Methods and devices for the treatment of ocular diseases in human subjects

Abstract

To provide methods and devices for the treatment of eye disorders in a human subject.SOLUTION: The present invention provides a method and device for non-surgically administering a drug formulation targeted to the suprachoroidal space (SCS) of the eye of a human subject in order to treat posterior ocular disorders or choroidal diseases. In one embodiment, the method comprises inserting hollow microneedle into the eye of an insertion site and injecting a drug formulation into suprachoroidal space through the inserted microneedle, wherein the injected drug formulation flows out of an insertion site and flows into suprachoroidal space during injection. In one embodiment, a fluid drug formulation comprises drug nanoparticles or drug microparticles.SELECTED DRAWING: None

Description

[Technical field]

[0001] Cross-reference to related applications This application claims priority from U.S. Provisional Application Nos. 61 / 724,144, filed November 8, 2012, 61 / 734,872, filed December 7, 2012, 61 / 745,237, filed December 21, 2012, 61 / 773,124, filed March 5, 2013, 61 / 785,229, filed March 14, 2013, 61 / 819,388, filed May 3, 2013, 61 / 873,660, filed September 4, 2013, and 61 / 898,926, filed November 1, 2013, all of which are incorporated by reference herein in their entireties for all purposes.

[0002] 2. Background of the Invention The present invention is generally in the field of ophthalmic therapeutics, and more particularly, relates to the use of microneedles for the injection of fluid drug formulations into ocular tissues for targeted localized drug delivery. [Background technology]

[0003] Delivery of drugs to the eye, especially macromolecular delivery and delivery to the posterior segment, is very difficult. Many inflammatory and proliferative diseases in the posterior segment require long-term pharmacological treatment. Examples of such diseases include macular degeneration, diabetic retinopathy, and uveitis. In addition, many choroidal diseases associated with inflammatory responses, proliferation, and angiogenesis require long-term pharmacological treatment. Delivery of effective doses of drugs to the posterior segment is difficult using traditional delivery methods such as topical application, which is less efficient, and systemic administration, which often causes significant side effects, and often does not reach the site of infection (Geroski & Edelhauser, Invest. Ophthalmol. Vis. Sci. 41:961-64 (2000)). For example, while eye drops are useful for treating conditions that develop on the outer surface of the eye or in the anterior tissues of the eye, eye drops are unable to significantly penetrate the eye, which may be necessary for the treatment of various retinal and choroidal diseases.

[0004] Direct injection into the eye using a conventional needle and syringe has been reported to be effective, but requires specialized training and has safety concerns (Maurice, J. Ocul. Pharmacol. Ther. 17:393-401 (2001)). It would also be desirable to be able to minimize the number and / or frequency of ocular injection procedures required to deliver a therapeutically effective amount of drug to the required ocular tissue site.

[0005] The suprachoroidal space (SCS) of the eye has been studied and described as a possible route of drug delivery for cannulation. See, e.g., Olsen et al., American J. Ophthalmology 142(5):777-87 (Nov. 2006); International Publication No. WO2007 / 100745.

[0006] Thus, it would be desirable to provide better, safer, and more effective techniques for delivering therapeutic agents directly to posterior ocular tissues to treat, for example, posterior ocular disorders. It would further be desirable to provide better, safer, and more effective techniques for delivering therapeutic agents directly to the SCS to treat choroidal diseases (e.g., choroidal diseases associated with vascular abnormalities). The present invention addresses these and other needs. [Prior art documents] [Patent documents]

[0007] [Patent Document 1] International Publication No. 2007 / 100745 [Non-patent literature]

[0008] [Non-Patent Document 1] Geroski & Edelhauser, Invest. Ophthalmol. Vis. Sci. 41:961-64 (2000) [Non-Patent Document 2] Maurice, J.Ocul.Pharmacol.Ther.17:393-401(2001) [Non-Patent Document 3] Olsen et al., American J. Ophthalmology 142(5):777-87(Nov.2006 Summary of the Invention [Means for solving the problem]

[0009] Summary of the Invention In one embodiment, the present invention relates to the injection of a drug formulation into the suprachoroidal space of the eye for targeted localized drug delivery for the treatment of non-surgical ophthalmic treatment in a human patient in need thereof, more particularly for the treatment of posterior ocular disorders, choroidal diseases, and other diseases associated with vascular abnormalities.

[0010] In one aspect of the present invention, a method for treating a posterior ocular disorder in a human subject in need of such treatment is provided. In one embodiment, the method comprises non-surgically administering an effective amount of a drug formulation to the suprachoroidal space (SCS) of the eye of a subject in need of such treatment. In a further embodiment, upon administration, the drug formulation flows out of the insertion site and is substantially localized in the posterior segment of the eye. In one embodiment, the posterior ocular disorder is an inflammatory condition of the eye, such as uveitis, scleritis, glaucoma, ocular sarcoidosis, optic neuritis, macular edema, diabetic retinopathy, macular degeneration, corneal ulcer, autoimmune disorder, ophthalmic manifestations of AIDS, optic nerve degeneration, geographic atrophy, choroidal disease, or retinitis. In one embodiment, the condition is acute. In another embodiment, the condition is chronic.

[0011] In another embodiment, a method for treating choroidal disease (e.g., ocular neovascularization, polypoidal choroidal vasculopathy, choroidal sclerosis, central sirrus choroidopathy, multifocal choroidopathy, or choroidal dystrophy (e.g., central gyrate choroidal dystrophy, serpiginous choroidal dystrophy, total central choroidal atrophy)) is provided. In one embodiment, the method comprises non-surgically administering to the SCS of a patient in need of treatment a drug formulation comprising an effective amount of an anti-inflammatory drug, a vascular endothelial growth factor (VEGF) regulator, a platelet-derived growth factor (PDGF) regulator, an angiogenesis inhibitor, an immunosuppressant, a vascular permeability inhibitor, or a combination thereof. In a further embodiment, administration of an effective amount of a drug to the SCS results in a greater efficiency or therapeutic effect of the drug compared to the same drug dose administered intravitreally, intracamerally, topically, parenterally, or orally. In yet a further embodiment, a patient treated with SCS drug therapy has not previously responded to a different type of treatment for the same condition.

[0012] In yet another embodiment, a method for reducing subretinal exudation and bleeding in a subject is provided.In a further embodiment, the method comprises non-surgically administering a drug formulation comprising an effective amount of an anti-inflammatory drug, a vascular endothelial growth factor (VEGF) regulator, a platelet-derived growth factor (PDGF) regulator, an angiogenesis inhibitor, an immunosuppressant, a vascular permeability inhibitor, or a combination thereof, to the SCS of a patient in need of treatment, and administering the drug formulation reduces the subretinal exudation and bleeding experienced by the patient compared to administering the same dosage of the drug to the patient intravitreally.

[0013] In one embodiment, a method of treating a posterior ocular disorder or choroidal malady in a human patient is provided. In a further embodiment, the method comprises non-surgically administering an effective amount of a drug formulation to the suprachoroidal space (SCS) of the eye of a subject in need of treatment for a posterior ocular disorder or choroidal malady. In a further embodiment, the intraocular elimination half-life (t 1 / 2 ) is the intraocular t 1 / 2 In another embodiment, the mean peak intraocular concentration (C max ) when administered to the SCS by the methods described herein, the intraocular C of a drug when administered intravitreally, intracamerally, topically, parenterally, or orally. max In another embodiment, the mean intraocular area under the curve (AUC 0-t ) is the intraocular AUC of a drug when administered intravitreally, intracamerally, topically, parenterally, or orally when administered to the SCS by the methods described herein. 0-t In yet another embodiment, the time to peak intraocular concentration of the drug (t max ) when administered to the SCS by the methods described herein, represents the intraocular t maxIn further embodiments, the drug formulation comprises an effective amount of an anti-inflammatory drug (e.g., a steroid or an NSAID), a VEGF modulator (e.g., a VEGF antagonist), a platelet-derived growth factor (PDGF) modulator, an angiogenesis inhibitor, an immunosuppressant, a vascular permeability inhibitor, or a combination thereof.

[0014] In one embodiment, a method for treating a posterior ocular disorder or choroidal disease in a human subject comprises delivering a drug formulation to the SCS of the eye of the human subject in need of treatment via a hollow microneedle. In a further embodiment, delivering the drug formulation comprises inserting a hollow microneedle into the eye of the human subject at an insertion site, the microneedle having a tip with an opening, and allowing the drug formulation to flow from the insertion site into the SCS cavity through the inserted microneedle for a period of time. The drug formulation administered to the SCS, in one embodiment, flows out of the insertion site and is substantially localized to the posterior segment of the eye, thereby increasing the therapeutic efficacy of the dose of drug compared to the therapeutic efficacy of the same drug dose administered by another means (e.g., intravitreal, intracavitary, topical, parenteral, and / or oral). In another embodiment, the dose of drug sufficient to induce a therapeutic response when administered to the SCS is less than the dosage of drug sufficient to induce a therapeutic response when administered intravitreal, topical, parenteral, or oral. In another embodiment, the drug formulation is delivered to the SCS by a hollow microneedle inserted into the sclera at the equator of the eye or between the equator and the limbus of the eye. In a further embodiment, the hollow microneedle is inserted at 90° (perpendicular) to the insertion site.

[0015] The drug formulation delivered by the methods described herein, in one embodiment, comprises an effective amount of an anti-inflammatory drug (e.g., a steroid or a nonsteroidal anti-inflammatory drug (NSAID)). In another embodiment, the drug delivered to the SCS by the methods described herein is a steroid, an immunosuppressant, an antimetabolite, a T-cell inhibitor, an alkylating agent, a biologic, a TNFα antagonist, an interleukin antagonist, a neuroprotectant, a vascular endothelial growth factor (VEGF) antagonist, a platelet-derived growth factor (PDGF) antagonist, or a combination thereof. In another embodiment, the drug affects inflammation, neuroprotection, complement inhibition, drusen formation, scar formation, reduction of the choriocapillaris or choroidal neocasvularization. In another embodiment, the drug formulation comprises microparticles and / or nanoparticles of the drug. In one embodiment, the drug formulation comprises a D 50 is 1μm or less and / or D 99 Contains fine particles smaller than 10 μm.

[0016] As provided above, one aspect of the present invention includes a method of treating a posterior ocular disorder in a human subject in need of such treatment, comprising non-surgically administering a drug formulation to the SCS of the eye of the human subject, wherein the drug formulation flows out of the insertion site and is substantially localized to the posterior segment upon administration. In one embodiment of the method, intraocular pressure is substantially constant during administration of the drug formulation to the SCS. In another embodiment, administration of the drug formulation to the SCS of the eye reduces the number of side effects or reduces the severity of one or more side effects compared to intravitreal, intracameral, topical, oral, or parenteral administration of the same drug dose.

[0017] In one aspect of the present invention, the present invention relates to a method for treating a choroidal malady in a human patient in need of such treatment. In one embodiment, the method comprises non-surgically administering to the suprachoroidal space (SCS) of the patient's eye a drug formulation comprising an effective amount of an anti-inflammatory drug, a vascular endothelial growth factor (VEGF) regulator, a platelet-derived growth factor (PDGF) regulator, an angiogenesis inhibitor, an immunosuppressant, or a vascular permeability inhibitor. In a further embodiment, the human patient has previously been treated for the choroidal malady and has not responded adequately to the treatment prior to administration of the drug formulation.

[0018] In another aspect of the present invention, the present invention relates to a method for treating ocular neovascularization in a human patient in need of such treatment. In one embodiment, the method comprises non-surgically administering to the suprachoroidal space (SCS) of the patient's eye a drug formulation comprising an effective amount of an anti-inflammatory drug, a vascular endothelial growth factor (VEGF) regulator (e.g., a VEGF antagonist), a platelet-derived growth factor (PDGF) regulator (e.g., a PDGF antagonist), an angiogenesis inhibitor, an immunosuppressant, or a vascular permeability inhibitor. In a further embodiment, the ocular neovascularization is choroidal neovascularization. In one embodiment, the human patient to be treated for ocular neovascularization has previously been treated for ocular neovascularization before administration of the drug formulation and has not responded adequately to the treatment.

[0019] The drug formulation delivered by the methods described herein, in one embodiment, comprises an effective amount of an anti-inflammatory drug (e.g., a steroidal compound or a nonsteroidal anti-inflammatory drug (NSAID)). In another embodiment, the drug delivered to the SCS by the methods described herein is a vascular permeability inhibitor, an angiogenesis inhibitor, or a VEGF modulator (e.g., a VEGF antagonist). In one embodiment, the VEGF antagonist is a VEGF receptor antagonist or a soluble VEGF receptor. In one embodiment, the drug formulation comprises a D 50 is 1μm or less and / or D 99 In a further embodiment, the drug formulation comprises triamcinolone.

[0020] In one embodiment of the present invention, a method of treating a choroidal or posterior ocular disorder in a human patient in need of such treatment is provided, comprising non-surgically administering a drug formulation to the SCS of the eye of the human subject, wherein the intraocular pressure is substantially constant during administration of the drug formulation to the SCS. In another embodiment, administration of the drug formulation to the SCS of the eye of a patient in need of such treatment reduces the number of side effects or reduces the severity of one or more side effects compared to intravitreal, intracameral, topical, oral, or parenteral administration of the same drug dose. In one embodiment, the side effect reduced by the methods described herein is subretinal exudation and / or subretinal hemorrhage. For example, the present invention provides the following: (Item 1) 1. A method of treating a posterior ocular disorder in a human subject in need thereof, comprising: non-surgically administering an effective amount of a drug formulation to the suprachoroidal space (SCS) of the eye of the human subject in need of treatment for the posterior ocular disorder; Upon administration, the drug formulation flows from the insertion site and is substantially localized in the posterior segment of the eye. (Item 2) 2. The method of claim 1, wherein the administering step comprises inserting a hollow microneedle into the sclera at an insertion site, the microneedle having a tip with an opening, and injecting the drug formulation into the SCS through the inserted microneedle. (Item 3) 3. The method of claim 2, wherein the insertion site is about the equator of the eye or between the equator and the limbus of the eye. (Item 4) Item 4. The method according to item 2 or 3, wherein the length of the microneedle is about 500 μm to about 1500 μm. (Item 5) 5. The method according to any one of items 2 to 4, wherein the microneedles have a diameter of about 200 μm to about 600 μm. (Item 6) 6. The method according to any one of items 2 to 5, wherein the bevel angle of the microneedle is about 5° to about 30°. (Item 7) 7. The method according to any one of items 2 to 6, wherein the height of the bevel is about 100 μm to about 500 μm. (Item 8) 8. The method according to any one of items 2 to 7, wherein the microneedle is inserted into the sclera without penetrating the sclera. (Item 9) 9. The method according to any one of items 2 to 8, wherein the microneedle is inserted into the sclera without penetrating the choroid. (Item 10) 10. The method according to any one of items 2 to 9, wherein the microneedles comprise beveled ends. (Item 11) Item 11. The method according to item 10, wherein the angle of the beveled end is about 10° to about 20°. (Item 12) 12. The method according to item 10 or 11, wherein the aspect ratio of the beveled end is about 1:1.5 to about 1:10. (Item 13) 13. The method according to any one of items 10 to 12, wherein the height of the bevel end is about 500 μm to about 1 mm. (Item 14) 14. The method according to any one of items 2 to 13, wherein the microneedles have a length of about 500 μm to about 1500 μm. (Item 15) Item 15. The method according to item 14, wherein the length of the microneedle is about 500 μm to about 1000 μm. (Item 16) 16. The method according to any one of items 2 to 15, wherein the microneedle comprises a cylindrical shaft having an outer diameter of about 200 microns to about 600 microns. (Item 17) 17. The method of any one of items 1 to 16, wherein the effective amount of the drug formulation is present in a volume of about 10 μL to about 200 μL. (Item 18) 18. The method according to any one of items 1 to 17, wherein the effective amount of the drug formulation is present in a volume of about 30 μL to about 100 μL. (Item 19) 19. The method according to any one of items 1 to 18, wherein the drug formulation comprises a suspension of microparticles. (Item 20) 20. The method according to any one of items 1 to 19, wherein the drug formulation comprises a suspension of nanoparticles. (Item 21) D of the fine particles 50 20. The method according to item 19, wherein the thickness is 2 μm or less. (Item 22) D of the nanoparticles 50 21. The method according to item 20, wherein the optical density is 1000 nm or less. (Item 23) D of the nanoparticles 50 21. The method according to item 20, wherein the optical density is 500 nm or less. (Item 24) D of the nanoparticles 50 21. The method according to item 20, wherein the optical density is 250 nm or less. (Item 25) D of the microparticles or nanoparticles 99 21. The method according to item 19 or 20, wherein the thickness is 10 μm or less. (Item 26) D of the microparticles or nanoparticles 99 21. The method according to item 19 or 20, wherein the thickness is 5 μm or less. (Item 27) 27. The method according to any one of items 2 to 26, wherein the microneedle is inserted into the surface of the sclera at an angle of about 70° to about 110°. (Item 28) 28. The method according to any one of items 2 to 27, wherein the microneedle is inserted into the surface of the sclera at an angle of about 90°. (Item 29) 29. The method according to any one of items 1 to 28, wherein the pharmaceutical formulation comprises an anti-inflammatory drug. (Item 30) 30. The method of claim 29, wherein the anti-inflammatory drug is selected from mycophenolate, infliximab, nepafenac, azathioprine, cyclosphosphamide, dexamethasone, difluprednate, fluocinolone, fluorometholone, loteprednol, prednisolone acetate, prednisolone sodium phosphate, rimexolone, triamcinolone, bromfenac, diclofenac, flurbiprofen, ketorolac, adalimumab, etanercept, certolizumab, golimumab, daclizumab, rituximab, abatacept, basiliximab, belimumab, anakinra, efalizumab, alefacept, and natalizumab. (Item 31) 31. The method of claim 29 or 30, wherein the anti-inflammatory drug is mycophenolate. (Item 32) 31. The method of item 29 or 30, wherein the anti-inflammatory drug is infliximab. (Item 33) 31. The method of claim 29 or 30, wherein the anti-inflammatory drug is nepafenac. (Item 34) 31. The method of claim 29 or 30, wherein the anti-inflammatory drug is azathioprine. (Item 35) 31. The method of claim 29 or 30, wherein the anti-inflammatory drug is cyclosphosphamide. (Item 36) 31. The method of claim 29 or 30, wherein the drug is dexamethsone. (Item 37) 31. The method of claim 29 or 30, wherein the anti-inflammatory drug is difluprednate. (Item 38) 31. The method of claim 29 or 30, wherein the anti-inflammatory drug is fluocinolone. (Item 39) 31. The method of claim 29 or 30, wherein the anti-inflammatory drug is loteprednol. (Item 40) 31. The method of claim 29 or 30, wherein the drug is triamcinolone. (Item 41) 41. The method of claim 40, wherein the triamcinolone is triamcinolone acetonide. (Item 42) 31. The method of claim 29 or 30, wherein the anti-inflammatory drug is bromfenac. (Item 43) 31. The method of claim 29 or 30, wherein the anti-inflammatory drug is diclofenac. (Item 44) 31. The method of claim 29 or 30, wherein the anti-inflammatory drug is flurbiprofen. (Item 45) 31. The method of claim 29 or 30, wherein the anti-inflammatory drug is ketorolac. (Item 46) 31. The method of item 29 or 30, wherein the anti-inflammatory drug is adalimumab. (Item 47) 31. The method of item 29 or 30, wherein the anti-inflammatory drug is etanercept. (Item 48) 31. The method of item 29 or 30, wherein the anti-inflammatory drug is certolizumab. (Item 49) 31. The method of claim 29 or 30, wherein the anti-inflammatory drug is gotimumab. (Item 50) 31. The method of item 29 or 30, wherein the anti-inflammatory drug is daclizumab. (Item 51) 31. The method of item 29 or 30, wherein the anti-inflammatory drug is rituximab. (Item 52) 31. The method of item 29 or 30, wherein the anti-inflammatory drug is abatacept. (Item 53) 31. The method of item 29 or 30, wherein the anti-inflammatory drug is basiliximab. (Item 54) 31. The method of item 29 or 30, wherein the anti-inflammatory drug is belimumab. (Item 55) 31. The method of item 29 or 30, wherein the anti-inflammatory drug is anakinra. (Item 56) 31. The method of claim 29 or 30, wherein the anti-inflammatory drug is efalizumab. (Item 57) 31. The method of claim 29 or 30, wherein the anti-inflammatory drug is alefacept. (Item 58) 31. The method of item 29 or 30, wherein the anti-inflammatory drug is natalizumab. (Item 59) 31. The method according to any one of items 1 to 30, wherein the pharmaceutical formulation comprises a steroid. (Item 60) 30. The method according to any one of items 1 to 29, wherein the pharmaceutical formulation comprises a non-steroidal anti-inflammatory drug (NSAID). (Item 61) 29. The method of any one of items 1 to 28, wherein the drug formulation comprises an angiogenesis inhibitor. (Item 62) 29. The method according to any one of items 1 to 28, wherein the pharmaceutical formulation comprises a vascular endothelial growth factor (VEGF) antagonist. (Item 63) 63. The method of item 62, wherein the VEGF antagonist is a VEGF-receptor kinase antagonist, an anti-VEGF antibody or fragment thereof, an anti-VEGF receptor antibody, an anti-VEGF aptamer, a small molecule VEGF antagonist, a thiazolidinedione, a quinoline, or a designed ankyrin repeat protein (DARPin). (Item 64) 29. The method according to any one of items 1 to 28, wherein the pharmaceutical formulation comprises a TNF-α antagonist or a TNF-α receptor antagonist. (Item 65) 29. The method according to any one of items 1 to 28, wherein the drug formulation comprises a platelet derived growth factor (PDGF) antagonist. (Item 66) 66. The method of claim 65, wherein the PDGF antagonist is a PDGF receptor (PDGFR) antagonist. (Item 67) 67. The method of item 66, wherein the PDGFR is PDGFR-α. (Item 68) 67. The method of item 66, wherein the PDGFR is PDGFR-β. (Item 69) The VEGF antagonist is selected from the group consisting of aflibercept, ziv-aflibercept, bevacizumab, ranibizumab, lapatinib, sunitinib, sorafenib, plitidepsin, regorafenib, verteporfin, bucillamine, axitinib, pazopanib, fluocinolone acetonide, nintedanib, AL8326, 2C3 antibody, AT001 antibody, XtendVEGF antibody, HuMax-VEGF antibody, body, R3 antibody, AT001 / r84 antibody, HyBEV, ANG3070, APX003 antibody, APX004 antibody, ponatinib, BDM-E, VGX100 antibody, VGX200, VGX300, COSMIX, DLX9 03 / 1008 antibody, ENMD2076, INDUS815C, R84 antibody, KD019, NM3, MGCD265, MG516, MP0260, NT503, anti-DLL4 / VEGF bispecific antibody, PAN9080 6, Palomid 529, BD0801 antibody, XV615, Lucitanib, Motesanib diphosphate, AAV2-sFLT01, Soluble Flt1 receptor, Cediranib, AV-951, Volasertib, CEP11981, KH903, Lenvatinib, Lenvatinib mesylate, Terameprocol, PF00337210, PRS050, SP01, Carboxyamidotriazole orotate, Hydroxychloroquine, Linifanib, ALG10 01, AGN150998, MP0112, AMG386, ponatinib, AVA101, BMS690514, KH902, golvatinib (E7050), dovitinib lactate (TKI258, CHIR258), ORA101, ORA102, axitinib (Inlyta, AG013736), PTC299, pegaptanib sodium, troponin, EG3306, vatalanib, Bmab100, GSK2136773, anti-VEGFR64. The method of claim 62 or 63, wherein the antibody is Alterase, Avila, CEP7055, CLT009, ESBA903, GW654652, HMPL010, GEM220, HYB676, JNJ17029259, TAK593, Nova21012, Nova21013, CP564959, Smart Anti-VEGF Antibody, AG028262, AG13958, CVX241, SU14813, PRS055, PG501, PG545, PTI101, TG100948, ICS283, XL647, Enzastaurin hydrochloride, BC194, COT601M06.1, COT604M06.2, Mabion VEGF, apatinib, or AL3818. (Item 70) 65. The method of item 64, wherein the VEGF antagonist is sorafenib. (Item 71) 63. The method of item 62, wherein the VEGF antagonist is axitinib. (Item 72) 63. The method of item 62, wherein the VEGF antagonist is aflibercept. (Item 73) 63. The method of item 62, wherein the VEGF antagonist is bevacizumab. (Item 74) 63. The method of item 62, wherein the VEGF antagonist is ranibizumab. (Item 75) 69. The method of any one of items 65 to 68, wherein the PDGF antagonist is an anti-PDGF aptamer, an anti-PDGF antibody or a fragment thereof, an anti-PDGFR antibody or a fragment thereof, or a small molecule antagonist. (Item 76) 66. The method of claim 65, wherein the PDGF antagonist is anti-PDGF-β aptamer E10030, sunitinib, axitinib, sorafenib, imatinib, imatinib mesylate, nintedanib, pazopanib HCl, ponatinib, MK-2461, dovitinib, pazopanib, crenolanib, PP-121, telatinib, imatinib, KRN633, CP673451, TSU-68, Ki8751, amuvatinib, tivozanib, masitinib, motesanib diphosphate, dovitinib dilactate, or linifanib (ABT-869). (Item 77) 77. The method according to any one of items 1 to 76, wherein the intraocular pressure of the subject's eye is substantially constant during administration of the drug formulation. (Item 78) 78. The method of any one of items 1-77, wherein the intraocular pressure of the subject's eye changes by no more than about 10% during said administering. (Item 79) 79. The method of any one of items 1-78, wherein administration of the drug to the SCS of the eye reduces the number of side effects or reduces the severity of one or more side effects compared to the same dosage of the drug administered intravitreally, intracamerally, topically, parenterally, or orally. (Item 80) 80. The method of any one of items 1-79, wherein the dosage of the drug sufficient to induce a therapeutic response when administered to the SCS is less than the dosage of the drug sufficient to induce a therapeutic response when administered intravitreally, intracamerally, topically, parenterally, or orally. (Item 81) Item 81. The method of item 80, wherein the dosage of the drug sufficient to induce a therapeutic response when administered to the SCS is 75% or less of the dosage of the drug sufficient to induce a therapeutic response when administered intravitreally, intracamerally, topically, parenterally, or orally. (Item 82) Item 81. The method of item 80, wherein the dosage of the drug sufficient to induce a therapeutic response when administered to the SCS is 50% or less of the dosage of the drug sufficient to induce a therapeutic response when administered intravitreally, intracamerally, topically, parenterally, or orally. (Item 83) Item 81. The method of item 80, wherein the dosage of the drug sufficient to induce a therapeutic response when administered to the SCS is 25% or less of the dosage of the drug sufficient to induce a therapeutic response when administered intravitreally, intracamerally, topically, parenterally, or orally. (Item 84) Item 81. The method of item 80, wherein the dosage of the drug sufficient to induce a therapeutic response when administered to the SCS is 10% or less of the dosage of the drug sufficient to induce a therapeutic response when administered intravitreally, intracamerally, topically, parenterally, or orally. (Item 85) 85. The method of any one of items 1-84, wherein retention of the drug in the posterior segment of the eye is greater than retention of the drug in the posterior segment of the eye when administered intravitreally, intracamerally, topically, parenterally, or orally. (Item 86) The drug t 1 / 2 of the drug when administered intravitreally, intracamerally, topically, parenterally, or orally 1 / 2 85. The method according to any one of items 1 to 84, wherein the (Item 87) 85. The method according to any one of items 1 to 84, wherein the systemic exposure of the drug is less than the systemic exposure of the drug when the drug is administered intravitreally, intracamerally, topically, parenterally, or orally. (Item 88) Intraocular T max However, the intraocular T of the drug when administered intravitreally, intracamerally, topically, parenterally, or orally at the same drug dose is max 88. The method according to any one of items 1 to 87, wherein the (Item 89) The T of the drug max is the T of the drug when administered intravitreally, intracamerally, topically, parenterally, or orally at the same drug dose. max 89. The method of claim 88, wherein the concentration of (Item 90) Intraocular C of the drug max the intraocular C of the drug when the drug dose is administered intravitreally, intracamerally, topically, parenterally, or orally max90. The method according to any one of items 1 to 89, wherein the (Item 91) Intraocular administration of the drug 1 / 2 However, the intraocular t 1 / 2 The method according to any one of items 1 to 90, wherein the (Item 92) Intraocular AUC of the drug 0-t the intraocular AUC of the drug when the same drug dose is administered intravitreally, intracamerally, topically, parenterally, or orally 0-t The method according to any one of items 1 to 90, wherein the (Item 93) 93. The method of any one of items 1 to 92, wherein the eye disease is uveitis, glaucoma, scleritis, ocular sarcoidosis, optic neuritis, macular edema, diabetic macular edema, age-related macular degeneration (AMD), diabetic retinopathy, macular degeneration, choroidal neovascularization, corneal ulcer, an autoimmune disorder of the eye, or retinitis. (Item 94) 94. The method of item 93, wherein the eye disease is uveitis. (Item 95) 94. The method of item 93, wherein the eye disease is cytomegalovirus retinitis. (Item 96) Item 94. The method of item 93, wherein the eye disease is AMD. (Item 97) Item 97. The method of item 96, wherein the AMD is dry AMD. (Item 98) Item 97. The method of item 96, wherein the eye disease is dry AMD. (Item 99) 99. The method of any one of items 1-98, further comprising non-surgically administering a second drug to the eye of the subject. (Item 100) 99. The method of claim 99, wherein the second drug is a VEGF antagonist. (Item 101) 99. The method of claim 99, wherein the second drug is a PDGF antagonist. (Item 102) 99. The method of claim 99, wherein the second drug is an anti-inflammatory agent. (Item 103) The method of any one of items 99 to 102, wherein the second drug is administered to the suprachoroidal space (SCS) of the subject's eye. (Item 104) administering to the subject's eye an SCS, inserting a hollow microneedle into the sclera at an insertion site, the microneedle having a tip with an opening; and injecting the drug formulation into the SCS through the microneedle; Item 104. The method according to item 103, comprising: (Item 105) The method according to any one of Items 99 to 102, wherein the second drug is administered intravitreally. (Item 106) 106. The method of any one of items 99 to 105, wherein the first drug and the second drug are administered to the subject at the same time. (Item 107) 107. The method according to any one of items 1 to 106, wherein administration of an effective amount of the drug to the SCS results in a greater therapeutic efficacy of the drug compared to the same drug dose administered intravitreally, intracamerally, topically, parenterally, or orally. (Item 108) 108. The method of any one of items 1-107, wherein the drug dose sufficient to elicit a therapeutic response is less than the drug dose sufficient to elicit the same or substantially the same therapeutic response when the drug is administered intravitreally, intracamerally, topically, parenterally, or orally. (Item 109) 1. A method of treating a choroidal malady in a human patient, comprising: The method comprises non-surgically administering to the suprachoroidal space (SCS) of the patient's eye a drug formulation comprising an effective amount of an anti-inflammatory drug, a vascular endothelial growth factor (VEGF) regulator, a platelet-derived growth factor (PDGF) regulator, an angiogenesis inhibitor, an immunosuppressant, a vascular permeability inhibitor, or a combination thereof. (Item 110) 1. A method of treating choroidal neovascularization in a human patient who has not responded adequately to a previous treatment for said choroidal neovascularization, comprising: The method comprises non-surgically administering to the suprachoroidal space (SCS) of the patient's eye a drug formulation comprising an effective amount of an anti-inflammatory drug, a vascular endothelial growth factor (VEGF) regulator, a platelet-derived growth factor (PDGF) regulator, an angiogenesis inhibitor, an immunosuppressant, a vascular permeability inhibitor, or a combination thereof. (Item 111) 1. A method of treating a human patient for a choroidal malady that has not responded adequately to a previous treatment for the choroidal malady, comprising: The method comprises non-surgically administering to the suprachoroidal space (SCS) of the patient's eye a drug formulation comprising an effective amount of an anti-inflammatory drug, a vascular endothelial growth factor (VEGF) regulator, a platelet-derived growth factor (PDGF) regulator, an angiogenesis inhibitor, an immunosuppressant, a vascular permeability inhibitor, or a combination thereof. (Item 112) 1. A method of treating ocular neovascularization in a human who has not responded adequately to a previous treatment for said ocular neovascularization, comprising: The method comprises non-surgically administering to the suprachoroidal space (SCS) of the patient's eye a drug formulation comprising an effective amount of an anti-inflammatory drug, a vascular endothelial growth factor (VEGF) regulator, a platelet-derived growth factor (PDGF) regulator, an angiogenesis inhibitor, an immunosuppressant, a vascular permeability inhibitor, or a combination thereof. (Item 113) 1. A method of reducing subretinal exudation and bleeding in a subject in need thereof, comprising: Non-surgically administering an effective amount of a drug formulation to the suprachoroidal space (SCS) of the eye of the subject, wherein the drug formulation comprises an effective amount of an anti-inflammatory drug, a vascular endothelial growth factor (VEGF) regulator, a platelet-derived growth factor (PDGF) regulator, an angiogenesis inhibitor, an immunosuppressant, a vascular permeability inhibitor, or a combination thereof; The method, wherein administration of the drug formulation to the SCS reduces subretinal exudation and bleeding experienced by the patient compared to intravitreal administration of the same dosage of the drug to the patient. (Item 114) 1. A method of reducing edema in a subject in need thereof, comprising: A method comprising the step of non-surgically administering an effective amount of a drug formulation comprising an effective amount of an anti-inflammatory drug, a vascular endothelial growth factor (VEGF) regulator, a platelet derived growth factor (PDGF) regulator, an angiogenesis inhibitor, an immunosuppressant, a vascular permeability inhibitor, or a combination thereof, wherein administration into the SCS reduces the swelling experienced by the patient compared to administration of the same dosage of the drug intravitreally to the patient. (Item 115) 1. A method of reducing ocular inflammation in a subject in need thereof, comprising: The method comprises non-surgically administering to the suprachoroidal space (SCS) of the subject's eye an effective amount of a drug formulation comprising an effective amount of an anti-inflammatory drug, a vascular endothelial growth factor (VEGF) regulator, a platelet-derived growth factor (PDGF) regulator, an angiogenesis inhibitor, an immunosuppressant, a vascular permeability inhibitor, or a combination thereof, wherein administration of the drug formulation to the SCS reduces the ocular inflammation compared to administration of the same dosage of the drug to the patient intravitreally. (Item 116) 116. The method of any one of items 109 to 115, wherein upon administration, the drug formulation flows out from the insertion site. (Item 117) 116. The method of any one of items 109-115, wherein upon administration, the drug formulation flows out of the insertion site and is substantially localized in the posterior segment of the eye. (Item 118) Item 109. The method of item 109, wherein the choroidal disease is polyploidal choroidal vaculopathy. (Item 119) 110. The method of claim 109, wherein the choroidal disease is ocular neovascularization, polypoidal choroidal vasculopathy, choroidal sclerosis, central sirrus choroidopathy, multifocal choroidopathy, or choroidal dystrophy. (Item 120) Item 120. The method of item 119, wherein the choroidal disease is a choroidal dystrophy, the choroidal dystrophy being central gyral choroidal dystrophy, dystrophic choroidal dystrophy, or total central choroidal atrophy. (Item 121) 113. The method of any one of items 110 to 112, wherein the previous treatment comprises intravitreal administration of the drug formulation. (Item 122) Prior to administration of the drug formulation, the patient has an intraocular polypoid lesion; 122. The method of any one of items 109 to 121, wherein administration of the effective amount of the drug to the patient's SCS reduces the size of the polypoid lesion compared to intravitreal administration of the same dosage of the drug. (Item 123) Prior to administration of the drug formulation, the patient has polypoid lesions of various sizes in the eye; 122. The method of any one of items 109 to 121, wherein administration of the effective amount of the drug to the SCS reduces variability in size of the polypoid lesions compared to intravitreal administration of the same dosage of the drug. (Item 124) 122. The method of any one of items 109 to 121, wherein administration of the effective amount of the drug to the SCS reduces vascular permeability of the eye compared to intravitreal administration of the same dosage of the drug. (Item 125) Item 123. The method of item 122, wherein the polypoid lesion is present in the peripapillary region of the eye. (Item 126) Item 124. The method of item 123, wherein the one or more polypoid lesions are present in the peripapillary region of the eye. (Item 127) Item 123. The method of item 122, wherein the polypoid lesion is located in the central macula of the eye. (Item 128) Item 124. The method of item 123, wherein the one or more polypoid lesions are present in the central macula of the eye. (Item 129) Prior to administration of the drug formulation, intrachoroidal dilated and branched blood vessels of various sizes are present in the patient's eye; 129. The method according to any one of items 109 to 128, wherein administration of the effective amount of the drug to the SCS reduces the variability in the size of the intrachoroidal blood vessels compared to intravitreal administration of the same dosage of the drug. (Item 130) Prior to administration of the drug formulation, atherosclerosis is present in the choroidal vessels of the patient's eye; 129. The method according to any one of items 109 to 128, wherein administration of the effective amount of the drug to the SCS reduces the level of atherosclerosis in the choroidal vessels compared to intravitreal administration of the same dosage of the drug. (Item 131) Prior to administration of the drug formulation, the patient's eye has hyalinized choroidal vessels; 129. The method according to any one of items 109 to 128, wherein administration of the effective amount of the drug to the SCS reduces the level of hyalinization of the choroidal blood vessels compared to intravitreal administration of the same dosage of the drug. (Item 132) Prior to administration of the drug formulation, the patient experiences a level of subretinal hemorrhage; 129. The method of any one of items 109 to 128, wherein administration of the effective amount of the drug to the SCS reduces the level of subretinal hemorrhage compared to intravitreal administration of the same dosage of the drug. (Item 133) 129. The method of any one of items 109 to 128, wherein administration of the effective amount of the drug to the SCS improves the patient's vision compared to intravitreal administration of the same dosage of the drug. (Item 134) Prior to administration of the drug formulation, the patient's eye experiences recurrent neovascularization or serous detachment; 129. The method of any one of items 109 to 128, wherein administration of the effective amount of the drug to the SCS reduces the recurrent neovascularization or serous detachment in the eye compared to intravitreal administration of the same dosage of the drug. (Item 135) the patient has subretinal lipid deposits in the eye prior to administration of the drug formulation; 129. The method of any one of items 109 to 128, wherein administration of the effective amount of the drug to the SCS reduces the subretinal lipid deposition compared to intravitreal administration of the same dosage of the drug. (Item 136) Both eyes of the subject are affected by the choroidal disease; The method according to any one of items 109 and 118 to 120, wherein administration of the drug formulation to the SCS is performed bilaterally. (Item 137) 137. The method according to any one of items 109 to 136, wherein the patient has concomitant drusen. (Item 138) 138. The method of any one of items 109 to 137, wherein the patient is Caucasian. (Item 139) 18. The method of any one of items 109 to 137, wherein the subject is a person of color. (Item 140) 18. The method of any one of items 109 to 137, wherein the subject is African American. (Item 141) 138. The method of any one of items 109 to 137, wherein the subject is Asian. (Item 142) the administering step comprises inserting a hollow microneedle into the sclera at an insertion site, the microneedle having a tip with an opening; and Injecting the drug formulation into the SCS through the inserted microneedle. The method according to any one of items 109 to 141, comprising: (Item 143) 143. The method of claim 142, wherein the insertion site is about the equator of the eye or between the equator and the limbus of the eye. (Item 144) Item 144. The method according to item 142 or 143, wherein the length of the microneedles is about 500 μm to about 1500 μm. (Item 145) Item 144. The method according to item 142 or 143, wherein the microneedle has a diameter of about 200 μm to about 600 μm. (Item 146) 146. The method of any one of items 142 to 145, wherein the microneedles comprise beveled ends. (Item 147) Item 147. The method according to item 146, wherein the bevel angle of the microneedle is about 5° to about 30°. (Item 148) Item 147. The method according to item 146, wherein the bevel height of the microneedle is about 100 μm to about 500 μm. (Item 149) Item 147. The method according to item 146, wherein the angle of the beveled end is about 10° to about 20°. (Item 150) 150. The method of any one of items 146 to 149, wherein the aspect ratio of the beveled end is about 1:1.5 to about 1:10. (Item 151) Item 147. The method according to item 146, wherein the height of the beveled end is about 500 μm to about 1 mm. (Item 152) 152. The method according to any one of items 146 to 151, wherein the microneedle is inserted into the sclera without penetrating the sclera. (Item 153) 152. The method according to any one of items 146 to 151, wherein the microneedle is inserted into the sclera without penetrating the choroid. (Item 154) 154. The method of any one of items 146 to 153, wherein the microneedle comprises a cylindrical shaft having an outer diameter of about 200 microns to about 600 microns. (Item 155) 155. The method according to any one of items 109 to 154, wherein the volume of the drug formulation is from about 10 μL to about 200 μL. (Item 156) 155. The method according to any one of items 109 to 154, wherein the volume of the drug formulation is from about 30 μL to about 100 μL. (Item 157) 157. The method according to any one of items 109 to 156, wherein the microneedle is inserted into the surface of the sclera at an angle of about 70° to about 110°. (Item 158) 155. The method of any one of items 109 to 154, wherein the microneedle is inserted into the surface of the sclera at an angle of about 90°. (Item 159) 159. The method according to any one of items 109 to 158, wherein administration of the drug formulation to the SCS reduces the number of side effects experienced by the patient or reduces the severity of side effects experienced by the patient compared to intravitreal administration of the same dosage of the drug. (Item 160) Item 159. The method of item 159, wherein administering the drug formulation to the SCS reduces the number of side effects experienced by the patient compared to the number of side effects experienced by the patient when the same dosage of the drug is administered intravitreally. (Item 161) Item 159. The method of item 159, wherein administration of the drug formulation to the SCS reduces the severity of the side effect experienced by the patient compared to the severity of the side effect experienced by the patient when the same dosage of the drug is administered intravitreally. (Item 162) The method according to any one of items 109 to 161, wherein the dosage of the drug sufficient to induce a therapeutic response in the patient when administered to the SCS is less than the dosage of the drug sufficient to induce a therapeutic response in the patient when administered intravitreally. (Item 163) Item 163. The method of item 162, wherein the dosage of the drug sufficient to induce a therapeutic response when administered to the SCS is 75% or less of the dosage of the drug sufficient to induce a therapeutic response when administered intravitreally. (Item 164) Item 163. The method of item 162, wherein the dosage of the drug sufficient to induce a therapeutic response when administered to the SCS is 50% or less of the dosage of the drug sufficient to induce a therapeutic response when administered intravitreally. (Item 165) Item 163. The method of item 162, wherein the dosage of the drug sufficient to induce a therapeutic response when administered to the SCS of the patient is 25% or less of the dosage of the drug sufficient to induce a therapeutic response when administered intravitreally to the patient. (Item 166) Item 163. The method of item 162, wherein the dosage of the drug sufficient to induce a therapeutic response when administered to the SCS of the patient is 10% or less of the dosage of the drug sufficient to induce a therapeutic response when administered intravitreally to the patient. (Item 167) 18. The method of claim 117, wherein retention of the drug in the posterior segment of the eye is greater than retention of the drug in the posterior segment of the eye when administered intravitreally. (Item 168) Intraocular t 1 / 2 However, the intraocular t 1 / 2 The method according to any one of items 109 to 167, wherein the (Item 169) 169. The method according to any one of items 109 to 168, wherein the systemic exposure of the drug administered to the SCS is less than the systemic exposure of the drug when administered intravitreally. (Item 170) 169. The method according to any one of items 109 to 169, further comprising subjecting the patient to at least one additional treatment selected from the group consisting of photodynamic therapy, laser photocoagulation, and transpupillary thermotherapy. (Item 171) The method of any one of items 109 to 170, wherein the patient has an additional macular abnormality and the patient is treated for one or more of the additional macular abnormalities by administering an effective amount of a second drug formulation to the SCS of the eye. (Item 172) Item 172. The method of item 171, wherein the further macular abnormality is sickle cell retinopathy, central serous chorioretinopathy, typical neovascular (type 1 or type 2) age-related macular degeneration, melanocytoma of the optic nerve, focal choroidal hemangioma, tilted disk syndrome, pathological myopia, or choroidal osteoma. (Item 173) 173. The method of any one of items 109 to 172, wherein the pharmaceutical formulation comprises an effective amount of a VEGF modulator. (Item 174) The method of item 173, wherein the VEGF modulator is a VEGF antagonist selected from the group consisting of a VEGF-receptor kinase antagonist, an anti-VEGF antibody or fragment thereof, an anti-VEGF receptor antibody, an anti-VEGF aptamer, a small molecule VEGF antagonist, a thiazolidinedione, a quinoline, and a designed ankyrin repeat protein (DARPin). (Item 175) The method of item 173, wherein the VEGF modulator is a VEGF antagonist selected from the group consisting of a VEGF-receptor kinase antagonist, an anti-VEGF antibody or fragment thereof, an anti-VEGF receptor antibody, an anti-VEGF aptamer, a small molecule VEGF antagonist, a thiazolidinedione, a quinoline, and a designed ankyrin repeat protein (DARPin). (Item 176) The VEGF regulator is selected from the group consisting of aflibercept, dib-aflibercept, bevacizumab, ranibizumab, vandetanib, cabozantinib, ponatinib, dib-afibercept, lapatinib, sunitinib, sorafenib, plitidepsin, regorafenib, verteporfin, bucillamine, axitinib, pazopanib, fluocinolone acetonide, nintedanib, AL8326, 2C3 antibody, AT001 antibody, XtendVEGF antibody, HuMax-VEGF antibody, R3 antibody, AT001 / r84 antibody, HyBEV, ANG3070, APX003 antibody, APX004 antibody, ponatinib, BDM-E, VGX100 antibody, VGX200, VGX300, COSMIX , DLX903 / 1008 antibody, ENMD2076, INDUS815C, R84 antibody, KD019, NM3, MGCD265, MG516, MP0260, NT503, anti-DLL4 / VEGF bispecific antibody, PAN90806, Palomid 529, BD0801 antibody, XV615, Lucitanib, Motesanib diphosphate, AAV2-sFLT01, Soluble Flt1 receptor, Cediranib, AV-951, Volasertib, CEP11981, KH903, Lenvatinib, Lenvatinib mesylate, Terameprocol, PF00337210, PRS050, SP01, Carboxyamidotriazole orotate, Hydroxychloroquine, Linifanib, ALG1001,AGN150998, MP0112, AMG386, AVA101, BMS690514, KH902, golvatibinib (E7050), dovitinib lactate (TKI258, CHIR258), ORA101, ORA102, axitinib (Inlyta, AG013736), PTC299, pegaptanib sodium, troponin, EG3306, vatalanib, Bmab100, GSK2136773, anti-VEGFR The method of item 173, wherein the VEGF antagonist is selected from the group consisting of Alterase, Avila, CEP7055, CLT009, ESBA903, GW654652, HMPL010, GEM220, HYB676, JNJ17029259, TAK593, Nova21012, Nova21013, CP564959, Smart Anti-VEGF Antibody, AG028262, AG13958, CVX241, SU14813, PRS055, PG501, PG545, PTI101, TG100948, ICS283, XL647, Enzastaurin Hydrochloride, BC194, COT601M06.1, COT604M06.2, Mabion VEGF, apatinib, and AL3818. (Item 177) 173. The method according to any one of items 109 to 172, wherein the pharmaceutical formulation comprises an effective amount of an angiogenesis inhibitor. (Item 178) The angiogenesis inhibitor is selected from the group consisting of angiopoietin-1, angiopoietin-2, angiostatin, endostatin, vasostatin, thrombospondin, calreticulin, platelet factor-4, TIMP, CDAI, interferon alpha, interferon beta, vascular endothelial growth factor inhibitor (VEGI) meth-1, meth-2, prolactin, VEGI, SPARC, osteopontin, maspin, canstatin, proliferin-related protein (PRP), restin, TSP-1, TSP-2, interferon gamma 1 beta, ACUHTR028, alpha V beta 5, potassium aminobenzoate, amyloid P, ANG1122, ANG1170, ANG3062, ANG3281, ANG3298, ANG4011, anti-CTGF RNAi, Aplidine, Astragalus membranaceus extract with salvia and Schisandra chinensis, atherosclerotic plaque blockers, Azoles, AZX100, BB3, Connective tissue growth factor antibodies, CT140, Danazol, Esbriet, EXC001, EXC002, EXC003, EXC004, EXC005, F647, FG3019, Fibrocollin, Follistatin, FT011, Galectin-3 inhibitors, GKT137831, GMCT01, GMCT02, GRMD01, GRMD02, GRN510, Heberon alpha R, Interferon alpha-2 beta, ITMN520, JKB119, JKB121, JKB122, KRX168, LPA1 receptor antagonists, MGN4220, MIA2, microRNA 29a oligonucleotide, MMI0100, noscapine, PBI4050, PBI4419, PDGFR inhibitor, PF-06473871, PGN0052, Pirespa, Pirfenex, Pirfenidone, plitidepsin, PRM151, Px102, PYN17, PYN17 containing PYN22, Relivergen, rhPTX2 fusion protein, RXI109, secretin, STX100, TGF-β inhibitor, transforming growth factor, beta-receptor 2 oligonucleotide, VA999260, or XV615. (Item 179) 173. The method according to any one of items 109 to 172, wherein the pharmaceutical formulation comprises an effective amount of an anti-inflammatory drug. (Item 180) 179. The method of claim 179, wherein the anti-inflammatory agent is a steroidal compound. (Item 181) The steroidal compound may be hydrocortisone, hydrocortisone-17-butyrate, hydrocortisone-17-aceponate, hydrocortisone-17-buteprate, cortisone, tixocortol pivalate, prednisolone, methylprednisolone, prednisone, triamcinolone, triamcinolone acetonide, mometasone, amcinonide, budesonide, desonide, fluocinonide, halcinonide, bethamethasone, betamethasone dipropionate, 181. The method of claim 180, wherein the active ingredient is fluocortolone, hydrocortisone-17-valerate, halometasone, alclometasone dipropionate, prednicarb, clobetasone-17-butyrate, clobetasol-17-propionate, fluocortolone caproate, fluocortolone pivalate, fluprednidene acetate, or prednicarb. (Item 182) Item 182. The method of item 181, wherein the steroidal compound is triamcinolone, triamcinolone acetonide, or dexamethasone. (Item 183) 179. The method of claim 179, wherein the anti-inflammatory drug is a nonsteroidal anti-inflammatory drug (NSAID). (Item 184) 184. The method of claim 183, wherein the nonsteroidal anti-inflammatory drug (NSAID) is a salicylate. (Item 185) 184. The method of claim 183, wherein the nonsteroidal anti-inflammatory drug (NSAID) is a propionic acid derivative. (Item 186) 184. The method of claim 183, wherein the nonsteroidal anti-inflammatory drug (NSAID) is an acetic acid derivative. (Item 187) 184. The method of claim 183, wherein the nonsteroidal anti-inflammatory drug (NSAID) is an enolic acid derivative. (Item 188) 184. The method of claim 183, wherein the nonsteroidal anti-inflammatory drug (NSAID) is a fenamic acid derivative. (Item 189) 184. The method of claim 183, wherein the nonsteroidal anti-inflammatory drug (NSAID) is a cyclooxygenase-2 (COX-2) inhibitor. (Item 190) 185. The method of claim 183 or 184, wherein the nonsteroidal anti-inflammatory drug (NSAID) is acetylsalicylic acid, diflunisal, or salsalate. (Item 191) 186. The method of claim 183 or 185, wherein the nonsteroidal anti-inflammatory drug (NSAID) is ibuprofen, dexibuprofen, naproxen, fenoprofen, ketoprofen, dexketoprofen, flurbiprofen, oxaprozin, or loxaprofen. (Item 192) 187. The method of claim 183 or 186, wherein the nonsteroidal anti-inflammatory drug (NSAID) is indomethacin, tolmetin, sulindac, etodolac, ketorolac, diclofenac, or nabumetone. (Item 193) 188. The method of claim 183 or 187, wherein the nonsteroidal anti-inflammatory drug (NSAID) is piroxicam, meloxicam, tenoxicam, droxicam, lornoxicam, or isoxicam. (Item 194) 189. The method of claim 183 or 188, wherein the nonsteroidal anti-inflammatory drug (NSAID) is mefanamic acid, meclofenamic acid, flufenamic acid, or tolfenamic acid. (Item 195) 189. The method of claim 183 or 189, wherein the nonsteroidal anti-inflammatory drug (NSAID) is celecoxib, rofecoxib (refecoxib), valdecoxib, parecoxib, lumiracoxib, etoricoxib, or firocoxib. (Item 196) 173. The method according to any one of items 109 to 172, wherein the pharmaceutical formulation comprises an effective amount of a platelet-derived growth factor (PDGF) modulating factor. (Item 197) 197. The method of item 196, wherein the platelet-derived growth factor (PDGF) modulator is a PDGF antagonist. (Item 198) 200. The method of claim 197, wherein the platelet-derived growth factor (PDGF) antagonist is a PDGF-receptor antagonist, an anti-PDGF antibody or fragment thereof, an anti-PDGF receptor antibody or fragment thereof, an anti-PDGF aptamer, or a small molecule PDGF antagonist. (Item 199) 198. The method of claim 197, wherein the platelet-derived growth factor (PDGF) antagonist is an antagonist of PDGF receptor-α (PDGFR-α) or PDGF receptor-β (PDGFR-β). (Item 200) 198. The method of claim 197, wherein the PDGF antagonist is anti-PDGF-β aptamer E10030, sunitinib, axitinib, sorafenib, imatinib, imatinib mesylate, nintedanib, pazopanib HCl, ponatinib, MK-2461, dovitinib, pazopanib, crenolanib, PP-121, telatinib, imatinib, KRN633, CP673451, TSU-68, Ki8751, amuvatinib, tivozanib, masitinib, motesanib diphosphate, dovitinib dilactic acid, or linifanib (ABT-869). (Item 201) 173. The method according to any one of items 109 to 172, wherein the pharmaceutical formulation comprises an effective amount of an immunosuppressant. (Item 202) 202. The method of claim 201, wherein the immunosuppressant is a glucocorticoid, a cytokine inhibitor, a cytostatic, an alkylating agent, an antimetabolite, a folic acid analog, a cytotoxic antibiotic, an interferon, an opioid, an antibody against a T cell receptor, or an antibody against an IL-2 receptor. (Item 203) 203. The method of claim 202, wherein the antimetabolite is a purine analog, a pyrimidine analog, a folate analog, or a protein synthesis inhibitor. (Item 204) The method according to claim 201, wherein the immunosuppressant is an interleukin-2 inhibitor. 202. The method of claim 201, wherein the immunosuppressant is cyclophosphamide, nitrosourea, methotrexate, azathioprine, mercaptopurine, fluorouracil, dactinomycin, anthracycline, mitomycin C, bleomycin, mithramycin, muromonab-CD3, cyclosporine, tacrolimus, sirolimus, or mycophenolate. (Item 206) 205. The method of claim 204, wherein the interleukin-2 inhibitor is basiliximab or daclizumab. (Item 207) 206. The method of claim 203 or 205, wherein the immunosuppressant is mycophenolate. (Item 208) 173. The method according to any one of items 109 to 172, wherein the pharmaceutical formulation comprises an effective amount of a vascular permeability inhibitor. (Item 209) 209. The method of claim 208, wherein the vascular permeability inhibitor is a vascular endothelial growth factor (VEGF) antagonist or an angiotensin-converting enzyme (ACE) inhibitor. (Item 210) 209. The method of claim 209, wherein the vascular permeability inhibitor is an angiotensin-converting enzyme (ACE) inhibitor, and the ACE inhibitor is captopril. (Item 211) 1. A method of treating or preventing polypoidal choroidal vasculopathy (PCV) in a patient, comprising: administering to the patient's eye an effective amount of an interfering RNA molecule targeting a gene selected from the group consisting of HTRA1, CFH, elastin, and ARMS2, such that administration of the interfering RNA downregulates expression of the gene targeted by said administration of the interfering RNA; The administering step comprises: inserting a hollow microneedle into the sclera at an insertion site, the microneedle having a tip with an opening; and Injecting the interfering RNA molecule into the SCS via the inserted microneedle. A method comprising: (Item 212) 212. The method of claim 211, wherein the interfering RNA molecule is an siRNA, miRNA, or shRNA. (Item 213) 213. The method of claim 211 or 212, wherein the targeted gene is CFH and the interfering RNA molecule targets a polymorphism selected from the group consisting of rs3753394, rs800292, rs3753394, rs6680396, rs1410996, rs2284664, rs1329428, and rs1065489. (Item 214) 214. The method according to any one of items 109 to 213, further comprising the step of administering a photosensitizer to the patient. (Item 215) 215. The method of item 214, wherein the photosensitizer is verteporfin. (Item 216) 1. A method for diagnosing a patient for choroidal disease, comprising: Administering a choroidal disease diagnostic agent to the SCS of one or both eyes of the patient; visualizing the diagnostic agent; and determining whether the patient has the choroidal disease based on the visualization. A method comprising: (Item 217) 217. The method of claim 216, wherein the diagnostic agent is delivered to the SCS of one or both eyes of the patient via a hollow microneedle comprising a tip and an opening. (Item 218) 1. A method of administering a triamcinolone composition to an eye of a patient, comprising: (a) inserting a hollow microneedle into the eye at an insertion site, the microneedle having a tip with an opening; (b) applying a selected pressure to the triamcinolone composition comprising triamcinolone microparticles to induce injection of the triamcinolone composition through the inserted microneedle; (c) determining whether the triamcinolone composition has flowed into the suprachoroidal space of the eye and out of the insertion site; (d) if it is determined in step (c) that the triamcinolone composition has flowed out of the insertion site and into the suprachoroidal space, injecting a selected volume of the triamcinolone composition and removing the pressure, or if it is determined in step (c) that the triamcinolone composition has not substantially flowed out of the insertion site and into the suprachoroidal space, repositioning the inserted microneedle and repeating steps (b) to (d) until a selected volume of the triamcinolone composition has been injected; and (e) retracting the microneedle from the eye. A method comprising: (Item 219) The method according to claim 218, wherein the triamcinolone is triamcinolone acetonide. 220. The method of claim 219, wherein the composition comprises nanoparticles. (Item 221) 221. The method of claim 219 or 220, wherein the composition comprises microparticles. (Item 222) D of the fine particles 50 Item 222. The method of item 221, wherein the thickness is 2 μm or less. (Item 223) D of the fine particles 99 The method according to claim 221 or 222, wherein the thickness is less than 10 μm. (Item 224) 224. The method of any one of items 219 to 223, wherein the triamcinolone is present in the composition at about 40 mg / mL. (Item 225) 224. The method according to any one of items 219 to 223, wherein the pharmaceutical formulation further comprises sodium chloride. (Item 226) 224. The method of any one of items 219 to 223, wherein the pharmaceutical formulation further comprises sodium carboxymethylcellulose. (Item 227) 224. The method according to any one of items 219 to 223, wherein the drug formulation further comprises polysorbate 80. (Item 228) 224. The method of any one of items 219-223, wherein the pharmaceutical formulation further comprises CaCl2, MgCl2, sodium acetate, sodium citrate, or a combination thereof. (Item 229) D 50 1. A pharmaceutical composition comprising triamcinolone particles having a diameter of less than 3 μm. (Item 230) 230. The pharmaceutical composition of claim 229, wherein the triamcinolone is present in the composition at 40 mg / mL. (Item 231) D of the particle 90 231. The pharmaceutical composition according to item 229 or 230, wherein the particle size is 10 μm or less. (Item 232) D of the particle 90 232. The pharmaceutical composition according to item 231, wherein the particle size is less than 10 μm. (Item 233) 233. The pharmaceutical composition according to any one of items 229 to 232, further comprising polysorbate 80. (Item 234) 234. The pharmaceutical composition according to any one of items 229 to 233, further comprising sodium carboxymethylcellulose. (Item 235) 235. The pharmaceutical composition according to any one of items 229 to 234, further comprising one or more of CaCl2, MgCl2, KCl, sodium acetate, sodium citrate. (Item 236) 236. The pharmaceutical composition according to any one of items 229 to 235, wherein the composition has a pH of about 6.0 to about pH 7.5. (Item 237) 237. The pharmaceutical composition according to any one of items 229 to 236, wherein the D50 of the particles is about 2 μm. (Item 238) 238. The pharmaceutical composition according to any one of items 229 to 237, wherein the D50 of the particles is less than about 2 μm. (Item 239) 239. The pharmaceutical composition according to any one of items 229 to 238, wherein the D50 of the particles is less than about 1 μm. (Item 240) 239. The pharmaceutical composition according to any one of items 229 to 239, wherein the triamcinolone is triamcinolone acetonide. [Brief description of the drawings]

