JP2019501200A - Methods and devices for treating posterior ocular disorders with aflibercept and other biologics - Google Patents

Abstract

The present invention relates to methods and devices for treating wet AMD, CNV, wet AMD associated with CNV and / or wet AMD associated with RVO in a human subject in need thereof. In one aspect, a device provided herein includes a lumen configured to contain a pharmaceutical product, a distal end of a pharmaceutical container including a coupling portion configured to be removably coupled to a needle assembly A piston assembly including a pharmaceutical container, a distal end portion movably disposed within the lumen of the pharmaceutical container, and a piston assembly defining a proximal end portion of the pharmaceutical container including a portion, a flange and a longitudinal groove shoulder; And a handle coupled to the proximal end portion.

Description

CROSS REFERENCE TO RELATED APPLICATIONS This application is filed in US Provisional Application No. 62 / 276,543, filed January 8, 2016, and US Provisional Application No. 62 /, filed April 19, 2016. No. 324,708 is claimed and the contents of each of these provisional applications are incorporated herein by reference in their entirety.

BACKGROUND OF THE INVENTION Treatment of chronic retinal diseases such as angiogenesis (wetting) age-related macular degeneration (AMD) is often a glass of biological drugs such as Lucentis, Airia, or Avastin to prevent vision loss Require internal injection. In addition, wet AMD patients often show the formation of new blood vessels from the choroid. Exudative AMD affects the choroid and retina, and specific targeting of these tissues may therefore be required in modulating disease progression.

  RVO is a condition that affects vision that results from obstruction in one of the venous return blood flow from the retina. RVO is the second most common cause of vision loss due to retinal vascular disease. RVO affects 16.4 million adults worldwide, according to a 2010 study published in the journal Ophthalmology (Rogers et al. (2010). Ophthalmology 117, pp. 313-319)) . Macular edema associated with improperly treated RVO can cause significant loss in vision and ultimately lead to blindness.

  The present invention relates to macular edema associated with uveitis, macular edema after retinal vein occlusion (RVO) (also referred to herein as wet AMD associated with RVO), wet AMD, diabetic macular Provide new methodologies and devices for the treatment of edema (DME), choroidal neovascularization (CNV), and / or wet AMD associated with CNV, thereby addressing an important need in the field of ophthalmology To do.

Ophthalmology (Rogers et al. (2010). Ophthalmology 117, pp. 313-319).

SUMMARY OF THE INVENTION The present invention relates generally to ophthalmic therapy, and more particularly to targeted and localized treatment, eg, related to wet AMD or RVO related to wet AMD or choroidal neovascularization. The present invention relates to a method and device that enables the injection of fluid drug formulations into posterior ocular tissue for the treatment of wet AMD. In some embodiments, the drug formulation comprises aflibercept and is injected into the SCS to provide localized drug in the choroid and retina. In some embodiments, the method comprises administering an anti-inflammatory, anti-VEGF, anti-PDGF, or anti-angiopoietin drug formulation to the subject's SCS. In a further embodiment, the method comprises administering a biological agent to the subject, concomitantly or sequentially, with administration of an anti-inflammatory agent, anti-VEGF, anti-PDGF, or anti-angiopoietin to the SCS. Including. In some embodiments, the biological agent is administered intravitreally. In some embodiments, the biological agent is a VEGF modulator (eg, aflibercept). In some embodiments, the anti-inflammatory drug formulation comprises triamcinolone acetonide (TA). Surprisingly, SCS administration of anti-inflammatory drugs, anti-VEGF, anti-PDGF, or anti-angiopoietin improves or improves the effectiveness of biological agents in the treatment of ocular diseases.

  In some embodiments, the drug formulation and biological agent administered to the SCS act synergistically to improve the treatment of ocular disease in the subject.

  In one embodiment of wet AMD, a method for treating choroidal neovascularization (CNV), and / or a method for treating wet AMD associated with CNV, following at least one dosing session, for example, From about 1 week to about 14 weeks after at least one dosing session, eg, about 12 weeks after the dosing session, the patient is ≧ 10 characters compared to the patient's vision prior to at least one dosing session An improvement in visual acuity was observed as measured by a maximum corrected visual acuity of ≧ 15 characters, or ≧ 25 characters. In one embodiment of the method for treating macular edema associated with uveitis, following at least one dosing session, eg, about 1 week to about 14 weeks after at least one dosing session, eg, After about 4 weeks, about 8 weeks, or about 12 weeks from at least one dosing session, the patient has a retinal thickness (eg, fovea) compared to the patient's retinal thickness prior to at least one dosing session. A decrease in sub-region thickness) was observed. In one embodiment, the decrease in retinal thickness is ≧ 25 μm, ≧ 50 μm, ≧ 75 μm, or ≧ 100 μm. In some embodiments, the methods described herein include a medical syringe by inserting a distal end portion of a needle of a medical syringe into the target tissue and defining a delivery passageway in the target tissue. This is done so that the distal end surface of the hub of the syringe is in contact with the target surface of the target tissue. When the hub distal end surface contacts the target surface, a force (eg, a manual force by the user) is applied on the actuator of the medical syringe. The medical syringe is configured such that when the distal end portion of the needle is positioned within the first region of the target tissue, the force is sufficient to move the distal end portion of the actuator within the pharmaceutical container. The The medical syringe is configured such that when the distal end portion of the needle is disposed within the second region of the target tissue, the force is insufficient to move the distal end portion of the actuator within the pharmaceutical container. Is done. In some embodiments, the force has a magnitude of less than about 6N. A substance, e.g., a drug formulation, is conveyed through the needle from the pharmaceutical container into the target tissue in response to application when the distal end portion of the needle is disposed within the first region of the target tissue. The The first region can be, for example, the upper choroidal space of the eye, the lower portion of the sclera, and / or the upper portion of the choroid. In some embodiments, the first region can be the retina of the eye.

  In some embodiments of the methods provided herein, a distal end portion of a medical syringe needle is inserted into the target tissue to define a delivery passageway in the target tissue. The insertion is performed such that the centerline of the needle and the surface line tangential to the target surface of the target tissue define an entry angle of about 75 degrees to about 105 degrees. The distal end surface of the medical syringe hub is placed in contact with the target surface of the target tissue and fluidly isolates the delivery passageway. After the hub distal end surface is placed in contact with the target surface, a substance, eg, a drug formulation, is delivered into the target tissue via the needle.

  In some embodiments, the distal end portion of the needle of the medical syringe is inserted into the eye and defines a delivery passageway in the sclera of the eye. After the distal end portion of the needle is inserted into the eye, the force (e.g., when the distal tip of the needle is placed in at least one of the upper choroidal space or the lower portion of the sclera) A manual force by the user) is applied to the medical syringe, and the force is used to transport the substance from the pharmaceutical container through the needle when the distal tip of the needle is placed in the upper portion of the sclera of the eye. It is insufficient. In some embodiments, provided herein are methods of treating wet age-related macular degeneration (AMD) or choroidal neovascularization (CNV) in a human subject in need thereof. The method non-surgically applies an effective amount of aflibercept drug formulation containing a first drug to the suprachoroidal space (SCS) of an eye of a human subject in need of wet AMD or CNV treatment in a dosing session. Administration step. In other embodiments, the method non-surgically applies an effective amount of an anti-inflammatory drug, anti-VEGF, anti-PDGF, or anti-angiopoietin to the SCS of an eye of a human subject in need of wet AMD or CNV treatment. Administering. In a further embodiment, the method further comprises intravitreal administration of the biological agent. In still further embodiments, the biological agent is anti-VEGF, anti-PDGF, or anti-angiopoietin. In a still further embodiment, the biological agent is aflibercept.

  In some embodiments, provided herein are methods of treating wet age-related macular degeneration (AMD) in a human subject in need thereof. In some embodiments, the method includes administering an effective amount of aflibercept drug formulation comprising a first drug in a dosing session in the suprachoroidal space (in the eye of a human subject in need of wet AMD treatment). SCS) non-surgically. Upon administration, aflibercept drug formulation flows out of the insertion site and is substantially localized to the back of the eye. In some embodiments, wet AMD is associated with choroidal neovascularization (CNV) in a human subject. In a further embodiment, the VEGF inhibitor is administered intravitreally to the patient.

  In one aspect, provided herein is a method of improving the effectiveness of a biological agent in the treatment of ocular disease in a human subject, wherein the administration of the biological agent is an anti-inflammatory agent, anti-VEGF, anti-PDGF, or anti-antibody. Combined with SCS administration of an angiopoietin agonist. In some embodiments, the biological agent and agent administered to the SCS act synergistically to improve the effectiveness of treatment of ocular disease. In some embodiments, the biological agent is a VEGF modulator such as aflibercept. In some embodiments, administration of the anti-inflammatory agent reduces the number of VEGF modulator drug treatments required to treat ocular disease. In another aspect, provided herein is a method of treating macular edema associated with retinal vein occlusion (RVO) in a human subject in need thereof. In some embodiments, the method comprises administering to a human subject an effective amount of a VEGF modulator and administering an effective amount of an anti-inflammatory agent to the suprachoroidal space (SCS) of the eye of the human subject. Administering. In some embodiments, the combination therapy acts synergistically as compared to administration of any of the drugs alone.

  In some embodiments, the anti-inflammatory drug is selected from the group consisting of steroids and non-steroidal inflammatory drugs (NSAIDs). In a further embodiment, the steroid is triamcinolone acetonide (TA). In some embodiments, TA is administered to the SCS of a human subject at a dose level of about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, or about 10 mg. The In some embodiments, TA is administered to the SCS of a human subject at a dose level of about 4 mg.

In some embodiments, the VEGF modulator is administered intravitreally to the subject. In some embodiments, the VEGF modulator is a VEGF-receptor kinase antagonist, anti-VEGF antibody or fragment thereof, anti-VEGF receptor antibody, anti-VEGF aptamer, small molecule VEGF antagonist, thiazolidinedione, quinoline, or design ankyrin repeat A VEGF antagonist selected from proteins (DARPin). In some embodiments, the VEGF antagonist is aflibercept, dibu-aflibercept, bevacizumab, sonepizumab, VEGF sticky trap, cabozantinib, foretinib, vandetanib, nintedanib, regorafenib, cediranib, ranibizimab, rapatibib , Regorafenib, verteporfin, busilamine, axitinib, pazopanib, fluocinolone acetonide, nintedanib, AL8326, 2C3 antibody, AT001 antibody, XtendVEGF antibody, HuMax-VEGF antibody, R3 antibody, AT001 / r84 antibody, HyBEVAP, ANG70 , APX004 antibody, ponatinib, BDM-E, VGX100 antibody, VGX200, VGX30 , COSMIX, DLX903 / 1008 antibody, ENMD2076, INDUS815C, R84 antibody, KD019, NM3, MGCD265, MG516, MP0260, NT503, anti-DLL4 / VEGF bispecific antibody, PAN90806, Paromid 529, BD0801 antibody, XV6 Diphosphate, AAV2-sFLT01, soluble Flt1 receptor, AV-951, boraseltib, CEP11981, KH903, lenvatinib, lenvatinib mesylate, terameprocol, PF00337210, PRS050, SP01, orotic acid carboxamidotriazole, hydroxy Chloroquine, linifanib, ALG1001, AGN150998, MP0112, AMG386, ponatinib, PD 73074, AVA101, BMS690514, KH902, Gorbatinib (E7050), Dobitinib, Dobitinib lactate (TKI258, CHIR258), ORA101, ORA102, Axitinib (Inwriter, AG013736), PTC299, Pegaptanib sodium, 306B, Troponin, G GSK2136773, Anti-VEGFR Arterase, Avila, CEP7055, CLT009, ESBA903, GW654465, HMPL010, GEM220, HYB676, JNJ17029259, TAK593, Nova21012, Nova21013, CP564U, AG882V13, AG895 S055, PG501, PG545, PTI101, TG100948, ICS283, XL647, enzastaurine hydrochloride, BC194, COT601M06.1, COT604M06.2, mabion VEGF, apatinib, RAF265 (CHIR-265), motesanib diphosphate (CHIR-265) 706), lenvatinib (E7080), TSU-68 (SU6668, orantinib), brivanib (BMS-540215), MGCD-265, AEE788 (NVP-AEE788), ENMD-2076, OSI-930, CYC116, Ki8751, RTN33, RN6 , SAR 131675, dobitinib (TKI-258) dilactic acid, apatinib, BMS-794833, brivanib alaninate (BMS-582664) , Gorubachinibu (E7050), semaxanib (SU5416), ZM323881HCl, Kabozanchinibu malic acid (XL184), ZM306416, AL3818, AL8326,2C3 antibody, AT001 antibody, HyBEV, bevacizumab (Avastin ^(TM)), ANG3070, APX003 antibody, APX004 antibody , Ponatinib (AP24534), BDM-E, VGX100 antibody (VGX100CIRCADIAN), VGX200 (c-fos-induced growth factor monoclonal antibody), VGX300, COSMIX, DLX903 / 1008 antibody, ENMD2076, sunitinib malate (Sutent ^{(registered trademark)} ) INDUS815C, R84 antibody, KD019, NM3, combined with anti-VEGF antagonist Allogeneic mesenchymal progenitor cells (eg, anti-VEGF antibody), MGCD265, MG516, VEGF-receptor kinase inhibitor, MP0260, NT503, anti-DLL4 / VEGF bispecific antibody, PAN90806, paromid 529, BD0801 antibody, XV615 , Lucitanib (AL3810, E3810), AMG706 (motesanib diphosphate), AAV2-sFLT01, soluble Flt1 receptor, cediranib (Recentin ^™ ), AV-951, tivozanib (KRN-951), regorafenib (Stivaga® ⁾ ), Boraseruchibu (BI6727), CEP11981, KH903, lenvatinib (E7080), Ren bee nibs mesylate, Terra Mepuro call (EM1421), ranibizumab (Lucentis ^(TM)), hydrochloric acid Zopanibu (Votoriento ^{TM), PF00337210, PRS050, SP01} ( curcumin), orotic acid carboxyamidotriazole, hydroxychloroquine, Rinifanibu (ABT 869, RG3635), fluocinolone acetonide (Irubien ^{(registered trademark)),} ALG1001, AGN150998, DARPin MP0112, AMG386, Ponatinib (AP24534), AVA101, Nintedanib (Valgatef ^™ ), BMS690514, KH902, Golbatinib (E7050), Everolimus (Affinitol ^{(registered trademark)} ), Dobitinib lactate (TKI258, ORA102, CHIR2581) Inraita ^{(registered trademark),} AG013736), Purichidepushin (Apuriji ^{(Registered trademark)),} PTC299, aflibercept (monkey trap ^{(registered trademark),} Airia ^{(registered trademark)),} pegaptanib sodium (Macugen ^TM, LI900015), verteporfin (Visudyne ^(TM)), bucillamine (Rimachiru , Lamin, brimani, lamit, boomik), R3 antibody, AT001 / r84 antibody, troponin (BLS0597), EG3306, batalanib (PTK787), Bmab100, GSK2136773, anti-VEGFR arterase, Avila, CEP7055, CLT0Eu, ESBA903H, ESBA903H , GW654465, HMPL010, GEM220, HYB676, JNJ17029259, TAK593, XtendVEGF antibody, Nova21012, No a21013, CP564959, smart anti-VEGF antibody, AG0282262, AG13958, CVX241, SU14813, PRS055, PG501, PG545, PTI101, TG100948, ICS283, XL647, enzastaurin hydrochloride (LY317615), BC194, CO1. 2. SIR sphere, apatinib (YN968D1), or AL3818 conjugated to mabion VEGF, anti-VEGF or VEGF-R antibody.

  In some embodiments, the VEGF modulator is aflibercept, wherein the aflibercept is about 0.5 mg, about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 4 mg. , About 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, or about 10 mg at a dosage level to a human subject intravitreally. In some embodiments, aflibercept is administered intravitreally to a human subject at a dose level of about 2 mg.

  In some embodiments, the VEGF modulator is administered intravitreally to the subject concomitant with SCS administration of the anti-inflammatory drug. In other embodiments, the VEGF modulator and the anti-inflammatory agent are administered sequentially.

  In some embodiments, the methods provided herein reduce retinal thickness and / or macular thickness compared to baseline measurements prior to treatment of a subject with a VEGF modulator or anti-inflammatory agent. Decrease. In other embodiments, the methods provided herein provide retinal thickness and / or macular as compared to a subject that has received a VEGF modulator administered to the SCS but has not received an anti-inflammatory agent. Reduce thickness. In some embodiments, the retinal thickness is the foveal subregion thickness (CST). In a further embodiment, CST is measured by spectral domain optical coherence tomography (SD-OCT). In some embodiments, the CST is reduced by at least about 20 μm at least about 40 μm at least about 50 μm at least about 100 μm, at least about 150 μm, or at least about 200 μm.

  In some embodiments, the methods provided herein include subject's highest corrected visual acuity (BCVA) compared to baseline measurements prior to treatment of the subject with a VEGF modulator or anti-inflammatory agent. ). In other embodiments, the methods provided herein increase a subject's BCVA as compared to a subject who received a VEGF modulator administered to an SCS but did not receive an anti-inflammatory agent. Let In some embodiments, BCVA is assessed using the Diabetes Retinopathy Early Treatment Study (ETDRS) visual acuity chart protocol. In further embodiments, the increase in BVCA is an increase in characters of about 5, about 6, about 7, about 8, about 9, about 10, about 15, about 20, about 25, about 30, or more.

  In some embodiments, the disclosure provides for improving anti-VEGF treatment (eg, aflibercept treatment) in a subject suffering from RVO by administering a steroid formulation to the SCS of the subject's eye. Provide a method. In some embodiments, the present disclosure provides a method for treating a subject suffering from RVO comprising administering an effective amount of a VEGF modulator and an anti-inflammatory agent to the subject's eye. In some embodiments, administration is surgical and includes, for example, insertion of a stent, shunt, or cannula. In other embodiments, administration is non-surgical, eg, via injection. In some embodiments, the RVO is BRVO or CRVO. In other embodiments, the RVO is an ischemic or non-ischemic RVO. In some embodiments, the RVO is ischemic CRVO. In some embodiments, the present disclosure surprisingly provides an effective treatment for ischemic CRVO patients. In some embodiments, the present disclosure provides 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, or more characters of BVCA A method of treatment for patients with ischemic CRVO is provided that results in an increase in. In some embodiments, the steroid formulation is administered to the SCS of the subject's eye. In some embodiments, the steroid formulation is non-surgically administered to the SCS of the subject's eye. In some embodiments, the steroid formulation is administered non-surgically to the SCS of the subject's eye and the VEGF modulator is administered by intravitreal injection.

  In some embodiments, the present disclosure provides a method for treating a subject suffering from ischemic CRVO, the method comprising administering aflibercept and TA. In some embodiments, aflibercept and / or TA are administered surgically. In other embodiments, aflibercept and / or TA are administered non-surgically. In some embodiments, aflibercept is administered intravitreally in one or more doses, and TA is administered non-surgically to the SCS in one or more doses. In some embodiments, the methods for treating RVO provided herein combine an administration of a VEGF modulator (eg, aflibercept) with an anti-inflammatory agent to provide additional doses of VEGF modulation. Reducing the need to re-treat the subject with the factor. In some embodiments, the assessment for the need for retreatment with a VEGF modulator is assessed by CST, BVCA, or a combination thereof. In some embodiments, the VEGF modulator is aflibercept, wherein aflibercept is administered intravitreally and the anti-inflammatory agent is TA.

FIG. 1 is a cross-sectional view of an example of a human eye.

2 is a cross-sectional view of a portion of the human eye of FIG. 1 taken along line 2-2.

3 and 4 are cross-sectional views of a portion of the human eye of FIG. 1 taken along line 3-3 illustrating the upper choroidal space, with or without fluid present, respectively. 3 and 4 are cross-sectional views of a portion of the human eye of FIG. 1 taken along line 3-3 illustrating the upper choroidal space, with or without fluid present, respectively.

FIG. 5 is a perspective view of a medical syringe, according to an embodiment.

FIG. 6 is a partially exploded view of the medical syringe of FIG.

7 is an exploded view of the medical syringe of FIG. 5 shown without a needle cap.

8 is a front view of a handle included in the medical syringe of FIG.

9 is a cross-sectional view of the handle of FIG. 8 taken along line 9-9.

FIG. 10 is a perspective view of a barrel included in the medical syringe of FIG.

11 is an exploded view of a needle hub included in the medical syringe of FIG.

12 is a front view of the needle hub of FIG.

13 is identified by the region Z _1, it is an enlarged view of a portion of the needle hub of Figure 12.

14 is a rear perspective view of a needle cap included in the medical syringe of FIG.

FIG. 15 is a front view of the medical syringe of FIG.

16 is a cross-sectional view of the medical syringe of FIG. 5 taken along line 16-16 in FIG.

17 is a diagram of the medical syringe of FIG. 5 in use during an injection procedure into the human eye.

Figure 18 is an enlarged view of a human eye which has been identified in Figure 17 by a part and the region Z ₂ of the medical injector of FIG.

19 is an exploded view of a needle hub configured for use with the medical syringe of FIG. 5, according to an embodiment.

20 is a front view of the needle hub of FIG.

FIG. 21 is a flow chart illustrating a method of injecting a pharmaceutical product into the eye using a medical syringe.

FIG. 22 is a graph of mean change in intraocular pressure versus time or weeks after treatment.

23 is a graph of the improvement in maximum corrected visual acuity (average change in visual acuity score (read characters)) from baseline (base log MAR) vs. weeks after treatment: 0.1 log MAR = 1 string = 5 characters.

FIG. 24 is a plot of the mean decrease in retinal thickness versus weeks after treatment.

FIG. 25 shows bilateral chronic uveitis patients with macular edema prior to (upper image) and subsequent (lower image) prior to SCSTA injection (left 2 images) or subtenon TA injection (right 2 images). It is an optical coherence tomography image of the eye.

FIG. 26 shows the macular prior to SCSTA injection (right 2 images, right eye) or Ozurdex (dexamethasone 0.7 mg intravitreal implant) (left 2 images, left eye) (upper image) and subsequent (lower image). 1 is an optical coherence tomography image of the eye of a patient with bilateral chronic uveitis with edema

FIG. 27 illustrates the distribution in various parts of the eye following intravitreal and SCS injection of triessence in rabbits.

Figures 28A-F illustrate the distribution of TA in various parts of the eye following trigenic intravitreal and SCS injections (28A: sclera-choroid-outer retina; Figure 28B: inner retina; Figure 28C: vitreous) FIG. 28D: aqueous humor; FIG. 28E: lens; FIG. 28F: iris-ciliary body). Figures 28A-F illustrate the distribution of TA in various parts of the eye following trigenic intravitreal and SCS injections (28A: sclera-choroid-outer retina; Figure 28B: inner retina; Figure 28C: vitreous) FIG. 28D: aqueous humor; FIG. 28E: lens; FIG. 28F: iris-ciliary body). Figures 28A-F illustrate the distribution of TA in various parts of the eye following trigenic intravitreal and SCS injections (28A: sclera-choroid-outer retina; Figure 28B: inner retina; Figure 28C: vitreous) FIG. 28D: aqueous humor; FIG. 28E: lens; FIG. 28F: iris-ciliary body).

FIGS. 29 and 30 illustrate the TA concentration for triessence and CLS-TA over a 90 day period, either in the sclera-choroid-outer retina layer (FIG. 29) or the inner retina layer (FIG. 30). FIGS. 29 and 30 illustrate the TA concentration for triessence and CLS-TA over a 90 day period, either in the sclera-choroid-outer retina layer (FIG. 29) or the inner retina layer (FIG. 30).

FIG. 31 is a bar graph showing cumulative fundus examination inflammation scores (mean ± SD) for each treatment group. Group 1: negative control (LPS / BSS SCS); group 2: oral high dose prednisone (LPS / prednisone 1 mg / kg / day PO); c: group 2 mean cumulative inflammation score on day 3 is significantly higher than group 1 Group 3: CLS-TA (LPS / 2 mg CLS-TA) a: Group 3 mean cumulative inflammation score on day 1 was significantly below group 1 (p = 0.04) B: Group 3 mean cumulative inflammation score on day 2 was significantly lower than group 1 (p = 0.023); d: Group 3 mean cumulative inflammation score on day 3 was significantly greater than group 1 Lower (p <0.034); Group 4: Oral low dose prednisone (LPS / prednisone 0.1 mg / kg / day PO).

