Methods and devices for treating ocular diseases in human subjects
阅读说明：本技术 用于在人类受试者中治疗眼部疾病的方法和装置 (Methods and devices for treating ocular diseases in human subjects ) 是由 V.扎尼茨英 S.帕特尔 D.怀特 G.诺罗纳 B.伯克 于 2013-11-08 设计创作，主要内容包括：本申请提供了用于将药物制剂靶向性非手术给药至人类受试者的眼睛的脉络膜周隙(SCS)的方法和装置,以用于治疗眼后部障碍或脉络膜疾病。在一个实施方案中,所述方法包括将中空的显微针在插入位点插入到眼睛中并通过插入的显微针输注药物制剂并输注到眼睛的脉络膜周隙中,其中所述输注的药物制剂在输注期间远离插入位点在脉络膜周隙中流动。在一个实施方案中,所述流体药物制剂包含药物纳米颗粒或微粒。(Methods and devices for targeted non-surgical administration of a drug formulation to the suprachoroidal space (SCS) of the eye of a human subject are provided for the treatment of a posterior ocular disorder or choroidal disease. In one embodiment, the method comprises inserting a hollow microneedle into the eye at an insertion site and infusing a drug formulation through the inserted microneedle and into the suprachoroidal space of the eye, wherein the infused drug formulation flows in the suprachoroidal space away from the insertion site during infusion. In one embodiment, the fluid pharmaceutical formulation comprises drug nanoparticles or microparticles.)
1. A method of treating a posterior ocular disorder in a human subject in need thereof, the method comprising,
non-surgically administering an effective amount of a drug formulation to the suprachoroidal space (SCS) of the eye of a human subject in need of treatment for said posterior ocular disorder,
wherein upon administration, the pharmaceutical formulation flows away from the insertion site and substantially concentrates in the posterior segment of the eye.
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 infusing the drug formulation into the SCS through the inserted microneedle.
3. The method of claim 2, wherein the insertion site is located at about the equator of the eye, or between the equator and the limbus of the eye.
4. The method of claim 2 or 3, wherein the microneedle has a length of about 500 μm to about 1500 μm.
5. The method of any one of claims 2-4, wherein the microneedle has a diameter of about 200 μm to about 600 μm.
6. The method of any one of claims 2-5, wherein the microneedle has a bevel angle of about 5 degrees to about 30 degrees.
7. The method of any one of claims 2-6, wherein the bevel height is from about 100 μm to about 500 μm.
8. The method of any one of claims 2-7, wherein the microneedle is inserted into the sclera without penetrating the sclera.
9. The method of any one of claims 2-8, wherein the microneedle is inserted into the sclera without penetrating the choroid.
10. The method of any one of claims 2-9, wherein the microneedle comprises a beveled tip.
11. The method of claim 10, wherein the beveled tip has an angle of about 10 degrees to about 20 degrees.
12. The method of claim 10 or 11, wherein the beveled tip has an aspect ratio of about 1:1.5 to about 1: 10.
13. The method of any one of claims 10-12, wherein the beveled tip has a height of about 500 μ ι η to about 1 mm.
14. The method of any one of claims 2-13, wherein the microneedle has a length of about 500 μ ι η to about 1500 μ ι η.
15. The method of claim 14, wherein the microneedle has a length of about 500 μm to about 1000 μm.
16. The method of any one of claims 2-15, wherein the microneedles comprise cylindrical rods having an outer diameter of about 200 microns to about 600 microns.
17. The method of any one of claims 1-16, wherein the effective amount of the pharmaceutical formulation is present in a volume of about 10 μ L to about 200 μ L.
18. The method of any one of claims 1-17, wherein the effective amount of the pharmaceutical formulation is present in a volume of about 30 μ L to about 100 μ L.
19. The method of any one of claims 1-18, wherein the pharmaceutical formulation comprises a suspension of microparticles.
20. The method of any one of claims 1-19, wherein the pharmaceutical formulation comprises a suspension of nanoparticles.
21. The method of claim 19, wherein said microparticles have D50Is 2 μm or less.
22. The method of claim 20, wherein the nanoparticle has D50Is 1000nm or less.
23. The method of claim 20, wherein the nanoparticle has D50Is 500nm or less.
24. The method of claim 20, wherein the nanoparticle has D50Is 250nm or less.
25. The method of claim 19 or 20, wherein the microparticles or nanoparticles have D99Is 10 μm or less.
26. The method of claim 19 or 20, wherein the microparticles or nanoparticles have D99Is 5 μm or less.
27. The method of any one of claims 2-26, wherein the microneedle is inserted into the scleral surface at an angle of about 70 degrees to about 110 degrees.
28. The method of any one of claims 2-27, wherein the angle of insertion of the microneedle into the scleral surface is about 90 degrees.
29. The method of any one of claims 1-28, wherein the pharmaceutical formulation comprises an anti-inflammatory agent.
30. The method of claim 29, wherein said anti-inflammatory agent is selected from the group consisting of mycophenolate mofetil, infliximab, nepafenac, azathioprine, cyclophosphamide, dexamethasone, difluprednate, fluocinolone, fluoromethalone, loteprednol, prednisolone acetate, prednisolone sodium phosphate, rimexolone, triamcinolone, bromfenac, diclofenac, flurbiprofen, ketoprofen, adalimumab, etanercept, certolizumab ozolomide, golimumab, daclizumab, rituximab, abatacept, basiliximab, belimumab, anakinra, efolizumab, alfasilizumab, and natalizumab.
31. The method of claim 29 or 30, wherein the anti-inflammatory agent is mycophenolate.
32. The method of claim 29 or 30, wherein the anti-inflammatory agent is infliximab.
33. The method of claim 29 or 30, wherein the anti-inflammatory agent is nepafenac.
34. The method of claim 29 or 30, wherein the anti-inflammatory agent is azathioprine.
35. The method of claim 29 or 30, wherein the anti-inflammatory agent is cyclophosphamide.
36. The method of claim 29 or 30, wherein the drug is dexamethasone.
37. The method of claim 29 or 30, wherein the anti-inflammatory agent is difluprednate.
38. The method of claim 29 or 30, wherein the anti-inflammatory agent is fluocinolone acetonide.
39. The method of claim 29 or 30, wherein the anti-inflammatory agent is loteprednol etabonate.
40. The method of claim 29 or 30, wherein the drug is triamcinolone.
41. The method of claim 40, wherein the triamcinolone is triamcinolone acetonide.
42. The method of claim 29 or 30, wherein the anti-inflammatory agent is bromfenac.
43. The method of claim 29 or 30, wherein the anti-inflammatory agent is diclofenac.
44. The method of claim 29 or 30, wherein the anti-inflammatory agent is flurbiprofen.
45. The method of claim 29 or 30, wherein the anti-inflammatory agent is ketorolac.
46. The method of claim 29 or 30, wherein the anti-inflammatory agent is adalimumab.
47. The method of claim 29 or 30, wherein the anti-inflammatory agent is etanercept.
48. The method of claim 29 or 30, wherein the anti-inflammatory agent is certolizumab ozogamicin.
49. The method of claim 29 or 30, wherein the anti-inflammatory agent is golimumab.
50. The method of claim 29 or 30, wherein the anti-inflammatory agent is daclizumab.
51. The method of claim 29 or 30, wherein the anti-inflammatory agent is rituximab.
52. The method of claim 29 or 30, wherein the anti-inflammatory agent is abatacept.
53. The method of claim 29 or 30, wherein the anti-inflammatory agent is basiliximab.
54. The method of claim 29 or 30, wherein the anti-inflammatory agent is belimumab.
55. The method of claim 29 or 30, wherein the anti-inflammatory agent is anakinra.
56. The method of claim 29 or 30, wherein the anti-inflammatory agent is efavirenzumab.
57. The method of claim 29 or 30, wherein the anti-inflammatory agent is alfapsin.
58. The method of claim 29 or 30, wherein the anti-inflammatory agent is natalizumab.
59. The method of any one of claims 1-30, wherein the pharmaceutical formulation comprises a steroid.
60. The method of any one of claims 1-29, wherein the pharmaceutical formulation comprises a non-steroidal anti-inflammatory drug (NSAID).
61. The method of any one of claims 1-28, wherein the pharmaceutical formulation comprises an angiogenesis inhibitor.
62. The method of any one of claims 1-28, wherein the pharmaceutical formulation comprises a Vascular Endothelial Growth Factor (VEGF) antagonist.
63. The method of claim 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).
64. The method of any one of claims 1-28, wherein the pharmaceutical formulation comprises a TNF- α antagonist or a TNF- α receptor antagonist.
65. The method of any one of claims 1-28, wherein the pharmaceutical preparation comprises a Platelet Derived Growth Factor (PDGF) antagonist.
66. The method of claim 65, wherein the PDGF antagonist is a PDGF receptor (PDGFR) antagonist.
67. The method of claim 66, wherein said PDGFR is PDGFR- α.
68. The method of claim 66, wherein said PDGFR is PDGFR- β.
69. The method of claim 62 or 63, wherein the VEGF antagonist is aflibercept, ziv-aflibercept, bevacizumab, ranibizumab, lapatinib, sunitinib, sorafenib, prilin, regorafenib, verteporfin, buclizine, axitinib, pazopanib, fluocinolone, nidanib, AL8326, 2C3 antibody, AT001 antibody, XtendVEGF antibody, HuMax-VEGF antibody, R3 antibody, AT001/R84 antibody, HyBEV, ANG3070, APX003 antibody, APX004 antibody, ponatinib, BDM-E, VGX antibody, VGX200, VGX300, COSMIX, DLX903/1008 antibody, ENMD2076, INDDUS 815C, R84 antibody, MGD 019, 3, MGCD 5630, NMP 265, MG 265, anti-DLL 9028/901008 antibody, ENMD 207615, INVERGIT 3546, FLD 01, FIT-PATIBA, AAV 01, FIT-PATIBA 3, FIC 3, SANT, BINAK-S35019, BIOTA-D-PATIBA, BIOTA 3, FIX-PATIBA, Voralacet, CEP11981, KH903, lanvatinib mesylate, taralarocco, PF00337210, PRS050, SP01, carboxyamidotriazole orotate, hydroxychloroquine, rilivanib, ALG1001, AGN150998, MP0112, AMG386, ponatinib, AVA101, BMS690514, KH902, golvatinib (E7050), polyvatinib lactate (TKI258, CHIR258), ORA101, ORA102, axitinib (Inlyta, AG013736), PTC299, pegaptanib sodium, troponin, EG3306, vatalanib, b100, GSK2136773, anti-VEGFR Alterase, avilam, CEP7055, CLT009, ESBA903, HMPL 654652, HMPL010, GEM220, HYB 170676, cvk 29492101, cvr 29492101, AG 5932, AG 6353, pgr 501, agva 6362, agva 501, agva 123, agva 6362, agva 51, agva 501, or borva 3852.
70. The method of claim 64, wherein the VEGF antagonist is sorafenib.
71. The method of claim 62, wherein the VEGF antagonist is axitinib.
72. The method of claim 62, wherein the VEGF antagonist is aflibercept.
73. The method of claim 62, wherein the VEGF antagonist is bevacizumab.
74. The method of claim 62, wherein the VEGF antagonist is ranibizumab.
75. The method of any one of claims 65-68, wherein the PDGF antagonist is an anti-PDGF aptamer, an anti-PDGF antibody or fragment thereof, an anti-PDGFR antibody or fragment thereof, or a small molecule antagonist.
76. The method of claim 65, wherein the PDGF antagonist is anti-PDGF- β aptamer E10030, sunitinib, axitinib, sorafenib, imatinib mesylate, nidanib, pazopanib hydrochloride, ponatinib, MK-2461, doratinib, pazopanib, crenolanib, PP-121, tiratinib, imatinib, KRN 633, CP673451, TSU-68, Ki8751, amuvatinib, tivozanib, masitinib, motertinib diphosphate, dolitinib dilitamide, rilivanib (ABT-869).
77. The method of any one of claims 1-76, wherein the intraocular pressure of the eye of the subject is substantially constant during administration of the pharmaceutical formulation.
78. The method of any one of claims 1-77, wherein the intraocular pressure of the eye of the subject does not change by more than about 10% during the administration.
79. The method of any one of claims 1-78, wherein administering the drug to the SCS of the eye provides a reduction in the number of side effects, or a reduction in the severity of one or more side effects, as compared to intravitreal, intracameral, topical, parenteral, or oral administration of the same dose of drug.
80. The method of any one of claims 1-79, wherein the dose of the drug sufficient to induce a therapeutic response when administered to the SCS is less than the dose of the drug sufficient to induce a therapeutic response when administered intravitreally, intracamerally, topically, parenterally or orally.
81. The method of claim 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.
82. The method of claim 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.
83. The method of claim 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.
84. The method of claim 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.
85. The method of any one of claims 1-84, wherein the retention of the drug in the posterior segment of the eye is greater than the retention of the drug in the posterior segment of the eye when administered intravitreally, intracamerally, topically, parenterally or orally.
86. The method of any one of claims 1-84, wherein t of the drug is1/2Greater than the t of said drug when administered intravitreally, intracamerally, topically, parenterally or orally1/2。
87. The method of any one of claims 1-84, wherein the systemic exposure of the drug is less than the systemic exposure of the drug when administered intravitreally, intracamerally, topically, parenterally or orally.
88. The method of any one of claims 1-87, wherein the intraocular T of the drug ismaxLess than the intraocular T of the same drug when administered intravitreally, intracamerally, topically, parenterally or orally at the same dosemax。
89. The method of claim 88, wherein the T of the drug ismaxCompared to the T of the same drug when administered intravitreally, intracamerally, topically, parenterally or orally at the same dosemaxAt least 10% smaller.
90. The method of any one of claims 1-89, wherein the intraocular C of the drug ismaxGreater than the intraocular C of said drug when said drug dose is administered intravitreally, intracamerally, topically, parenterally or orallymax。
91. The method of any one of claims 1-90, wherein the intraocular t of the drug is1/2Greater than the intraocular t of the same drug when administered intravitreally, intracamerally, topically, parenterally or orally at the same drug dose1/2。
92. The method of any one of claims 1-90, wherein the AUC in the eye of said drug0-tGreater than the intraocular AUC of said drug when administered intravitreally, intracamerally, topically, parenterally or orally at the same drug dose0-t。
93. The method of any one of claims 1-92, wherein the ocular 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 ulceration, an autoimmune disorder, or retinitis.
94. The method of claim 93, wherein the ocular disease is uveitis.
95. The method of claim 93, wherein the ocular disease is cytomegalovirus retinitis.
96. The method of claim 93, wherein the ocular disease is AMD.
97. The method of claim 96, wherein said AMD is dry AMD.
98. The method of claim 96 wherein the ocular disease is dry AMD.
99. The method of any one of claims 1-98, further comprising non-surgically administering a second medicament to the eye of the subject.
100. The method of claim 99, wherein the second drug is a VEGF antagonist.
101. The method of claim 99 wherein the second agent is a PDGF antagonist.
102. The method of claim 99, wherein the second agent is an anti-inflammatory agent.
103. The method of any one of claims 99-102, wherein the second drug is administered to the suprachoroidal space (SCS) of the eye of the subject.
104. The method of claim 103, wherein the SCS administered to the eye of the subject comprises:
inserting a hollow microneedle into the sclera at an insertion site, the microneedle having a tip with an opening, and
infusing a drug formulation into the SCS through the inserted microneedle.
105. The method of any one of claims 99-102, wherein the second medicament is administered intravitreally.
106. The method of any one of claims 99-105, wherein the first agent and the second agent are administered to the subject simultaneously.
107. The method of any of claims 1-106, wherein the effective amount of the drug administered to the SCS provides a higher drug therapeutic effect as compared to the same drug dose administered intravitreally, intracamerally, topically, parenterally or orally.
108. The method of any one of claims 1-107, wherein the dose of the agent sufficient to induce a therapeutic response is lower than the dose of the agent sufficient to elicit the same or substantially the same therapeutic response when the agent is administered intravitreally, intracamerally, topically, parenterally or orally.
109. A method of treating a choroidal disease in a human patient, the method comprising:
non-surgically administering to the suprachoroidal space (SCS) of the eye of the patient a pharmaceutical formulation comprising an effective amount of an anti-inflammatory drug, a Vascular Endothelial Growth Factor (VEGF) modulator, a platelet-derived growth factor (PDGF) modulator, an angiogenesis inhibitor, an immunosuppressant, a vascular permeability inhibitor, or a combination thereof.
110. A method of treating choroidal neovascularization in a human patient who has not responded adequately to prior therapy for choroidal neovascularization, said method comprising:
non-surgically administering to the suprachoroidal space (SCS) of the eye of the patient a pharmaceutical formulation comprising an effective amount of an anti-inflammatory drug, a Vascular Endothelial Growth Factor (VEGF) modulator, a platelet-derived growth factor (PDGF) modulator, an angiogenesis inhibitor, an immunosuppressant, a vascular permeability inhibitor, or a combination thereof.
111. A method of treating a choroidal disease in a human patient who has not responded adequately to prior therapy for the choroidal disease, the method comprising:
non-surgically administering to the suprachoroidal space (SCS) of the eye of the patient a pharmaceutical formulation comprising an effective amount of an anti-inflammatory drug, a Vascular Endothelial Growth Factor (VEGF) modulator, a platelet-derived growth factor (PDGF) modulator, an angiogenesis inhibitor, an immunosuppressant, a vascular permeability inhibitor, or a combination thereof.
112. A method of treating ocular neovascularization in a human who has not responded appropriately to prior therapy for ocular neovascularization, the method comprising:
non-surgically administering to the suprachoroidal space (SCS) of the eye of the patient a pharmaceutical formulation comprising an effective amount of an anti-inflammatory drug, a Vascular Endothelial Growth Factor (VEGF) modulator, a platelet-derived growth factor (PDGF) modulator, an angiogenesis inhibitor, an immunosuppressant, a vascular permeability inhibitor, or a combination thereof.
113. A method of reducing subretinal exudation and hemorrhage in a subject in need thereof, the method 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) modulator, a platelet-derived growth factor (PDGF) modulator, an angiogenesis inhibitor, an immunosuppressive agent, a vascular permeability inhibitor, or a combination thereof,
wherein administering the drug formulation to the SCS reduces subretinal exudation and hemorrhage experienced by the patient compared to the same drug dose intravitreally administered to the patient.
114. A method of reducing edema in a subject in need thereof, the method comprising:
non-surgically administering an effective amount of a pharmaceutical formulation comprising an effective amount of an anti-inflammatory drug, a Vascular Endothelial Growth Factor (VEGF) modulator, a platelet-derived growth factor (PDGF) modulator, an angiogenesis inhibitor, an immunosuppressive agent, a vascular permeability inhibitor, or a combination thereof, wherein the administration to the SCS reduces edema experienced by the patient as compared to the same dose of drug administered intravitreally to the patient.
115. A method of reducing ocular inflammation in a subject in need thereof, the method comprising:
non-surgically administering an effective amount of a drug formulation to the suprachoroidal space (SCS) of the eye of the subject, the drug formulation comprising an effective amount of an anti-inflammatory drug, a Vascular Endothelial Growth Factor (VEGF) modulator, a platelet-derived growth factor (PDGF) modulator, an angiogenesis inhibitor, an immunosuppressant, a vascular permeability inhibitor, or a combination thereof, wherein administration of the drug formulation to the SCS reduces ocular inflammation as compared to the same drug dose administered intravitreally to the patient.
116. The method of any one of claims 109-115 wherein the pharmaceutical formulation, once administered, flows away from the insertion site.
117. The method of any one of claims 109-115 wherein, once administered, the pharmaceutical formulation flows away from the insertion site and substantially concentrates in the posterior segment of the eye.
118. The method of claim 109, wherein the choroidal disease is polypoidal choroidal vasculopathy.
119. The method of claim 109, wherein the choroidal disorder is ocular neovascularization, polypoidal choroidal vasculopathy, choroidal sclerosis, central serous choroidopathy, multifocal choroidopathy, or choroidal dystrophy.
120. The method according to claim 119, wherein the choroidal disorder is choroidal dystrophy, and the choroidal dystrophy is central circumcision, paranoid degeneration, or complete central choroidal atrophy.
121. The method of any one of claims 110-112, wherein the prior therapy comprises intravitreal administration of the pharmaceutical agent.
122. The method as set forth in any one of claims 109-121,
wherein prior to administration of the pharmaceutical formulation, polypoid lesions are present in the eye of the patient, and
administering an effective amount of a drug to the SCS of the patient reduces the size of the polypoid lesion as compared to the same drug dose administered intravitreally.
123. The method as set forth in any one of claims 109-121,
wherein prior to administration of the pharmaceutical formulation, polypoid lesions of variable size are present in the eye of the patient, and
administering an effective amount of drug to the SCS reduces variability in polypoid lesion size as compared to the same drug dose administered intravitreally.
124. The method as set forth in any one of claims 109-121,
wherein administering an effective amount of the drug to the SCS reduces vascular permeability of the eye compared to the same dose of the drug administered intravitreally.
125. The method of claim 122, wherein said polypoid lesion is present in the perioptic papillary region of the eye.
126. The method of claim 123, wherein said one or more polypoid lesions are present in the perioptic papillary region of the eye.
127. The method of claim 122, wherein said polypoid lesion is present in the central macula of an eye.
128. The method of claim 123, wherein said one or more polypoid lesions are present in the central macula of the eye.
129. The method as set forth in any one of claims 109-128,
wherein before administration of the pharmaceutical formulation, there are dilated and branched inner choroidal vessels of variable size in the eye of the patient, and
administering an effective amount of a drug to the SCS reduces variability in the size of the inner choroidal vessels as compared to the same drug dose administered intravitreally.
