proteins, gene-therapy constructs, nucleic-acid therapeutics, or other functionally equivalent agents that reduce complement activation or formation of the membrane-attack complex (MAC). In some embodiments, complement inhibitors are used for treating posterior-segment diseases such as geographic atrophy (GA), age-related macular degeneration (AMD), diabetic macular edema (DME), or non-infectious posterior uveitis, or for preventing complement-mediated tissue damage associated with retinal inflammation or degeneration.

[0513] As used herein, “anti-VEGF agents” include pharmaceutically active substances that inhibit or modulate the vascular endothelial growth factor (VEGF) pathway, including inhibition of VEGF-A, VEGF-B, VEGF-C, VEGF-D, placental growth factor (P1GF), or the VEGF receptors VEGFR-1, VEGFR-2, or VEGFR-3. Exemplary anti-VEGF agents include antibodies or antibody fragments such as bevacizumab, ranibizumab, aflibercept, brolucizumab, faricimab, conbercept, and abicipar pegol; nucleic-acid-based inhibitors such as aptamers (for example, pegaptanib); and small-molecule tyrosine-kinase inhibitors of VEGF receptors such as pazopanib, regorafenib, axitinib, sunitinib, sorafenib, cediranib, and PAN-90806, as well as pharmaceutically acceptable salts, solvates, prodrugs, and sustained-release formulations thereof. In some embodiments, anti- VEGF agents are used for treating posterior-segment diseases including neovascular age-related macular degeneration (nAMD), diabetic macular edema (DME), retinal vein occlusion (RVO), myopic choroidal neovascularization, or other sight-threatening conditions characterized by pathological angiogenesis or vascular leakage.

[0514] As used herein, “steroids” or “steroidal agents” refer to pharmaceutically active corticosteroids suitable for ophthalmic use, including natural or synthetic glucocorticoids and their pharmaceutically acceptable salts, esters, solvates, or prodrugs. Exemplary steroids include dexamethasone, fluocinolone acetonide, triamcinolone acetonide, difluprednate, prednisolone acetate, prednisolone sodium phosphate, fluorometholone, loteprednol etabonate, hydrocortisone, methylprednisolone, and betamethasone, as well as combinations or sustained-release formulations thereof. In some embodiments, steroids are used to suppress ocular inflammation, reduce vascular permeability, or prevent macular edema associated with posterior-segment diseases such as diabetic macular edema (DME), retinal vein occlusion (RVO), non-infectious posterior uveitis, age-related macular degeneration (AMD), or other inflammatory or edematous retinal conditions.

[0515] As used herein, “non-steroidal anti-inflammatory agents” or “NSAIDs” refer to pharmaceutically active compounds that reduce ocular inflammation or pain by inhibiting cyclooxygenase (COX)-mediated prostaglandin synthesis. Exemplary NSAIDs suitable for ophthalmic administration include diclofenac, ketorolac, bromfenac, nepafenac, flurbiprofen, indomethacin, ibuprofen, and celecoxib, as well as pharmaceutically acceptable salts, esters, prodrugs, or sustained-release formulations thereof. In some embodiments, NSAIDs are used for treating or preventing ocular inflammation, discomfort, or macular edema associated with surgical procedures, diabetic macular edema (DME), retinal vein occlusion (RVO), non-infectious uveitis, or other posterior-segment diseases involving prostaglandin-mediated vascular permeability.

[0516] As used herein, “immunomodulatory agents” refer to pharmaceutically active substances that suppress, modulate, or regulate immune responses involved in ocular inflammation. Exemplary immunomodulatory agents suitable for ophthalmic use include methotrexate, cyclosporine, tacrolimus, sirolimus (rapamycin), azathioprine, mycophenolate mofetil, and leflunomide, as well as biologic agents that inhibit immune mediators such as adalimumab, infliximab, rituximab, or interferon- a2b. Pharmaceutically acceptable salts, esters, prodrugs, sustained-release formulations, or locally-acting analogues thereof are encompassed. In some embodiments, immunomodulatory agents are used for treating posterior-segment inflammatory diseases such as non-infectious posterior uveitis, retinal vasculitis, or diabetic macular edema with an inflammatory component, optionally in combination with or as an alternative to corticosteroids to achieve long-term control while minimizing systemic exposure.