FIG. 32 is a bar graph showing intraocular pressure (mmHg; mean ± SD) for each treatment group over the study period. Group 1: negative control (LPS / BSS SCS); group 2: oral high dose prednisone (LPS / prednisone 1 mg / kg / day PO); group 3: CLS-TA (LPS / 2 mg CLS-TA); group 4: oral low Dose prednisone (LPS / prednisone 0.1 mg / kg / day PO); group 4 mean IOP on day 3 was significantly lower than groups 1, 2, and 3 (P <0.0065).

FIG. 33 is a graph showing the average histological score of the various treatment groups for the front (left) and back (right).

FIG. 34A is a bar graph showing the mean lesion area 3 weeks after laser-induced choroidal neovascularization in a rat model, where the rats are treated via the suprachoroidal space with either saline or Eire. It was done. FIG. 34B is a bar graph showing the mean lesion area 22 days after laser-induced choroidal neovascularization in a rat model, where the rat was treated with either saline, anti-VEGF antibody, or Eire in the intravitreal lumen. Was treated through.

FIG. 35 is a chart showing the experimental protocol for laser-induced choroidal neovascularization in a rat model.

FIG. 36 is a time line for the experimental protocol of FIG.

FIG. 37A is a bar graph showing the mean lesion area 3 weeks after laser-induced choroidal neovascularization in a rat model, including the bar graph of FIG. 34A as a single injection treated animal, and further for a double injection treated animal Includes additional plots to show data. FIG. 37B illustrates the bar graph of FIG. 34B and is repeated here for a direct comparison with FIG. 37A.

FIG. 38 is a bar graph showing mean lesion area 3 weeks after laser-induced choroidal neovascularization in a rat model, where rats were treated with saline or Eyre and treated via the suprachoroidal space. Single injection animals, double injection animals treated via the suprachoroidal space, and single injection animals treated via the intravitreal lumen.

FIG. 39 is a bar graph showing some of the plots of FIG. 38 for direct comparison, using a single injection animal treated with the Eliere via the suprachoroidal space and saline or Eire Includes single-injected animals treated via intravitreal lumen.

FIG. 40 is a bar graph showing some of the plots of FIG. 38 for direct comparison, single injection animals treated via the suprachoroidal space and double injections treated via the suprachoroidal space Including animals.

FIG. 41 shows the aflibercept required for the control treatment group (IVT aflibercept alone) vs. the active treatment group (aflibercept + SCS CLS-TA) in the study provided in Example 4 (Eirea® ^). ) Is a bar graph showing the number of further IVT injections.

FIG. 42 is a bar graph showing BCVA improvement at month 3 in the active treatment group (Aflibercept + SCS CLS-TA) compared to the control treatment group (Aflibercept only) in the study provided in Example 4. It is.

FIG. 43 shows BCVA at 1, 2, and 3 months in the active treatment group (Aflibercept + SCS CLS-TA) compared to the control treatment group (Aflibercept only) in the study provided in Example 4. 6 is a bar graph showing improvement (y-axis represents change in read BCVA characters from baseline). In the first month, the control group exhibited an increase of 11.4 characters in BCVA characters, and the active drug group exhibited an increase of 16.1 characters. Thus, at 1 month, the active treatment group resulted in an increase of 4.7 letters compared to the control. At month 2, the control group exhibited an increase of 11.9 characters in BCVA characters and the active drug group exhibited an increase of 20.4 characters. Thus, at 2 months, the active treatment group resulted in an 8.5 letter increase compared to the control. At 3 months, the control group exhibited an 11.3 character increase in BCVA characters and the active drug group exhibited an 18.9 character increase. Thus, at 3 months, the active treatment group resulted in a 7.6 letter increase compared to the control.

Figure 44 compares the real drug treatment group (SCS CLS-TA + IVT aflibercept (Airia ^(R))) is the third month, the control treatment group (IVT aflibercept (Airia ^(R)) only) It is a bar graph which shows having improved macular edema. Subjects in the active group exhibited a 446 micron decrease in foveal subregion thickness (CST), while subjects in the control group exhibited a 343 micron decrease in CST, with respect to the active group The increase in retinal thickness decreased by 103 microns over the group.

FIG. 45 is a bar graph showing that improvement in macular edema was also observed at 1 and 2 months. At month 1, subjects in the active group exhibited a 446 reduced CST compared to a 405 CST reduction in the control group. At month 2, subjects in the active group exhibited a CST reduced by 459 compared to a 344 CST reduction in the control group.

FIG. 46 shows the number and percentage of patients eligible for further Ilea treatment (Aflibercept) for patients with branch retinal vein occlusion (BRVO) and central retinal vein occlusion (CRVO) in both the active and control groups. . Both BRVO and CRVO patients in the active group had lower additional african, compared to the percentage of patients who were eligible for further aflibercept in the control treatment group in BRVO and CRVO patients (67% and 71%, respectively). Presented percentages that were eligible for Bercept (21% and 22%, respectively).

FIG. 47 shows foveal subregion thickness in subjects with retinal vein branch occlusion (BRVO) treated with either aflibercept + Zuplater (active group) or aflibercept + sham (control group) The average of (CST) is shown. At month 1, subjects in both treatment groups exhibited a mean CST (about 300 μm) decrease. At month 2, subjects in the active group maintained a similar mean CST (291 μm vs. 455 μm) compared to the mean CST increase in subjects in the control group. At 3 months, subjects in both treatment groups exhibited a similar mean CST (approximately 300 μm). IVT: in the vitreous.

FIG. 48 shows the foveal subregion thickness in subjects with retinal vein branch occlusion (BRVO) treated with either aflibercept + zuplater (active group) or aflibercept + mock (control group) The average change in (CST) is shown. At month 1, subjects in the active group exhibited a CST reduced by 343 μm compared to a 272 μm decrease in CST in the control group (71 μm difference between groups). At month 2, subjects in the active group exhibited a CST that was reduced by 347 μm compared to a 130 μm reduction in CST in the control group (217 μm difference between groups). At month 3, subjects in the active group exhibited a CST reduced by 343 μm compared to a 281 μm decrease in CST in the control group (62 μm difference between groups). IVT: in the vitreous.

FIG. 49 shows the mean maximum corrected visual acuity in subjects with branch retinal vein occlusion (BRVO) treated with either aflibercept + zuplata (active group) or aflibercept + mock (control group) BCVA). Subjects in both treatment groups exhibited an increase in BCVA from baseline to 3 months. At month 2, subjects in the active group exhibited higher average BCVA compared to the average BCVA in the control group (71 vs. 67, respectively). IVT: in the vitreous.

FIG. 50 shows best corrected visual acuity (BCVA) in a subject with branch retinal vein occlusion (BRVO) treated with either aflibercept + zuplata (active group) or aflibercept + simulated (control group). ) Mean change. At month 1, subjects in the active group exhibited an increase in average BCVA of 13 scores compared to an increase in average BCVA of 14 scores in the control group (difference between groups 1 score). At 2 months, subjects in the active group exhibited an increase in average BCVA of 16 scores compared to an increase in average BCVA of 12 scores in the control group (4 scores of differences between groups). At month 3, subjects in the active group exhibited an increase in average BCVA of 17 scores compared to an increase in average BCVA of 18 scores in the control group (1 score difference between groups).

FIG. 51 shows the foveal subregion thickness (CRVO) in subjects with central retinal vein occlusion (CRVO) treated with either aflibercept + zuplater (active group) or aflibercept + sham (control group) CST) average. At month 1 subjects in both treatment groups exhibited a decrease in mean CST (268 μm vs. 326 μm) compared to mean CST at baseline (876 μm vs. 778 μm). From month 1 to month 3, subjects within the active group consistently exhibited a lower average CST compared to the average CST of the control group. IVT: in the vitreous.

FIG. 52 shows the foveal subregion thickness in subjects with central retinal vein occlusion (CRVO) treated with either aflibercept + zuplater (active group) or aflibercept + mock (control group) (CRVO). The average change in CST) is shown. At month 1 subjects in the active group exhibited a CST reduced by 607 μm compared to a 452 μm decrease in CST in the control group (inter-group decrease of 156 μm). At month 2, subjects in the active group exhibited a CST reduced by 632 μm compared to a 420 μm decrease in CST in the control group (212 μm reduction between groups). At month 3, subjects in the active group exhibited a CST reduced by 603 μm compared to a 365 μm decrease in CST in the control group (reduction between groups 238 μm). IVT: in the vitreous.

FIG. 53 shows mean maximum corrected visual acuity (BVCA) in subjects with central retinal vein occlusion (CRVO) treated with either aflibercept + zuplata (active group) or aflibercept + sham (control group) ). Subjects in both treatment groups exhibited an increase in BCVA from baseline to month 1 (40 vs 47 to 61 vs 57). At month 2, subjects in the active group exhibited an even higher average BCVA compared to a decrease in average BCVA in the control group (67 vs. 55, respectively). At month 3, subjects in the active group exhibited a 62-score average BCVA compared to a 52-score average BCVA in the control group. IVT: in the vitreous.

FIG. 54: Best corrected visual acuity (BCVA) in subjects with central retinal vein occlusion (CRVO) treated with either aflibercept + zuplata (active group) or aflibercept + sham (control group) The average change in is shown. At month 1, subjects in the active group exhibited an increase in average BCVA of 21 scores compared to an increase in average BCVA of 10 scores in the control group (11 differences between groups). At 2 months, subjects in the active group exhibited an increase in average BCVA of 27 scores compared to an increase in average BCVA of 9 scores in the control group (18 differences between groups). At month 3, subjects in the active group exhibited an increase in average BCVA of 22 scores compared to an increase in average BCVA of 6 scores in the control group (16 differences between groups). IVT: in the vitreous.

FIG. 55 shows patients eligible for aflibercept retreatment at any time during the study stratified by non-ischemic (left panel) and ischemic (right panel) perfusion types (independent of treatment). Indicates the total number.

FIG. 56 shows the number of ischemic patients eligible for aflibercept retreatment during the study in control (left panel) versus active (right panel) treatment group subjects.

FIG. 57 shows the number of non-ischemic patients eligible for aflibercept retreatment during the study in control (left panel) versus active (right panel) treatment group subjects.

58A-D show BVCA and CST data for treatment-independent ischemic versus non-ischemic patients at 1, 2, and 3 months of the study. FIG. 58A shows BVCA in ischemic versus non-ischemic patients. FIG. 58B shows changes in BVCA in ischemic versus non-ischemic patients. FIG. 58C shows CST in ischemic versus non-ischemic patients. FIG. 58D shows changes in CST in ischemic versus non-ischemic patients.

FIGS. 59A-D show BVCA and CST data for non-ischemic patients within each treatment group at months 1, 2, and 3 of the study. FIG. 59A shows BVCA in non-ischemic patients in the control treatment group (aflibercept + mock) vs. the active treatment group (aflibercept + zuplata). FIG. 59B shows the change in BVCA in non-ischemic patients within the control treatment group (Aflibercept + Simulation) versus the active treatment group (Aflibercept + Zuplater). FIG. 59C shows CST in a non-ischemic patient in the control treatment group (Aflibercept + Simulation) versus the active treatment group (Aflibercept + Zuplata) FIG. 59D shows the change in CST in non-ischemic patients within the control treatment group (Aflibercept + simulation) versus the active treatment group (Aflibercept + Zuplater).

Figures 60A-D show BVCA and CST data for ischemic patients within each treatment group at months 1, 2, and 3 of the study. FIG. 60A shows BVCA in ischemic patients in the control treatment group (aflibercept + mock) vs. the active treatment group (aflibercept + zuplata). FIG. 60B shows the change in BVCA in ischemic patients in the control treatment group (Aflibercept + simulation) versus the active treatment group (Aflibercept + Zuplater). FIG. 60C shows CST in ischemic patients in the control treatment group (Aflibercept + Simulation) versus the active drug treatment group (Aflibercept + Zuplater). FIG. 60D shows the change in CST in ischemic patients within the control treatment group (Aflibercept + Simulation) versus the active treatment group (Aflibercept + Zuplater).

Figures 61A-D show BVCA data by treatment group stratified into ischemic or non-ischemic BRVO or CRVO groups at 1, 2, and 3 months of the study. FIG. 61A shows BVCA in patients with ischemic BRVO in the control treatment group (Aflibercept + simulation) versus the active treatment group (Aflibercept + Zuplater). FIG. 61B shows BVCA in non-ischemic BRVO patients in the control treatment group (aflibercept + simulation) vs. the active treatment group (aflibercept + zuplata). FIG. 61C shows BVCA in ischemic patients in the control treatment group (aflibercept + simulation) vs. the active treatment group (aflibercept + zuplata). FIG. 61D shows BVCA in non-ischemic patients in the control treatment group (aflibercept + mock) vs. the active treatment group (aflibercept + zuplata).

FIG. 62 provides an overview of the data schematically shown in FIGS. 61A-D.

  Methods, devices, and drug formulations in human subjects in need thereof include posterior ocular disorders such as wet AMD, CNV, wet AMD associated with CNV, macular edema associated with uveitis (eg , Infectious or non-infectious uveitis), and macular edema associated with retinal vein occlusion (RVO) are provided herein. In one embodiment, the RVO is retinal vein branch occlusion (BRVO), hemilateral retinal vein occlusion (HRVO), or central retinal vein occlusion (CRVO). In one embodiment, the uveitis is intermediate, posterior, or panuveitis and can be infectious or non-infectious uveitis. In some embodiments, the drug formulation comprises aflibercept.

  Intravitreal injection results in drug diffusion throughout the eye, including the lens, iris, and ciliary body in front of the eye, for some drugs, such as cataract and high intraocular pressure (IOP) levels Associated with safety issues. Specifically, intravitreal administration of triamcinolone (TA) has been associated with increased cataracts and IOP levels in 20% to 60% of patients. SCS injections of drugs are not desired to be bound by theory, but result in drugs that remain localized in the retina and choroid without substantial diffusion to the vitreous or frontal portion of the eye As such, SCS injections have the potential to reduce the incidence of these side effects.

  Current treatments for chronic retinal disease often require intravitreal injection of anti-VEGF drugs. However, these diseases often affect the choroid and retina, and thus specific targeting of these tissues may be more beneficial in modulating disease progression. The present invention addresses this need.

  For example, for the treatment of macular edema associated with uveitis, macular edema associated with RVO, wet AMD and / or diabetic macular edema (DME), choroidal neovascularization (CNV), wet AMD associated with CNV The method and device provided herein are, in one embodiment, the retina, which is primarily the tissue that is part of the eye that primarily covers the interior of the eye and is responsible for vision Used to restore or improve visual function by reducing macular edema, which affects the choroid, the layer adjacent to the retina that supplies blood, oxygen, and nutrients. Macular edema is the accumulation of fluid that can cause abnormal swelling of the macula, the part of the retina responsible for central vision and color perception. This swelling can rapidly lead to visual deterioration and can ultimately lead to blindness.

  The two main types of retinal vein occlusion (RVO) are retinal vein branch occlusion (BRVO) and central retinal vein occlusion (CRVO). BRVO is the most common form and is characterized by venous occlusion in any smaller branch of the central retinal vein. CRVO is characterized by obstruction of the main vein in the retina. Occlusions that occur in the main branch from the central retinal vein can be characterized as hemispheric retina or hemilateral retinal vein occlusion (HRVO). RVO can be further classified as perfusion (non-ischemic) or non-perfusion (ischemic). Any class of non-ischemic RVO (BRVO, HRVO, or CRVO) is more common and less serious than ischemic RVO. Ischemic CRVO is characterized by an acute onset of venous obstruction resulting in reduced retinal perfusion, capillary closure, and retinal hypoxia. This type of CRVO can cause severe vision loss. In particular, there is a need in the art for effective treatment for severe conditions of ischemic CRVO.

  As used herein, “non-surgical” ocular drug delivery devices and methods are for drug delivery that does not require general anesthesia and / or posterior ocular anesthesia (also referred to as posterior ocular block). Refers to methods and devices. Alternatively or in addition, “non-surgical” ocular drug delivery methods are performed using instruments having 28 gauge or smaller diameter. Alternatively or in addition, “non-surgical” ocular drug delivery methods typically do not require the guidance mechanism required for ocular drug delivery via a shunt or cannula.

  As used herein, “surgical” ocular drug delivery is via surgical means, eg, through an incision to expose and provide access to an area of the eye, including the posterior area. And / or device insertion or drug administration via insertion of a stent, shunt, or cannula.

  The surgical and non-surgical posterior ocular lesion treatment methods and devices described herein are particularly useful in posterior regions of the eye, such as retinal choroid tissue, macula, retinal pigment epithelium (RPE), and posterior segment of the eye. Useful for local delivery of drugs to the optic nerve. In another embodiment, the non-surgical methods and microneedles provided herein can be used to target drug delivery to a specific posterior ocular tissue or region within the eye or nearby tissue. it can. In one embodiment, the methods described herein include drugs, specifically the sclera, choroid, Bruch's membrane, retinal pigment epithelium, subretinal space in the eye of a human subject in need of treatment. Delivered to the retina, macular, optic disc, optic nerve, ciliary body, trabecular meshwork, aqueous humor, vitreous humor, and / or other ocular or nearby tissues. The methods and microneedles provided herein can be used, in one embodiment, to target drug delivery to a specific posterior ocular tissue or region within the eye or nearby tissue.

  In one embodiment of the methods described herein, a patient in need of treatment receives a drug, such as aflibercept or triamcinolone acetonide, over one or both eyes over at least one dosing session. Administered into the choroidal space. Non-surgical administration, in one embodiment, inserts the microneedle into one or both eyes of the patient, eg, the sclera, and through the inserted microneedle into the suprachoroidal space of the eye. Achieved by injection or infusion. Surgical administration, in another embodiment, is performed by making a periconjunctival incision in the eye, exposing and providing access to the posterior region of the eye, or accessing the posterior region of the eye as known in the art. Accomplished by any other conventional surgical means. In some embodiments, the treatment is administered via a shunt, stent, or cannula surgically placed in the subject's eye.

  In one embodiment, the effective amount of drug administered to the SCS is the therapeutic effect of the drug when the same dosage is administered intravitreally, locally, in the anterior chamber, parenterally, or orally. Provides higher therapeutic efficacy of the drug compared to gender. In one embodiment, the microneedle drug delivery method described herein provides the drug in the SCS for subsequent local delivery to nearby posterior ocular tissues (eg, retina and choroid) in need of treatment. Deliver precisely. The drug is injected into the ocular tissue from the volume injected (or from, for example, microparticles or nanoparticles in the drug formulation) for a long period of time, for example several hours after the non-surgical drug administration is completed. Or it may be released over days or weeks or months. This can be beneficial, for example, increased bioavailability of the drug, or oral, parenteral, same drug dosage compared to delivery by topical application of the drug formulation to the ocular tissue surface. Or it can provide increased bioavailability compared to intravitreal administration. In some embodiments, the drug formulation comprises aflibercept. In some embodiments, the drug formulation comprises triamcinolone acetonide.

  By using the methods and microneedle devices described herein, the SCS drug delivery method advantageously has a microneedle tip placed in the eye and a drug formulation placed in the suprachoroidal space. And precise control of the depth of insertion into the ocular tissue so that it can flow into one or more posterior eye tissues surrounding the SCS, such as the choroid and retina. In one embodiment, the insertion of the microneedle is performed in the sclera of the eye. In one embodiment, drug flow into the SCS is accomplished using microneedles without contacting underlying tissues such as the choroid and retinal tissue.

  The methods provided herein can, in one embodiment, achieve delivery of a drug to the suprachoroidal space, thereby obtaining via local, parenteral, intracameral, or intravitreal drug delivery. Allows drug access to posterior eye tissues (eg, choroid and retina), which is not possible. The methods provided herein are for treatment in a human subject treated using the methods provided herein to deliver drugs to posterior ocular tissue for the treatment of posterior ocular disorders. Suprachoroidal drug doses and / or frequency of dosing sufficient to achieve a response is sufficient to elicit the same or substantially the same therapeutic response intravitreal, local, parenteral, or oral drug dose or dosing It is less than the schedule. In one embodiment, the SCS delivery methods described herein are compared to intravitreal, local, anterior chamber parenteral, or oral drug doses sufficient to elicit the same or substantially the same therapeutic response. Thus allowing a drug for the treatment of ocular disorders after a reduced drug dose. In a further embodiment, the suprachoroidal drug dose sufficient to elicit a therapeutic response is 75% or less, or 50% of the intravitreal, local, parenteral, or oral drug dose sufficient to elicit a therapeutic response or Less than, or 25% or less. The therapeutic response is, in one embodiment, to a posterior ocular disorder (macular edema associated with uveitis, macular edema associated with RVO, wet AMD, choroidal neovascularization (CNV), CNV) in which the patient is undergoing treatment. Relevant wet AMD) symptoms / clinical symptoms or reduced posterior ocular disorders / clinical symptoms in which the patient is being treated.

  The term “suprachoroidal space” is used synonymously with the suprachoroidal space, SCS, suprachoroid, and suprachorodia, and is located between the sclera and choroid Describe the potential space within the eye area. This region mainly consists of closely packed layers of long pigmented protrusions derived from each of two adjacent tissues. However, space can also develop in this region as a result of fluid or other material accumulation in the suprachoroidal space and adjacent tissue. One skilled in the art understands that the suprachoroidal space is frequently dilated by fluid accumulation due to some disease state in the eye or as a result of some trauma or surgical intervention. However, in the present description, fluid accumulation is intentionally generated by infusion of the drug formulation into the suprachoroidal layer to generate the suprachoroidal space (filled with the drug formulation). While not wishing to be bound by theory, the SCS region is a natural process of the eye that moves the fluid from one region of the eye to another region for uveoscleral outflow. ), And in the case of choroidal detachment from the sclera, it is considered to be an actual space.

  As used herein, “eyeball tissue” and “eye” are the anterior portion of the eye (ie, the portion of the eye in front of the lens) and the back of the eye (ie, the portion of the eye behind the lens). Including both. For reference, FIGS. 1-4 are various views of the human eye 10 (FIGS. 2-4 are cross-sectional views). Although specific regions are identified, those skilled in the art will recognize that the series of identified regions does not constitute the entire eye 10; rather, the identified regions are suitable for discussion of the embodiments herein. It is recognized that this is presented as a simplified example. The eye 10 includes both an anterior portion 12 (the portion of the eye that is in front of and includes the lens) and a posterior portion 14 (the portion of the eye behind the lens). The anterior portion 12 is bounded by the cornea 16 and the crystalline lens 18, while the posterior portion 14 is bounded by the sclera 20 and the crystalline lens 18. The anterior portion 12 is further subdivided into an anterior chamber 22 between the iris 24 and the cornea 16 and a posterior chamber 26 between the lens 18 and the iris 24. The cornea 16 and sclera 20 collectively form an edge 38 at the point where they meet. The exposed portion of the sclera 20 on the anterior portion 12 of the eye is protected by a transparent membrane called the conjunctiva 45 (see, eg, FIGS. 2 and 3). Below the sclera 20 are the choroid 28 and the retina 27, collectively referred to as retinal choroid tissue. The vitreous humor 30 (also referred to as “vitreous”) is disposed between the ciliary body 32 (including ciliary muscles and ciliary processes) and the retina 27. The front portion of the retina 27 forms a serrated edge 34. The loose connective tissue or potential space between the choroid 28 and the sclera 20 is referred to as the superior choroid layer. FIG. 2 illustrates the cornea 16, consisting of the epithelium 40, Bowman layer 41, parenchyma 42, Descemet's membrane 43, and endothelium 44. FIG. 3 shows that there is substantially no fluid and / or tissue separation within the suprachoroidal space 36 (ie, in this configuration, the space is a “potential” suprachoroidal space), with a Tenon's capsule 46 or conjunctiva 45. Illustrated are the sclera 20, the suprachoroidal space 36, the choroid 28, and the retina 27. As shown in FIG. 3, the sclera 20 has a thickness of about 500 μm to 700 μm. FIG. 4 illustrates the sclera 20, the suprachoroidal space 36, the choroid 28, and the retina 27 surrounded by a surrounding Tenon capsule 46 or conjunctiva 45 with fluid 50 in the suprachoroidal space 36.