130. The method as set forth in any one of claims 109-128,
wherein prior to administration of the pharmaceutical formulation, atherosclerosis is present in choroidal blood vessels of the eye of the patient, and
administering an effective amount of a drug to the SCS reduces the level of atherosclerosis of the choroidal vessels as compared to the same drug dose administered intravitreally.
131. The method as set forth in any one of claims 109-128,
wherein the choroidal vessels of the eye of the patient are transparentized prior to administration of the pharmaceutical formulation, an
Administering an effective amount of a drug to the SCS reduces the level of hyalinization of the choroidal vessels as compared to the same drug dose administered intravitreally.
132. The method as set forth in any one of claims 109-128,
wherein prior to administration of the pharmaceutical formulation, the patient experiences a level of sub-retinal hemorrhage, an
Administering an effective amount of the drug to the SCS reduces the level of subretinal hemorrhage compared to the same drug dose administered intravitreally.
133. The method as set forth in any one of claims 109-128,
wherein upon administration of an effective amount of a drug to the SCS, the patient's visual acuity is improved as compared to the same drug dose administered intravitreally.
134. The method as set forth in any one of claims 109-128,
wherein prior to administration of the pharmaceutical formulation, the eye of the patient undergoes recurrent neovascularization or separation of serum blood, and
administering an effective amount of drug to the SCS reduces recurrent neovascularization or separation of serum blood in the eye, as compared to the same drug dose administered intravitreally.
135. The method as set forth in any one of claims 109-128,
wherein there is subretinal lipid deposition in the eye of the patient prior to administration of the pharmaceutical formulation, and
administering an effective amount of drug to the SCS reduces subretinal lipid deposition as compared to the same drug dose administered intravitreally.
136. The method as set forth in any one of claims 109 and 118-120,
wherein the choroidal disease affects both eyes of the subject, and
the administration of the drug formulation to the SCS was performed in both eyes.
137. The method of any one of claims 109-136 wherein the patient has concomitant drusen.
138. The method of any one of claims 109-137, wherein the patient is caucasian.
139. The method of any one of claims 109-137, wherein the subject is a pigmented human.
140. The method of any one of claims 109-137, wherein the subject is african-american.
141. The method of any one of claims 109-137, wherein the subject is asian.
142. The method as set forth in any one of claims 109-141,
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
infusing a drug formulation into the SCS through the inserted microneedle.
143. The method of claim 142, wherein the insertion site is located about the equator of the eye, or between the equator and the limbus of the eye.
144. The method of claim 142 or 143, wherein the microneedle has a length of about 500 μ ι η to about 1500 μ ι η.
145. The method of claim 142 or 143, wherein the microneedle has a diameter of about 200 μ ι η to about 600 μ ι η.
146. The method of any one of claims 142-145 wherein the microneedle comprises a beveled tip.
147. The method of claim 146, wherein the microneedle has an oblique angle of about 5 degrees to about 30 degrees.
148. The method of claim 146, wherein the microneedle has a bevel height of about 100 μ ι η to about 500 μ ι η.
149. The method of claim 146, wherein the beveled tip has an angle of about 10 degrees to about 20 degrees.
150. The method of any one of claims 146-149, wherein the beveled tip has an aspect ratio of from about 1:1.5 to about 1: 10.
151. The method of claim 146, wherein the beveled tip has a height of about 500 μm to about 1 mm.
152. The method of any one of claims 146-151 wherein the microneedle is inserted into the sclera without penetrating the sclera.
153. The method of any one of claims 146-151 wherein the microneedle is inserted into the sclera without penetrating the choroid.
154. The method of any one of claims 146-153 wherein the microneedle comprises a cylindrical shaft having an outer diameter of from about 200 microns to about 600 microns.
155. The method of any one of claims 109-154 wherein the pharmaceutical formulation has a volume of from about 10 μ L to about 200 μ L.
156. The method of any one of claims 109-154 wherein the pharmaceutical formulation has a volume of about 30 μ L to about 100 μ L.
157. The method of any one of claims 109-156 wherein the microneedle is inserted into the scleral surface at an angle of about 70 degrees to about 110 degrees.
158. The method of any one of claims 109-154 wherein the microneedle is inserted into the scleral surface at an angle of about 90 degrees.
159. The method of any one of claims 109-158, wherein administering the drug formulation to the SCS results in a reduction in the number of side effects experienced by the patient, or a reduction in the severity of side effects experienced by the patient, as compared to the same drug dose administered intravitreally.
160. The method of claim 159, wherein administering the drug formulation to the SCS results in a reduction in the number of side effects experienced by the patient as compared to the number of side effects experienced by the patient when the same drug dose is administered intravitreally.
161. The method of claim 159, wherein administering the drug formulation to the SCS results in a reduction in severity of side effects experienced by the patient as compared to the severity of side effects experienced by the patient when the same drug dose is administered intravitreally.
162. The method of any one of claims 109-161 wherein the dose of the drug sufficient to induce a therapeutic response in the patient when administered to the SCS is less than the dose of the drug sufficient to induce a therapeutic response in the patient when administered intravitreally.
163. The method of claim 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.
164. The method of claim 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.
165. The method of claim 162 wherein the dose of the drug sufficient to induce a therapeutic response when administered to the SCS of the patient is 25% or less of the dose of the drug sufficient to induce a therapeutic response when intravitreally administered to the patient.
166. The method of claim 162 wherein the dose of the drug sufficient to induce a therapeutic response when administered to the SCS of the patient is 10% or less of the dose of the drug sufficient to induce a therapeutic response when intravitreally administered to the patient.
167. The method of claim 117, wherein the retention of the drug in the posterior segment of the eye is greater than the retention of the drug in the posterior segment of the eye upon intravitreal administration.
168. The method of any one of claims 109-167 wherein the intraocular t of the drug administered to the SCS1/2Greater than the intraocular t of said drug when administered intravitreally1/2。
169. The method of any one of claims 109-168 wherein the systemic exposure of the drug administered to the SCS is less than the systemic exposure of the drug when the drug is administered intravitreally.
170. The method of any one of claims 109-169, further comprising subjecting the patient to at least one additional therapy selected from the group consisting of: photodynamic therapy, laser photocoagulation, and transpupillary thermotherapy.
171. The method of any one of claims 109-170, wherein the patient has an additional macular abnormality, and wherein the one or more additional macular abnormalities in the patient are treated by administering an effective amount of the second drug formulation to the SCS of the eye.
172. The method of claim 171, wherein the additional macular abnormality is sickle cell retinopathy, central serous chorioretinopathy, neovascular (type 1 or type 2) age-related macular degeneration, melanocytoma of the optic nerve, localized choroidal hemangioma, optic disc tilt syndrome, pathologic myopia, or choroidal osteoma.
173. The method of any one of claims 109-172 wherein the pharmaceutical formulation comprises an effective amount of a VEGF modulator.
174. The method of claim 173, wherein said 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, quinoline, and a designed ankyrin repeat protein (DARPin).
175. The method of claim 173, wherein said 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, quinoline, and a designed ankyrin repeat protein (DARPin).
176. The method of claim 173, wherein said VEGF modulator is a VEGF antagonist selected from the group consisting of: abbesyp, ziv-Abbesyp, Bevacizumab, Ranitumumab, vandetanib, cabozantinib, ponatinib, ziv-Abbesyp, lapatinib, sunitinib, sorafenib, pridopeptide neo, regorafenib, Veteporfin, Buxiramin, Axitinib, Pazopanib, fluocinolone, nidanib, AL8326, 2C3, AT001, XtendVEGF, HuMax-VEGF, R3, AT001/R84, HyBEV, ANG3070, APX003, APX004, ponatinib, BDM-E, VGX, VGX200, VGX300, COSMIX, DLX903/1008, MGC 2076, INDUS 35815, R84, 019, NM 36KD 265, MG516, MP026, MP0260, FMD 026 503, FLX 08017/080, FLX 7328, FLD 3, FLD-SV 01, AAV 36493, AAV 9, AAV 367346, SALT 3, AAV 9, SALT 3, Voralacet, CEP11981, KH903, lanvatinib mesylate, taralarocco, PF00337210, PRS050, SP01, carboxyamidotriazole orotate, hydroxychloroquine, rilivanib, ALG1001, AGN150998, MP0112, AMG386, AVA101, BMS 0514, KH902, golvatinib (E7050), dolvatinib lactate (TKI258, CHIR258), ORA101, ORA102, axitinib (Inlyta, AG013736), PTC299, pegaptanib sodium, troponin, EG3306, vatalantinib, Bmab100, GSK2136773, anti-VEGFR Alterase, avilata, CEP7055, CLT009, ESBA903, GW654652, hm010 pl, jnm 220, pamb, hyj 170170170283, TAK 1703, TAK 29676, cvarva 492101, novalva 3859, AG 10032, asonic prg 201, agx 3853, tacrolin 501, tacrolin 51, tacrolin 501, tacrolin 202, AG 6353, tacrolin 51, tacrolin 53, tacrolin 52, tacrolin.
177. The method of any one of claims 109-172 wherein the pharmaceutical formulation comprises an effective amount of an angiogenesis inhibitor.
178. The method of claim 177, wherein the angiogenesis inhibitor is an angiopoietin-1, angiopoietin-2, angiostatin, endostatin, angiostatin, thrombostatin, thrombospondin, calreticulin, platelet factor-4, TIMP, CDAI, interferon α, interferon β, vascular endothelial growth factor inhibitor (VEGI) meth-1, meth-2, prolactin, VEGI, SPARC, osteopontin, mammary staphylistatin, angiostatin, proliferator-related protein (PRP), lestein, TSP-1, TSP-2, interferon gamma 1 β, achtr 028, α V β, potassium aminobenzoate, amyloid P, ANG, ANG1170, ANG3062, ANG3281, ANG3298, ANG4011, anti-CTGF RNAi, aplidine, combined salvia miltiorrhiza and schizandra chinensis, atherosclerotic plaque agent, Azol, aztrex 3, gnx 3512, pgr α, pg7, pgr 102, pg7, pgr 5, pgr 5, pgr 5, pgr 5, pgr 5, pgr 5, pgr.
179. The method of any one of claims 109-172 wherein the pharmaceutical formulation comprises an effective amount of an anti-inflammatory agent.
180. The method of claim 179, wherein the anti-inflammatory agent is a steroid.
181. The method of claim 180, wherein the steroid is hydrocortisone, hydrocortisone-17-butyrate, hydrocortisone-17-aceylate, hydrocortisone-17-butyrate propionate, cortisone, ticortisone pivalate, prednisolone, methylprednisolone, prednisone, triamcinolone acetonide, mometasone, amcinonide, budesonide, desonide, fluocinolone acetate, halcinonide, betamethasone dipropionate, dexamethasone, fluocortolone, hydrocortisone-17-valerate, halomethasone, alclometasone dipropionate, prednisolone, clobetasone-17-butyrate, clobetasol-17-propionate, fluocortolone caproate, fluocortolone pivalate, fluorometholone acetate, or prednisone.
182. The method of claim 181, wherein the steroid is triamcinolone, triamcinolone acetonide, or dexamethasone.
183. The method of claim 179, wherein the anti-inflammatory agent is a non-steroidal anti-inflammatory drug (NSAID).
184. The method of claim 183, wherein the non-steroidal anti-inflammatory drug (NSAID) is a salicylate.
185. The method of claim 183, wherein said non-steroidal anti-inflammatory drug (NSAID) is a propionic acid derivative.
186. The method of claim 183, wherein said non-steroidal anti-inflammatory drug (NSAID) is an acetic acid derivative.
187. The method of claim 183, wherein the non-steroidal anti-inflammatory drug (NSAID) is an enolic acid derivative.
188. The method of claim 183, wherein said non-steroidal anti-inflammatory drug (NSAID) is a fenamic acid derivative.
189. The method of claim 183, wherein said non-steroidal anti-inflammatory drug (NSAID) is a cyclooxygenase-2 (COX-2) inhibitor.
190. The method of claim 183 or 184, wherein the non-steroidal anti-inflammatory drug (NSAID) is acetylsalicylic acid, diflunisal, or salsalate.
191. The method of claim 183 or 185, wherein the non-steroidal anti-inflammatory drug (NSAID) is ibuprofen, dexibuprofen, naproxen, fenoprofen, ketoprofen, dexketoprofen, flurbiprofen, oxaprozin, or loxoprofen.
192. The method of claim 183 or 186, wherein the non-steroidal anti-inflammatory drug (NSAID) is indomethacin, tolmetin, sulindac, etodolac, ketorolac, diclofenac, or nabumetone.
193. The method of claim 183 or 187 wherein said non-steroidal anti-inflammatory drug (NSAID) is piroxicam, meloxicam, tenoxicam, droxicam, lornoxicam or isoxicam.
194. The method of claim 183 or 188, wherein the non-steroidal anti-inflammatory drug (NSAID) is mefenamic acid, meclofenamic acid, flufenamic acid, or tolfenamic acid.
195. The method of claim 183 or 189, wherein said non-steroidal anti-inflammatory drug (NSAID) is celecoxib, rofecoxib, valdecoxib, parecoxib, lumiracoxib, etoricoxib, or felicoxib.
196. The method of any one of claims 109-172, wherein the pharmaceutical preparation comprises an effective amount of a Platelet Derived Growth Factor (PDGF) modulator.
197. The method of claim 196, wherein said Platelet Derived Growth Factor (PDGF) modulator is a PDGF antagonist.
198. 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.
199. 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).
200. The method of claim 197, wherein the PDGF antagonist is anti-PDGF- β aptamer E10030, sunitinib, axitinib, sorafenib, imatinib mesylate, nidanib, pazopanib hydrochloride, ponatinib, MK-2461, doratinib, pazopanib, crenolanib, PP-121, tiratinib, imatinib, KRN 633, CP673451, TSU-68, Ki8751, amuvatinib, tivozanib, masitinib, motertinib diphosphate, dolatinib dilitanium diphosphate, or rilivanib (ABT-869).
201. The method of any one of claims 109-172 wherein the pharmaceutical preparation comprises an effective amount of an immunosuppressive agent.
202. The method of claim 201, wherein the immunosuppressive agent is a glucocorticoid, a cytokine inhibitor, a cytostatic agent, an alkylating agent, an antimetabolite, a folic acid analog, a cytotoxic antibiotic, an interferon, an opioid, a T-cell receptor-directed antibody, or an IL-2 receptor-directed antibody.
203. The method of claim 202, wherein the antimetabolite is a purine analog, a pyrimidine analog, a folic acid analog, or a protein synthesis inhibitor.
204. The method of claim 201, wherein the immunosuppressive agent is an interleukin-2 inhibitor.
205. The method of claim 201, wherein the immunosuppressive agent is cyclophosphamide, nitrosourea, methotrexate, azathioprine, mercaptopurine, fluorouracil, dactinomycin, an anthracycline, mitomycin C, bleomycin, mithramycin, molomab-CD 3, cyclosporine, tacrolimus, sirolimus, or mycophenolate.
206. The method of claim 204, wherein the interleukin-2 inhibitor is basiliximab or daclizumab.
207. The method of claim 203 or 205, wherein the immunosuppressive agent is mycophenolate.
208. The method of any one of claims 109-172 wherein the pharmaceutical formulation comprises an effective amount of a vascular permeability inhibitor.
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.
210. The method of claim 209, wherein the vascular permeability inhibitor is an Angiotensin Converting Enzyme (ACE) inhibitor and the ACE inhibitor is captopril.
211. A method of treating or preventing Polypoidal Choroidal Vasculopathy (PCV) in a patient, the method comprising:
administering to the eye of the patient an effective amount of an interfering RNA molecule targeting a gene selected from the group consisting of: HTRA1, CFH, elastin, and ARMS2 such that expression of the targeted gene is down-regulated upon administration of the interfering RNA, and
wherein the step of administering comprises:
inserting a hollow microneedle into the sclera at an insertion site, the microneedle having a tip with an opening, and
interfering RNA molecules were infused into SCS through inserted microneedles.
212. The method of claim 211, wherein the interfering RNA molecule is an siRNA, miRNA, or shRNA.
213. The method of claim 211 or 212, wherein the targeted gene is CFH, and wherein the interfering RNA molecule targets a polymorphism selected from the group consisting of rs3753394, rs800292, rs3753394, rs6680396, rs1410996, rs2284664, rs1329428, and rs 1065489.
214. The method of any one of claims 109-213, further comprising administering a photosensitizer to the patient.
215. The method of claim 214, wherein said photosensitizer is verteporfin.
216. A method of diagnosing a patient for a choroidal disease comprising
Administering a choroidal disease diagnostic agent to the SCS of one or both eyes of the patient,
visualising the diagnostic agent, and
determining whether the patient has choroidal disease based on the visualization.
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.
218. A method of administering a triamcinolone composition to the 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 to induce infusion of the triamcinolone composition through the inserted microneedle, the triamcinolone composition comprising triamcinolone microparticles;
(c) determining whether the triamcinolone composition flows into the suprachoroidal space of the eye and away from the insertion site;
(d) infusing a selected volume of the triamcinolone composition if it is determined in step (c) that the triamcinolone composition has flowed into the suprachoroidal space distal to the insertion site, and thereby removing the pressure, or if it is determined in step (c) that the triamcinolone composition has not substantially flowed into the suprachoroidal space distal to the insertion site, resetting the inserted microneedle and repeating steps (b) - (d) until the selected volume of the triamcinolone composition has been infused; and
(e) retracting the microneedle from the eye.
219. The method of claim 218, wherein the triamcinolone is triamcinolone acetonide.
220. The method of claim 219, wherein the composition comprises nanoparticles.
221. The method of claim 219 or 220, wherein the composition comprises microparticles.
222. The method of claim 221, wherein said microparticle has D50Is 2 μm or less.
223. The method of claim 221 or 222, wherein said microparticle has D99Less than 10 μm.
224. The method of any one of claims 219-223, wherein the triamcinolone is present in the composition at about 40 mg/mL.
225. The method of any one of claims 219-223, wherein the pharmaceutical formulation further comprises sodium chloride.
226. The method of any one of claims 219-223, wherein the pharmaceutical formulation further comprises sodium carboxymethylcellulose.
227. The method of any one of claims 219-223, wherein the pharmaceutical formulation further comprises polysorbate 80.
228. The method of any of claims 219-223, wherein the pharmaceutical formulation further comprises CaCl2、MgCl2Sodium acetate, sodium citrate, or a combination thereof.
229. Pharmaceutical composition comprising D50Particles of triamcinolone smaller than 3 μm.
230. The pharmaceutical composition of claim 229, wherein triamcinolone is present in the composition at 40 mg/mL.
231. The pharmaceutical composition of claim 229 or 230, wherein D of the particles90Less than or equal to 10 μm.
232. The pharmaceutical composition of claim 231, wherein D of said particles90Less than 10 μm.
233. The pharmaceutical composition of any one of claims 229-232, further comprising polysorbate 80.
234. The pharmaceutical composition of any one of claims 229-233, further comprising sodium carboxymethylcellulose.
235. The pharmaceutical composition of any one of claims 229-234, further comprising CaCl2、MgCl2One or more of KCl, sodium acetate and sodium citrate.
236. The pharmaceutical composition of any one of claims 229-235, wherein the pH of the composition is from about 6.0 to about 7.5.
237. The pharmaceutical composition of any one of claims 229-236, wherein D of the particle is50Is about 2 μm.
238. The pharmaceutical composition of any one of claims 229-237, wherein D of the particle50Less than about 2 μm.
239. The pharmaceutical composition of any one of claims 229-238, wherein D of the particle is50Less than about 1 μm.
240. The pharmaceutical composition of any one of claims 229-239 wherein the triamcinolone is triamcinolone acetonide.
241. A method of retinal electrography, comprising the steps of:
pigs were anesthetized on days-1, 0, and 3, pupils were dilated with 1% tropicamide HCl, corneas were anesthetized with 0.5% proparacaine HCl, and full-field ERGs were recorded from the left eye prior to injection;
all animals were acclimatized to darkness for 15 minutes prior to ERG;
a monopolar contact lens electrode (ERG-jet, La Chaux des Fonds, Switzerland) was placed on the cornea to serve as an active electrode;
subcutaneous electrodes at the outer canthus act as ineffective electrodes;
barraquer palpebral speculum was placed to maintain the eyelid open and a hypodermic needle electrode was inserted on the dorsal side, serving as the ground electrode;
ERGs were initiated with brief flashes of light delivered at 0.33Hz at maximum intensity by a mini-ganzfeld photostimulator (Roland Instruments, wissbaden, Germany);
amplifying, filtering, and averaging 20 responses (Retiport electrophysiology diagnostic System, RolandInstruments, Wiesbaden, Germany);
b-wave amplitude from each pig was recorded at the indicated times.
Background
The present invention is generally in the field of ophthalmic therapy, and more particularly relates to the infusion of fluid drug formulations into ocular tissue using microneedles for targeted, localized drug delivery.
Delivery of drugs to the eye is extremely difficult, particularly delivery of macromolecules and delivery to the posterior segment. Many inflammatory and proliferative diseases in the posterior region of the eye require long-term drug therapy. Examples of such diseases include macular degeneration, diabetic retinopathy, and uveitis. In addition, many choroidal disorders associated with inflammatory responses, proliferation and neovascularization require long-term drug therapy. It is difficult to deliver an effective dose of drug to the posterior segment using conventional delivery methods such as local administration, which has poor efficiency, and systemic administration, which often causes significant side effects and often fails to reach the site of infection (Geroski & Edelhauser, invest. For example, while eye drops are used in the front of the eye to treat conditions that infect the outer surface of the eye or tissue, eye drops do not significantly penetrate into the eye, which may be required for the treatment of a variety of retinal and choroidal diseases.