[0517] As used herein, “neuroprotective agents” refer to pharmaceutically active substances that preserve the structure or function of retinal or optic-nerve neurons, limit apoptosis, oxidative stress, or excito toxicity, or enhance mitochondrial stability and cellular resilience. Exemplary neuroprotective agents include brimonidine, citicoline, memantine, N-acetylcysteine, rasagiline, riluzole, isopropyl unoprostone, Risuteganib (Luminate®), Nesvategrast, and Coenzyme Q10, as well as pharmaceutically acceptable salts, esters, prodrugs, sustained-release formulations, or combinations thereof. In some embodiments, neuroprotective agents are used for treating or preventing neurodeg enerative ocular conditions such as age-related macular degeneration (AMD), geographic atrophy (GA), glaucoma, retinal vein occlusion (RVO), or diabetic macular edema (DME), particularly to preserve photoreceptor or ganglion-cell viability and maintain visual function.

[0518] As used herein with reference to quantity or value, the term “about” means “within ± 10 % of’.

[0519] The terms “comprises”, “comprising”, “includes”, “including”, “has”, “having” and their conjugates mean “including but not limited to”.

[0520] The term “consisting of’ means “including and limited to”.

[0521] The term “consisting essentially of’ means that the composition, method or structure may include additional ingredients, steps and / or parts, but only if the additional ingredients, steps and / or parts do not materially alter the basic and novel characteristics of the claimed composition, method or structure.

[0522] As used herein, the singular forms “a”, “an” and “the” include plural references unless the context clearly dictates otherwise. For example, the term “a compound” or “at least one compound” may include a plurality of compounds, including mixtures thereof.

[0523] Throughout this application, embodiments of this invention may be presented with reference to a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as “from 1 to 6” should be considered to have specifically disclosed subranges such as “from 1 to 3”, “from 1 to 4”, “from 1 to 5”, “from 2 to 4”, “from 2 to 6”, “from 3 to 6”, etc.; as well as individual numbers within that range, for example, 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range.

[0524] Whenever a numerical range is indicated herein (for example “10-15”, “10 to 15”, or any pair of numbers linked by these another such range indication), it is meant to include any number (fractional or integral) within the indicated range limits, including the range limits, unless the context clearly dictates otherwise. The phrases “range / ranging / ranges between” a first indicate number and a second indicate number and “range / ranging / ranges from” a first indicate number “to”, “up to”, “until” or “through” (or another such range-indicating term) a second indicate number are used herein interchangeably and are meant to include the first and second indicated numbers and all the fractional and integral numbers therebetween.

[0525] Unless otherwise indicated, numbers used herein and any number ranges based thereon are approximations within the accuracy of reasonable measurement and rounding errors as understood by persons skilled in the art.

[0526] As used herein the term “method” refers to manners, means, techniques and procedures for accomplishing a given task including, but not limited to, those manners, means, techniques and procedures either known to, or readily developed from known manners, means, techniques and procedures by practitioners of the chemical, pharmacological, biological, biochemical and medical arts.

[0527] As used herein, the term “treating” includes abrogating, substantially inhibiting, slowing or reversing the progression of a condition, substantially ameliorating clinical or aesthetical symptoms of a condition or substantially preventing the appearance of clinical or aesthetical symptoms of a condition. It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination or as suitable in any other described embodiment of the invention. Certain features described in the context of various embodiments are not to be considered essential features of those embodiments, unless the embodiment is inoperative without those elements.

[0528] Various embodiments and aspects of the present invention as delineated hereinabove and as claimed in the claims section below find experimental support in the following examples.

[0529] EXAMPLES

[0530] Reference is now made to the following examples, which together with the above descriptions illustrate some embodiments of the invention in a non-limiting fashion.

[0531] Pharmacokinetic studies

[0532] In some embodiments, the API delivered to the posterior surface of the eye, to treat a condition of the posterior eye segment (e.g., diabetic macular edema; cystoid macular edema; retinal vein occlusion, or age-related macular degeneration) is dexamethasone. Dexamethasone is preferably more than 2% w / w of the insert, for example, 2%, 3%, 4%, 5%, 6%, or 7%, 10%, 15%, or 20%.