  The broken line in FIG. 1 represents the equator of the eye 10. In some embodiments, the insertion site for any of the microneedles and / or methods described herein is between the equator and the edge 38 (ie, within the anterior portion 12 of the eye 10). For example, in some embodiments, the insertion site is about 2 millimeters to 10 millimeters (mm) behind edge 38. In other embodiments, the insertion site for the microneedle is centered on the equator of the eye 10. In yet other embodiments, the insertion site is at the back of the equator of eye 10. In this way, the drug formulation can be introduced into the suprachoroidal space 36 at the insertion site (eg, via a microneedle), during an infusion event (eg, during injection), and at the insertion site. From the upper choroidal space 36. In some embodiments, the drug formulation comprises aflibercept or triamcinolone acetonide.

  The microneedle may extend from the base of the microneedle device at any angle suitable for insertion into the eye 10. In certain embodiments, the microneedle extends from the base at an angle of about 90 degrees to provide a substantially vertical insertion of the microneedle into the eye surface. In another embodiment, the microneedle extends from the base at an angle of about 60 degrees to about 110 degrees, about 70 degrees to about 100 degrees, about 80 degrees to about 90 degrees, or about 85 degrees to about 95 degrees. To do.

  The microneedle device may comprise means for controllably inserting the microneedle into the ocular tissue and optionally retracting it. In addition, the microneedle device may include means for controlling the angle at which at least one microneedle is inserted into the ocular tissue (eg, the surface of the ocular tissue at an angle of about 90 degrees at least one microneedle). By inserting in).

  In one embodiment, the depth of microneedle insertion into the ocular tissue can be controlled by the length of the microneedle as well as other geometric features of the microneedle. For example, other rapid changes in flange or microneedle width can be used to limit the depth of microneedle insertion. Microneedle insertion may also be operated to move the microneedle through the controlled distance into the eyeball tissue, and similarly, for example, conversely, retract the microneedle through the controlled distance. It can be controlled using a mechanical micropositioning system with mechanical components. The depth of insertion can also be controlled by the rate at which the microneedle is inserted into the ocular tissue. The retraction distance is controlled by the elastic recoil of the eyeball tissue into which the microneedle is inserted, or by including an elastic element that pulls the microneedle back a defined distance after the insertion force is released into the microneedle device. Can.

  The angle of insertion can be directed by positioning the microneedle with respect to the microneedle base at a first angle and the base with respect to the eyeball surface at a second angle. In one embodiment, the first angle can be about 90 ° and the second angle can be about 0 °. The angle of insertion can also be directed by projecting the microneedle through a channel in the housing that is oriented at a defined angle from the device housing.

  As provided throughout, in one embodiment, the methods described herein are performed using hollow or solid microneedles, eg, rigid microneedles. As used herein, the term `` microneedle '' refers to a conduit body having a base, a shaft, and a distal end suitable for insertion into the sclera and other ocular tissues, As described herein, it has suitable dimensions for minimally invasive insertion and drug formulation injection. That is, the microneedles have a length or effective length that does not exceed about 2,000 microns and a diameter that does not exceed about 600 microns. Both the “length” and “effective length” of the microneedle include the length of the microneedle shaft and the bevel height of the microneedle. In some embodiments, a microneedle used to perform the methods described herein is an international application filed May 2, 2014 and entitled “Apparatus and Method for Ocular Injection”. One of the devices disclosed in Patent Application Publication No. WO 2014/179698 (Application No. PCT / US2014 / 036590), which is incorporated herein by reference in its entirety for all purposes. Prepare. In some embodiments, the microneedles used to perform the methods described herein were filed on August 27, 2013 and entitled “Apparatus and Method for Drug Delivery Microneedles”. One of the devices disclosed in International Patent Application Publication No. WO 2014/036009 (Application No. PCT / US2013 / 056863), which is incorporated herein by reference in its entirety for all purposes. With one.

  In another embodiment, the microneedles are designed to have a length that is longer than the desired penetration depth, but the microneedles are controllably inserted into the tissue to some extent. Partial insertion may be controlled by the mechanical properties of the tissue that flex and dent during the microneedle insertion process. Thus, as the microneedle is inserted into the tissue, its movement partially elastically deforms the tissue and partially penetrates into the tissue. By controlling the degree to which the tissue deforms, the depth of microneedle insertion into the tissue can be controlled.

  In one embodiment, a device used to perform one of the methods described herein was filed on October 14, 2014 and entitled “Medical Injector for Ocular Injection”. No. 29 / 506,275, the disclosure of which is hereby incorporated by reference in its entirety for all purposes.

  In one embodiment, the microneedle is inserted into the eye of a human patient using rotation / drilling techniques and / or vibrational action. Thus, the microneedles can be inserted to a desired depth, for example, by drilling the microneedles for a desired number of rotations corresponding to the desired depth into the tissue. See, eg, US Patent Application Publication No. 2005/0137525 (incorporated herein by reference) for a description of microneedle perforation. Rotation / drilling techniques and / or vibration effects may be applied during the insertion step, the retraction step, or both.

  As used herein, the words “proximal” and “distal” are each by an operator (eg, surgeon, doctor, nurse, technician, etc.) inserting a medical device into a patient. Pointing toward and away from it, the tip end (ie, the distal end) of the device is first inserted inside the patient's body. Thus, for example, the end of a microneedle described herein, which is initially inserted inside the patient's body, becomes the distal end while the end of the opposite end of the microneedle (eg, manipulated by an operator) The end of the medical device that is being used becomes the proximal end of the microneedle.

  As used herein, the terms “about” and “approximately” are generally an average of the stated values ± 10%. For example, about 0.5 includes 0.45 and 0.55, about 10 includes 9-11, and about 1000 includes 900-1100.

  The term “liquid tight” is understood to encompass both hermetic seals (ie, gas impermeable seals) as well as seals that are liquid only impermeable. The term “substantially” as used in connection with “liquid tightness”, “gas impervious”, and / or “liquid impervious” is desirable for full fluid impermeability, but with manufacturing tolerances or Due to other practical considerations (eg, applied in seals and / or fluids, etc.) suggests that some minimal leakage can occur even within a “substantially liquid tight” seal Intended to be. Thus, a “substantially liquid tight” seal is one where the seal is in place and less than about 5 pounds per square inch gauge (psig), less than about 10 psig, less than about 20 psig, less than about 30 psig, less than about 50 psig, less than about 75 psig, A seal is included that prevents passage of fluid (including gases, liquids, and / or slurries) through it when maintained at less than about 100 psig and all values of fluid pressure therebetween. Similarly, a “substantially liquid tight” seal is one in which the seal is maintained in place, less than about 5 psig, less than about 10 psig, less than about 20 psig, less than about 30 psig, less than about 50 psig, less than about 75 psig, less than about 100 psig, and Includes a seal that prevents passage of liquid (eg, liquid pharmaceuticals) therethrough when exposed to all values of liquid pressure therebetween.

  As used herein, the term “hollow” refers not only to a single straight bore through the center of the microneedle, but also to a plurality of bores, a bore following a complex path through the microneedle, a plurality from the bore. Including entry and exit points, and bore intersections or nets. That is, the hollow microneedle has a structure that includes one or more continuous paths from the base of the microneedle to the exit point (opening) in the shaft and / or the tip portion of the proximal microneedle. .

  The microneedle device, in one embodiment, is a fluid reservoir for containing a therapeutic formulation (eg, a drug or cell formulation), eg, as a solution or suspension, and a distal tip of the microneedle tip. A drug reservoir (which may contain any therapeutic formulation) in operation with a microneedle bore in operation. The fluid reservoir may be integral with the microneedle, integral with the extension body, or separate from both the microneedle and the extension body.

  Any of the microneedles and / or components included in the embodiments described herein can be any suitable biocompatible material or combination of materials, including metals, glasses, semiconductor materials, ceramics, or polymers. Formed and / or constructed from Examples of suitable metals include pharmaceutical grade stainless steel, gold, titanium, nickel, iron, gold, tin, chromium, copper, and alloys thereof. The polymer can be biodegradable or non-biodegradable. Examples of suitable biocompatible and biodegradable polymers are polylactide, polyglycolide, polylactide-co-glycolide (PLGA), polyanhydride, polyorthoester, polyetherester, polycaprolactone, polyesteramide, polyamide (Butyric acid), poly (valeric acid), polyurethane, and copolymers and hybrids thereof. Exemplary non-biodegradable polymers include various thermoplastic materials or other polymeric structural materials known in medical device processing. Examples include nylon, polyester, polycarbonate, polyacrylate, ethylene-vinyl acetate and other acyl substituted cellulose acetate polymers, non-degradable polyurethane, polystyrene, polyvinyl chloride, polyvinyl fluoride, poly (vinyl imidazole). ), Chlorosulfonate polyolefins, polyethylene oxide, hybrids and copolymers thereof. Biodegradable microneedles provide an increased level of safety compared to non-biodegradable ones so that they are essentially harmless even if inadvertently broken into ocular tissue Can do.

  In one embodiment, the hollow microneedles provided herein are fabricated using a laser or similar optical energy source. In one example, the microcannula may be cut using a laser to represent the desired microneedle length. The laser may also be used to shape single or multiple tip openings. Single or multiple cuts may be made on a single micron cannula to shape the desired microneedle structure. In one example, the microcannula may be made from a metal such as stainless steel and cut using a laser with a wavelength in the infrared region (eg, about 0.7 to about 300 μm) of the light spectrum. Further refinement may be performed using metal electropolishing techniques well known to those skilled in the art. In another embodiment, the microneedle length and optional bevel are formed by a physical grinding process that may include, for example, grinding a metal cannula against a moving abrasive surface. The processing process may further include precision grinding, microbead jet blasting, and ultrasonic cleaning to form the desired precise tip shape of the microneedle.

  Further details of possible manufacturing techniques can be found in, for example, US Patent Application Publication No. 2006/0086689, US Patent Application Publication No. 2006/0084942, US Patent Application Publication No. 2005/0209565, and US Patent Application Publication No. 2002. No./0082543, US Pat. No. 6,334,856, US Pat. No. 6,611,707, US Pat. No. 6,743,211 and PCT / US2014 / filed on May 2, 2014. No. 36590, which is incorporated herein by reference in its entirety for all purposes.

  In some embodiments, the device includes a pharmaceutical container, a piston assembly, and a handle. The drug container defines a lumen configured to contain a drug. The distal end portion of the pharmaceutical container includes a coupling portion configured to be removably coupled to the needle assembly. The proximal end portion of the pharmaceutical container includes a flange and a longitudinal groove shoulder. The distal end portion of the piston assembly includes an elastomeric member that is movably disposed within the lumen of the pharmaceutical container. The handle is coupled to the proximal end portion of the piston assembly such that movement of the handle results in movement of the elastomeric member within the pharmaceutical container. A proximal end portion of the pharmaceutical container is movably disposed within the handle. A portion of the handle is configured to contact the flange and limit proximal movement of the handle relative to the pharmaceutical container. The handle includes a protrusion configured to engage a longitudinal groove shoulder of the pharmaceutical container and limit rotation of the handle relative to the pharmaceutical container.

  Any of the compositions described herein can be injected using any suitable syringe of the type shown and described herein. Any of the methods described herein can be performed using any suitable syringe of the type shown and described herein. In this way, the benefits of targeted drug delivery via a non-surgical approach can be realized. For example, in some embodiments, the device includes a pharmaceutical container, a needle assembly, and a piston assembly. A pharmaceutical container contains a dose of a pharmaceutical such as, for example, a drug or a cell therapy, eg, a steroid formulation or a cell suspension (eg, a stem cell suspension). The dose has a delivered volume of at least about 20 μL, at least about 50 μL, at least about 100 μL, at least about 200 μL, or at least about 500 μL. In one embodiment, the amount of therapeutic formulation delivered from the device described herein into the suprachoroidal space is from about 10 μL to about 200 μL, such as from about 50 μL to about 150 μL. In another embodiment, about 10 [mu] L to about 500 [mu] L, such as about 50 [mu] L to about 250 [mu] L, is non-surgically administered to the suprachoroidal space.

  The needle assembly is coupled to the distal end portion of the pharmaceutical container and includes a contact surface and a needle. The contact surface is configured to contact the target surface of the eye, as described herein, and can include a convex surface and / or a sealing portion. The needle is coupled to the base. The distal end portion of the piston assembly includes an elastomer member that is movably disposed within the pharmaceutical container. The proximal end portion of the piston assembly is configured to receive force, move the elastomer within the drug container, and deliver a dose of drug through the needle assembly. Collectively, the needle assembly and the piston assembly are such that the intraocular pressure measured within 30 minutes after delivery of a dose is 5 percent, 10 percent, 15 percent of the intraocular pressure measured before delivery of the dose, 15 It is configured to deliver that dose of the pharmaceutical into the suprachoroidal space of the eye so that it is within percent, 20 percent, or 25 percent.

  In some embodiments, the device includes a pharmaceutical container, a needle assembly, and a piston assembly. A pharmaceutical container contains a dose of a pharmaceutical such as, for example, a steroid composition such as a triamcinolone composition. The needle assembly is coupled to the distal end portion of the pharmaceutical container and includes a contact surface and a needle. The contact surface is configured to contact the target surface of the eye, as described herein, and can include a convex surface and / or a sealing portion. The needle is coupled to the base. The distal end portion of the piston assembly includes an elastomer member that is movably disposed within the pharmaceutical container. The proximal end portion of the piston assembly is configured to receive a force, move the elastomer within the drug container, and deliver a dose of drug through the needle assembly. The needle assembly and piston assembly collectively address the therapeutic response resulting from a dose via any one of an intravitreal delivery method, a local delivery method, a parenteral delivery method, or an oral delivery method. The dose is configured to be delivered into the suprachoroidal space of the eye such that it is substantially equivalent to the therapeutic response resulting from the delivery of the dose. The amount of the dose is less than about 75 percent of the corresponding dose amount.

  In some embodiments, the device includes a pharmaceutical container, a needle assembly, and a piston assembly. A pharmaceutical container contains a dose of a pharmaceutical such as, for example, a steroid composition such as a triamcinolone composition. The needle assembly is coupled to the distal end portion of the pharmaceutical container and includes a contact surface and a needle. The contact surface is configured to contact the target surface of the eye, as described herein, and can include a convex surface and / or a sealing portion. The needle is coupled to the base. The distal end portion of the piston assembly includes an elastomer member that is movably disposed within the pharmaceutical container. The proximal end portion of the piston assembly is configured to receive a force, move the elastomer within the drug container, and deliver a dose of drug through the needle assembly. The needle assembly and piston assembly collectively enable intraocular Cmax resulting from a dose to be addressed via any one of an intravitreal delivery method, a local delivery method, a parenteral delivery method, or an oral delivery method. Delivering the dose of the drug into the suprachoroidal space of the eye to exceed the intraocular Cmax resulting from the delivery of the dose of the drug, e.g., at least about 1.25, 1.5, or 2 times Configured as follows.

  The needle assembly and the piston assembly collectively accommodate intraocular AUC resulting from a dose via any one of intravitreal delivery methods, local delivery methods, parenteral delivery methods, or oral delivery methods. Deliver the dose of the drug into the suprachoroidal space of the eye to exceed the intraocular AUC resulting from the delivery of the dose of the drug, e.g., at least about 1.25, 1.5, or 2 Configured as follows.

  FIGS. 5-18 illustrate a medical syringe 100 configured to deliver a pharmaceutical agent, for example, to ocular tissue, according to an embodiment. The medical syringe 100 can be used in conjunction with any of the methods and therapeutic formulations described herein. More specifically, the medical syringe 100 (also referred to herein as a “syringe”) is at least partially limited by limitations and / or associated with delivering a drug formulation into ocular tissue. It may have a size, shape, and / or configuration based on the task. For example, as described in further detail herein, drug delivery into ocular tissue using conventional devices and / or needles may result in incomplete delivery of doses, efficacy of the injected drug. It can lead to reduction, unwanted cell seeding, trauma, etc. Accordingly, the medical syringe 100 can have a size and / or configuration that effectively delivers the medication to a portion of the eye, such as the posterior region.

  As shown, the medical syringe 100 includes a handle 110, a barrel 130, a piston 150, a needle hub 160, and a cap 170. The handle 110 can be any suitable shape, size, and / or configuration. For example, in some embodiments, the handle 110 can have an ergonomic shape and / or size that can allow the syringe 100 to be operated with one or both hands. The handle 110 has a proximal end portion 111 and a distal end portion 112 and defines an inner volume 113 (see, eg, FIG. 9). As described in further detail herein, the inner volume 113 of the handle 110 is configured to receive and / or store at least a portion of the barrel 130 and the piston 150.

  As shown in FIGS. 7-9, the handle 110 is formed by coupling the first handle member 115A to the second handle member 115B. Handle member 115A and handle member 115B can be relatively thin shells or the like and can be formed from any suitable material, such as the biocompatible materials described above. In other words, handle members 115A and 1158B can be substantially hollow and / or can define an inner volume (eg, inner volume 113). The first handle member 115A has a proximal end portion 116A and a distal end portion 117A. Further, any of the first handle members 115A may facilitate coupling of the first handle member 115A and the second handle member 115B and / or engage a portion of the piston 150 and / or barrel 130. It has an inner surface 118A that can include any suitable features, cutouts, couplers, walls, etc. that can be used. For example, as shown in FIG. 9, the inner surface 118A of the first handle member 115A can include, inter alia, a barrel 130, a piston 150, and / or a second, respectively, as described in more detail herein. A rib 120A, a retaining member 119A, and at least one coupler 121A can be formed that can be used to engage the other handle member 115B.

  Similarly, the second handle member 115B has a proximal end portion 116B and a distal end portion 117B. The second handle member 115B can also be used to engage the barrel 130, the piston 150, and the first handle member 115A, respectively, as described in further detail herein. Retaining member 119B and inner surface 118B forming at least one coupler 121B. As shown in FIG. 9, for example, the first handle member 115 </ b> A and the second handle member 115 </ b> B are coupled together to collectively form the handle 100. The first handle member 115A and the second handle member 115B can be combined in any suitable member. For example, in some embodiments, the retention member 119B of the second handle member 115B is an opening or equivalent configured to engage and receive a portion of the retention member 119A of the first handle member 115A. Things can be defined. Similarly, at least one coupler 121B of the second handle member 119B defines an opening configured to mate with and receive a portion of the associated coupler 121A of the first handle member 115A. can do. In some embodiments, the retention member 119A and coupler 121B of the first handle member 115A can be operable to couple the first handle member 115A to the second handle member 115B, a second The retaining member 119B of the handle member 115B and the inner surface of the coupler 121B can be configured to form an interference or friction fit. In other embodiments, the first handle member 115A and the second handle member 115B may be via any suitable method such as, for example, adhesives, ultrasonic welding, mechanical fasteners, and / or the like. Can be combined. Further, when the first handle member 115A is coupled to the second handle member 115B, the inner surfaces 118A and 118B of the handle members 115A and 115B, respectively, collectively, as shown in FIG. An inner volume 113 of 110 is defined.

  The barrel 130 of the syringe 100 can be any suitable shape, size, or configuration. As shown in FIG. 10, the barrel 130 has a proximal end portion 131 and a distal end portion 132 through which a lumen 133 is defined. In addition, the barrel 130 has an outer surface that defines a set of slots 136 (only one is shown in FIG. 10) and a gripping portion 137. The gripping portion 137 can be configured to facilitate use of the device by providing a predetermined location for the user to engage the syringe 100. The gripping portion 137 can have any suitable surface finish or equivalent, which in some cases can increase the friction between the gripping portion 137 and the user's fingers and / or hands. it can. In other embodiments, the barrel 130 does not include a gripping portion.

  The lumen 133 of the barrel 130 movably receives at least a portion of the piston 150, as described in further detail herein. Further, at least a portion of lumen 133 receives, stores, stores, and / or otherwise stores a pharmaceutical (eg, a corticosteroid such as triamcinolone acetonide or any other pharmaceutical described herein). A pharmaceutical volume configured to contain can be defined. In some embodiments, at least a portion of the barrel 130 can be substantially transparent and / or the user visually sees the volume of fluid (eg, pharmaceutical / therapeutic formulation) within the lumen 133. May include an indicator or the like configured to allow automatic inspection. In some instances, such an indicator can be any number of lines and / or markings associated with, for example, the volume of fluid disposed within the barrel 130. In other embodiments, the barrel 130 can be substantially opaque and / or does not include an indicator or equivalent.

  The distal end portion 132 includes and / or forms a coupler 138 that is configured to be physically and fluidly coupled to the needle hub 160 as described in more detail herein. . The proximal end portion 131 of the barrel 130 includes a flanged end 135 and defines a set of slots 136 (only one slot is shown in FIG. 10). As described above, at least a portion of the barrel 130 is disposed within the inner volume 113 of the handle 110 (see, eg, FIG. 16). Specifically, at least the proximal end portion 131 of the barrel 130 can be inserted into the handle 110 in a manner that allows the handle 110 to be moved relative to the barrel 130. In other words, at least the proximal end portion 131 of the barrel 130 can be movably disposed within the inner volume 113 defined by the handle 110. Further, when the proximal end portion 131 of the barrel 130 is disposed within the handle 110, the ribs 120A and 120B of the handle members 115A and 115B, respectively, move into their associated slots 136 defined by the barrel 130. Arranged as possible. Such an arrangement can define the range of motion of the handle 110 relative to the barrel 130, for example. Such an arrangement can also limit the rotational movement of the handle 110 about the barrel 130 while allowing translational movement of the handle 110 relative to the barrel 130 in the proximal or distal direction. Thus, substantially all of the force applied by the user during the injection operation urges the handle 110 (and thus the piston 150) distally and does not cause rotation of the piston 150 within the barrel 130. . By limiting the rotational movement of the piston 150 (especially the elastomeric member 155) within the barrel 130, the injection operation can be performed consistently. For example, by limiting the rotational motion of the elastomeric member 155 within the barrel 130, the force required to overcome the static coefficient of friction between the elastomeric member 155 and the barrel 130 is parallel to the applied force. It is more consistent (including between parts and / or injections) than it includes both moving (ie, distal) and rotational components. This arrangement facilitates a more consistent “loss of resistance” being felt at the handle 110 during the injection operation, as described below.

  In addition, the arrangement of flanged end 135 of barrel 130 and inner surfaces 118A and 118B of handle members 115A and 115B define the range of motion of translation of handle 110 relative to barrel 130 in the proximal or distal direction, respectively. (See, for example, FIG. 16).

  The piston 150 of the syringe 100 can be any suitable shape, size, and / or configuration. For example, referring back to FIG. 7, the piston 150 is associated with the handle 110 and / or the barrel 130, respectively, and thus, at least a portion of the piston 150 is disposed within the handle 110 and / or the barrel 130. It can have a size and shape that can be made possible. More specifically, the piston 150 has a proximal end portion 151 and a distal end portion 152. Proximal end portion 151 of piston 150 is configured to be disposed within inner volume 113 of handle 110. As shown in FIG. 7, the proximal end portion 151 of the piston 150 defines an opening 154 and thus can receive at least a portion of the retaining members 119A and 119B of the handle members 115A and 115B, respectively. , Tab 153 or equivalent. For example, in some embodiments, the proximal end portion 151 of the piston 150 is secured by at least a portion of the retaining member 119B by the piston 150 prior to coupling of the handle members 115A and 115B during the assembly and / or manufacturing process. The second handle member 115B can be positioned relative to the retaining member 119B so as to be disposed within the defined opening 154. In other words, the proximal end portion 151 of the piston 150 or the tab 153 in the vicinity thereof is centered about a portion of the retaining member 119B prior to coupling the first handle member 115A to the second handle member 115B. Can be done. Accordingly, the piston 150 can be fixedly coupled to the handle 110.

  The distal end portion 152 of the piston 150 is configured to be movably disposed within the lumen 133 of the barrel 130. As shown in FIG. 7, the distal end portion 152 of the piston 150 includes and / or is coupled to an elastomeric member 155. In some embodiments, the elastomeric member 155 can be monolithically formed with the piston 150 (eg, overmolded or equivalent). In other embodiments, the elastomeric member 155 can be formed independently of the piston 150 and coupled thereto. The elastomeric member 155 can be made from an inert and / or biocompatible material that can have any suitable hardness and / or hardness. For example, in some embodiments, the elastomeric member 155 can be formed / constructed from rubber, silicone, plastic, nylon, polymer, any other suitable material, or combinations thereof. In some embodiments, at least a portion of the elastomeric member 155 can be configured to deform or equivalent while substantially maintaining its original shape. That is, the elastomeric member 155 may have a hardness that is sufficiently low to allow at least some deformation thereof while preventing the elastomeric member 155 from undergoing substantially reconfiguration and / or equivalent. it can.