Direct injection into the eye using conventional needles and syringes has been reported to be effective, but requires professional training and raises concerns about safety (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 treatments required to deliver therapeutically effective amounts of drugs to the ocular tissue site where needed.
The suprachoroidal space (SCS) of the eye has been studied, and cannulation has been described as a possible route of drug delivery. See, e.g., Olsen, et al American j. ophthalmology 142(5):777-87 (nov.2006); PCT patent application publication No. WO 2007/100745.
It would therefore be desirable to provide better, safer, more effective techniques for delivering therapeutic agents directly to the posterior segment tissues of the eye, for example, for treating posterior ocular disorders (stereos ocular disorders). It would also be desirable to provide better, safer, more efficient techniques for delivering therapeutic agents directly to SCS for the treatment of choroidal disorders, e.g., choroidal disorders associated with vascular abnormalities. The present invention addresses these and other needs.
Disclosure of Invention
In one aspect, the present invention relates to non-surgical ophthalmic treatment in human patients in need of such treatment, and more particularly to the infusion of pharmaceutical formulations into the suprachoroidal space of the eye for targeted, local drug delivery for the treatment of posterior ocular disorders, choroidal diseases, and other diseases associated with vascular abnormalities.
In one aspect of the invention, a method of treating a posterior ocular disorder in a human subject in need of 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 treatment for a posterior ocular disorder or a choroidal disease. In further embodiments, once administered, the pharmaceutical formulation flows away from the insertion site and substantially concentrates in the posterior segment of the eye. In one embodiment, the posterior ocular disorder is an ocular inflammatory disorder such as uveitis, scleritis, glaucoma, ocular sarcoidosis, optic neuritis, macular edema, diabetic retinopathy, macular degeneration, corneal ulcers, autoimmune disorders, the ophthalmic manifestations of AIDS, optic neurodegeneration, geographic atrophy (choroidal disease), choroidal disease, or retinitis. In one embodiment the disorder is acute. In another embodiment, the disorder is chronic.
In another embodiment, the method is provided for treating a choroidal disorder, e.g., ocular neovascularization, polypoidal choroidal vasculopathy, choroidal sclerosis, central serous choroidopathy, multifocal choroidopathy, or choroidal dystrophy (e.g., central circular choroidopathy, creeping choroidopathy, complete central choroidal atrophy). In one embodiment, the method comprises non-surgically administering to SCS in a patient in need of treatment a pharmaceutical formulation comprising an effective amount of an anti-inflammatory drug, a Vascular Endothelial Growth Factor (VEGF) modulator, a Platelet Derived Growth Factor (PDGF) modulator, an angiogenesis inhibitor, an immunosuppressant, a vascular permeability inhibitor, or a combination thereof. In further embodiments, an effective amount of drug administered to the SCS provides a higher efficacy or greater therapeutic effect of the drug as compared to the same drug dose administered intravitreally, intracamerally, topically, parenterally or orally. In still further embodiments, a patient treated with SCS drug therapy has not previously responded to a different type of therapy for the same disorder.
In another embodiment, a method of reducing subretinal leakage and hemorrhage in a subject is provided. In a further embodiment, the method comprises non-surgically administering to SCS in a patient in need of treatment a pharmaceutical formulation comprising an effective amount of an anti-inflammatory drug, a Vascular Endothelial Growth Factor (VEGF) modulator, a platelet-derived growth factor (PDGF) modulator, an angiogenesis inhibitor, an immunosuppressive agent, a vascular permeability inhibitor, or a combination thereof, wherein administration of the pharmaceutical formulation reduces subretinal exudation and hemorrhage experienced by the patient as compared to the same pharmaceutical dose intravitreally administered to the patient.
In one embodiment, a method of treating a posterior ocular disorder or choroidal disease 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 of a posterior ocular disorder or choroidal disease. In a further embodiment, the intraocular elimination half-life (t) of the drug administered to the SCS1/2) Greater than the intraocular t of the drug when administered intravitreally, intracamerally, topically, parenterally or orally1/2. In another embodiment, the mean intraocular maximum concentration of the drug (C) when administered to SCS by the methods described hereinmax) Intraocular C greater than that of a drug administered intravitreally, intracamerally, topically, parenterally or orallymax. In another embodiment, the mean area under the intraocular curve (AUC) of the drug when administered to SCS by the methods described herein0-t) Greater than the intraocular AUC of the drug when administered intravitreally, intracamerally, topically, parenterally or orally0-t. In another embodiment, the time to peak intraocular concentration of drug when administered to SCS by the methods described herein (t;) ismax) Greater than the intraocular t of the same drug when administered intravitreally, intracamerally, topically, parenterally or orallymax. In a further embodiment, the pharmaceutical formulation comprises an effective amount of an anti-inflammatory agent (e.g., a steroid or NSAID), a VEGF modulator (e.g., a VEGF antagonist), a platelet-derived growth factor (PDGF) modulator, an angiogenesis inhibitor, an immunosuppressive agent, an vascular permeability inhibitor, or a combination thereof.
In one embodiment, a method of 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 further embodiments, delivering the pharmaceutical 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 infusing the drug formulation through the inserted microneedle and into the SCS space distal to the insertion site over a period of time. In one embodiment, the drug formulation administered to the SCS flows away from the insertion site and substantially focuses on the posterior segment of the eye, thereby increasing the therapeutic effect of the dose of drug as compared to the therapeutic effect of the same drug dose administered by other means (e.g., intravitreal, intracameral, topical, parenteral, and/or oral). In another embodiment, the dosage 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 intravitreally, topically, parenterally or orally. In another embodiment, the drug formulation is delivered to the SCS via a hollow microneedle inserted into the sclera at the equator of the eye or between the equator and limbus (limbus) of the eye. In a further embodiment, the hollow microneedles are inserted at a90 degree angle (vertical) at the insertion site.
In one embodiment, the drug formulation delivered by the methods described herein comprises an effective amount of an anti-inflammatory agent, such as a steroidal anti-inflammatory agent or a non-steroidal anti-inflammatory agent (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 TNF α antagonist, an interleukin antagonist, a neuroprotective agent, a Vascular Endothelial Growth Factor (VEGF) antagonist, a platelet-derived growth factor (PDGF) receptor antagonist, or a combination thereof50Is1 μm or less and/or D99Is10 μm or less.
As described above, one aspect of the invention includes a method of treating a posterior ocular disorder in a human subject in need thereof, comprising non-surgically administering a drug formulation to the SCS of the eye of the human subject, wherein upon administration, the drug formulation flows away from the insertion site and substantially concentrates in the posterior segment. In one embodiment of the method, the intraocular pressure of the eye remains substantially constant during administration of the drug formulation to the SCS. In another embodiment, administration of the pharmaceutical formulation to the SCS of the eye results in a reduction in the number of side effects or a reduction in the severity of one or more side effects, as compared to the same drug dose administered intravitreally, intracamerally, topically, orally, or parenterally.
In one aspect of the invention, the invention relates to a method of treating a choroidal disease in a human patient in need of treatment. In one embodiment, the method comprises non-surgically administering to the suprachoroidal space (SCS) of the eye of the patient a drug formulation comprising an effective amount of an anti-inflammatory drug, a Vascular Endothelial Growth Factor (VEGF) modulator, a platelet-derived growth factor (PDGF) modulator, an angiogenesis inhibitor, an immunosuppressive agent, or a vascular permeability inhibitor. In a further embodiment, the human patient has previously been treated for choroidal disease and not responded appropriately to the treatment prior to administration of the pharmaceutical formulation.
In another aspect of the invention, the invention relates to a method of 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 eye of the patient a drug formulation comprising an effective amount of an anti-inflammatory drug, a Vascular Endothelial Growth Factor (VEGF) modulator (e.g., a VEGF antagonist), a platelet-derived growth factor (PDGF) modulator (e.g., a PDGF antagonist), an angiogenesis inhibitor, an immunosuppressant, or a vascular permeability inhibitor. In further embodiments, the ocular neovascularization is choroidal neovascularization. In one embodiment, the human patient being treated for ocular neovascularization has previously been treated for ocular neovascularization and has not responded appropriately to the treatment prior to administration of the pharmaceutical formulation.
In one embodiment, the pharmaceutical formulation delivered via the methods described herein comprises an effective amount of an anti-inflammatory agent, such as a steroid or a non-steroidal anti-inflammatory drug (NSAID). In another embodiment, the drug delivered to the SCS by the methods described herein is a vascular permeability inhibitor, angiogenesis inhibitor, or 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 pharmaceutical formulation comprises D50Is1 μm or less and/or D99Drug particles of 10 μm or less. In a further embodiment, the pharmaceutical formulation comprises triamcinolone.
In one embodiment of the present invention, there is provided a method of treating a choroidal disease or a posterior ocular disorder in a human subject in need thereof, comprising non-surgically administering a drug formulation to the SCS of the eye of the human subject, wherein the intraocular pressure of the eye remains substantially constant. In another embodiment, administration of the pharmaceutical formulation to the SCS of the eye of a patient in need of treatment of a posterior ocular disorder or a choroidal disease results in a reduction in the number of side effects or a reduction in the severity of one or more side effects, as compared to the same drug dose administered intravitreally, intracamerally, topically, orally, or parenterally. In one embodiment, the side effect reduced by the methods described herein is subretinal leakage and/or hemorrhage.
Drawings
FIGS. 1A, 1B, 1C and 1D are cross-sectional illustrations of the tissue structure of a human eye. Eye as a whole (a), a close-up of the cornea (1B), and a close-up of the sclera and associated tissues of the eye with no fluid in the suprachoroidal space (1C) or a close-up of the sclera and associated tissues of the eye with fluid in the suprachoroidal space (1D).
Fig. 2 is a cross-sectional view of a microneedle device comprising hollow microneedles disposed in an elongate body, according to one embodiment.
Fig. 3 is a cross-sectional view of the elongate body of the microneedle device shown in fig. 2.
Fig. 4 is an illustration of a microneedle device according to one embodiment.
Fig. 5 is an illustration of a microneedle device according to one embodiment.
Fig. 6A and 6B illustrate one embodiment of a method of delivering a drug into the suprachoroidal space of an eye using a hollow microneedle, wherein the method comprises inserting the hollow microneedle into the sclera and infusing a fluid drug formulation into the suprachoroidal space.
Fig. 7A shows a comparison of the tips of hollow microneedles according to one embodiment with conventional 30-gauge hypodermic needles. Fig. 7B shows a schematic of a custom plastic mold shaped to hold the entire eye.
Fig. 8A and 8B are bright field microscopic images of sagittal cross sections of porcine eyes before and after sulforhodamine infusion, respectively.
Fig. 9A, 9B, 9C, and 9D are fluorescence images of frozen sections of pig eyes not infused to the suprachoroidal space (9A), rabbit eyes after infusion of 500nm fluorescent particles in the axial plane and tiled to form a panoramic view (9B), pig eyes after infusion of 500nm fluorescent particles in the sagittal direction and tiled to show the gap anterior and posterior to the microneedle insertion site (9C), and human eyes after infusion of 500nm fluorescent particles in the sagittal direction and tiled to show the gap anterior and posterior to the microneedle insertion site (9D). The insert of fig. 9B, 9C and 9D show magnified views of the microneedle insertion site.
Fig. 10A and 10B are microscopic computed tomography images showing the diffusion around of 1 μm contrast agent particles infused into the perichoroidal space of a porcine eye in a cross-sectional image (10A) and three-dimensional reconstruction of the cross-sectional image (10B).
11A, 11B, 11C, and 11D are graphs showing the effect of infusion pressure and microneedle length on the success rate of suprachoroidal delivery of 20nm particles (1A), 100nm particles (11B), 500nm particles (11C), and 1000nm particles (11D) into porcine eyes.
Fig. 12A and 12B are sagittal fluorescence images of cryosections of porcine eyes following infusion of 20nm particles (12A) and 1000nm particles (12B) and are collaged to show the gap between the anterior and posterior sides of the microneedle insertion site. The insert of fig. 12A and 12B shows an enlarged view of the insertion site of the microneedle.
Fig. 13A and 13B are graphs showing the effect of intraocular pressure and microneedle length on the success rate of 1000nm particle delivery on the choroid at simulated intraocular pressures of 18mmHg (13A) and 36mmHg (13B).
Fig. 14 is a one-dimensional line-of-sight scan of a rabbit eye taken after injection of sodium fluorescein into the suprachoroidal space, where the x-axis represents the location in the eye from posterior (0) to anterior (160) and the y-axis represents the fluorescence intensity at that location.
Fig. 15 is a graph showing clearance of sodium fluorescein from the suprachoroidal space over time.
Fig. 16 is a graph showing clearance of 20nm particles from the suprachoroidal space over time.
Fig. 17 is a graph showing clearance of 500nm particles from the suprachoroidal space over time.
Fig. 18 is a block diagram of a method of administering a drug to an eye according to one embodiment.
Fig. 19A is a graph showing the amount of Triamcinolone (TA) remaining in the posterior segment of the eye as a function of time post-dose. (circle-SCS injection, diamond-intravitreal injection).
Fig. 19B is a graph showing increased retention of Triamcinolone (TA) in the choroid and retina when administered to SCS (bottom) compared to intravitreal administration of TA (top).
Fig. 19C is a graph at the top showing the ratio of the amount of Triamcinolone (TA) in the lens of the eye to the amount of TA behind the eye (choroid) as a function of time post-dose. The bottom of fig. 19C is a graph showing the ratio of the amount of TA in the lens of the eye to the amount of TA at the back of the eye (retina) as a function of time (days) post-dose.
Fig. 20A is a graph of intraocular pressure (IOP, mmHg) of a rabbit eye as a function of time following TA administration. On
Fig. 20B is a cross-sectional image of a rabbit eye after suprachoroidal injection of 3.2mg triamcinolone (left) or vehicle (right).
Fig. 20C is a graph showing TA plasma concentration (ng/mL) after administration of TA to SCS in rabbit eyes as a function of time after administration of TA.
Fig. 20D is a graph showing the retention of Triamcinolone (TA) (μ g TA/g tissue) in various tissues after administration to SCS. The largest amount of the drug remains in the tissues behind the eye (choroid, retina) and the smaller amount remains in the front of the eye (lens, vitreous humor).
Fig. 20E is a graph showing the amount of Triamcinolone (TA) in the sclera and choroid (μ g) as a function of time following administration of TA.
Fig. 20F is a graph showing the amount of Triamcinolone (TA) in the retina (μ g) as a function of time following administration of TA.
Figure 21A is a graph showing the cumulative McDonald-shaduck score for eyes treated with vehicle (left), 4mg Triamcinolone (TA) administered to SCS (center), or 4mg triamcinolone administered intravitreally (right), as a function of time post treatment and time post LPS toxin administration. The McDonald-Shadduck score provides a model of posterior uveitis.
Fig. 21B is a representative fundus photograph showing the effect of Triamcinolone (TA) administered to SCS or intravitreally in a posterior uveitis model of NZW rabbits.
Fig. 21C is a graph showing the overall severity of inflammation in NZW rabbits at the final time point as measured histologically. The following tissues were analyzed: ciliary process, scleral-choroid, vitreous, retina and optic nerve (grade 0-4, max score 20).
Fig. 21D is a graph showing intraocular pressure (mmGh) in NZW rabbits in response to IVT or SCS TA dosing.
FIG. 22A is a graph showing the average Hackett/McDonald eye scores for porcine eyes challenged with: (i) lipopolysaccharide (LPS) toxin followed by vehicle (left), (ii) LPS toxin followed by 2mg triamcinolone administered to SCS (middle), or (iii) balanced salt solution followed by vehicle. Treatment with SCS TA at a dose of 2mg significantly reduced the ocular inflammatory response in this porcine uveitis model.
FIG. 22B is a graph showing the average cumulative Hackett/McDonald eye scores for porcine eyes challenged with: (i) a Lipopolysaccharide (LPS) toxin followed by a vehicle, (ii) an LPS toxin followed by 2mg Triamcinolone (TA) administered to SCS, (iii) an LPS toxin followed by 2mg triamcinolone administered intravitreally, or (iv) an LPS toxin followed by 0.2mg triamcinolone administered to SCS. A reduction in inflammation was observed within 3 days, where the dose of TA administered to SCS was 10% of the dose of TA required at intravitreal administration.
Fig. 23 is a graph showing the mean (± standard deviation) cumulative inflammatory ocular score for animals treated with or without toxin administration followed by low or high dose TA treatment by administration to SCS or intravitreal administration. The average inflammation score of the eyes treated with SCSTA was lower than the score of the eyes treated with IVT TA at1, 2 or 3 days post treatment.
Mean (+/-SD) cumulative inflammatory ocular scores at uveitis induction (i.e., toxin administration) (day-1), at drug administration (day 0). The eye was dosed with: the suprachoroidal space (SCS) or Intravitreal (IVT) was injected with 0.2mg (low dose) or 2.0mg (high dose) Triamcinolone Acetonide (TA) and the ocular score was calculated 1, 2 or 3 days after treatment. On
Fig. 24 is a graph showing the mean intraocular pressure in the eyes of animals treated with or without toxin administration on day-1, then low or high dose TA treatment by administration to SCS or intravitreal administration on
Fig. 25A-B are wide field fundus images of animal eyes from low or high dose TA treatment with or without toxin administration, then by administration to SCS or intravitreal administration. The wide-field fundus image was imaged at the following times: just prior to injection with Lipopolysaccharide (LPS) on day-1, just prior to injection with vehicle, 0.2mg (low dose) or 2.0mg (high dose) triamcinolone acetonide on
FIG. 26 shows ocular histopathology of the eye three days after intravitreal injection of Balanced Salt Solution (BSS) or 100ng Lipopolysaccharide (LPS), and 72 hours after administration of vehicle, 0.2mg TA or 2.0mg TA, by SCS or IVT. None of the examined eyes had evidence of substantial histopathological, structural or toxicological changes. Ocular histopathology of the eye three days after Intravitreal (IVT) injection of Balanced Salt Solution (BSS) or 100ng Lipopolysaccharide (LPS) and 72 hours after suprachoroidal (SCS) or IVT injection of vehicle, 0.2mg triamcinolone acetonide (low dose TA) or 2.0mg triamcinolone acetonide (high dose TA). Hematoxylin and eosin staining.
A. The anterior segment of the eye, injection of BSS IVT and vehicle in SCS was performed (group 1). Scale bar: 1 mm.
B. Posterior segment of the eye, injection of BSS IVT and vehicle in SCS was performed (group 1). Scale bar: 200 μm.
C. Anterior segment of eye, LPS IVT and vehicle injection in SCS was performed (group 2). Scale bar: 1 mm.
D. Posterior segment of the eye, LPS IVT and vehicle injection in SCS was performed (group 2). Scale bar: 200 μm.
E. Anterior segment of eye, LPS IVT and low dose TA injection in SCS was performed (group 3). Scale bar: 1 mm.
F. In the posterior segment of the eye, LPS IVT and low dose TA injections in SCS were performed (group 3). Scale bar: 200 μm.
G. Anterior segment of eye, LPS IVT and high dose TA injection in SCS was performed (group 4). Scale bar: 1 mm.
H. In the posterior segment of the eye, LPS IVT and high dose TA injections in SCS were performed (group 4). Arrows indicate the presence of TA in SCS. Scale bar: 200 μm.
I. In the anterior segment of the eye, LPS IVT and low dose TA IVT injections were performed (group 5). Scale bar: 1 mm.
J. In the posterior segment of the eye, LPS IVT and low dose TA IVT injections were performed (group 5). Scale bar: 200 μm.
K. In the anterior segment of the eye, LPS IVT and high dose TA IVT injections were performed (group 6). Scale bar: 1 mm.
L. posterior segment of eye, injection of LPS IVT and high dose TA IVT (group 6). Scale bar: 200 μm.
Figure 27 shows the mean ocular histopathological inflammation scores for anterior and
Figure 28 shows mean Aqueous Humor (AH) and Vitreous Humor (VH) cell counts after 3 days Intravitreal (IVT) injection of either Balanced Salt Solution (BSS) or 100ng Lipopolysaccharide (LPS) and 72 hours suprachoroidal (SCS) or IVT injection of either vehicle, 0.2mg triamcinolone acetonide (low dose TA) or 2.0mg triamcinolone acetonide (high dose TA). a. The mean cell count for
Fig. 29 is a graph showing the concentration of Triamcinolone (TA) in plasma after SCS or IVT administration.
Fig. 30 is an Optical Coherence Tomography (OCT) image of patient No. 3 before (left image) and 56 days after injection of bevacizumab into the suprachoroidal space (right image). A decrease in the intraretinal fluid can be observed.
FIG. 31 is a graph showing intraocular pressure (IOP) after SCS administration of 4mg (40mg/mL) TA or vehicle.
FIG. 32 is a graph showing central corneal thickness on
FIG. 33 is a graph showing TA concentration in plasma over time after SCS administration of 4mg (40mg/mL) TA.
Detailed Description
The present application provides methods, devices and pharmaceutical formulations for treating posterior ocular disorders and choroidal diseases in a human subject in need thereof. The methods, devices, and formulations provided herein allow for effective posterior segment drug delivery to treat posterior ocular disorders and choroidal diseases, and are generally characterized by: (1) the method is non-surgical, thereby minimizing invasiveness and is safe; (2) the drug formulations are administered in such a way that they are sufficiently targeted to the posterior segment of the eye and/or the suprachoroidal space (SCS) of the eye while limiting drug exposure to the anterior segment or other regions of the eye; (3) the methods and formulations are capable of delivering drugs in a sustained and/or controlled manner; (4) the method and apparatus are user-friendly. The non-surgical SCS delivery methods, devices for implementing the methods, and drug formulations for SCS delivery described herein achieve these desirable features.