[0021] [Figure 1A] 1A, 1B, 1C, and 1D are cross-sectional views of the tissue structure of the human eye: a full eye (A), a close-up of the cornea (1B), and a close-up of the sclera and associated tissues in an eye with no fluid in the suprachoroidal space (1C) or with fluid in the suprachoroidal space (1D). [Figure 1B] 1A, 1B, 1C, and 1D are cross-sectional views of the tissue structure of the human eye: a full eye (A), a close-up of the cornea (1B), and a close-up of the sclera and associated tissues in an eye with no fluid in the suprachoroidal space (1C) or with fluid in the suprachoroidal space (1D). [Figure 1C] 1A, 1B, 1C, and 1D are cross-sectional views of the tissue structure of the human eye: a full eye (A), a close-up of the cornea (1B), and a close-up of the sclera and associated tissues in an eye with no fluid in the suprachoroidal space (1C) or with fluid in the suprachoroidal space (1D). [Figure 1D] 1A, 1B, 1C, and 1D are cross-sectional views of the tissue structure of the human eye: a full eye (A), a close-up of the cornea (1B), and a close-up of the sclera and associated tissues in an eye with no fluid in the suprachoroidal space (1C) or with fluid in the suprachoroidal space (1D).

[0022] [Diagram 2]FIG. 2 is a cross-sectional view of a microneedle device including a hollow microneedle disposed within an elongate body in one embodiment.

[0023] [Diagram 3] FIG. 3 is a cross-sectional view of the elongate body of the microneedle device shown in FIG.

[0024] [Figure 4] FIG. 4 is a diagram of a microneedle device in one embodiment.

[0025] [Diagram 5] FIG. 5 is a diagram of a microneedle device in one embodiment.

[0026] [Figure 6] 6A and 6B illustrate one embodiment of a process for using hollow microneedles to deliver drugs into the suprachoroidal space of the eye. The process includes inserting a hollow microneedle into the sclera and injecting a fluid drug formulation into the suprachoroidal space.

[0027] [Figure 7] Figure 7A shows the hollow microneedle of one embodiment compared to the tip of a conventional 30 gauge hypodermic needle, and Figure 7B shows a schematic of a custom made acrylic mold molded to fit the entire eye.

[0028] [Figure 8] 8A and 8B are bright field microscopy images of saggital cross sections of pig eyes before and after injection of sulforhadamine, respectively.

[0029] [Figure 9]Figures 9A, 9B, 9C, and 9D are fluorescent images of a pig eye cryosection without injection into the suprachoroidal space (9A), a rabbit eye cryosection in axial section (9B) collaged to form an overview after injection of 500 nm fluorescent particles, a pig eye cryosection in saggital direction (9C) collaged to show the cavities both anterior and posterior to the microneedle insertion site after injection of 500 nm fluorescent particles, and a human eye cryosection in saggital direction (9D) collaged to show the cavities both anterior and posterior to the microneedle insertion site after injection of 500 nm fluorescent particles. The insets in Figures 9B, 9C, and 9D show a close-up of the microneedle insertion site.

[0030] [Figure 10] 10A and 10B are micro-computed tomography images (10A) and three-dimensional reconstructions (10B) of cross-sectional images showing the circumferential spread of 1 μm contrast particles injected into the suprachoroidal space of a pig eye.

[0031] [Figure 11A] 11A, 11B, 11C, and 11D are graphs showing the effect of injection pressure and microneedle length on the success rate of suprachoroidal delivery of 20 nm particles (1A), 100 nm particles (11B), 500 nm particles (11C), and 1000 nm particles (11D) into pig eyes. [Figure 11B] 11A, 11B, 11C, and 11D are graphs showing the effect of injection pressure and microneedle length on the success rate of suprachoroidal delivery of 20 nm particles (1A), 100 nm particles (11B), 500 nm particles (11C), and 1000 nm particles (11D) into pig eyes. [Figure 11C] 11A, 11B, 11C, and 11D are graphs showing the effect of injection pressure and microneedle length on the success rate of suprachoroidal delivery of 20 nm particles (1A), 100 nm particles (11B), 500 nm particles (11C), and 1000 nm particles (11D) into pig eyes. [Figure 11D]11A, 11B, 11C, and 11D are graphs showing the effect of injection pressure and microneedle length on the success rate of suprachoroidal delivery of 20 nm particles (1A), 100 nm particles (11B), 500 nm particles (11C), and 1000 nm particles (11D) into pig eyes.

[0032] [Figure 12] Figures 12A and 12B are fluorescence images of frozen sections of pig eyes in the saggital direction collaged after injection of 20 nm particles (12A) and 1000 nm particles (12B) to show the cavities both anterior and posterior to the microneedle insertion site. The insets in Figures 12A and 12B show a close-up of the microneedle insertion site.

[0033] [Figure 13] 13A and 13B are graphs showing the effect of intraocular pressure and microneedle length on the success rate of suprachoroidal delivery of 1000 nm particles for simulated intraocular pressures of 18 mmHg (13A) and 36 mmHg (13B).

[0034] [Figure 14] 14 is a one-dimensional line cytoscan of a rabbit eye taken after injection of sodium fluorescein into the suprachoroidal space. The x-axis represents the position of the eye from posterior (0) to anterior (160), and the y-axis represents the fluorescence intensity at that position.

[0035] [Figure 15] FIG. 15 is a graph showing the clearance rate of sodium fluorescein from the suprachoroidal space over time.

[0036] [Figure 16] FIG. 16 is a graph showing the clearance rate of 20 nm particles from the suprachoroidal space over time.

[0037] [Figure 17] FIG. 17 is a graph showing the clearance rate of 500 nm particles from the suprachoroidal space over time.

[0038] [Figure 18] FIG. 18 is a block diagram of a method for administering a drug to the eye in one embodiment.

[0039] [Figure 19A] FIG. 19A is a graph showing the retention of triamcinolone (TA) in the posterior segment of the eye as a function of time after administration (circles - SCS injections, diamonds - intravitreal injections).

[0040] [Figure 19B] FIG. 19B is a graph showing increased retention of triamcinolone (TA) in the choroid and retina when administered via SCS (bottom) compared to intravitreal administration of TA (top).

[0041] [Figure 19C] Figure 19C (top) is a graph showing the ratio of the amount of triamcinolone (TA) in an eye lens to the amount of TA in the back of the eye (choroid) as a function of time after administration. Figure 19C (bottom) is a graph showing the ratio of the amount of TA in an eye lens to the amount of TA in the back of the eye (retina) as a function of time (days) after administration.

[0042] [Figure 20A] 20A is a graph of intraocular pressure (IOP, mmHg) in rabbit eyes as a function of time after TA administration. Rabbits were injected with vehicle, 3.2 mg TA, or 5.2 mg TA on study day 0.

[0043] [Figure 20B] FIG. 20B is a cross-sectional image of a rabbit eye after suprachoroidal injection of 3.2 mg triamcinolone (left) or vehicle (right).

[0044] [Figure 20C] FIG. 20C is a graph showing TA plasma concentrations (ng / mL) following TA administration to the SCS of rabbit eyes as a function of time after TA administration.

[0045] [Figure 20D] FIG. 20D is a graph showing the retention of triamcinolone (TA) in various tissues (μg TA / g tissue) following administration to the SCS. The greatest amount of drug is retained in the tissues at the back of the eye (choroid, retina) and less in the front portion of the eye (lens, vitreous humor).

[0046] [Figure 20E] FIG. 20E is a graph showing the amount of triamcinolone (TA) (μg) in the sclera and choroid as a function of time after TA administration.

[0047] [Figure 20F] FIG. 20F is a graph showing the amount of triamcinolone (TA) (μg) in the retina as a function of time after TA administration.

[0048] [Figure 21A] 21A is a graph showing the cumulative McDonald-Shadduck score for eyes treated with vehicle (left), 4 mg triamcinolone administered in the SCS (TA) (center), or 4 mg triamcinolone administered intravitreally (right) as a function of time after treatment and time after LPS toxin administration. The McDonald-Shadduck score provides a model of posterior uveitis.

[0049] [Figure 21B] FIG. 21B is a representative fundus photograph showing the effects of SCS or intravitreally administered triamcinolone (TA) in a posterior uveitis model in NZW rabbits.

[0050] [Figure 21C] Figure 21C is a graph showing the overall severity of inflammation in NZW rabbits as measured by histology at the final time point. The following tissues were analyzed: ciliary process, sclera-choroid, vitreous, retina, and optic nerve (scored 0-4, maximum score = 20).

[0051] [Figure 21D] FIG. 21D is a graph showing intraocular pressure (mmGh) in NZW rabbits in response to TA administration into IVT or SCS.

[0052] [Figure 22A] 22A is a graph showing the mean Hackett / McDonald ocular scores of pig eyes challenged with (i) lipopolysaccharide (LPS) toxin followed by vehicle (left), (ii) LPS toxin followed by 2 mg triamcinolone in the SCS (center), or (iii) balanced salt solution followed by vehicle. Treatment with SCS TA at a dose of 2 mg significantly reduces the ocular inflammatory response in this pig uveitis model.

[0053] [Figure 22B] 22B is a graph showing the mean cumulative Hackett / McDonald ocular scores for pig eyes challenged with (i) lipopolysaccharide (LPS) toxin followed by vehicle, (ii) LPS toxin followed by 2 mg triamcinolone (TA) in the SCS, (iii) LPS toxin followed by 2 mg triamcinolone in the vitreous, or (iv) LPS toxin followed by 0.2 mg triamcinolone in the SCS. Reduction in inflammation was observed within 3 days using a dose of TA administered in the SCS that was 10% of the TA dose required when administered intravitreally.

[0054] [Diagram 23] 23 is a graph showing the mean (± standard deviation) cumulative inflammatory ocular scores for animals treated with or without toxin and then with low or high doses of TA administered either SCS or intravitreally. The mean inflammatory scores for eyes treated with SCS TA were lower than the scores for eyes treated with IVT TA at 1, 2, and 3 days.

[0055] Mean (+ / - SD) cumulative inflammatory ocular scores at the time of uveitis induction (i.e., at the time of toxin administration) (day -1) and at the time of drug administration (day 0). Eyes were administered 0.2 mg (low dose) or 2.0 mg (high dose) of triamcinolone acetonide (TA) by injection into the suprachoroidal space (SCS) or intravitreal (IVT) and ocular scores were calculated 1, 2, and 3 days after administration. Group 1 mean cumulative inflammatory score was significantly lower than groups 2-6 on day 0 (Wilcoxon; P<0.028); a. Group 2 mean cumulative inflammatory score was significantly higher than groups 1, 3, 4, 5, and 6 on day 1 (Wilcoxon; P<0.028); c. Group 5 mean cumulative inflammatory score was significantly higher than groups 1, 3, 4, and 6 on day 1 (Wilcoxon; P<0.029); d. Group 6 mean cumulative inflammatory score was significantly higher than group 1 on day 1 (Wilcoxon; P=0.02); e. Group 2 mean cumulative inflammatory score was significantly higher than groups 1, 3, 4, and 6 on day 2 (Wilcoxon; P<0.028); f. Group 5 mean cumulative inflammatory score was significantly higher than groups 1 and 3 on day 2 (Wilcoxon; P<0.042); g. Group 6 The mean cumulative inflammatory score was significantly higher than group 1 on day 2 (Wilcoxon; P=0.028); h. Group 2 mean cumulative inflammatory score was significantly higher than groups 1, 3, 4, 5, and 6 on day 3 (Wilcoxon; P<0.02); i. Group 5 mean cumulative inflammatory score was significantly higher than groups 1 and 6 on day 3 (Wilcoxon; P<0.047); j. Group 6 mean cumulative inflammatory score was significantly higher than group 1 on day 3 (Wilcoxon; P=0.018). G1=group 1; G2=group 2; G3=group 3; G4=group 4; G5=group 5; G6=group 6.

[0056] [Figure 24]24 is a graph showing the mean intraocular pressure of animals treated with or without toxin on day -1, then with low or high doses of TA administered either SCS or intravitreally on day 0. Mean (+ / -SD) intraocular pressure (IOP) in pig eyes prior to uveitis induction (day -1) and at the time of drug administration (day 0) using suprachoroidal space (SCS) or intravitreal (IVT) injection of 0.2 mg (low dose) or 2.0 mg (high dose) triamcinolone acetonide (TA). IOP was measured 1 hour, 3 hours, 6 hours, 1 day, 2 days, and 3 days after treatment. a. IOP in Group 1 eyes was significantly higher than Group 2 eyes 1 hour and 3 hours after treatment injection (P=0.01; 0.04).