  Elastomer member 155 can be disposed in lumen 113 such that the outer surface of elastomer member 155 contacts the inner surface of barrel 130 that defines lumen 133. In some embodiments, the elastomeric member 155 and the inner surface of the barrel 130 collectively form a substantially liquid tight seal and / or hermetic seal, which can be, for example, a substance ( For example, leakage of pharmaceuticals), outgassing, contamination, and / or the like can be prevented. Further, the elastomeric member 155 can have a size, shape such that movement of the piston 150 and / or elastomeric member 155 within the barrel 130 is limited when the applied force exceeds a predetermined threshold, and / or Or it can be constructed from such materials. In this way, the piston 150 can be barreled until, for example, the force applied on the handle 110 is sufficient to inject the drug into the target tissue, as described in more detail herein. It can be maintained in a substantially fixed position relative to 130. In some embodiments, the size, shape, and / or configuration of the elastomeric member 155 can be varied to increase or decrease the amount of force used to move the piston 150 within the barrel 130, for example. This can be based on one or more characteristics associated with the target tissue and / or the equivalent in some cases, as described in more detail herein.

Needle hub 160 of syringe 100 can be any suitable shape, size, and / or configuration. As shown in FIGS. 11-13, 15, and 16, needle hub 160 has a proximal end portion 161, a distal end portion 162, an indicator portion 168, and a pair of tabs 164, and a lumen 167 (see, eg, FIG. 16). The proximal end portion 161 of the needle hub 160 is configured to be coupled to the distal end portion 132 of the barrel 130. For example, the needle hub 160 meshes and engages the coupler 138 of the barrel 130 to couple the needle hub 160 to the barrel 130 and fluidly communicate the lumen 167 of the needle hub 160 with the lumen 133 of the barrel 130. A coupler 163 (see, eg, FIG. 16) can be included. In some embodiments, the coupler 163 of the needle hub 160 and the coupler 138 of the barrel 130 can form a threaded coupling or the like. In such an embodiment, the user may, for example, engage the tab 164 and rotate the needle hub 160 relative to the barrel 130, thereby causing the coupler 163 of the needle hub 160 onto the coupler 138 of the barrel 130. Can be screwed together. In some embodiments, the coupler 163 of the needle hub 160 is configured to form a fluid tight seal with the distal end portion 132 of the barrel 130 when coupled thereto, for example, Luer-Lok ⁽ Can be a locking mechanism such as ( ^{registered trademark)} (or other locking mechanism) and / or the like. The distal end portion 162 of the needle hub 160 includes and / or coupled to a base 165, which in turn is coupled to and / or coupled to the microneedle 166, as described below. Form. The indicator portion 168 of the needle hub 160 is configured to provide a visual indication related to one or more characteristics of the microneedle 166. For example, in this embodiment, indicator portion 168 is configured to provide a visual indication related to the effective length of microneedle 166 (eg, “900” micrometers as shown in FIG. 12). be able to.

  The base 165 can be any suitable shape, size, and / or configuration and can be configured to contact a portion of ocular tissue during an injection event. For example, as shown, the base 165 has a convex distal end surface that is configured to contact the target surface of the target tissue as the substance is conveyed through the needle and into the target tissue (eg, FIG. 18). In some embodiments, the distal end surface includes a seal portion (not identified in the figure) configured to define a substantially fluid tight seal with the target surface when the distal end surface contacts the target surface. Including. For example, the distal end surface of the base 165 can deform the target surface such that the seal portion is continuous with the target surface and forms a substantially fluid tight seal. In some embodiments, the seal portion can be symmetric about the microneedle 166.

  In some embodiments, the base 165 can be formed from a material or combination of materials that is relatively flexible and / or has a relatively low hardness. In some cases, the base 165 can be formed from a material with a hardness that is low enough to limit and / or prevent damage to ocular tissue when placed in contact therewith. In some cases, the base 165 can be configured to deform (eg, elastically or plastically) when placed in contact with ocular tissue. In other embodiments, the base 165 is sufficient such that when the base 165 is placed in contact with and / or pressed against the target tissue, the target tissue (and not the base) is deformed. It can be formed from a material of hardness. In some embodiments, for example, the base 165 is constructed from medical grade stainless steel and has a surface finish of less than about 1.6 μm Ra. As such, the surface finish can facilitate the formation of a substantially fluid tight seal between the base 165 and the target tissue.

  Further, when the base 165 is coupled to the needle hub 160, the lumen 169 defined by the microneedle 166 is in fluid communication with the lumen 167 of the needle hub 160 (see, eg, FIG. 16). Thus, the substance can flow through the lumen 167 of the needle hub 160 and the lumen 169 of the microneedle 166 and be injected into the target tissue, as described in further detail herein.

The microneedle 166 can be any suitable device or structure configured to penetrate the target tissue of the patient. For example, the microneedle 166 can be any of the microneedles described herein configured to penetrate eyeball tissue. In some embodiments, the microneedle 166 can be a 30 gauge microneedle, a 32 gauge microneedle, or a 34 gauge microneedle. As shown in FIG. 13, the microneedle 166 extends a distance D ₁ (also referred to herein as “effective length”) from the distal surface of the base 165. In some embodiments, the shape and / or size of the microneedle 166 can correspond to at least a portion of the target tissue. For example, in some embodiments, the effective length of the microneedle 166 (eg, the portion of the microneedle 166 that is outside or distal to the base 165) is such that when the microneedle 166 is inserted into ocular tissue, A portion of the microneedle 166 can correspond to a portion of the ocular tissue such that the portion of the microneedle 166 is placed within the sclera or the superior choroidal space of the eye. Specifically, in this embodiment, the effective length and / or distance D ₁ is about 900 micrometers (μm). Further, the indicator portion 168 of the needle hub 160 may be the user, it is configured to provide a visual indication relating to the effective length and / or distance D _1. Although not illustrated in FIGS. 11-13, in some embodiments, the microneedle 166 can have a bevel geometry (eg, bevel angle, bevel height, bevel aspect ratio, or the like) This can facilitate puncture and / or insertion of the tip of the microneedle 166 into the target tissue, and the opening of the microneedle 166 (not shown) is within the desired area during the injection event. Can be maintained. In some embodiments, the microneedle 166 or any of the microneedles described herein is filed on August 27, 2013 and is entitled “Apparatus and Method for Drug Delivery Microneedles”. Patent Application Publication No. WO2014 / 036009 (Application No. PCT / US2013 / 056863) and / or International Patent Application Publication No. WO2014 filed May 2, 2014 and entitled “Apparatus and Method for Ocular Injection”. / 179698 (International Application No. PCT / US2014 / 036590), each of which is incorporated herein by reference in its entirety for all purposes. Type of bevel or other properties that are illustrated and described may include.

  As described above, the base 165 can be coupled to the needle hub 160, which in turn is a barrel lumen 133, a needle hub 160 lumen 167, and a microneedle 166 lumen 169. Is coupled to the barrel 130 such that a pharmaceutical and / or substance contained within the barrel 130 flows therethrough, for example, can be injected into the target tissue.

  The cap 170 of the syringe 100 is removably disposed adjacent to the distal end portion 132 of the barrel 130 and is configured to substantially store, cover, enclose, protect, isolate, etc. at least a portion of the needle hub 160. Is done. More specifically, the cap 170 can be moved relative to the remainder of the medical syringe 100 to position at least a portion of the needle hub 160 within the inner volume 174 of the cap 170 (see, eg, FIG. 14). ). Accordingly, the cap 170 can have a size and / or shape that is related to and / or at least partially based on the size and / or shape of the needle hub 160. In some embodiments, the cap 170 and a portion of the needle hub 160 can collectively define a friction fit or the like, which substantially separates the cap 170 from the needle hub 160. It can be operable in maintaining a fixed position. In addition, in some embodiments, the cap 170 and a portion of the needle hub 160 collectively form a substantially fluid-tight and / or substantially hermetic seal, which in turn can be associated with the drug delivery device 100. Prior to use, the sterility of the microneedle 166 can be maintained. For example, although not shown, the cap 170 is configured to maintain the sterility of the microneedle 166 prior to use, a plug, seal, sterilizing member (eg, wipe, pad, etc.), and / or the like. Can be included. Further, as shown in FIG. 14, the cap 170 that can provide the user with visual indications related to the size and / or effective length of the microneedle 166 includes an indicator portion 173. In some embodiments, the indicator portion 173 can be substantially similar in form and function to the indicator portion 168 of the needle hub 160 and is configured to provide substantially the same visual indication. be able to.

  As shown in FIGS. 15-18, in some cases, a user (eg, a doctor, technician, nurse, physician, ophthalmologist, etc.) may operate the syringe 100 and use a drug, according to an embodiment. The formulation can be delivered to the suprachoroidal space of the eye. In some embodiments, the drug formulation comprises aflibercept and is used to treat a patient for wet AMD, CNV, wet AMD associated with CNV, or wet AMD associated with RVO. The In some embodiments, the drug formulation comprises triamcinolone acetonide and is used in conjunction with aflibercept for wet AMD, CNV, wet AMD associated with CNV, or wet AMD associated with RVO Used to treat patients, or to improve any VEGF therapy in ocular disease. In some cases, prior to the injection event, the user may, for example, couple the distal end portion 132 of the barrel 130 to a fluid reservoir or equivalent and / or any suitable transfer device (not shown). A volume of pharmaceutical product and / or drug formulation can be transferred into the lumen of barrel 130. For example, in some embodiments, the distal end portion 132 of the barrel 130 has a penetrating member configured to penetrate a fluid reservoir containing a drug formulation, such as those described herein. It can be physically and fluidly coupled to the transfer adapter and / or the like. Such a transfer adapter is filed on May 2, 2014 and is published in International Patent Application Publication No. WO 2014/179698 (Application No. PCT / US2014 / 036590) entitled “Apparatus and Method for Ocular Injection” (any PCT / US2014 / 036590) For purposes of reference, it may be similar to the adapter 21280 illustrated and described herein, which is incorporated herein by reference in its entirety. Accordingly, the penetrating member installs the transfer adapter in fluid communication with the fluid reservoir. When the transfer adapter is physically and fluidly coupled to the barrel 130, the transfer adapter similarly places the lumen 133 of the barrel 130 in fluid communication with the fluid reservoir.

  When the barrel 130 is in fluid communication with a fluid reservoir (not shown), the user can manipulate the syringe 100 by moving the handle 110 proximally relative to the barrel 130, which in turn is the barrel. The piston 150 disposed in the 130 lumens 133 is moved in the proximal direction. Thus, the volume associated with the portion of lumen 133 defined by the distal barrel 130 of the elastomeric member 155 of the piston 150 increases and the volume associated with the portion of the lumen 133 proximal of the elastomeric member 155. Decrease. In some embodiments, the friction fit and / or fluid seal defined between the elastomeric member 155 and the inner surface of the barrel 130 may cause proximal movement of the piston 150 (eg, a distal tube of the elastomeric member 155). As the volume of the portion of the cavity 133) increases the volume of the drug and / or drug formulation from the fluid reservoir into the portion of the lumen 133 distal to the elastomeric member 155 (eg, the drug volume). Can be operable to cause a negative pressure difference to be introduced into a portion of the lumen 133. In some embodiments, a predetermined volume of drug formulation can be drawn into the lumen 133 of the barrel 130. In other embodiments, the volume of drug formulation drawn into lumen 133 is not determined in advance. Once the desired amount of drug formulation is contained within the barrel 130, the user can, for example, uncouple the barrel 130 from a transfer adapter (not shown). Further, in some embodiments, the coupler 138 and / or the distal end portion 132 of the barrel 130 is configured to fluidly isolate the lumen 133 of the barrel 130 from the outer volume of the barrel 130. A sealing port and / or any other suitable port can be included. While described above to transfer a volume of drug form from the fluid reservoir into the lumen 133 of the barrel 130, in other embodiments, the syringe 100 may be manufactured, for example, in the manufacturing process and / or any other During time, it can be pre-filled prior to use.

In some cases, once the desired amount of drug formulation is contained in the barrel 130, the user operates the syringe 100 and is placed within the needle hub 160 (eg, cap 170 or within cap 170). To the distal end portion 132 of the barrel 130 so that the lumen 169 of the microneedle 166 can be placed in fluid communication with the lumen 133 of the barrel 130. Once the needle hub 160 is coupled to the barrel 130, the user can remove the cap 170 from the needle hub 160 when positioned about it. In other cases, the cap 170 can be removed in advance. Thus, the user can position the syringe 100 relative to the ocular tissue so that the microneedle 166 is positioned at or near the desired injection site. In some cases, the injection site can be a predetermined distance from the edge 32, for example. For example, as shown in FIG. 17, the injection site can be about 1 mm, about 2 mm, about 3 mm, about 4 mm, about 5 mm, about 6 mm, about 7 mm, about 8 mm, about 9 mm, about 10 mm, or more. can from 32 a distance _{D 2.} In other cases, the injection site can be to any suitable part of the eye.

  When the microneedle 166 is at or near the desired injection site, the base 165 of the needle hub 160 can be pressed against the target surface of the eye 10 as the microneedle 166 is inserted into the target surface. it can. Accordingly, the base 165 of the needle hub 160 deforms the target surface (eg, the conjunctiva 45 of the eye 10 as shown in FIG. 18), defines an intrusion therein, and / or otherwise is therein. A “recess” can be formed. The “recess” can facilitate the desired transfer of drug from the barrel 130 to the target area via the microneedle 166. The base 165 of the needle hub 160, and thus the indentation, can be maintained in such a position throughout the procedure (eg, injection of a pharmaceutical agent into the SCS 36). In this way, the “indentation” (eg, the interface between the distal surface of the base 165 and the surface of the target location) limits and / or prevents the exudation of the drug from the target area during and after the injection. , Thereby facilitating the desired transfer of the medicament to the target area (eg, SCS 36). As described above, in some embodiments, the distal (or contact) surface of the base 165 can include a seal portion, which has a convex surface, a smooth finish (eg, Ra = Surface (with a surface finish of less than 1.6 μm), or the like.

  In addition, in some embodiments, the microneedle 166 is inserted into the eye 10 at a substantially vertical or angle of about 80 ° to about 100 ° and has a short penetration distance (eg, about 1.1 mm, about At 1 mm, about 0.9 mm or less), the suprachoroidal space is reached. This approaches the suprachoroidal space at a steep angle and takes a longer penetration path through the sclera 20 and other ocular tissues, increasing the invasiveness of the method, the size of the microneedle traces, resulting in infection and In contrast to long conventional microneedles 166 or cannulas that increase the risk of vascular rupture. With such a long microneedle 166, the ability to precisely control the insertion depth is reduced compared to the micromicroneedle 166 approach described herein.

  Once the distal end portion of the microneedle 166 is placed in at least one of the SCS 36 of the eye 10, the lower portion of the sclera 20, and / or the upper portion of the choroid 28 (FIG. 18), the pharmaceutical product Can be transported from the barrel 130. More specifically, while maintaining the indentation in the conjunctiva 45, the user can apply force to the handle 110 to initiate an infusion event. In some cases, the force applied on the handle 110 by the user, such as during insertion, may occur when the distal tip of the microneedle 166 is not placed in the desired position (eg, the microneedle 166 is It may be insufficient to move the piston 150 within the barrel 130 (when in the sclera 20 and not in the SCS 36). In other words, the syringe 100 is configured or “calibrated” to limit and / or prevent delivery to another different area while assisting the user in delivering at least a portion of the drug formulation to the area. Can be configured.

  In some embodiments, the syringe 100 informs the user when the distal tip of the microneedle 166 is within the target area, for example, so that the drug formulation can be delivered to the target area with high reliability. Can be configured as follows. For example, the syringe 100 moves the piston 150 within the lumen 133 of the barrel 130 when the distal tip of the microneedle 166 is positioned within an area of the eye 10 that has a greater density, such as the sclera 20. Can be configured to limit. In some cases, the syringe 100 can limit the movement of the piston 150 within the lumen 133 when the applied force falls below a predetermined threshold, such as about 6 Newtons (N). Conversely, the syringe 100 is configured such that when the distal tip of the microneedle 166 is placed in a target location (eg, a region having a lower density, such as the SCS 36), a force having a magnitude of less than about 6N is applied to the piston 150. And / or when applied on the handle 110 may allow movement of the piston 150 within the barrel 130. In this way, the system is configured or “calibrated” to provide feedback (eg, tactile feedback) to the user and allow the user to deliver the drug formulation to the target area with a high degree of confidence. Can be done. In some instances, the user can observe the movement or lack of movement of the piston 150 within the barrel 130 to determine whether the medication has been delivered to the eye. When the medicine is not being transported, the user can respond appropriately. For example, the user can realign the system, reposition to a different injection site, and / or use a different size microneedle 166 (eg, a different microneedle 166 length).

  As an example, the user can operate the syringe 100 to insert the microneedle 166 into the eye 10 at the desired injection site. In some cases, if the distal tip of the microneedle 166 is not placed in the desired location, but instead is placed in the sclera 20, the force applied by the user on the handle 110 is the piston 150 May be insufficient to move the barrel in the barrel 130. For example, the sclera 20 is a force applied by the user, along with resistance to flow caused by friction and drug properties (eg, viscosity, density, or the like) between the elastomeric member 155 and the inner surface of the barrel 130. , Thereby providing back pressure that prevents and / or limits delivery of the drug formulation to the sclera 20. In other words, the syringe 100 is specifically configured or “calibrated” such that the force is insufficient to deliver the drug formulation to the sclera 20. Conversely, when the distal tip of the microneedle 166 is placed within the SCS 36 of the eye 10, for example, the same force applied by the user is at least partially between the sclera 20 and the SCS 36. It may be sufficient to move the piston 150 within the barrel based on anatomical differences and / or differences in material properties (eg, density or equivalent). In other words, the force can be sufficient to overcome the back pressure provided by the SCS 36. Thus, syringe 100 has a drug formulation (eg, a drug such as a corticosteroid (eg, triamcinolone) VEGF inhibitor, combinations thereof, or any other drug described herein) in its area. Can be configured to ensure that an injection is initiated only when the distal tip of the microneedle 166 is in and / or near the SCS 36 so that it can only be delivered. Further, the SCS 36 provides a first pressure that resists and / or counters flow from the distal tip of the microneedle 166 and the sclera 20 is higher than the first pressure, the distal tip of the microneedle 166. Resulting in a second pressure that resists and / or counters flow from the Thus, the user can be informed by the loss of resistance felt at the handle 110 when the distal tip of the microneedle 166 is transitioned from the sclera 20 to or near the SCS 36.

  In some embodiments, the applied force can be about 2N, about 3N, about 4N, about 5N, about 6N, or more, and can include all ranges in between. In some embodiments, the piston 150 and the barrel 130 can be configured to collectively provide an injection pressure in the barrel 130 of about 100 kPa to about 500 kPa. For example, in some embodiments, the injection pressure is about 100 kPa, 110 kPa, 120 kPa, 130 kPa, 140 kPa, 150 kPa, 160 kPa, 170 kPa, 180 kPa, 190 kPa, 200 kPa, 220 kPa, 240 kPa, 260 kPa, 280 kPa, 300 kPa, 320 kPa, 340 kPa, 360 kPa, 380 kPa, 400 kPa, 420 kPa, 440 kPa, 460 kPa, or about 480 kPa, and can include all ranges and values therebetween. The injection pressure is sufficient to overcome the back pressure provided by the SCS 36, but can be insufficient to overcome the back pressure provided by the sclera 20. In some embodiments, the force can be varied depending on the diameter of barrel 130 and / or piston 150, the viscosity of the drug formulation, and / or the material of barrel 130 and / or piston 150. Thus, regardless of variations in the piston 150, barrel 130, and / or drug formulation, the syringe 100 provides an injection pressure in the barrel 130 of about 100 kPa to about 500 kPa. In some embodiments, the drug formulation includes aflibercept and is used to treat a patient for wet AMD, CNV, wet AMD associated with CNV, or wet AMD associated with RVO . In some embodiments, the drug formulation comprises triamcinolone acetonide and is used in conjunction with aflibercept for wet AMD, CNV, CNV related wet AMD, or RVO related wet AMD Used to treat patients or improve any VEGF therapy in ocular disease.

  In some embodiments, the syringe 100 is configured such that the injection distance traversed by the piston 150 is sufficient to deliver substantially the entire desired dose of drug formulation into the SCS 36. Can do. In other embodiments, the syringe 100 may be configured such that the injection distance traversed by the piston 150 is sufficient to deliver only a portion of the desired dose of drug formulation into the SCS 36. it can. In such an embodiment, the syringe 100 initiates delivery of the drug formulation into the SCS 36, eg, configured to inform the user that the distal tip of the microneedle 166 is positioned within the SCS 36. (E.g., the user recognizes or otherwise detects that the piston 150 has moved and thus indicates the desired positioning of the microneedle 166). In other words, the syringe 100 can assist the user in determining whether the distal tip of the microneedle 166 is in the SCS 36 or by not initiating delivery of the drug formulation. In such embodiments, the injection distance can be the first injection distance. The user then moves the distal end of the piston 150, for example, by applying a manual force on the piston 150 (eg, by moving the handle 110 relative to the barrel 130 as described herein). The end portion can be moved by a second injection distance.

  After the desired delivery of the drug from the drug container, the hub 160 can be maintained in contact with the target surface for a period of time to allow the desired drug absorption by the eye. In this way, the drug can diffuse through the tissue behind the eye without the drug leaching from the injection site (eg, where the microneedle 166 has punctured the conjunctiva). As described above, in some embodiments, the distal end surface of the base 165 forms a substantially fluid tight seal with the conjunctiva so as to limit drug movement from the eye along the needle track. And a sealing portion configured. Thus, the syringe 100 and the methods described herein can facilitate delivery of a desired dose to a desired region of the eye.

Although microneedles 166 are described above as having an effective length that is approximately 900 μm, in other embodiments, syringe 100 is coupled to a needle hub that includes microneedles with any suitable effective length. Can. For example, FIGS. 19 and 20 illustrate a needle hub 260 according to another embodiment. Needle hub 260 has a proximal end portion 261, a distal end portion 262, and an indicator portion 268. In some embodiments, the needle hub 260 can be substantially similar in form and function to the needle hub 160 described in detail above with reference to FIGS. 11-13. Accordingly, portions of needle hub 260 are not described in further detail herein. However, the needle hub 260 can differ by being coupled to a base 265 that includes a microneedle 266 with an effective length that exceeds the effective length of the microneedle 160. For example, in this embodiment, the microneedle 266 extends from the base 265 by a distance D _{3 of} about 1100 μm. Further, indicator portion 268 of needle hub 260 is configured to present a visual indication related to effective length and / or distance D ₃ (eg, in FIGS. 19 and 20, with text “1100”). expressed).

  In still other embodiments, the syringe can include microneedles having an effective length of about 200 μm to about 1500 μm. Short effective length microneedles (eg, about 200 μm to about 400 μm long) can be used, for example, in various subcutaneous injection procedures. Syringes with longer effective length microneedles (eg, length of about 1200 μm to about 1500 μm) can be used in various ocular procedures such as, for example, injection into the subretinal space.

  Referring now to FIG. 21, a flowchart illustrating a method 1000 for delivering a drug formulation to ocular tissue using a medical syringe according to an embodiment is shown. In some embodiments, the drug formulation includes aflibercept and is used to treat a patient for wet AMD, CNV, wet AMD associated with CNV, or wet AMD associated with RVO . In some embodiments, the drug formulation comprises triamcinolone acetonide and is used in conjunction with aflibercept for wet AMD, CNV, CNV related wet AMD, or RVO related wet AMD Used to treat patients or improve any VEGF therapy in ocular disease. The method 1000 includes, at 1001, placing a syringe needle hub in contact with an eye surface at a target location. The medical syringe (also referred to herein as a “syringe”) can be any suitable syringe. For example, in some embodiments, the syringe can be substantially similar or identical to the syringe 100 described above. Thus, the syringe can include at least a handle, a barrel, a piston, and a needle hub. As explained above, the piston can be at least partially disposed within the handle and fixedly coupled thereto. A portion of the barrel can be movably disposed within the handle, for example, to allow relative movement in the proximal or distal direction. The barrel is configured to movably receive a portion of the piston and may define a lumen that may receive, store, and / or contain a volume of drug formulation. The needle hub is coupled to the barrel and can be placed in fluid communication with the microneedle lumen coupled thereto.