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 known as retrobulbar block). Alternatively or additionally, the "non-surgical" ocular drug delivery method is performed with an instrument having a diameter of 28 gauge (gauge) or less. Alternatively or additionally, the "non-surgical" ocular drug delivery method does not require the guiding mechanism typically required for ocular drug delivery via a shunt or cannula.
The non-surgical posterior ocular disorders and choroidal disease treatment methods described herein are particularly useful for the local delivery of drugs to the posterior region of the eye, such as the retinochoroidal tissue, the macula, the Retinal Pigment Epithelium (RPE), and the optic nerve of the posterior segment of the eye. In another embodiment, the non-surgical methods and microneedles provided herein can be used for targeted drug delivery to specific posterior ocular tissues or regions in the eye, or adjacent tissues. In one embodiment, the methods described herein deliver drugs, inter alia, 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 tissues or adjacent tissues in the eye of a human subject in need of treatment. In one embodiment, the methods and microneedles provided herein can be used for targeted drug delivery to specific posterior ocular tissues or regions in the eye, or adjacent tissues.
In one embodiment of the methods described herein, for the treatment of a posterior ocular disorder or a choroidal disease, non-surgical delivery of a drug (e.g., an anti-inflammatory drug (e.g., triamcinolone), a Vascular Endothelial Growth Factor (VEGF) modulator (e.g., a VEGF antagonist), a platelet-derived growth factor (PDGF) antagonist) to the suprachoroidal space is achieved by: the micro-needles are inserted into a patient's eye, such as the sclera, and the drug formulation is injected or infused through the inserted micro-needles and into the suprachoroidal space of the eye. In one embodiment, the effective amount of drug administered to the SCS provides a higher therapeutic effect of the drug as compared to the therapeutic effect of the drug when the same dose is administered intravitreally, topically, intracamerally, parenterally or orally. In one embodiment, the microneedle drug delivery methods described herein precisely deliver the drug into the SCS for subsequent local delivery to nearby posterior ocular tissues in need of treatment. Upon completion of the non-surgical drug administration, the drug may be released from the infused volume (or, e.g., from microparticles or nanoparticles in the pharmaceutical formulation) into the ocular tissue for an extended period of time, e.g., hours or days or weeks or months. This may advantageously provide for improved bioavailability of the drug relative to, for example, topical administration of the drug formulation to the ocular tissue surface; or provides improved bioavailability compared to the same dosage of drug administered orally, parenterally or intravitreally.
Using the methods and microneedle devices described herein, the SCS drug delivery methods advantageously include precisely controlling the depth of insertion into ocular tissue, such that the microneedle tips can be placed in the eye such 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 point of insertion of the microneedle is in the sclera of the eye. In one embodiment, drug influx into the SCS is achieved without concomitant contact of underlying tissues, such as choroidal and retinal tissues, with the microneedles.
In one embodiment, the methods provided herein achieve delivery of a drug to the suprachoroidal space, thereby allowing the drug to enter posterior ocular tissues that are not accessible for local, parenteral, intracameral, or intravitreal drug delivery. Because the methods provided herein deliver a drug to a posterior ocular tissue for treatment of a posterior ocular disorder or a choroidal disease, a choroidal drug dose sufficient to achieve a therapeutic response in a human subject treated with the methods provided herein is less than a intravitreal, topical, parenteral, or oral drug dose sufficient to elicit the same or substantially the same therapeutic response. In one embodiment, the SCS delivery methods described herein allow for a reduction in drug dose of a drug to treat a posterior ocular disorder or a drug to treat a choroidal disease, as compared to intravitreal, topical, intracameral, parenteral, or oral drug dose sufficient to elicit the same or substantially the same therapeutic response. In further embodiments, the choroidal drug dose sufficient to induce a therapeutic response is 75% or less, or 50% or less, or 25% or less of the intravitreal, topical, parenteral, or oral drug dose sufficient to induce a therapeutic response. In one embodiment, the therapeutic response is a reduction in the severity of the symptoms/clinical manifestations of the posterior ocular disorder or choroidal disease in the patient undergoing treatment, or a reduction in the number of one or more symptoms/one or more clinical manifestations of the posterior ocular disorder or choroidal disease in the patient undergoing treatment.
The term "suprachoroidal space" is used interchangeably with suprachoroidal (suprachoroidal), SCS, suprachoroidal (suprachoroidal), and suprachoroidal (suprachoroidia), and describes the possible spaces in the region of the eye that line between the sclera and the choroid. This region is composed primarily of a tightly packed layer of long pigmented processes derived from two adjacent tissues, however, gaps may form in this region due to the accumulation of fluids or other substances in the suprachoroidal space and adjacent tissues. Those skilled in the art will appreciate that the suprachoroidal space is typically expanded by fluid accumulation due to some disease state in the eye or as a result of some trauma or surgery. However, in the present specification, the suprachoroidal space (which is filled with the drug formulation) is intentionally created by infusion of the drug formulation onto the choroid to establish fluid accumulation. Without wishing to be bound by theory, it is believed that the SCS region serves as a pathway for uveoscleral outflow (i.e., the natural process of the eye that moves fluid from one region of the eye to other regions) and becomes a true gap in the event that the choroid detaches from the sclera.
As used herein, "ocular tissue" and "eye" 10 include both the
As provided throughout, in one embodiment, the methods described herein are performed with hollow or solid microneedles, e.g., rigid microneedles. The term "microneedle" as used herein refers to a catheter body (catheter body) having a base (base), a shaft (draft), and a tip, which is adapted for insertion into the sclera and other ocular tissues and has dimensions suitable for minimally invasive insertion and for infusion of pharmaceutical formulations as described herein. In other words, the microneedles are no more than about 2000 microns in length or effective length, and no more than about 600 microns in diameter. Both the "length" and "effective length" of the microneedle encompass the length of the shaft of the microneedle and the height of the bevel of the microneedle.
The term "hollow" as used herein includes single, straight bores through the center of the microneedles, as well as multiple bores, bores through the microneedles along complex paths, entry and exit points from one or more of the bores, and intersecting or reticulated bores. In other words, hollow microneedles have a structure that includes one or more continuous paths from the base of the microneedle to an exit point (opening) in the tip portion of the microneedle located in the shaft and/or distal to the base.
Fig. 2-5 illustrate exemplary embodiments of microneedle devices. In one embodiment, as illustrated in fig. 2-3,
The microneedle device can also comprise a fluid reservoir containing a drug formulation, e.g., as a solution or suspension, and a drug reservoir in operable communication with the bore of the microneedle at a location remote from the tip of the microneedle. The fluid reservoir may be integral with the microneedle, integral with the elongated body, or separate from both the microneedle and the elongated body.
The microneedles may be formed/constructed of different biocompatible materials including metals, glasses, 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 polymer may be biodegradable or non-biodegradable. Examples of suitable biocompatible biodegradable polymers include polylactide, polyglycolide, polylactide-co-glycolide (PLGA), polyanhydrides, polyorthoesters, polyetheresters, polycaprolactone, polyesteramides, poly (butyric acid), poly (valeric acid), polyurethanes, and copolymers and blends thereof. Representative non-biodegradable polymers include various thermoplastic or other polymeric structural materials known in the manufacture of medical devices. Examples include nylon, polyesters, polycarbonates, polyacrylates, polymers of ethylene vinyl acetate and other acyl substituted cellulose acetates, non-degradable polyurethanes, polystyrenes, polyvinyl chlorides, polyvinyl fluorides, poly (vinyl imidazoles), chlorosulfonic polyolefins, polyethylene oxides, and blends and copolymers thereof. Biodegradable microneedles can provide an increased level of safety compared to non-biodegradable microneedles, such that they are inherently harmless, even if inadvertently broken into ocular tissue.
The microneedles may be fabricated by various methods known in the art or as described in the examples below. In one embodiment, hollow microneedles are fabricated using a laser or similar source of light energy. In one example, a laser may be used to cut a blunt micro-needle to represent the desired microneedle length. A laser may also be used to shape a single or multiple tip openings. A single or multiple cuts may be made on a single blunt micro-needle to shape the desired microneedle structure. In one example, the micro-blunt needle may be made of a metal, such as stainless steel, and cut using a laser having a wavelength in the infrared region of the spectrum (e.g., about 0.7 to about 300 μm). Further refinement may be carried out using metal electropolishing techniques well known in the art. In another embodiment, the microneedle length and optional bevel are formed by a physical grinding process, which may include, for example, grinding the metal cannula against a moving abrasive surface. The manufacturing method may further include precision grinding, micro-bead blasting (micro-bead blasting) and ultrasonic cleaning to form the desired shape of the precision tip of the microneedle.
Further details of possible preparation 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.
The methods and devices provided herein allow for suprachoroidal drug delivery to be achieved in a minimally invasive, non-surgical manner, which is superior to other non-surgical (e.g., conventional needles) and surgical approaches. For example, in one embodiment, the methods provided herein are performed by using one or more microneedles. In one embodiment, the microneedles are inserted into the eye perpendicularly or at an angle of about 80 ° to about 100 °, e.g., into the sclera, to reach the suprachoroidal space with a short penetration distance. This is in contrast to long conventional needles or cannulas, which must reach the suprachoroidal space at a steep angle, taking a longer penetration path through the sclera and other ocular tissues, increasing the invasiveness of the procedure and the size of the needle track, and thus increasing the risk of infection and/or vascular rupture. With such a long needle, the ability to precisely control the depth of insertion is reduced relative to the microneedle approach described herein.
In one embodiment, the microneedle is part of a set of two or more microneedles, such that the method further comprises inserting at least a second microneedle into the sclera without passing through the sclera. In one embodiment, the drug formulation of each of the two or more microneedles may be the same or different from each other in terms of drug, formulation, volume/amount of drug formulation, or a combination of these parameters when a set of two or more microneedles are inserted into ocular tissue. In one instance, different types of drug formulations can be injected through one or more microneedles. For example, insertion of a second hollow microneedle comprising a second drug formulation into ocular tissue will result in delivery of the second drug formulation into the ocular tissue.
In another embodiment, the microneedle devices described herein are adapted to remove substances such as fluids, tissues or molecular samples from the eye.
However, one skilled in the art will appreciate that other types of microneedles (e.g., solid microneedles) and other methods of delivering drug formulations into the suprachoroidal space and the posterior ocular tissues may be used in place of or in combination with the delivery methods described herein. Non-limiting examples include at least partially dissolving a layer of the drug formulation from the microneedle; at least partially detaching a layer of the pharmaceutical formulation from the microneedles (e.g., as a substantially complete insert or in a segmented form); breaking or dissolving the microneedles away from a base to which the microneedles are integrally formed or attached; or any combination thereof.
The microneedle devices described herein can also be adapted to use one or more microneedles as sensors to detect analytes, electrical activity, and optical or other signals. The sensors may include sensors for pressure, temperature, chemicals, and/or electromagnetic fields (e.g., light). The biosensor may be located on or within the microneedle, or inside a device that communicates with body tissue via the microneedle. Microneedle biosensors can be any of the following four main classes of sensors: potentiometric sensors, amperometric sensors, optical sensors, and physicochemical sensors. In one embodiment, the hollow microneedles are filled with a substance having a sensing functionality associated therewith, such as a gel. Where sensing is applied based on a reaction that is bound to a substrate or mediated by an enzyme, the substrate or enzyme may be immobilized inside the needle. In another embodiment, the waveguide can be introduced into a microneedle device to direct light to a specific location, or detected using a tool such as a pH dye to assess color. Similarly, heat, electricity, light, ultrasound or other forms of energy may be delivered precisely to directly stimulate, damage or heal a particular tissue or for diagnostic purposes.
In one embodiment, a microneedle device for non-surgical delivery of a drug to the suprachoroidal space of an eye of a human subject comprises a hollow microneedle. The device may include an elongate housing for receiving the proximal ends of the microneedles. The device may further comprise means for guiding the drug formulation through the microneedles. For example, the tool may be a flexible or rigid catheter in fluid communication with the base or proximal end of the microneedle. The tool may also include a pump or other device for establishing a pressure gradient to induce fluid flow through the device. The catheter may be operably connected to a source of a pharmaceutical agent. 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.
In one embodiment, the microneedles are about 50 μm to about 2000 μm in effective length. In another specific embodiment, the microneedles have an effective length of about 150 μm to about 1500 μm, or about 300 μm to about 1250 μm, or about 500 μm to about 1500 μm, or about 600 μm to about 1000 μm, or about 700 μm to about 1000 μm. In one embodiment, the microneedles are about 600 μm, or about 700 μm, or about 800 μm or about 1000 μm in effective length. In various embodiments, the proximal portion of the microneedle has a maximum width or cross-sectional dimension of about 50 μm to 600 μm, or about 50 μm to about 400 μm, or about 50 μm to about 500 μm, or about 100 μm to about 400 μm, or about 200 μm to about 600 μm, or about 100 μm to about 250 μm, wherein the pore diameter is about 5 μm to about 400 μm. In a specific embodiment, the proximal portion of the microneedle has a maximum width or cross-sectional dimension of about 600 μm. However, one skilled in the art will appreciate that in embodiments where the microneedle tip is beveled, the bore diameter may be greater than the outer diameter of the proximal portion of the microneedle. Microneedles can be fabricated with an aspect ratio (width: length) of about 1:1.5 to about 1: 10. In one embodiment, the microneedles have an aspect ratio of about 1:3 to about 1: 5. In another embodiment, the microneedles have an aspect ratio of about 1:4 to about 1: 10.
The microneedles may have straight or tapered rods. In one embodiment, the diameter of the microneedle is largest at the base end of the microneedle and tapers to a point at the end distal from the base. Microneedles can also be fabricated having a shaft that includes both straight (i.e., non-tapered) and tapered (e.g., beveled) portions. In various embodiments, the microneedle has a bevel angle of about 5 degrees to about 30 degrees, about 5 degrees to about 25 degrees, about 5 degrees to about 20 degrees, about 10 degrees to about 20 degrees, and about 10 degrees to about 30 degrees. The microneedles may be formed from rods having a circular cross-section in the vertical direction, or the cross-section may be non-circular. The sharp portion of the microneedle can have a variety of configurations. The tips of the microneedles may be symmetrical or asymmetrical about the longitudinal axis of the shaft. The tip may be beveled, tapered, square or rounded. In various embodiments, the microneedles have a bevel height of about 50 μm to 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 particular embodiments, the microneedles can be designed such that the tip portion of the microneedle is substantially the only portion of the microneedle that is inserted into the ocular tissue (i.e., the tip portion is greater than 75% of the total length of the microneedle, greater than 85% of the total length of the microneedle, or greater than about 95% of the total length of the microneedle). In other specific embodiments, the microneedles may be designed such that the tip portion is the only portion of the microneedle that is inserted into the ocular tissue and is typically 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 microneedle has a total effective length in the range of 500 μm to 1500 μm, wherein the tip portion has a length of less than about 400 μm, less than about 300 μm, or less than about 200 μm.
In one embodiment, the height of the bevel is from 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 from about 200 μm to about 500 μm, or from about 100 μm to about 700 μm, or from about 200 μm to about 700 μm. In other embodiments, the height of the bevel is from about 500 μm to about 900 μm, or from about 500 μm to about 800 μm, or from about 500 μm to about 700 μm. In this manner, the arrangement of the bevels may be such that the distal edge is sufficiently sharp, such as to pierce palladium tissue and penetrate into the vitreous, without (i) substantially causing elastic deformation of the target tissue or (ii) damaging internal structures of the eye, such as the lens or retina.
In one embodiment, the microneedles extend from the base. The base may be integral with the microneedles or separate from the microneedles. The base may be rigid or resilient. The base may be substantially planar or curved, e.g., in the shape of the ocular tissue surface at the injection site, or curved away from the ocular surface (e.g., convex) to minimize contact between the base and the ocular tissue, for example. Desirably, the base is shaped to provide minimal contact with the surface of the eye at the injection site. For example, in one embodiment, the base may extend only a minimal distance from the substantially vertical microneedle shaft. In another embodiment, the base can be shaped to raise ocular tissue toward the microneedles to offset the deflection of the ocular tissue and facilitate insertion of the microneedles into the ocular tissue (e.g., the base can extend from the microneedles to the pointed portions of the microneedles to "pinch" the ocular tissue). Some such embodiments may be based, at least in part, on the apparatus described in U.S. patent No. 6,743,211, which is incorporated herein by reference.
In a specific embodiment, the microneedle device has a single microneedle. In one embodiment illustrated in fig. 5,
The microneedles can extend from the base of the microneedle device at any angle suitable for insertion into the eye. In a specific embodiment, the microneedles extend from the base at an angle of about 90 degrees to insert the microneedles substantially perpendicular to the surface of the eye. In another specific embodiment, the microneedles extend from the base at an angle of about 60 to about 110 degrees, or about 70 degrees to about 100 degrees, or about 80 degrees to about 90 degrees, or about 85 degrees to about 95 degrees.
The microneedle device can comprise means for controllably inserting microneedles into ocular tissue, and optionally retracting the microneedles. In addition, the microneedle device can include means for controlling the angle of insertion of the at least one microneedle into the ocular tissue (e.g., inserting the at least one microneedle into the surface of the ocular tissue at an angle of about 90 degrees).
The depth of insertion of a microneedle into ocular tissue can be controlled by the length of the microneedle as well as other geometric features of the microneedle. For example, a flange (flare) or other abrupt change in microneedle width can be used to limit the depth of insertion of the microneedle. Microneedle insertion can also be controlled using a mechanical micropositioning system that includes gears or other mechanical components that move the microneedles a controlled distance into ocular tissue, and likewise can be reversed to retract the microneedles a controlled distance. The depth of insertion can also be controlled by the speed of insertion of the microneedles into the ocular tissue. The retraction distance may be controlled by elastic recoil of the ocular tissue into which the microneedle is inserted, or by including an elastic element in the microneedle device that pulls the microneedle back a specific distance after the insertion force is released.
The angle of insertion may be oriented as follows: the microneedles are positioned at a first angle relative to the microneedle base and the base is positioned at a second angle relative to the ocular surface. In one embodiment, the first angle may be about 90 ° and the second angle may be about 0 °. The angle of insertion can also be oriented as follows: the microneedles are caused to protrude from a device housing through channels in the housing oriented at a particular angle.
Those skilled in the art can adapt the mechanical systems known in the art to incorporate the disclosure described in the present application and examples to design suitable structures, which can be manually operable, motor operable, or a combination thereof, to controllably advance the insertion of the microneedle.
The delivery of the drug formulation or biological fluid through the hollow microneedles can be controlled or monitored using, for example, 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, with a microprocessor programmed to control the pump or valve to control the rate of delivery of the drug formulation through the microneedles and into ocular tissue. Flow through the microneedles can be driven by diffusion, capillary action, mechanical pumping, electroosmosis, electrophoresis, convection, or other driving force. The device and microneedle design can be modified to utilize these drivers using known pumps and other devices. In one embodiment, the microneedle device can further comprise an iontophoretic device similar to that described in U.S. patent 6,319,240 to Beck for enhancing delivery of a drug formulation to ocular tissue. In another embodiment, the microneedle device can also include a flow meter or other means to monitor flow through the microneedles and to coordinate the use of pumps and valves.
The flow of the pharmaceutical agent or biological fluid may be regulated using various valves or gates known in the art. The valve may be a selectively and repeatedly openable and closable door, or it may be of a single-use type, such as a divisible barrier (fracturable barrier). Other valves or gates used in the microneedle devices can be activated thermally, electrochemically, mechanically, or magnetically to selectively initiate, regulate, or stop the flow of a substance through the microneedles. In one embodiment, the flow is controlled with a rate-limiting membrane that acts as a valve.
In another embodiment, the device comprises a set of two or more microneedles. For example, the device may comprise a set of 2-1000 (e.g., 2-100) microneedles. In one embodiment, a device comprises 1-10 microneedles. A set of microneedles can comprise a mixture of different microneedles. For example, a set of microneedles may include microneedles having different lengths, base portion diameters, tip portion shapes, spacing between microneedles, drug coatings, and the like. In embodiments in which the microneedle device comprises a set 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 set extends from the base.
The SCS drug delivery methods provided herein allow for delivery of drug formulations over larger tissue areas and to more difficult to deliver target tissues in a single dose than previously known needle devices. Without wishing to be bound by theory, it is believed that once inside the SCS, the drug formulation flows from the insertion site circumferentially to the retinochoroidal tissue, plaque, and optic nerve at the posterior segment of the eye, as well as onward to the uveal tract and ciliary body. In addition, a portion of the infused drug formulation can be kept in the SCS as a reservoir (depot); or in tissue above the SCS, such as the sclera near the insertion site of the microneedle, serves as an additional reservoir for the drug formulation, which can then diffuse into the SCS and into other adjacent posterior tissue.
The microneedle devices and non-surgical methods described herein can be used to deliver a drug formulation to the eye of a human subject, particularly for treating, diagnosing, or preventing a posterior ocular disorder or choroidal disease. In one embodiment, the pharmaceutical formulation comprises an effective amount of an anti-inflammatory agent, an immunosuppressive agent, a VEGF modulator (e.g., a VEGF antagonist), an angiogenesis inhibitor (e.g., a PDGF antagonist), or a vascular permeability inhibitor. In another embodiment, the formulation comprises an anti-inflammatory agent selected from the group consisting of a steroidal compound and a non-steroidal anti-inflammatory drug (NSAID). In a further embodiment, the pharmaceutical formulation is a triamcinolone formulation, e.g., a triamcinolone acetonide formulation.