[0533] Referring now to Figures 6a-c showing the results of a pharmacokinetic study that investigated the delivery of dexamethasone to the posterior eye segment, and particularly to the choroid-retina, of New-Zealand albino rabbits. Inserts were placed in the rabbit’s eyes, and after predetermined time, the animals were sacrificed, their eyes inoculated, taken apart to segments including tear fluid, cornea, and retina, homogenized, and were frozen until measurements were taken.

[0534] As can be seen in Figure 6a, Dexamethasone was found in tears, the cornea and in the retina. The concentration of Dexamethasone after administration of an insert carrying dexamethasone particles dispersed in demulcent rich matrix in rabbits’ eyes was measured by UPLC-MS / MS in tears, cornea, and retina. The final concentration of Dexamethasone (in ng / g) is presented as mean ± SD at 2h, 6h, and 24h timepoints. In all graphs the number of rabbits’ eyes n=4, except for the 24h, in which n=3, because in one of the eyes the matrix was not visible at that timepoint. It is noted that in some embodiments, dexamethasone levels of as little as lOng / g may be therapeutically effective in the retina, so Fig. 6a demonstrates that effective levels may be retained for 24 hours or more. Experimental data support the assumption that dexamethasone and other APIs delivered to the retina and choroid via the conjunctival route would also reach the optic nerve at therapeutically relevant concentrations.

[0535] Additionally, as can be seen in Figure 6b, the graphs showing results obtained from animals that received 2 products / eye (n=2). The final concentration of dexamethasone in each tissue was measured by UPLC-MS / MS, and the results are represented as mean of the data ± SD.

[0536] The results are shown from rabbits sacrificed 6 hours after placement of an insert under their eyelid. However, the inserts were taken out of half of the eyes after two hours. Eyes with the insert for the entire 6 hours had higher concentration of dexamethasone than eyes in which the inserts were removed at two hours. In the Figure, at the time-point of 6-hours, the higher values were measured in eyes that had the products in them for the entire 6 hours, and the lower values were measured in the eyes that had the product removed at t=2h. These results may be indicative of the clearance rate of dexamethasone from the different tissues.

[0537] Fig. 6b clearly shows that once the insert is taken out, dexamethasone levels drop sharply over time, while keeping the insert in the eye allows for a continuous presence of Dexamethasone in all the locations measured, with the dexamethasone levels between 2 and 6 hours after insert placement in the rabbit’s eye decreasing less steeply in the tears and cornea, and increase in the retina.

[0538] Eastly, a comparison between the product described herein and commercial eye drops (Tobradex® and Maxidex®) was assessed in the cornea and in the tear fluid, as shown in the graphs in Figure 6c.

[0539] The PK (pharmacokinetic) studies conducted with a dexamethasone insert as described herein showed a prolonged delivery of the drug to the front and to the back of the eye compared to commercial eye drops. Importantly, at 24h timepoint, there is still a low but significant level of dexamethasone detected in the retina if the product stays in the eye for the entire 24h period. The continuous delivery of the drug is believed to be a result of the continuous dissolution of the product in the eye, and the drug in the product.

[0540] Referring now to Figure 6d, showing a graph presenting the comparative results between conventional eye drops and an insert formulated as described herein. Dexamethasone concentrations were measured in human tear fluid at different times. It can be seen that at 6 hours, the concentration of Dexamethasone using conventional eye drops was below 10 pg / ml, while the concentration of Dexamethasone using the described insert was above 100 pg / ml.

[0541] Referring now to Figures 7a-c, which show clinical results obtained from three patients (Patients 1, 2, and 3), each self-administered one dexamethasone-containing insert as described herein twice daily. In each case, only one eye was treated, while the contralateral eye was left untreated as a control. The results demonstrate that treatment with the insert reduced central subfield thickness (CST) relative to the untreated control eye. In Patient 3, removal of the insert at week 3 was followed by an increase in CST, indicating a reversal of the improvement observed during treatment.

[0542] Figures 8a-c show examination results for patients 1, 2, and 3 at baseline, week 3 , and week 4. Each figure presents a representative optical coherence tomography (OCT) image and a corresponding foveal cross-sectional view illustrating the retinal layers around the fovea of an eye treated with dexamethasone twice daily. In Patients 1 and 2, areas of edema are circled to facilitate qualitative assessment of the improvement observed between time points.