  A first force is applied at 1002 on a portion of the syringe to deform a portion of the ocular surface associated with the target location. For example, in some cases, the user can align the syringe and target location along the surface of the eye, move the syringe, insert the microneedle into the eye, and place the needle hub on the eye surface. Can be placed in contact. The user can then apply a first force on the handle, and in response, at least a portion of the first force is transmitted from the needle hub to the eye surface. For example, in some cases, a needle hub can be applied over the conjunctiva, which can result in a recess being formed in the conjunctiva. In some cases, the needle hub can remain in contact with the eye and can continue to deform a portion of the eye until after the injection event, which in turn can cause exudation and / or equivalents. Can be prevented.

  A second force is applied at 1003 onto a portion of the syringe and the syringe needle (eg, a microneedle) is moved through the sclera until the distal surface of the needle is placed in the eye at a predetermined depth. Move through. In some embodiments, the syringe arrangement allows the second force applied on the portion of the syringe to force the needle through the ocular tissue prior to the distal surface of the needle being placed at a predetermined depth. It can be sufficient to move, but not enough to move the piston in the barrel. For example, in some embodiments, the piston may form a friction fit with the inner surface of the barrel, which in turn may define a reactive force that resists movement of the piston within the barrel. (Eg, a plunger or the like). Further, in some cases, the ocular tissue provides back pressure or the like in response to needle insertion. Thus, the amount of force applied to move the needle through the ocular tissue (eg, sclera) is the amount of force to move the piston within the barrel and / or otherwise inject the drug formulation. Can be less than.

  A volume of drug formulation is expelled at 1004 through the needle into the region of the eye associated with the suprachoroidal space. In some cases, the eye region may be placed in the eye at a predetermined depth. More specifically, the syringe is described above to move the needle through the eye without substantially expelling the drug formulation in response to the second force, but one of the second syringes. The force applied on the part (eg, handle) can be sufficient to expel the drug formulation through the needle and into the suprachoroidal space when the needle is positioned at a predetermined depth. For example, in some cases, the sclera density and the frictional force between the piston and the inner surface of the barrel collectively cause the piston to resist distal movement in response to the second force. It is enough. Conversely, once the distal surface of the needle is placed in the eye at a certain depth (eg, at or near the suprachoroidal space), the density of that portion of the eye should be less than that of the sclera Can do. Accordingly, the collective force imparted by the frictional force and the eye anatomy in response to the second force is reduced. In this way, the second force can be sufficient to move the piston distally within the barrel and expel the drug formulation into the suprachoroidal space. In some cases, a user applying a second force on a portion of the syringe may be an indication that the distal surface of the needle has been placed at the desired depth and / or equivalent resistance. Can feel.

Although method 1000 is described above as including a set of steps, in some instances, method 1000 may include any number of optional steps and / or pre-procedure or post-procedure steps. For example, in some embodiments, a method of delivering a drug formulation to ocular tissue in a clinical study can be similar to method 1000 and can include at least some of the following steps.
1. Ensure that study participants' eyes remain inflated.
2. Anesthetize the study eye (eg, using local anesthesia).
3. Wait an appropriate amount of time after applying anesthesia.
4). The eye is sterilized and prepared, an eyelid is inserted, ensuring that the eyelid is fully retracted according to medical standards, and the injection site is measured using a caliper.
5. Obtain a research drug kit.
6). Remove the drug formulation vial and shake vigorously for 10 seconds before use to ensure a uniform suspension.
7). Remove the plastic top from the vial and prepare the vial using standard aseptic techniques.
8). Prepare a syringe. The syringe can be any of the syringes shown and described herein, such as syringe 100.
a. Attach the provided drug transfer needle (sterile, disposable, hypodermic needle) to the microsyringe.
b. A drug delivery needle is inserted into the vial by puncturing the septum.
c. Withdraw the> 200 μL drug formulation by inverting the vial, infusing air, and pulling back the microsyringe handle.
d. Pull the drug transfer needle out of the vial.
e. The drug transfer needle is removed from the microinjector handle and attached to a microneedle (900 μm). The microneedle can include a hub 160 as shown and described above.
f. Prime the syringe to ensure that enough drug is available to deliver 100 μL of the drug formulation into the SCS.
9. After priming, the drug formulation should be injected without delay to prevent sedimentation of the drug in the syringe.
10. Hold the microinjector and insert the microneedle into the sclera perpendicular to the eyeball surface. The target location should be about 4-5 mm from the edge, and the superior outer quadrant is the recommended location for superior choroidal injection. Ensure that the approach is as perpendicular to the sclera as possible. Do not bend or angle the microneedle at any time during the procedure.
11. Once the microneedle is inserted into the sclera, ensure that the microneedle hub is in intimate contact with the conjunctiva. Close contact between the microneedle injection system and the conjunctiva is observed as a slightly localized depression in the eyeball around the microneedle hub.
12 With one hand, the microneedle is stabilized while applying this constant downward force throughout the injection procedure.
13. Using the other hand (as needed), advance the syringe handle over a period of 5-10 seconds until a maximum of 100 μL of the drug formulation has been injected. Ensure that nominal pressure continues to be applied on the needle so that it is in intimate contact with the conjunctiva during the process.
14 If there is resistance to flow through the microneedle, the microneedle is removed from the eye and the eye is examined for any problems. If there is no risk to subject safety, the investigator will choose to verify the patency of the microneedle and use the best medical judgment to resume the injection procedure at a new site adjacent to the original injection site Or longer microneedle lengths (1100 μm) may be used. Prime the replacement microneedle to ensure that enough drug formulation remains in the microsyringe to deliver a 100 μl dose. Step 9 repeats the microinjector process as described above.
15. Once the injection is complete, maintain a light pressure on the microneedle and hold for 5-10 seconds.
16. Prepare a cotton swab and slowly remove the microneedle from the eye. At the same time, the injection site is covered with a cotton swab.
17. Hold the swab over the injection site with light pressure for a few seconds to ensure minimal backflow upon removal. Remove the swab.
18. Remove the opener.
19. Following the SCS injection, the eye is evaluated via an indirect ophthalmoscope.

  In some embodiments, the drug formulation includes aflibercept and is used to treat a patient for wet AMD, CNV, wet AMD associated with CNV, or wet AMD associated with RVO . In some embodiments, the drug formulation comprises triamcinolone acetonide and is used in conjunction with aflibercept for wet AMD, CNV, CNV related wet AMD, or RVO related wet AMD Used to treat patients or improve any VEGF therapy in ocular disease. In some embodiments, triamcinolone acetonide is administered to the SCS using the methods provided herein and aflibercept is administered intravitreally.

Alternatively, a syringe preparation (eg, step 8 above), which may be any of the syringes shown and described herein, such as syringe 100, may include:
a. Attach the provided vial access device (sterile, disposable) to the research drug vial by inserting it into the vial while placing it on a flat surface.
b. Remove the cap from the vial access device.
c. Pull the plunger handle completely back to draw air into the syringe.
d. Attach a microinjector handle (syringe) to the vial access device and inflate air.
e. Withdraw the> 200 μL drug formulation by inverting the vial and pulling back the microsyringe handle.
f. Replace vial access device with 900 μm needle.
g. Recap the vial access device.
h. Mark the injection site using a needle cap or caliper.
i. Prime microinjector to remove excess air.
j. Push down the handle until the plunger reaches the 100 μL mark on the syringe.

  While the medical syringes and methods described herein are shown to include a device that includes a needle and a reservoir that includes a pharmaceutical, in other embodiments, the medical device or kit includes a simulated pharmaceutical syringe. be able to. In some embodiments, the simulated pharmaceutical syringe can correspond to an actual pharmaceutical syringe (eg, medical syringe 100 described above), for example, the user can operate the corresponding actual medical syringe. And can be used to make “mock” injections as part of a clinical trial protocol or equivalent.

  The simulated medical syringe can simulate an actual medical syringe in any number of ways. For example, in some embodiments, the pseudo-medical syringe has a shape that corresponds to the shape of the actual medical syringe (eg, syringe 100), a size that corresponds to the size of the actual medical syringe (eg, syringe 100). And / or have a weight corresponding to the weight of the actual medical syringe (eg, syringe 100). Further, in some embodiments, the pseudo-medical syringe can include components that correspond to the components of the actual medical syringe. In this way, the pseudo medical injector can simulate the appearance, feel, and sound of an actual medical injector. For example, in some embodiments, a pseudo-medical syringe can include an external component (eg, a base, a handle, or the like) that corresponds to the external component of the actual medical syringe. In some embodiments, the pseudo-medical syringe can include an internal component (eg, a plunger) that corresponds to the internal component of the actual medical syringe.

  However, in some embodiments, the pseudo-medical syringe can lack a drug and / or their components (eg, microneedles) that deliver the drug. In this way, the pseudo-medical syringe can be used by a user to train the use of an actual medical syringe without exposing the user to the needle and / or medication. In addition, the pseudo-medical syringe can have features that identify it as a training device and prevent the user from misunderstanding that the pseudo-medical syringe can be used to deliver pharmaceuticals.

In some embodiments, a method of delivering a drug formulation to ocular tissue in a clinical study can be similar to method 1000 and can include at least some of the following steps.
1. Ensure that study participants' eyes remain inflated.
2. Anesthetize the study eye (eg, using local anesthesia).
3. Wait an appropriate amount of time after applying anesthesia.
4). The eye is sterilized and prepared, an eyelid is inserted, ensuring that the eyelid is fully retracted according to medical standards, and the injection site is measured using a caliper.
5. Obtain a research drug kit.
6). Prepare a microinjector. The microinjector can be any of the syringes shown and described herein, such as syringe 100. Further, the microinjector can be a simulated microinjector that includes a needle hub. This preparation includes:
a. Attach a needleless hub to the microinjector handle.
7). Prepare a simulation (or training) procedure.
a. Hold the microinjector and push the simulated needleless hub into the sclera at the target location.
b. Ensure that the approach is as perpendicular to the sclera as possible. Do not angle the microinjector at any time during the procedure.
c. Ensure that the needleless hub is in good contact with the conjunctiva. Close contact between the microinjector and the conjunctiva is observed as a slightly localized depression in the eyeball around the needleless hub.
8). Perform a simulation procedure.
a. The needle hub is maintained against the eye while gently pushing the handle throughout the injection procedure. A simulated suprachoroidal injection is given to the study eye over a 5-10 second period.
b. Following the sham injection, the needleless hub is maintained against the eye for 5-10 seconds.
c. Remove the swab and slowly remove the needleless hub from the eye. At the same time, the simulated area is covered with a cotton swab.
d. Hold the swab over the injection site for a few seconds and then remove the swab.
9. Remove the opener.
10. Following the SCS injection, the eye is evaluated via an indirect ophthalmoscope.

  The microneedle devices described herein may also be adapted to detect analytes, electroactivity, and optical or other signals using one or more microneedles as sensors. Sensors may include pressure, temperature, chemical, and / or electromagnetic (eg, light) sensors. A biosensor can be located on or in the microneedle or inside a device in communication with body tissue via the microneedle. Microneedle biosensors can be any of the four main transducer classes: potentiometry, amperometry, optics, and physiochemistry. In one embodiment, the hollow microneedles are filled with a substance, such as a gel, having sensing functionality associated therewith. For sensing applications based on binding to a substrate or reaction mediated by an enzyme, the substrate or enzyme can be immobilized within the needle. In another embodiment, the waveguide is in the microneedle device for directing light to a specific location or for detection using means such as, for example, a pH dye for color evaluation. Can be incorporated. Similarly, heat, electricity, light, ultrasound, or other forms of energy may be precisely transmitted to directly stimulate, damage or heal specific tissue, or for diagnostic purposes.

  A microneedle device for non-surgically delivering a drug to the upper choroidal space of a human subject's eye comprises, in one embodiment, a hollow microneedle. The device may include an elongate housing for holding the proximal end of the microneedle. The device may further comprise means for conducting the drug formulation through the microneedle. For example, the means may be a flexible or rigid conduit that is in fluid connection with the base or proximal end of the microneedle. The means may also include a pump or other device to generate a pressure gradient to induce fluid flow through the device. The conduit may be operatively connected to a drug formulation source. 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 some embodiments, the drug formulation includes aflibercept and is used to treat a patient for wet AMD, CNV, wet AMD associated with CNV, or wet AMD associated with RVO . In some embodiments, the drug formulation comprises triamcinolone acetonide and is used in conjunction with aflibercept for wet AMD, CNV, CNV related wet AMD, or RVO related wet AMD Used to treat patients or improve any VEGF therapy in ocular disease.

  The transfer of the drug formulation or biological fluid through the hollow microneedle can be controlled or monitored using, for example, one or more valves, pumps, sensors, actuators, and a microprocessor. . For example, in one embodiment, the microneedle device may include a micropump, a microvalve, and a positioning device, where the microprocessor controls the pump or valve and prescribes the drug into the ocular tissue through the microneedle. Programmed to control the delivery rate of objects. The flow through the microneedles may be driven by diffusion, capillary action, mechanical pumps, electroosmosis, electrophoresis, convection, or other driving forces. The device and microneedle design can be adjusted using known pumps and other devices to take advantage of these drives. In one embodiment, the microneedle device further comprises an iontophoresis device similar to that described in Beck US Pat. No. 6,319,240 to enhance delivery of drug formulations to ocular tissue. But you can. In another embodiment, the microneedle device can further include a flow meter or other means to monitor flow through the microneedle and coordinate the use of pumps and valves.

  In some embodiments, the flow of the drug formulation or biological fluid can be adjusted using various valves or gates known in the art. The valve may be selectively and repeatedly open and closed, or may be a single use type such as a breakable barrier. Other valves or gates used in the microneedle device are activated thermally, electrochemically, mechanically or magnetically to selectively initiate the flow of material through the microneedle, Can be modulated or stopped. In one embodiment, the flow is controlled using a rate limiting membrane that acts as a valve.

  In other embodiments, the flow of the drug formulation or biological fluid is adjusted by the internal friction of the various components, the properties of the pharmaceutical to be injected (eg, viscosity) and / or the properties of the desired injection site. Can. For example, as described above, in some embodiments, a drug product can be configured for delivery of a specific formulation to a specific location. In such embodiments, the drug product comprises a microinjector (eg, microinjector 100) and a pharmaceutical product (eg, triamcinolone or herein) configured to deliver the pharmaceutical product to a specific target area (eg, SCS). Any other formulation described in the document). In this example, the drug product can be configured such that the flow of the drug is limited when injections are attempted into different target areas (eg, sclera) having a higher density. Thus, the drug product is configured to regulate flow by allowing flow when an injection is attempted into the desired target area.

  The microneedles, in one embodiment, include two or more microneedles such that the method includes inserting at least a second microneedle into the sclera without penetrating across the sclera. Part of an array of needles. In one embodiment, an array of two or more microneedles is inserted into the eyeball tissue. In one embodiment, each drug formulation of the two or more microneedles is a drug formulation, a volume of the drug formulation. / Amount, or combinations of these parameters may be the same or different from each other. In some cases, different types of drug formulations may be injected through one or more microneedles. For example, inserting a second hollow microneedle comprising a second drug formulation into ocular tissue results in delivery of the second drug formulation into the ocular tissue.

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

  The SCS drug delivery methods provided herein allow drug formulations to be delivered to tissues that are more difficult to target in a single administration over a larger tissue area compared to previously known needle devices. Enable delivery. While not wishing to be bound by theory, upon entry into the SCS, the drug formulation is transferred from the insertion site toward the retinal choroidal tissue, macula, and optic nerve in the posterior part of the eye and anteriorly. It is thought that it flows in the circumferential direction toward the uvea and ciliary body. In addition, some of the injected drug formulation remains in the SCS as a reservoir, or remains in the tissue overlying the SCS near the microneedle insertion site, eg, the sclera, as a further reservoir of drug formulation. It can play a role, which can subsequently diffuse into the SCS and into other adjacent posterior tissue.

  The human subject treated using the methods and devices provided herein can be an adult or a child. In one embodiment, the patient exhibits a retinal thickness greater than 300 μm (eg, foveal subregion thickness measured by optical coherence tomography). In another embodiment, a patient in need of treatment has a BCVA score (eg, approximate Snellen vision 20/400) that reads ≧ 20 characters in each eye. In yet another embodiment, patients in need of treatment are read ≧ 20 characters in each eye (eg, approximate Snellen vision 20/400), but BCVA in which ≦ 70 characters are read in the eye in need of treatment Have a score.

  The patient, in one embodiment, has macular edema (ME) with a fovea. In one embodiment, in a method for treating ME associated with uveitis, the ME is due to uveitis and not due to any other cause. In one embodiment for treating ME following RVO, the ME is due to RVO and not due to any other cause of ME. In further embodiments, the RVO is retinal vein branch occlusion (BRVO), hemilateral retinal vein occlusion (HRVO), or central retinal vein occlusion (CRVO). In one embodiment, a patient in need of treatment suffers from vision loss due to ME.

  The microneedle devices and non-surgical methods described herein are particularly relevant to uveitis (eg, non-infectious, infectious, intermediate, posterior, or panuveitis), uveitis Drug formulations are used in human subjects for the treatment, diagnosis, or prevention of macular edema, for example, non-infectious, middle, posterior, or panuveitis, and macular edema associated with RVO It may be used for delivery to the eyes of the body. In one embodiment, the drug formulation comprises an effective amount of an anti-inflammatory drug. In one embodiment, the patient is in need of treatment for uveitis-related macular edema or RVO-related macular edema, and the drug formulation is selected from steroidal compounds and non-steroidal anti-inflammatory drugs (NSAIDs) With anti-inflammatory drugs. In a further embodiment, the drug formulation is a triamcinolone formulation, eg, a triamcinolone acetonide formulation.

  Posterior eye disorders that are indicated for treatment with the methods, devices, and drug formulations described herein include, but are not limited to, uveitis (eg, infectious uveitis, non-infectious uveitis Chronic uveitis, and / or acute uveitis), macular edema, diabetic macular edema (DME), macular edema associated with uveitis (macular edema associated with infectious uveitis and non-infected grapes Including macular edema associated with membrane inflammation), macular edema after retinal vein occlusion (RVO), macular edema associated with RVO. In some embodiments, the posterior ocular disorder is macular edema associated with uveitis. In a further embodiment, the uveitis is non-infectious uveitis.

  The uveitis can be either acute or chronic uveitis. Uveitis and macular edema associated with uveitis can be caused by infectious causes that lead to infectious uveitis, such as infection by viruses, fungi, parasites, and / or the like. Uveitis can also be caused by non-infectious causes such as the presence of non-infectious foreign bodies in the eye, autoimmune diseases, surgical and / or traumatic injury, and / or the like. Disorders caused by pathogenic organisms that can lead to infectious uveitis and macular edema associated with infectious uveitis include, but are not limited to, toxoplasmosis, toxopathosis, histoplasmosis, herpes simplex or herpes zoster infection, Tuberculosis, syphilis, sarcoidosis, Forked-Koyanagi-Harada syndrome, Behcet's disease, idiopathic retinal vasculitis, Forked-Koyanagi-Harada syndrome, acute posterior multiple platelet pigmented epitheliopathy (APMPPE), putative ocular histoplasma syndrome (POHS) , Bird shot choroidopathy, multiple sclerosis, sympathetic ophthalmitis, punctate choroidal stromal disease, ciliary labyrinth, or iridocyclitis. Acute uveitis and / or macular edema associated with acute uveitis develops suddenly and can last up to about 6 weeks. In chronic uveitis and / or macular edema associated with chronic uveitis, the onset of signs and / or symptoms is gradual and symptoms last for more than about 6 weeks.

  Signs of uveitis include ciliary hyperemia, aqueous humor flares, accumulation of cells found in ophthalmic examinations (such as aqueous humor cells, posterior lens cells, and vitreous cells), retrocorneal deposits, and anterior chamber bleeding included. Symptoms of uveitis include pain (such as ciliary spasm), redness, photophobia, increased lacrimation, and decreased vision. Posterior uveitis affects the posterior or choroidal part of the eye. Inflammation of the choroid portion of the eye is also often referred to as choroiditis. Posterior uveitis can also be associated with inflammation that occurs in the retina (retinitis) or blood vessels in the posterior eyeball (vasculitis). In one embodiment, the methods provided herein provide an effective amount for a patient with uveitis suffering from macular edema associated with a uveitis in need thereof (eg, non-infectious uveitis). Non-surgically administering the anti-inflammatory drug formulation to the SCS of the patient's eye. In a further embodiment, the patient has a reduced severity of macular edema symptoms associated with uveitis after administration of the drug formulation. In one embodiment, the drug is a steroid compound. In a further embodiment, the drug is triamcinolone. In some embodiments, the drug formulation includes aflibercept and is used to treat a patient for wet AMD, CNV, wet AMD associated with CNV, or wet AMD associated with RVO . In some embodiments, the drug formulation comprises triamcinolone acetonide and is used in conjunction with aflibercept for wet AMD, CNV, CNV related wet AMD, or RVO related wet AMD Used to treat patients or improve any VEGF therapy in ocular disease.

  In one embodiment, a patient undergoing one of the treatment methods provided herein, eg, treatment of macular edema associated with uveitis or macular edema associated with RVO, is fluid retention, inflammation Neuroprotection, complement inhibition, drusen formation, reduced scar formation, and / or reduced choroidal capillary layer or choroidal neovascularization.

  While not wishing to be bound by theory, in response to non-surgical SCS administration, the drug remains localized in the back of the eye, specifically the choroid and retina. Limiting the exposure of drugs to other ocular tissues, in one embodiment, reduces the incidence of side effects associated with prior art methods.

  In one embodiment, about 2 to about 24 dosing sessions are employed, for example, about 2 to about 24 intraocular dosing sessions (eg, intravitreal or suprachoroidal injection). In further embodiments, from about 3 to about 30, or from about 5 to about 30, or from about 7 to about 30, or from about 9 to about 30, or from about 10 to about 30, or from about 12 to about 30, or from about 12 to Approximately 24 medication sessions are employed.

  Treatment regimens will vary based on the therapeutic formulation to be delivered and / or the indication being treated. In one embodiment, a single dosing session is effective in treating one of the indications described herein. However, in another embodiment, multiple dosing sessions are employed. In one embodiment where multiple dosing sessions are employed, the dosing session is from about 10 days to about 70 days, or from about 10 days to about 60 days, or from about 10 days to about 50 days, or from about 10 days. The interval is about 40 days, or about 10 days to about 30 days, or about 10 days to about 20 days. In another embodiment where multiple dosing sessions are employed, the dosing session is about 20 days to about 60 days, or about 20 days to about 50 days, or about 20 days to about 40 days, or about 20 days. Leave an interval of ~ 30 days. In yet another embodiment, the multiple dosing sessions are every week (about every 7 days), every 2 weeks (eg, every about 14 days), every about 21 days, every month (eg, every about 30 days), or Every two months (for example, about every 60 days). In yet another embodiment, the dosing session is a monthly dosing session (eg, about 28 days to about 31 days), with at least 3 dosing sessions being employed.

  In one embodiment, the non-surgical SCS delivery method uses a macular edema associated with uveitis (eg, non-infectious uveitis) using, for example, one of the devices provided herein. Used to treat patients in need of treatment. In one embodiment, SCS administration of a drug (eg, an anti-inflammatory compound such as a steroid or NSAID) via the methods described herein reduces the vitreous turbidity experienced by the patient.

In one embodiment, vitreous turbidity is assessed using a standard photographic scale ranging from 0 to 4 via inverse ophthalmoscopic examination, where 0 to 4 are defined in Table 1 below ( (Nussenblatt 1985, modified in Lower 2011), which is incorporated herein by reference in its entirety. Vitreous haze is categorized from color fundus photographs according to a similar scale in another embodiment.

  In yet another embodiment, the non-surgical SCS delivery methods provided herein reduce macular edema suffered by a patient suffering from RVO-related macular edema.