In one aspect, the invention relates to treating a choroidal disease in a human patient in need thereof. In one embodiment, the method comprises non-surgically delivering a pharmaceutical formulation comprising an effective amount of a drug for treating a choroidal disorder to the suprachoroidal space of one or both eyes of a patient in need of treatment. It should be understood that a patient with one eye will receive treatment of only one eye.
In one aspect, the methods and microneedles described herein relate to non-surgical administration of a drug formulation for treatment of a choroidal disease or posterior ocular disorder, wherein a majority of the drug formulation remains in the SCS in one or both eyes of a patient in need of treatment of the 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, retention of the drug formulation in the SCS contributes to the sustained release profile of the drug formulation described herein.
The human subject treated by the methods provided herein can be an adult or a child. A wide range of posterior ocular disorders and conditions, as well as choroidal diseases, may be treated with the methods, devices, and pharmaceutical formulations described herein.
Examples of posterior ocular disorders amenable to treatment by the methods, devices, and pharmaceutical 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, ocular cancer, one or more genetic diseases, autoimmune diseases affecting the posterior segment of the eye, retinitis (e.g., cytomegalovirus retinitis), and corneal ulcers. Posterior ocular disorders amenable to treatment with the methods, devices, and pharmaceutical formulations described herein may be acute or chronic. For example, the ocular disease may be acute or chronic uveitis. Uveitis can be caused by: infection with a virus, fungus or parasite; the presence of non-infectious foreign bodies in the eye; (ii) an autoimmune disease; or surgical or traumatic injury. Disorders caused by pathogenic organisms that can lead to uveitis or other types of ocular inflammation include, but are not limited to, toxoplasmosis, toxocariasis, histoplasmosis, herpes simplex or herpes zoster infection, tuberculosis, syphilis, sarcoidosis, Vogt-Koyanagi-Harada syndrome, behcet's disease, idiopathic retinal vasculitis, Vogt-small salix-pristina syndrome, acute posterior multifocal squamous pigment epithelial lesion (APMPPE), pseudohistoplasmosis syndrome (POHS), shotgun-bullet-like choroidopathies disease (birdshocholoroidopathy), multiple sclerosis, cross-sensibility, punctate intimal choroidopathy, pars plana, or iridocyclitis. Acute uveitis occurs suddenly and can last for up to about 6 weeks. Chronic uveitis is a form of uveitis with gradual onset of signs and/or symptoms, and symptoms persist for more than about 6 weeks.
Signs of uveitis include ciliary hyperemia, aqueous humor flare, accumulation of cells visible in ophthalmic examinations (such as aqueous humor cells, cells behind the lens, and vitreous cells), post-corneal deposits, and anemia. Symptoms of uveitis include pain (such as ciliary muscle 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 also commonly referred to as choroiditis. Posterior uveitis may also be associated with inflammation occurring in the retina (retinitis) or in the blood vessels of the posterior segment of the eye (vasculitis). In one embodiment, the methods provided herein include non-surgically administering to a uveitis patient in need thereof an effective amount of a drug for treating uveitis to the SCS of the eye of the patient. In further embodiments, the patient experienced a reduction in the severity of the symptoms after administration of a drug to SCS to treat uveitis.
In one embodiment, delivery of the drug formulation to the SCS results in the patient experiencing a decrease as follows: inflammation, neuroprotection, complement inhibition, drusen formation, scar formation, and/or a decrease in choroidal capillaries or choroidal neovascularization.
The non-surgical methods described herein are particularly useful for the local delivery of drugs to the posterior region of the eye, such as the retinochoroidal tissue, plaques, and the optic nerve of the posterior segment of the eye. In one embodiment, the non-surgical treatment methods and devices described herein can be used in gene-based therapy applications. For example, in one embodiment, the method comprises administering a pharmaceutical formulation into the suprachoroidal space to deliver a selected DNA, RNA or oligonucleotide to the targeted ocular tissue.
As provided throughout, the methods described herein are also amenable to treatment of choroidal disorders in patients in need of such treatment. In one embodiment, the patient in need of treatment for the choroidal disease is unresponsive to non-SCS methods of previously treating the choroidal disease. Examples of choroidal disorders amenable to treatment by the methods, devices, and pharmaceutical formulations described herein include, but are not limited to, choroidal neovascularization, polypoidal choroidal vasculopathy, central serous choroidopathy, multifocal choroidopathy, or choroidal atrophy (e.g., central circular choroidopathy, creeping choroidopathy, or complete central choroidal atrophy). Choroidal disorders are described in further detail below.
In one embodiment, the agent for treating a choroidal disease is an angiogenesis inhibitor, vascular permeability inhibitor, or anti-inflammatory agent. In one embodiment, the angiogenesis inhibitor is a Vascular Endothelial Growth Factor (VEGF) modulator or a platelet-derived growth factor (PDGF) modulator. In one embodiment, the method of treating a choroidal disorder comprises microneedle administration of a drug formulation to the SCS of one or both eyes of a patient in need of treatment. In a further embodiment, the microneedle is a hollow microneedle having a tip and an opening, and the drug formulation is infused into the SCS of one or both eyes through the tip of the hollow microneedle.
In one embodiment, a method of treating a posterior ocular disorder or a choroidal disease in a human subject in need thereof comprises non-surgically administering a drug formulation to the suprachoroidal space of the eye of the human subject, wherein upon administration, the drug formulation flows away from the insertion site and substantially concentrates in the posterior segment of the eye. In one embodiment, the non-surgical methods provided herein allow for longer retention of the drug in the eye as compared to the same drug dose administered intravitreally, topically, parenterally, intracamerally, or orally.
In one embodiment, the choroidal drug dose sufficient to achieve a therapeutic response in a human subject treated with the non-surgical SCS drug delivery method is less than the intravitreal, parenteral, intracameral, topical, or oral drug dose sufficient to elicit the same or substantially the same therapeutic response. In further embodiments, the choroidal drug dose is at least 10% lower than the oral, parenteral, or intravitreal dose sufficient to achieve the same or substantially the same therapeutic response. In further embodiments, the choroidal dose is about 10% to about 25% lower, or about 10% to about 50% lower than an oral, parenteral, intracameral, topical, or intravitreal dose sufficient to achieve the same or substantially the same therapeutic response. Thus, in one embodiment, the methods of treating posterior ocular disorders or choroidal diseases described herein achieve greater therapeutic efficacy than other routes of administration. In one embodiment, the non-surgical methods provided herein include inserting a hollow microneedle into the sclera of an eye of a human subject and infusing a drug formulation through the hollow microneedle and into the suprachoroidal space of the eye. As described in more detail below, in one embodiment, the pharmaceutical formulation is a solution or suspension of the drug.
In one embodiment, wherein the non-surgical method for treating a posterior ocular disorder or a choroidal disease in a human subject comprises delivering a drug to the SCS of one or both eyes of the patient via a microneedle (hollow or solid) inserted at a site between the equator and limbus of each eye.
In another embodiment, the insertion site is between about 2mm to about 10mm posterior to the limbus of the eye. In one embodiment, the microneedle insertion site is at a flat portion. However, in other embodiments the insertion site is outside of the flat portion. In one embodiment, the insertion site of the microneedle is at about the equator of the eye.
In another embodiment, the insertion site is 2-10mm anterior to the limbus of the eye, e.g., about 5mm anterior to the limbus of the eye.
In another embodiment, the drug formulation is introduced into the SCS at the injection site (i.e., at the tip of the microneedle) and then flows through the SCS away from the injection site as the injection is performed. In another embodiment, the injection site (i.e., at 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., at 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 of the eye during injection (i.e., as the drug formulation continues to flow out of the microneedle).
In one embodiment, the depth of insertion of the microneedles into ocular tissue is precisely controlled. A variety of methods can be used to control the insertion depth of the microneedles described herein. In a particular embodiment, the insertion depth is limited by the length or effective length of the microneedle selected. The "effective length" is the portion available for tissue insertion, i.e., the length extending from the base and to be inserted (if tissue deformation is zero). The "effective length" ignores the proximal portion of any microneedle that extends into or through the base and thus cannot be inserted into tissue, and includes both microneedle shaft length and bevel length. In other words, the microneedle has an effective length approximately equal to the desired penetration depth. In one embodiment, the microneedles are short enough so that the tips of the microneedles are inserted substantially into the base of the sclera (i.e., near the interface of the sclera and choroid) without passing completely through the sclera. In another embodiment, the tip of the microneedle is inserted into the suprachoroidal space through the sclera without passing through the choroid.
In another embodiment, the microneedles are designed to have a length longer than the desired penetration depth, but the microneedles are controllably only partially inserted into the tissue. Partial insertion may be controlled by the mechanical properties of the tissue, which bends and sags during insertion of the microneedle. In this manner, when the microneedles are inserted into tissue, their motion causes the tissue to deform elastically in part and to penetrate partially into the tissue. By controlling the degree of tissue deformation, the depth of insertion of the microneedle into the tissue can be controlled.
In one embodiment, the microneedle is inserted into the eye of a human patient using a rotary/drilling technique and/or a wiggle action. In this way, the microneedles may be inserted to a desired depth by: for example, microneedles are drilled at a desired number of rotations, which corresponds to a desired depth of insertion into tissue. For a description of drilling microneedles, see, e.g., U.S. patent application publication No. 2005/0137525, which is incorporated herein by reference. The rotation/drilling technique and/or the rocking action may be used during the insertion step, the retraction step, or both.
In one embodiment, the drug formulation is infused into the suprachoroidal space through a hollow microneedle as follows: a pressure gradient (e.g., pump, syringe) is used to push the drug formulation from the source reservoir into the ocular tissue. In other embodiments, the drug formulation is pushed from the source reservoir into the ocular tissue using an electric field (e.g., iontophoresis) or another externally applied energy (e.g., ultrasound/sonic energy).
In one embodiment, the amount of drug formulation infused into the suprachoroidal space from the non-surgical drug delivery methods described herein is from about 10 μ L to about 200 μ L, e.g., from about 50 μ L to about 150 μ L. In another embodiment, about 10 μ L to about 500 μ L, e.g., about 50 μ L to about 250 μ L, is administered non-surgically to the suprachoroidal space. For example, in one embodiment, the non-surgical method comprises inserting a hollow microneedle into the sclera at an insertion site, the microneedle having a tip with an opening, and infusing a drug formulation through the hollow microneedle and into the suprachoroidal space. As described above, about 10 μ L to about 200 μ L, or about 50 μ L to about 150 μ L, or about 10 μ L to about 500 μ L, or about 50 μ L to about 250 μ L can be delivered via one or more hollow microneedles described herein.
In one embodiment, the impulse or pressure of infusing the drug formulation through the hollow microneedle during administration (i.e., during infusion) causes the infused drug formulation to flow within the suprachoroidal space and reach the back of the eye. This may occur in less than 1 or2 minutes, such as from about 1 second to about 100 seconds, e.g., from about 10 seconds to about 30 seconds. In one aspect, during and after infusion of the drug to the SCS, the drug formulation flows away from the insertion site. In further embodiments, the drug flows around in the suprachoroidal space during infusion to a site at least 2.5mm from the insertion site, or at least 5mm from the insertion site, or at least 7.5mm from the insertion site, or at least 10mm from the insertion site. In one embodiment, the pharmaceutical formulation flows around in the suprachoroidal space, from the insertion site to the posterior (posterior) segment of the eye (i.e., the retinochoroidal tissue, the macula, and the optic nerve at the posterior segment of the eye).
The amount of drug delivered in the SCS can also be controlled by the type of microneedle used and how it is used. In one embodiment, a hollow microneedle is inserted into ocular tissue and progressively retracted from the ocular tissue after insertion to deliver a fluidic drug, wherein after a dose is reached, delivery can be stopped by deactivating a fluidic impulse 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 pushing the fluid drug formulation at a suitable infusion pressure. In one embodiment, the infusion pressure may be at least 150kPa, at least 250kPa, or at least 300 kPa. In another embodiment, the infusion pressure is from about 150kPa to about 300 kPa. Suitable infusion pressures may vary with the particular patient or species.
It should be noted that the desired infusion pressure to deliver a suitable amount of the drug formulation may be influenced by the depth of insertion of the microneedle and the composition of the drug formulation. For example, in embodiments where the pharmaceutical formulation for delivery into the eye is in the form of or includes nanoparticles or microparticles or microbubbles encapsulating the active agent, greater infusion pressure may be required. Nanoparticle or microparticle encapsulation techniques are well known in the art. In one embodiment, the pharmaceutical formulation consists of D in a suspension99Is composed of drug particles of 10 μm or less. In one embodiment, the pharmaceutical formulation consists of D in a suspension99Is composed of drug particles of 7 μm or less. In another embodiment, the pharmaceutical formulation consists of D in a suspension99Is composed of drug particles of 3 μm or less. In another embodiment, the pharmaceutical formulation consists of D in a suspension50Is composed of drug particles of 5 μm or less. In one embodiment, the pharmaceutical formulation consists of D in a suspension50Is composed of drug particles of 1 μm or less.
In one embodiment, the non-surgical method of administering a drug to the SCS further comprises partially retracting the hollow microneedle after inserting the microneedle into the eye and before and/or during infusion of the drug formulation into the suprachoroidal space. In a specific embodiment, the partial retraction of the microneedles occurs prior to the step of infusing the drug formulation into the ocular tissue. This insertion/retraction step can form a pocket and beneficially allow the drug formulation to flow out of the microneedle without or with less obstruction by ocular tissue at the opening of the tip portion of the microneedle. The pocket may be filled with a drug formulation, but may also act as a conduit through which a drug formulation may flow from the microneedle, through the pocket and into the suprachoroidal space. Fig. 6A shows a
In one embodiment, the microneedles infuse drug formulations through the sclera into the suprachoroidal space for controlled (i.e., sustained, prolonged, or modulated over time) release of the drug to one or more of the eye or adjacent tissues. This "controlled release" or "sustained release" or "extended release" or "modified release" is generally more extended than the release obtainable by topical administration or intravitreal injection of a pharmaceutical formulation into ocular tissue. In one embodiment, there is controlled, prolonged, sustained or modulated release of the drug formulation after the at least one microneedle is withdrawn from the ocular tissue. This method of delivery is particularly beneficial to ocular tissues, where it is desirable that the insertion and withdrawal process occur over as short a time as possible to minimize patient discomfort — as opposed to transdermal microneedle patch administration, where the patch is more likely to wear (with microneedles inserted) over an extended period of time without causing patient discomfort.
In another aspect, a method of treating a posterior ocular disorder or a choroidal disease by non-surgically administering a drug to the suprachoroidal space of the eye of a human subject comprises monitoring insertion of the microneedle and/or infusion of the fluid drug formulation to ensure accurate delivery of the fluid drug formulation to the SCS (see, e.g., fig. 18). The monitoring may be accomplished in one or more of these steps using an image-guided feedback method, non-limiting examples of which include conventional microscopy, MRI, X-ray, confocal microscopy, ocular coherence tomography (e.g., anterior segment optical coherence tomography, haddock retinal tomography, spectral domain optical coherence tomography), fluorescein angiography, indocyanine green angiography, high resolution stereo fundus photography, autofluorescence imaging, ultra-wide field imaging, and various ultrasound techniques. Thus, the method may further comprise determining whether the initially infused fluid drug formulation flowed into the suprachoroidal space of the eye and away from the insertion site. If it is determined that the initial infusion was successful, a desired volume of the fluid drug formulation may be infused and the infusion interrupted by removing the hydrodynamic force, such as pressure, and retracting the microneedles from the eye. However, if it is determined that the initial infusion of the fluid drug formulation was unsuccessful (i.e., substantially no drug formulation flowed into the suprachoroidal space of the eye and away from the insertion site), the microneedles can be repositioned and the process repeated until successful delivery is achieved.
Targeting drug formulations to SCS and posterior ocular tissues allows high concentrations of drug to be delivered to the choroid/sclera and retina with little or no drug deliveryThe drug is delivered to the aqueous humor of the anterior chamber. In addition, the methods provided herein allow more drug to be retained in the eye than other drug delivery methods, e.g., a greater amount of drug is retained in the eye when delivered by the methods provided herein, as compared to the same dose delivered by intracameral, intravitreal, topical, parenteral, or oral drug delivery methods. Thus, in one embodiment, the intraocular elimination half-life (t) of the drug when delivered by the methods described herein1/2) Greater than the intraocular t of the same drug when administered intravitreally, intracamerally, topically, parenterally or orally at the same drug dose1/2. In another embodiment, the intraocular C of the drug when delivered by the methods described hereinmaxGreater than the intraocular C of the same drug when administered intravitreally, intracamerally, topically, parenterally or orally at the same drug dosemax. In another embodiment, the mean area under the intraocular curve (AUC) of the drug when administered to SCS by the methods described herein0-t) Greater than the intraocular AUC of said drug when administered intravitreally, intracamerally, topically, parenterally or orally0-t. In another embodiment, the time to peak intraocular concentration (t) of the drug when administered to SCS by the methods described hereinmax) Greater than the intraocular t of the same drug when administered intravitreally, intracamerally, topically, parenterally or orally at the same drug dosemax. In further embodiments, the drug is 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. In still further embodiments, the drug is triamcinolone, infliximab, mycophenolate mofetil, sorafenib, axitinib, or nepafenac.
In one embodiment, the intraocular t of the drug when administered by the non-surgical SCS drug delivery methods provided herein is1/2Longer than the intraocular t of the same dose administered topically, intracamerally, intravitreally, orally or parenterally1/2. In further embodiments, the non-hand is provided hereinIntraocular t of surgical SCS drug delivery method upon administration of said drug1/2Intraocular t of said drug for topical, intracameral, intravitreal, oral or parenteral administration of the same dose1/2From about 1.1 times to about 10 times, or from about 1.25 times to about 10 times, or from about 1.5 times to about 10 times, or from about 2 times to about 5 times. In further embodiments, the drug is 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.
In another embodiment, the intraocular C of the drug when delivered by the methods described hereinmaxGreater than the intraocular C of the same drug when administered intravitreally, intracamerally, topically, parenterally or orally at the same drug dosemax. In further embodiments, intraocular C of the drug when administered by the non-surgical SCS drug delivery methods provided hereinmaxIntraocular C of said drug for topical, intracameral, intravitreal, oral or parenteral administration of the same dosemaxAt least 1.1 times, or at least 1.25 times, or at least 1.5 times, or at least 2 times, or at least 5 times. In one embodiment, intraocular C of the drug when administered by the non-surgical SCS drug delivery methods provided hereinmaxIntraocular C of said drug for topical, intracameral, intravitreal, oral or parenteral administration of the same dosemaxFrom about 1 to about 2 times, or from about 1.25 to about 2 times, or from about 1 to about 5 times, or from about 1 to about 10 times, or from about 2 to about 5 times, or from about 2 to about 10 times. In further embodiments, the drug is 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. In one embodiment, the drug is triamcinolone, infliximab, mycophenolate mofetil, methotrexate, sorafenib, axitinib, or nepafenac.
In another embodiment, the mean area under the intraocular curve (AUC) of the drug when administered to SCS by the methods described herein0-t) Greater than in and before the vitreous bodyIntraocular AUC of said drug upon intracameral, topical, parenteral, or oral administration0-t. In further embodiments, the AUC in the eye of the drug when administered by the non-surgical SCS drug delivery methods provided herein0-tIs the intraocular AUC of the drug when the same dose is administered topically, intracamerally, intravitreally, orally or parenterally0-tAbout at least 1.1 times, or at least 1.25 times, or at least 1.5 times, or at least 2 times, or at least 5 times greater. In one embodiment, the intraocular AUC of the drug when administered by the non-surgical SCS drug delivery methods provided herein0-tIs the intraocular AUC of the drug when the same dose is administered topically, intracamerally, intravitreally, orally or parenterally0-tFrom about 1 to about 2 times, or from about 1.25 to about 2 times, or from about 1 to about 5 times, or from about 1 to about 10 times, or from about 2 to about 5 times, or from about 2 to about 10 times. In further embodiments, the drug is 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. In still further embodiments, the drug is triamcinolone, infliximab, mycophenolate mofetil, methotrexate, sorafenib, axitinib, or nepafenac.
In one embodiment, a pharmaceutical 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 immunosuppressive agent, or a vascular permeability inhibitor) is substantially retained in the SCS for a period of time once delivered thereto. For example, in one embodiment, about 80% of the drug formulation remains in the SCS for about 30 minutes, or about 1 hour, or about 4 hours or about 24 hours or about 48 hours or about 72 hours. In view of this, a reservoir of drug is formed in the SCS and/or surrounding tissue, allowing for sustained release of the drug over a period of time.
In one embodiment, the suprachoroidal space, once loaded with a drug (e.g., drug microparticles or nanoparticles), provides sustained release of the drug to the retina or other posterior ocular tissues over a period of time. Targeting a drug to the posterior ocular tissue via the methods described herein allows for greater therapeutic efficacy in treating one or more posterior ocular disorders or choroidal diseases (e.g., PCV) as compared to other methods of administration of the same drug dose, such as intravitreal, intracameral, oral, parenteral, and topical delivery of the same drug dose. In further embodiments, the therapeutic effect of the drug delivered to the SCS is achieved at a lower dose than an intravitreal, intracameral, 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 with the methods provided herein result in a reduced number of side effects of the drug, and/or a reduced severity of one or more side effects, as compared to higher or the same drug dose delivered to a human patient via a non-choroidal route of administration (e.g., intravitreal, intracameral, topical, parenteral, oral). For example, the methods provided herein result in a reduction in the number of side effects, or a reduction in the severity of one or more side effects or clinical manifestations, as compared to the administration of the same drug at the same dose orally, topically, intracamerally, parenterally, or intravitreally. In one embodiment, the reduced side effects or clinical manifestations in the treated patient are subretinal exudation and/or subretinal hemorrhage.