[0543] Figures 9a-b present pre-clinical results obtained in albino New Zealand rabbits administered with one insert per eye (Figure 9a) or two inserts per eye (Figure 9b).

[0544] In Figure 9a, each time point represents the amount of drug remaining in an insert retrieved from the rabbit eye at that time point. The residual drug content within each matrix was quantified by HPEC, showing the relationship between matrix weight and drug concentration. The initial drug loading at time 0 was approximately 600 pg per insert. At the 24-hour time point, one insert was not recovered; it is unknown whether it had completely dissolved or been dislodged, and when this occurred within the preceding 18 hours. At 2 hours and 6 hours, approximately 110 pg of dexamethasone had been released. At 24 hours, the amount of drug released was approximately 410 pg (based on the average of the three eyes in which the insert was recovered) or 255 pg (if the missing insert is included as having no remaining drug).

[0545] Figure 9b presents results obtained in rabbits having one insert per eye together with results obtained in rabbits having two inserts per eye. The X-axis represents the amount of drug remaining in the insert recovered from the eye, and the Y-axis represents the weight of the recovered insert. The data were collected after various residence times of the inserts in the eyes, which are not indicated in the figure. A substantially linear relationship is observed between the amount of drug remaining in the matrix and the residual matrix weight, indicating that both drug and matrix material are gradually lost into the tear fluid. When two inserts were applied in the same eye, the amount of drug remaining per insert was approximately double that observed with a single insert, suggesting that drug release and matrix degradation occur independently for each insert. The amount of drug remaining in the matrix decreased with increasing residence time. Although the invention has been described in conjunction with specific embodiments thereof, it is evident that many alternatives, modifications and variations will be apparent to those skilled in the art. Accordingly, it is intended to embrace all such alternatives, modifications and variations that fall within the spirit and broad scope of the appended claims.

[0546] It is the intent of the applicant(s) that all publications, patents and patent applications referred to in this specification are to be incorporated in their entirety by reference into the specification, as if each individual publication, patent or patent application was specifically and individually noted when referenced that it is to be incorporated herein by reference. In addition, citation or identification of any reference in this application shall not be construed as an admission that such reference is available as prior art to the present invention. To the extent that section headings are used, they should not be construed as necessarily limiting. In addition, any priority document(s) of this application is / are hereby incorporated herein by reference in its / their entirety.

Claims

1. WHAT IS CLAIMED IS:

1. An elastomeric matrix comprising a pharmaceutically active ingredient (API) for use in delivering the API to the posterior segment of an eye by a method comprising placing the elastomeric matrix on a bulbar conjunctiva under an eyelid and allowing the API to be released from the elastomeric matrix to the bulbar conjunctiva.

2. The elastomeric matrix for use according to claim 1, wherein the API reaches therapeutically effective levels in at least one of the retina, choroid, or optic nerve.

3. The elastomeric matrix for use according to claim 1 or 2, wherein the elastomeric matrix comprises dispersed or suspended particles of the API within the matrix.

4. The elastomeric matrix for use according to any one of claims 1-3, wherein the allowing comprises allowing for at least one hour.

5. The elastomeric matrix for use according to any one of claims 1-4, wherein allowing the API to be released comprises allowing micrometric solid particles of the API to dissolve in tear fluid on the bulbar conjunctiva for a period of at least 4 hours.

6. The elastomeric matrix for use according to any one of claims 1-5, wherein the elastomeric matrix comprises at least 30% by weight of ophthalmic demulcents.

7. The elastomeric matrix for use according to any one of claims 1-6, wherein a solubility of the API in water at 25°C and neutral pH is less than Img / ml.

8. The elastomeric matrix for use according to any one of claims 1-7, wherein the API comprises one or more of: Dexamethasone, Triamcinolone acetonide, Fluocinolone acetonide, Difluprednate, Pazopanib, Regorafenib, Axitinib, Sunitinib, or PAN-90806.

9. The elastomeric matrix for use according to any one of claims 1-8, wherein the API comprises a steroid selected from the group consisting of dexamethasone and fluocinolone acetonide.