[0057] [Figure 25A] 25A-B are widefield fundus images of eyes from animals treated with or without toxin and then with low or high doses of TA administered either in the SCS or intravitreally. Widefield fundus images were taken immediately prior to injection with liopolysaccharide (LPS) on day -1, immediately prior to injection with vehicle, 0.2 mg (low dose), or 2.0 mg (high dose) of triamcinolone acetonide on day 0, and 3 days after treatment. Group 1 eyes injected with balanced salt solution and vehicle maintained a normal appearance. All eyes except Group 1 eyes had substantial opacification of the posterior segment 24 hours after LPS injection. Low and high doses (mg) of TA treatment in the SCS and high dose TA IVT treatment produced fundus images close to pretreatment appearance, while low dose TA IVT treatment produced images that were slightly improved over vehicle-treated eyes. The eye that received an IVT injection of 2.0 mg TA showed a large solid collection of TA (arrow) in the central vitreous. [Figure 25B]25A-B are widefield fundus images of eyes from animals treated with or without toxin and then with low or high doses of TA administered either in the SCS or intravitreally. Widefield fundus images were taken immediately prior to injection with liopolysaccharide (LPS) on day -1, immediately prior to injection with vehicle, 0.2 mg (low dose), or 2.0 mg (high dose) of triamcinolone acetonide on day 0, and 3 days after treatment. Group 1 eyes injected with balanced salt solution and vehicle maintained a normal appearance. All eyes except Group 1 eyes had substantial opacification of the posterior segment 24 hours after LPS injection. Low and high doses (mg) of TA treatment in the SCS and high dose TA IVT treatment produced fundus images close to pretreatment appearance, while low dose TA IVT treatment produced images that were slightly improved over vehicle-treated eyes. The eye that received an IVT injection of 2.0 mg TA showed a large solid collection of TA (arrow) in the central vitreous.

[0058] [Figure 26-1]FIG. 26 shows ocular histopathology of eyes 3 days after intravitreal injection of balanced salt solution (BSS) or 100 ng lipopolysaccharide (LPS) and 72 hours after SCS or IVT administration of vehicle, 0.2 mg TA, or 2.0 mg TA. No evidence of substantial tissue, structural, or toxicological changes in histopathology was observed in the examined eyes. Ocular histopathology of eyes 3 days after intravitreal (IVT) injection of balanced salt solution (BSS) or 100 ng lipopolysaccharide (LPS) and 72 hours after suprachoroidal (SCS) or IVT injection of vehicle, 0.2 mg triamcinolone acetonide (low dose TA), or 2.0 mg triamcinolone acetonide (high dose TA). Hematoxylin and eosin staining. A. Anterior eye injected with BSS IVT and vehicle in SCS (group 1). Scale bar: 1 mm. B. Retrobulb injected with BSS IVT and vehicle in SCS (group 1). Scale bar: 200 μm. C. Anterior eye injected with LPS IVT and vehicle in SCS (group 2). Scale bar: 1 mm. D. Retrobulb injected with LPS IVT and vehicle in SCS (group 2). Scale bar: 200 μm. E. Anterior eye injected with LPS IVT and low dose TA in SCS (group 3). Scale bar: 1 mm. F. Retrobulb injected with LPS IVT and low dose TA in SCS (group 3). Scale bar: 200 μm. G. Anterior eye injected with LPS IVT and high dose TA in SCS (group 4). Scale bar: 1 mm. H. Retrobulbar injected with LPS IVT and high dose TA in SCS (group 4). Arrows indicate the presence of TA in the SCS. Scale bar: 200 μm. I. Anterior bulb injected with LPS IVT and low dose TA IVT (group 5). Scale bar: 1 mm. J. Retrobulbar injected with LPS IVT and low dose TA IVT (group 5). Scale bar: 200 μm. K. Anterior bulb injected with LPS IVT and high dose TA IVT (group 6). Scale bar: 1 mm. L. Retrobulbar injected with LPS IVT and high dose TA IVT (group 6). Scale bar: 200 μm. [Figure 26-2]FIG. 26 shows ocular histopathology of eyes 3 days after intravitreal injection of balanced salt solution (BSS) or 100 ng lipopolysaccharide (LPS) and 72 hours after SCS or IVT administration of vehicle, 0.2 mg TA, or 2.0 mg TA. No evidence of substantial tissue, structural, or toxicological changes in histopathology was observed in the examined eyes. Ocular histopathology of eyes 3 days after intravitreal (IVT) injection of balanced salt solution (BSS) or 100 ng lipopolysaccharide (LPS) and 72 hours after suprachoroidal (SCS) or IVT injection of vehicle, 0.2 mg triamcinolone acetonide (low dose TA), or 2.0 mg triamcinolone acetonide (high dose TA). Hematoxylin and eosin staining. A. Anterior eye injected with BSS IVT and vehicle in SCS (group 1). Scale bar: 1 mm. B. Retrobulb injected with BSS IVT and vehicle in SCS (group 1). Scale bar: 200 μm. C. Anterior eye injected with LPS IVT and vehicle in SCS (group 2). Scale bar: 1 mm. D. Retrobulb injected with LPS IVT and vehicle in SCS (group 2). Scale bar: 200 μm. E. Anterior eye injected with LPS IVT and low dose TA in SCS (group 3). Scale bar: 1 mm. F. Retrobulb injected with LPS IVT and low dose TA in SCS (group 3). Scale bar: 200 μm. G. Anterior eye injected with LPS IVT and high dose TA in SCS (group 4). Scale bar: 1 mm. H. Retrobulbar injected with LPS IVT and high dose TA in SCS (group 4). Arrows indicate the presence of TA in the SCS. Scale bar: 200 μm. I. Anterior bulb injected with LPS IVT and low dose TA IVT (group 5). Scale bar: 1 mm. J. Retrobulbar injected with LPS IVT and low dose TA IVT (group 5). Scale bar: 200 μm. K. Anterior bulb injected with LPS IVT and high dose TA IVT (group 6). Scale bar: 1 mm. L. Retrobulbar injected with LPS IVT and high dose TA IVT (group 6). Scale bar: 200 μm. [Figure 26-3]FIG. 26 shows ocular histopathology of eyes 3 days after intravitreal injection of balanced salt solution (BSS) or 100 ng lipopolysaccharide (LPS) and 72 hours after SCS or IVT administration of vehicle, 0.2 mg TA, or 2.0 mg TA. No evidence of substantial tissue, structural, or toxicological changes in histopathology was observed in the examined eyes. Ocular histopathology of eyes 3 days after intravitreal (IVT) injection of balanced salt solution (BSS) or 100 ng lipopolysaccharide (LPS) and 72 hours after suprachoroidal (SCS) or IVT injection of vehicle, 0.2 mg triamcinolone acetonide (low dose TA), or 2.0 mg triamcinolone acetonide (high dose TA). Hematoxylin and eosin staining. A. Anterior eye injected with BSS IVT and vehicle in SCS (group 1). Scale bar: 1 mm. B. Retrobulb injected with BSS IVT and vehicle in SCS (group 1). Scale bar: 200 μm. C. Anterior eye injected with LPS IVT and vehicle in SCS (group 2). Scale bar: 1 mm. D. Retrobulb injected with LPS IVT and vehicle in SCS (group 2). Scale bar: 200 μm. E. Anterior eye injected with LPS IVT and low dose TA in SCS (group 3). Scale bar: 1 mm. F. Retrobulb injected with LPS IVT and low dose TA in SCS (group 3). Scale bar: 200 μm. G. Anterior eye injected with LPS IVT and high dose TA in SCS (group 4). Scale bar: 1 mm. H. Retrobulbar injected with LPS IVT and high dose TA in SCS (group 4). Arrows indicate the presence of TA in the SCS. Scale bar: 200 μm. I. Anterior bulb injected with LPS IVT and low dose TA IVT (group 5). Scale bar: 1 mm. J. Retrobulbar injected with LPS IVT and low dose TA IVT (group 5). Scale bar: 200 μm. K. Anterior bulb injected with LPS IVT and high dose TA IVT (group 6). Scale bar: 1 mm. L. Retrobulbar injected with LPS IVT and high dose TA IVT (group 6). Scale bar: 200 μm.

[0059] [Figure 27] FIG. 27 shows the mean anterior and posterior ocular histopathological inflammation scores 4 days after intravitreal (IVT) injection of balanced salt solution (BSS) or 100 ng lipopolysaccharide (LPS) and 3 days after suprachoroidal (SCS) or IVT injection of vehicle, 0.2 mg triamcinolone acetonide (low dose TA), or 2.0 mg triamcinolone acetonide (high dose TA). a. Group 1 mean histopathological inflammation scores were significantly lower than groups 2-6 (P<0.04). b. Group 5 mean histopathological inflammation scores were significantly higher than groups 4 and 6 (P<0.04). c. Group 4 mean histopathological inflammation scores were significantly lower than groups 2, 5, and 6 (P<0.04). d. Group 6 mean histopathological inflammation scores were significantly lower than group 2 (P=0.018).

[0060] [Figure 28] FIG. 28 shows the mean aqueous humor (AH) and vitreous humor (VH) cell counts 3 days after intravitreal (IVT) injection of balanced salt solution (BSS) or 100 ng lipopolysaccharide (LPS) and 72 hours after suprachoroidal (SCS) or IVT injection of vehicle, 0.2 mg triamcinolone acetonide (low dose TA), or 2.0 mg triamcinolone acetonide (high dose TA). a. Group 2 mean cell counts were significantly higher than groups 1, 3, 4, 5, and 6 (P<0.002). b. Group 5 mean cell counts were significantly higher than group 1 (P<0.002). c. Group 6 mean cell counts were significantly higher than group 1 (P<0.002). d. Group 3 mean cell counts were significantly higher than groups 1 and 4 (P<0.048). e. Group 5 mean cell count was significantly higher than groups 1 and 4 (P<0.034).

[0061] [Figure 29] FIG. 29 is a graph showing plasma triamcinolone (TA) concentrations following SCS or IVT administration.

[0062] [Diagram 30]30 shows optical coherence tomography (OCT) images taken before (left image) and 56 days after (right image) injection of bevacizumab into the suprachoroidal space of patient No. 3. A reduction in intraretinal fluid can be seen.

[0063] [Diagram 31] FIG. 31 is a graph showing intraocular pressure (IOP) following SCS administration of 4 mg (40 mg / mL) TA or vehicle.

[0064] [Diagram 32] FIG. 32 is a graph showing central corneal thickness 1 day and 90 days after SCS administration of 4 mg (40 mg / mL) TA or vehicle.

[0065] [Diagram 33] FIG. 33 is a graph showing plasma TA concentrations over time following SCS administration of 4 mg (40 mg / mL) TA. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0066] Detailed Description of the Invention Provided herein are methods, devices, and drug formulations for treating posterior ocular disorders and choroidal diseases in human subjects in need of such treatment. The methods, devices, and formulations provided herein can effectively deliver drugs to the posterior to treat posterior ocular disorders and choroidal diseases, and generally exemplify the following characteristics: (1) the methods are non-surgical, and therefore minimally invasive and safe; (2) the drug formulations are administered in a manner that adequately targets the posterior and / or suprachoroidal space (SCS) of the eye, while limiting exposure of the drug to the anterior or other areas of the eye; (3) the methods and formulations can deliver drugs in a sustained and / or controlled manner; (4) the methods and devices are user-friendly. The non-surgical SCS delivery methods, devices for carrying out the methods, and drug formulations for SCS delivery described above achieve these desired characteristics.

[0067] As used herein, a "non-surgical" ocular drug delivery method refers to a drug delivery method that does not require general anesthesia and / or retrobulbar anesthesia (also referred to as retrobulbar block). Alternatively or additionally, a "non-surgical" ocular drug delivery method is performed using a device with a diameter of 28 gauge or less. Alternatively or additionally, a "non-surgical" ocular drug delivery method does not require a guidance mechanism that is typically required for ocular drug delivery via a shunt or cannula.

[0068] The non-surgical methods for treating posterior ocular disorders and choroidal diseases described herein are particularly useful for localized delivery of drugs to the posterior segment (e.g., retinal choroidal tissues at the back of the eye, macula, retinal pigment epithelium (RPE), and optic nerve). In another embodiment, the non-surgical methods and microneedles provided herein can be used to target drug delivery to specific posterior ocular tissues or regions within the eye or adjacent tissues. In one embodiment, the methods described herein specifically deliver drugs to the sclera, choroid, Brach's membrane, retinal pigment epithelium, subretinal space, retina, macula, optic disc, optic nerve, ciliary body, trabecular meshwork, aqueous humor, vitreous humor, and / or other ocular or adjacent tissues within the eye of a human subject in need of delivery. In one embodiment, the methods and microneedles provided herein can be used to target drug delivery to specific posterior ocular tissues or regions within the eye or adjacent tissues.

[0069] In one embodiment of the methods described herein, a drug (e.g., an anti-inflammatory drug (e.g., triamcinolone), a vascular endothelial growth factor (VEGF) regulator (e.g., a VEGF antagonist), a platelet-derived growth factor (PDGF) antagonist) is delivered non-surgically to the suprachoroidal space for the treatment of a posterior ocular disorder or choroidal disease by inserting a microneedle into the patient's eye (e.g., intrascleral) and injecting or infusing a drug formulation into the suprachoroidal space of the eye through the inserted microneedle. In one embodiment, delivery of an effective amount of a drug to the SCS increases the therapeutic efficacy of the drug compared to the therapeutic efficacy of the drug when the same dosage is administered intravitreally, topically, intracavitary, parenterally, or orally. In one embodiment, the microneedle drug delivery method described herein precisely delivers the drug into the SCS for subsequent localized delivery near the posterior ocular tissue requiring treatment. The drug can be released from the injected volume (i.e., microparticles or nanoparticles in the drug formulation, for example) into the ocular tissue over an extended period of time (e.g., hours, days, weeks, or months) after completion of non-surgical drug administration. This can advantageously increase the bioavailability of the drug, for example, compared to delivery by topical application of the drug formulation to the ocular tissue surface, or increase the bioavailability compared to oral, parenteral, or intravitreal administration of the same drug dosage.

[0070] Using the methods and microneedle devices described herein, the SCS drug delivery method advantageously allows precise control of the insertion depth into ocular tissue, so that the microneedle tip can be positioned within the eye so that the drug formulation flows into the suprachoroidal space and, in some embodiments, into the posterior ocular tissue surrounding the SCS. In one embodiment, the microneedle is inserted into the sclera of the eye. In one embodiment, the drug flows into the SCS without contacting the underlying tissues (such as choroidal and retinal tissues) with the microneedle.

[0071] The methods provided herein, in one embodiment, allow delivery of drugs to the suprachoroidal space, thereby providing access to posterior ocular tissues that are not possible via topical, parenteral, intracavitary, or intravitreal drug delivery. Because the methods provided herein deliver drugs to posterior ocular tissues for the treatment of posterior ocular disorders or choroidal diseases, the drug dose to the suprachoroid sufficient to achieve a therapeutic response in a human subject treated with the methods provided herein is less than the intravitreal, topical, parenteral, or oral drug dose sufficient to induce the same or substantially the same therapeutic response. In one embodiment, the SCS delivery methods described herein allow for a reduced drug dose of a posterior ocular disorder treatment drug or choroidal disease treatment drug compared to an intravitreal, topical, intracavitary parenteral, or oral drug dose sufficient to induce the same or substantially the same therapeutic response. In further embodiments, the suprachoroidal drug dose sufficient to induce a therapeutic response is 75% or less, 50% or less, or 25% or less of the intravitreal, topical, parenteral, or oral drug dose sufficient to induce a therapeutic response. A therapeutic response, in one embodiment, is a reduction in the severity of the symptoms / clinical symptoms of the posterior ocular disorder or choroidal disease for which the patient is treated, or a reduction in the number of symptoms / clinical symptoms of the posterior ocular disorder or choroidal disease for which the patient is treated.

[0072] The terms "suprachoroidal space" are used interchangeably with suprachoroid, SCS, suprachoroid, and suprachoroidal plate to describe a potential air gap in the ocular region located between the sclera and the choroid. This region is primarily composed of densely packed layers of elongated pigmented processes originating from each of the two adjacent tissues, but cavities may develop in this region as a result of accumulation of fluid or other materials in the suprachoroidal space and adjacent tissues. Those skilled in the art will recognize that the suprachoroidal space frequently expands due to fluid accumulation in the eye caused by some pathologies or as a result of some trauma or surgical intervention. However, in this description, the accumulation of fluid is intentionally created by injection of a drug formulation into the suprachoroid to create a suprachoroidal space (filled with a drug formulation). Without wishing to be bound by theory, it is believed that the SCS region serves as a uveoscleral pathway (i.e., the natural process of the eye that moves fluid from one region of the eye to another), forming an actual cavity, for example, upon detachment of the choroid from the sclera.

[0073] As used herein, "ocular tissue" and "eye" 10 include both the anterior segment 12 of the eye (i.e., the portion of the eye in front of the lens) and the posterior segment 14 of the eye (i.e., the portion of the eye behind the lens), as illustrated in FIG. 1A. The anterior segment 12 is bounded by the cornea 16 and the lens 18, and the posterior segment 14 is bounded by the sclera 20 and the lens 18. The anterior segment 12 is further subdivided into an anterior chamber 22 between the iris 24 and the cornea 16, and a posterior chamber 26 between the lens 18 and the iris 24. The exposed portion of the sclera 20 on the anterior segment 12 of the eye is protected by a transparent membrane called the conjunctiva (not shown). Beneath the sclera 20 resides the choroid 28 and the retina 27 (collectively referred to as retinachoroidal tissue). The loose connective tissue (i.e., the potential air space) between the choroid 28 and the sclera 20 is referred to as the suprachoroidal space (SCS) (not shown). FIG. 1B illustrates the cornea 16, which is composed of the epithelium 30, Bowman's layer 32, stroma 34, Descemet's membrane 36, and endothelium 38. FIGs. 1C and 1D illustrate the sclera 20, surrounded by Tenon's capsule 40 or conjunctiva 41, the suprachoroidal space 42, the choroid 28, and the retina 27, with FIGs. 1C and 1D showing no or no fluid in the suprachoroidal space, respectively.

[0074] As provided throughout, in one embodiment, the method described herein is carried out using a hollow or solid microneedle (e.g., a solid microneedle). As used herein, the term "microneedle" refers to a conduit body having a base, shaft, and tip suitable for insertion into the sclera and other ocular tissues, the microneedle having dimensions suitable for minimally invasive insertion and injection of drug formulations as described herein. That is, the microneedle has a length or effective length not exceeding about 2000 microns and a diameter not exceeding about 600 microns. Both the "length" and "effective length" of the microneedle include the shaft length of the microneedle and the bevel height of the microneedle.

[0075] As used herein, the term "hollow" includes a single straight perforation through the center of the microneedle, multiple perforations, perforations that follow a complex path through the microneedle, perforations with multiple entrances and exits, and intersecting or network perforations. That is, hollow microneedles have a structure that includes one or more continuous paths from the base of the microneedle to an exit (opening) in the shaft and / or the tip of the microneedle distal to the base.

[0076] 2-5 illustrate exemplary embodiments of a microneedle device. In one embodiment illustrated in FIGS. 2-3, the microneedle device 110 includes a hollow microneedle 114 having a hollow bore 140 through which a fluid drug formulation (not shown) can be delivered to the eye or through which bodily fluids can be withdrawn from the eye. The microneedle includes a proximal end 116 and a tip end 118. The microneedle 114 can extend from a base including an elongated body 112 having a distal end from which the proximal end 116 and tip end 118 of the microneedle extend. The elongated body can further include a fastening means 111 (such as a screw or pin) at the base of the microneedle that extends beyond the distal end of the base 112. An exemplary embodiment of an elongated body 112 for fastening the microneedle is shown in FIG. 3, which includes a cap portion 113 and a base portion 115 having a hollow bore 117. The cap portion 113 and base portion 115 of the elongate body 112 desirably include a means for manually adjusting the length of the needle (i.e., the proximal and distal ends of the microneedle extending from the base 112) that protrudes from the cap portion of the elongate body. Such means may include, for example, threads 119 that screw the cap portion 113 onto and off the base portion 115 of the elongate body. In the exemplary embodiment shown in FIG. 4, the base portion 115 of the elongate body may be operably connected to an actuator 120 for controlling the injection of the fluid drug formulation through the microneedle into the suprachoroidal space.

[0077] The microneedle device may further include a fluid reservoir for containing a drug formulation (e.g., as a solution or suspension), the drug reservoir being in operable communication with the microneedle perforations at a location distal to the tip of the microneedle. The fluid reservoir may be integral with the microneedle, integral with the elongate body, or separate from both the microneedle and the elongate body.

[0078] The microneedles can be formed / constructed from different biocompatible materials, including metals, glass, semiconductor materials, ceramics, or polymers. Examples of suitable metals include pharmaceutical grade stainless steel, gold, titanium, nickel, iron, gold, tin, chromium, copper, and alloys thereof. The polymers can be biodegradable or non-biodegradable. Examples of suitable biocompatible biodegradable polymers include polylactides, polyglycolides, polylactide-co-glycolides (PLGA), polyanhydrides, polyorthoesters, polyetheresters, polycaprolactones, polyesteramides, poly(butyric acid), poly(valeric acid), polyurethanes, and copolymers and blends thereof. Representative non-biodegradable polymers include various thermoplastics or other polymeric structural materials known in medical device fabrication. Examples include nylon, polyester, polycarbonate, polyacrylate, polymers of ethylene-vinyl acetate and other acyl-substituted cellulose acetates, non-degradable polyurethanes, polystyrene, polyvinyl chloride, polyvinyl fluoride, poly(vinylimidazole), chlorosulfonated polyolefins, polyethylene oxide, blends and copolymers thereof. Biodegradable microneedles can provide an improved level of safety compared to non-biodegradable microneedles, such that they are essentially harmless even if inadvertently broken within ocular tissue.

[0079] Microneedles can be made by a variety of methods known in the art or as described in the Examples below. In one embodiment, hollow microneedles can be made using a laser or similar light energy source. In one example, a microcannula can be cut to the desired microneedle length using a laser. A laser can also be used to form single or multiple tip openings. A single microcannula can be cut single or multiple times to form the desired microneedle structure. In one example, a microcannula can be made from a metal such as stainless steel and cut using a laser with a wavelength in the infrared region of the light spectrum (e.g., about 0.7 to about 300 μm). Further refinement can be made using metal electropolishing techniques well known to those skilled in the art. In another embodiment, the microneedle length and any bevel are formed by a physical grinding process, which can include, for example, grinding the metal cannula with a moving abrasive surface. The fabrication process can further include precision grinding, microbead jet blasting, and ultrasonic cleaning to shape the desired precise tip of the microneedle.

[0080] Further details of possible manufacturing techniques are described, for example, in U.S. Patent Application Publication No. 2006 / 0086689, U.S. Patent Application Publication No. 2006 / 0084942, U.S. Patent Application Publication No. 2005 / 0209565, U.S. Patent Application Publication No. 2002 / 0082543, U.S. Patent No. 6,334,856, U.S. Patent No. 6,611,707, U.S. Patent No. 6,743,211 (all of which are incorporated by reference in their entirety for all purposes).

[0081] The methods and devices provided herein allow for minimally invasive non-surgical delivery of drugs to the suprachoroidal membrane, which is superior to other non-surgical (e.g., conventional needle) and surgical approaches. For example, in one embodiment, the methods provided herein are performed by the use of one or more microneedles. In one embodiment, the microneedle is inserted into the eye (e.g., into the sclera) at a vertical angle or at an angle of about 80° to about 100°, and reaches the suprachoroidal space with a short penetration distance. This is in contrast to the traditional long needles or cannulas that must approach the suprachoroidal space at an acute angle, resulting in a longer penetration path through the sclera and other ocular tissues, the invasiveness of the method, the large size of the injection site, and therefore an increased risk of infection and / or blood vessel rupture. When using such long needles, the ability to precisely control the depth of insertion is reduced compared to the microneedle approach described herein.

[0082] In one embodiment, the microneedle is part of a series of two or more microneedles, such that the method further comprises inserting at least one second microneedle into the sclera without penetrating the sclera. In one embodiment, when inserting a series of two or more microneedles into ocular tissue, the drug formulation of each of the two or more microneedles can be the same or different from each other in terms of drug, formulation, volume / amount of drug formulation, or combination of these parameters. In one case, different types of drug formulations can be injected through one or more microneedles. For example, inserting a second hollow microneedle containing a second drug formulation into ocular tissue will deliver the second drug formulation into ocular tissue.

[0083] In another embodiment, the microneedle devices described herein are adapted to remove substances, such as fluids, tissues, or molecular samples, from the eye.

[0084] However, those skilled in the art will recognize that other microneedle types (e.g., solid microneedles) and other methods of delivery of the drug formulation into the suprachoroidal space and posterior ocular tissues can be used in place of or in combination with the delivery methods described herein. Non-limiting examples include at least partially dissolving the coating of the drug formulation from the microneedle; at least partially peeling the coating of the drug formulation from the microneedle (e.g., as a substantially intact sleeve or in fragments); destroying or dissolving the microneedle from a base that is integrally formed with or connected to the microneedle; or any combination thereof.

[0085] The microneedle devices described herein can also be adapted to use one or more microneedles as sensors for detecting analytes, electrical activity, and optical or other signals. Sensors can include pressure, temperature, chemical, and / or electromagnetic field (e.g., light) sensors. Biosensors can be located on or within the microneedles or inside the device in communication with body tissues via the microneedles. Microneedle biosensors can be any of four main transducer classes: potentiometric, amperometric, optical, and physiochemical. In one embodiment, the hollow microneedles are filled with a substance such as a gel that has a sensing function associated with the hollow microneedle. For sensing applications based on binding to a substrate or reactions mediated by an enzyme, a substrate or enzyme can be immobilized inside the needle. In another embodiment, a waveguide can be incorporated into the microneedle device to direct light to a specific location or for detection using, for example, a color assessment means (such as a pH dye). Similarly, heat, electricity, light, ultrasound, or other forms of energy can be precisely delivered to directly stimulate, damage, or heal specific tissues, or for diagnostic purposes.

[0086] A microneedle device for non-surgically delivering a drug to the suprachoroidal space of the eye of a human subject, in one embodiment, comprises a hollow microneedle. The device may comprise an elongated housing for holding the base end of the microneedle. The device may further comprise a means for directing a drug formulation through the microneedle. For example, the means may be a flexible or rigid conduit in fluid communication with the base or base end of the microneedle. The means may also comprise a pump or other device for obtaining a pressure gradient to induce a flow of the fluid through the device. The conduit may be operably coupled to a source of the drug formulation. The source may be any suitable container. In one embodiment, the source may be in the form of a conventional syringe. The source may be a disposable unit dose container.

[0087] In one embodiment, the effective length of the microneedle is about 50 μm to about 2000 μm. In another specific embodiment, the effective length of the microneedle is about 150 μm to about 1500 μm, about 300 μm to about 1250 μm, about 500 μm to about 1250 μm, about 500 μm to about 1500 μm, about 600 μm to about 1000 μm, or about 700 μm to about 1000 μm. In one embodiment, the effective length of the microneedle is about 600 μm, about 700 μm, about 800 μm, or about 1000 μm. In various embodiments, the maximum width or cross-sectional dimension of the base end of the microneedle is about 50 μm to about 600 μm, about 50 μm to about 400 μm, about 50 μm to about 500 μm, about 100 μm to about 400 μm, about 200 μm to about 600 μm, or about 100 μm to about 250 μm, and the opening diameter is about 5 μm to about 400 μm. In certain embodiments, the maximum width or cross-sectional dimension of the base end of the microneedle is about 600 μm. However, one skilled in the art will recognize that in embodiments where the tip of the microneedle is beveled, the opening diameter may exceed the outer diameter of the base end of the microneedle. The microneedle can be fabricated with an aspect ratio (width:length) of about 1:1.5 to about 1:10. In one embodiment, the aspect ratio of the microneedle is about 1:3 to about 1:5. In another embodiment, the aspect ratio of the microneedles is from about 1:4 to about 1:10.

[0088] The microneedle may have a straight or tapered shaft. In one embodiment, the diameter of the microneedle is greatest at the base end of the microneedle and tapers toward the end point distal to the base. The microneedle may also be fabricated to have a shaft that includes both straight (i.e., non-tapered) and tapered (e.g., beveled) portions. In various embodiments, the bevel angle of the microneedle is about 5° to about 30°, about 5° to about 25°, about 5° to about 20°, about 10° to about 20°, and about 10° to about 30°. Microneedles can be formed with shafts that have a circular cross section in the vertical direction, or the cross section may be non-circular. The tip of the microneedle may have various configurations. The tip of the microneedle may be symmetric or asymmetric with respect to the anterior-posterior axis of the shaft. The tip may be beveled, tapered, square, or circular. In various embodiments, the height of the microneedle bevel is about 50 μm to 500 μm, about 100 μm to about 500 μm, about 100 μm to about 400 μm, about 200 μm to about 400 μm, and about 300 μm to about 500 μm. In certain embodiments, the microneedle can be designed such that the tip of the microneedle is substantially the only portion of the microneedle inserted into the ocular tissue (i.e., the tip is more than 75% of the total length of the microneedle, more than 85% of the total length of the microneedle, or more than about 95% of the total length of the microneedle). In other specific embodiments, the microneedle can be designed such that the tip is the only portion of the microneedle inserted into the ocular tissue, generally less than about 75% of the total length of the microneedle, less than about 50% of the total length of the microneedle, or less than about 25% of the total length of the microneedle. For example, in one embodiment, the total effective length of the microneedle is between 500 μm and 1500 μm, with the tip length being less than about 400 μm, less than about 300 μm, or less than about 200 μm.

[0089] In one embodiment, the height of the bevel is about 100 μm to about 500 μm. In another embodiment, the height of the bevel is about 500 μm or less, about 450 μm or less, about 400 μm or less, or about 350 μm or less. In another embodiment, the height of the bevel is about 200 μm to about 500 μm, about 100 μm to about 700 μm, or about 200 μm to about 700 μm. In yet another embodiment, the height of the bevel is about 500 μm to about 900 μm, about 500 μm to about 800 μm, or about 500 μm to about 700 μm. In this manner, the bevel can be positioned such that the distal edge is sharp enough to (i) elastically deform the target tissue, or (ii) penetrate the target tissue and penetrate the vitreous without damaging the internal structures of the eye (e.g., the lens or retina).

[0090] In one embodiment, the microneedle extends from a base. The base can be integral with the microneedle or separate. The base can be rigid or flexible. The base can be substantially planar, for example, curved to the shape of the ocular tissue surface at the injection site, or curved inversely to the ocular surface (e.g., convex) to minimize contact between the base and the ocular tissue. Desirably, the base is shaped to minimize contact with the ocular surface at the insertion point. For example, in one embodiment, the base can extend only a minimal distance in a substantially perpendicular direction from the microneedle shaft. In another embodiment, the base can be shaped to lift the ocular tissue toward the microneedle to counteract distortion of the ocular tissue and facilitate insertion of the microneedle into the ocular tissue (e.g., the base can extend from the microneedle toward the tip of the microneedle to "pinch" the ocular tissue). Some such embodiments can be based, at least in part, on the devices described in U.S. Pat. No. 6,743,211, which is incorporated herein by reference.

[0091] In certain embodiments, the microneedle device has a single microneedle. In one embodiment shown in Figure 5, the microneedle device 130 includes a hollow microneedle 134 having a convex base 132 and a fenestration 140 through which a fluid drug formulation (not shown) can be delivered to the eye or bodily fluids can be withdrawn from the eye. The hollow microneedle 134 includes a proximal end 136 and a tip end 138.

[0092] The microneedles can extend from the base of the microneedle device at any angle suitable for insertion into the eye. In certain embodiments, the microneedles extend from the base at an angle of about 90° to insert the microneedles approximately perpendicularly into the ocular surface. In other specific embodiments, the microneedles extend from the base at an angle of about 60° to about 110°, about 70° to about 100°, about 80° to about 90°, or about 85° to about 95°.

[0093] The microneedle device may include means for controllably inserting and optionally retracting the microneedles into the ocular tissue. Additionally, the microneedle device may include means for controlling the angle at which the at least one microneedle is inserted into the ocular tissue (e.g., by inserting the at least one microneedle at about 90° into the ocular tissue surface).

[0094] The insertion depth of the microneedle into the ocular tissue can be controlled by the length of the microneedle and other geometric features of the microneedle.For example, a flange or other abrupt change in the width of the microneedle can be used to limit the insertion depth of the microneedle.The microneedle insertion can also be controlled using a mechanical micropositioning system that includes gears or other mechanical components that can be operated to move the microneedle into the ocular tissue a controlled distance, and also, for example, to retract the microneedle inversely a controlled distance.The insertion depth can also be controlled by the speed at which the microneedle is inserted into the ocular tissue.The retraction distance can be controlled by including an elastic recoil of the ocular tissue into which the microneedle is inserted or an elastic element in the microneedle device that retracts the microneedle a certain distance after releasing the insertion force.

[0095] The insertion angle can be directed by positioning the microneedle at a first angle relative to the microneedle base and positioning the base at a second angle relative to the ocular surface. In one embodiment, the first angle can be about 90° and the second angle can be about 0°. The insertion angle can also be directed by having the microneedle protrude from the device housing through a groove in the housing oriented at a particular angle.

[0096] One skilled in the art will be able to adapt mechanical systems known in the art in combination with the disclosure herein and in the Examples below to devise suitable structures for controllably driving microneedle insertion, said structures being manually operable, electromechanically operable, or a combination thereof.

[0097] The transport of drug formulations or bodily fluids through hollow microneedles can be controlled or monitored, for example, using one or more valves, pumps, sensors, actuators, and microprocessors. For example, in one embodiment, the microneedle device can include a micropump, a microvalve, and a positioner, and the microprocessor is programmed to control the pump or valve so that the rate of delivery of drug formulations through the microneedle into ocular tissue is controlled. The flow through the microneedle can be driven by diffusion, capillary action, mechanical pumps, electroosmosis, electrophoresis, convection, or other driving forces. The design of the device and microneedle can be adapted to utilize these drives using known pumps and other devices. In one embodiment, the microneedle device can further include an iontophoretic device similar to the device described in Beck's U.S. Patent No. 6,319,240 to enhance the delivery of drug formulations to ocular tissue. In another embodiment, the microneedle device can further include a flow meter or other means for monitoring the flow through the microneedle and coordinating the use of pumps and valves.

[0098] The flow of drug formulations or bodily fluids can be regulated using various valves or gates known in the art. The valves can be valves that can be selectively and repeatedly opened and closed, or the valves can be single-use types (such as breakable barriers). Other valves or gates used in microneedle devices can be thermally, electrochemically, mechanically, or magnetically actuated to selectively start, regulate, or stop the flow of material through the microneedle. In one embodiment, flow is controlled using a rate-limiting membrane that acts as a valve.

[0099] In another embodiment, the device includes an array of two or more microneedles. For example, the device may include an array of 2-1000 (e.g., 2-100) microneedles. In one embodiment, the device includes between 1 and 10 microneedles. The array of microneedles may include a mixture of different microneedles. For example, an array may include microneedles having various lengths, base diameters, tip shapes, microneedle spacing, drug coatings, etc. In embodiments where the microneedle device includes an array of two or more microneedles, the angle at which a single microneedle extends from the base may be independent of the angle at which another microneedle in the array extends from the base.

[0100] The SCS drug delivery method provided herein allows drug formulations to be delivered to larger tissue areas and tissues that are more difficult to target with a single dose compared to known needle devices.Without wishing to be bound by theory, it is believed that the drug formulation flows peripherally from the insertion site toward the retina-choroid tissue, macula, and optic nerve at the back of the eyeball, and toward the uvea and ciliary body at the front, upon entry into the SCS.In addition, some of the injected drug formulation may remain in the SCS as a depot near the microneedle insertion site or remain in the tissues covering the SCS (e.g., sclera), and serve as an additional depot for the drug formulation that can then diffuse into the SCS and other adjacent posterior tissues.

[0101] The microneedle device and non-surgical method described herein can be used to deliver drug formulations to the eye of a human subject, particularly for the treatment, diagnosis, or prevention of posterior ocular disorders or choroidal diseases.In one embodiment, the drug formulation comprises an effective amount of an anti-inflammatory drug, an immunosuppressant, a VEGF regulator (e.g., a VEGF antagonist), an angiogenesis inhibitor (e.g., a PDGF antagonist), or a vascular permeability inhibitor.In a further embodiment, the formulation comprises an anti-inflammatory drug selected from a steroid compound and a nonsteroidal anti-inflammatory drug (NSAID).In yet a further embodiment, the drug formulation is a triamcinolone formulation (e.g., a triamcinolone acetonide formulation).

[0102] In one aspect, the present invention relates to the treatment of choroidal malady in a human patient in need of such treatment. In one embodiment, the method comprises non-surgically administering a drug formulation comprising an effective amount of a choroidal malady treatment drug to the suprachoroidal space of one or both eyes of a patient in need of choroidal malady treatment. It should be understood that a patient with one eye will only receive treatment in one eye.