  In one embodiment, a method is provided for treating a human patient for wet AMD, CNV, wet AMD associated with CNV, or wet AMD associated with RVO. The method includes the step of surgically or non-surgically administering aflibercept to the SCS of one or both eyes of the patient, and depending on the administration, the drug is in the SCS and / or another posterior region of the eye. Is substantially reserved. In further embodiments, upon administration, the drug is substantially localized to one or more of the SCS, choroid, and / or retina. The effectiveness of the method is measured in one embodiment by measuring the patient's mean change from baseline in macular thickness at one or more time points after the patient has been treated. For example, from a procedure in which an anti-inflammatory drug is delivered non-surgically to the SCS, for example, a period of 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, or longer (all in between) The average change from baseline in retinal thickness and / or macular thickness is measured. In a further embodiment, a second drug formulation comprising a VEGF modulator (eg, VEGF antagonist) is administered to the patient's eye via intravitreal injection. In a further embodiment, the VEGF modulator is ranibizumab, aflibercept, or bevacizumab.

  Reduction in retinal thickness and / or macular thickness is one metric for the treatment effectiveness of the methods provided herein. For example, in one embodiment, a patient treated by one of the methods provided herein using, for example, one of the devices described herein is a baseline (eg, From at least one dosing session (at least about 20 μm or at least about 40 μm, or at least about 50 μm, or at least about 100 μm or at least about 150 μm or at least) A decrease in retinal thickness is observed at any given time point after about 200 μm or about 50-100 μm and all values in between (single or multiple dosing sessions). In another embodiment, the patient observes a ≧ 5%, ≧ 10%, ≧ 15%, ≧ 20%, ≧ 25% decrease in retinal thickness (eg, CST) following at least one dosing session. .

  In one embodiment, the decrease in retinal thickness is measured about 2 weeks, about 1 month, about 2 months, about 3 months, or about 6 months after at least one dosing session. In another embodiment, the decrease in retinal thickness is measured at least about 2 weeks, at least about 1 month, at least about 2 months, at least about 3 months, or at least about 6 months after at least one dosing session. In one embodiment where multiple dosing sessions are employed, the decrease in retinal thickness is at least about 2 weeks, at least about 1 month, at least about 2 months, at least about 3 months, or at least about 6 months from each dosing session. Later, persisted by the patient.

  In one embodiment, patients with macular edema (eg, non-infectious uveitis) associated with uveitis treated by the methods provided herein are baseline (ie, retinal thickness prior to treatment). From any, a decrease in the retinal thickness of about 20 μm to about 200 μm, about 40 μm to about 200 μm, about 50 μm to about 200 μm, about 100 μm to about 200 μm, or about 150 μm to about 200 μm is observed at any given time point. In one embodiment, the change in retinal thickness from baseline is measured as a change in CST, for example by spectral domain optical coherence tomography (SD-OCT).

  In yet another embodiment, the therapeutic response is a change from baseline in macular thickness at one or more time points after the patient has been treated. For example, from a dosing session with an anti-inflammatory drug such as triamcinolone delivered non-surgically to the SCS, eg, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, or After exceeding (including all durations in between), the change from baseline in macular thickness is measured. Reduction in macular thickness (compared to pre-treatment) is one metric for therapeutic response (eg, about 10%, or about 20%, or about 30%, or about 40%, or about 50%, Or about 60% and above, including all values in between).

  Efficacy, in another embodiment, measures the average change in visual acuity at 1 and / or 2 months after treatment (eg, from baseline, ie, maximum corrected visual acuity (BCVA) prior to treatment) Be evaluated). In one embodiment, patients treated by one or more of the methods provided herein can be treated at any given time point (eg, 2 weeks after administration, 4 At least 2 letters, at least 3 letters, at least 5 letters, compared to the patient's BVCA prior to at least 1 medication session, We see an improvement in BCVA from baseline of at least 8, at least 12, at least 13, at least 15, at least 20, and all values in between.

  In one embodiment, a patient, e.g., a patient with macular edema associated with uveitis or a patient with macular edema associated with RVO, has a dosing regimen, e.g., 1 After completion of the monthly dosing regimen, the BCVA measurement is about 5 characters or more, about 10 characters or more, 15 characters or more, about 20 characters or more, about 25 characters or about 25 characters. Or increase above that. In a further embodiment, the patient has about 5 to about 30 characters in the BCVA measurement, upon completion of at least one dosing session, as compared to the patient's BCVA measurement prior to at least one dosing session. About 30 characters, about 15 characters to about 25 characters, or about 15 characters to about 20 characters. In one embodiment, the BCVA increase is about 2 weeks, about 1 month, about 2 months, about 3 months, or about 6 months after at least one dosing session. In another embodiment, BCVA is measured at least about 2 weeks, at least about 1 month, at least about 2 months, at least about 3 months, or at least about 6 months after at least one dosing session.

  In one embodiment, BCVA is assessed at an initial distance of 4 meters based on the Diabetes Retinopathy Early Treatment Study (ETDRS) vision chart.

  In another embodiment, for example, a patient undergoing a method of treatment using one of the devices provided herein has a maximum corrected visual acuity as compared to the patient's BCVA measurement prior to receiving the treatment. In (BCVA) measurements, that vision is substantially maintained after treatment (eg, a single dose session or multiple dose sessions) as measured by loss of less than 15 characters. In further embodiments, the patient loses less than 10 characters, less than 8 characters, less than 6 characters, or less than 5 characters in a BCVA measurement compared to the patient's BCVA prior to receiving the measurement treatment.

  The decrease in vitreous haze can also be used as a measure of the effectiveness of the method. Reduction in vitreous turbidity includes, but is not limited to, photo grading, scoring system, multipoint scale, multiprocess scale (eg, multiprocess logarithmic scale, and / or manual screening by one or more testers, And / or the like) and the like.

  In one embodiment, the decrease in vitreous haze is observed about 2 weeks, about 1 month, about 2 months, about 3 months, or about 6 months after at least one dosing session. In another embodiment, the decrease in retinal thickness is observed at least about 2 weeks, at least about 1 month, at least about 2 months, at least about 3 months, or at least about 6 months after at least one dosing session. In one embodiment where multiple dosing sessions are employed, a decrease in vitreous haze is noted by the patient and is at least about 2 weeks, at least about 1 month, at least about 2 months, at least about 3 from each dosing session. Months, or at least about 6 months later.

  In one embodiment, the methods provided herein have been previously treated for wet AMD, CNV, wet AMD associated with CNV, or wet AMD associated with RVO, but after individual Provide effective treatment of patients who have not responded or responded appropriately to previous treatments for eye disorders As those skilled in the art will appreciate, patients who do not respond or respond appropriately to treatment do not exhibit an improvement in the symptoms of macular edema associated with the disorder or an improvement in clinical symptoms. In one embodiment, the symptom or clinical symptom is lesion size, inflammation, edema, visual acuity and / or vitreous haze.

  In patients who have undergone eye treatment via a shunt or cannula or other surgical method, a significant increase or decrease in intraocular pressure has been reported after initiation of the treatment method. In one embodiment, the intraocular pressure (IOP) of a patient undergoing treatment for macular edema associated with uveitis (eg, non-infectious uveitis), macular edema associated with RVO is provided herein. Treating uveitis-related macular edema 2 minutes, 10 minutes, 15 minutes, 30 minutes, or 1 hour after suprachoroidal drug administration according to devices (eg, device 100) and / or methods disclosed in the literature Compared to the IOP of the patient's eye prior to administration of the drug to do so. In one embodiment, macular edema associated with uveitis (eg, non-infectious uveitis), macular edema associated with RVO, or wet AMD, choroidal neovascularization (CNV), wet AMD associated with CNV IOPs in the eyes of patients who have received treatment for macular edema associated with uveitis (eg, non-infectious) 2 minutes, 10 minutes, 15 minutes, 30 minutes, or 1 hour after suprachoroidal drug administration Uveitis), macular edema associated with RVO, or IOP in the patient's eye prior to administration of drugs to treat wet AMD varies by only 10%. In one embodiment, the IOP of a patient undergoing treatment for uveitis-related macular edema (eg, non-infectious uveitis), RVO-related macular edema, or wet AMD is: Drugs for treating uveitis-related macular edema (eg, non-infectious uveitis), RVO-related macular edema 2 minutes, 10 minutes, 15 minutes, or 30 minutes after suprachoroidal drug administration It varies by only 20% compared to the IOP of the patient's eye prior to administration of. In one embodiment, macular edema associated with uveitis (eg, non-infectious uveitis), macular edema or wet AMD associated with RVO, choroidal neovascularization (CNV), wet AMD associated with CNV, The IOP in the eye of a patient who has received treatment for wet AMD associated with RVO is 2 minutes, 10 minutes, 15 minutes or 30 minutes after administration of suprachoroidal drug (e.g., macular edema associated with uveitis (e.g. Non-infectious uveitis), macular edema associated with RVO, wet AMD, choroidal neovascularization (CNV), or IOP in the patient's eye prior to administration of drugs to treat wet AMD associated with CNV As compared with the above, it varies by only 10% to 30%. In further embodiments, macular edema associated with uveitis (eg, non-infectious uveitis), macular edema associated with RVO, wet AMD, choroidal neovascularization (CNV), or wet AMD associated with CNV An effective amount of the drug for treating comprises an effective amount of an anti-inflammatory drug (eg, triamcinolone). In some embodiments, the drug formulation comprises aflibercept.

  In one aspect, the methods described herein include uveitis (infectious or non-infectious), macular edema, macular edema associated with non-infectious uveitis, macular associated with infectious uveitis With regard to administration of drug formulations for the treatment of edema, macular edema associated with RVO, the majority of drug formulations require treatment of posterior ocular disorders over a period of time after the treatment method is complete Retained in the SCS and / or other posterior segment tissues in one or both eyes of the patient. While not wishing to be bound by theory, drug formulation retention within the SCS contributes to the sustained release profile of the drug formulation described herein. As described herein, in some embodiments where the patient is treated for macular edema associated with RVO, the patient is non-surgical with an anti-inflammatory compound (eg, a steroid such as triamcinolone). Or in addition to surgical administration, a VEGF modulator is further administered intravitreally.

  In human subjects in need thereof, uveitis (eg, non-infectious uveitis), macular edema associated with uveitis, macular edema associated with RVO, wet AMD, choroidal neovascularization (CNV), Alternatively, a method of treating wet AMD associated with CNV includes, in one embodiment, administering a drug formulation surgically or non-surgically to the upper choroidal space of an affected eye of a human subject. In response, the drug formulation flows out of the insertion site and is substantially localized to the posterior segment of the eye, eg, the posterior segment of the eye, such as the retina and / or choroid. In one embodiment, the methods provided herein provide for the administration of a drug in the eye, for example, the posterior part of the eye, as compared to intravitreal, topical, parenteral, anterior chamber, or oral administration of the same drug dose. Allows longer reservations.

  In one embodiment, a suprachoroidal drug dose sufficient to achieve a therapeutic response in a human subject treated using a non-surgical SCS drug delivery method is sufficient to elicit the same or substantially the same therapeutic response Less than intravitreal, parenteral, anterior chamber, topical, or oral drug dose. In further embodiments, the suprachoroidal drug dose is at least 10 percent less than an oral, parenteral, or intravitreal dose sufficient to achieve the same or substantially the same therapeutic response. In a further embodiment, the suprachoroidal dose is about 10 percent to about 25 percent less than an oral, parenteral, anterior chamber, topical, or intravitreal dose sufficient to achieve the same or substantially the same therapeutic response, or About 10 percent to about 50 percent less. Thus, in one embodiment, the non-surgical SCS administration method of treating macular edema associated with uveitis, macular edema associated with RVO achieves higher therapeutic efficacy than other routes of administration. In one embodiment, the method provided herein non-surgically inserts a hollow microneedle into the sclera of an eye of a human subject and passes the drug formulation through the hollow microneedle in the upper choroidal space of the eye. Injecting into. As described in more detail below, the drug formulation is, in one embodiment, a solution or suspension of drug. In some embodiments, the drug formulation comprises aflibercept.

  In one embodiment, the amount of therapeutic formulation delivered from the device described herein into the suprachoroidal space is from about 10 μL to about 200 μL, such as from about 50 μL to about 150 μL. In another embodiment, about 10 [mu] L to about 500 [mu] L, such as about 50 [mu] L to about 250 [mu] L, is non-surgically administered to the suprachoroidal space.

  The amount of drug delivered into the SCS may also be controlled in part by the type of microneedle used and the method in which it is used. In one embodiment, after the hollow microneedles are inserted into the eyeball tissue and after insertion, it is gradually retracted from the eyeball tissue to deliver the fluid drug and achieve a certain dosage, after which the delivery is (eg, a syringe By deactivating fluid drive forces such as pressure or electric fields (from mechanical devices such as, etc.), it can be stopped to avoid drug leakage / uncontrolled delivery. Desirably, the amount of drug being delivered is controlled by driving the fluid drug formulation at a suitable infusion pressure. In one embodiment, the injection pressure may be at least 150 kPa, at least 250 kPa, or at least 300 kPa. In another embodiment, the injection pressure is from about 150 kPa to about 300 kPa. Suitable infusion pressure may vary with the particular patient or species. In another embodiment, the methods provided herein are as described above (eg, Syringe 100) or PCT / US2014 filed May 2, 2014 and entitled “Apparatus and Method for Ocular Injection”. Implemented with one of the devices described in US / 36590 (for all purposes, incorporated herein by reference in its entirety).

It should be noted that the desired injection pressure for delivering a suitable amount of drug formulation can be affected by the insertion depth of the microneedle and the composition of the drug formulation. For example, in embodiments where the drug formulation for delivery into the eye is in or includes the form of nanoparticles or microparticles encapsulating the active agent or microbubbles, a higher injection pressure is Can be required. Nanoparticle or microparticle encapsulation techniques are well known in the art. In one embodiment, the drug formulation consists of drug particles in suspension with D ₉₉ of 10 μm or less. In one embodiment, the drug formulation consists of drug particles in suspension with D ₉₉ of 7 μm or less. In another embodiment, the drug formulation consists of drug particles in suspension with D ₉₉ of 3 μm or less. In another embodiment, the drug formulation consists of drug particles in suspension with a D ₅₀ of 5 μm or less. In one embodiment, the drug formulation consists of drug particles in suspension with a D ₅₀ of 1 μm or less. In some embodiments, the drug formulation comprises aflibercept.

  In one embodiment, the non-surgical method of administering the drug to the SCS further includes a hollow micro-needle after insertion of the microneedle into the eye and before and / or during injection of the drug formulation into the suprachoroidal space. Partially retracting the needle. In certain embodiments, the partial retraction of the microneedle occurs prior to the step of injecting the drug formulation into the ocular tissue. This insertion / retraction step forms a pocket and beneficially allows the drug formulation to flow out of the microneedle with little or no obstruction by the eye tissue at the opening at the tip of the microneedle. obtain. The pocket can be filled with a drug formulation, but also serves as a conduit through which the drug formulation can flow from the microneedle through the pocket and into the suprachoroidal space. In some embodiments, the drug formulation comprises aflibercept and, via suprachoroidal administration, human AMD for wet AMD, CNV, wet AMD associated with CNV, or wet AMD associated with RVO Used to treat. In some embodiments, the drug formulation comprises triamcinolone acetonide, administered via suprachoroidal administration, used in conjunction with aflibercept, and wet AMD associated with wet AMD, CNV, CNV Or treat human patients for wet AMD associated with RVO.

In one embodiment, the methods provided herein allow for more drug retention in the eye compared to other drug delivery methods, e.g., in the anterior chamber, subtenon, intravitreal. When compared to the same dose delivered via a local, parenteral, or oral drug delivery method, a greater amount of drug is delivered intraocularly when delivered via the methods provided herein. Reserved. Thus, in one embodiment, the intraocular elimination half-life (t _1/2 ) of a drug is delivered intravitreally in the vitreous when delivered via the methods described herein. In addition, it exceeds the intraocular t _1/2 of the drug when administered locally, parenterally or orally. In another embodiment, when the intraocular Cmax of a drug is delivered via the methods described herein, the same drug dose is administered intravitreally, in the anterior chamber, subtenonally, locally. And exceeds the intraocular Cmax of the drug when administered parenterally or orally. In another embodiment, the mean area under the intraocular curve (AUC0-t) of the drug is administered into the vitreous, into the anterior chamber, into the Tenon capsule when administered to the SCS via the methods described herein. Below the drug's intraocular AUC0-t when administered locally, parenterally or orally. In yet another embodiment, the intraocular peak blood concentration arrival time (tmax) of a drug is administered to the SCS via the methods described herein when the same drug dose is injected into the vitreous. Exceeds the intraocular tmax of the drug when administered into the chamber, locally, parenterally, or orally. In a further embodiment, the drug is aflibercept.

In one embodiment, when the intraocular t _1/2 of the drug is administered via the non-surgical SCS drug delivery methods provided herein, the same dose is locally, intraocularly, Longer than intraocular t _1/2 of the drug when administered intravitreally, orally or parenterally. In a further embodiment, when the intraocular t _1/2 of the drug is administered via the non-surgical SCS drug delivery methods provided herein, the same dosage is locally and intrathecally. About 1.1 to about 10 times longer than the intraocular t1 / 2 of the drug when administered subtenonally, intravitreally, orally or parenterally, or about 1.25 to about 10 It is twice as long, or about 1.5 times to about 10 times longer, or about 2 times to about 5 times longer. In a further embodiment, the drug is aflibercept.

  In another embodiment, when the intraocular Cmax of a drug is delivered via the methods described herein, the same drug dose is administered intravitreally, from within the anterior chamber, locally, parenterally. Or above the intraocular Cmax of the drug when administered orally. In further embodiments, the intraocular Cmax of a drug is administered locally via the non-surgical SCS drug delivery method provided herein, wherein the same dose is locally, intravitreally, intravitreally. At least 1.1 times, or at least 1.25 times, or at least 1.5 times, or at least 2 times above the intraocular Cmax of the drug when administered orally or parenterally, or at least 5 times higher. In one embodiment, the intraocular Cmax of the drug is administered locally via the non-surgical SCS drug delivery method provided herein, locally, in the anterior chamber, About 1 to about 2 times, or about 1.25 to about 2 times, or about 1 to about 5 times the intraocular Cmax of the drug when administered intravitreally, orally or parenterally. Greater than, or about 1 to about 10 times greater, or about 2 to about 5 times greater, or about 2 to about 10 times greater. In a further embodiment, the drug is aflibercept.

In another embodiment, the mean area under the intraocular curve (AUC _0-t ) of a drug is administered into the vitreous, into the anterior chamber, and into the tenon when administered to the SCS via the methods described herein. Exceeds the intraocular AUC _0-t of the drug when administered subcapsularly, locally, parenterally, or orally. In a further embodiment, when the intraocular AUC _0-t of a drug is administered via the non-surgical SCS drug delivery method provided herein, the same dose is locally, intraocularly, At least 1.1 times, or at least 1.25 times, or at least 1.5 times the intraocular AUC0-t of the drug when administered subtenonally, intravitreally, orally or parenterally Greater than, or at least two times greater, or at least five times greater. In one embodiment, when the intraocular AUC _0-t of a drug is administered via the non-surgical SCS drug delivery methods provided herein, the same dose is locally, intraocularly, About 1 to about 2 times, or about 1.25 to about 2 times greater than or about 1.25 to about 2 times the intraocular AUC0-t of the drug when administered subtenonally, intravitreally, orally or parenterally 1 to about 5 times greater, or about 1 to about 10 times greater, or about 2 to about 5 times greater, or about 2 to about 10 times greater. In a further embodiment, the drug is aflibercept.

  In one embodiment, a drug formulation comprising an effective amount of a drug (e.g., an anti-inflammatory drug (e.g., a steroid such as triamcinolone or NSAID), is delivered within the SCS for a period of time once delivered to the SCS. For example, in one embodiment, about 80% of the drug formulation is about 30 minutes, or about 1 hour, or about 4 hours, or about 24 hours, or about 48 hours, or about 72 hours. In this respect, a drug reservoir is formed in the SCS and / or surrounding tissue to allow for sustained release of the drug over a period of time. Afribercept.

  In one embodiment, the suprachoroidal drug delivery methods provided herein are increased compared to oral, parenteral, subtenon, and / or intravitreal drug delivery methods of the same or similar drug dosage. Provide therapeutic efficacy and / or improved therapeutic response. In one embodiment, the SCS drug dose sufficient to provide a therapeutic response is sufficient intravitreal, anterior chamber, local, oral or parenteral drug dose to provide the same or substantially the same therapeutic response. About 90%, or about 75%, or about 1/2 (eg, about one-half or less). In another embodiment, an SCS dose sufficient to provide a therapeutic response is sufficient intravitreal, anterior chamber, subtenon, local, oral or oral to provide the same or substantially the same therapeutic response. About 1/4 of the parenteral drug dose. In yet another embodiment, the SCS dose sufficient to provide a therapeutic response is sufficient intravitreal, intraanterior, subtenon, local, oral, to provide the same or substantially the same therapeutic response. Or 1/10 of the parenteral drug dose. 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 reduction in the number of ocular lesions or a reduction in ocular lesion size. In another embodiment, the therapeutic response is fluid accumulation and / or reduction of intraocular pressure.

  The therapeutic response is determined at the time after treatment, for example, 5 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 days after treatment, Week, 10 weeks, 11 weeks, or 12 weeks, and all values in between).

  The therapeutic efficacy of a drug formulation delivered by the methods described herein and the therapeutic response of a human subject can be assayed by standard means in the art, as is known to those skilled in the art. In general, the therapeutic efficacy of any particular drug can be assessed by measuring the response of the human subject after administration of the drug. Drugs with high therapeutic efficacy show symptom improvement and / or blockage over drugs with lower therapeutic efficacy. In non-limiting examples, the efficacy of the drug formulations provided herein can include, for example, changes in pain intensity, changes in eye lesions (size or number), intraocular pressure, fluid accumulation, inflammation (eg, hacketts) / By measuring changes in McDonald's eye score), ocular hypertension, and / or observing visual acuity.

  In another embodiment, the effectiveness of the therapeutic formulation is measured by observing changes in measurements, inflammation, visual acuity, and / or edema according to the Hackett / McDonald eye score. In another embodiment, the effectiveness of the treatment formulation is measured by observing changes in measurements, inflammation, visual acuity, and / or edema according to, for example, the Hackett / McDonald eye score.

  In one embodiment, uveitis (eg, non-infectious uveitis), macular edema associated with uveitis, macular edema associated with RVO, wet AMD, CNV, wet AMD associated with RVO, or Non-surgical administration of an effective amount of drug formulation to the SCS to treat wet AMD associated with CNV is the same drug dose administered intravitreally, intraanteriorly, orally, or parenterally Results in a reduced number of adverse side effects or clinical symptoms in the patient being treated compared to the number of side effects or clinical symptoms caused by. In another embodiment, non-surgical administration of an effective amount of the drug formulation to the SCS is by virtue of the same drug dose administered intravitreally, intrathecally, subtenonally, orally, or parenterally. It results in a reduced number of one or more adverse side effects or clinical symptoms compared to the adverse side effects or clinical symptoms that occur.

  Examples of side effects and clinical symptoms that may be reduced or ameliorated include, but are not limited to, inflammation, gastrointestinal side effects (eg, diarrhea, nausea, gastroenteritis, vomiting, gastrointestinal tract, rectal and duodenal bleeding, hemorrhagic Pancreatitis, black or bloody stool from colon perforation, and / or hemoptysis); hematological side effects (eg leukopenia, anemia, pancytopenia and agranulocytosis, thrombocytopenia, neutropenia, true red blood cells) System agenesis (PRCA), deep vein thrombosis prone to bruising, and / or abnormal bleeding from the nose, mouth, vagina, or rectum); immune side effects / clinical symptoms (eg, immunosuppression, immunosuppression that causes sepsis) Opportunistic infections (herpes simplex virus, herpes zoster, and invasive Candida infections, and / or increased infection); oncological side effects / clinical symptoms (eg, lymphoma, phosphorus Proliferative disease and / or non-melanoma skin cancer); renal side effects / clinical symptoms (eg, dysuria, urgency, urinary tract infection, hematuria, renal tubular necrosis, and / or BK virus related nephropathy); Metabolic side effects / clinical symptoms (eg edema, hyperphosphatemia, hypokalemia, hyperglycemia, hyperkalemia, swelling, rapid weight gain, and / or thyroid hypertrophy); respiratory side effects / clinical Symptoms (eg, respiratory infection, dyspnea, increased cough, early tuberculosis dry cough, wheezing, and / or nasal congestion); dermatological side effects / clinical symptoms (eg, acne, rash, allergic eczema, papules) Scaly psoriasis-like rash, blisters, exudation, oral pain, and / or hair loss); musculoskeletal side effects / clinical symptoms (eg, myopathy and / or myalgia), liver side effects / clinical symptoms (eg, hepatotoxicity and / or Or yellow ), Abdominal pain, increased incidence of early pregnancy loss, cessation of menstruation, severe headache, confusion, changes in mental state, vision loss, seizures (convulsions), increased photosensitivity, dry eye, redness of the eyes, itchy eyes And / or hypertension. As provided above, the reduction or improvement of side effects or clinical symptoms is reduced or improved compared to the severity of the side effects or clinical symptoms prior to administration of the drug formulation to the SCS of the patient's eye, or the same drug Reduction or amelioration of in-patient side effects or clinical symptoms compared to the reduction or improvement observed in response to intravitreal, anterior chamber, parenteral, or oral administration.