In one embodiment, the non-surgical suprachoroidal drug delivery methods provided herein result in increased therapeutic efficacy and/or improved therapeutic response as compared to oral, parenteral, and/or intravitreal drug delivery methods at the same or similar drug doses. In one embodiment, the dosage of SCS drug sufficient to provide a therapeutic response is about 90%, or about 75%, or about half (e.g., about half or less) of the intravitreal, intracameral, topical, oral, or parenteral drug dosage sufficient to provide the same or substantially the same therapeutic response. In another embodiment, the dosage of SCS sufficient to provide a therapeutic response is about one-fourth of the dosage of intravitreal, intracameral, topical, oral, or parenteral drug sufficient to provide the same or substantially the same therapeutic response. In another embodiment, the dosage of SCS sufficient to provide a therapeutic response is one tenth of the dosage of intravitreal, intracameral, topical, oral, or parenteral drug sufficient to provide the same or substantially the same therapeutic response. In one embodiment, the therapeutic response is a decrease 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.
In one embodiment, the total amount of effective amount of drug in the pharmaceutical formulation is from about 0.05mg to about 5 mg. In one embodiment, the total amount of drug in the pharmaceutical formulation is from about 0.2mg to about 4 mg. In another embodiment, the total amount of drug in the pharmaceutical formulation is from about 1mg to about 4 mg. The drug dosage may be varied according to methods known to those skilled in the art and will vary, for example, based on the age of the patient and the clinical manifestations of the posterior ocular disorder or choroidal disease.
The therapeutic effect of a pharmaceutical formulation delivered by the methods described herein and the therapeutic response of the human subject can be determined by standard means in the art, as known to those skilled in the art. In general, the therapeutic effect of any particular drug can be determined by measuring the response of the human subject after administration of the drug; a drug with a high therapeutic effect will show a greater improvement and/or cessation of symptoms than a drug with a lower therapeutic effect. In non-limiting examples, the efficacy of a pharmaceutical formulation provided herein (e.g., an angiogenesis inhibitor, an anti-inflammatory agent (e.g., a steroid or NSAID), a VEGF modulator (e.g., a VEGF antagonist), a PDGF modulator (e.g., a PDGF antagonist), an immunosuppressive agent, or a vascular permeability inhibitor formulation) can be measured as follows: for example, changes in pain intensity, ocular damage (size or number), intraocular pressure, inflammation (e.g., measuring changes in a Hackett/McDonald ocular score), ocular hypertension, and/or changes in visual acuity are observed.
In another embodiment, the effect of a drug such as 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 can be measured as follows: example (b)For example, changes in inflammation, visual acuity and/or edema as measured by a Hackett/McDonald ocular score are observed. In another embodiment, the effect of a drug such as triamcinolone or mycophenolate can be measured as follows: for example, changes in inflammation, visual acuity and/or edema as measured by a Hackett/McDonald ocular score are observed. In another embodiment, the therapeutic effect of a drug, such as sorafenib and/or axitinib, can be measured as follows: for example, the growth and/or number of lesions is observed. In another embodiment, a drug such as infliximab can be measured as follows
In another embodiment, the effect of a drug, e.g., an anti-inflammatory agent, such as a TNF family antagonist, e.g., a TNF- α antagonist, a lymphotoxin α antagonist, a lymphotoxin β antagonist, a CD27L antagonist, a CD20L antagonist, a FASL antagonist, a 4-BBL antagonist, an OX40L antagonist, a TNF-related apoptosis-inducing ligand (TRAIL) antagonist, a Janus kinase (JAK) antagonist, or an interleukin antagonist, can be measured, e.g., by observing changes in inflammation, injury, cell death, and/or visual acuity.
In one embodiment, non-surgical administration of an effective amount of the drug formulation to the SCS results in a reduction in the number of adverse side effects or clinical manifestations compared to the number of side effects or clinical manifestations 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 results in a reduction in the number of one or more adverse side effects or clinical manifestations compared to those caused by the same drug dose administered intravitreally, intracamerally, orally, or parenterally. Examples of side effects and clinical manifestations that may be reduced or ameliorated include, but are not limited to, inflammation, gastrointestinal side effects (e.g., diarrhea, nausea, gastroenteritis, vomiting, gastrointestinal, rectal, duodenal bleeding, hemorrhagic pancreatitis, perforation of the large intestine, black or bloody stools, and/or hemoptysis); hematologic side effects (e.g., leukopenia, anemia, pancytopenia and agranulocytosis, thrombocytopenia, neutropenia, pure red blood cell regeneration disorder (PRCA), deep vein thrombosis, easy abrasion, and/or unusual bleeding from the nose, mouth, vagina, or rectum); immunological side effects/clinical manifestations (e.g., immunosuppression leading to sepsis, opportunistic infections (herpes simplex virus, herpes zoster, and invasive candida infections), and/or increased infections); oncological side effects/clinical manifestations (e.g., lymphoma, lymphoproliferative disease and/or non-melanoma skin cancer); renal side effects/clinical manifestations (e.g., dysuria, urgency, urinary tract infection, hematuria, tubular necrosis, and/or BK virus-associated renal disease); metabolic side effects/clinical manifestations (e.g., edema, hyperphosphatemia, hypokalemia, hyperglycemia, hyperkalemia, swelling, increased weight gain, and/or swollen thyroid); respiratory side effects/clinical manifestations (e.g., respiratory tract infections, dyspnea, increased cough, primary tuberculosis, dry cough, wheezing, and/or nasal congestion); dermatological side effects/clinical manifestations (e.g., acne, skin rash, sweat blister, papulosquamous psoriasis-like rash, blister, exudation, mouth ulcer, and/or hair loss); musculoskeletal side effects/clinical manifestations (e.g., myopathy and/or muscle pain), hepatic side effects/clinical manifestations (e.g., hepatotoxicity and/or jaundice), abdominal pain, increased incidence of miscarriage during the first trimester of pregnancy, missed menstrual periods, severe headaches, confusion, altered mental status, vision loss, seizures (convulsions), increased sensitivity to light, dry eye, redness, itching of the eye, and/or high blood pressure. As noted above, the reduction or improvement in the side effect or clinical manifestation is a reduction or improvement in the severity of the side effect or clinical manifestation as compared to prior to administration of the pharmaceutical formulation to the SCS of the eye of the patient, or as compared to the reduction or improvement experienced by the patient upon intravitreal, intracameral, parenteral or oral administration of the same drug.
In one embodiment, non-surgical administration of an effective amount of a drug formulation to the SCS results in a reduction in the number of choroidal disease symptoms compared to the number of symptoms experienced by the patient prior to administration of the drug to the SCS, or after treatment with the same drug dose administered intravitreally, intracamerally, orally, or parenterally.
In one embodiment, non-surgical administration of a pharmaceutical formulation comprising an effective amount of a drug for treating a choroidal disorder to the SCS of one or both eyes of a patient results in a reduction in the number of adverse side effects or adverse clinical manifestations compared to the number of adverse side effects or clinical manifestations caused by the same drug dose administered intravitreally, intracamerally, orally, topically or parenterally. In another embodiment, non-surgical administration of an effective amount of the drug formulation to the SCS results in a reduction in severity of side effects or clinical manifestations in patients with choroidal disorders. In a further embodiment, the severity of the side effects or clinical manifestations is reduced compared to the severity of adverse side effects or clinical manifestations caused by the same dose of drug administered intravitreally, intracamerally, orally, topically or parenterally. For example, in one embodiment, the subretinal leakage and/or the subretinal bleeding are reduced in a patient with a choroidal disorder upon administration of a drug formulation to the SCS of the eye of the patient, as compared to the subretinal leakage and/or the subretinal bleeding prior to administration of the drug to the SCS. In further embodiments, there is a reduction in subretinal extravasation and/or a reduction in subretinal hemorrhage in the patient, as compared to the reduction in severity experienced when the same drug is administered intravitreally, intracamerally, orally, topically, or parenterally.
Delivering the drug formulation to the SCS allows greater retention of the drug in the posterior tissues of the eye compared to delivering the same drug via topical, intravitreal, intracameral, oral, or parenteral routes. In one embodiment, the drug concentration achieved after a single dose may be greater than 10 μ g/g of posterior ocular tissue for 28 days or longer. In another embodiment, the drug concentration achieved after a single dose may be greater than 100 μ g/g of posterior ocular tissue for 28 days or more. In another embodiment, the drug concentration achieved after a single dose may be greater than 1000 μ g/g tissue for more than 28 days. More hydrophobic drugs have been found to be slowly cleared from the SCS compared to more water soluble drugs. In one embodiment, the drug formulation administered to the SCS comprises a more hydrophobic drug.
In one embodiment, a method of treating a choroidal disorder in a patient is provided, wherein the method comprises non-surgically administering a drug formulation comprising an effective amount of a choroidal disorder treating drug (e.g., an angiogenesis inhibitor such as a VEGF modulator) to the SCS of one or both eyes of the patient in need of treatment, wherein upon administration, the drug formulation substantially concentrates in the posterior segment of the eye. In a further embodiment, the pharmaceutical formulation is substantially concentrated in the RPE. In one embodiment, the drug is substantially concentrated in the macula or the subretinal space. In one embodiment, the method is performed using one or more of the microneedles described herein.
In one embodiment, a method of treating a choroidal disease in a human subject in need thereof comprises non-surgically administering a pharmaceutical formulation comprising an effective amount of a choroidal disease treating drug to the suprachoroidal space of one or both eyes of the human subject. In a further embodiment, the effective amount of the medicament for treating a choroidal disease comprises an effective amount of an anti-inflammatory agent, a Vascular Endothelial Growth Factor (VEGF) modulator, a platelet-derived growth factor (PDGF) modulator, an angiogenesis inhibitor, an immunosuppressant, or a vascular permeability inhibitor. In one embodiment, once administered, the pharmaceutical formulation for treating choroidal disorders flows away from the insertion site and substantially concentrates in the posterior segment of the eye. In one embodiment, the non-surgical methods provided herein allow for longer retention of the drug in the eye as compared to intravitreal, topical, parenteral, or oral administration of the same drug dose.
In patients undergoing ocular treatment via a shunt or cannula or other surgical methods, significant increases or decreases in intraocular pressure have been reported after initiation of the treatment method. In one embodiment, the intraocular pressure (IOP) of the eye of the patient undergoing treatment for the posterior ocular disorder or the choroidal disease is substantially the same IOP after 2 minutes, 10 minutes, 15 minutes, or 30 minutes of suprachoroidal drug administration as compared to the IOP of the eye of the patient prior to administration of the posterior ocular disorder or the choroidal disease therapeutic drug. In one embodiment, the IOP of the eye of the patient undergoing treatment for the posterior ocular disorder or the choroidal disease does not change by more than 10% after 2 minutes, 10 minutes, 15 minutes, or 30 minutes of suprachoroidal drug administration as compared to the IOP of the eye of the patient prior to administration of the posterior ocular disorder or the choroidal disease therapeutic drug. In one embodiment, the IOP of the eye of the patient undergoing treatment for the posterior ocular disorder or the choroidal disease does not change by more than 20% after 2 minutes, 10 minutes, 15 minutes, or 30 minutes of suprachoroidal drug administration as compared to the IOP of the eye of the patient prior to administration of the posterior ocular disorder or the choroidal disease therapeutic drug. In one embodiment, the IOP of the eye of the patient undergoing treatment for the posterior ocular disorder or the choroidal disease does not change by more than 10% to 30% after 2 minutes, 10 minutes, 15 minutes, or 30 minutes of suprachoroidal drug administration as compared to the IOP of the eye of the patient prior to administration of the posterior ocular disorder or the choroidal disease therapeutic drug. In a further embodiment, the effective amount of the medicament for treating a posterior ocular disorder or a choroidal disease comprises an effective amount of an anti-inflammatory agent, a Vascular Endothelial Growth Factor (VEGF) modulator, a platelet-derived growth factor (PDGF) modulator, an angiogenesis inhibitor, an immunosuppressant, or an inhibitor of vascular permeability.
In one embodiment, the choroidal disorder amenable to treatment by the methods described herein is choroidal neovascularization, choroidal sclerosis, polypoidal choroidal vasculopathy, central serous choroidal pathology, multifocal choroidal pathology, or choroidal dystrophy. Choroidal dystrophy, for example central circular choroidal degeneration, paranoid degeneration or complete central choroidal atrophy. In some embodiments, a patient in need of treatment for a choroidal disorder experiences subretinal exudation and hemorrhage, and the methods provided herein reduce subretinal exudation and/or hemorrhage compared to the subretinal exudation and/or hemorrhage 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 leakage and bleeding, and after one of the non-surgical treatments provided herein, the patient experiences subretinal leakage and bleeding that is less than the patient experiences subretinal leakage and bleeding after intravitreal therapy with the same drug at the same dose.
In one embodiment, the methods provided herein provide effective treatment of patients who have previously been treated for a choroidal disease or posterior ocular disorder, but who have failed to respond or failed to respond appropriately to the previous treatment. For example, in one embodiment, a patient undergoing a method of treating a choroidal disease or a posterior ocular disorder of the present invention has previously been treated for the same choroidal disease or posterior ocular disorder, but has failed to respond or has not responded appropriately. As will be appreciated by those skilled in the art, patients who do not respond to treatment or do not respond appropriately do not exhibit improvement in symptoms of choroidal disease or posterior ocular disorders or improvement in clinical manifestations. In one embodiment, the symptom or clinical manifestation is lesion size, inflammation, edema, visual acuity, or vitreous opacity.
In one embodiment, a patient in need of treatment for polypoidal choroidal vasculopathy is treated with one of the non-surgical SCS drug delivery methods provided herein. For example, in one embodiment, a patient in need of treatment is administered: a pharmaceutical formulation comprising an effective amount of a PCV therapeutic drug is administered to the SCS of one or both eyes. In further embodiments, the microneedle devices described herein are used for administration of a pharmaceutical formulation. In still further embodiments, the effective amount of a PCV therapeutic comprises an effective amount of an anti-inflammatory agent, a Vascular Endothelial Growth Factor (VEGF) modulator, a platelet-derived growth factor (PDGF) modulator, an angiogenesis inhibitor, an immunosuppressive agent, or a vascular permeability inhibitor.
PCV is an aberrant choriovasculopathy believed to be a variant of
Clinical manifestations of patients with PCV include vascular abnormalities and separation of serum blood, a variable size serous fluid of the sensory neurogenic retina and the pigmented epithelium around the optic nerve or in the central macula. Patients with PCV may also experience subretinal exudation and/or hemorrhage. In another embodiment, the PCV patient has lipid deposits in the eye. The present invention provides for a reduction in the incidence and/or severity of clinical manifestations of PCV experienced by PCV patients treated with the methods described herein, as compared to the incidence and/or severity of said clinical manifestations prior to treatment. For example, a patient receiving PCV therapy with one of the non-surgical treatment methods provided herein experiences a reduction in the incidence and/or severity of vascular abnormalities as compared to the incidence and/or severity of vascular abnormalities that were shown prior to treatment with the non-surgical SCS drug delivery method. In another embodiment, the severity of subretinal leakage and/or hemorrhage is reduced in a PCV patient as compared to the severity of subretinal leakage and/or hemorrhage prior to treatment with a non-surgical SCS drug delivery method described herein. PCV therapeutic agents, such as angiogenesis inhibitors, VEGF modulators, PDGF modulators, anti-inflammatory agents, vascular permeability inhibitors are described in more detail below.
In one embodiment, a patient treated for PCV by one of the non-surgical methods described herein is also treated for a second ocular disease. In a further embodiment, the additional ocular disease is drusen, sickle cell retinopathy, central serous chorioretinopathy, typical neovascular (
In another embodiment, the SCS of a non-surgical drug delivery to one or both eyes of a patient is a method of treating Central Serous Chorioretinopathy (CSC), also known as Central Serous Retinopathy (CSR), in a patient. CSR is exudative chorioretinopathy and is characterized by exudative sensory neuroretinal detachment with or without associated detachment of retinal pigment epithelial cells (RPEs). In some examples, CSR causes ocular deformity and ocular smallness. In some examples, CSR is characterized by leakage of subretinal fluid. In addition, patients with CSR often experience reduced visual acuity. In one embodiment, a method of treating CSR in a patient is provided comprising non-surgically administering to the SCS of one or both eyes of the patient a pharmaceutical formulation comprising an effective amount of a CSR therapeutic drug. In one embodiment, the drug is administered with one of the microneedles described herein. In further embodiments, the CSR therapeutic agent is an anti-inflammatory agent, a Vascular Endothelial Growth Factor (VEGF) modulator (e.g., a VEGF antagonist), a platelet-derived growth factor (PDGF) modulator (e.g., a PDGF antagonist), an angiogenesis inhibitor, an immunosuppressant, or a vascular permeability inhibitor. In a further embodiment, a patient treated for CSR by one of the methods described herein experiences an increase in visual acuity compared to the visual acuity of the patient prior to the treatment. In another embodiment, the patient experienced a decrease in the leakage of subretinal fluid after CSR treatment compared to the leakage of subretinal fluid experienced by the patient prior to treatment with non-surgical SCS drug delivery.
In 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 pharmaceutical formulation is administered with one of the microneedles described herein. In further embodiments, the effective amount of the MFC therapeutic comprises an effective amount of an anti-inflammatory agent, a Vascular Endothelial Growth Factor (VEGF) modulator (e.g., a VEGF antagonist), a Platelet Derived Growth Factor (PDGF) modulator (e.g., a PDGF antagonist), an angiogenesis inhibitor, an immunosuppressant, or a vascular permeability inhibitor. In one embodiment, the MFC patient is moderately myopic, and in one embodiment, bilaterally diseased. In some embodiments, the MFC patient has symptoms of posterior uveitis, including decreased visual acuity, muscae volitantes, light flashes, and has anterior segment symptoms such as photophobia. In one embodiment, the MFC patient has vitreal cells and/or anterior chamber cells. Fundoscopic findings in MFC patients included yellow to gray lesions at the level of Retinal Pigment Epithelium (RPE) and choriocapillaris. The lesions range in size from about 50 μm to about 1,000 μm and have a distribution in the peripapillary area. In one embodiment, the methods provided herein reduce the size and/or number of lesions in a patient receiving treatment. In some examples, the activity impairment is associated with subretinal fluid and a fluffy border. Active disease may also be associated with optic nerve head congestion and edema, cystoid macular edema, and macular and perioptic choroidal neovascularization.
In one embodiment, a method of treating MFC in a patient comprises non-surgically administering a drug formulation comprising an effective amount of an MFC therapeutic drug to the SCS of one or both eyes of a patient in need of treatment. In further embodiments, the method comprises administering the drug formulation to the SCS of one or both eyes of the patient with one microneedle described herein. For example, in one embodiment, the drug formulation is delivered to the SCS of the eye of the patient via a hollow microneedle having a tip and an opening, through the opening and into the SCS. In a further embodiment, the effective amount of the MFC therapeutic agent is an effective amount of an anti-inflammatory agent, an angiogenesis inhibitor, a VEGF modulator, or a vascular permeability inhibitor. In further embodiments, the patient treated for MFC experiences a decrease in the number of one or more lesions (e.g., a decrease in the number of one or more lesions in the RPE), a decrease in the size of one or more lesions (e.g., a decrease in the size of one or more lesions present in the RPE), a decrease in the amount of subretinal fluid, an increase in visual acuity, or a decrease in choroidal neovascularization as compared to the number of one or more lesions, the size of one or more lesions, the amount of subretinal fluid, visual acuity, and choroidal neovascularization in the eye of the patient prior to performing the MFC treatment methods of the present invention. In another embodiment, a patient treating MFC experiences a reduction in papilla hyperemia and edema as compared to the patient experienced prior to treatment with non-surgical SCS drug delivery of the present invention.
In one embodiment, a patient in need of treatment for choroidal neovascularization is treated with a non-surgical SCS drug delivery method provided herein. For example, in one embodiment, a pharmaceutical formulation comprising an effective amount of a drug for treating choroidal neovascularization is administered to a patient in need of treatment to the SCS in one or both eyes. In a further embodiment, administration of the pharmaceutical formulation is carried out with a microneedle device as described herein. In one embodiment, the effective amount of the agent for treating choroidal neovascularization is an anti-inflammatory agent, an angiogenesis inhibitor, a VEGF modulator (e.g., a VEGF antagonist), a platelet-derived growth factor (PDGF) modulator (e.g., a PDGF antagonist), an angiogenesis inhibitor, an immunosuppressant, or an vascular permeability inhibitor.
In one embodiment, a patient in need of treatment for choroidal dystrophy is treated with one of the non-surgical SCS drug delivery methods provided herein. For example, in one embodiment, a pharmaceutical formulation comprising an effective amount of a drug for treating choroidal dystrophy 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 medicament comprises an effective amount of an anti-inflammatory agent, a Vascular Endothelial Growth Factor (VEGF) modulator, a platelet-derived growth factor (PDGF) modulator, an angiogenesis inhibitor, an immunosuppressant, or a vascular permeability inhibitor. In a further embodiment, administration of the pharmaceutical formulation is carried out with a microneedle device as described herein. In one embodiment, the present application provides a method of treating choroidal dystrophy that ameliorates the symptoms or clinical manifestations of choroidal dystrophy to a greater extent than the same drug administered to a patient by the topical, oral, parenteral, intravitreal, or intracameral routes.