[0103] In one embodiment, the methods and microneedles described herein relate to non-surgical administration of a drug formulation for the treatment of choroidal disease or posterior ocular disorder, wherein the majority of the drug formulation remains in the SCS of one or both eyes of a patient in need of treatment of either a choroidal disease or posterior ocular disorder for a period of time after completion of the non-surgical treatment method. Without wishing to be bound by theory, the persistence of the drug formulation in the SCS contributes to the sustained release profile of the drug formulation described herein.

[0104] The human subjects treated using the methods provided herein can be adults or children. A wide range of posterior ocular disorders and choroidal diseases are treatable using the methods, devices, and drug formulations described herein.

[0105] Examples of posterior ocular disorders treatable by the methods, devices, and drug formulations described herein include, but are not limited to, uveitis, glaucoma, macular edema, diabetic macular edema, retinopathy, age-related macular degeneration (e.g., wet AMD or dry AMD), scleritis, optic nerve degeneration, geographic atrophy, choroidal disease, ocular sarcoidosis, optic neuritis, choroidal neovascularization, eye cancer, genetic disease, autoimmune disease affecting the posterior part of the eye, retinitis (e.g., cytomegalovirus retinitis), and corneal ulcer. The posterior ocular disorders treatable by the methods, devices, and drug formulations described herein can be acute or chronic. For example, the eye disease can be acute or chronic uveitis. Uveitis can be caused by viral, fungal, or parasitic infection; the presence of non-infectious foreign substances in the eye; autoimmune disease; or surgical or traumatic injury. Injuries caused by pathogenic organisms that may develop uveitis or other types of ocular inflammation include, but are not limited to, toxoplasmosis, toxocariasis, histoplasmosis, herpes simplex or varicella zoster virus infection, tuberculosis, syphilis, sarcoidosis, Vogt-Koyanagi-Harada syndrome, Behçet's disease, idiopathic retinal vasculitis, Vogt-Koyanagi-Harada syndrome, acute posterior multifocal placoid pigment epitheliopathy (APMPPE), presumed ocular histoplasmosis syndrome (POHS), birdshot chroidopathy, multiple sclerosis, sympathetic opthalmia, punctate inner choroidopathy, pars planitis, or iridocyclitis. Acute uveitis develops suddenly and can last up to about six weeks. Chronic uveitis is a form of uveitis in which the signs and / or symptoms develop slowly and symptoms persist beyond about six weeks.

[0106] Signs of uveitis include ciliary injection, aqueous humor flare, accumulation of cells visible on ophthalmic examination (such as aqueous humor, retrolental, and vitreous cells), posterior corneal deposits, and hypema. Symptoms of uveitis include pain (such as ciliary spasm), redness, photophobia, increased lacrimation, and decreased vision. Posterior uveitis affects the posterior or choroidal portion of the eye. Inflammation of the choroidal portion of the eye is often also referred to as choroiditis. Posterior uveitis may also be associated with inflammation occurring in the retina (retinitis) or blood vessels in the posterior portion of the eye (vasculitis). In one embodiment, the method provided herein comprises non-surgically administering an effective amount of a uveitis treatment drug to the SCS of a uveitis patient in need thereof. In a further embodiment, the patient experiences a decrease in the severity of symptoms following administration of a uveitis treatment drug to the SCS.

[0107] In one embodiment, with the drug formulation delivered to the SCS, the patient experiences reduced inflammation, neuroprotection, complement inhibition, drusen formation, scarring, and / or reduced choriocapillaris or choroidal neocasvularization.

[0108] The non-surgical method described herein is particularly useful for localized delivery of drugs to the posterior segment of the eye (e.g., the retina-choroidal tissue, macula, and optic nerve in the posterior segment of the eye).In one embodiment, the non-surgical treatment method and device described herein can be used in gene-based therapeutic applications.For example, the method, in one embodiment, includes administering a drug formulation into the suprachoroidal space to deliver selected DNA, RNA, or oligonucleotide to target eye tissue.

[0109] As provided throughout, the methods described herein can also treat choroidal malady in subjects in need of such treatment. In one embodiment, the patient in need of choroidal malady treatment has not responded to previous non-SCS choroidal malady treatment methods. Examples of choroidal malady that can be treated with the methods, devices, and drug formulations described herein include, but are not limited to, choroidal neovascularization, polypoidal choroidal vasculopathy, central sirrus choroidopathy, multifocal choroidopathy, or choroidal dystrophy (e.g., central gyral choroidal dystrophy, ocular choroidal dystrophy, or total central choroidal atrophy). Choroidal malady is described in more detail below.

[0110] In one embodiment, the choroidal disease treatment drug is an angiogenesis inhibitor, a vascular permeability inhibitor, or an anti-inflammatory drug. In one embodiment, the angiogenesis inhibitor is a vascular endothelial growth factor (VEGF) regulator or a platelet-derived growth factor (PDGF) regulator. In one embodiment, the choroidal disease treatment method comprises administering a drug formulation to the SCS of one or both eyes of a patient in need of treatment via a microneedle. In a further embodiment, the microneedle is a hollow microneedle having a tip and an opening, and the drug formulation is injected into the SCS of one or both eyes via the tip of the hollow microneedle.

[0111] A method for treating a posterior ocular disorder or choroidal malady in a human subject in need thereof, in one embodiment, comprises non-surgically administering a drug formulation to the suprachoroidal space of the eye of the human subject, whereby the drug formulation flows out of the insertion site and is substantially localized in the posterior segment of the eye. In one embodiment, the non-surgical methods provided herein allow for increased retention of the drug in the eye compared to intravitreal, topical, parenteral, intracameral, or oral administration of the same drug dose.

[0112] In one embodiment, the suprachoroidal drug dose sufficient to achieve a therapeutic response in a human subject treated using a non-surgical SCS drug delivery method is less than the intravitreal, parenteral, intracavitary, topical, or oral drug dose sufficient to induce the same or substantially the same therapeutic response. In a further embodiment, the suprachoroidal drug dose is at least 10% less than the oral, parenteral, or intravitreal dose sufficient to achieve the same or substantially the same therapeutic response. In a further embodiment, the suprachoroidal dose is about 10% to about 25% less, or about 10% to about 50% less, than the oral, parenteral, intracavitary, topical, or intravitreal dose sufficient to achieve the same or substantially the same therapeutic response. Thus, in one embodiment, the method of treating a posterior ocular disorder or choroidal malady described herein achieves greater therapeutic efficacy than other routes of administration. In one embodiment, the non-surgical method provided herein includes inserting a hollow microneedle into the sclera of the eye of a human subject and injecting a drug formulation into the suprachoroidal space of the eye through the hollow microneedle. As described in more detail below, the drug formulation, in one embodiment, is a solution or suspension of the drug.

[0113] In one embodiment, where the method of non-surgically treating a posterior ocular disorder or choroidal disease in a human subject includes drug delivery to the SCS of one or both eyes of a patient via a microneedle (hollow or solid), the microneedle insertion site is between the equator and limbus of each eye.

[0114] In another embodiment, the insertion site is between about 2 mm and about 10 mm posterior to the limbus of the eye. In one embodiment, the microneedle insertion site is in the pars plana. However, in other embodiments, the insertion site is outside the pars plana. In one embodiment, the microneedle insertion site is near the equator of the eye.

[0115] In another embodiment, the insertion site is 2-10 mm anterior to the limbus of the eye (eg, about 5 mm anterior to the limbus).

[0116] In another embodiment, the drug formulation is introduced into the SCS at an injection site (i.e., the tip of the microneedle) and then flows from the injection site into the SCS during injection. In another embodiment, the injection site (i.e., the tip of the microneedle) is in front of the equator of the eye, and at least a portion of the drug formulation flows behind the equator of the eye during injection (i.e., as the drug formulation continues to flow out of the microneedle). In another embodiment, the injection site (i.e., the tip of the microneedle) is in front of the equator of the eye, and at least a portion of the drug formulation flows near the macula during injection (i.e., as the drug formulation continues to flow out of the microneedle).

[0117] In one embodiment, the insertion depth of the microneedle into the ocular tissue is precisely controlled. Various methods can be used to control the insertion depth of the microneedles described herein. In certain embodiments, the insertion depth is limited by the selection of the length or effective length of the microneedle. The "effective length" is the portion available for tissue insertion (i.e., the length that extends from the base and is inserted when tissue deformation is zero). The "effective length" ignores any proximal end of the microneedle that extends into or through the base and therefore cannot be inserted into tissue, and includes both the shaft length and the bevel length of the microneedle. That is, the microneedle may have an effective length approximately equal to the desired penetration depth. In one embodiment, the microneedle is short enough to allow the tip of the microneedle to be substantially inserted into the bottom of the sclera (i.e., near the boundary between the sclera and the choroid) without penetrating completely across the sclera. In another embodiment, the tip of the microneedle is inserted through the sclera into the suprachoroidal space without penetrating the choroid.

[0118] In another embodiment, the microneedle is designed to be longer than the desired penetration depth, but the microneedle is controllably inserted only to a certain extent into the tissue. The partial insertion is controlled by the mechanical properties of the tissue, which allows the microneedle to bend and create a depression during the microneedle insertion process. In this way, as the microneedle is inserted into the tissue, its movement partially elastically deforms the tissue and partially penetrates into the tissue. By controlling the degree to which the tissue is deformed, the insertion depth of the microneedle into the tissue can be controlled.

[0119] In one embodiment, the microneedle is inserted into the eye of a human patient using a rotating / drilling technique and / or a vibration action.In this way, the microneedle can be inserted to a desired depth, for example, by drilling the microneedle at a desired number of rotations corresponding to the desired depth into tissue.See, for example, US Patent Application Publication No. 2005 / 0137525 (incorporated herein by reference) for a description of drilling microneedles.The rotating / drilling technique and / or a vibration action can be applied during the insertion process, during the withdrawal process, or both.

[0120] In one embodiment, the drug formulation is injected into the suprachoroidal space through a hollow microneedle by driving the drug formulation from a supply reservoir into the ocular tissue using a pressure gradient (e.g., pumping, syringe). In other embodiments, the drug formulation is driven from a supply reservoir into the ocular tissue using an electric field (e.g., iontophoresis) or another externally applied energy (e.g., ultrasound / acoustic energy).

[0121] In one embodiment, the amount of drug formulation injected into the suprachoroidal space resulting from the non-surgical drug delivery method described herein is about 10 μL to about 200 μL (e.g., about 50 μL to about 150 μL). In another embodiment, about 10 μL to about 500 μL (e.g., about 50 μL to about 250 μL) is non-surgically administered into the suprachoroidal space. For example, in one embodiment, the non-surgical method includes inserting a hollow microneedle into an insertion site in the sclera, the microneedle having a tip with an opening, and injecting the drug formulation into the suprachoroidal space through the hollow microneedle. As provided above, about 10 μL to about 200 μL, about 50 μL to about 150 μL, about 10 μL to about 500 μL, or about 50 μL to about 250 μL can be delivered through one or more hollow microneedles described herein.

[0122] In one embodiment, the driving force or pressure of injecting the drug formulation through the hollow microneedle causes the injected drug formulation to flow into the suprachoroidal space and reach the back of the eye during the administration process (i.e., during injection). This can occur in less than 1 or 2 minutes, such as from about 1 second to about 100 seconds (e.g., from about 10 seconds to about 30 seconds). In one aspect, the drug formulation flows out of the insertion site during and after injection of the drug into the SCS. In a further embodiment, the drug formulation flows out of the suprachoroidal space at a site at least 2.5 mm away from the insertion site, at a site at least 5 mm away from the insertion site, at a site at least 7.5 mm away from the insertion site, or at least 10 mm away from the insertion site during the drug injection process. In one embodiment, the drug formulation flows out of the suprachoroidal space at a site at the back of the eye (i.e., the retina-choroidal tissue, macula, and optic nerve at the back of the eye) while spreading.

[0123] The amount of drug delivered into the SCS can be controlled in part by the type of microneedle used and the method of use. In one embodiment, a hollow microneedle is inserted into the ocular tissue and gradually retracted from the ocular tissue after insertion to deliver the fluid drug, and after a certain dosage is achieved, delivery can be stopped by ceasing the fluid driving force (such as pressure (e.g., from a mechanical device such as a syringe) or an electric field) to avoid leakage / uncontrolled delivery of the drug. Desirably, the amount of drug delivered is controlled by driving the fluid drug formulation with an appropriate injection pressure. In one embodiment, the injection pressure can be at least 150 kPa, at least 250 kPa, or at least 300 kPa. In another embodiment, the injection pressure is about 150 kPa to about 300 kPa. The appropriate injection pressure can vary depending on the particular patient or species.

[0124] It should be noted that the desired injection pressure to deliver an adequate amount of drug formulation may be affected by the insertion depth of the microneedle and the composition of the drug formulation. For example, in embodiments where the drug formulation for intraocular delivery is in the form of or includes nanoparticles or microparticles that encapsulate the active agent or microbubbles, higher injection pressures may be required. Nanoparticle or microparticle encapsulation techniques are well known in the art. In one embodiment, the drug formulation is D 99 In one embodiment, the drug formulation comprises a suspension of drug particles having a diameter of 10 μm or less. 99 In another embodiment, the drug formulation comprises a suspension of drug particles having a diameter of 7 μm or less. 99 In another embodiment, the drug formulation comprises a suspension of drug particles having a diameter of 3 μm or less. 50 In one embodiment, the drug formulation comprises a suspension of drug particles having a diameter of 5 μm or less. 50 It consists of a suspension of drug particles smaller than 1 μm.

[0125] In one embodiment, the method of non-surgical administration of a drug to the SCS further comprises partially retracting the hollow microneedle after insertion of the microneedle into the eye and before and / or during injection of a drug formulation into the suprachoroidal space. In certain embodiments, partial retraction of the microneedle is performed before injecting the drug formulation into the ocular tissue. This insertion / retraction step creates a pocket that advantageously allows the drug formulation to flow out of the microneedle at the opening at the tip of the microneedle without being blocked or significantly blocked by the ocular tissue. This pocket can be filled with the drug formulation, but also serves as a conduit, allowing the drug formulation to flow from the microneedle through the pocket into the suprachoroidal space. FIG. 6A shows a hollow microneedle 130 inserted into the sclera 20 with a drug formulation 131 transiently positioned in the hollow perforation of the microneedle (fluid communication to the reservoir of the drug formulation is not shown). FIG. 6B shows the microneedle 130 after partial retraction and the injection of the drug formulation 131 into the suprachoroidal space. The arrows indicate the peripheral flow of the drug formulation through the suprachoroidal space.

[0126] In one embodiment, the microneedle injects the drug formulation through the sclera into the suprachoroidal space for controlled release (i.e., sustained, extended, or regulated release over an extended period of time) of the drug to one or more ocular or adjacent tissues. This "controlled release", "sustained release", "extended release", or "regulated release" is generally longer than can be obtained by topical application or intravitreal injection of the drug formulation to the ocular tissue. In one embodiment, the drug formulation is controlled, extended, sustained, or regulated release after at least one microneedle is retracted from the ocular tissue. This delivery method may be advantageous, particularly in ocular tissues where it is desirable to perform the insertion and retraction process in as short a time as possible to minimize patient discomfort. In contrast to transdermal microneedle patching, this delivery method is more likely to allow the patient to wear the patch (insert the microneedle) for an extended period of time without discomfort.

[0127] In another embodiment, a method for treating a posterior ocular disorder or choroidal disease by non-surgical administration of a drug to the suprachoroidal space of the eye of a human subject includes monitoring the insertion of a microneedle and / or injection of a fluid drug formulation to ensure accurate delivery of the fluid drug formulation to the SCS (see, e.g., FIG. 18). Such monitoring can be performed using image-guided feedback during one or more of these steps, non-limiting examples of which include conventional microscopy, MRI, X-ray, confocal microscopy, ocular coherence tomography (e.g., anterior optical coherence tomography, Heidelberg retinal tomography, spectral domain optical coherence tomography), fluorescein angiography, indocyanine green angiography, high-resolution fundus stereophotography, autofluorescence imaging, ultra-widefield imaging, and various ultrasound techniques. Thus, the method can further include determining whether the initial injection of the fluid drug formulation flows into the suprachoroidal space of the eye and out of the insertion site. If the initial injection is determined to be successful, the desired volume of the fluid drug formulation can be injected and the injection can be interrupted by removing the injection driving force (e.g., pressure) and retracting the microneedle from the eye. However, if the initial injection of the fluid drug formulation is determined to be unsuccessful (i.e., the drug formulation does not substantially flow into the suprachoroidal space of the eye and out of the insertion site), the microneedle can be repositioned and the process repeated until successful delivery.

[0128] Targeting of drug formulations to the SCS and posterior ocular tissues allows for high concentrations of drug to be delivered to the choroid / sclera and retina, with little to no drug delivery to the aqueous humor of the anterior chamber. Additionally, the methods provided herein allow for longer retention of the drug in the eye compared to other drug delivery methods. For example, a greater amount of drug is retained in the eye when delivered by the methods provided herein compared to the same dose delivered by intracavitary, intravitreal, topical, parenteral, or oral drug delivery methods. Thus, in one embodiment, the intraocular elimination half-life (t 1 / 2) is the intraocular t value of a drug when the same drug dose is administered intravitreally, intracamerally, topically, parenterally, or orally. 1 / 2 In another embodiment, the intraocular C max When delivered by the methods described herein, the intraocular C of a drug is increased when the same drug dose is administered intravitreally, intracamerally, topically, parenterally, or orally. max In another embodiment, the mean intraocular area under the curve (AUC 0-t ) is the intraocular AUC of a drug when administered intravitreally, intracamerally, topically, parenterally, or orally when administered to the SCS by the methods described herein. 0-t In yet another embodiment, the time to peak intraocular concentration of the drug (t max ) when administered to the SCS by the methods described herein, represents the intraocular t max It is higher. In a further embodiment, the drug is an angiogenesis inhibitor, an anti-inflammatory drug (e.g., steroid or NSAID), a VEGF regulator (e.g., VEGF antagonist), a PDGF regulator (e.g., PDGF antagonist), an immunosuppressant, or a vascular permeability inhibitor. In yet a further embodiment, the drug is triamcinolone, infliximab, mycophenolate, sorafenib, axitinib, or nepafenac.

[0129] In one embodiment, the intraocular t 1 / 2 is the intraocular t value of a drug when administered at the same dose topically, intracamerally, intravitreally, orally, or parenterally. 1 / 2 In a further embodiment, the intraocular t 1 / 2 is the intraocular t value of a drug when administered at the same dose topically, intracamerally, intravitreally, orally, or parenterally. 1 / 2about 1.1 to about 10 times or more, about 1.25 to about 10 times or more, about 1.5 to about 10 times or more, or about 2 to about 5 times or more. In further embodiments, the drug is an angiogenesis inhibitor, an anti-inflammatory drug (e.g., a steroid or an NSAID), a VEGF regulator (e.g., a VEGF antagonist), a PDGF regulator (e.g., a PDGF antagonist), an immunosuppressant, or a vascular permeability inhibitor.

[0130] In another embodiment, the intraocular C max When delivered by the methods described herein, the intraocular C of a drug is increased when the same drug dose is administered intravitreally, intracamerally, topically, parenterally, or orally. max In further embodiments, the intraocular C of the drug when administered via the non-surgical SCS drug delivery methods provided herein is max is the intraocular C of a drug when administered at the same dose topically, intracamerally, intravitreally, orally, or parenterally. max In one embodiment, the intraocular C of the drug when administered by the non-surgical SCS drug delivery methods provided herein is at least 1.1 times or more, at least 1.25 times or more, at least 1.5 times or more, at least 2 times or more, or at least 5 times or more. max is the intraocular C of a drug when administered at the same dose topically, intracamerally, intravitreally, orally, or parenterally. max about 1 to about 2 times or more, about 1.25 to about 2 times or more, about 1 to about 5 times or more, about 1 to about 10 times or more, about 2 to about 5 times or more, or about 2 to about 10 times or more. In further embodiments, the drug is an angiogenesis inhibitor, an anti-inflammatory drug (e.g., a steroid or an NSAID), a VEGF regulator (e.g., a VEGF antagonist), a PDGF regulator (e.g., a PDGF antagonist), an immunosuppressant, or a vascular permeability inhibitor. In one embodiment, the drug is triamcinolone, infliximab, mycophenolate, methotrexate, sorafenib, axitinib, or nepafenac.

[0131] In another embodiment, the mean intraocular area under the curve (AUC 0-t) is the intraocular AUC of a drug when administered intravitreally, intracamerally, topically, parenterally, or orally when administered to the SCS by the methods described herein. 0-t In a further embodiment, the intraocular AUC of the drug when administered via the non-surgical SCS drug delivery methods provided herein is 0-t is the intraocular AUC of a drug when the same dose is administered topically, intracamerally, intravitreally, orally, or parenterally. 0-t In one embodiment, the intraocular AUC of the drug when administered by the non-surgical SCS drug delivery methods provided herein is at least 1.1 times or more, at least 1.25 times or more, at least 1.5 times or more, at least 2 times or more, or at least 5 times or more. 0-t is the intraocular AUC of a drug when the same dose is administered topically, intracamerally, intravitreally, orally, or parenterally. 0-t about 1 to about 2 times or more, about 1.25 to about 2 times or more, about 1 to about 5 times or more, about 1 to about 10 times or more, about 2 to about 5 times or more, or about 2 to about 10 times or more. In a further embodiment, the drug is an angiogenesis inhibitor, an anti-inflammatory drug (e.g., a steroid or an NSAID), a VEGF regulator (e.g., a VEGF antagonist), a PDGF regulator (e.g., a PDGF antagonist), an immunosuppressant, or a vascular permeability inhibitor. In yet a further embodiment, the drug is triamcinolone, infliximab, mycophenolate, methotrexate, sorafenib, axitinib, or nepafenac.

[0132] In one embodiment, a drug formulation comprising an effective amount of a drug (e.g., an angiogenesis inhibitor, an anti-inflammatory drug (e.g., a steroid or NSAID), a VEGF modulator (e.g., a VEGF antagonist), a PDGF modulator (e.g., a PDGF antagonist), an immunosuppressant, or a vascular permeability inhibitor) is substantially retained in the SCS for an extended period of time once delivered to the SCS. For example, in one embodiment, about 80% of the drug formulation is retained in the SCS for about 30 minutes, about 1 hour, about 4 hours, about 24 hours, about 48 hours, or about 72 hours. In this regard, a depot of the drug is formed in the SCS and / or surrounding tissues to allow for sustained release of the drug over an extended period of time.

[0133] In one embodiment, once the suprachoroidal space is loaded with drug (e.g., drug microparticles or nanoparticles), the drug is released to the retina or other posterior ocular tissues over an extended period of time. Targeting of drugs to posterior ocular tissues by the methods described herein may result in greater therapeutic efficacy in treating one or more posterior ocular disorders or choroidal diseases (e.g., PCV) compared to other administration methods of the same drug dose (such as intravitreal, intracavitary, oral, parenteral, and topical delivery of the same drug dose). In a further embodiment, the therapeutic effect of the drug delivered to the SCS is achieved at a lower intravitreal, intracavitary, topical, parenteral, or oral dose sufficient to achieve the same therapeutic effect in a human subject. Furthermore, without wishing to be bound by theory, the lower doses achievable using the methods provided herein reduce the number of side effects of the drug and / or reduce the severity of one or more side effects compared to higher doses of the drug or the same dose delivered to a human patient by a non-suprachoroidal administration route (e.g., intravitreal, intracavitary, topical, parenteral, oral). For example, the methods provided herein reduce the number of side effects or reduce the severity or clinical symptoms of one or more side effects compared to oral, topical, intracameral, parenteral, or intravitreal administration of the same drug at the same dose. In one embodiment, the side effect or clinical symptom that is reduced in treated patients is subretinal exudation and / or subretinal hemorrhage.

[0134] In one embodiment, the non-surgical suprachoroidal drug delivery methods provided herein provide increased therapeutic efficacy and / or improved therapeutic response compared to oral, parenteral, and / or intravitreal drug delivery methods of the same or similar drug dose. In one embodiment, the SCS drug dose sufficient to obtain a therapeutic response is about 90%, about 75%, or about half (e.g., about half or less) of the intravitreal, intracavitary, topical, oral, or parenteral drug dose sufficient to obtain the same or substantially the same therapeutic response. In another embodiment, the SCS dose sufficient to obtain a therapeutic response is about 1 / 4 of the intravitreal, intracavitary, topical, oral, or parenteral drug dose sufficient to obtain the same or substantially the same therapeutic response. In yet another embodiment, the SCS dose sufficient to obtain a therapeutic response is 1 / 10 of the intravitreal, intracavitary, topical, oral, or parenteral drug dose sufficient to obtain the same or substantially the same therapeutic response. In one embodiment, the therapeutic response is a reduction in inflammation as measured by methods known to those skilled in the art. In another embodiment, the therapeutic response is a decrease in the number of ocular lesions or a decrease in the size of ocular lesions.

[0135] In one embodiment, the total amount of the effective amount of the drug in the drug formulation is about 0.05 mg to about 5 mg. In one embodiment, the total amount of the drug in the drug formulation is about 0.2 mg to about 4 mg. In another embodiment, the total amount of the drug in the drug formulation is about 1 mg to about 4 mg. The drug dose may vary by methods known to those skilled in the art, and will vary, for example, based on the age of the patient and the clinical symptoms of the posterior ocular disorder or choroidal disease.

[0136] The therapeutic efficacy of the drug formulation delivered by the methods described herein and the therapeutic response of a human subject can be assayed by standard means in the art, as known to those skilled in the art. In general, the therapeutic efficacy of any particular drug can be evaluated by measuring the response of a human subject after drug administration, and a drug with a high therapeutic efficacy will improve and / or block symptoms more than a drug with a low therapeutic efficacy. In a non-limiting example, the efficacy of the drug formulation provided herein (e.g., angiogenesis inhibitor, anti-inflammatory drug (e.g., steroid or NSAID), VEGF regulator (e.g., VEGF antagonist), PDGF regulator (e.g., PDGF antagonist), immunosuppressant, or vascular permeability inhibitor formulation) can be measured, for example, by observing changes in pain intensity, changes in ocular lesions (size or number), intraocular pressure, inflammation (e.g., by measuring changes in Hackett / McDonald eye score), ocular hypertension, and / or visual acuity.

[0137] In another embodiment, the effectiveness of a drug (e.g., an angiogenesis inhibitor, an anti-inflammatory drug (e.g., a steroid or an NSAID), a VEGF regulator (e.g., a VEGF antagonist), a PDGF regulator (e.g., a PDGF antagonist), an immunosuppressant, or a vascular permeability inhibitor) can be measured, for example, by observing changes in measurements, inflammation, visual acuity, and / or edema according to the Hackett / McDonald eye score. In another embodiment, the effectiveness of a drug (e.g., triamcinolone or mycophenolate) can be measured, for example, by observing changes in measurements, inflammation, visual acuity, and / or edema according to the Hackett / McDonald eye score. In another embodiment, the therapeutic effectiveness of a drug (e.g., sorafenib and / or axitinib) can be measured, for example, by observing changes in the growth and / or number of lesions. In another embodiment, the effectiveness of a drug (e.g., infliximab (Remicade®)) can be measured by observing changes in, for example, retinal thickness, inflammation, visual acuity, photophobia, time between typical flares, corneal ulcers, and / or edema. In another embodiment, the effectiveness of a drug (e.g., nepafenac) can be measured by observing changes in, for example, optical coherence tomography (OCT) measurements of retinal thickness and volume, inflammation, visual acuity, pain, and / or intraocular pressure.

[0138] In another embodiment, the effectiveness of a drug (e.g., azathiopine) can be measured, for example, by observing changes in measurements of visual acuity, macular edema, intraocular pressure, inflammation, and / or SF-36 body composition score. In another embodiment, the effectiveness of a drug (e.g., an anti-inflammatory drug (TNF family antagonists, e.g., TNF-α antagonists, lymphotoxin-α antagonists, lymphotoxin-β antagonists, CD27L antagonists, CD20L antagonists, FASL antagonists, 4-BBL ... The efficacy of a therapeutic agent (such as an antagonist, OX40L antagonist, TNF-related apoptosis-inducing ligand (TRAIL) antagonist, Janus kinase (JAK) antagonist, or interleukin antagonist) can be measured, for example, by observing changes in inflammation, lesions, cell death, and / or vision. In another embodiment, the therapeutic efficacy of cyclophosphamide can be measured, for example, by observing changes in lesion size and / or number, lesion growth, vision, macular edema, intraocular pressure, and / or inflammation.

[0139] In one embodiment, non-surgical administration of an effective amount of the drug formulation to the SCS reduces the number of adverse side effects or clinical symptoms compared to the number of adverse side effects or clinical symptoms caused by the same drug dose administered intravitreally, intracamerally, orally, or parenterally. In another embodiment, non-surgical administration of an effective amount of the drug formulation to the SCS reduces the number of one or more adverse side effects or clinical symptoms compared to the number of adverse side effects or clinical symptoms caused by the same drug dose administered intravitreally, intracamerally, orally, or parenterally.Examples of side effects and clinical symptoms that may be reduced or ameliorated include inflammation, gastrointestinal side effects (e.g., diarrhea, nausea, gastroenteritis, vomiting, gastrointestinal, rectal, and duodenal bleeding, hemorrhagic pancreatitis, black or bloody stools due to colon perforation, and / or hemoptysis); hematological side effects (e.g., leukopenia, anemia, pancytopenia and agranulocytosis, thrombocytopenia, neutropenia, true erythroid aplasia (PRCA), easy bruising, deep vein thrombosis, and / or abnormal bleeding from the nose, mouth, vagina, or rectum; immunological side effects / clinical symptoms (e.g., immunosuppression, immunosuppression resulting in sepsis, opportunistic infections (herpes simplex virus, herpes zoster, and invasive Candida infections), and / or increased infection); oncological side effects / clinical symptoms (e.g., lymphoma, lymphoproliferative disorders, and / or non-melanoma skin cancer); renal side effects / clinical symptoms (e.g., dysuria, urgency, urinary tract infection, hematuria, renal tubular necrosis, and / or or BK virus-associated nephropathy); metabolic side effects / clinical symptoms (e.g., edema, hyperphosphatemia, hypokalemia, hyperglycemia, hyperkalemia, swelling, rapid weight gain, and / or thyroid enlargement); respiratory side effects / clinical symptoms (e.g., respiratory infection, dyspnea, increased cough, early tuberculous dry cough, wheezing, and / or nasal congestion); dermatological side effects / clinical symptoms (e.g., acne, rash, dyshidrotic eczema, papular scaly psoriasiform skin rash, blisters, oozing, oral pain, and and / or hair loss); muscoskeletal side effects / clinical symptoms (e.g., myopathy and / or myalgia), hepatic side effects / clinical symptoms (e.g., hepatoxicity and / or jaundice), abdominal pain, increased incidence of early pregnancy loss, cessation of menstruation, severe headache, confusion, altered mental status, loss of vision, seizures (convulsions), increased photosensitivity, dry eye, eye redness, itchy eyes, and / or high blood pressure. As provided above, a reduction or improvement in a side effect or clinical symptom is a reduction or improvement in a side effect or clinical symptom in a patient compared to the severity of the side effect or clinical symptom prior to administration of the drug formulation to the SCS of the patient's eye, or a reduction or improvement in a side effect or clinical symptom in a patient compared to the reduction or improvement experienced with intravitreal, intracameral, parenteral, or oral administration of the same drug.

[0140] In one embodiment, non-surgical administration of an effective amount of a drug formulation to the SCS reduces the number of symptoms of choroidal disease compared to the number of symptoms experienced by the patient prior to administration of the drug to the SCS or compared to the number of symptoms experienced by the patient following treatment with the same drug dose administered intravitreally, intracamerally, orally, or parenterally.

[0141] In one embodiment, non-surgical administration of a drug formulation comprising an effective amount of a choroidal disease treating drug to the SCS of one or both eyes of a patient reduces the number of adverse side effects or adverse clinical symptoms compared to the number of adverse side effects or clinical symptoms caused by the same drug dose administered intravitreally, intracamerally, orally, topically, or parenterally. In another embodiment, non-surgical administration of an effective amount of a drug formulation to the SCS reduces the severity of a side effect or clinical symptom in a patient suffering from a choroidal disease. In a further embodiment, the severity of a side effect or clinical symptom is reduced compared to the severity of an adverse side effect or clinical symptom caused by the same drug dose administered intravitreally, intracamerally, orally, topically, or parenterally. For example, in one embodiment, administration of a drug formulation to the SCS of a patient's eye reduces subretinal exudation and / or reduces subretinal hemorrhage in a patient suffering from a choroidal disease compared to the subretinal exudation and / or subretinal hemorrhage prior to administration of the drug to the SCS. In further embodiments, the patient experiences reduced subretinal exudation and / or reduced subretinal hemorrhage compared to the reduced severity experienced when the same drug is administered intravitreally, intracamerally, orally, topically, or parenterally.

[0142] Drug formulation delivery to the SCS increases retention of the drug in posterior ocular tissues compared to delivery of the same drug via topical, intravitreal, intracameral, oral, or parenteral routes. In one embodiment, a drug concentration of greater than 10 μg / g posterior ocular tissue can be achieved for 28 days or more after a single administration. In another embodiment, a drug concentration of greater than 100 μg / g posterior ocular tissue can be achieved for 28 days or more after a single administration. In another embodiment, a drug concentration of greater than 1000 μg / g tissue can be achieved for 28 days or more after a single administration. It has been found that more hydrophobic drugs are cleared slower from the SCS than more water-soluble drugs. In one embodiment, the drug formulation administered to the SCS comprises a more hydrophobic drug.

[0143] In one embodiment, a method of treating a choroidal malady in a patient is provided, comprising non-surgically administering a drug formulation comprising an effective amount of a choroidal malady treating drug (e.g., an angiogenesis inhibitor such as a VEGF modulator) to the SCS of one or both eyes of a patient in need of treatment, wherein the drug formulation is substantially localized to the posterior segment of the eye upon administration. In a further embodiment, the drug formulation is substantially localized to the RPE. In one embodiment, the drug is substantially localized to the macula or subretinal space. In one embodiment, the method is performed using one or more microneedles as described herein.

[0144] A method for treating a choroidal malady in a human subject in need of such treatment, in one embodiment, comprises non-surgically administering a drug formulation comprising an effective amount of a choroidal malady treatment drug to the suprachoroidal space of one or both eyes of the human subject. In a further embodiment, the effective amount of the choroidal malady treatment drug comprises an effective amount of an anti-inflammatory drug, a vascular endothelial growth factor (VEGF) regulator, a platelet-derived growth factor (PDGF) regulator, an angiogenesis inhibitor, an immunosuppressant, or a vascular permeability inhibitor. In one embodiment, the drug formulation for treating the choroidal malady upon administration flows out of the insertion site and is substantially localized in the posterior segment of the eye. In one embodiment, the non-surgical method provided herein allows for increased retention of the drug in the eye compared to intravitreal, topical, parenteral, or oral administration of the same drug dose.

[0145] Patients undergoing ocular treatment via shunts or cannulas or other surgical methods have reported a significant increase or decrease in intraocular pressure after the start of the treatment method. In one embodiment, the intraocular pressure (IOP) of the eye of a patient undergoing treatment for posterior ocular disorders or choroidal maladay 2 minutes, 10 minutes, 15 minutes, or 30 minutes after administration of a drug to the suprachoroid is substantially the same IOP as compared to the IOP of the patient's eye before administration of the drug for treating posterior ocular disorders or choroidal maladay. In one embodiment, the IOP of the eye of a patient undergoing treatment for posterior ocular disorders or choroidal maladay 2 minutes, 10 minutes, 15 minutes, or 30 minutes after administration of a drug to the suprachoroid changes by 10% or less as compared to the IOP of the patient's eye before administration of the drug for treating posterior ocular disorders or choroidal maladay. In one embodiment, the IOP of the patient's eye undergoing treatment for a posterior ocular disorder or choroidal disease (maladay) 2 minutes, 10 minutes, 15 minutes, or 30 minutes after administration of the drug to the suprachoroid changes by 20% or less compared to the IOP of the patient's eye before administration of the drug to treat a posterior ocular disorder or choroidal disease. In one embodiment, the IOP of the patient's eye undergoing treatment for a posterior ocular disorder or choroidal disease (maladay) 2 minutes, 10 minutes, 15 minutes, or 30 minutes after administration of the drug to the suprachoroid changes by 10% to 30% or less compared to the IOP of the patient's eye before administration of the drug to treat a posterior ocular disorder or choroidal disease. In a further embodiment, the effective amount of the posterior ocular disorder treating drug or choroidal disease treating drug comprises an effective amount of an anti-inflammatory drug, a vascular endothelial growth factor (VEGF) regulator, a platelet-derived growth factor (PDGF) regulator, an angiogenesis inhibitor, an immunosuppressant, or a vascular permeability inhibitor.