10. The elastomeric matrix for use according to any one of claims 1-9, wherein the API comprises one or more of: Bevacizumab, Ranibizumab, Aflibercept, Brolucizumab, Faricimab, Pegaptanib, Conbercept, Prednisolone sodium phosphate, FluoromethoIone, Sirolimus (Rapamycin), Squalamine lactate, Isopropyl unoprostone, Nepafenac, Lifitegrast, Volociximab, Abicipar pegol, Risuteganib, Nesvategrast, Eplerenone, Acrizanib, OTT166 (SF0166).

11. The elastomeric matrix for use according to any one of claims 1-10, wherein the elastomeric matrix is free of native cyclodextrins.

12. The elastomeric matrix for use according to any one of claims 1-11, wherein the ophthalmic demulcents include polyvinyl alcohol (PVOH).

13. The elastomeric matrix for use according to any one of claims 1-12, further comprising maintaining the API in the tear fluid for at least 6 hours after the placing.

14. The elastomeric matrix for use according to any one of claims 1-13, wherein a peak concentration of the API is observed in the tear fluid at 1 hour after the placing.

15. The elastomeric matrix for use according to any one of claims 1-14, wherein the placing is at a frequency lower than three times daily.

16. The elastomeric matrix for use according to any one of claims 1-15, wherein the elastomeric matrix is formed as an insert having a shape with an ascent greater than 45°, and the placing is with the ascent intersecting the opening of the eyelid.

17. The elastomeric matrix for use according to any one of claims 1-16, wherein the API is water insoluble or very slightly water insoluble.

18. The elastomeric matrix for use according to any one of claims 1-17, wherein the API has water solubility of less than Ig / L at 25 °C and neutral pH.

19. The elastomeric matrix for use according to any one of claims 1-18, wherein the API has a molecular weight of less than 1000 Da and a log P value between 1 and 5.

20. The elastomeric matrix for use according to any one of claims 1-19, wherein the API has a scleral permeability coefficient of at least 1 x 107cm / s.

21. The elastomeric matrix for use according to any one of claims 1-20, wherein the use comprises treatment of a condition of the posterior segment of an eye by a method comprising placing the elastomeric matrix on a bulbar conjunctiva under an eyelid and allowing the API to be released from the elastomeric matrix to the bulbar conjunctiva.

22. The elastomeric matrix for use according to any one of claims 1-21, wherein the API is selected from the group consisting of fluocinolone acetonide, triamcinolone acetonide, difluprednate, regorafenib, pazopanib, axitinib, sunitinib, PAN-90806, and dexamethasone.

23. The elastomeric matrix for use according to any one of claims 1-22, wherein the posterior segment condition is selected from diabetic macular edema, posterior uveitis, age-related macular degeneration, geographic atrophy or retinal vein occlusion.

24. The elastomeric matrix for use according to any one of claims 1-23, wherein the use is for treating a subject diagnosed with a posterior segment condition in a mild form characterized by one or more of:(a) CMT < 300 pm on OCT using the device’s normative database ;(b) BCVA > 20 / 40 ;(c) no intraretinal or subretinal fluid on OCT ;(d) no choroidal neovascular membrane on OCT- A or fluorescein angiography; or(e) SUN vitreous haze < 1+25. The elastomeric matrix for use according to any one of claims 1 to 24, wherein the elastomeric matrix is placed and retained under the eyelid by the subject without clinical assistance.

26. The elastomeric matrix for use according to any one of claims 1 to 25, wherein the elastomeric matrix comprises two types of PVOH that differ in chain length and / or degree of hydrolysis.

27. The elastomeric matrix for use according to any one of claims 1-26, wherein the two types being long chain fully hydrolyzed (LCFH) and short chain partially hydrolyzed (SCPH).

28. The elastomeric matrix for use according to any one of claims 1-27, wherein a ratio between the two types is about 1: 1.

29. The elastomeric matrix for use according to any one of claims 1-28, wherein the matrix is substantially free of cyclodextrin.

30. The elastomeric matrix for use according to any one of claims 1-29, wherein the matrix is substantially free of solubilizing agents.

31. The elastomeric matrix for use according to any one of claims 1-30, wherein the eye is permitted to blink normally during the use of the insert.

32. The elastomeric matrix for use according to any one of claims 1-31, wherein the lower eyelid completely covers the insert.