In another embodiment, the method of treating a choroidal disorder described herein, i.e., the non-surgical SCS drug delivery method described herein, is a method of treating a punctate inner layer choroidal disorder (PIC) in a patient. In one embodiment, a method of treating a patient's PIC comprises non-surgically administering a pharmaceutical formulation comprising an effective amount of a PIC therapeutic drug to the SCS of one or both eyes of the patient. In further embodiments, the method comprises delivering a drug with one of the microneedles described herein. In one embodiment, the effective amount of the PIC therapeutic agent is an anti-inflammatory agent, an angiogenesis inhibitor, an immunosuppressant, a VEGF modulator (e.g., a VEGF antagonist), a PDGF modulator (e.g., a PDGF antagonist), or a vascular permeability inhibitor.
In one embodiment, PIC patients undergoing one of the SCS treatment methods provided herein experience an improvement in PIC symptoms/clinical manifestations, or a reduction in the number of PIC symptoms/clinical manifestations, as compared to the symptoms/clinical manifestations experienced prior to SCS drug administration. In further embodiments, the symptom/clinical manifestation is inflammation, blurred vision, glistening sensation, central and/or peripheral scotomas or metamorphosis. In another embodiment, the symptom/clinical manifestation is decreased visual acuity, one or more lesions (e.g., about 100 μm to about 200 μm in diameter) of the white-yellow chorioretinal bilateral at the level of the inner choroid and retinal pigment epithelium. The one or more lesions are generally not associated with vitritis and do not generally extend to the equator of the retina. PIC lesions develop into atrophic scars and leave halos (halo) with depigmentation. In one embodiment, a PIC patient treated with one of the non-surgical SCS drug delivery methods described herein experiences a reduction in inflammation, a reduction in the number of one or more lesions, or a reduction in the size of one or more lesions, as compared to the inflammation, the number of one or more lesions, or the size of one or more lesions that the patient exhibited prior to treatment. In another embodiment, a PIC patient treated with one of the non-surgical SCS drug delivery methods described herein experiences a reduction in inflammation, a reduction in the number of one or more lesions, or a reduction in the size of one or more lesions as compared to inflammation, the number of one or more lesions, or the size of one or more lesions following intravitreal, oral, topical, parenteral, or intracameral drug therapy with the same drug dose as administered to the SCS.
In one embodiment, the method of treating a choroidal disorder 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 pharmaceutical formulation comprising an effective amount of a medicament for treating choroidal dystrophy 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 the patient via a hollow microneedle having a tip and an opening. In a further embodiment, the effective amount of the medicament for treating choroidal dystrophy comprises an effective amount of an anti-inflammatory agent, a Vascular Endothelial Growth Factor (VEGF) modulator (e.g., a VEGF antagonist), a platelet-derived growth factor (PDGF) modulator (e.g., a PDGF antagonist), an angiogenesis inhibitor, an immunosuppressive agent, or a vascular permeability inhibitor. In one embodiment, the microneedle is inserted into the sclera and the drug formulation is infused into the SCS through the opening of the inserted microneedle. In one embodiment, the choroidal dystrophy is Central Areolar Choroidal Dystrophy (CACD), central cyclic choroidal degeneration, paranoid degeneration, or complete central choroidal atrophy. In further embodiments, the patient is treated for CACD, and the CACD is CACD1, CACD2, or
In one embodiment, the methods of treatment for choroidal dystrophy provided herein reduce the number of one or more symptoms of choroidal dystrophy experienced by said patient prior to treatment. In another embodiment, the methods of treatment for choroidal dystrophy provided herein reduce the severity of one or more symptoms of choroidal dystrophy experienced by said patient prior to treatment.
In one embodiment of the methods of treating a choroidal disorder described herein, non-surgical delivery of a drug formulation comprising an effective amount of a drug for treating a choroidal disorder, for example, an effective amount of an anti-inflammatory drug (e.g., a steroid or NSAID), a Vascular Endothelial Growth Factor (VEGF) modulator (e.g., a VEGF antagonist), an immunosuppressant, an angiogenesis inhibitor (e.g., a platelet-derived growth factor (PDGF) antagonist) or a vascular permeability inhibitor, to SCS in one or both eyes of a patient in need of treatment is achieved by: inserting a microneedle into a patient's eye, and infusing a drug through the microneedle into the SCS, or infusing into the SCS via a coating on a solid or hollow microneedle. In one embodiment, the solid or hollow microneedles are 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 through the inserted microneedle and into the suprachoroidal space of the eye. In another embodiment, solid microneedles coated with an effective amount of a drug for treating choroidal disorders at the microneedles are inserted into the sclera and the drug is dispersed into the SCS of the patient's eye.
The pharmaceutical formulation for the treatment of a posterior ocular disorder or a choroidal disease, delivered to the suprachoroidal space of the eye of a human subject, may be in the form of a liquid drug, a liquid solution or a liquid suspension comprising the drug in a suitable solvent. Liquid suspensions may include microparticles or nanoparticles dispersed in a suitable liquid vehicle for infusion. In various embodiments, the agent is contained in a liquid vehicle, in a microparticle or nanoparticle, or in both a vehicle and a particle. The drug formulation is sufficiently mobile to flow into and within the suprachoroidal space, as well as to the surrounding posterior ocular tissues. In one embodiment, the fluid pharmaceutical formulation has a viscosity of about 1cP at 37 ℃.
A wide range of drugs can be formulated for delivery to the suprachoroidal space and the posterior ocular tissues using the microneedle devices and methods of the present invention. The term "drug" as used herein refers to any prophylactic, therapeutic or diagnostic agent, i.e., a component useful in medical applications. The drug may be selected from small molecules, proteins, peptides and fragments thereof, which may be naturally occurring, synthetic 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 fragment thereof (e.g., a Fab, Fv, or Fc fragment). In certain embodiments, the agent is a sub-immunoglobulin antigen binding molecule, such as an Fv immunoglobulin fragment, a small molecule antibody (minibody), a bispecific antibody, and the like, as described in U.S. patent No. 6,773,916, which is incorporated herein by reference in its entirety for all purposes. In one embodiment, the drug is a humanized antibody or fragment thereof.
In one embodiment, the drug is selected from a suitable oligonucleotide (e.g., an antisense oligonucleotide agent), polynucleotide (e.g., therapeutic DNA), ribozyme, double-stranded RNA, siRNA, RNAi, gene therapy vector, and/or vaccine. In further embodiments, the drug is an aptamer (e.g., an oligonucleotide or peptide molecule that binds to a particular target molecule). In another embodiment, the pharmaceutical formulation delivered by the methods provided herein comprises a small molecule drug, an endogenous protein or fragment thereof, or an endogenous peptide or fragment thereof.
Representative examples of the types of drugs for delivery to ocular tissues include anti-inflammatory agents, including, but not limited to steroids, immunosuppressive agents, antimetabolites, T-cell inhibitors, alkylating agents, biologics, TNF antagonists (e.g., TNF- α antagonists), VEGF antagonists, and/or non-steroidal anti-inflammatory drugs (NSAIDs). non-limiting examples of specific drugs and classes of drugs that can be delivered to the suprachoroidal space to treat posterior ocular disorders include miotics (e.g., pilocarpine, carbachol, physostigmine), sympathomimetics (e.g., epinephrine, dipivefrin), carbonic anhydrase inhibitors (e.g., acetazolamide, dorzolamide), VEGF antagonists, PDGF antagonists, NSAIDs, steroids, prostaglandins, antimicrobial compounds including antibacterial and antifungal agents (e.g., chloramphenicol, chlortetracycline, ciprofloxacin, neomycin B, fusidic acid, gentamycin, neomycin, norfloxacin, oxymatrifloxacin, polymyxin, propaferin, tetracycline, tobramycin, quinoline, and anti-steroidal/antifungal agents such as diclofenac, triamcinolone, dexamethasone, prednisolone, dexamethasone, and other compounds such as chlordimerate, bromelasone, bromelamin, doxazone, dexamethasone, and antimycotics,Tiaprofenic acidCromolyn sodium), artificial tear/dry eye treatment drugs, local anesthetics (e.g., tetracaine, lidocaine, oxybuprocaine, proparacaine), cyclosporine, diclofenac, urogastrodine, and growth factors such as epidermal growth factor, mydriatic and cycloplegic agents, mitomycin C and collagenase inhibitors, and age-related macular degeneration treatments such as guazatinib sodium, ranibizumab, and bevacizumab.
As provided throughout, in some embodiments, methods are provided for delivering a pharmaceutical formulation comprising an effective amount of an angiogenesis inhibitor, an anti-inflammatory agent (e.g., a steroid or NSAID), a VEGF modulator (e.g., a VEGF antagonist), a PDGF modulator (e.g., a PDGF antagonist), an immunosuppressive agent, or a vascular permeability inhibitor to SCS of an eye of a patient in need thereof.
In one embodiment, the angiogenesis inhibitor is an integrin antagonist, a selection antagonist, an adhesion molecule antagonist (such as an antagonist of intercellular adhesion molecule (ICAM) -1, ICAM-2, ICAM-3, platelet endothelial adhesion molecule (PCAM), Vascular Cell Adhesion Molecule (VCAM)), lymphocyte function-associated antigen-1 (LFA-1)), a basic fibroblast growth factor antagonist, a Vascular Endothelial Growth Factor (VEGF) modulator, or a platelet-derived growth factor (PDGF) modulator (such as a PDGF antagonist). in one embodiment, the integrin antagonist delivered by the methods described herein is a small molecule integrin antagonist, such as described by paolio et al (Mini Rev Med Chem,2009,
In one embodiment, the intraocular elimination half-life (t) of the angiogenesis inhibitor administered to the SCS1/2) Intraocular t-rays greater than the angiogenesis inhibitor when the same dose of the angiogenesis inhibitor is administered intravitreally, intracamerally, topically, parenterally or orally1/2. In another embodiment, the mean intraocular maximum concentration (C) of the angiogenesis inhibitor when the same dose of the angiogenesis inhibitor is administered to the SCS by the methods described hereinmax) Greater than the same dose administered intravitreally, intracamerally, topically, parenterally or orallyIntraocular C of the formulationmax. In another embodiment, the mean area under the intraocular curve (AUC) of the angiogenesis inhibitor when administered to SCS by the methods described herein0-t) Greater than the intraocular AUC of said angiogenesis inhibitor when administered intravitreally, intracamerally, topically, parenterally or orally at the same dose of angiogenesis inhibitor0-t。
In one embodiment, the angiogenesis inhibitors delivered by the methods and devices described herein are
Specific endogenous angiogenesis inhibitors for delivery by the methods described herein include endostatin, a 20kDa C-terminal fragment derived from collagen XVIII, angiostatin (a 38kDa fragment of plasmin), or a member of the Thrombospondin (TSP) family of proteins in further embodiments, the angiogenesis inhibitors are TSP-1, TSP-2, TSP-3, TSP-4, and TSP-5 other endogenous angiogenesis inhibitors amenable to delivery by the methods of treatment of choroidal disorders described herein include soluble VEGF receptors such as soluble VEGFR-1 and neuropilin 1(NPR1), angiopoietin-1, angiopoietin-2, angiostatin, calreticulin, thrombopoietin-4, inhibitors of metalloproteinases Tissue (TIMPs) (such as TIMP1, TIMP2, TIMP3, TIMP4), cartilage derived angiogenesis inhibitors (such as the peptidtroponin I and thrombomodulin I), a protein
In one embodiment, the angiogenesis inhibitor delivered to treat choroidal disease by the methods described herein is an antibody. In a further embodiment, the antibody is a humanized monoclonal antibody. In a still further embodiment, the humanized monoclonal antibody is bevacizumab.
In one embodiment, the non-surgical treatment methods and devices described herein can be used in gene-based therapy applications. For example, in one embodiment, the method comprises administering a fluid drug formulation into the suprachoroidal space to deliver a selected DNA, RNA, or oligonucleotide to a targeted ocular tissue.
In one embodiment, the medicament is for treating a choroidal disease. In a further embodiment, the choroidal disease treatment agent is a nucleic acid administered to inhibit gene expression. For example, in one embodiment, the nucleic acid is a microribonucleic 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 methods of treating a choroidal disease provided herein comprise administering an RNA molecule to SCS in a patient in need thereof. In further embodiments, the RNA molecule is delivered to the SCS via one microneedle described herein. In one embodiment, the patient is treated for PCV and the RNA molecule targets HTRA1, CFH, elastin, or ARMS2 such that expression of the targeted gene is down-regulated upon administration of the RNA. In a further embodiment, the targeted gene is CFH and the RNA molecule targets a polymorphism (polymorphism) selected from the group consisting of rs3753394, rs800292, rs3753394, rs6680396, rs1410996, rs2284664, rs1329428, and rs 1065489. In another embodiment, the patient is treated for choroidal dystrophy and the RNA molecule targets the PRPH2 gene. In further embodiments, the RNA molecule targets a mutation in the PRPH2 gene.
In one embodiment, the drug delivered to the suprachoroidal space using the non-surgical methods of the present application (e.g., microneedle devices and methods) is sirolimus
In one embodiment, the angiogenesis inhibitor delivered to the perichoroidal space using the non-surgical methods described herein is an antagonist of a member of the platelet-derived growth factor (PDGF) family, e.g., a drug that inhibits, reduces, or modulates signal transduction and/or activity of the PDGF receptor (PDGFR). for example, in one embodiment, the PDGF antagonist delivered to the perichoroidal space for treatment of choroidal diseases is 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 intraocular elimination half-life (t) of the PDGF antagonist administered to the SCS1/2) Greater than the intraocular t-of said PDGF antagonist upon intravitreal, intracameral, topical, parenteral, or oral administration of the same dose of said PDGF antagonist1/2. In another embodiment, the mean intraocular maximum concentration (Cmax) of the PDGF antagonist when administered to the SCS by the methods described herein is greater than the intraocular Cmax of the PDGF antagonist when the same dose of the PDGF antagonist is administered intravitreally, intracamerally, topically, parenterally or orally. In another embodiment, the mean intraocular area under the curve (AUC) of the PDGF antagonist when administered to the SCS by the methods described herein0-t) Greater than an intraocular AUC of the PDGF antagonist when the same dose of the PDGF antagonist is administered intravitreally, intracamerally, topically, parenterally or orally0-t。
In certain embodiments, the drug delivered to the suprachoroidal space using the microneedle devices and methods disclosed herein is a Vascular Endothelial Growth Factor (VEGF) modulator. For example, in one embodiment, the VEGF modulator is a VEGF antagonist. In one embodiment, the VEGF modulator 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).
In one embodiment, the VEGF antagonist delivered by the non-surgical methods described herein is an antagonist of the VEGF receptor (VEGFR), i.e., an agent that inhibits, reduces, or modulates signal transduction and/or activity of VEGFR. The VEGFR may be membrane bound or soluble VEGFR. In further embodiments, the VEGFR is VEGFR-1, VEGFR-2, or VEGFR-3. In one embodiment, the VEGF antagonist targets VEGF-C protein. In another embodiment, the VEGF modulator is an antagonist of a tyrosine kinase or a tyrosine kinase receptor. In another embodiment, the VEGF modulator is a modulator of VEGF-A protein. In another embodiment, the VEGF antagonist is a monoclonal antibody. In another embodiment, the monoclonal antibody is a humanized monoclonal antibody.
In one embodiment, the intraocular elimination half-life (t) of the VEGF antagonist administered to the SCS1/2) Greater than the intraocular t of the VEGF antagonist when the same dose of the VEGF antagonist is administered intravitreally, intracamerally, topically, parenterally or orally1/2. In another embodiment, the mean intraocular maximum concentration (C) of the VEGF antagonist when administered to SCS by a method described hereinmax) Greater than the intraocular C of the VEGF antagonist when the same dose of the VEGF antagonist is administered intravitreally, intracamerally, topically, parenterally or orallymax. In another embodiment, the mean intraocular area under the curve (AUC) of the VEGF antagonist when administered to SCS by a method described herein0-t) Greater than the intraocular AUC of the VEGF antagonist when the same dose of the VEGF antagonist is administered intravitreally, intracamerally, topically, parenterally or orally0-t。
In one embodiment, the non-surgical methods, needles and/or devices described herein are used to deliver one or more of the following VEGF modulators to the suprachoroidal space of the eye to treat one or more posterior ocular disorders or choroidal diseases described herein: AL8326, 2C3 antibody, AT001 antibody, HyBEV, bevacizumab
In one embodiment, a VEGF antagonist is delivered to the suprachoroidal space of the eye of a human subject using microneedle devices and methods disclosed herein to treat, prevent and/or ameliorate one or more posterior ocular disorders or choroidal diseases. For example, in one embodiment, the posterior ocular disorder is a retinal disease. In another embodiment, the posterior ocular disorder is a choroidal disease. In another embodiment, the posterior ocular disorder is an optic nerve disease. In one embodiment, the posterior ocular disorder is selected from the group consisting of macular degeneration, age-related macular degeneration, neovascular age-related macular degeneration, subcapillary neovascular age-related macular degeneration, macular edema following retinal vein occlusion, macular edema with Retinal Vein Occlusion (RVO), diabetic macular edema, macular edema secondary to retinal branch vein occlusion, macular edema secondary to retinal central vein occlusion, retinal branch vein occlusion, retinal central vein occlusion, neovascularization, choroidal neovascularization, subcapillary choroidal neovascularization, vision defects due to diabetic macular edema, diabetic retinopathy, dry eye syndrome (inflammation of dry eye and corneal tissue damage), retinal detachment, retinal disorder, retinitis pigmentosa, retinal detachment, retinitis pigmentosa, retinal degeneration, retinal vein occlusion, retinal branch vein occlusion, central retinal vein occlusion, myopia, pathologic myopia, neurodegenerative disease, ocular neovascularization, ocular cancer, uveitis, glaucoma, scleritis, ocular sarcoidosis, optic neuritis, corneal ulceration, ocular autoimmune disease, or retinitis.
In one embodiment, the present application provides a method of treating a choroidal disorder (e.g., choroidal neovascularization, polypoidal choroidal vasculopathy, central serous choroidopathy, multifocal choroidopathy) comprising administering to a patient in need thereof a pharmaceutical formulation comprising an effective amount of an anti-inflammatory agent to the perichoroidal space of the eye of said patient.
In one embodiment, the drug delivered to the suprachoroidal space of the eye of a human patient by a non-surgical treatment of a posterior ocular disorder or a choroidal disease described herein reduces, inhibits, prevents and/or ameliorates inflammation, i.e., is an anti-inflammatory drug. In one embodiment, the drug formulation of SCS delivered to the eye of a patient in need thereof via the methods described herein comprises an effective amount of an immunosuppressive agent. For example, in one embodiment, the immunosuppressive agent is a glucocorticoid, a cytokine inhibitor, a cytostatic agent, an alkylating agent, an antimetabolite, a folic acid analog, a cytotoxic antibiotic, an interferon, an opioid, a T cell receptor-directed antibody, or an IL-2 receptor-directed antibody. In one embodiment, the immunosuppressive agent 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 immunosuppressive agent is an interleukin-2 inhibitor (e.g., basiliximab or daclizumab). Other immunosuppressive agents amenable to the methods and formulations described herein include, but are not limited to, cyclophosphamide, nitrosourea, methotrexate, azathioprine, mercaptopurine, fluorouracil, dactinomycin, anthracyclines, mitomycin C, bleomycin, mithramycin, Moluomab-
In one embodiment, the intraocular elimination half-life (t) of the immunosuppressant administered to the SCS1/2) Greater than the t of the immunosuppressive agent when the same dose of the immunosuppressive agent is administered intravitreally, intracamerally, topically, parenterally or orally1/2. In another embodiment, the mean intraocular maximum concentration of the immunosuppressant administered to the SCS by the methods described herein (C)max) Intraocular C of the immunosuppressive agent greater than when the same dose of the immunosuppressive agent is administered intravitreally, intracamerally, topically, parenterally or orallymax. In another embodiment, the mean area under the intraocular curve (AUC) of the immunosuppressant administered to the SCS by the methods described herein0-t) Greater than the intraocular AUC of the immunosuppressive agent when the same dose of the immunosuppressive agent is administered intravitreally, intracamerally, topically, parenterally or orally0-t。
In one embodiment, the drug formulation of SCS delivered to the eye of a patient in need thereof by 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.