[0146] The choroidal malady that can be treated using the methods described herein is, in one embodiment, choroidal neovascularization, choroidal sclerosis, polypoidal choroidal vasculopathy, central sirrus choroidopathy, multifocal choroidopathy, or choroidal dystrophy. Choroidal dystrophy is, for example, central gyral choroidal dystrophy, ocular choroidal dystrophy, or total central choroidal atrophy. In some embodiments, a patient in need of treatment for a choroidal malady experiences subretinal exudation and bleeding, and the methods provided herein reduce the subretinal exudation and / or bleeding compared to the subretinal exudation and / or bleeding experienced by the patient prior to administration of the drug formulation to the SCS. In another embodiment, a patient in need of treatment experiences subretinal exudation and bleeding, and the subretinal exudation and bleeding experienced by the patient after undergoing one of the non-surgical treatment methods provided herein is less than the subretinal exudation and bleeding experienced by the patient after intravitreal treatment with the same drug at the same dose.

[0147] In one embodiment, the methods provided herein provide effective treatment for patients who have previously been treated for choroidal disease or posterior ocular disorder, but who have not responded or have not responded adequately to the previous treatment. For example, in one embodiment, a patient who receives the choroidal disease treatment method or posterior ocular disorder treatment method of the present invention has previously been treated for the same choroidal disease or posterior ocular disorder, but has not responded or has not responded adequately. As one skilled in the art will recognize, a patient who does not respond or has not responded adequately to a treatment does not show improvement in symptoms or clinical symptoms of the choroidal disease or posterior ocular disorder. In one embodiment, the symptoms or clinical symptoms are lesion size, inflammation, edema, visual acuity, or vitreous opacity.

[0148] In one embodiment, a patient in need of treatment for polypoidal choroidal vasculopathy is treated using one of the non-surgical SCS drug delivery methods provided herein. For example, in one embodiment, a drug formulation comprising an effective amount of a PCV treatment drug is administered to the SCS of one or both eyes of a patient in need of treatment. In a further embodiment, the drug formulation is administered using a microneedle device as described herein. In yet a further embodiment, the effective amount of the PCV treatment drug comprises an effective amount of an anti-inflammatory drug, a vascular endothelial growth factor (VEGF) regulator, a platelet-derived growth factor (PDGF) regulator, an angiogenesis inhibitor, an immunosuppressant, or a vascular permeability inhibitor.

[0149] PCV is an abnormal choroidal vasculopathy that is considered a variant of type 1 neovascularization, but it has been proposed that PCV is a distinct vascular abnormality of choroidal vessels (Imamura et al. (2010). Survey of Ophthalmology, volume 55, pp. 501-515, incorporated herein by reference). PCV has been reported to be more frequent in people of color, but has also been reported to be present in Caucasian patients (Imamura et al. (2010). Survey of Ophthalmology, volume 55, pp. 501-515, incorporated herein by reference). The methods described herein are used in both patients of color and non-colored patients. For example, the patient undergoing PCV treatment is, in one embodiment, a patient of African, Hispanic, Middle Eastern, or Asian descent. In another embodiment, the patient undergoing treatment is Caucasian.

[0150] Clinical symptoms of PCV patients include vascular abnormalities and serous detachments of various sizes in the neurosensory retina and pigment epithelium around the optic nerve or in the central macula. PCV patients may also experience subretinal exudation and / or hemorrhage. In another embodiment, PCV patients have lipid deposits in the eye. The present invention reduces the incidence and / or severity of PCV clinical symptoms experienced by PCV patients treated with the methods described herein compared to the incidence and / or severity of clinical symptoms before treatment. For example, patients treated for PCV using one of the non-surgical treatment methods provided herein have a reduced incidence and / or severity of vascular abnormalities compared to the incidence and / or severity of vascular abnormalities that occurred before treatment using the non-surgical SCS drug delivery method. In another embodiment, the severity of subretinal exudation and / or hemorrhage is reduced in PCV patients compared to the severity of subretinal exudation and / or hemorrhage before treatment using one of the non-surgical SCS drug delivery methods described herein. PCV treatment drugs (eg, angiogenesis inhibitors, VEGF modulators, PDGF modulators, anti-inflammatory drugs, vascular permeability inhibitors) are described in more detail below.

[0151] In one embodiment, the patient who is treated for PCV using one of the non-surgical methods described herein is also treated for a second eye disease. In a further embodiment, the further eye disease is drusen, sickle cell retinopathy, central serous chorioretinopathy, typical neovascular (type 1 or type 2) age-related macular degeneration, optic nerve melanocytoma, focal choroidal hemangioma, tilted disk syndrome, pathological myopia, choroidal osteoma, retinal microangiopathy. The second eye disease can be treated using the non-surgical SCS drug delivery method described herein or other methods known in the art (e.g., intravitreal or topical drug administration).

[0152] In another embodiment, the method of treating choroidal malady described herein (i.e., non-surgical drug delivery to the SCS of one or both eyes of a patient) is a method of treating a patient with central serous chorioretinopathy (CSC) (also known as central serous retinopathy (CSR)). CSR is an exudative chorioretinopathy characterized by exudative neurosensory retinal detachment with or without associated detachment of the retinal pigment epithelium (RPE). In some instances, CSR results in metamorphopsia and micropsia. In some instances, CSR is characterized by leakage of subretinal fluid. In addition, CSR patients often experience decreased vision. In one embodiment, a method of treating a CSR patient is provided, comprising non-surgically administering a drug formulation comprising an effective amount of a CSR treatment drug to the SCS of one or both eyes of the patient. In one embodiment, the drug is administered using one of the microneedles described herein. In further embodiments, the CSR treatment drug is an anti-inflammatory drug, a vascular endothelial growth factor (VEGF) regulator (e.g., a VEGF antagonist), a platelet-derived growth factor (PDGF) regulator (e.g., a PDGF antagonist), an angiogenesis inhibitor, an immunosuppressant, or a vascular permeability inhibitor. In further embodiments, a patient treated for CSR by one of the methods described herein has improved visual acuity compared to the patient's visual acuity prior to undergoing treatment. In another embodiment, a patient after undergoing CSR treatment has reduced subretinal fluid leakage compared to the subretinal fluid leakage experienced by the patient prior to undergoing treatment via non-surgical SCS drug delivery.

[0153] In yet another embodiment, a method of treating multifocal choroiditis (MFC) in a patient is provided. In one embodiment, the MFC treatment method comprises non-surgically administering a drug formulation comprising an effective amount of an MFC treatment drug to the SCS of one or both eyes of a patient in need of MFC treatment. In one embodiment, the drug formulation is administered using one of the microneedles described herein. In a further embodiment, the effective amount of the MFC treatment drug comprises an effective amount of an anti-inflammatory drug, a vascular endothelial growth factor (VEGF) regulator (e.g., a VEGF antagonist), a platelet-derived growth factor (PDGF) regulator (e.g., a PDGF antagonist), an angiogenesis inhibitor, an immunosuppressant, or a vascular permeability inhibitor. The MFC patient, in one embodiment, is moderately myopic, and in one embodiment, both eyes are affected. The MFC patient, in some embodiments, presents with posterior uveitis symptoms (including reduced vision, floaters, photopsia) and anterior symptoms (such as photophobia). In one embodiment, MFC patients present with vitreous and / or anterior chamber cells. Fundusoscopic findings in MFC patients consist of yellow to gray lesions at the retinal pigment epithelium (RPE) level and at the choriocapillaris layer level. The lesions range in size from about 50 μm to about 1,000 μm and are distributed in the peripapillary region. The methods provided herein, in one embodiment, reduce the size and / or number of lesions in treated patients. Active lesions in some cases are associated with subretinal fluid and cotton-like borders. Active disease may also be associated with optic disc congestion and edema, cystoid macular edema, and macular and peripapillary choroidal neovascularization.

[0154] In one embodiment, the method of treating the MFC of a patient includes non-surgically administering a drug formulation comprising an effective amount of an MFC treatment agent to the SCS of one or both eyes of a patient in need of treatment. In a further embodiment, the method includes administering the drug formulation to the SCS of one or both eyes of the patient using one of the microneedles described herein. For example, in one embodiment, the drug formulation is delivered to the SCS of the patient's eye by delivery into the SCS through an opening of a hollow microneedle having a tip and an opening. In a further embodiment, the effective amount of the MFC treatment agent is an effective amount of an anti-inflammatory drug, an angiogenesis inhibitor, a VEGF regulator, or a vascular permeability inhibitor. In further embodiments, the patient treated with MFC has reduced lesion counts (e.g., reduced lesion counts in the RPE), reduced lesion size (e.g., reduced size of lesions present in the RPE), reduced subretinal fluid volume, improved visual acuity, or reduced choroidal neovascularization compared to the number of lesions, size of lesions, volume of subretinal fluid, visual acuity, and choroidal neovascularization in the patient's eye prior to undergoing the MFC treatment method of the present invention. In another embodiment, the patient treated with MFC has reduced optic nerve head congestion and edema compared to the optic nerve head congestion and edema experienced by the patient prior to undergoing treatment via the non-surgical SCS drug delivery method of the present invention.

[0155] In one embodiment, a patient in need of choroidal neovascularization treatment is treated using one of the non-surgical SCS drug delivery methods provided herein. For example, in one embodiment, a drug formulation comprising an effective amount of a choroidal neovascularization treatment drug is administered to the SCS of one or both eyes of a patient in need of treatment. In a further embodiment, the drug formulation is administered using a microneedle device as described herein. In one embodiment, the effective amount of the choroidal neovascularization treatment drug is an anti-inflammatory drug, an angiogenesis inhibitor, a VEGF regulator (e.g., a VEGF antagonist), a platelet-derived growth factor (PDGF) regulator (e.g., a PDGF antagonist), an angiogenesis inhibitor, an immunosuppressant, or a vascular permeability inhibitor.

[0156] In one embodiment, a patient in need of treatment for choroidal dystrophy is treated using one of the non-surgical SCS drug delivery methods provided herein. For example, in one embodiment, a drug formulation comprising an effective amount of a choroidal dystrophy treatment drug is administered to the SCS of one or both eyes of a patient in need of treatment. In a further embodiment, the effective amount of the choroidal dystrophy treatment drug comprises an effective amount of an anti-inflammatory drug, a vascular endothelial growth factor (VEGF) regulator, a platelet-derived growth factor (PDGF) regulator, an angiogenesis inhibitor, an immunosuppressant, or a vascular permeability inhibitor. In a further embodiment, the drug formulation is administered using a microneedle device described herein. In one embodiment, the choroidal dystrophy method provided herein improves a wide range of symptoms or clinical symptoms of choroidal dystrophy compared to the same drug administered to a patient via topical, oral, parenteral, intravitreal, or intracavitary routes.

[0157] In yet another embodiment, the method of treating a choroidal malady described herein (i.e., the non-surgical SCS drug delivery method described herein) is a method of treating a patient with punctuate inner choroidopathy (PIC). In one embodiment, the method of treating a patient with PIC comprises non-surgically administering a drug formulation comprising an effective amount of a PIC treating drug to the SCS of one or two eyes of the patient. In a further embodiment, the method comprises drug delivery using one of the microneedles described herein. In one embodiment, the effective amount of the PIC treating drug is an anti-inflammatory drug, an angiogenesis inhibitor, an immunosuppressant, a VEGF regulator (e.g., a VEGF antagonist), a PDGF regulator (e.g., a PDGF antagonist), or a vascular permeability inhibitor.

[0158] In one embodiment, a PIC patient undergoing one of the SCS treatment methods provided herein experiences an improvement in symptoms / clinical symptoms of PIC or a reduction in the number of symptoms / clinical symptoms of PIC compared to the symptoms / clinical symptoms experienced prior to SCS drug administration. In a further embodiment, the symptoms / clinical symptoms are inflammation, blurred vision, photopsia, central and / or peripheral scotoma, or metamorphopsia. In another embodiment, the symptoms / clinical symptoms are reduced vision at the level of the inner choroid and retinal pigment epithelium, bilateral white-yellow chorioretinal lesions (e.g., about 100 μm to about 200 μm in diameter). The lesions are typically not associated with vitreous inflammation and typically do not extend to the central retinal zone. The PIC lesions progress to atrophic scars, leaving a halo of depigmentation. In one embodiment, a PIC patient treated using one of the non-surgical SCS drug delivery methods described herein experiences a reduction in inflammation, a reduction in the number of lesions, or a reduction in the size of the lesions compared to the inflammation, number of lesions, or size of the lesions the patient presented with prior to treatment. In another embodiment, a PIC patient treated using one of the non-surgical SCS drug delivery methods described herein experiences reduced inflammation, reduced lesion count, or reduced lesion size compared to inflammation, lesion count, or lesion size following intravitreal, oral, topical, parenteral, or intracameral drug treatment using the same drug dose administered with SCS.

[0159] In one embodiment, the method of treating choroidal diseases described herein is a method of treating choroidal dystrophy in a patient. In one embodiment, the method of treating choroidal dystrophy in a patient comprises non-surgically administering a drug formulation comprising an effective amount of a choroidal dystrophy treatment drug to the SCS of one or both eyes of a patient in need of treatment. In a further embodiment, the method comprises delivering the drug formulation to the SCS of one or both eyes of a patient through a hollow microneedle having a tip and an opening. In a further embodiment, the effective amount of the choroidal dystrophy treatment drug comprises an effective amount of an anti-inflammatory drug, a vascular endothelial growth factor (VEGF) regulator (e.g., a VEGF antagonist), a platelet-derived growth factor (PDGF) regulator (e.g., a PDGF antagonist), an angiogenesis inhibitor, an immunosuppressant, or a vascular permeability inhibitor. In one embodiment, a microneedle is inserted into the sclera, and the drug formulation is injected into the SCS through the opening of the inserted microneedle. In one embodiment, the choroidal dystrophy is central areolar chroidal dystrophy (CACD), central gyral choroidal dystrophy, ocular choroidal dystrophy, or total central choroidal atrophy. In a further embodiment, the patient is treated with CACD, and the CACD is CACD1, CACD2, or CACD3. In one embodiment, the CACD is accompanied by drusen. In another embodiment, the CACD is not accompanied by drusen.

[0160] In one embodiment, the choroidal dystrophy treatment methods provided herein reduce the number of choroidal dystrophy symptoms experienced by the patient prior to treatment. In another embodiment, the choroidal dystrophy treatment methods provided herein reduce the severity of the choroidal dystrophy symptoms experienced by the patient prior to treatment.

[0161] In one embodiment of the choroidal malady treatment method described herein, a drug formulation comprising an effective amount of a choroidal malady treatment drug (e.g., an effective amount of an anti-inflammatory drug (e.g., a steroidal compound or an NSAID), a vascular endothelial growth factor (VEGF) regulator (e.g., a VEGF antagonist), an immunosuppressant, an angiogenesis inhibitor (e.g., a platelet-derived growth factor (PDGF) antagonist), or a vascular permeability inhibitor) is delivered non-surgically to the SCS of one or both eyes of a patient in need of treatment by inserting a microneedle into the patient's eye and injecting the drug into the SCS through the microneedle or into the SCS via a coating on a solid or hollow microneedle. The solid or hollow microneedle, in one embodiment, is inserted into the sclera. In one embodiment, a hollow microneedle having a tip and an opening is inserted into the sclera, and the drug formulation is injected or infused into the suprachoroidal space of the eye through the inserted microneedle. In another embodiment, a solid microneedle having an effective amount of a choroidal malady treatment drug coated on the microneedle is inserted into the sclera and the drug is allowed to diffuse into the SCS of the patient's eye.

[0162] The drug formulation delivered to the suprachoroidal space of the human subject's eye for the treatment of posterior ocular disorders or choroidal diseases can be in the form of a liquid drug, a solution containing a drug dissolved in a suitable solvent, or a suspension. The suspension can contain microparticles or nanoparticles dispersed in a liquid vehicle suitable for injection. In various embodiments, the drug is contained in a liquid vehicle, in microparticles or nanoparticles, or in both a vehicle and particles. The drug formulation exhibits sufficient fluidity to flow into and within the suprachoroidal space and around the posterior ocular tissues. In one embodiment, the viscosity of the fluid drug formulation is about 1 cP at 37°C.

[0163] A wide range of drugs can be formulated for delivery to the suprachoroidal space and posterior ocular tissues using the microneedle devices and methods of the present invention. As used herein, the term "drug" refers to any prophylactic, therapeutic, or diagnostic agent (i.e., a component useful for medical applications). Drugs can be selected from small molecules, proteins, peptides, and fragments thereof that can be naturally occurring, synthesized, or recombinantly produced. For example, in one embodiment, the drug delivered to the suprachoroidal space using the non-surgical methods described herein is an antibody or a fragment thereof (e.g., Fab, Fv, or Fc fragment). In certain embodiments, the drug is a sub-immunoglobulin antigen-binding molecule (such as an Fv immunoglobulin fragment, a minibody, and a bispecific antibody) described in U.S. Pat. No. 6,773,916 (incorporated herein by reference in its entirety for all purposes). In one embodiment, the drug is a humanized antibody or a fragment thereof.

[0164] In one embodiment, the drug is selected from a suitable oligonucleotide (e.g., an antisense oligonucleotide drug), polynucleotide (e.g., a therapeutic DNA), ribozyme, dsRNA, siRNA, RNAi, gene therapy vector, and / or vaccine. In a further embodiment, the drug is an aptamer (e.g., an oligonucleotide or peptide molecule that binds to a specific target molecule). In another embodiment, the drug formulation delivered via the methods provided herein comprises a small molecule drug, an endogenous protein or fragment thereof, or an endogenous peptide or fragment thereof.

[0165] Representative examples of drug types for delivery to ocular tissue include anti-inflammatory drugs, including, but not limited to, steroids, immunosuppressants, antimetabolites, T-cell inhibitors, alkylating agents, biologics, TNF antagonists (e.g., TNF-α antagonists), VEGF antagonists, and / or nonsteroidal anti-inflammatory drugs (NSAIDs). Non-limiting examples of specific drugs and drug classes that can be delivered to the suprachoroidal space to treat posterior ocular disorders include miotics (e.g., pilocarpine, carbachol, physostigmine), sympathomimetics (e.g., adrenaline, dipivefrin), carbonic anhydrase inhibitors (e.g., acetazolamide, dorzolamide), VEGF antagonists, PDGF antagonists, NSAIDs, steroids, prostaglandins, antibacterial compounds (antibacterial and antifungal agents (e.g., chloramphenicol, chlortetracycline, ciprofloxacin, framycetin, fusidic acid, gentamicin, neomycin, norfloxacin, ofloxacin, polymyxin, propamidine, tetracycline, tobramycin, quinoline)), aldose reductase inhibitors, anti-inflammatory compounds, and and / or anti-allergy compounds (e.g., steroidal compounds (such as triamcinolone, betamethasone, clobetasone, dexamethasone, fluorometholone, hydrocortisone, prednisolone, etc.) and non-steroidal compounds (such as antazoline, bromfenac, diclofenac, indomethacin, lodoxamide, saprofen, sodium cromoglycate, etc.), artificial tears / dry eye treatments, local anesthetics (e.g., amethocaine, lignocaine, oxbuprocaine, proxymetacaine), cyclosporine, diclofenac, urogastrone and growth factors (such as epidermal growth factor), mydriatics and cycloplegics, mitomycin C, and collagenase inhibitors, and treatments for age-related macular degeneration (such as pegagtanib sodium, ranibizumab, and bevacizumab).

[0166] As provided throughout, in some embodiments, methods are provided for delivering a drug formulation comprising an effective amount of an angiogenesis inhibitor, an anti-inflammatory drug (e.g., a steroid or an NSAID), a VEGF modulator (e.g., a VEGF antagonist), a PDGF modulator (e.g., a PDGF antagonist), an immunosuppressant, or a vascular permeability inhibitor to the SCS of an eye of a patient in need thereof.

[0167] In one embodiment, the angiogenesis inhibitor is an integrin antagonist, a selectin antagonist, an adhesion molecule antagonist (e.g., an intercellular adhesion molecule (ICAM)-1, ICAM-2, ICAM-3, platelet endothelial adhesion molecule (PCAM), vascular cell adhesion molecule (VCAM)), an antagonist of lymphocyte function-associated antigen 1 (LFA-1), a basic fibroblast growth factor antagonist, a vascular endothelial growth factor (VEGF) regulator, or a platelet-derived growth factor (PDGF) regulator (e.g., a PDGF antagonist). The integrin antagonist delivered via the methods described herein, in one embodiment, is a small molecule integrin antagonist, such as those described in Paolillo et al. (Mini Rev Med Chem, 2009, volume 12, pp. 1439-1446), which is incorporated by reference in its entirety, or an antagonist of a leukocyte adhesion-inducing cytokine or growth factor, such as tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), monocyte chemotactic protein-1 (MCP-1), and vascular endothelial growth factor (VEGF), as described in U.S. Pat. No. 6,524,581, which is incorporated by reference in its entirety. In another embodiment, the drug can be a diagnostic agent, such as an imaging agent, known in the art.

[0168] In one embodiment, the intraocular elimination half-life (t 1 / 2 ) is the intraocular t value of an angiogenesis inhibitor when the same dosage of the angiogenesis inhibitor is administered intravitreally, intracamerally, topically, parenterally, or orally. 1 / 2In another embodiment, the mean peak intraocular concentration (C ) of an angiogenesis inhibitor is higher than that of an angiogenesis inhibitor administered to the SCS via the methods described herein when the same dosage of the angiogenesis inhibitor is administered to the SCS via the methods described herein. max ) is the intraocular C of angiogenesis inhibitors when administered at the same dose intravitreally, intracamerally, topically, parenterally, or orally. max In another embodiment, the mean intraocular area under the curve (AUC) of an angiogenesis inhibitor when administered to the SCS via the methods described herein is 0-t ) is the intraocular AUC of an angiogenesis inhibitor when the same dose of the angiogenesis inhibitor is administered intravitreally, intracamerally, topically, parenterally, or orally. 0-t Higher.

[0169] The angiogenesis inhibitors delivered via the methods and devices described herein are, in one embodiment, interferon gamma 1β, pirfenidone-containing interferon gamma 1β (Actimmune®), ACUHTR028, αVβ5, potassium aminobenzoate, amyloid P, ANG1122, ANG1170, ANG3062, ANG3281, ANG3298, ANG4011, anti-CTGF RNAi, Aplidine, Astragalus membranaceus extract with salvia and Schisandra chinensis, atherosclerotic plaque blockers, Azoles, AZX100, BB3, Connective tissue growth factor antibodies, CT140, Danazol, Esbriet, EXC001, EXC002, EXC003, EXC004, EXC005, F647, FG3019, Fibrocollin, Follistatin, FT011, Galectin-3 inhibitors, GKT137831, GMCT01, GMCT02, GRMD01, GRMD02, GRN510, Heberon alpha R, Interferon alpha-2 beta, ITMN520, JKB119, JKB121, JKB122, KRX168, LPA1 receptor antagonists, MGN4220, MIA2, microRNA 29a oligonucleotide, MMI0100, noscapine, PBI4050, PBI4419, PDGFR inhibitor, PF-06473871, PGN0052, Pirespa, Pirfenex, Pirfenidone, plitidepsin, PRM151, Px102, PYN17, PYN22 containing PYN17, Relivergen, rhPTX2 fusion protein, RXI109, secretin, STX100, TGF-beta inhibitor, transforming growth factor, beta-receptor 2 oligonucleotide, VA999260, or XV615.

[0170] Particular endogenous angiogenesis inhibitors for delivery via the methods described herein include endostatin, a 20 kDa C-terminal fragment from collagen XVIII, angiostatin (a 38 kDa fragment of plasmin), or members of the thrombospondin (TSP) protein family. In further embodiments, the angiogenesis inhibitor is TSP-1, TSP-2, TSP-3, TSP-4, and TSP-5. Other endogenous angiogenesis inhibitors that can be delivered via the choroidal disease treatment methods described herein include soluble VEGF receptors (e.g., soluble VEGFR-1 and neuropilin 1 (NPR1)), angiopoietin-1, angiopoietin-2, vasostatin, calreticulin, platelet factor-4, tissue inhibitors of metalloproteinases (TIMPs) (e.g., TIMP1, TIMP2, TIMP3, TIMP4), cartilage-derived angiogenesis inhibitors (e.g., peptides troponin I and chondromodulin I). I)), thrombospondin motif 1-containing disintegrins and metalloproteinases, interferons (IFNs) (e.g., IFN-α, IFN-β, IFN-γ), chemokines (e.g., chemokines having a C-X-C motif (e.g., CXCL10, also known as interferon-gamma-inducible protein 10 or small inducible cytokine B10)), interleukin cytokines (e.g., IL-4, IL-12, IL-18), prothrombin, antithrombin III fragment, prolactin, the protein encoded by the TNFSF15 gene, osteopontin, maspin, canstatin, and proliferin-related protein.

[0171] In one embodiment, the angiogenesis inhibitor delivered via the methods described herein to treat choroidal disease is an antibody. In a further embodiment, the antibody is a humanized monoclonal antibody. In yet a further embodiment, the humanized monoclonal antibody is bevacizumab.

[0172] In one embodiment, the non-surgical treatment method and device described herein can be used in gene-based therapeutic applications.For example, in one embodiment, the method includes administering a fluid drug formulation into the choroidal space to deliver selected DNA, RNA, or oligonucleotide to target ocular tissue.

[0173] In one embodiment, the drug is useful in choroidal disease treatment. In a further embodiment, the choroidal disease treatment drug is a nucleic acid administered to inhibit gene expression. For example, the nucleic acid is, in one embodiment, a micro-ribonucleic acid (microRNA), a small interfering RNA (siRNA), a small hairpin RNA (shRNA), or a double-stranded RNA (dsRNA) that targets a gene involved in angiogenesis. In one embodiment, the method of treating choroidal disease provided herein comprises administering an RNA molecule to the SCS of a patient in need of treatment. In a further embodiment, the RNA molecule is delivered to the SCS via one of the microneedles described herein. In one embodiment, the patient is undergoing treatment for PCV, and the RNA molecule targets HTRA1, CFH, elastin, or ARMS2, such that the expression of the targeted gene is downregulated in the patient by RNA administration. In a further embodiment, the gene targeted is CFH, and the RNA molecule targets the polymorphism selected from rs3753394, rs800292, rs3753394, rs6680396, rs1410996, rs2284664, rs1329428 and rs1065489.In another embodiment, the patient is treated for choroidal dystrophy, and the RNA molecule targets the PRPH2 gene.In a further embodiment, the RNA molecule targets the mutation of the PRPH2 gene.

[0174] In one embodiment, the drug delivered to the suprachoroidal space using the non-surgical methods (e.g., microneedle devices and methods) herein is sirolimus (Rapamycin®, Rapamune®).In one embodiment, the non-surgical drug delivery methods disclosed herein are used to treat a wide range of diseases or disorders, including abdominal neoplasms, acquired immune deficiency syndromes, acute coronary syndromes, acute lymphoblastic leukemia, acute myeloid leukemia, acute nonlymphoblastic leukemia, adenocarcinoma, adenoma, adenomyoepithelioma, adnexal disease, anaplastic astrocytoma, anaplastic large cell lymphoma, anaplastic plasmacytoma, anemia, angina pectoris, angioimmunoblastic lymphadenopathy with dysproteinemia, angiomyolipoma, arterial occlusive disease, arteriosclerosis, astrocytoma, atherosclerosis, autoimmune diseases, B cell lymphoma, blood clotting disorders, blood protein disorders, bone cancer, bone marrow disorders, brain diseases, brain neoplasms, breast neoplasms, beoplasm), bronchial neoplasm, carcinoid syndrome, carcinoid tumor, carcinoma, squamous cell carcinoma, central nervous system disease, central nervous system neoplasm, choroidal disease, choroid plexus neoplasm, choroidal neovascularization, choroiditis, chronic lymphocytic leukemia, chronic myelogenous leukemia, chronic myelomonocytic leukemia, chronic myeloproliferative disorder, chronic neutrophilic leukemia, renal clear cell carcinoma, colon disease, colon neoplasm, colorectal neoplasm, coronary artery disease, coronary disease, coronary obstruction, Coronary restenosis, Coronary stenosis, Coronary thrombosis, Cutaneous T-cell lymphoma, Diabetes mellitus, Digestive system neoplasms, Dry eye syndrome, Ear disease, Edema, Endocrine gland neoplasms, Endocrine system diseases, Endometrial neoplasms, Endometrial stromal tumors, Ewing's sarcoma, Rash, Eye neoplasms, Fibrosis, Follicular lymphoma, Gastrointestinal diseases, Gastrointestinal neoplasms, Genital neoplasms, Glioblastoma, Gliomas, Gliosarcomas, Graft versus host disease, Blood diseases, Blood neoplasms, Bleeding disorders, and / or amelioration of hemostatic disorders, Hodgkin's disease, Hodgkin's lymphoma, allograft wasting disease, immunoblastic lymphadenopathy, immunodeficiency syndromes, immunoproliferative disorders, infarction, inflammation, intestinal diseases, intestinal neoplasms, ischemia, kidney cancer, kidney diseases, kidney neoplasms, leukemia (B cell), leukemia (lymphatic), liver cancer, liver diseases, lung diseases, lymphatic diseases, lymphoblastic lymphoma, lymphoma, macular degeneration, macular edema, melanoma, oral neoplasms, multiple myeloma, myelodysplastic syndromes, myelofibrosis, myeloproliferative disorders, neuroectodermal tumors, neuroendocrine tumors, neuroepithelioma, neurofibroma, kidney cancer, airway diseases, retinal degeneration, retinal diseases, retinal neoplasms, retinoblastoma, rhabdomyosarcoma, breast neoplasms, uveitis, vascular diseases, Waldenstrom's macroglobulinemia, and wet macular degeneration.Additionally, delivery of rapamycin using the microneedle devices and methods disclosed herein can be combined with one or more of the agents listed herein or other agents known in the art.

[0175] In one embodiment, the angiogenesis inhibitor delivered to the suprachoroidal space using the non-surgical methods described herein is an antagonist of a platelet-derived growth factor (PDGF) family member (e.g., a drug that inhibits, reduces, or modulates the signal transduction and / or activity of a PDGF-receptor (PDGFR). For example, the PDGF antagonist delivered to the suprachoroidal space for the treatment of choroidal disease is, in one embodiment, an anti-PDGF aptamer, an anti-PDGF antibody or fragment thereof, an anti-PDGFR antibody or fragment thereof, or a small molecule antagonist. In one embodiment, the PDGF antagonist is an antagonist of PDGFR-α or PDGFR-β. In one embodiment, the PDGF antagonist is the anti-PDGF-β aptamer E10030, sunitinib, axitinib, sorefenib, imatinib, imatinib mesylate, nintedanib, pazopanib HCl, ponatinib, MK-2461, dovitinib, pazopanib, crenolanib, PP-121, telatinib, imatinib, KRN633, CP673451, TSU-68, Ki8751, amuvatinib, tivozanib, masitinib, motesanib diphosphate, dovitinib dilactic acid, linifanib (ABT-869).

[0176] In one embodiment, the intraocular elimination half-life (t 1 / 2 ) is the intraocular t value of a PDGF antagonist when the same dose of the PDGF antagonist is administered intravitreally, intracamerally, topically, parenterally, or orally. 1 / 2 In another embodiment, the mean peak intraocular concentration (C max) when administered to the SCS by the methods described herein, is greater than the intraocular C of a PDGF antagonist when the same dosage of the PDGF antagonist is administered intravitreally, intracamerally, topically, parenterally, or orally. max In another embodiment, the mean intraocular area under the curve (AUC 0-t ) is the intraocular AUC of a PDGF antagonist when administered to the SCS via the methods described herein, relative to the intraocular AUC of a PDGF antagonist when the same dosage of the PDGF antagonist is administered intravitreally, intracamerally, topically, parenterally, or orally. 0-t Higher.

[0177] In certain embodiments, the drug delivered to the suprachoroidal space using the microneedle device and method disclosed herein is a vascular endothelial growth factor (VEGF) regulator.For example, in one embodiment, the VEGF regulator is a VEGF antagonist.In one embodiment, the VEGF regulator is a VEGF-receptor kinase antagonist, an anti-VEGF antibody or its fragment, an anti-VEGF receptor antibody, an anti-VEGF aptamer, a small molecule VEGF antagonist, a thiazolidinedione, a quinoline, or a designed ankyrin repeat protein (DARPin).

[0178] In one embodiment, the VEGF antagonist delivered via the non-surgical methods described herein is an antagonist of a VEGF receptor (VEGFR) (i.e., a drug that inhibits, reduces, or modulates the signaling and / or activity of a VEGFR). The VEGFR can be a membrane-bound or soluble VEGFR. In a further embodiment, the VEGFR is VEGFR-1, VEGFR-2, or VEGFR-3. In one embodiment, the VEGF antagonist targets the VEGF-C protein. In another embodiment, the VEGF regulator is an antagonist of a tyrosine kinase or a tyrosine kinase receptor. In another embodiment, the VEGF regulator is a regulator of a VEGF-A protein. In yet another embodiment, the VEGF antagonist is a monoclonal antibody. In a further embodiment, the monoclonal antibody is a humanized monoclonal antibody.

[0179] In one embodiment, the intraocular elimination half-life (t 1 / 2 ) is the intraocular t value of a VEGF antagonist when the same dose of the VEGF antagonist is administered intravitreally, intracamerally, topically, parenterally, or orally. 1 / 2 In another embodiment, the mean peak intraocular concentration (C max ) when administered to the SCS by the methods described herein, is greater than or equal to the intraocular C of a VEGF antagonist when the same dosage of the VEGF antagonist is administered intravitreally, intracamerally, topically, parenterally, or orally. max In another embodiment, the mean intraocular area under the curve (AUC 0-t ) is the intraocular AUC of a VEGF antagonist when administered to the SCS via the methods described herein, compared to the intraocular AUC of the same dose of the VEGF antagonist administered intravitreally, intracamerally, topically, parenterally, or orally. 0-t Higher.

[0180] In one embodiment, the non-surgical methods, needles, and / or devices described herein are used to deliver one of the following VEGF modulators to the suprachoroidal space of the eye to treat one or more of the posterior ocular disorders or choroidal diseases described herein: AL8326, 2C3 antibody, AT001 antibody, HyBEV, bevacizumab (Avastin®), ANG3070, APX003 antibody, APX004 antibody, ponatinib (AP24534), BDM-E, VGX100 antibody (VGX100 CIRCADIAN), VGX200 (c-fos inducible growth factor monoclonal antibody), VGX300, COSMIX, DLX903 / 1008 antibody, ENMD2076, sunitinib malate (Sutent®), INDUS815C, R84 antibody, KD019, NM3, allogeneic mesenchymal progenitor cells in combination with an anti-VEGF antagonist (e.g., anti-VEGF antibody), MGCD265, MG516, VEGF-receptor kinase inhibitor, MP0260, NT503, anti-DLL4 / VEGF bispecific antibody, PAN90806, Palomido 529, BD0801 antibody, XV615, Lucitanib (AL3810, E3810), AMG706 (motesanib diphosphate), AAV2-sFLT01 , soluble Flt1 receptor, cediranib (Resentin™), AV-951, tivozanib (KRN-951), regorafenib (Stivarga™), volasertib (BI6727), CEP11981, KH903, lenvatinib (E7080), lenvatinib mesylate, telameprocol (EM1421), ranibizumab (Lucentis™), pazopanib hydrochloride (Votrient™), PF00337210, PRS050, SP01 (curcumin), carboxyamidotriazole orotate, hydroxychloroquine, linifanib (ABT869, RG3635), fluocinolone acetonide (Iluvien™), ALG1001, AGN150998, DARPinMP0112, AMG386, ponatinib (AP24534), AVA101, nintedanib (Baragatef™), BMS690514, KH902, golvatinib (E7050), everolimus (Afinitor®), dovitinib lactate (TKI258, CHIR258), ORA101, ORA102, axitinib (Inlyta®, AG013736), plitidepsin (Aplidin®), PTC29 9, Aflibercept (Zaltrap®, Eylea®), Pegaptanib Sodium (Macugen™, LI900015), Verteporfin (Visudyne®), Bucillamine (Rimatil, Lamin, Brimani, Lamit, Bhumik), R3 antibody, AT001 / r84 antibody, Troponin (BLS0597), EG3306, Vatalanib (PTK787), Bmab100, GSK2136773, Anti-VEGFR Alterase, Avila, CEP7055, CLT009, ESBA903, HuMax-VEGF antibody, GW654652, HMPL010, GEM220, HYB676, JNJ170292 59, TAK593, XtendVEGF antibody, Nova21012, Nova21013, CP564959, smart anti-VEGF antibody, AG028262, AG13958, CVX241, SU 14813, PRS055, PG501, PG545, PTI101, TG100948, ICS283, XL647, enzastaurin hydrochloride (LY317615), BC194, quinoline, COT601M06.1, COT604M06.2, Mabion VEGF, SIR-Spheres conjugated to anti-VEGF or VEGF-R antibodies, apatinib (YN968D1), and AL3818. Additionally, delivery of VEGF antagonists using the microneedle devices and non-surgical methods disclosed herein can be combined with one or more of the agents listed herein or other agents known in the art in a single formulation or multiple formulations.