  A wide range of therapeutic formulations, such as those involving one or more drugs and / or cell therapies, are formulated for delivery to the suprachoroidal space and posterior ocular tissue using the present microneedle device and method May be. As used herein, the term “drug” refers to any prophylactic, therapeutic, or diagnostic agent, ie, a component that is useful for medical applications. Drugs include naturally occurring, synthesized, or recombinantly produced proteins, peptides, and fragments thereof, cell therapeutics such as nucleic acids, including nucleic acid gene therapy-encoding vectors, small molecules, organisms May be selected from pharmacological formulations. 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 (eg, a Fab, Fv, or Fc fragment). In certain embodiments, the drug is an Fv immunoglobulin fragment, as described in US Pat. No. 6,773,916, which is incorporated herein by reference in its entirety for all purposes, Sub-immunoglobulin antigen binding molecules such as minibodies, and bispecific antibodies, and the like. In one embodiment, the drug is a humanized antibody or fragment thereof.

  In one embodiment, the non-surgical treatment methods and devices described herein may be used in gene-based therapeutic applications. For example, the method comprises, in one embodiment, administering a drug formulation into the suprachoroidal space and delivering selected DNA, RNA, or oligonucleotide to the targeted ocular tissue. Thus, in one embodiment, the drug is from a suitable oligonucleotide (eg, antisense oligonucleotide drug), polynucleotide (eg, therapeutic DNA), ribozyme, dsRNA, siRNA, RNAi, gene therapy vector, and / or vaccine. Selected. In further embodiments, the drug is an aptamer (eg, an oligonucleotide or peptide molecule that binds to a specific target molecule).

  In one embodiment, the nucleic acid therapeutic is delivered by one of the devices and / or methods provided herein. In a further embodiment, the nucleic acid therapeutic is delivered via a viral particle (viral vector). The viral particle is, in one embodiment, an adenovirus (Ad), an adeno-associated virus (AAV), or a lentivirus. In another embodiment, the viral vector is self-complementary AAV (scAAV) or helper-dependent adenovirus (HD-Ad). In another embodiment, a plasmid vector that expresses siRNA or other nucleic acid therapeutic is delivered via one of the devices and / or methods described herein. Alternatively or additionally, the nucleic acid therapeutic is delivered via (1) a polymer, (2) a lipid (eg, a liposome), (3) a protein, or (4) a dendrimer nanocarrier delivery system.

  In another embodiment, the drug formulation delivered via the methods provided herein comprises a small molecule drug, an endogenous protein or fragment thereof, or an endogenous peptide or fragment thereof.

  Uveitis (eg, non-infectious uveitis), macular edema associated with uveitis (eg, non-infectious uveitis), macular edema associated with RVO, wet AMD, CNV, RVO Representative examples of types of drugs for delivery to ocular tissue for the treatment of wet AMD, or wet AMD associated with CNV include, but are not limited to, anti-inflammatory drugs (steroids (eg, triamcinolone) ), Immunosuppressants, antimetabolites, T cell inhibitors, alkylating agents, biologics, TNF antagonists (eg, TNF-α antagonists), vascular endothelial growth factor (VEGF) modulators (eg, VEGF antagonists) And / or non-steroidal anti-inflammatory drugs (NSAIDs) in the suprachoroidal space to treat macular edema associated with uveitis Non-limiting examples of specific drugs and classes of drugs that can be reached include miotics (eg, pilocarpine, carbachol, physostigmine), sympathomimetics (eg, adrenaline, dipivefrin), carbonic anhydrase inhibitors (Eg, acetazolamide, dorzolamide), VEGF antagonists, platelet derived growth factor (PDGF) modulators (eg, PDGF antagonists), NSAIDs, steroids, prostaglandins, antibacterial compounds (eg, antibacterial and antifungal agents (eg, chloram) Phenicol, chlortetracycline, ciprofloxacin, flamicetin, fusidic acid, gentamicin, neomycin, norfloxacin, ofloxacin, polymyxin, propamidine, tetracycline, tobramycin, quinoline) ), Aldose reductase inhibitors, anti-inflammatory compounds and / or anti-allergic compounds (eg, steroidal compounds (triamcinolone, betamethasone, clobetasone, dexamethasone, fluorometholone, hydrocortisone, prednisolone, etc.) and non-steroidal compounds (antazoline, bromfenac, diclofenac) , Indomethacin, rhodoxamide, suprofen, cromoglycate sodium, etc.), artificial tears / dry eye treatment, local anesthetics (eg, amesokine, lignocaine, oxybuprocaine, proxymetacaine), cyclosporine, diclofenac, urogastron and growth factors (Epidermal growth factor, etc.), mydriatic and ciliary muscle palsy, mitomycin C, and collagenase inhibitor and age-related macular degeneration置薬 (pegaptanib sodium, ranibizumab, and bevacizumab, and the like). In one embodiment, the drug delivered by one of the devices and / or methods described herein is ranibizumab, axitinib, bevacizumab, and / or aflibercept.

In one embodiment, an angiogenesis inhibitor is administered to the SCS of a patient in need thereof. Angiogenesis inhibitors delivered via the methods and devices described herein, in one embodiment, the interferon Ganma1beta, pirfenidone containing interferon Ganma1beta (activate mu emissions ^{(registered trademark)),} ACUHTR028, ^αVβ5, aminobenzoic acid Potassium, amyloid P, ANG1122, ANG1170, ANG3062, ANG3281, ANG3298, ANG3298, ANG4011, anti-CTGFRNAi, apridin, salvia and datura extract, atherosclerotic plaque blocker, azole, AZX100, BB3, connective tissue growth factor antibody, CT140 , Danazol, esbriette, EXC001, EXC002, EXC003, EXC004, EXC005, F647, FG3019, fibrocholine, foris Chin, FT011, Galectin-3 inhibitor, GKT137831, GMCT01, GMCT02, GRMD01, GRMD02, GRN510, Heberon alpha R, interferon α-2β, ITMN520, JKB119, JKB121, JKB122, KRX168, LPA1 receptor antagonist, MGN42 , MicroRNA29a oligonucleotide, MMI0100, noscapine, PBI4050, PBI4419, PDGFR inhibitor, PF-066473871, PGN0052, pyrespa, pilfenex, pirfenidone, plitidepsin, PRM151, Px102, PYN17, PYN2, Reh fusion protein RXI109, secretin, STX 00, TGF-beta inhibitors, transforming growth factor, beta-receptor 2 oligonucleotides, VA999260, or XV615.

In one embodiment, the drug is delivered to the upper choroid lumen, sirolimus is (rapamycin ^(R), Rapamune ^(R)). In one embodiment, the non-surgical drug delivery methods disclosed herein are used in conjunction with rapamycin to treat, prevent, and / or treat macular edema associated with uveitis or macular edema associated with RVO. Improve. In addition, delivery of rapamycin using the microneedle devices and methods disclosed herein may be combined with one or more agents listed herein or other agents known in the art. May be. In a further embodiment, the macular edema associated with uveitis is macular edema associated with non-infectious uveitis.

  In one embodiment, macular edema or RVO associated with uveitis using non-surgical methods (eg, microneedle devices and methods) or surgical methods (eg, via shunts, stents, or cannulas). The drug that is delivered to the suprachoroidal space to treat macular edema associated with is triamcinolone (eg, triamcinolone acetonide). In one embodiment, the non-surgical and surgical drug delivery methods disclosed herein are used in conjunction with triamcinolone to produce macular edema associated with uveitis (eg, non-infectious uveitis or infectious Treat, prevent, and / or ameliorate uveitis). In addition, delivery of rapamycin using the microneedle devices and methods disclosed herein may be combined with one or more agents listed herein or other agents known in the art. May be. In a further embodiment, the macular edema associated with uveitis is macular edema associated with non-infectious uveitis. In some embodiments, the drug formulation comprises aflibercept.

  In one embodiment, the VEGF modulator is delivered via one of the devices described herein. In one embodiment, the VEGF modulator is a VEGF antagonist. In one embodiment, the VEGF modulator is a VEGF-receptor kinase antagonist, anti-VEGF antibody or fragment thereof, anti-VEGF receptor antibody, anti-VEGF aptamer, small molecule VEGF antagonist, thiazolidinedione, quinoline, or design ankyrin repeat protein ( DARPin). As described herein, in some embodiments for the treatment of macular edema associated with RVO, the anti-inflammatory drug is intravitreal delivery of a VEGF modulator (eg, VEGF antagonist) to the same eye. And delivered to the SCS of the patient's eye in need thereof. In one embodiment, a VEGF antagonist is an antagonist of VEGF receptor (VEGFR), ie, a drug that inhibits, reduces or modulates VEGFR signaling and / or activity. The VEGFR can be a 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 a tyrosine kinase or an antagonist of a tyrosine kinase receptor. In another embodiment, the VEGF modulator is a modulator of VEGF-A protein. In yet another embodiment, the VEGF antagonist is a monoclonal antibody. In a further embodiment, the monoclonal antibody is a humanized monoclonal antibody. In some embodiments, the drug formulation comprises aflibercept.

In one embodiment, VEGF adjustment factor, AL8326,2C3 antibody, AT001 antibody, HyBEV, bevacizumab (Avastin ^(TM)), ANG3070, APX003 antibody, APX004 antibody, Ponachinibu (AP24534), BDM-E, VGX100 antibody (VGX100CIRCADIAN ), VGX200 (c-fos-induced growth factor monoclonal antibody), VGX300, COSMIX, DLX903 / 1008 antibody, ENMD2076, sunitinib malate (Sutent ^{(registered trademark)} ), INDUS815C, R84 antibody, KD019, NM3, anti-VEGF antagonist and Combined allogeneic mesenchymal progenitor cells (eg, anti-VEGF antibody), MGCD265, MG516, VEGF-receptor kinase inhibitor, MP026 , NT503, anti-DLL4 / VEGF bispecific antibody, PAN90806, paromid 529, BD0801 antibody, XV615, lucitanib (AL3810, E3810), AMG706 (motesanib diphosphate), AAV2-sFLT01, soluble Flt1 receptor, cediranib ( Resentin ^™ ), AV-951, tivozanib (KRN-951), regorafenib (Stibaga ^{(registered trademark)} ), boraseltib (BI6727), CEP11981, KH903, lenvatinib (E7080), lenvatinib mesylate, terameprocol (EM1421) ), ranibizumab (Lucentis ^(TM)), hydrochloric pazopanib (Votoriento ^{TM), PF00337210, PRS050, SP01} ( curcumin), orotic acid carboxamide DOO Azole, hydroxychloroquine, Rinifanibu (ABT869, RG3635), fluocinolone acetonide (Irubien ^{(registered trademark)),} ALG1001, AGN150998, DARPin MP0112, AMG386, Ponachinibu (AP24534), AVA101, nintedanib (Barugatefu ^TM), BMS690514, KH902 , Gorbatinib (E7050), Everolimus (Affinitol ^{(registered trademark)} ), Dobitinib lactate (TKI258, CHIR258), ORA101, ORA102, Axitinib (Inwriter ^{(registered trademark)} , AG013736), Pritidepsin ^{(registered trademark} ), PTC299 aflibercept (monkey trap ^{(registered trademark),} Airia ^{(registered trademark)),} Pegaputanibunato Um (Macugen ^TM, LI900015), verteporfin (Visudyne ^(TM)), bucillamine (Rimachiru, lamin, Burimani, Ramitto, Bumiku), R3 antibody, AT001 / R84 antibody, troponin (BLS0597), EG3306, vatalanib (PTK787) , Bmab100, GSK2136773, anti-VEGFR arterase, Avila, CEP7055, CLT009, ESBA903, HuMax-VEGF antibody, GW654546, HMPL010, GEM220, HYB676, JNJ17029259, TAK593V, AGtndVet antibody AG13958, CVX241, SU14813 PRS055, PG501, PG545, PTI101, TG100948, ICS283, XL647, enzastaurin hydrochloride (LY317615), BC194, quinoline, COT601M06.1, COT604M06.2, Mavion VEGF, anti-VEGF or VEGF-R antibody One or more of Sphere, Apatinib (YN968D1), and AL3818. In addition, delivery of VEGF antagonists using the microneedle devices and non-surgical methods disclosed herein may include one or more of the listed herein, either in single or multiple formulations. Or other agents known in the art may be combined.

  In one embodiment, the immunosuppressive drug is delivered via one of the devices described herein. In further embodiments, the immunosuppressive drug is a glucocorticoid, a cytokine inhibitor, a cytostatic drug, an alkylating agent, an antimetabolite, a folate analog, a cytotoxic antibiotic, an interferon, an opioid, an antibody to a T cell receptor, Or it is an antibody with respect to IL-2 receptor. In one embodiment, the immunosuppressive drug is an antimetabolite, wherein the antimetabolite is a purine analog, pyrimidine analog, folate analog, or protein synthesis inhibitor. In another embodiment, the immunosuppressive drug is an interleukin-2 inhibitor (eg, basiliximab or daclizumab). Other immunosuppressive drugs indicated for use in combination with the methods and formulations described herein include, but are not limited to, cyclophosphamide, nitrosourea, methotrexate, azathioprine, mercaptopurine, fluorouracil, dac Examples include tinomycin, anthracycline, mitomycin C, bleomycin, mitramycin, muromonab-CD3, cyclosporine, tacrolimus, sirolimus, or mycophenolate. In one embodiment, the drug formulation comprises an effective amount of mycophenolate.

  In one embodiment, a drug formulation delivered to the SCS of a patient's eye in need thereof via a method 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 drug is a steroid or a non-steroidal anti-inflammatory drug (NSAID). In another embodiment, the anti-inflammatory drug is an antibody or fragment thereof, an anti-inflammatory peptide, or an anti-inflammatory aptamer. As provided throughout the specification, the delivery of an anti-inflammatory drug to the suprachoroidal space is to administer the same drug delivered via the oral, intravitreal, intraanterior, local and / or parenteral route of administration. Offers advantages over For example, in one embodiment, the therapeutic effect of a drug delivered to the suprachoroidal space is the same drug delivered at the same dosage when the drug is delivered via the oral, intravitreal, local or parenteral route Exceeds the therapeutic effect. In one embodiment, the intraocular elimination half-life (t1 / 2) of an anti-inflammatory drug administered to the SCS is the same dosage of the anti-inflammatory drug in the vitreous, in the anterior chamber, locally, parenterally. Or greater than the intraocular t1 / 2 of anti-inflammatory drugs when administered orally. In another embodiment, the mean maximum intraocular blood concentration (Cmax) of an anti-inflammatory drug is administered intravitreally, intravitreally, locally when administered to the SCS via the methods described herein. In particular, it exceeds the intraocular Cmax of anti-inflammatory drugs when administered parenterally or orally. In another embodiment, the mean area under the intraocular curve (AUC0-t) of the anti-inflammatory drug is the same dosage of the anti-inflammatory drug when administered to the SCS via the methods described herein. Exceeds the intraocular AUC0-t of anti-inflammatory drugs when administered intravitreally, into the anterior chamber, locally, parenterally or orally.

  Steroid compounds that can be administered via the methods provided herein include hydrocortisone, hydrocortisone-17-butyrate, hydrocortisone-17-aceponate, hydrocortisone-17-buteprate, cortisone, thixocortol pivalate, prednisolone, Methylprednisolone, prednisone, triamcinolone, triamcinolone acetonide, mometasone, amsinonide, budesonide, desonide, fluocinonide, harsinonide, betamethasone, betamethasone dipropionate, dexamethasone, fluocorthozone, hydrocortisone-17-valeridione Donicalart, clobetasone-17-butyrate, clobetasol-17-propionate, cap Phosphate fluocortolone, pivalate fluocortolone include acetic fluprednidene, and pre-Denis culvert.

  Specific classes of NSAIDs that can be administered via the methods provided herein include salicylates, propionic acid derivatives, acetic acid derivatives, enolic acid derivatives, fenamic acid derivatives, and cyclooxygenase-2 (COX-2) inhibition Agent is included. In one embodiment, the methods provided herein include acetylsalicylic acid, diflunisal, salsalate, ibuprofen, dexbuprofen, naproxen, fenoprofen, ketoprofen, dexketoprofen, flurbiprofen, oxaprozin, loxoprofen, indomethacin , Tolmetine, sulindac, etodolac, ketorolac, diclofenac or nabmeton, piroxicam, meloxicam, tenoxicam, droxicam, lornoxicam or isoxicam, mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid, celecoxib, rodecoxib, valdecoxib, valdecoxib, valdecoxib, One or more of the phylocoxib NSAIDs Used to deliver the SCS eye of patients with essential.

Other examples of anti-inflammatory agents that can be used in the methods provided herein to treat macular edema associated with uveitis (infectious or non-infectious uveitis) include, but are not limited to: None but mycophenolate, remicase, nepafenac, 19AV agonist, 19GJ agonist, 2MD analog, 4SC101, 4SC102, 57-57, 5-HT2 receptor antagonist, 64G12, A804598, A96779, AAD2004, AB1010, AB224050, abatacept, etalacizumab (Abegrin ^TM ), Abebak ^{(Registered trademark)} , AbGn134, AbGn168, Abki, ABN912, ABR215062, ABR224050, cyclosporine (Abramun ^{(Registered trademark)} ), Docosanol (behenyl alcohol, abreva) ^{(Registered trademark)} ), ABS15, ABS4, ABS6, ABT122, ABT325, ABT494, ABT874, ABT963, ABXIL8, ABXRB2, AC430, Acinetra, lysozyme chloride (Acdeum) ^{(Registered trademark)} ), ACE772, aceclofenac (ace block, ace bid, ace snack), acetaminophen, chlorzoxazone, serrapeptase, tizanidine hydrochloride, betadex, aceclogesic plus, aceclon, acechlorene, acechlorism, aceclona, acephein, acemetacin, inspirin (aspr) (Acecentrin), acetal-SP (aceclofenac-combination, ibuprofen, acetyl-G, acetylsalicylate dl-lysine, acetylsalicylic acid, ashicot, asifine, asic, acrocene, acrofram-P, acromore, acron, A-CQ, ACS15, Actarit, Actemra, Acceleriophylizad, ActiFirst, Actimab-B, Actiquim, Actily , Actis plus, activated leukocyte cell adhesion molecule antibody, Ackler X, AD452, Adalimumab, ADAMTS5 inhibitor, ADC1001, Adco-diclofenac, Adco-indomethacin, Adco-meloxicam, Adco-naproxen, Adco-piroxicam, Adcoat, Adco-Sulindac , Adenosine triphosphate disodium, adenosine A2a receptor agonist, azimod, azinos, adiocto, adiodol, adipoplus, adipose-derived stem cells and / or neoplastic cells, azizene, adpep, advacan, advagraf, adbel, adwiflam, AEB071, Ental, Afenac, Aphenplus, Afiansen, Affinitol, Aframin, Afrazacoat, Aphrogen, Afloxan, AFM 5, AFM16, AFM17, AFM23, Afred Dexa, AFX200, AG011, Agafen, Aganilsen, AGI1096, Aguidex, AGS010, Agdol, A-hydrocolt, AIK1, AIN457, Airtal, AIT110, AJM300, Ajuremic acid, AK106, 24 -2A1, AL4-1A1, araquat, arantz, albumin immunoglobulin, alcromethasone dipropionate, ALD518, aldesleukin, aldoderma, alefacept, alemtuzumab, alexel ^TM , Allergolone, Allergoson, Alletraxon, Alfenac, Argason, Argin Bek Coat, Argioflex, Argilex, Argivin Plus, Aricaforsen sodium, Arin, Alinea, Aribiodol, Aliviosin, Alkaline Phosphatase, ALKS6931, Allantoin, Albupen , Almole, alocrisin, allogeneic endothelial cells, allogeneic mesenchymal progenitor cells, allogeneic mesenchymal stem cells, aluminoprofen, α1 antitrypsin, α7 nicotine agonist, α amylase, α chymotrypsin, α fetoprotein, α Linolenic acid, α-1-antitrypsin, α2β1 integrin inhibitor, alpha coat, alphaphen, α-hexidine, α-trypsin, alfintern, alpiname mobility ω3, al Axen, AL-Rev1, Arterase, ALX0061, ALX0761, ALXN1007, ALXN1102, AM3840, AM3876, AMAP, AMAP102, Amazon, Amben, Ambedim G, Amcinonide, AME133v, Amesin, Amelotex, A-Metad AM, GAM AM16 G , AMG181, AMG191, AMG220, AMG623, AMG674, AMG714, AMG719, AMG729, AMG827, Amidol, Amifamipridin phosphate, Diclofenac (emifenac) ^{(Registered trademark)} ), Amymetacin, Amiprilose hydrochloride, Amiprofen, Ammophos, Amofram, AMP110, Ampicui, Ampion, Ampiroxicam, Amtormetic acyl, AMX256, AN6415, ANA004, ANA506, Anabu, Anacene, Anafram, Anaflex ACI, Anida, Anakinra, Anal Genal Tortis, Anapan, Anaprox, Anaban, Anax, Anko, Andrography, Aneol, Anelix, Anelbux. RA ^TM (Therapeutic peptide vaccine), amfrene, ANG797, anilixin, ammersin, annexin 1 peptide, annexin A5, anodyne, anside, anspirin, antalene, anti-BST2 antibody, anti-C5aMAb, anti-ILT7 antibody, anti-VLA1 antibody, anti-α11 antibody, anti-antibody CD4802-2, anti-CD86 monoclonal antibody, anti-chemokine, anti-DC-SIGN, anti-HMGB-1 MAb, anti-IL-18 Mab, anti-IL-1RMAb, anti-IL-1RMAb, anti-IL23 Bristol, anti-interleukin-1β antibody, anti-LIGHT Antibody, anti-MIF antibody, anti-MIF antibody, anti-miR181a, antioxidant inflammation regulator, antiflamin, anti-RAGEMAb, antithrombin III, anti-TIRC-7MAb, anusole-HC, anifene, AP105, A P1089, AP1189, AP401, AP501, Apazone, APD334, Apentac, APG103, Apidone, Apyrimod mesylate, Apitak, Apitoxin, Apizel, APN inhibitor, Apo-azathioprine, Apo-dexamethasone, ApoE mimetic, ApoFasinL, ApoFindosine Apo-phenamic, apo-methotrexate, apo-nabumetone, apo-Napro-NA, apo-naproxen, aponidine, apo-phenylbutazone, apo-piroxicam, apo-thrin, apo-tenoxicam, apo-thiaprofenic, aplanax , Apremilast, apricoxib, aprofen, aprose, aproxen, APX001 antibody, APX007 antibody, APY0201, AqvoDex, AQX 08, AQX1125, AQX131135, AQX140, AQX150, AQX200, AQX356, AQXMN100, AQXMN106, ARA290, Alaba, Alkalist, Alkoxya, Aretin, Alfurur, ARG098, ARG301, Arginine aestin, Arginine deiminase (Pegylated) ARGX109 antibody, ARGX110, Ariuma, Aristocoat, Aristospan, Ark-AP, ARN4026, Allophane, Alofe EZ, Alloref, Allotar, Alpiburu, Alpimun, Alpsunggixin, ARQ101, Arrestin SP, Alox, ARRY162, ARRY371797, ARRY614, ARRY872, ART621, Altamine, Arsfree, Arsotech, Al Rekishin, Ars squirrels play, ortho-Tech, Eterunasame cartilage extract (Arusurobasu ^TM , Neo Letna ^TM , Sobascal ^TM ), Artifit, Artigo, Artin, Artinoa, Artisid, Altoflex, Altrenhypergel, Altoridol, Altorilase, Altorocaptin, Altorofen, Altropane, Arthrosyl, Arthrosilene, Altrotin, Altrox, Artifram , Alzera, AS604850, AS605858, Asacol, ASA-Grindex, Asadipam, Acecro, ASF1096, ASF1096, ASK8007, ASKP1240, ASLAN003, Asmo ID, Asonep, ASP015K, ASP2408, ASP2A , Astaxanthin, Astrocoat, Aszes, AT002 antibody, A 007, AT008 antibody, AT008 antibody, AT010, AT1001, Atacicept, Atapine, Atepaden, Atgam, ATG-Fresenius, Athrophen, ATI003, Atiprimmod, ATL1222, ATN103, ATN192, ATR107, Atri, Atolmin, Atro3A, ATX3105 Nophine, aurobin, auropan, aurothio, aurothioprolol, autologous adipose-derived neoplastic cell, autonek, avantia, AVE9897, AVE9940, avelox, avent, AVI3378, abroquin, AVP13546, AVP13748, AVP28225, AVX002, axelcrofenac, axelpapine , AZ17, AZ175, azacortide, AZA DR, azafurin, azamun, azanin, azapine, azapine, azaprene, azapurine, azalam, azasan, azathioprine, AZD0275, AZD0902, AZD2315, AZD5672, AZD6703, AZD7140, AZD9056A, AZD9056A Azofit, azolide, azolane, azulene, azulfidine, azulphine, B1 antagonist, balconette, BAF312, BAFF inhibitor, baguess, bailey S. et al. P. , Bareston, Barsolone, Baminercept α, Bardoxolone methyl, Balicitinib, Barotase, Basecam, Basiliximab, Baxmun, Baxo, BAY 869766, BB2827, BCX34, BCX4208, Becfine, Becrate-C, Beclat-N, Beclolabon Q, Dipropione Q , Becloin, becmet-CG, begeta, beguci, belatacept, berimumab, belosaric, bemethonson, ben, benebat, benexam, benphlogin, benisan, benrista, benlista, benolylate, benoson, benoxaprofen, bentol, benzidamine hydrochloride, benzidamine , Berafen, belinate, berlofen, bertanel, bestamin, bestfen, beta-niship, betacoat, Betacorten G, Betaform, Betaglucan, Betaler, Beta-M, Betamed, Betamethol, Betamethasone, Betamethasone Dipropionate, Betamethasone Sodium, Betamethasone Sodium Phosphate, Betamethasone Valerate, Betane, Betanex, Betapansen, Betapearl, Betared, Betason, Betasonate, Betathone, Betatrinta, Betabal, Betazone, Betazone, Bethesyl, Vinetonecote, Vitonesol, Betanobert, Vectra, BFPC13, BFPC18, BFPC21, BFPT6864, BG12, BG9924, BI695500, BI695550, BI02550 -Cushicam, Bingo, Biobee, Bio-Cultureridge, Bio-C-Sinkchi, Odexone, Biofenac, Bioloycam, Bioson, Biosporin, BIRB796, Vitonova, Vitobio, Bibigam, BKT140, BKTP46, BL2030, BL3030, BL4020, BL6040, BL7060, BLI1300, Bricibimod, Brochium B41, Brochium B0, B BMS470539, BMS561392, BMS56619, BMS582949, BMS587101, BMS817399, BMS936557, BMS945429, BMS-A, BN006, BN00