In one embodiment, the intraocular ablation of the vascular permeability inhibitor administered to the SCSPeriod (t)1/2) Greater than the t of the vascular permeability inhibitor when the same dose of the vascular permeability inhibitor is administered intravitreally, intracamerally, topically, parenterally or orally1/2. In another embodiment, the mean intraocular maximum concentration (C) of the vascular permeability inhibitor administered to the SCS by the methods described hereinmax) Intraocular C of the vascular permeability inhibitor greater than the same dose of the vascular permeability inhibitor administered intravitreally, intracamerally, topically, parenterally or orallymax. In another embodiment, the mean area under the intraocular curve (AUC) of the vascular permeability inhibitor administered to the SCS by the methods described herein0-t) Greater than the intraocular AUC of the vascular permeability inhibitor when the same dose of the vascular permeability inhibitor is administered intravitreally, intracamerally, topically, parenterally or orally0-t。
In one embodiment, the drug is a steroidal anti-inflammatory drug or a non-steroidal anti-inflammatory drug (NSAID). In another embodiment, the anti-inflammatory agent is an antibody or fragment thereof, one or more anti-inflammatory peptides, or one or more anti-inflammatory aptamers. As provided throughout the specification, delivery of an anti-inflammatory agent to the suprachoroidal space provides benefits over delivery of the same agent by oral, intravitreal, intracameral, topical, and/or parenteral routes of administration. For example, in one embodiment, the therapeutic effect of the drug delivered to the suprachoroidal space is greater than the therapeutic effect of the same drug when delivered at the same dose by oral, intravitreal, topical, or parenteral routes. In one embodiment, the intraocular elimination half-life (t) of the anti-inflammatory agent administered to the SCS1/2) Greater than the t of the anti-inflammatory agent when the same dose of the anti-inflammatory agent is administered intravitreally, intracamerally, topically, parenterally or orally1/2. In another embodiment, the mean intraocular maximum concentration of the anti-inflammatory agent (C) administered to the SCS by the methods described hereinmax) Intraocular C greater than the anti-inflammatory agent when administered intravitreally, intracamerally, topically, parenterally or orallymax. In another embodiment, the mean area under the intraocular curve (AUC) of the anti-inflammatory drug administered to the SCS by the methods described herein0-t) Greater than the intraocular AUC of the anti-inflammatory agent when administered intravitreally, intracamerally, topically, parenterally or orally at the same dose of the anti-inflammatory agent0-t。
Steroids that can be administered by the methods provided herein include hydrocortisone, hydrocortisone-17-butyrate, hydrocortisone-17-acepropionate, hydrocortisone-17-butyrate propionate, cortisone, ticortisone pivalate, prednisolone, methylprednisolone, prednisone, triamcinolone acetonide, mometasone, amcinonide, budesonide, desonide, fluocinolone acetate, halcinonide, betamethasone dipropionate, dexamethasone, fluocortolone, hydrocortisone-17-valerate, halomethasone, alclometasone dipropionate, prednisone, clobetasone-17-butyrate, clobetasol-17-propionate, fluocortolone hexanoate, fluocortolone pivalate, fluorometholone acetate, and prednisolone.
Specific classes of NSAIDs that can be administered by 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, one or more of the following NSAIDs are delivered to SCS of an eye of a patient in need thereof using the methods provided herein: acetylsalicylic acid, diflunisal, salsalate, ibuprofen, dexibuprofen, naproxen, fenoprofen, ketoprofen, dexketoprofen, flurbiprofen, oxaprozin, loxoprofen, indomethacin, tolmetin, sulindac, etodolac, ketorolac, diclofenac or nabumetone, piroxicam, meloxicam, tenoxicam, droxicam, lornoxicam or isoxicam, mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid, celecoxib, rofecoxib, valdecoxib, parecoxib, lumiracoxib, etoricoxib or felicoxib.
Other examples of anti-inflammatory agents that may be used in the methods provided herein to treat posterior ocular disorders or choroidal diseases, choroidal neovascularization, or subretinal leakage include, but are not limited to: mycophenolate mofetil, reminicase, nepafenac, one or more 19AV agonists, 19GJ agonists, 2MD analogs, 4SC101,4SC102, 57-57, 5-HT2 receptor antagonists, 64G12, A804598, A967079, AAD2004, AB1010, AB224050, Brazilian, Iressbeads (Abegrin)TM)、
In one embodiment, anti-inflammatory agents are non-surgically delivered to the suprachoroidal space of the eye using microneedle devices and methods disclosed herein and are used to treat, prevent and/or ameliorate posterior ocular disorders in a human patient in need thereof. For example, the posterior ocular disorder or disorder is selected from the group consisting of 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, agnostic symptoms without classical Choroidal Neovascularization (CNV) in age-related macular degeneration (ocult), stargardt's disease, wet age-related macular degeneration in the fovea, and vitreous macular adhesion associated with neovascular age-related macular degeneration (VMA)), macular edema, diabetic macular edema, uveitis, scleritis, chorioretinal inflammation, chorioretinitis, choroiditis, retinitis, retinoitis, retinochoroiditis, macular inflammation, macular degeneration, Focal retinochoroiditis, focal retinochoroidal retinitis, focal retinochoroidal retinoitis, focal retinochoroiditis, focal retinitis, focal retinochoroidal choroiditis, diffuse retinochoroidal retinoitis, diffuse retinochoroidal retinitis, diffuse retinochoroidal retinoitis, diffuse retinochoroidal choroiditis, posterior ciliary inflammation, Hodgkin's disease, chorioretinal scars (e.g., posterior macular scar, solar retinopathy), choroidal degeneration (e.g., atrophy, sclerosis), hereditary choroidal dystrophy (e.g., choroidal absence, choroidal dystrophy, gyrate atrophy), choroidal hemorrhage and rupture, choroidal detachment, retinal cleavage, allergic retinopathy, retinopathy of prematurity, epiretinal degeneration, peripheral retinal degeneration, hereditary retinal dystrophy, Retinitis pigmentosa, retinal hemorrhages, detachment of the retinal layer, central serous retinopathy, glaucoma, ocular hypertension, suspected glaucoma, primary open angle glaucoma, primary angle-closure glaucoma, muscovine mosquitoes, leber's hereditary optic neuropathy, optic disc drusen, inflammatory disorders of the eye, inflammatory lesions in fungal infections, inflammatory lesions, inflammatory pain, inflammatory skin diseases or disorders, Sjogren's syndrome, ophthalmic diseases of Sjogren's syndrome.
For example, in one embodiment, a PDGF antagonist delivered to the suprachoroidal space for the treatment of one or more posterior ocular disorders or choroidal diseases is an anti-PDGF aptamer, an anti-PDGF antibody or fragment thereof, an anti-PDGFR antibody or fragment thereof, or a small molecule antagonistPanini, ponatinib, MK-2461, polyvirtinib, pazopanib, crenolanib, PP-121, tiratinib, imatinib, KRN 633, CP673451, TSU-68, Ki8751, amuvatinib, tivozanib, masitinib, motertinib diphosphate, polyvirtinib dilactate, rilivanib (ABT-869). In one embodiment, the intraocular elimination half-life (t) of the PDGF antagonist administered to the SCS1/2) Greater than the intraocular t of said PDGF antagonist when administered intravitreally, intracamerally, topically, parenterally or orally1/2. In another embodiment, the mean intraocular maximum concentration (C) of the PDGF antagonist when administered to the SCS by the methods described hereinmax) Greater than the intraocular C of said PDGF antagonist when administered intravitreally, intracamerally, topically, parenterally or orallymax. In another embodiment, the mean intraocular area under the curve (AUC) of the PDGF antagonist when administered to the SCS by the methods described herein0-t) Greater than the intraocular AUC of said PDGF antagonist when administered intravitreally, intracamerally, topically, parenterally or orally0-t。
In one embodiment, a drug delivered non-surgically to the suprachoroidal space using the devices and methods disclosed herein treats, prevents and/or ameliorates a posterior ocular disorder, macular degeneration, or a disease or disorder 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, agnostic symptoms that do not have classical Choroidal Neovascularization (CNV) in age-related macular degeneration, stargardt disease, wet infraorbital age-related macular degeneration, or vitreous macular adhesion associated with neovascular age-related macular degeneration (VMA) in a human patient in need of treatment.
Examples of drugs that may be delivered to the suprachoroidal space via the devices and methods described herein to treat, prevent and/or ameliorate macular degeneration include, but are not limited to: a0003A36 peptide, AAV2-sFLT01, ACE041, ACU02, ACU3223, ACU4429, AdPEDF, aflibercept, AG13958, arganibiose, AGN150998, AGN745, AL39324, AL78898A, AL8309B, ALN-VEG01, alprostadil, AM1101, amyloid β antibody, anecortave acetate, anti-VEGFR-2 Alterase, Aptocine, APX003, ARC1905, Invitropin, ATG3, ATP-binding cassette subfamily A member 4 gene, ATXS10, avastin combined with vesudadale, T101, AVT2, cyprotemu mab, bevacizumab combined with vetiporfin, bevacizinil sodium, bevacizumab, bri sodium tartrate, tartaric acid, vitamin A301, CAVANTA, CALCT 8225, CETAB 10051, CEIFTAE-7, CETAE-PEG-7, CEF-ACE-7, ACE-CEF-7, ACE-E-S-IV, CANFE-E, CAB-E, CAB-E, CAB-E, CAB-E, CAB-E, CAB-iCo-008, Icon1, I-Gold, Ilaris, Iluvien-Hokukoppe, immunoglobulins, integrin α 5 β 1 immunoglobulin fragment, integrin inhibitors, IRIS xanthophylls, I-Sense OcushieldIsononep, isopropyl unoprostone, JPE1375, JSM6427, KH902, LentiVue, LFG316, LP590, LPO1010AM, nordstrand in combination with Visudyne, Lutein ekstra, Lutein in combination with bilberry extract, Lutein in combination with zeaxanthin, M200 in combination with nordstrand, Macugen, MC1101, MCT355, mecamylamine, microplasmin, motoxafen lutetium, MP0112, NADPH oxidase inhibitor, aetera shark cartilage extract (Arthrovas)TM、NeoretnaTM、PsovascarTM) The neurotrophic factor 4 gene, Nova21012, Nova21013, NT501, NT503, Nutri-Stulln, oxkalin, OcuXan, Oftan Macula, Optrin, ORA102 in combination with bevacizumab
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 further embodiments, the triamcinolone or triamcinolone acetonide is delivered for the treatment of sympathetic ophthalmia, temporal arteritis, uveitis, and/or other inflammatory conditions of the back of the eye. 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 ophthalmia using the methods and devices described herein. In another embodiment, triamcinolone or triamcinolone acetonide is delivered to the suprachoroidal space of an eye of a human subject in need of treatment for temporal arteritis 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 uveitis 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 one or more posterior ocular inflammatory conditions using the methods and devices described herein. In another embodiment, the triamcinolone or triamcinolone acetonide is delivered by one of the methods described herein.
In one embodiment, the triamcinolone compositions provided herein are suspensions comprising microparticles or nanoparticles of triamcinolone or triamcinolone acetonide. In one embodiment, D of the microparticle50Is about 3 μm or less. In further embodiments, said D is50Is about 2 μm. In another embodiment, said D is50Is about 2 μm or less. In even another embodiment, said D50About 1000nm or less. In one embodimentOf particles D99Is about 10 μm or less. In another embodiment, said D is99Is about 10 μm. In another embodiment, said D is99About 10 μm or less, or about 9 μm or less.
In one embodiment, the triamcinolone present in the composition is from about 1mg/mL to about 400 mg/mL. In a further embodiment, the triamcinolone present in the composition is from about 2mg/mL to about 300 mg/mL. In a further embodiment, the triamcinolone present in the composition is from about 5mg/mL to about 200 mg/mL. In a further embodiment, the triamcinolone present in the composition is from about 10mg/mL to about 100 mg/mL. In a further embodiment, the triamcinolone present in the composition is from about 20mg/mL to about 75 mg/mL. In a further embodiment, the triamcinolone present in the composition is from about 30mg/mL to about 50 mg/mL. In one embodiment, the triamcinolone present in the composition is 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, the triamcinolone present in the composition is about 40 mg/mL.
In one embodiment, the triamcinolone composition comprises sodium chloride. In another embodiment, the triamcinolone composition comprises sodium carboxymethylcellulose.
In one embodiment, the triamcinolone composition comprises triamcinolone microparticles. In a further embodiment, the composition comprises
In one embodiment, the pH of the composition is from about 5.0 to about 8.5. In a further embodiment, the pH of the composition is from about 5.5 to about 8.0. In still further embodiments, the pH of the composition is from about 6.0 to about 7.5.
In another aspect, the present invention provides a method of diagnosing a patient for a choroidal disease. In one embodiment, the method comprises administering a choroidal disease diagnostic agent to the SCS of one or both eyes of a patient, visualizing the diagnostic agent, and determining whether the patient has choroidal disease based on the visualization. In further embodiments, the diagnostic agent is delivered to the SCS of one or both eyes of the patient via one microneedle described herein.
In one embodiment, a method of diagnosing a patient for choroidal disease is provided. The method comprises administering an indocyanine green (ICG) molecule to the SCS of one or both eyes of a patient. ICG molecules are excited by absorbing infrared light in the range of about 790nm to about 805 nm. ICG molecules allow visualization of choroidal vasculature. In one embodiment, a positive diagnosis of choroidal disease is provided when pulsating polypoidal vessels (pulse polypoidal vessels) are visualized in the macula. In a further embodiment, the choroidal disease is PCV.
In one embodiment, one or more drugs provided herein are delivered to the suprachoroidal space of the eye of a patient in need thereof for the treatment of one or more posterior ocular disorders or choroidal diseases, as described above, using the microneedle devices and methods disclosed herein 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 skin fibrosis).
In one embodiment, one or more drugs provided herein are delivered to the suprachoroidal space of the eye of a patient in need thereof for the treatment of choroidal disorders using microneedle devices and methods disclosed herein to treat, prevent and/or ameliorate choroidal dystrophy, as described above.
In one embodiment, agents for treating, preventing and/or ameliorating fibrosis are used in conjunction with the devices and methods described herein and are delivered to the suprachoroidal space of the eye. In a further embodiment, the drug is interferon gamma 1b
In one embodiment, a medicament for treating, preventing and/or ameliorating diabetic macular edema is used in conjunction with the devices and methods described herein and delivered to the suprachoroidal space of the eye. In a further embodiment, the drug is AKB9778, bevacizinil sodium, Cand5, fenofibrate choline, Cortiject, c-raf 2-methoxyethyl phosphorothioate oligonucleotide, DE109, dexamethasone, DNA damage induced
In one embodiment, a drug for treating, preventing and/or ameliorating macular edema is used in conjunction with the devices and methods described herein and is delivered to the suprachoroidal space of the eye. In further embodiments, the drug is delivered via a hollow microneedle to the suprachoroidal space of a human subject in need of treatment for a posterior ocular disorder or a choroidal disease. In one embodiment, the drug is dineful tetrasodium salt, dexamethasone, icaritin, pegaptanib sodium, ranibizumab, or triamcinolone. In addition, the drugs listed above that are delivered to ocular tissue using the microneedle devices and methods disclosed herein to treat, prevent and/or ameliorate macular edema can be combined with one or more of the drugs listed above or in the present application or with other drugs known in the art.
In a further embodiment, the drug is 2-MeS- β γ -CCl2-ATP, acetazolamide, Aristomol, arteoptitic, AZD4017, betalmilol hydrochloride, betamol, fibrate (betotic S), Brimodin, brimonidine tartrate, Brinidin, calcium, carteolol hydrochloride, Cosopt, CS088, DE092, DE104, DE111, dorzolamide hydrochloride, timolol maleate, timolol, drytimolol, forol, Glaumol, hypadimul, isotypic, isopropyl, isotretinol, valsartan, valnemulin, valsartan, valnemulin, vallatanolat, valol, valnemulin hydrochloride, valnemulin, valnemadectin, vallatanolatanolatanolatanolatanolatanolatanolatanolatanolatanolol, valol, valnemulin, vallatanolatanolatanolatanolatanolatanolatanolatanolatanolatanolatanolatanolatanolatanolat, valol, vallatanolatanolatanolatanolatanolatanolat, valol, vallatanolatanolatanolatanolatanolatanolatanolatanolatanolat, vallatanolatanolatanolatanolatanolatanolatanolatanolat, vallatanolatanolatanolatanolatanolatanolatanolat, vallatanolatanolat, vallat, vallatanolatanolatanolatanolatanolatanolatanolatanolatanolatanolatanolatanolat, vallatanolat, vallatanolatanolatanolatanolatanolat, vallatanolat, vallatanolatanolatanolatanolatanolatanolatanolatanolat, vallatanolatanolatanolatanolatanolat, vallatanolatanolatanolat, vallat, vallatanolat, vallatanolatanolat, vallatanolatanolatanolatanolatanolatanolatanolatanolat, vallatano.
The drug delivered to the suprachoroidal space by the non-surgical methods described herein is present as a drug formulation. In one embodiment, the "pharmaceutical formulation" is an aqueous solution or suspension and comprises an effective amount of the drug. Thus, in some embodiments, the pharmaceutical formulation is a fluid pharmaceutical formulation. The "pharmaceutical formulation" is a formulation of a drug, which typically includes one or more pharmaceutically acceptable excipient substances known in the art. The term "excipient" refers to any inactive ingredient of the formulation intended to facilitate handling, stability, dispersibility, wettability, release kinetics and/or injection of the drug. In one embodiment, the excipient may comprise or consist of water or saline.
In one embodiment, the pharmaceutical formulation (e.g., a fluid pharmaceutical formulation) comprises microparticles or nanoparticles, either of which comprises at least one drug. Desirably, the microparticles or nanoparticles provide controlled release of the drug into the suprachoroidal space and surrounding posterior ocular tissues. The term "microparticle" as used herein encompasses microspheres, microcapsules, microparticles, and beads having a number average diameter of from about 1 μm to about 100 μm, for example from about 1 to about 25 μm, or from about 1 μm to about 7 μm. "nanoparticles" are particles having an average diameter of from about 1nm to about 1000 nm. In one embodiment, the microparticle has D50Is about 3 μm or less. In further embodiments, said D is50Is about 2 μm. In another embodiment, D of the particles in the pharmaceutical formulation50Is about 2 μm or less. In another embodiment, D of the particles in the pharmaceutical formulation50About 1000nm or less. In one embodiment, the pharmaceutical formulation comprises D99Are particles of about 10 μm or less. In one embodiment, the microparticle has D50Is about 3 μm or less. In the further implementationIn embodiments, the D50Is about 2 μm. In another embodiment, D of the particles in the pharmaceutical formulation50Is about 2 μm or less. In another embodiment, D of the particles in the pharmaceutical formulation50About 1000nm or less. In one embodiment, the pharmaceutical formulation comprises D99Are particles of about 10 μm or less. In one embodiment, the microparticle has D50Is about 3 μm or less. In further embodiments, said D is50Is about 2 μm. In another embodiment, D of the particles in the pharmaceutical formulation50Is about 2 μm or less. In another embodiment, D of the particles in the pharmaceutical formulation50From about 100nm to about 1000 nm. In one embodiment, the pharmaceutical formulation comprises D99From about 1000nm to about 10 μm. In one embodiment, the microparticle has D50From about 1 μm to about 5 μm or less. In another embodiment, the pharmaceutical formulation comprises D99About 10 μm particles. In another embodiment, D of the particles in the formulation99Less than about 10 μm, or less than about 9 μm, or less than about 7 μm or less than about 3 μm. In a further embodiment, the microparticle or nanoparticle comprises an anti-inflammatory agent. In a further embodiment, the anti-inflammatory agent is triamcinolone.
The microparticles and nanoparticles may or may not be spherical in shape. "microcapsules" and "nanocapsules" are defined as microparticles and nanoparticles having a shell surrounding a core composed of another substance. The core may be a liquid, gel, solid, gas, or a combination thereof. In one case, the micro-or nanocapsules may be "microbubbles" or "nanobubbles" having a shell surrounding a gas core, wherein the drug is disposed at the surface of the shell, in the shell itself, or in the core. (microbubbles and nanobubbles may be responsive to acoustic vibrations as is known in the art for diagnosing or disrupting microbubbles to release their payload (payload) at or into a selected ocular tissue site). "microspheres" and "nanospheres" can be solid spheres, can be porous and comprise a sponge-like or honeycomb-like structure formed of pores or voids in a matrix material or shell, or can comprise a plurality of discrete voids in a matrix material or shell. The microparticles or nanoparticles may further comprise a matrix material. The shell or matrix material may be a polymer, amino acid, sugar, or other material known in the art of microencapsulation.
The drug-containing microparticles or nanoparticles may be suspended in an aqueous or non-aqueous liquid vehicle. The liquid vehicle can be a pharmaceutically acceptable aqueous solution and optionally can also include a surfactant. The microparticles or nanoparticles of the drug may themselves include excipient materials such as polymers, polysaccharides, surfactants, and the like, which are materials known in the art to control the kinetics of drug release from the particles.
In one embodiment, the pharmaceutical formulation further comprises an agent effective to degrade collagen or GAG fibers in the sclera, which may enhance penetration/release of the drug into the ocular tissue. The agent can be, for example, an enzyme, such as hyaluronidase, collagenase, or a combination thereof. In one variation of the method, the enzyme is administered to the ocular tissue in a separate step-either before or after infusion of the drug. The enzyme is administered at the same site as the drug.
In another embodiment, once administered, the pharmaceutical formulation is an agent that undergoes a phase change. For example, a liquid drug formulation can be injected into the suprachoroidal space through a hollow microneedle, where the formulation then gels, and the drug diffuses out of the gel for controlled release.
As noted above, the drug delivered to the suprachoroidal space via the methods described herein, i.e., for the treatment of one or more posterior ocular disorders or choroidal diseases, may 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 therapeutic drug or the choroidal disease therapeutic 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 for a posterior ocular disorder or a choroidal disease. In one embodiment, a VEGF antagonist is delivered to the suprachoroidal space of an eye of a human subject in need of treatment for a posterior ocular disorder or a 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, the PDGF antagonist is delivered to the suprachoroidal space of the eye of the human subject in combination with the VEGF antagonist via the methods described herein. The PDGF antagonist and the VEGF antagonist may be administered in the same formulation or in separate formulations.
In addition to suprachoroidal delivery, one or more additional drugs delivered to a human subject may be delivered via Intravitreal (IVT) administration (e.g., intravitreal injection, intravitreal implant or eye drop) examples of drugs that may be administered via IVT include, but are not limited to, A0003, A0006, AcedolF, AdPEDF, Aborciprep, AG13958, arganibos, AGN208397, AKB9778, AL78898A, amyloid P, angiogenesis inhibitor gene therapy, ARC1905, auroc, bevacizidine sodium, Brimonidine (Brimonidine), brivitendine (Brimonidine), Brimonidine tartrate, bromfenac sodium bromfenac, Cand5, CERE140, Cigancillor, CLT001, CLT003, CLT004, CLT005, component 5 (pegylated), complement factor D, antibody, Cand5,