[0181] In one embodiment, delivery of a VEGF antagonist to the suprachoroidal space of the eye of a human subject using the microneedle devices and methods disclosed herein is used to treat, prevent, and / or ameliorate one or more posterior ocular disorders or choroidal maladies. For example, the posterior ocular disorder, in one embodiment, is a disease of the retina. In another embodiment, the posterior ocular disorder is a disease of the choroid. In yet another embodiment, the posterior ocular disorder is an optic nerve disease. In one embodiment, the posterior ocular disorder is macular degeneration, age-related macular degeneration, neovascular age-related macular degeneration, subfoveal neovascular age-related macular degeneration, macular edema, macular edema following retinal vein occlusion, macular edema with retinal vein occlusion (RVO), diabetic macular edema, macular edema secondary to branch retinal vein occlusion, macular edema secondary to central retinal vein occlusion, branch retinal vein occlusion, central retinal vein occlusion, neovascularization, choroidal neovascularization, subfoveal choroidal neovascularization. The condition is selected from: vision loss due to diabetic macular edema, diabetic retinopathy, dry eye syndrome (inflammation and corneal tissue damage from dry eye), retinal detachment, retinopathy, retinitis pigmentosa, retinal vein occlusion, branch retinal vein occlusion, central retinal vein occlusion, myopia, pathologic myopia, neurodegenerative disease, ocular neovascularization, cancer of the eye, uveitis, glaucoma, scleritis, ocular sarcoidosis, optic neuritis, corneal ulcer, autoimmune disorder of the eye, or retinitis.

[0182] In one embodiment, the methods provided herein for treating choroidal malady (e.g., choroidal neovascularization, polyploidal choroidal vasculopathy, central sirrus choroidopathy, multifocal choroidopathy) include administering to the suprachoroidal space of the eye of a patient in need of treatment an effective amount of a drug formulation comprising an anti-inflammatory drug.

[0183] In one embodiment, the drug delivered to the suprachoroidal space of the eye of a human patient via the non-surgical posterior ocular disorder or choroidal disease treatment methods described herein reduces, inhibits, prevents, and / or ameliorates inflammation (i.e., is an anti-inflammatory drug). In one embodiment, the drug formulation delivered to the SCS of the eye of a patient in need of a drug formulation via the methods described herein comprises an effective amount of an immunosuppressant. For example, in one embodiment, the immunosuppressant is a glucocorticoid, a cytokine inhibitor, a cytostatic drug, an alkylating agent, an antimetabolite, a folic acid analog, a cytotoxic antibiotic, an interferon, an opioid, an antibody against a T cell receptor, or an antibody against an IL-2 receptor. In one embodiment, the immunosuppressant is an antimetabolite, and the antimetabolite is a purine analog, a pyrimidine analog, a folic acid analog, or a protein synthesis inhibitor. In another embodiment, the immunosuppressant is an interleukin-2 inhibitor (e.g., basiliximab or daclizumab). Other immunosuppressants that can be used with the methods and formulations described herein include, but are not limited to, cyclophosphamide, nitrosoureas, methotrexate, azathioprine, mercaptopurine, fluorouracil, dactinomycin, anthracyclines, mitomycin C, bleomycin, mithramycin, muromonab-CD3, cyclosporine, tacrolimus, sirolimus, or mycophenolate. In one embodiment, the drug formulation comprises an effective amount of mycophenolate.

[0184] In one embodiment, the intraocular elimination half-life (t 1 / 2 ) is the intraocular t-test of immunosuppressants when the same dose of the drug is administered intravitreally, intracamerally, topically, parenterally, or orally. 1 / 2 In another embodiment, the mean peak intraocular concentration (C max ) when administered to the SCS by the methods described herein, is a measure of the intraocular C of an immunosuppressant when the same dosage of the immunosuppressant is administered intravitreally, intracamerally, topically, parenterally, or orally. max In another embodiment, the mean intraocular area under the curve (AUC 0-t) is the intraocular AUC of an immunosuppressant when administered to the SCS via the methods described herein, compared to the intraocular AUC of an immunosuppressant when the same dose of the immunosuppressant is administered intravitreally, intracamerally, topically, parenterally, or orally. 0-t Higher.

[0185] In one embodiment, the drug formulation delivered to the SCS of the eye of a patient in need of the drug formulation via the methods described herein comprises an effective amount of a vascular permeability inhibitor. In one embodiment, the vascular permeability inhibitor is a vascular endothelial growth factor (VEGF) antagonist or an angiotensin-converting enzyme (ACE) inhibitor. In a further embodiment, the vascular permeability inhibitor is an angiotensin-converting enzyme (ACE) inhibitor, and the ACE inhibitor is captopril.

[0186] In one embodiment, the intraocular elimination half-life (t 1 / 2 ) is the intraocular t value of a vascular permeability inhibitor when the same dose of the inhibitor is administered intravitreally, intracamerally, topically, parenterally, or orally. 1 / 2 In another embodiment, the mean peak intraocular concentration (C max ) when administered to the SCS by the methods described herein, is a measure of the intraocular C of a vascular permeability inhibitor when the same dosage of the inhibitor is administered intravitreally, intracamerally, topically, parenterally, or orally. max In another embodiment, the mean intraocular area under the curve (AUC 0-t ) is the intraocular AUC of a vascular permeability inhibitor when administered to the SCS via the methods described herein, relative to the intraocular AUC of a vascular permeability inhibitor when the same dosage of the inhibitor is administered intravitreally, intracamerally, topically, parenterally, or orally. 0-t Higher.

[0187] In one embodiment, the drug is a steroid or a nonsteroidal anti-inflammatory drug (NSAID). In another embodiment, the anti-inflammatory drug is an antibody or fragment thereof, an anti-inflammatory peptide, or an anti-inflammatory aptamer. As provided throughout this specification, delivery of an anti-inflammatory drug to the suprachoroidal space provides advantages over administration of the same drug delivered via oral, intravitreal, intracavitary, topical, and / or parenteral administration routes. For example, in one embodiment, the therapeutic effect of a drug delivered to the suprachoroidal space is greater than the therapeutic effect of the same drug delivered at the same dosage when the drug is delivered via oral, intravitreal, topical, or parenteral routes. In one embodiment, the intraocular elimination half-life (t 1 / 2 ) is the intraocular t-value of an anti-inflammatory drug when the same dose of the drug is administered intravitreally, intracamerally, topically, parenterally, or orally. 1 / 2 In another embodiment, the mean peak intraocular concentration (C max ) when administered to the SCS by the methods described herein, reduces the intraocular C of anti-inflammatory drugs when administered intravitreally, intracamerally, topically, parenterally, or orally. max In another embodiment, the mean intraocular area under the curve (AUC 0-t ) is the intraocular AUC of an anti-inflammatory drug when administered to the SCS via the methods described herein, compared to the intraocular AUC of an anti-inflammatory drug when the same dose of the drug is administered intravitreally, intracamerally, topically, parenterally, or orally. 0-t Higher.

[0188] Steroidal compounds that can be administered via the methods provided herein include hydrocortisone, hydrocortisone-17-butyrate, hydrocortisone-17-aceponate, hydrocortisone-17-buteprate, cortisone, tixocortol pivalate, prednisolone, methylprednisolone, prednisone, triamcinolone, triamcinolone acetonide, mometasone, amcinonide, budesonide, desonide, fluocinonide, halcinonide, bethamethasone, betamethasone dipropionate ... dipropionate), dexamethasone, fluocortolone, hydrocortisone-17-valerate, halometasone, alclometasone dipropionate, prednicarbate, clobetasone-17-butyrate, clobetasol-17-propionate, fluocortolone caproate, fluocortolone pivalate, fluprednidene acetate, and prednicarbate.

[0189] Specific NSAID classes that can be administered via the methods provided herein include salicylates, propionic acid derivatives, acetic acid derivatives, enolic acid derivatives, fenamic acid derivatives, and cyclooxygenase-2 (COX-2) inhibitors. In one embodiment, the methods provided herein are used to deliver one or more of the following NSAIDs to the SCS of the eye of a patient in need thereof: acetylsalicylic acid, diflunisal, salsalate, ibuprofen, dexibuprofen, naproxen, fenoprofen, ketoprofen, dexketoprofen, flurbiprofen, oxaprozin, loxaprofen, indomethacin, tolmetin, sulindac, etodolac, ketorolac, diclofenac or nabumetone, piroxicam, meloxicam, tenoxicam, droxicam, lornoxicam or isoxicam, mefanamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid, celecoxib, rofecoxib, valdecoxib, parecoxib, lumiracoxib, etoricoxib, or firocoxib.