33. The elastomeric matrix for use according to any one of claims 1-32, wherein the elastomeric matrix has tensile strength of between 0.01 MPa and 2 MPa, Young’s modulus of between 0.01 MPa and 2 MPa, elongation at break of between 100% and 1000%, or any combination thereof.

34. The elastomeric matrix for use according to any one of claims 1 to 33, wherein the use is for treating diabetic macular edema at an early stage of disease progression.

35. The elastomeric matrix for use according to claim 34, wherein the diabetic macular edema at an early stage of disease progression is characterized by one or more of the following criteria:(a) leakage on fluorescein angiography graded as mild according to the Early Treatment Diabetic Retinopathy Study (ETDRS) or equivalent clinical guidelines and central macular thickness (CMT) less than 300 pm as measured by optical coherence tomography (OCT) using a normative database; and(b) leakage on fluorescein angiography graded as mild according to the Early Treatment Diabetic Retinopathy Study (ETDRS) or equivalent clinical guidelines and visual acuity of 20 / 40 or better.

36. The elastomeric matrix for use according to claim 34, wherein the API for treating diabetic macular edema is selected from the group consisting of: corticosteroids, anti-VEGF agents, and nonsteroidal anti-inflammatory agents.

37. The elastomeric matrix for use according to any one of claims 1 to 33, wherein the use is for treating age related macular degeneration (AMD) at an early stage of disease progression.

38. The elastomeric matrix for use according to claim 37, wherein the AMD at an early stage of disease progression is characterized by one or more of the following criteria:(a) small or intermediate drusen (<125 pm) with no pigment epithelial detachment or hemorrhage;(b) absence of subretinal or intraretinal fluid confirmed by OCT;(c) absence of neovascular membrane as assessed by OCT-A or fluorescein angiography; and(d) pigment alteration of the retinal pigment epithelium with or without atrophy.

39. The elastomeric matrix for use according to claim 37, wherein the API for treating age related macular degeneration (AMD) is selected from the group consisting of complement inhibitors, anti-inflammatory agents, neuroprotective agents.

40. The elastomeric matrix for use according to any one of claims 1 to 33, wherein the use is for treating early-stage retinal vein occlusion.

41. The elastomeric matrix for use according to claim 40, wherein the early-stage retinal vein occlusion is characterized by one or both of the following criteria:(a) mild cystoid changes on OCT without center-involving macular edema and a central macular thickness (CMT) less than 300 pm on OCT relative to the device’s normative database; and(b) mild cystoid changes on OCT without center-involving macular edema and best corrected visual acuity of 20 / 40 or better.

42. The elastomeric matrix for use according to claim 40, wherein the API for treating early-stage retinal vein occlusion is selected from the group consisting of corticosteroids, immunomodulatory agents and anti-VEGF agents.

43. The elastomeric matrix for use according to any one of claims 1-33, wherein the use is for treating early-stage non-infectious posterior uveitis.

44. The elastomeric matrix for use according to claim 43, wherein the early-stage non- infectious posterior uveitis is characterized by any two or more of the following criteria:(a) mild vitreous haze or cells graded as <1+ on the Standardization of Uveitis Nomenclature (SUN) scale;(b) absence of macular edema on OCT;(c) inflammation limited to a level that is controllable with local corticosteroids; and(d) anterior segment inflammation.

45. The elastomeric matrix for use according to claim 43, wherein the API for treating early-stage non-infectious posterior uveitis is selected from the group consisting of complement inhibitors and anti-VEGF agents.

46. The elastomeric matrix for use according to any one of claims 1 to 33, wherein the use is for treating geographic atrophy at an early stage of disease progression.

47. The elastomeric matrix for use according to claim 46, wherein the geographic atrophy at an early stage of disease progression is characterized by one or more of the following criteria:(a) one or more small, well-demarcated atrophic lesions not involving the foveal center, as confirmed by fundus autofluorescence (FAF) or near-infrared imaging; and(b) absence of choroidal neovascularization as confirmed by optical coherence tomography angiography (OCT- A) or fluorescein angiography; and(c) OCT finding of atrophy at the level of the retinal pigment epithelium.

48. The elastomeric matrix for use according to claim 46, wherein the API for treating geographic atrophy is a complement inhibitor.

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