[0190] Other examples of anti-inflammatory agents that can be used in the methods provided herein to treat posterior ocular disorders or choroidal diseases, choroidal neovascularization, or subretinal exudation include, but are not limited to, mycophenolate, remicase, nepafenac, 19AV agonist, 19GJ agonist, 2MD analog, 4SC101, 4SC102, 57-57, 5-HT2 receptor antagonist, 64G12, A804598, A967079, AAD2004, AB1010, AB224050, abatacept, etaracizumab (Abeglin™). , Abevac (registered trademark), AbGn134, AbGn168, Abki, ABN912, ABR215062, ABR224050, cyclosporine (Abramun (registered trademark)), docosanol (behenyl alcohol, Abreva (registered trademark)), ABS15, ABS4, ABS6, ABT122, ABT325, ABT494, ABT874, ABT963, ABXIL8, ABXRB2, AC430, Acenetra, lysozyme chloride (Acdeam (registered trademark)), ACE772, aceclofenac (Aceblock, Acevid, AceSnack), Ace Toaminophen, chlorzoxazone, serrapeptase, tizanidine hydrochloride, betadex, aceclogesic plus, acecloron, aceclolen, aceclorism, aceclona, ​​acefeine, acemetacin, aspirin (asprin) (aceterin), acetal-SP (aceclofenac-combination, ibuprofen, acetyl-G, acetylsalicylate dl-lysine, acetylsalicylic acid, asicot, asifine, asic, acrosen, acroflam-P, acromore, acron, A-CQ, ACS15, actarit, actemra, Axelaria oliofilizad, Actifast, Actimab-B, Actiquim, Actilin, Actisplus, Activated leukocyte cell adhesion molecule antibody, Aclar-X, AD452, Adalimumab, ADAMTS5 inhibitor, ADC1001, Adco-diclofenac, Adco-indomethacin, Adco-meloxicam, Adco-naproxen, Adco-piroxicam, Adcort, Adco-sulindac, Adenosine triphosphate disodium, Adenosine A2a receptor agonist, Azimod, Azinos, Adioct, Adidol, Adipoplus,Adipose-derived stem cells and / or regenerative cells, Ajzen, Adopep, Advacan, Advagraf, Advel, Adwiflam, AEB071, Ental, Afenac, Afenplus, Afianthene, Afinitor, Aflamin, Aflazacort, Afrogen, Afloxan, AFM15, AFM16, AFM17, AFM23, Afpred-dexa, AFX200, AG011, Agafen, Aganilsen, AGI1096, Agidex, AGS010, Agdol, A-Hydrocort, AIK1, AIN457, Airtal, AIT110, AJM300, Ajulemic Acid, AK106, AL-24-2A1, AL4-1A1, Alacort, Alantz, Albumin immunoglobulin, Alclometasone dipropionate, ALD518, Aldesleukin, Aldoderma, Alefacept, Alemtuzumab, Alekel(trademark), Allergolon, Allergosone, Aletraxone, Alfenac, Argason, Argin-vec-cort, Argioflex, Argilex, Argivin Plus, Alicaforsen sodium, Alin, Alinia, Alibiodor, Alibiocin, Alkaline phosphatase, ALKS6931, Arant In, Albupen, Almol, Allochrysin, Allogeneic Endothelial Cells, Allogeneic Mesenchymal Progenitor Cells, Allogeneic Mesenchymal Stem Cells, Alminoprofen, α1-Antitrypsin, α7 Nicotinic Agonist, α-Amylase, α-Chymotrypsin, α-Fetoprotein, α-Linolenic Acid, α-1-Antitrypsin, α2β1 Integrin Inhibitor, Alphacoat, Alphaphen, α-Hexidine, α-Trypsin, Alfintern, Alpinamed Mobility ω3, Alpoxene, AL-Rev1, Alterase, ALX0061, ALX0761, ALXN1007, A LXN1102, AM3840, AM3876, AMAB, AMAP102, Amason, Amven, Ambezim G, Amcinonide, AME133v, Ameshin, Amerotex, A-Metapred, Amebiv, AMG108, AMG139, AMG162, AMG181, AMG191, AMG220, AMG623, AMG674, AMG714, AMG719, AMG729, AMG827, Amidor, Amifamipridine phosphate, Diclofenac (Emifenac (registered trademark)), Amimetacin, Amiprilose hydrochloride, Amiprofen, Ammophos , Amofuram, AMP110, Ampikyi, Ampion, Ampiroxicam, Amtolmetin Guacyl, AMX256, AN6415, ANA004, ANA506, Anab, Anasen, Anaphram, Anaflex ACI, Anaida, Anakinra, Analgen Altritis, Anapan, Anaprox, Anavan, Anax, Anco, Andrographis, Aneol, Anergix, Anervax.RA (trademark) (therapeutic peptide vaccine), Amfurene, ANG797, Anilixin, Ammelsin, Annexin 1 peptide, Annexin A5,Anodyne, Anside, Anspirin, Antalen, anti-BST2 antibody, anti-C5a MAb, anti-ILT7 antibody, anti-VLA1 antibody, anti-α11 antibody, anti-CD4 802-2, anti-CD86 monoclonal antibody, anti-chemokine, anti-DC-SIGN, anti-HMGB-1 MAb, anti-IL-18 MAb, anti-IL-1R MAb, anti-IL23 Bristol, anti-interleukin-1β antibody, anti-LIGHT antibody, anti-MIF antibody, anti-MIF antibody, anti-miR181a, antioxidant inflammatory regulator, antiflamin, AntiRAGE MAb, anti-thrombin III, anti-TIRC-7 MAb, Anusol-HC, Anifen, AP105, AP1089, AP1189, AP401, AP501, Apazone, APD334, Apentac, APG103, Apidon, Apilimod mesylate, Apitac, Apitoxin, Apizel, APN inhibitor, Apo-azathioprine, Apo-dexamethasone, ApoE mimetic, ApoFasL, Apo-indomethacin, Apo-phenamic, Apo-met. Trexate, Apo-Nabumetone, Apo-Napro-NA, Apo-Naproxen, Aponidine, Apo-Phenylbutazone, Apo-Piroxicam, Apo-Thrin, Apo-Tenoxicam, Apo-Tiaprofenic, Apranax, Apremilast, Apricoxib, Aprofen, Approse, Aproxen, APX001 antibody, APX007 antibody, APY0201, AqvoDex, AQX108, AQX1 125, AQX131135, AQX140, AQX150, AQX200, AQX356, AQXMN100, AQXMN106, ARA290, Arava, Alcalist, Alkoxya, Aretin, Alfleur, ARG098, ARG301, Arginine Aestin, Arginine Deiminase (PEGylated), ARGX109 Antibody, ARGX110, Ariuma, Aristocort, Aristospan, Ark-AP, ARN4026, Allophane, Allof EZ, Alloref, Arotar, Alpibul, Alpimun, Alpsyuangixin, ARQ101, Arestin SP, Alox, ARRY162, ARRY371797, ARRY614, ARRY872, ART621, Artamin, Arsfree, Arsotech, Arsrexin, Arslispray, Orthotech, Eterna Shark Cartilage Extract (Arslobas(trademark),Neoretna(trademark), Sovascal(trademark), Ultifit, Artigo, Artin, Altinoa, Altisid, Altoflex, Altren Hipergel, Altridol, Altylase, Altrocaptin, Altrodiet, Altrophen, Altropan, Altrosil, Altrosilene, Altrotin, Altrox, Altiflam, Alzera, AS604850, AS605858, Asacol, ASA-Grindex, Asazipam, Aceclo, ASF1096, ASF1096, ASK8007, ASKP1240, ASLAN0 03, Asmo ID, Asonep, ASP015K, ASP2408, ASP2409, Aspagin, Aspeol, Aspicum, Aspirimex, AST120, Astaxanthin, Astrocort, Aszes, AT002 antibody, AT007, AT008 antibody, AT008 antibody, AT010, AT1001, Atacicept, Ataspin, Atepadene, Atgam, ATG-Fresenius, Aslophen, ATI003, Atiprimod, ATL1222, ATN103, ATN192, ATR107, Atoli, Atolmin, Atrosab antibody, ATX3105, AU801, Auranofin, Aurobin, Auropan, Aurothio, Aurothioprole, Autologous adipose-derived neoplastic cells, Autonec, Avanzia, AVE9897, AVE9940, Avelox, Avent, AVI3378, Abrokin, AVP13546, AVP13748, AVP28225, AVX002, Accel diclofenac, Accel papain, Axene, AZ17, AZ175, Azacortide, AZA-DR, Azafrin, Azamun, Azanin, Azap, Azapine, Azaprene, Azapurine, Azalam, Azasan, Azathioprine, A ZD0275, AZD0902, AZD2315, AZD5672, AZD6703, AZD7140, AZD8309, AZD8566, AZD9056, Azet, Azintrel, Azithromycin, Az-od, Azofit, Azolide, Azolan, Azulen, Azulfidine, Azulfin, B1 antagonist, Balconet, BAF312, BAFF inhibitor, Bages, Bayley SP, Barreston, Barsolon, Baminercept alfa, Bardoxolone methyl, Baricitinib, Barotase, Basecam, Basiliximab, Baxmun, Baxo,BAY869766, BB2827, BCX34, BCX4208, Becfine, Beclate-C, Beclate-N, Beclorab Q, Beclomethasone dipropionate, Becloin, Bekmet-CG, Vegita, Beguchi, Belatacept, Belimumab, Belosalic, Bemetson, Ben, Benebat, Benexam, Benflogin, Benisan, Benlysta, Benlysta, Benorilate, Benonson, Benoxaprofen, Bentol, Benzydamine hydrochloride, Benzimine, Beofenac, Belafen, Verinert, Berlofen, Bertanel, Bestamin, Best Fen, Beta-Nicip, Betacort, Betacorten G, Betaform, Beta-Glucan, Betalar, Beta-M, Betamed, Betamesol, Betamethasone, Betamethasone Dipropionate, Betamethasone Sodium, Betamethasone Sodium Phosphate, Betamethasone Valerate, Betan, Betanex, Betapanthene, Betapearl, Betapred, Betason, Betasonate, Betasone, Betatorinta, Betaval, Betazone, Betazone, Betesil, Betnecort, Betnesol, Betnovate, Bextra, BFPC13, BFPC18, BFPC21, BFPT68 64, BG12, BG9924, BI695500, BI695501, BIA12, Big-Joint-D, BIIB023 antibody, Bi-Xicam, Bingo, Biobee, Bio-Cultiridge, Bio-C-Sinckie, Biodexon, Biofenac, Bioleucam, Bioson, Biosporin, BIRB796, Vitonoval, Vitobio, Bibigam, BKT140, BKTP46, BL2030, BL3030, BL4020, BL6040, BL7060, BLI1300, Blisibimod, Brocium B12, Brocium Gesic, Brocium, BMS066 , BMS345541, BMS470539, BMS561392, BMS566419, BMS582949, BMS587101, BMS817399, BMS936557, BMS945429, BMS-A, BN006, BN007, BNP166, Bonacort, Bonas, Bone marrow stromal cell antigen 2 antibody, Bonflex, Bonifen, Bumik, Borbit, Bosong, BR02001, BR3-FC, Branzykinin B1 receptor antagonist, Brezinin, Brexecam, Brexin, Brexodine, Briakinumab, Brimani, Briobercept,Bristaflam, Britten, Broven, Brodalumab, Broen-C, Bromelains, Bromelin, Bronax, Bropain, Brosilar, Bruace, Brufadol, Brufen, Brugel, Brukill, Brucil, BT061, BTI9, BTK kinase inhibitor, BTT1023 antibody, BTT1507, Bucillamine, Bucillate, Bucolagis, Bucolome, Budenofalk, Budesonide, Budex, Bufect, Bufencone, Bukwanketoprofen, Bunide, Bunofen, Busilvex, Busulfan, Busul Fex, Buslipo, Butaltrol, Butalt B12, Butazona, Butazolidinedione, Butezone, Butiziona, BVX10, BXL628, BYM338, B-zone, C1 esterase inhibitor, C243, c4462, c5997, C5aQb, c7198, c9101, C9709, c9787, CAB101, cadherin 11 antibody, Caerromysion A, CAL263, Calcort, Calmatel, CAM3001, camel antibody, Camlox, Camorra, Campus, Camlox, Camtenam, Canakinumab, candida albicans antigen, Candine, Cannabidiol, CAP1.1, CAP1.2, CAP2.1, CAP2.2, CAP3.1, CAP3.2, Caleram, Karimun, Karyodent, Cultifix, Cultijoint, Cultirago, Cultisafe-DN, Cultishine, Cultivit, Cultril-S, Caldol, Caspa CIDe, Caspa CIDe, Cassin, CAT1004, CAT1902, CAT2200, Cataflam, Cathepsin S inhibitor, Catrep, CB0114, CB2 agonist, CC0478765, CC10004, CC100 15, CC1088, CC11050, CC13097, CC15965, CC16057, CC220, CC292, CC401, CC5048, CC509, CC7085, CC930, CCR1 antagonist, CCR6 inhibitor, CCR7 antagonist, CCRL2 antagonist, CCX025, CCX354, CCX634, CD diclofenac, CD102, CD103 antibody, CD103 antibody, CD137 antibody, CD16 antibody, CD18 antibody, CD19 antibody, CD1d antibody, CD20 antibody, CD200Fc, CD209 antibody, CD24, CD3 antibody,CD30 antibody, CD32A antibody, CD32B antibody, CD4 antibody, CD40 ligand, CD44 antibody, CD64 antibody, CDC839, CDC998, CDIM4, CDIM9, CDK9 inhibitor, CDP146, CDP323, CDP484, CDP6038, CDP870, CDX1, 135, CDX301, CE224535, Ceanele, Cebedex, Sebutide, Seclonac, Seeks, CEL2000, Ceract, Selbex, Selcox, Celebiox, Celebrex, Celebrin, Celecox, Celecoxib, Celedor, Celestone, Celebex, Selex, CELG4, Cell adhesion molecule antagonist, Cellcept, Celmun, Cerosti, Ceroxib, Cellprot, Celdex, Cenicriviroc mesylate, Senpracel-l, CEP11004, CEP37247, CEP37248, Cefil, Ce Profen, Certican, Certolizumab pegol, Cetofenide, Cetoprofeno, Cetylpyridinium chloride, CF101, CF402, CF502, CG57008, CGEN15001, CGEN15021, CGEN15051, CGEN15091, CGEN25017, CGEN25068, CGEN40, CGEN54, CGEN768, CGEN855, CGI1746, CGI560, CGI676, Cgtx-peptide, CH1504, CH4051, CH4446, Chaperonin 10, Chemokine CC motif ligand 2 , chemokine CC motif ligand 2 antibody, chemokine CC motif ligand 5 antibody, chemokine CC motif receptor 2 antibody, chemokine CC motif receptor 4 antibody, chemokine CXC motif ligand 10 antibody, chemokine CXC motif ligand 12 aptamer, chemotaxis inhibitor, tilmetacin, chitinase 3-like 1, clochodemin, cloquin, chlorhexidine gluconate, chloroquine phosphate, choline magnesium trisalicylate, chondroitin sulfate, chondroscat, CHR3620, CHR4432, CHR5154, chrysaline , Chuanxinlian, Chimapra, Chymotase, Chymotrypsin, Chitomtryp, CI202, CI302, Cycloderm-C, Cycloprene, Cycloporal, Silamine, Cimzia, Cincophen, Cinmetacin, Cinoxicam, Sinoderm, Cinolone-S, Cinrise, Cipcorrin, Cipemastat, Cypol-N, Cypridanol, Cypzen, Sitax F, Cytogan, Cytoken T, Civamide, CJ042794, CJ14877, c-Kit monoclonal antibody, Cladribine, Clafen, Cranza, Clavelsal, Clazakizumab,Clearoid, Crease, Clevagen, Clevian, Crydol, Clindac, Clinoril, Cry, Putol, Clobenate, Clobecad, Clobetasol Butyrate, Clobetasol Propionate, Clodol, Clofarabine, Clophen, Clofenal LP, Chloral, Clonac, Clongamma, Clonixiridine, Clotasose, Clobacoat, Clobana, Cloxin, CLT001, CLT008, C-MAF Inhibitor, CMPX1023, Cnac, CNDO201, CNI1493, CNTO136, CNTO148, CNTO1959, Cobefen, Covencoderm, Cobix, Cofenac, Cofenac, COG241, COL 179, colchicine, colchicum dispart, colchimax, colcibra, coredes A, coresol, colliform, collist, collagen (type V), comcort, complement component (3b / 4b) receptor 1, complement component C1s inhibitor, complement component C3, complement factor 5a receptor antibody, complement factor 5a receptor antibody, complement factor D antibody, chondrosulf, chondrotec, chondrosin, conestat alpha, connective tissue growth factor antibody, courpan, copaxone, copilon, coldefla, collidron, coat S, coatan, coltart, coat-dome, cortesetin, col ... Teff, Cortelloid, Corticap, Corticus, Cortic-DS, Corticotropin, Cortiderm, Cortidex, Cortiflam, Cortinet M, Cortinil, Cortipiren B, Cortilan, Cortis, Cortisol, Cortisone acetate, Cortibal, Cortone acetate, Cortopin, Cortral, Cortrill, Cortipiren, Cosamine, Coson, Cosyntropin, COT kinase inhibitor, Cotyram, Cotrizone, Cotosone, Cobox, Cox B, COX-2 / 5-LO inhibitor, Coxetone, Coxflam, Coxicam, Coxi Toll, Coxitral, Coxipal, CP195543, CP412245, CP424174, CP461, CP629933, CP690550, CP751871, CPSI2364, C-kin, CR039, CR074, CR106, CRA102, CRAC channel inhibitor, CRACM ion channel inhibitor, Clathizon, CRB15, CRC4273, CRC4342, C-reactive protein 2-methoxyethyl phosphorothioate oligonucleotide, CreaVax-RA, CRH regulator, Critic-Aid, Clocam,Clonesvax, cromoglycate, cromolyn sodium, clonocorticoid, clonodicasone, CRTX803, CRx119, CRx139, CRx150, CS502, CS670, CS706, CSF1R kinase inhibitors, CSL324, CSL718, CSL742, CT112, CT1501R, CT200, CT2008, CT2009, CT3, CT335, CT340, CT5357 , CT637, CTP05, CTP10, CT-P13, CTP17, cuprenyl, cuprimine, cuprind, cupripene, kraquin, ctofen, CWF0808, CWP271, CX1020, CX1030, CX1040, CX5011, Cx611, Cx621, Cx911, CXC chemokine receptor 4 antibody, CXCL13 antibody, CXCR3 antagonist, CXCR4 antagonist, ciasus1104 B, Cyclo-2, Cyclocort, Cyclooxygenase-2 inhibitor, Cyclophosphamide, Cyclolin, Cyclosporine A prodrug, Cyclosporine analog A, Cyclosporine, Silevier, Sylinclaris, CYT007TNFQb, CYT013IL1bQb, CYT015IL17Qb, CYT020TNFQb, CYT107, CYT387, CYT99007, Cytokine inhibitor, Cytopan, Cytoreg, CZC24832, D1927, D9421C, Daclizumab, Danazol, Danilase, Dantes, Danzen, Dapsone, Dase-D, Daypro, Dayproalta, Dyrun, Dazen, DB295, DBTP2, D-cort, DD1, DD3, DE096, DE098, Debio 0406, Debio 0512, Debio 0615, Debio 0618, Debio 1036, Decaderm, Decadrel, Decadron, Decadronal, Decalon, Decane, Decason, Decdan, Desilon, Declofen, Decopen, Decorex, Decorten, Dedema, Dedron, Deexa, Defcort, De-flam, Deflamat, Defran, Defranil, Deflarene, Deflaz, Deflazacort, Defnac, Defnarone, Defnil, Defosalic, Defsule, Defza, Dehydrocortisone, Decort, Delagil, Delcasertib, Dermitide, Delficort, Deltacorsolone Prednisolone (Deltacortril), Deltafluorene, Deltasolone, Deltason, Deltastab,Deltonin, Demarin, Demison, Denebola, denileukin diftitox, denosumab, Denzo, depocortin, depo-medrol, depo-methotrexate, depotred, deposet, depyrin, delinase, delmol, delmolar, delmonat, delmoson, delzon, desketo, desonide, desoxycorticosterone acetate, deswon, dexa, dexaben, dexap, dexacort, dexacortisone, dexacortisil, dexadiq, dexadrine, dexadrone, dexafal, dexahil, dexarab, dexaraf, dexa Retto, Dexargen, Dexarion, Dexalocal, Dexalone, Dexa-M, Dexamecortin, Dexamed, Dexamedis, Dexameral, Dexametha, Dexamethasone, Dexamethasone acetate, Dexamethasone palmitate, Dexamethasone phosphate, Dexamethasone sodium metasulfobenzoate, Dexamethasone sodium phosphate, Dexamine, Dexapanthene, Dexa-S, Dexason, Dextab, Dexatopic, Dexabal, Dexaben, Dexazolidine, Dexazona, Dexason, Dexcol, Dexibu, Dexibuprofen, Dexco, Dexifene, Dexmun, Dexketoprofen, Dexketoprofen trometamol, Dexmark, Dexometh, Dexon I, Dexonarin, Dexonex, Dexony, Dexoptifen, Dexipin, Dexitan-Plus, Dextran Sulfate, Dezacol, Dfz, Diacerein, Diannexin, Diaston, Dicalol, Dicason, Diknol, Diclo, Diclobon, Diclobonse, Diclobonzox, Diclofast, Diclofen, Diclofenac, Diclofenac β-Dimethylaminoethanol, Diclofenac De Anol, Diclofenac Diethylamine, Diclofenac Epolamine, Diclofenac Potassium, Diclofenac Resinate, Diclofenac Sodium, Diclogen AGIO, Diclogen Plus, Diclokim, Diclomed, Diclo-NA, Diclonac, Dichloramine, Dicloran, Dichloreum, Dichlorism, Diclotec, Diclovit, Diclowal, Diclozem, Dico-P, Dicophen, Dicorib, Dicorson, Diclon, Dixel, Difena, Diftab, Diflunisal, Dilmapimod, Dilora, Dimethylsulfone, Dinac, D-Indomethacin,Dioxaflex Protect, Zipagesik, Zipenopen, Zipexin, Zipro AS, Ziprobeta, Ziprobetason, Ziproclenat, Ziprometh, Zipronova, Ziproson, Ziprobate, Ziproxen, Disalmine, Zisar, Disopain, Dispain, Dispercam, Distamine, Zizox, DLT303, DLT404, DM199, DM99, DMI9523, dnaJP1, DNX02070, DNX04042, DNX2000, DNX4000, Docosanol, Docz-6, Dolamid, Dolaren , Dolkis, Dolex, Dolfram, Dolfre, Dorugit, Dormax, Dorumina, Dorokatazone, Dorobest, Dorobid, Dorock, Dorocam, Dorocalcigen, Dorofit, Dorokind, Doromed, Dronac, Dronex, Dorotren, Dorozen, Dolkin, Dom0100, Dom0400, Dom0800, Domet, Dometon, Dominador, Dongipap, Donica, Donisanin, Drampimod, Dorixinarelax, Dolmelox, Doruginplus, Doxathal, Doxtran, DP NEC, DP4577, DP50, DP6221, D-Penamine, DPIV / APN inhibitor, DR1 inhibitor, DR4 inhibitor, DRA161, DRA162, Drenex, DRF4848, DRL15725, Drossadine, DSP, Dukes, Duo-Decadron, Duoflex, Duonase, DV1079, DV1179, DWJ425, DWP422, Dimol, DYN15, Dynapar, Dismen, E5090, E6070, Easydays, Ebetrexat, EBI007, EC0286, EC0565, EC0746, Ekax, Echinacea purpurea extract, EC-Naprosyn, Econac, Ecosprin 300, Ecosprin 300, Eclidoxan, Eculizumab, Edecam, Efalizumab, Efcortesol, Effigel, Efragen, Efridol, EGFR antibody, EGS21, eIF5A1 siRNA, Ecardidin, Elafin, Eldoflam, Elidel, Eliflam, Ellison, Elmes, Elmetacin, ELND001, ELND004, Elocalcitol, Elocom, Elsivcol, Emanzen, Emcort, Emifen, Emifenac, Emorfazone, Empinace, Emricasan, Emtor, Enable,Enbrel, Ensaid, Encostat, Encortron, Encorton, Endace, Endogesic, Endoxan, Encorten, Encela, Entocort, Enzylan, Epanova, Epalang, Epatek, Epicotil, epidermal growth factor receptor 2 antibody, epidermal growth factor receptor antibody, epidixon, Epidolone, Epicrin, EPPA1, epratuzumab, EquiO, Elac, Elazone, ERB041, ERB196, Eldon, Elidex, Escherichia coli enterotoxin B subunit, Estin, E-selectin antagonist, Esfenac , ESN603, Esonarimod, Esprofen, Estetrol, Estopein, Estrogen receptor beta agonist, Etanercept, Etaracizumab, ETC001, Propolis ethanol extract, ETI511, Ethiprednol dicloacetate, Ethodine, Ethodine, Etodol, Etodolac, Etodi, Etofenamate, Ethorfort, Etrac, Etopine, Etoricoxib, Etrix, Etosafe, Etoba, Etozox, Etura, Eucob, Euphan, Eukaryotic translation initiation factor 5A oligonucleotide, Eunac, Eurocox, Eurogesic, everolimus, ebinopon, EVT401, Exaflam, EXEL9953, Exicoat, Expene, Extra Feverlet, Extrapan, Extrauma, Exdase, F16, F991, Falcam, Falcol, Farzy, Farbovir, Farcomesacin, Farnerate, Farnazone, Farnezone, Farotrin, fas antibody, Fastflam, FasTRACK, Fastum, Fould Metro, FcγRIA antibody, FE301, Febrofen, Febrofide, Felbina K, Felden, Feldex, Ferroran, Felxicam, Fenac, Fenacop, Fenadol, Fenafuran, Fenamic, Fenalen, Fenatone, Fenbid, Fenbufen, Fengsigtong, Fenicort, Fenopain, Fenoprofen calcium, Fenopron, Fenris, Fensap, Fenoxicam, Feprazinol, Ferrovisc, Feverlet, Fezakinumab, FG3019, FHT401, FHTCT4, FID114657, Figitumumab, Fillex, Filgrastim, Filase,Final, Findoxin, Fingolimod hydrochloride, Filategrast, Ferdapse, Physiodal, Fibasa, FK778, Flacoxit, Fladaldine, Flagon, Flamer, Flamcid, Flamfort, Flamid, Flaminase, Flamirexgesic, Furanide, Franzen, Fullerene, Fullerene, , FlashAct, Flavonoid Anti-inflammatory Molecule, Flebogamma DIF, Flenac, Flex, Flexaphen 400, Flexi, Flexidol, Flexium, Flexion, Flexono, Floggen, Flogiatrin B12, Flogomin, Flogoral, Flogosan, Flogotar, Flo-Pred, Flosterone, Flotrip Forte, Flt3 Inhibitor, Fluasterone, Flucam, Flucinal, Fludrocortisone Acetate, Aluminum Flufenamate, Flumethasone, Flumidone, Flunixin, Fluocinolone, Fluocinolone Ace Tonidol, fluocinonide, fluocortolone, fluonide, fluorometholone, flur, flurbiprofen, flurivec, fluromesolone, flutal, fluticasone, fluticasone propionate, flutisone, fluzone, FM101 antibody, fms-related tyrosine kinase 1 antibody, follitrax, fontolizumab, formic acid, fortecortin, fospeg, fostamatinib disodium, FP1069, FP13XX, FPA008, FPA031, FPT025, FR104, FR167653, flamevin, fram, floben, florix ,FROUNT inhibitor,Fubifen PAP,Fucol Ibuprofen,Flamothol,Fulpen,Fungifin,Flotargin,Sodium Fusidate,FX002,FX141L,FX201,FX300,FX87L,Galectin Regulatory Factor,Gallium Maltolate,Gamimun N,Gammaguard,Gamma-IV,Gammakin,Gammavenin,Gamnex,Galzen,Gaspirin,Gatex,GBR500,GBR500 Antibody,GBT009,G-CSF,GED0301,GED0414,Gefenec,Gelofen,Genepril,Gengraf , Genimun, Genikine, Genotropin, Genz29155, Gelvin, Gelvin, Gevokizumab, GF01564600, Gilenya, Gilenya, Gibinostat, GL0050, GL2045, Glatiramer acetate, Globulin, Glorsoforte, Globarox, Globenin-I, GLPG0259, GLPG0555, GLPG0634, GLPG0778, GLPG0974, Gluco, Glucoserine, Glucosamine, Glucosamine hydrochloride, Glucosamine sulfate, Glucotin, Gludex, Glutirage, GLY079, GLY145, Glycanic,Grisefort Up, Grygesic, Grisopep, GMCSF Antibody, GMI1010, GMI1011, GMI1043, GMR321, GN4001, Goanasalve, Goflex, Gold Sodium Thiomalate, Golimumab, GP2013, GPCR Modulators, GPR15 Antagonist, GPR183 Antagonist, GPR32 Antagonist, GPR83 Antagonist, G Protein-Coupled Receptor Antagonist , Graceptor, GrafTac, Granulocyte colony-stimulating factor antibody, Granulocyte-macrophage colony-stimulating factor antibody, Gravix, GRC4039, Glelyse, GS101, GS9973, GSC100, GSK1605786, GSK1827771, GSK2136525, GSK2941266, GSK315234, GSK681323, GT146, GT442, Gusiksaothong, Gusiksera, Gusiksone hydrochloride Risperimus, GW274150, GW3333, GW406381, GW856553, GWB78, GXP04, Gynestrel, Haloart, Halopredone acetate, Haloxine, HANALL, Hanal Souldacortin, Havisco, Hawonbucillamine, HB802, HC31496, HCQ200, HD104, HD203, HD205, HDAC inhibitors, HE2500, HE3177, HE3413, Hecori A, hectomytasin, hephasolon, helen, helenil, hemamax, hematome, hematopoietic stem cells, hematorol, hemner, hemryl, heparinoid, heptax, HER2 antibody, herponil, hESC-derived dendritic cells, hESC-derived hematopoietic stem cells, hespercorbin, hexacortin, hexadrol, hexetidine, hexoderm, hexodermsaric, HF0220, HF1020, HFT-401, hG-CSFR, ED Fc, Hiberna, high mobility group box 1 antibody, Hironide, Hinocam, Hirudin, Hirudoid, Hison, histamine H4 receptor antagonist, Hitenercept, Hizentra, HL036, HL161, HMPL001, HMPL004, HMPL004, HMPL011, HMPL342, HMPL692, honeybee venom, Hongkian, Hotemin, HPH116, HTI101, HuCAL antibody, human adipose mesenchymal stem cell, anti-MHC class II monoclonal antibody, human immunoglobulin, human placental tissue hydrolysate, HuMaxCD4, HuMax-TA C, Humeton, Humicade, Humira, Huons Betamethasone Sodium Phosphate, Huons Dexamethasone Sodium Phosphate, Huons Piroxicam, Huons Talniflumate, Hurofen, Hurma, Huvap, ​​HuZAF, HX02, Hyalogel, Sodium Hyaluronate, Hyaluronic Acid, Hyaluronidase, Hyalon, Hikosin, Hi-Coat, Hy-Cortisone, Hydrocortisone, Hydrocortisone Acetate, Hydrocortisone Butyrate, Hydrocortisone Hemisuccinate, Hydrocortisone Sodium Phosphate, Hydrocortisone Citrate Cortisone sodium, hydrocortistab, hydrocortone, hydrolin, hydroquin, hydro-Rx, hydrosone HIKMA, hydroxychloroquine, hydroxychloroquine sulfate, hyrazedessou, HyMEX, hypen, HyQ, Hysonart, HZN602, IM75, IAP inhibitor, ibargin, ibargin, ibex, ibrutinib, IBsolvMIR, ebu, ibcon, ebudrome, ibufen, ibflam, ibflex, ibgesic, ebu-hepa, ibukim, ibmal, ibnal, ibpental, ibupill, ibupill Prof, Ibuprofen, Ivcent, Evesoft, Eve Skipension, Eve Suspense, Ivtard, Eve Top, Eve Top, Eve Trex, IC487892, Ichthammol, ICRAC blocker, IDEC131, IDECCE9.1, Ides, Idishin, Idizone, IDN6556, Idomethine, IDR1, Idyll SR, Ifen, Iguratimod, IK6002, IKK-β inhibitor, IL17 antagonist, IL-17 inhibitor, IL-17RC, IL18, IL1Hy1, IL1R1, IL-23 adnectin,IL23 inhibitor, IL23 receptor antagonist, IL-31 mAb, IL-6 inhibitor, IL6Qb, Iracox, Ilaris, Ilodecaquin, ILV094, ILV095, Imaxetil, IMD0560, IMD2560, Imesel Plus, Iminoral, Imojin, IMMU103, IMMU106, Imcept, Imfine, Immunex Syrup, Immunoglobulin, Immunoglobulin G, Immunopurin, Immunorel, Imulin, IMO8400, IMP731 antibody, Im Muplanta, Immunocel, Imran, Imurek, Imsafe, Imsporin, Imtrex, IN0701, Inal, INCB039110, INCB18424, INCB28050, INCB3284, INCB3344, Indexon, Indic, Indo, Indo-A, Indo-Bid, Indo-Bros, Indo-Caf, Indo-Carsil, Indo-Cid, Indo-Cin, Indo-Mehotopas, Indo-Men, Indo-Met , indomethacin, indomethacin, indomethasone, indometine, indomine, indopal, indolone, indotroxin, INDUS830, INDUS83030, inflammasin, inflammamac, inflammasome inhibitor, inflavis, inflaxene, inflectra, infliximab, ingalipt, inicox dp, inmesin, inmunoaltro, innamit, InnoD06006, INO7997, inosine, inoten, inovan, inpra, insidepap, insider-P, instasil, instacool, interfenac, interflam, inteban, intevanspansul, integrin, alpha 1 antibody, integrin, alpha 2 antibody, intenase, interferon alpha, interferon beta-1a, interferon gamma, interferon gamma antibody, interking, interleukin 1 Hy1, interleukin 1 antibody, interleukin 1 receptor antibody, interleukin 1, beta antibody, interleukin 10, interleukin 10 antibody, interleukin 12, interleukin 12 antibody, interleukin 13 antibody, interleukin 15 antibody, interleukin 17 antibody, interleukin 17 receptor C, interleukin 18, interleukin 18 binding protein, interleukin 18 antibody, interleukin 2 receptor, alpha antibody,Interleukin 20 antibody, Interleukin 21 mAb, Interleukin 23 aptamer, Interleukin 31 antibody, Interleukin 34, Interleukin 6 inhibitor, Interleukin 6 antibody, Interleukin 6 receptor antibody, Interleukin 7, Interleukin 7 receptor antibody, Interleukin 8, Interleukin 8 antibody, Interleukin-18 antibody, Inchidrol, Intradex, Intragam P, Intragesic, Intraglobin F, Intratect, Insel, Iomab B, IOR-T3, IP751, IPH2201, IPH2301, IPH2 4, IPH33, IPI145, Ipocort, IPP201007, I-profen, Iprox, Ipson, Ipton, IRAK4 inhibitor, Iremod, Ilton Python, IRX3, IRX5183, ISA247, ISIS104838, ISIS2302, ISISCRPRx, Ismaphron, IsoQC inhibitor, Isox, ITF2357, Ivy Gum EN, Ibepred, IVIG-SN, IW001, Idilox, J607Y, J775Y, JAK inhibitor, JAK3 inhibitor, JAK3 kinase inhibitor Inhibitor, JI3292, JI4135, Jinanrida, JNJ10329670, JNJ18003414, JNJ26528398, JNJ27390467, JNJ28838017, JNJ31001958, JNJ38518168, JNJ39758979, JNJ40346527, JNJ7777120, JNT-Plus, Joflam, Joint Glucosamine, Jointech, JointStem, Join Up, JPE1375, JSM10292, JSM7717, JSM8757, JTE051, JTE052, J TE522, JTE607, Jasgo, K412, K832, Kafram, KAHR101, KAHR102, KAI9803, Karimine, Campresol, Cameton, KANAb071, Kappaproct, KAR2581, KAR3000, KAR3166, KAR4000, KAR4139, KAR4141, KB002, KB003, KD7332, KE298, Keliximab, Chemanat, Chemlox, Kenacort, Kenalog, Kenaxyl, Kenketubenoglobulin-IH, Keplat, Ketalgipan, Ketopine, Keto, Ketobos,Ketofan, Ketophen, Ketulgan, Ketonal, Ketoplus Cataplasma, Ketoprofen, Ketores, Ketolin, Ketorolac, Ketorolac Tromethamine, Ketoselect, Ketotop, Ketovale, Ketolysin, Ketoroc, Ketam, Kay, Kaben, KF24345, K-Fenac, K-Fenac, K-Gesic, Kifadene, Kilcoat, Kildolol, KIM127, Kimotab, Kinasein Inhibitor 4SC, Kinase N, Kincort, Kindlase, Kineret, Kineto, Kitadol, Kitex, Kitrac, KLK1 inhibitor, Clophen-L, Crotaren, KLS-40or, KLS-40ra, KM277, Navon, Kodroolabase, Succinine, Koide, Koidexa, Corbet, Konac, Chondro, Chondromin, Conciene, Contab, Cordexa, Kosa, Kotase, KP, E06001, KRP107, KRP203, KRX211, KRX252, KSB302, K-Sep, Kv1.3 blocker, Kv1.3 4SC, Kv1.3 inhibitor, KVK702, Kynol, L156602, Rabizon, Labohydro, Labopen, Lacoxa, Lamin, Lamit, Ranfetil, Laquinimod, Larazotide acetate, LAS186323, LAS187247, LAS41002, Laticort, LBEC0101, LCP3301, LCP-Sciro, LCP-Tacro, LCsA, LDP392, Leap-S, Redelcort, Redelphen, Redelon, Redelon Luspan, Refenin, Leflunomide, Reflux, Refno, Refura, Reftose, Refmid, Refnodine, Lefuva, Lenalidomide, Lenercept, LentiRA, LEO15520, Leudase, Leukine, Leukocyte function-associated antigen-1 antagonist, Leukocyte immunoglobulin-like receptor subfamily A member 4 antibody, Leucothera, Leuprolide acetate, Levalbuterol, Levomenthol, LFA-1 antagonist, LFA4 51, LFA703, LFA878, LG106, LG267 inhibitor, LG688 inhibitor, LGD5552, Relife, Lidamantol, Lidex, Lidocaine, Lidocaine hydrochloride, Lignocaine hydrochloride, LIM0723, LIM5310, Limethasone, Limus, Limustine, Lindac, Lymphonex, Linolacut, Lipsy, Lisofylline, Ristran, Liver X receptor modulator, Rizak, LJP1207, LJP 920, Lobafen, Rob, Lokafluo, Lokalin, Locaceptil-Neo, Lokpren, Rosin, Lodotra, Rofegic, Roflam, Lofnac, Lorcam, Lonac, Lonazolac calcium, Roprofen, Loracort, Lorcam, Lorphenamine, Lorinden Lothio, Lonclat, Lornoxicam, Lorox, Rosmapimod, Loteprednol etabonate, Loteprednol, Lotilac, Small molecule Ganoderma Lucidum polysaccharide, Loxaphen, Roxiphenine, Roxicam, Loxofen, Loxonal, Loxonin, Loxoprofen sodium, Loxolone, LP183A1, LP183A2, LP204A1, LPCN1019, LT1942, LT1964, LTNS101, LTNS103, LTNS106, LTNS108,LTS1115, LTZMP001, Lebeau, Lumiracoxib, Lumitect, LX2311, LX2931, LX2932, LY2127399, LY2189102, LY2439821, LY294002, LY3009104, LY309887, LY333013, Lymphocyte activation gene 3 antibody, Lymphoglobulin, Lyser, Lysine aspirin, Lysobact, Lysoflam, Lysozyme hydrochloride, M3000, M834, M923, mAb hG-CSF, MABP1, Macrophage migration inhibitory factor antibody, Maitongna, Majamilprongatum, Major histocompatibility complex class II DR antibody, major histocompatibility complex class II antibody, Maridens, Marival, mannan-binding lectin, mannan-binding lectin-associated serine protease-2 antibody, MapKap kinase 2 inhibitor, maraviroc, Marlex, masitinib, Maso, MASP2 antibody, MAT304, matrix metalloproteinase inhibitor, mavrilimumab, maxiflam, maxilase, maximus, maxisona, maxius, maxipro, maxirel, maxislid, maxi12, maxi30, maxi4, maxi735, maxi740, Mayfenamic, MB11040, MBPY003b, MCAF5352A, Maccam, Macrophy, MCS18, MD707, MDAM, MDcort, MDR06155, MDT012, Mevicam, Mebutone, meclofenamate sodium, meclofen, Mecoq Medacom, Medaphen, Medamol, Medeson, MEDI2070, MEDI5117, MEDI541, MEDI552, MEDI571, Medicox, Medifen, Medisol, Medixon, Mednisol, Medrol, Medrolone, Medroxyprogesterone acetate, Mefalzine, Mefenamic acid, Mephenix, Mefentan, Meflen, Mefnetraforte, Meftagesic-DT, Mephthal, Megakaryocyte growth differentiation factor, Megapath, Megastar, Megestrol acetate, Mayte, Mexun, Melbrex, Melcam, Melcam, Melflam, Meric, Merica, Merix, Meric, Merocam, Melocox, Mel-one, Meroprol, Merosteral, Melox, Meloxane, Meloxicam, Meloxic, Meloxicam, Meloxifene, Meloxine, Meloxib, Melpred, Melpros,Merulidine, Menamine, Menison, Mensomketo, Menthoneurin, Menthocin, Mepa, Mephalen, Meprednisone, Mepresso, Mepsolone, Mercaptopurine, Melban, Methadrone, Mesalamine, Methasal, Mesatec, Mesenchymal progenitor cells, Mesenchymal stem cells, Meshipol, Methurene, Methlan, Methulide, Metacin, Metadaxane, Metaflex, Metalcaptase, Metalloenzyme inhibitor, Metapred, Metax, Metaz, Meted, Metedic, Metacin, Methaderm, Metasone, Mesotrax, Methotrexate, Methotrexate sodium, Mespread, Vinegar Methylprednisolone acetate, methyl salicylate, methylsulfonylmethane, methylone, methylpred, methylprednisolone, methylprednisolone acetate, methylprednisolone sodium succinate, methylprednisolone succinate, methylprednisolone, methisol, methindol, methoate, metject, metolate, metoral, metocin, metotab, metolacin, metrex, metronidazole, methypred, mevamox, mevedal, mevirox, mevin SR, mexilal, mexipharm, mext, mextran, MF280, M-FasL, MHC class II β-chain peptide, micar, microfen, microfenac, microfenolatomofetil, mycoson, microdase, microRNA 181a-2 oligonucleotide, MIF inhibitor, MIFQb, MIKA-ketoprofen, Micametane, Milogistim, Mirtax, Minafen, Minalfen, Minalfen, Minestrin, Minocort, Mioflex, Myorox, Miprofen, Miridacin, Milrox, Misoclon, Misofenac, MISTB03, MISTB04, Michiro, Mizoribine, MK0359, MK0812, MK0873, MK2 inhibitor, MK 50, MK8457, MK8808, MKC204, MLN0002, MLN0415, MLN1202, MLN273, MLN3126, MLN3701, MLN3897, MLNM002, MM093, MM7XX, MN8001, Mobic, Mobicam, Mobicox, Mobifen Plus, Mobilat, Mobitil, Mocox, Modigraf, Modrasone, Modulin, Mofecept, Mofetil, Mofezolac Sodium, Mofillet, Molace,Molgramostim, Morsulide, Momekine, Momengele, Momento 100, Momeson, Momesun, Mometamed, Mometasone, Mometasone Floate, Monimate, α-luminol monosodium, Mopic, MOR103, MOR104, MOR105, MOR208 antibody, MORAb022, Moricam, Morniflumate, Mosolit, Motral, Mobaxin, Movar, Mobex, Mobix, Moboxicam, Moxforte, Moxene, Moxifloxacin hydrochloride, Mozovir, MP, MP0210, MP0 270, MP1000, MP1031, MP196, MP435, MPA, mPGES-1 inhibitor, MPSS, MRX7EAT, MSL, MT203, MT204, mTOR inhibitor, MTRX1011A, Mucolase, Multicoat, Multistem, Muramidase, Muramidase, Muramidase hydrochloride, Muromonab-CD3, Muslax, Muspinil, Mutase, Mbera, MX68, Mycept, Mycocel, Mycocept, Mycophenolate mofetil Actavis (Mycofenolatmofetil Actavis), Mycofet, Mycofit, Mycolate, Mycoldosa, Mycomun, Myconol, Mycophenolate mofetil, Mycophenolate sodium, Mycophenolic acid, Mycotil, Myeloid progenitor cells, Mifenax, Mifetil, Mifortic, Migraft, Myoclidin, Myocrisin, Miprodol, Myson, nab-Cyclosporin, Nabentac, Nabiximols, Nabuton, Nabco, Nabcox, Nabflam, Nabmet, Nabumetone, Nabuton, Nacplus, Nakta, Nakton, Nadium, Naclofen SR, NAL1207, NAL1216, NAL1 219, NAL1268, NAL8202, Nalhon, Nalgesin S, Namilumab, Namsafe, Nandrolone, Nanocoat, Nanogum, Nanosomal tacrolimus, Napageln, Napirac, Naprelan, Napro, Naprodil, Napronax, Napropal, Naproson, Naprosyn, Naproval, Naprox, Naproxen, Naproxen sodium, Naproxin, Naprozen, Narvon, Nalexin, Nalil, Nasida, Natalizumab, Naxidom, Naxene, Naxin, Nazobel, NC2300, ND07, NDC01352, Nebumetone, NecLipGCSF, Nexlid,Nexnim, Nersid-S, Neoclobenate, Neoswifox FC, NeoCofran, Neo-Drol, Neo-Everymon, Neo-Hydro, Neoplanta, Neoporin, Neopreol, Neoprox, Neoral, Neotrexate, Neozen, Nepra, Nestacort, Neumega, Neupogen, Neuplex, Neurofenac, Neurogesic, Neurolab, Neuroteradol, Neuroxic, Neutalin, Neutrazem, Neutezyme, Neuparazox, Neufenstop, Neugam, Neumaf EN, Pneumatal, Pneucicam, NEX1285, sFcRIIB, Nextomab, NF-κB inhibitor, NF-kB inhibitor, NGD20001, NHP554B, NHP554P, NI0101 antibody, NI0401, NI0501 antibody, NI0701, NI071, NI1201 antibody, NI1401, Niship, Niconas, Nickal, Nicocode, Nicox, Niflumat, Nigaz, Nicum, Nilits, Nimas, Nimaid, Nimark-P, Nimas, Nimset Juicy, Nime, Nimed, Nimepast, Nimesulide, Nimesulide S, Nimeslon, Nimica Plus, Nimcul, Nimlin, Nimnat, Nimodol, Nimpidase, Nimside-S, Nimsah, Nimsee-SP, Nimpep, Nimsol, Nimtal, Nimwin, Nimbon-S, Nincote, Niofen, Nipan, Nipent, Nize, Nisolon, Nisopred, Nisoplex, Nisulid, Nitazoxanide, Nitocon, Nitric Oxide, Nisvisal B, Nizone, NL, NMR1947, NN8209, NN8210, NN8226, NN8555, NN8765, NN8828, NNC014100000100, NN C051869, Noac, Nodevex, Nodia, Nofenac, Nophragma, Noflam, Noflamen, Noflax, Non-Antibacterial Tetracycline, Nonpyrone, Nopain, Normferon, Notopel, Notritis, Novacort, Novagent, Novalin, Novigesic, NOXA12, NOXD19, Noxene, Noxon, NPI1302a-3, NPI1342, NPI1387, NPI1390, NPRCS1, NPRCS2, NPRCS3, NPRCS4, NPRCS5, NPRCS6, NPS3, NPS4, nPT-ery, NU3450,Nuclear factor NF-κ-B p65 subunit oligonucleotide, Nucort, Nulogics, Numed Plus, Nuroquind Ortho, Nuson-H, Nutrichemia, Nuvion, NV07α, NX001, Nicrobert, Niox, Nysa, Obacort, OC002417, OC2286, Ocaratuzumab, OCTSG81, 5, Oedemase, Oedemase-D, Ofatumumab, Ofgil-O, Ofvista, OHR118, OKi, Okifen, Oxamen, Orai, Olokizumab, Omeprose E, Omnacortil, Omniid, Omniclaw, Omnigel, Omniwell, Onercept, ONO4057, ONS1210, ONS1220, Ontac Plus, Ontac, ONX0914, OPC6535, Opebacan, OPN101, OPN201, OPN302, OPN305, OPN401, Oprelvekin, OPT66, Optifer, Optiflu, Optimira, Orabase Hca, Oradexon, Oraflex, Oralfenac, Orallog, OralPred, Ora-Sed, Orason, orBec, Orbon Forte, Okl, ORE10002, ORE10002, Orencia, Org214007, Org217993, Org219517, Org223119, Org37663, Org39141, Or487 62, Org48775, Orgadron, Ormoxene, Orofen Plus, Oromylazebiogalan, Orsal Forte, Orthoflex, Orthoclon OKT3, Ortofen, Orthoflam, Orthogesic, Orthoglu, Ortho-II, Orthomak, Ortho-Plus, Ortinimus, Ortofen, Orgis, Orbile, OS2, Oscato, Osmeton, Ospein, Ossilife, Osterox, Ostelac, Osteocerin, Osteopontin , osteral, otelixizumab, otipax, owning, obasave, OX40 ligand antibody, oxa, oxagesic CB, oxargin DP, oxaprozin, OXCQ, oxeno, oxybu MD, oxybut, oxicam, oxychlorin, oxymal, oxynal, oxyphenbutazone, oxyphenbutazone, ozoralizumab, P13 peptide, P1639, P21, P2X7 antagonist, p38α inhibitor, p38 antagonist, p38 MAP Kinase Inhibitors, p38α MAP Kinase Inhibitors, P7 Peptides, P7170, P979, PA401, PA517, Pabi-Dexamethasone, PAC, PAC10649, Paclitaxel, Peinoxam, Pardon, Parima, Pamapimod, Pamatase, Panafucort, Panafucorterone, Panewin, Pangraph,Panimum Bioral, Panmeson, Panodin SR, Pansray, Panzem, Panzem NCD, PAP1, Papain, Papyrdin, Pappen K Pap, Paptinim-D, Pankinimod, PAR2 antagonist, Paracetanol, Paradic, Paraphen TAJ, Paramidin, Paranac, Parapar, Parsi, Parecoxib, Palixam, Parly-S, Partaject Busulfan, Pateclizumab, Paxceed, PBI0032, PBI1101, PBI1308, PBI1393, PBI1 607, PBI1737, PBI2856, PBI4419, PBI4419, P-Cam, PCI31523, PCI32765, PCI34051, PCI45261, PCI45292, PCI45308, PD360324, PD360324, PDA001, PDE4 inhibitors, PDE-IV inhibitors, PDL241 antibodies, PDL252, Pediapred, Pefly, Pegacalistim, Peganix, Peg-interleukin 12, Pegsnercept, Pegylated Arginine deiminase, Perdecin, Perbiprofen, Penacle, Penicillamine, Penostop, Pentalguin, Pentasa, Pentaud, Pentostatin, Peon, Peptase, Pepsa, Peptilase, Pepzen, Pepsol, Percutalgin, Periochip, Peroxisome proliferator-activated receptor gamma regulator, Peptizen, PF00344600, PF04171327, PF04236921, PF04308515, PF05230905, PF05280586, PF251802 , PF3475952, PF3491390, PF3644022, PF4629991, PF4856880, PF5212367, PF5230896, PF547659, PF755616, PF9184, PG27, PG562, PG760564, PG8395, PGE3935199, PGE527667, PH5, PH797804, PHA408, Pharmaniagamenamic acid, Pharmaniagameroxicam, Feruzin, Fenocept, Phenylbutazone, PHY702, PI3K delta inhibitors, PI3K gamma / delta inhibitors, PI3K inhibitors, picalum, pidotimod, piketoprofen, pyrulif, piropyr, pyrovate, pimecrolimus, pipetanen, piractam, pirexil,Pirobet, Pirok, Pirocam, Pirofel, Pirogel, Piromed, Pirosol, Pirox, Piroxen, Piroxicam, Piroxicam betadex, Piroxifer, Piroxyl, Piroxime, Pixim, Pixicaine, PKC θ inhibitor, PL3100, PL5100 diclofenac, placental polypeptide, plaquinil, plerixafor, procuphene, PLR14, PLR18, Pulchin, PLX3397, PLX5622, PLX647, PLX-BMT, pms-diclofenac, pms-ibuprofen, pms-leflunomide, pms-meloxicam, pms-piroxicam, pms-prednisolone, pms-sulfasalazine, pms-thiaprofenic, PMX53, PN0615, PN10 0, PN951, Podofilox, POL6326, Polcortolone, Polyderm, Polygam S / D, Polyflogin, Poncif, Ponstan, Ponstil Forte, Porin-A Neoral, Potava, Potassium Aminobenzoate, Potencort, Povidone, Povidone-iodine, Pralnacasan, Plangin, Prevel, Precodyl, Precortisil Forte, Precortil, Predoform, Predicort, Prezicorten, Prezilab, Presilon, Predomethyl, Predomix, Predna, Pre Donesol, Predni, Prednicarb, Prednicort, Prednidib, Prednipharma, Prednilaska, Prednisolone, Deltacoltril (Prednisolone), Prednisolone acetate, Prednisolone sodium phosphate, Prednisolone sodium succinate, Prednisolone sodium succinate, Prednisone, Prednisone acetate, Prednitop, Prednol-L, Prednox, Predon, Prednema, Predosol, Predsolone, Predsone, Predval, Pred Flam, Prelon, Prenaxol, Prenolon, Preserbex, Preservin, Presol, Preson, Prexige, Priliximab, Primacort, Primno, Primofenac, Prinaberel, Pribigen, Prixam, Probuxil, Procarne, Proximal, Procidar-EF, Proctosil, Prodase, Prodel B, Prodent, Prodent Verde, Proepa, Profecom, Profenac L, Profenide, Profenol, Proflam, Proflex, Progesic Z,Proglumetacin, Proglumetacin Maleate, Prograf, Prolase, Prolixan, Promethazine Hydrochloride, Promostem, Promun, Prona B, Pronase, Pronat, Prongs, Pronisone, Prontoflam, Propaderm-L, Propodezas, Propolisol, Proponol, Propyl Nicotinate, Prostaloc, Prostapol, Protasin, Protase, Protease Inhibitor, Protectan, Proteinase Activated Receptor 2 Inhibitor, Protofen, Protrin, Proxarioc, Proxidol, Proxigel, Proki Sil, Proxim, Prozyme, PRT062070, PRT2607, PRTX100, PRTX200, PRX106, PRX167700, Prysolone, PS031291, PS375179, PS386113, PS540446, PS608504, PS826957, PS873266, Solido, PT, PT17, PTL101, P-transporter peptide, PTX3, Pulminic, Pulsonide, Prazen, Pulsin, PVS40200, PX101, PX106491, PX114, PXS2000, PXS2076, PYM6000 1, Pirarbex, Piranim, Pyrazinobutazone, Pyrenol, Piricam, Pyrodex, Piroxy-Kid, QAX576, Qianbobyan, QPI1002, QR440, qT3, Chiacort, Kidophil, R107s, R125224, R1295, R132811, R1487, R1503, R1524, R1628, R333, R348, R548, R7277, R788, Rabeximod, Radix Isatiz, Radofen, Lipec, Rambazole, Randazima, Lapacan, Lapamun, Laputiva, Lavax, Rayos, RD EA119, RDEA436, RDP58, Reactin, Rebif, REC200, Recaltix-DN, Receptor for advanced glycation end products antibody, Recrust, Reclofen, recombinant HSA-TIMP-2, recombinant human alkaline phosphatase, recombinant interferon gamma, recombinant human alkaline phosphatase, Reconil, Lectagel HC, Lecticin, Lectomenaderm, Lectos, Redipred, Redlet, Refastin, Regenica, REGN88, Relafen, Relaxiv, Relev, Relex, Relifen, Relifex, Relifex, Relich, Rematov,Remestemcel-l, Remethrism, Remicade® (infliximab), Remsima, Remsima, ReN1869, Lenacept, Renfol, Lenodapt, Lenodapt-S, Lenta, Leosan, Repare-AR, Reparilexin, Reparixin, Repatarxin, Lepisprin, Resoquin, Resol, Resolvin E1, Resulgil, Re-Tin-Colloid, Letoz, Leumacap, Leumacon, Leumadrol, Leumadol, Leumasal, Leumazine, Leumel, Leumotek, Leukinol, Levamilast, Revascol, Reviroc , Revlimid, Revmoxicam, Rewalk, Lexargan, RG2077, RG3421, RG4934 antibody, RG7416, RG7624, Lyra, Reoma, Reprox, Leudenolone, Leufen, Leugesic, Leumacid, Leumacort, Rheumatrex, Leumecer, Leumid, Leumon, Leimox, Leuxib, Leurin, Leucin, Ludex, Lyuref, Rivox, Ribunal, Ridaura, Rifaximin, Rilonacept, Rimakarib, Rimase, Rimate, Rimatil, Rimesid, Risedronate Nat Ritamine, Rit, Rituxan, Rituximab, RNS60, RO1138452, Ro313948, RO3244794, RO5310074, Rob803, Locamix, Locas, Rofeb, Rofecoxib, Rofi, Rofewal, Rofiship Plus, Rojepen, Locam, Rologikym, Romacoxfort, Romatim, Romazarit, Lonaven, Lonacarelet, Lonoxicin, RORγT antagonist, RORγt inverse agonist, Rothesin, Rosiglitazone, Rosmarinic acid, Rotan, Rotec, Rosasin, Roxam, Ro Xib, Roxicam, Loxopro, Roxyzine DT, RP54745, RPI78, RPI78M, RPI78MN, RPIMN, RQ00000007, RQ00000008, RTA402, R-Tiflum, Rubicalm, Rubifen, Lumapap, Lumalef, Lumidol, Lumifen, Lunomex, Rusalatide acetate, Ruxolitinib, RWJ445380, RX10001, Lycloser MR, Lydol, S1P receptor agonist, S1P receptor modulator, S1P1 agonist, S1P1 receptor agonist, S2474, S3013, SA237,SA6541, Saaz, S-Adenosyl-L-methionine-sulfate-p-toluenesulfonate, Sara, Salazidin, Salazin, Salazopyrin, Sarcon, Saricam, Salsalate, Sameron, SAN300, Sanaben, Sandimmun, Sandoglobulin, Sanexon, Sangusiya, SAR, 153191, SAR302503, SAR479746, Sarapep, Sargramostim, Sativex, Savantac, Sabu, Saxizone, Sazo, SB1578, SB210396, SB217969, SB242235, SB273005, SB281832, SB683698, SB751689, SBI087, SC080036, SC12267, SC409, Scafram, SCD ketoprofen, SCIO323, SCIO469, SD-15, SD281, SDP051 antibody, Sd-rxRNA, Secukinumab, Sedase, Sedilac Cefden, Seizyme, SEL113, Serazin, Celecox, Selectin P ligand antibody, glucocorticoid receptor agonist, Selectphen, Selectin, SelK1 antibody, Celox, Cellspot, Selzen, Selzenta, Selzentry, Semapimod, Semapimod hydrochloride, Semparatide, Semparatide, Senafen, Senzipen, Centelllic, SEP119249, Sepdase, Septilose, Seractyl, Serafen-P, Serase, Seratide D, Serratiopeptidase, Serat-M, Seratomaforte, Serazyme, Serezon , Sero, Serodase, Serpicum, Serra, Serrapeptase, Serratin, Serratthiopeptidase, Serrazyme, Serbizone, Seven EP, SGI1252, SGN30, SGN70, SGX203, Shark Cartilage Extract, Cheryl, Shield, Sifazen, Sifazen-Fault, Syncoat, Syncoat, Shiozol, ShK186, Shwanhwan Showyen, SI615, SI636, Sigmasporin, Sigmasporin, SIM916, Simpon, Simrect, Sinacort, Sinalgia, Sinapol, Sinatrole, Sinthia, Siponimod, Siro Rim, Sirolimus, Siropan, Shirota, Shiroba, Sirukumab, Cystalforte, SKF105685, SKF105809, SKF106615, SKF86002, Skinner, Skinim, Skytrip, SLAM family member 7 antibody, Slo-Indo, SM101, SM201 antibody, SM401, SMAD family member 7 oligonucleotide, SMART anti-IL-12 antibody, SMP114, SNO030908, SNO070131, Sodium gold thiomalate, Sodium chondroitin sulfate, Sodium deoxyribonucleotide,Gualenate sodium, naproxen sodium, sodium salicylate, sodixene, sofeo, soleton, soluhydrol, solicam, soliqui, soliris, Sol-melcort, Solomet, Sorondo, Solon, Sol-cort, Sol-cortef, Sol-decortin H, Solfen, Sol-ket, Solmark, Sol-medrol, Solpred, Somalgen, somatropin, Sonap, Son, sonepcizumab, Sonexa, Sonim, Sonim P, Sunil, Solal, Solenil, sotrastaurin acetate, SP-10, SP600125, Spanidin, SP-cortil, SPD550 ,Spedace,Sperm adhesion molecule 1,Spictol,Spleen tyrosine kinase oligonucleotide,Sporin,S-purine,SPWF1501,SQ641,SQ922,SR318B,SR9025,SRT2104,SSR150106,SSR180575,SSS07 antibody,ST1959,STA5326,Stabilin 1 antibody,Stacoat,Starogesic,Stanozolol,Starlen,Starmelox,StedexIND-SWIFT,Stelara,Stemin,Stenilol,Stelapread,SteridemS,Sterio,Sterizon,Sterone,stichodactyla helianthus peptide, stizenol A, stifocort, stimulan, STNM01, store-operated calcium channel (SOCC) modulator, STP432, STP900, stratasyn, stridum, strigul, SU medrol, subreum, subuton, succicort, succimed, sulane, sulcolone, sulfasalazine hale, sulfasalazine, sulfosalazine, sulfobid, suidac, sulide, sulindac, sulindex, sulinton, sulfafine, smil, SUN597 , Suprafen, Splectic, Spucidin, Surgam, Surgamin, Surgam, Suspen, Stone, Suvenil, Sway, SW Dexason, Syk family kinase inhibitor, Syn1002, Synaclan, Synaxene, Synarar C, Synarar, Synabib, Sinercort, Cypresta, T cell cytokine-induced surface molecule antibody, T cell receptor antibody, T5224, T5226, TA101, TA112, TA383, TA5493, Tatalumab, Tasedin, Tacograph, TACIFc5, Taclobell, Taclofen,Tacrolimus, tadecinig alpha, tadrak, TAFA93, tafilolaltro, tyzen, TAK603, TAK715, TAK783, takfa, takusta, talarozole, talfin, talmaine, talmapimod, talmea, talnif, talniflumate, talos, talpain, talmat, tamargin, tamseton, tamezon, tandrax, tannin, tanosint, tantam, tanzisertib, tapain-beta, tapoain, talenac, tarenflurbil, talimus, Talproxen, Tauxib, Tazomst, TBR652, TC5619, T cells, immunomodulatory factor 1, ATPase, H+ transport, lysosomal V0 subunit A3 antibody, TCK1, T-coat, T-dexa, Teserac, Tecon, Teduglutide, Teecoat, Tegerin, Tementil, Temoporfin, Tencam, Tendron, Tenefuse, Tenfly, Tenidap sodium, Tenocam, Tenoflex, Tenoxan, Tenochil, Tenoxicam, Tenoxime, Tepadina, Teracort, Terado ru, tetomilast, TG0054, TG1060, TG20, TG20, tgAAC94, Th1 / Th2 cytokine synthase inhibitor, Th-17 cell inhibitor, thalid, thalidomide, thalomid, semisera, thenyl, terafectin, serapiace, thiarabine, thiazolopyrimidine, thioctic acid, thiotepa, THR090717, THR0921, surinofen, thrombate III, thymic peptide, thymo-depressin, thymoglobin, thymogum, thymoglobulin Phosphorus, Thymoject thymic peptide, Thymomodulin, Thymopentin, Thymopolypeptide, Tiaprofenic acid, Tibezonium iodide, Ticoflex, Tilmacoxib, Chirua, T-Immun, Timocon, Thiolase, Chisop, TKB662, TL011, TLR4 antagonist, TLR8 inhibitor, TM120, TM400, TMX302, TNFα inhibitor, TNFα-TNF receptor antagonist, TNF antibody, TNF receptor superfamily antagonist, TNF TWEAK bispecific, TNF-kinoid, TNFQb, TNFR1 antagonist, TNR001, TNX100, TNX224, TNX336, TNX558, Tocilizumab, Tofacitinib, Tokuhonhap, TOL101,TOL102, Tolectin, Trelimab, Trelostem, Trinidol, Toll-like receptor 4 antibody, Toll-like receptor antibody, Tolmetin sodium, Tonguekeeper, Tonmex, Topflame, Topicort, Toproicon, Topnac, Topinichthammol, Toralizumab, Tralen, Tolkixia, Trox, Tory, Tocerac, Totaril, Touch-Med, Touchron, Tobok, Toxic Apis, Toyolizom, TP4179, TPCA1, TPI526, TR14 035, Trazylfort, Traphicet-EN, Tramase, Tramadol hydrochloride, Tranilast, Transimun, Transporina, Trazul, Trexal, Triaquat, Triaquat, Trialon, Triam, Triamcinolone, Triamcinolone acetate, Triamcinolone acetonide, Triamcinolone acetonide acetate, Triamcinolone hexacetonide, Triamcort, Triamcicort, Trianex, Tricin, Triquat, Tricortone, TricOs T, Triderm, Trilac, Trilisate, Trincourt, Trinolon, Triolex, Triptolide, Trisphen, Trivalis, TRK170, TRK530, Trocard, Trollamine Salicylate, Trolobol, Trosera, Trosera D, Troeucourt, TRX1 antibody, TRX4, Trimoto, Trimoto-A, TT301, TT302, TT32, TT32, TT33, TTI314, tumor necrosis factor, tumor necrosis factor 2-methoxyethyl phosphorothioate oligonucleotide, tumor necrosis factor antibody, tumor necrosis factor kinoid, tumor necrosis factor oligonucleotide, tumor necrosis factor receptor superfamily member 1B antibody, tumor necrosis factor Receptor superfamily 1B oligonucleotide, tumor necrosis factor superfamily member 12 antibody, tumor necrosis factor superfamily member 4 antibody, tumor protein p53 oligonucleotide, tumor necrosis factor alpha antibody, TuNEX, TXA127, TX-RAD, TYK2 inhibitor, Tysabri, ubidecarenone, Uselase, Urodesine, Ultiflam, Ultrafastin, Ultrafen, Ultralan, U-Nice-B, Uniplus, Unitrexate, Unizen, Ufaxicam, UR13870, UR5269, UR67767, Uremol-HC, Urigone, U-Ritis, Ustekinumab, V85546,Valsib, Valcox, Valdecoxib, Valdez, Valdix, Valdi, Valentac, Baloxib, Valtune, Vals AT, Vals, Valzel, Vamido, Vantal, Vantelin, VAP-1 SSAO inhibitor, Bapaliximab, Valespladib methyl, Varicosin, Validase, Vascular adhesion protein-1 antibody, VB110, VB120, VB201, VBY285, Vectra-P, Vedolizumab, Befuren, VEGFR-1 antibody, Verdona, Veltuzumab, Bendexin, Benimam N, Benoforte, Venoglobulin-IH, Venozel, Veral, Velux, Versimon, Vero-dexamethasone, Vero-cladribine, Betazone, VGX1027, VGX750, Vivex MTX, Vivex Dofludimus, Bifenac, Vimovo, Bimuratisa, Vincort, Vingraf, Bioform-HC, Bioxyl, Vioxx, Virobron, Visilizumab, Vivaglobin, Vivaldeplus, Vivian-A, VLST002, VLST003, VLST004, VLST005, VLST007, Boala, Voclosporin, Vocam, Vocumo, Volmax, Borna-K, Voltador, Voltagesic, Voltanase, Voltanec, Voltaren, Voltariel, Voltic, Boren, Borsetuzumab, Vol Tan-SR, VR909, VRA002, VRP1008, VRS826, VRS826, VT111, VT214, VT224, VT310, VT346, VT362, VTX763, Vurdon, VX30 antibody, VX467, VX5, VX509, VX702, VX740, VX745, VX850, W54011, Wallacote, Wallix, WC3027, Wilgraf, Winfram, Winmol, Winpred, Winsolve, Wintogeno, WIP901, Wonkok s, WSB711 antibody, WSB712 antibody, WSB735, WSB961, X071NAB, X083NAB, Xanthomycin Forte, Xedenol, Xefo, Xefocam, Xenal, Xepol, X-Flam, Xybra, Xycam, Xicotil, Xifaxan, XL499, XmAb5483, XmAb5485, XmAb5574, XmAb5871, XOMA052, Xpress, XPro1595, XtendTNF, XToll, Xtra, Xylex-H, Xynophen SR,Yansh-IVIG, YHB14112, YM974, Ioferin, Iofenac, Yuma, Yumerol, Yuroben, YY Piroxicam, Z104657A, Zashi, Zaltokin, Zaltoprofen, Zap70 inhibitor, Z-pain, Xeroxime Fort, Zema-Pak, Zem-Pak, , Zempred, Zenapax, Zenas, Zenol, Zenos, Zenoxon, Zelax, Xelcam, Xerospasm, ZFNs, zinc oxide, Zypsor, Dillalimumab, Ditis, Zix-S, Zocort, Zodixiam, Zoftadex, Zoledronic acid, Zorfin, Zolterol, Zopirin, Zolarone, Zolprin, Zoltres, ZP1848, Zucapsaicin, Znovate, Zwitterionic polysaccharide, ZY1400, Zibodis, Zycel, Zylophen, Zyrogen inhibitor, Zycel, Zytrim, and Ziwin-Forte. Additionally, the anti-inflammatory agents listed above can be combined with one or more agents listed above or herein or other agents known in the art.

[0191] In one embodiment, an anti-inflammatory drug is non-surgically administered to the suprachoroidal space of the eye using the microneedle devices and methods disclosed herein to treat, prevent, and / or improve a posterior ocular disorder in a human patient in need of an anti-inflammatory drug. For example, the posterior ocular disorder is macular degeneration (e.g., age-related macular degeneration, dry age-related macular degeneration, exudative age-related macular degeneration, geographic atrophy associated with age-related macular degeneration, neovascular (wet) age-related macular degeneration, neovascular maculopathy and age-related macular degeneration, occult age-related macular degeneration without classical choroidal neovascularization (CNV), Stargardt's disease, subfoveal wet age-related macular degeneration, and and vitreomacular adhesion (VMA) associated with neovascular age-related macular degeneration), macular edema, diabetic macular edema, uveitis, scleritis, chorioretinal inflammation, chorioretinitis, choroiditis, retinitis, retinochoroiditis, focal chorioretinal inflammation, focal chorioretinitis, focal choroiditis, focal retinitis, focal retinochoroiditis, disseminated chorioretinal inflammation, disseminated chorioretinitis, disseminated choroiditis, disseminated Disseminated retinitis, disseminated chorioretinitis, posterior cyclitis, Harada's disease, chorioretinal scarring (e.g., posterior pole macular scarring, solar retinopathy), choroidal degeneration (e.g., atrophy, sclerosis), hereditary choroidal dystrophies (e.g., choroidermia, choroidal dystrophy, gyrate atrophy), choroidal hemorrhage and rupture, choroidal detachment, retinal detachment, retinoschisis, hypersentitive retinopathy, retinopathy, retinopathy of prematurity, epiretinal membrane, peripheral retinal degeneration, hereditary retinal dystrophies, retinitis pigmentosa, retinal hemorrhage, separation of retinal layers, central serous retinopathy, glaucoma, ocular hypertension, suspected glaucoma, primary open angle glaucoma, primary angle-closure glaucoma, floaters, Leber's hereditary optic neuropathy hereditary optic neropathy, optic disc drusen, ocular inflammatory disorder, inflammatory lesions in fungal infections, inflammatory lesions, inflammatory pain, inflammatory skin diseases or disorders, Sjogren's syndrome, and eye diseases associated with Sjogren's syndrome.

[0192] In one embodiment, the drug delivered to the suprachoroidal space using the non-surgical methods described herein is an antagonist of a platelet-derived growth factor (PDGF) family member (e.g., a drug that inhibits, reduces, or modulates the signaling and / or activity of a PDGF-receptor (PDGFR). For example, the PDGF antagonist delivered to the suprachoroidal space for the treatment of one or more posterior ocular disorders or choroidal diseases is, in one embodiment, an anti-PDGF aptamer, an anti-PDGF antibody or fragment thereof, an anti-PDGFR antibody or fragment thereof, or a small molecule antagonist. In one embodiment, the PDGF antagonist is an antagonist of PDGFRα or PDGFRβ. In one embodiment, the PDGF antagonist is the anti-PDGF-β aptamer E10030, sunitinib, axitinib, sorafenib, imatinib, imatinib mesylate, nintedanib, pazopanib HCl, ponatinib, MK-2461, dovitinib, pazopanib, crenolanib, PP-121, telatinib, imatinib, KRN633, CP673451, TSU-68, Ki8751, amuvatinib, tivozanib, masitinib, motesanib diphosphate, dovitinib dilactate, linifanib (ABT-869). In one embodiment, the intraocular elimination half-life (t 1 / 2 ) is a study of the intraocular t 1 / 2 In another embodiment, the mean peak intraocular concentration (C max ) when administered to the SCS by the methods described herein, reduces the intraocular C of PDGF antagonists when administered intravitreally, intracamerally, topically, parenterally, or orally. max In another embodiment, the mean intraocular area under the curve (AUC 0-t ) is the intraocular AUC of a PDGF antagonist when administered intravitreally, intracamerally, topically, parenterally, or orally, when administered to the SCS by the methods described herein. 0-t Higher.

[0193] In one embodiment, the drugs delivered non-surgically to the suprachoroidal space using the devices and methods disclosed herein treat, prevent, and / or ameliorate posterior ocular disorders, macular degeneration, or diseases or disorders associated with macular degeneration. In one embodiment, the methods described herein are used to treat or ameliorate age-related macular degeneration, dry age-related macular degeneration, exudative age-related macular degeneration, geographic atrophy associated with age-related macular degeneration, neovascular (wet) age-related macular degeneration, neovascular maculopathy and age-related macular degeneration, occult without classical choroidal neovascularization (CNV) in age-related macular degeneration, Stargardt's disease, subfoveal wet age-related macular degeneration, or vitreomacular adhesion (VMA) associated with neovascular age-related macular degeneration in a human patient in need of treatment.

[0194] Examples of drugs that treat, prevent, and / or ameliorate macular degeneration that can be delivered to the suprachoroidal space via the devices and methods described herein include, but are not limited to, A0003, A36 peptide, AAV2-sFLT01, ACE041, ACU02, ACU3223, ACU4429, AdPEDF, aflibercept, AG13958, aganilsen, AGN150998, AGN745, AL39324, AL78898A, AL8 309B, ALN-VEG01, alprostadil, AM1101, amyloid beta antibody, anecortave acetate, anti-VEGFR-2 alterase, aptosin, APX003, ARC1905, ARC1905 containing lucentis, ATG3, ATP-binding cassette, subfamily A, member 4 gene, ATXS10, Avastin containing visudyne, AVT101, AVT2, vertilimumab, bevacizumab containing verteporfin, bevasiranib sodium, ranibizumab containing bevasiranib sodium, brimonidine tartrate, BVA301, canakinumab, Cand5, Cand5 with Lucentis, CERE140, ciliary neurotrophic factor, CLT009, CNTO2476, collagen monoclonal antibody, complement component 5 aptamer (pegylated), ranibizumab with complement component 5 aptamer (pegylated), complement component C3, complement factor B antibody, complement factor D antibody, lutein, vitamin C, vitamin E, and copper oxide with zinc oxide, dalantercept, D E109, bevacizumab, ranibizumab, triamcinolone, triamcinolone acetonide, triamcinolone acetonide with verteporfin, dexamethasone, dexamethasone with ranibizumab and verteporfin, dicitertide, DNA damage-inducible transcript 4 oligonucleotide, E10030, E10030 with Lucentis, EC400, eculizumab, EGP, EHT204, embryonic stem cells, human stem cells, endoglin monoclonal antibody, EphB4 RTK inhibitors, EphB4 soluble receptor, ESBA1008, ETX6991, Ebizone, Ibar, Ipromise Five, Ivy, Eylea, F200, FCFD4514S, fenretinide, fluocinolone acetonide, ranibizumab containing fluocinolone acetonide, fms-related tyrosine kinase 1 oligonucleotide,Kinase insert domain receptor 169 containing fms-related tyrosine kinase 1 oligonucleotide, fosbretabulin tromethamine, Gamnex, GEM220, GS101, GSK933776, HC31496, human n-CoDeR, HYB676, IBI-20089 containing ranibizumab (Lucentis®), iCo-008, Icon 1, I-Gold, Ilaris, Iluvien, Iluvien containing Lucentis, immunoglobulin, integrin alpha 5 beta 1 immunoglobulin fragment, integrin inhibitor, IRIS Lutein, I-Sense OcuShield, Isonep, Isopropyl Unoprostone, JPE1375, JSM6427, KH902, Lenvue, LFG316, LP590, LPO1010AM, Lucentis, Lucentis with Visudyne, Lutein Extra, Lutein with myrtillus extract, Lutein with Zeaxanthin, M200, Lucentis with M200, Macugen, MC1101, MCT355, Mecamylamine, Microplasmin, Lutetium motexafin, MP0112, NADPH oxidase inhibitor, Eterna shark cartilage extract (Arthro Bass (trademark), Neoretna (trademark), Sovascal (trademark), neurotrophin 4 gene, Nova21012, Nova21013, NT501, NT503, Nutri-Stulln, Ocriplasmin, OcuXan, Ofutanmacula, Optrin, Bevacizumab-containing ORA102 (Avastin (registered trademark)), P144, P17, Palomido 529, PAN90806, Panzem, Panzem, PARP inhibitor, Pazopanib hydrochloride, Pegaptanib sodium, PF4523655, PG11047, Piribedil, Platelet-derived growth factor beta polysaccharide Polypeptide aptamer (PEGylated), ranibizumab containing platelet-derived growth factor beta polypeptide aptamer (PEGylated), PLG101, PMX20005, PMX53, POT4, PRS055, PTK787, ranibizumab, ranibizumab containing triamcinolone acetonide, ranibizumab containing verteporfin, ranibizumab containing volociximab, RD27, Rescula, Retaane, retinal pigment epithelial cells, retinostat, RG7417, RN6G, RT101, RTU007, SB267268, serpin peptidase inhibitors, clade F membrane 1 genes,Shark Cartilage Extract, Shef1, SIR1046, SIR1076, Sirna027, Sirolimus, SMTD004, Snervit, SOD Mimetic, Soliris, Sonepcizumab, Squalamine Lactate, ST602, StarGen, T2TrpRS, TA106, Talaporfin Sodium, Tauroursodeoxycholic Acid, TG100801, TKI, TLCx99, TRC093, TRC105, Trivastalretard, TT30, Ursa, Ursodiol, Vangiolax, VAR10200, vascular endothelial growth factor antibodies, vascular endothelial growth factor B, vascular endothelial growth factor kinoids, vascular endothelial growth factor oligonucleotides, VAST compounds, vatalanib, VEGF antagonists (e.g., as described herein), verteporfin, visudyne, lucentis and visudyne with dexamethasone, visudyne with triamcinolone acetonide, vivis, volociximab, votrient, XV615, zeaxanthin, ZFP TF, zinc-monocysteine, and zybrestat. In one embodiment, one or more of the macular degeneration treatment drugs described herein are combined with one or more of the agents listed above or herein or other agents known in the art.

[0195] In one embodiment, the methods and devices provided herein are used to deliver triamcinolone or triamcinolone acetonide to the suprachoroidal space of the eye of a human subject in need of treatment for a posterior ocular disorder or choroidal disease. In a further embodiment, triamcinolone or triamcinolone acetonide is delivered for the treatment of sympathetic ophthalmia, temporal arteritis, uveitis, and / or other posterior ocular inflammatory conditions. In one embodiment, triamcinolone or triamcinolone acetonide is delivered to the suprachoroidal space of the eye of a human subject in need of treatment for sympathetic opthalmia using the methods and devices described herein. In another embodiment, triamcinolone or triamcinolone acetonide is delivered to the suprachoroidal space of the eye of a human subject in need of treatment for temporal arteritis using the methods and devices described herein. In yet another embodiment, triamcinolone or triamcinolone acetonide is delivered to the choroidal space of the eye of a human subject in need of treatment for uveitis using the methods and devices described herein. In another embodiment, triamcinolone or triamcinolone acetonide is delivered to the choroidal space of the eye of a human subject in need of treatment for one or more posterior ocular inflammatory conditions using the methods and devices described herein. In another embodiment, triamcinolone or triamcinolone acetonide is delivered via one of the methods described herein.

[0196] The triamcinolone compositions provided herein, in one embodiment, are suspensions containing microparticles or nanoparticles of triamcinolone or triamcinolone acetonide. In one embodiment, the microparticles are 50 In a further embodiment, D 50 In another embodiment, D 50 In yet another embodiment, D 50 is about 1000 nm or less. In one embodiment, the D 99 In another embodiment, D 99 In another embodiment, D99 is about 10 μm or less, or about 9 μm or less.

[0197] In one embodiment, triamcinolone is present in the composition at about 1 mg / mL to about 400 mg / mL. In a further embodiment, triamcinolone is present in the composition at about 2 mg / mL to about 300 mg / mL. In a further embodiment, triamcinolone is present in the composition at about 5 mg / mL to about 200 mg / mL. In a further embodiment, triamcinolone is present in the composition at about 10 mg / mL to about 100 mg / mL. In a further embodiment, triamcinolone is present in the composition at about 20 mg / mL to about 75 mg / mL. In a further embodiment, triamcinolone is present in the composition at about 30 mg / mL to about 50 mg / mL. In one embodiment, triamcinolone is present in the composition at about 10, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 55, about 60, or about 75 mg / mL. In one embodiment, triamcinolone is present in the composition at about 40 mg / mL.

[0198] In one embodiment, the triamcinolone composition comprises sodium chloride. In another embodiment, the triamcinolone composition comprises sodium carboxymethylcellulose.

[0199] In one embodiment, the triamcinolone composition comprises triamcinolone microparticles. In a further embodiment, the composition comprises polysorbate 80. In another embodiment, the triamcinolone composition comprises one or more of CaCl2, MgCl2, sodium acetate, and sodium citrate. In one embodiment, the composition comprises at or about 0.02%, 0.015%, or about 0.015% w / v polysorbate 80.

[0200] In one embodiment, the pH of the composition is about 5.0 to about 8.5. In a further embodiment, the pH of the composition is about 5.5 to about 8.0. In yet a further embodiment, the pH of the composition is about 6.0 to about 7.5.

[0201] In another aspect, the present invention provides a method for diagnosing a patient for choroidal disease. In one embodiment, the method includes administering a choroidal disease diagnostic agent to the SCS of one or both eyes of the patient, visualizing the diagnostic agent, and determining whether the patient has choroidal disease based on the visualization. In a further embodiment, the diagnostic agent is delivered to the SCS of one or both eyes of the patient via one of the microneedles described herein.

[0202] In one embodiment, a method of diagnosing a patient for choroidal disease is provided. The method includes administering an indocyanine green (ICG) molecule to the SCS of one or both eyes of the patient. The ICG molecule is stimulated by infrared absorption in the range of about 790 nm to about 805 nm. The ICG molecule allows visualization of choroidal vasculature. In one embodiment, a positive choroidal disease diagnosis is made when pulsatile polypoid vessels are visualized in the macula. In a further embodiment, the choroidal disease is PCV.

[0203] In one embodiment, as provided above, one or more of the drugs provided herein are delivered to the suprachoroidal space of the eye of a patient in need thereof using the microneedle devices and methods disclosed herein for the treatment of one or more posterior ocular disorders or choroidal diseases to treat, prevent, and / or ameliorate fibrosis in the posterior segment of the eye (e.g., myelofibrosis, fibrosis in diabetic nephropathy, cystic fibrosis, scarring, and dermal fibrosis).

[0204] In one embodiment, as provided above, one or more of the drugs provided herein are delivered to the suprachoroidal space of the eye of a patient in need thereof using the microneedle devices and methods disclosed herein for the treatment of choroidal malady to treat, prevent, and / or ameliorate choroidal dystrophy.

[0205] In one embodiment, a drug that treats, prevents, and / or ameliorates fibrosis is used in conjunction with the devices and methods described herein to deliver to the suprachoroidal space of the eye. In a further embodiment, the drug is pirfenidone-containing interferon gamma 1b (Actimmune®), ACUHTR028, αVβ5, potassium aminobenzoate, amyloid P, ANG1122, ANG1170, ANG3062, ANG3281, ANG3298, ANG4011, anti-CTGF RNAi, Aplidine, Astragalus membranaceus extract with salvia and Schisandra chinensis, atherosclerotic plaque blockers, Azoles, AZX100, BB3, Connective tissue growth factor antibodies, CT140, Danazol, Esbriet, EXC001, EXC002, EXC003, EXC004, EXC005, F647, FG3019, Fibrocollin, Follistatin, FT011, Galectin-3 inhibitors, GKT137831, GMCT01, GMCT02, GRMD01, GRMD02, GRN510, Heberon alpha R, Interferon alpha-2b, Interferon gamma-1b with pirfenidone, ITMN520, JKB119, JKB121, JKB122, KRX168, LPA1 receptor antagonists, MGN4220, MIA2, microRNA 29a oligonucleotide, MMI0100, noscapine, PBI4050, PBI4419, PDGFR inhibitor, PF-06473871, PGN0052, Pirespa, pirfenex, pirfenidone, plitidepsin, PRM151, Px102, PYN17, PYN22 containing PYN17, Relivergen, rhPTX2 fusion protein, RXI109, secretin, STX100, TGF-β inhibitor, transforming growth factor, beta receptor 2 oligonucleotide, VA999260, or XV615. In one embodiment, one or more of the fibrosis treatment drugs described herein are combined with one or more of the agents listed above or herein or other agents known in the art.

[0206] In one embodiment, the drug for treating, preventing and / or improving diabetic macular edema is used in conjunction with the device and method described herein to be delivered to the suprachoroidal space of the eye.In a further embodiment, the drug is AKB9778, bevasiranib sodium, Cand5, choline fenofibrate, Cortiject, c-raf 2-methoxyethyl phosphorothioate oligonucleotide, DE109, dexamethasone, DNA damage-induced transcript 4 oligonucleotide, FOV2304, iCo007, KH902, MP0112, NCX434, Optina, Ozurdex, PF4523655, SAR1118, sirolimus, SK0503, or Trilipix.In one embodiment, one or more diabetic macular edema treatment drugs described herein are combined with one or more of the drugs listed above or herein or other drugs known in the art.

[0207] In one embodiment, a drug that treats, prevents, and / or improves macular edema is used in conjunction with the devices and methods described herein to be delivered to the suprachoroidal space of the eye. In a further embodiment, the drug is delivered to the suprachoroidal space of a human subject in need of treatment for posterior ocular disorders or choroidal diseases via hollow microneedles. In one embodiment, the drug is denufosol tetrasodium, dexamethasone, ecallantide, pegaptanib sodium, ranibizumab, or triamcinolone. In addition, the above-listed drugs delivered to ocular tissues using the microneedle devices and methods disclosed herein for treating, preventing, and / or improving macular edema can be combined with one or more of the drugs listed above or herein or other drugs known in the art.

[0208] In one embodiment, drugs that treat, prevent, and / or ameliorate ocular hypertension are used in conjunction with the devices and methods described herein to be delivered to the suprachoroidal space of the eye. In further embodiments, the drug is 2-MeS-βγ-CCl2-ATP, acetadiazole, acetazolamide, Aristomol, Arteoptic, AZD4017, Betalmic, Betaxolol HCl, Betimol, Betoptic S, Brimodine, Brimonal, Brimonidine, Brimonidine Tartrate, Brinidin, Carte, Carteolol HCl, Cosopt, CS088, DE092, DE104, DE111, Dorzolamide, Dorzolamide HCl, Dorzolamide HCl with Timolol Maleate, Droptimol, Fortinol, Granol, Hypadil, Ismotic, Isopropyl Unoprostone, Isosorbide, Latarax, Latanoprost, Maley latanoprost with timolol nitrate, levobunolol hydrochloride, lotensin, mannigen, mannitol, metipranolol, mifepristone, mikeran, minimus metipranolol, mirol, nipradilol, nortenz, ocupress, olmesartan, oftalol, pilocarpine nitrate, piobagi, rescula, RU486, rismon TG, SAD448, saflutan, shemol, taflotan, tafluprost, tafluprost with timolol, thiabut, timocomodo, timolol, timolol actavis, timolol hemihydrate, timolol maleate, travast, travoprost, unilat, xalacam, xalatan, or zomilol. Additionally, the drugs listed above that are delivered to the suprachoroidal space using the microneedle devices and methods disclosed herein for treating, preventing and / or ameliorating ocular hypertension can be combined with one or more of the drugs listed above or herein or other drugs known in the art, as listed above.

[0209] The drug delivered to the suprachoroidal space via the non-surgical methods described herein is present as a drug formulation. The "drug formulation" is, in one embodiment, an aqueous solution or suspension, containing an effective amount of drug. Thus, in some embodiments, the drug formulation is a fluid drug formulation. A "drug formulation" is typically a formulation of a drug that contains one or more pharma- ceutically acceptable excipients known in the art. The term "excipient" refers to any non-active ingredient of the formulation intended to facilitate handling, stability, dispersibility, wettability, release rate, and / or injection of the drug. In one embodiment, the excipient may include or consist of water or saline.

[0210] In one embodiment, the drug formulation (e.g., a fluid drug formulation) comprises microparticles or nanoparticles, either of which comprises at least one drug. Desirably, the microparticles or nanoparticles provide controlled release of the drug in the suprachoroidal space and surrounding posterior ocular tissues. As used herein, the term "microparticles" includes microspheres, microcapsules, microparticles, and beads, the number average diameter of which is about 1 μm to about 100 μm (e.g., about 1 to about 25 μm or about 1 μm to about 7 μm). "Nanoparticles" are particles with an average diameter of about 1 nm to about 1000 nm. In one embodiment, the D of the microparticles is 50 In a further embodiment, D 50 In another embodiment, the D of the particles in the drug formulation is about 2 μm. 50 In another embodiment, the D of the particles in the drug formulation is about 2 μm or less. 50 In one embodiment, the drug formulation has a D 99 In one embodiment, the D of the microparticles is about 10 μm or less. 50 In a further embodiment, D 50 In another embodiment, the D of the particles in the drug formulation is about 2 μm. 50 In another embodiment, the D of the particles in the drug formulation is about 2 μm or less. 50 In one embodiment, the drug formulation has a D 99 In one embodiment, the D of the microparticles is about 10 μm or less.50 In a further embodiment, D 50 In another embodiment, the D of the particles in the drug formulation 50 In another embodiment, the D of the particles in the drug formulation is about 2 μm or less. 50 In one embodiment, the drug formulation is D 99 In one embodiment, the D of the microparticles is about 1000 nm to about 10 μm. 50 In another embodiment, the drug formulation has a D 99 In another embodiment, the D of the particles in the formulation is about 10 μm. 99 is less than about 10 μm, less than about 9 μm, less than about 7 μm, or less than about 3 μm. In further embodiments, the microparticles or nanoparticles comprise an anti-inflammatory drug. In further embodiments, the anti-inflammatory drug is triamcinolone.

[0211] Microparticles and nanoparticles may or may not be spherical. "Microcapsules" and "nanocapsules" are defined as microparticles and nanoparticles in which the shell surrounds a core of another material. The core may be liquid, gel, solid, gas, or a combination thereof. In one case, the microcapsule or nanocapsule may be a "microbubble" or "nanobubble" in which the shell surrounds a gas core and the drug is located on the shell surface, within the shell itself, and also in the core (microbubbles and nanobubbles may respond to accoustic vibrations known in the art for diagnostics or the microbubbles may burst to release the payload into the selected ocular tissue site / ocular tissue site). "Microspheres" and "nanospheres" may be solid spheres, may be porous, may include a sponge-like or honeycomb structure formed by pores or voids in a matrix material or shell, or may include multiple individual voids in a matrix material or shell. The microparticle or nanoparticle may further include a matrix material. The shell or matrix material may be a polymer, an amino acid, a saccharide, or other material known in the art for microencapsulation.

[0212] The drug-containing microparticles or nanoparticles can be suspended in an aqueous or non-aqueous liquid vehicle. The liquid vehicle can be a pharma-ceutically acceptable aqueous solution, which can optionally further include a surfactant. The drug microparticles or nanoparticles themselves can include excipients (polymers, polysaccharides, surfactants, etc.) known in the art to control the rate of drug release from the particles.

[0213] In one embodiment, the drug formulation further comprises an agent that is effective in degrading collagen or GAG fibers in the sclera, which can enhance the penetration / release of the drug into ocular tissue.The agent can be, for example, an enzyme, such as hyaluronidase, collagenase, or a combination thereof.In a variation of this method, the enzyme is administered to ocular tissue in a separate step from the drug injection (before or after the drug injection).The enzyme and the drug are administered to the same site.

[0214] In another embodiment, the drug formulation is a drug that undergoes a phase transition upon administration. For example, a liquid drug formulation can be injected into the suprachoroidal space through a hollow microneedle, and then the gel and drug diffuse out of the gel for controlled release.

[0215] As described above, the drug delivered to the suprachoroidal space (i.e., for the treatment of one or more posterior ocular disorders or choroidal diseases) via the methods described herein can be administered with one or more additional drugs. In one embodiment, the one or more additional drugs are present in the same formulation as the first posterior ocular disorder or choroidal disease treatment drug. In another embodiment, the one or more additional drugs are delivered intravitreally, orally, topically, or parenterally to a human subject in need of treatment of a posterior ocular disorder or choroidal disease. In one embodiment, a VEGF antagonist is delivered to the suprachoroidal space of the eye of a human subject in need of treatment of a posterior ocular disorder or choroidal disease via one of the methods disclosed herein in combination with a PDGF antagonist. The PDGF antagonist is administered, for example, intravitreally or into the suprachoroidal space. In another embodiment, a PDGF antagonist is delivered to the suprachoroidal space of the eye of a human subject in need of treatment of a posterior ocular disorder or choroidal disease via the methods described herein in combination with a VEGF antagonist. The PDGF antagonist and the VEGF antagonist can be administered in the same formulation or in separate formulations.

[0216] In addition to suprachoroidal delivery, one or more additional drugs delivered to a human subject can be delivered via intravitreal (IVT) administration (e.g., intravitreal injection, intravitreal implant, or eye drops). Methods for administering IVT are well known in the art. Examples of drugs that can be administered via IVT include, but are not limited to, A0003, A0006, Acedron, AdPEDF, Aflibercept, AG13958, Aganirsen, AGN208397, AKB9778, AL78898A, Amyloid P, Angiogenesis Inhibitor Gene Therapy, ARC1905, Aurocort, Bevasiranib Sodium, Brimonidine, Brimonidine, Brimonidine Tartrate, Bromfenac Sodium, Cand5, CERE140, Shiganclo, CLT001, CLT003, CLT004, CLT005, Complement Component 5 Aptamer (PEGylated), Complement Factor D Antibody, Cortiject, c-raf2-Methoxyethyl phosphorothioate oligonucleotide, cyclosporine, triamcinolone, DE109, denufosole tetrasodium, dexamethasone, dexamethasone phosphate, dicitertide, DNA damage-induced transcript 4 oligonucleotide, E10030, ecallantide, EG3306, Eos013, ESBA1008, ESBA105, Eylea, FCFD4514S, fluocinolone acetonide, fms-related tyrosine kinase 1 oligonucleotide, fomivirsen sodium , fosbretabulin tromethamine, FOV2301, FOV2501, ganciclovir, ganciclovir sodium, GS101, GS156, hyaluronidase, IBI20089, iCo007, Iluvien, INS37217, Isonep, JSM6427, Carbitar, KH902, lerdelimumab, LFG316, Lucentis, M200, Macugen, Macuaid, microplasmin, MK0140, MP0112, NCX434, neurotrophin 4 gene, OC10X, O Criplasmin, ORA102, Ozurdex, P144, P17, Palomid 529, Pazopanib hydrochloride, Pegaptanib sodium, Plasma kallikrein inhibitor, Platelet-derived growth factor beta polypeptide aptamer (pegylated), POT4, PRM167, PRS055, QPI1007, Ranibizumab, Resveratrol, Retilon, Retinal pigment epithelium-specific protein 65 kDa gene, Retisert, Rod-derived complex survival factor, RPE65 gene therapy, RPGR gene therapy, RTP801, Sd- rxRNA, serpin peptidase inhibitor clade F membrane 1 gene, Sirna027, sirolimus, sonepcizumab, SRT501, STP601, TG100948, Trabio, triamcinolone, triamcinolone acetonide, Trivalis, tumor necrosis factor antibody, VEGF / rGel-Op, verteporfin, visudyne, vitrase, vitrasert, vitraven, vitreals, volociximab, votrient, XG102, xibrom, XV615, and zybrestat. Thus, the method of the present invention includes administering one or more of the above-listed drugs via IVT in combination with one or more of the drugs disclosed herein that are administered into the suprachoroidal space using the microneedle device described herein. EXAMPLES

[0217] The present invention will be further illustrated by reference to the following examples, however, it should be noted that these examples, like the above embodiments, are illustrative and should not be construed as limiting the scope of the invention in any way.

[0218] Materials and Methods Unless otherwise specified, whole rabbit eyes (Pel-Freez Biologicals, Rogers, AR), porcine eyes (Sioux-Preme Packing, Sioux Center, IA), and human eyes (Georgia Eye Bank, Atlanta, GA) (all with the optic nerve attached) were shipped on ice and stored humidified at 4° C. for up to 3 days. Prior to use, eyes were brought to room temperature and any fat and conjunctiva were removed to expose the sclera.

[0219] Unless otherwise specified, hollow microneedles were fabricated from borosilicate micropipette tubing (Sutter Instrument, Novato, CA) as previously described (J. Jiang et al., Pharm. Res. 26:395-403 (2009)). Figure 7A shows the hollow microneedle compared to the tip of a 30-gauge hypodermic needle (scale = 500 μm). A custom pen-like device with a threaded cap is fabricated to position the microneedle and precisely adjust its length. The device is attached to a micropipette holder with tubing (MMP-KIT, World Precision Instruments, Sarasota, FL), which is attached to a carbon dioxide gas cylinder to apply injection pressure. The holder is attached to a micromanipulator (KITE, World Precision Instruments), which is used to control the insertion of the microneedle into the sclera.

[0220] Carboxylate-modified FluoSpheres® (Invitrogen, Carlsbad, CA) were injected as a 2 wt% solid suspension of particles with diameters of 20 nm, 100 nm, 500 nm, and 1000 nm. A final concentration of 0.5 wt% Tween 80 (Sigma-Aldrich, St. Louis, MO) was added to the suspension and sonicated before use. Sulforhodamine B (Sigma-Aldrich) was dissolved in Hank's Balanced Salt Solution (Mediatech, Manassas, VA) at 10 -4 A sulforhodamine solution of M was prepared by suspending barium sulfate particles (Fisher Scientific, Waltham, MA) with a diameter of 1 μm in balanced salt solution (BSS Plus, Alcon, Fort Worth, TX) to prepare a 1.5 wt % suspension.

[0221] A custom acrylic mold molded to fit all eyes was constructed to hold the eye stably and was used in all experiments (Figure 7B). A catheter was inserted into the vitreous via the optic nerve and connected to a bottle of BSS Plus, which was elevated to obtain an internal intraocular pressure (18 or 36 mm Hg). A channel in the mold was aspirated to hold the outer surface of the eye stable during insertion and manipulation of the microneedle. Each microneedle was pre-filled with the desired volume of material to be injected. The microneedle was placed in a device holder with a set microneedle length, attached to a micromanipulator, and connected to a constant pressure source. The microneedle was then inserted perpendicularly to the scleral tiss...

Claims

[Claim 1] A method for treating a posterior ocular disorder in a human subject in need thereof, comprising: non-surgically administering an effective amount of a drug formulation to the suprachoroidal space (SCS) of the eye of the human subject in need of treatment for the posterior ocular disorder; Upon administration, the drug formulation flows from the insertion site and is substantially localized in the posterior segment of the eye.

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