7, BNP166, Bonacoat, Bonus, bone marrow stromal cell antigen 2 antibody, Bonflex, Bonifen, Boomik, Volbit, Bosong, BR02001, BR3-FC, Brandikinin B1 receptor antagonist, Bredinin, Brexecam, Brexin, Brexodine, Briakinumab, Brimani, Briobacept, Blisterflam, Britain, Broben, Brodalumab, Broen-C, Bromelain, Bromelin, Bronax, Bropine, Brocillary, Bruce, Brufadol, Brufen, Brugel, Brukir, Brusil, BT061, BTI9, BTK kinase inhibitor, BTT1023 antibody, BTT1507, bucillamine, bucylate, bukoregis, bucolome, budenofalk, budesonide, budex, bufek , Bufencon, bukuwanketoprofen, bunido, buphene, bucilbex, busulfan, busulfex, busullipo, butoltrol, butalto B12, butasona, butazolidine, butezon, butiziona, BVX10, BXL628, BYM338, B-zone, C1 esterase inhibitor 44, C243 , C5997, C5aQb, c7198, c9101, C9709, c9787, CAB101, cadherin-11 antibody, frog romionion A, CAL263, Calcoat, Carmatel, CAM3001, camel antibody, Camrocks, Camora, Campus, Camrox, Camtenum, Kanakinumab, Candida Albicans antigen, candin, cannabidiol, CAP1.1, CAP1.2, CAP2.1, CAP2 2, CAP3.1, CAP3.2, Calelem, Karimun, Cariodent, cultifix, cultijoint, kartilago, cultisafe-DN, cultishine, cultibit, kartoril-S, kardor, caspa CIDe, caspa CIDe, cassin, CAT1004, CAT1902, CAT2200, Catafram, Cathepsin S inhibitor, Catrep, CB0114, CB2 agonist, CC0478765, CC10004, CC10015, CC1088, CC11050, CC13097, CC15965, CC16057, CC220, CC292, CC401, CC5048, CC509, CC7085, CC930, CR930 , CCR6 inhibitor, CCR7 antagonist, CCRL2 antagonist CCX025, CCX354, CCX634, CD diclofenac, CD102, CD103 antibody, CD103 antibody, CD137 antibody, CD16 antibody, CD18 antibody, CD19 antibody, CD1d antibody, CD20 antibody, CD200Fc, CD209 antibody, CD24, CD3 antibody, CD30 antibody, CD32A Antibody, CD32B antibody, CD4 antibody, CD40 ligand, CD44 antibody, CD64 antibody, CDC839, CDC998, CDIM4, CDIM9, CDK9 inhibitor, CDP146, CDP323, CDP484, CDP6038, CDP870, CDX1135, CDX301, CE224535, Cenel, Cebedex, , SECLONAC, SEIX, CEL2000, SELECT, SELVEX, SELCOX, CELEVIOX, SE Blex, celebrin, celecox, celecoxib, celedole, celeston, celebex, selex, CELG4, cell adhesion molecule antagonist, celcept, selmun, celosti, celoxib, cellplot, celdex, senicrabilok mesylate, senpracell-1, CEP110247, CEP37247, CEP37248 , Cefil, Ceprofen, Certican, Sertolizumab pegol, Setofenide, Setoprofeno, Cetylpyridinium chloride, CF101, CF402, CF502, CG57008, CGEN15001, CGEN15021, CGEN15051, CGEN15091, CGEN25017, CGEN25068, CGEN25068, CGEN25068, CGEN25068, CGEN25068 C I1746, CGI560, CGI676, Cgtx-peptide, CH1504, CH4051, CH4446, chaperonin 10, chemokine CC motif ligand 2, chemokine CC motif ligand 2 antibody, chemokine CC motif ligand 5 antibody, chemokine CC motif Receptor 2 antibody, chemokine C-C motif receptor 4 antibody, chemokine C-X-C motif ligand 10 antibody, chemokine C-X-C motif ligand 12 aptamer, chemotaxis inhibitor, tilmetacin, chitinase 3-like 1, Crocodemine, croquine, chlorhexidine gluconate, chloroquine phosphate, choline magnesium trisalicylate, chondroitin sulfate, chondro skirt, CHR3620, CHR4432, CHR5154, chrysaline, Chuan Xinlian, kimpura, chymotase, chymotrypsin, chitomtryp, CI202, CI302, cycloderm-C, cycloprene, cycloral, silamine, simdia, cinchophene, synmetacin, cinnoxicam, synodrum, cinolone-S, synthesize, cycorlin, cyperat, cypol-N, priole-N, priol-N CIPZEN, CITAX F, CITOGAN, CITOKEN T, CIVAMID, CJ042794, CJ14877, c-Kit monoclonal antibody, cladribine, krafen, clanza, clavel monkey, clazakizumab, creatoid, clease, clebegen, clevian, clindol, clindam, clinolyl, cryptol, clobenart , Clobecad, Clobetasol butyrate, Clobetasol propionate, Clodo , Clofarabine, clofen, clofenal LP, chloral, clonac, cron gamma, clonixine lysine, crota sauce, clobacoat, clobana, cloxin, CLT001, CLT008, C-MAF inhibitor, CMPX1023, Cnc, CNDO201, CNI1493, CNTO136, CNTO148, CNTO1959 , Cobefen, cobencoderm, covix, cofenac, cofenac, COG241, COL179, colchicine, colchicum dispart, colhimax, corsibura, coredes A, corresol, coriform, coryrest, collagen (type V), comcoat, complement component ( 3b / 4b) receptor 1, complement component C1s inhibitor, complement component C3, complement factor 5a receptor antibody, complement factor 5a receptor antibody Complement factor D antibody, chondrosulfur, chondrotech, chondrocin, connestat alpha, connective tissue growth factor antibody, coupan, copaxone, copirone, cordefura, corridron, coat S, kotan, coultato, coat-dome, cortecetin, cortef, corteroid, corti Cap, Corticus, Cortic-DS, Corticotropin, Cortidelm, Cortidex, Cortiflam, Cortinet M, Cortinyl, Cortipyrene B, Cortilan, Cortis, Cortisol, Cortisone acetate, Cortibal, Colton acetate, Cortopine, Cortral, Cortril, Cortipyrene, Cosamine, Cosone, Cosyntropin, COT kinase inhibitor, Cochiram, Cotrizone, Cotoson, Cobox, Cox B, COX-2 / 5-LO inhibitor, Koxe , Coxfram, Coxicam, Coxitol, Coxitoral, Coxipal, CP195543, CP41245, CP424174, CP461, CP629933, CP690550, CP751871, CPSI2364, C-Kin, CR039, CR0774, CR106, CRA102, CRAC channel inhibitor, CRACM ion channel inhibitor Agent, clatizone, CRB15, CRC4273, CRC4342, C-reactive protein 2-methoxyethyl phosphorothioate oligonucleotide, CreaVax-RA, CRH modulator, critic-aid, crocam, clones bucks, cromoglycic acid, cromolyn sodium, Chronocorteroid, Cronodikazone, CRTX803, CRx119, CRx139, C x150, CS502, CS670, CS706, CSF1R kinase inhibitor, CSL324, CSL718, CSL742, CT112, CT1501R, CT200, CT2008, CT2009, CT3, CT335, CT340, CT5357, CT637, CTP05, CTP10, CT-P13, CTP17, cuprenyl , Cuprimin, cuprin, cupripen, claquine, ktophene, CWF0808, CWP271, CX1020, CX1030, CX1040, CX5011, Cx611, Cx621, Cx911, CXC chemokine receptor 4 antibody, CXCL13 antagonist, CXCR3 antagonist, CXCR4 antagonist, CXCR4 antagonist 2, cyclocort, cyclooxygenase-2 inhibitor, siku Lofosfamide, cycloline, cyclosporin A prodrug, cyclosporin analog A, cyclosporine, silevia, syringlaris, CYT007TNFQb, CYT013IL1bQb, CYT015IL17Qb, CYT020TNFQb, CYT107C, CYT387C, CYT9907C Daclizumab, Danazol, Danylase, Dantes, Danzen, Dapsone, Dase-D, Daypro, Dipro Alta, Dairun, Dazen, DB295, DBTP2, D-Coat, DD1, DD3, DE096, DE098, Devio0406, Devio0512, Devio0615, Devio 0618, Debio 1036, Decaderm, Decadorail, Cadron, Decadronal, Decalon, Deccan, Decason, Dekudan, Decilon, Declofen, Decopen, Decolex, Decolten, Dedema, Dedron, Deexa, Defcoat, Defram, Deframat, Defranc, Defuranil, Deflaren, Deflaz, Deflazacort, Defronac , Defunil, defosalic, defsle, defza, dehydrocortisone, decote, deragil, delcasertiv, dermitide, delficote, deltacorsolone prednisolone (deltacortril), deltafluorene, deltasolone, deltason, deltastub, deltonin, demarine, demison, denebora , Denileukin diftitox, denosumab, denzo, depocortin, depo-medrol, depomethrexate, depotred, depot , Depilin, Delinase, Delmor, Delmorer, Delmonate, Delmoson, Delzon, Desket, Desonide, Desoxycorticosterone acetate, Deswon, Dexaben, Dexaben, Dexacip, Dexacoat, Dexacortisone, Dexacoltisil, Dexadic, Dexadrone, Dexadolone , Dexachil, Dexarab, Dexaraf, Dexalet, Dexalgen, Dexalion, Dexarocar, Dexalone, Dexam-M, Dexamecoltin, Dexamedo, Dexamedis, Dexameral, Dexamethas, Dexamethasone, Dexamethasone Acetate, Dexamethasone Palmitate, Dexamethasone Phosphate, Metasulfobenzoate Dexamethasone sodium phosphate, Dexamine, Dexanthane Dexa-S, dexason, dextab, dexatopic, dexabar, dexaben, dexazolidine, dexazona, dexazone, dexcol, dexib, dexibprofen, dexico, dexfen, deximone, dexketoprofen, dexketoprofentrometamol, dexmark, Dexome, Dexone I, Dexonaline, Dexonex, Dexony, Dexoptiphene, Dexipin, Dexitane-Plus, Dextran sulfate, Dezacol, Dfz, Diacerein, Dianexin, Diathon, Dicarol, Dikason, Dikunol, Diclo, Diclobon, Diclobonze, Diclobonzo diox , Diclofen, diclofenac, diclofenac β-dimethylaminoethanol, diclofenac deanol, Black Fe diclofenac diethylamine, diclofenac epo lamin, diclofenac potassium, diclofenac resinate, sodium diclofenac, Jikurogen Agio, dichloride Gen Plus, Jikurokimu, Jikuromedo, dichloroethane -NA, Jikuronaku, dichloramine, dichloran,



Dichloreum, Dichlorism, Diclotech, Diclobit, Dicrowal, Diclozem, ZicoP, Dicofen, Dicorib, Dicorson, Dicron, Dixel, Difena, Difutab, Diflunisal, Zirmapimod, Dilora, Dimethylsulfone, Zinac, D-Indomethacin, Dioxaflex Protect , Dipenopen, dipexin, diploAS, diplobeta, diplobetason, diplocrenato, diplometh, diplonova, diprosone, diprobate, diploxene, disalmine, dicer, disopain, dyspain, dyspercam, distamine, dizox, DLT303, DLT404, DM199, DM99D, DM199, DM99D , DNX02070, DNX04042, DNX2000, DNX4000, Docosa , Docz-6, Doramide, Doralene, Dorkis, Dorex, Dorfram, Dolfre, Dolgit, Dormax, Dolmina, Dorokatazon, Drobest, Drobid, Drok, Drocam, Drocarchigen, Drofit, Drokind, Dromed, Dronac, Dronex, Drotoren , Drozen, Dolkin, Dom0100, Dom0400, Dom0800, Domet, Dometon, Dominadol, Donggipap, Donica, Donisanin, Dramapimod, Dorixina Relax, Dormelox, Dordinplus, Doxatar, Doxtran, DP NEC, DP4577, DP50, DP6221 D-Penamine, DPIV / APN inhibitor, DR1 inhibitor, DR4 inhibitor, DRA161, DRA162, Drenex, DR 4848, DRL 15725, Drossazine, DSP, Dukis, Duo-Decadron, Duofrex, Duonase, DV1079, DV1179, DWJ425, DWP422, Dimor, DYN15, Dynaper, Dismen, E5090, E6070, Easy Days, Evetrex65, E028605, EC02007 EC0746, Ecax, Murasakibarengiku extract, EC-naprosin, Econac, Ecosprin 300, EcoSprin 300, Eculidoxan, Eculizumab, Edecam, Efalizumab, Efucortesol, Efigel, Ephragen, Eflidol, EGFR antibody, EGS21, eIF5A1 sRNA , Eldram, eridel, eriphram, eri , Hermes, Ermethasin, ELND001, ELND004, Erocalcitol, Erocom, Elsibucol, Emansen, Emcourt, Emifene, Emifenac, Emorphazon, Empiners, Emlicasan, Emto, Enable, Embrell, Ensaid, Encorthon, Encorthon, Encordon, Encordon Endogenic, Endoxan, Encorten, Encera, Encort, Enzylan, Epanonova, Eparang, Epatec, Epicotyl, Epidermal growth factor receptor 2 antibody, Epidermal growth factor receptor antibody, Epidixone, Epidrone, Epiclin, EPPA1, Epratuzumab, ExO, Elak , Erazone, ERB041, ERB196, Eldon, Erdex, E. coli enterotoxin B subunit, Estine, E-selectin antagonist, esfenac, ESN603, esonalymod, esprofen, estetrol, estopain, estrogen receptor β agonist, etanercept, etaracizumab, ETC001, propolis ethanol extract, ETI511, ethipredonol dicloacetate, ethodin, Etodyne, etodol, etodolac, etodi, etofenamate, etorfort, etorac, ethopin, etoroxib, etix, ethosafe, etova, etozox, etura, eucob, euphans, eukaryotic translation initiation factor 5A oligonucleotide, unac, Eurocox, Eurogesic, Everolimus, Ebinopon, EVT401, Exafram, EXEL9953, Excicoat Expen, Extra Feverlet, Extra Bread, Extra Horse, Exdase, F16, F991, Falcum, Farcol, Falsey, Farbovir, Farcomesacin, Farnerato, Farnezone, Farnezone, Farothrin, fas Antibody, Fastfram, FasTRACK, Fastum, Foul Dometro, FcγRIA antibody, FE301, febrofen, febrofide, felbinac, felden, ferdex, ferrolan, felxicam, fenac, fenacop, phenador, fenafuran, phenamic, phenalene, phenaton, fenbid, fenbufen, fengsignong, fenicine , Fenoprofen Calcium, Fenopron, Fenris, F Nsapp, phenoxycam, feprazinol, ferrobisque, feverlet, fezaquinumab, FG3019, FHT401, FHTCT4, FID114657, figitumumab, filexi, filgrastim, phylase, final, findoxin, fingolimod hydrochloride, filategrassio, fadafice fisio FK778, fracoxite, fladalzine, flagon, framer, flamcid, flamfort, flamide, flaminase, flamirex gechic, furanide, flanzen, fullerene, fullerene, flashact, flavonoid anti-inflammatory molecule, flavogamma DIF, flenac, flex, flexaphene 400 , Flexi, flexidol, flexium, flexion, flex Sono, Phlogen, Phlogatriin B12, Fragomin, Fragoral, Fragosan, Fralogter, Fro-Pread, Frosterone, Frotripforte, Flt3 inhibitor, Fluasterone, Flucam, Flucinal, Fludrocortisone acetate, Flufenamic acid aluminum, Flumethasone, Flumidone, Flunixin, Fluocinolone, fluocinolone acetonide, fluocinonide, fluocortron, fluonide, fluorometholone, fleur, flurbiprofen, flulibec, fluromesolone, furtal, fluticasone, fluticasone propionate, flutisone, fluzone, FM101 antibody, fms related tyrosine kinase 1 Antibody, follitrax, fontlizumab, formic acid, fortecortin, fospeg, hosta matinib jina Thorium, FP1069, FP13XX, FPA008, FPA031, FPT025, FR104, FR167653, Flamevin, Freyme, Froben, Florix, FROUNT inhibitor, Fubifen PAP, Fucolebuprofen, Framotol, Fulpene, Fungifin, Furotagin, X-L , FX201, FX300, FX87L, galectin regulator, gallium maltolate, Gamimun N, gamma guard, gamma-I. V. , Gammakin, Gammabenin, Gumnex, Garzen, Gaspirin, Gatex, GBR500, GBR500 antibody, GBT009, G-CSF, GED0301, GED0414, Gefenec, Gelofen, Genepril, Gengraph, Genimin, Genikin, Genotropin, Genz29155, Gelvingelvin GF015564600, Gilenia, Gilenya, Gibinostat, GL0050, GL2045, Glatiramer acetate, globulin, Glorosforte, Globarox, Globenin-I, GLPG0259, GLPG0555, GLPG0634, GLPG0778, GLPG0974, gluco, glucoserine, glucosamine sulfate, glucosamine hydrochloride Glucotin, gurdex, glutilla , GLY079, GLY145, Glycanic, Glycefort Up, Grigetic, Glysopep, GMCSF antibody, GMI1010, GMI1011, GMI1043, GMR321, GN4001, Goanasalbe, Goflex, Gold sodium thiomalate, Golimumab, GP2013, GPCR15 antagonist, GPR15 antagonist Antagonist, GPR32 antagonist, GPR83 antagonist, G protein-coupled receptor antagonist, graceptor, graphtack, granulocyte colony stimulating factor antibody, granulocyte-macrophage colony stimulating factor antibody, gravix, GRC4039, grerise, GS101, GS9973, GSC100, GSK1605786 , GSK1827771, GSK2136 25, GSK2941266, GSK315234, GSK681323, GT146, GT442, Gusixatoong, Gufisella, Gupison, Grisperimus hydrochloride, GW274150, GW3333, GW406381, GW856553, GWB78, GXP04, Ginestrel, Halocortin H , Hawonbusilamine, HB802, HC31496, HCQ200, HD104, HD203, HD205, HDAC inhibitor, HE2500, HE3177, HE3413, Hecolia, hectomycin, hephasolone, Helen, Helenyl, Hemax, Hematom, hematopoietic stem cell, hematol, hemyl, hemyl Heparinoid, heptax, HE R2 antibody, herponyl, hESC-derived dendritic cells, hESC-derived hematopoietic stem cells, hespercorbine, hexacortin, hexadolol, hexetidine, hexoderm, hexodermsaliq, HF0220, HF1020, HFT-401, hG-CSFREDFc, hiberna, high Mobility group box1 antibody, HIRONIDE, HINOCAM, hirudin, hirudoid, hison, histamine H4 receptor antagonist, hytenercept, hyzentra, HL036, HL161, HMPL001, HMPL004, HMPL004, HMPL011, HMPL342, HMPL692, honey bee , HTI101, HuCAL antibody, human adipose mesenchymal stem cell, anti-MHC class II monoclonal antibody, human immunoglobulin, To placenta tissue hydrolyzate, HuMaxCD4, HuMax-TAC, Humeton, Humicade, Humira, Huons betamethasone sodium phosphate, Huons dexamethasone sodium phosphate, Huons piroxicam, Huons tarniflumate, hurofen, Huruma, HuZ Hugel , Sodium hyaluronate, hyaluronic acid, hyaluronidase, hyaluronic acid, hycosine, high coat, Hy-cortisone, hydrocortisone, hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone hemisuccinate, hydrocortisone sodium phosphate, sodium hydrocortisone citrate, hydrocortistab, hydrocorton, Hydroline, hydroquine, hydro-Rx, hydroson HI MA, hydroxychloroquine, hydroxychloroquine sulfate, Hirazedesso, HyMEX, Haipen, HyQ, Haisonato, HZN602, I. M.M. 75, IAP inhibitor, Ibargin, Ibargin, Ibex, Ibrutinib, IBsolv MIR, Eve, Ibcon, Ibdraw, Ibfen, Ibuflam, Ibflex, Ibgethic, Eve-Hepa, Ibukim, Ibmaru, Ibnal, Ibpental, Ibupentibu , Evesoft, Eveski Pension, Eve Suspen, Ibutado, Evetop, Evetop, Evetrex, IC448792, Ikutamol, ICRAC Blocker, IDEC131, IDECCE9.1, Ides, Ijicine, Idizone, IDN6556, Idomesin, IDR1, Idyll SR, Ifen Iguratimod, IK6002, IKK-β inhibitor, IL17 antagonist, IL-17 inhibitor, IL-17RC, L18, IL1Hy1, IL1R1, IL-23 Adnectin, IL23 inhibitor, IL23 receptor antagonist, IL-31 mAb, IL-6 inhibitor, IL6Qb, Iracox, Ilaris, Irodecakin, ILV094, ILV095, Imaxetil, IMD0560, IMD2560, Imcell Plus , Iminoral, imodine, IMMU103, IMMU10



6, Imcept, Imfine, Imnex Syrup, Immunoglobulin, Immunoglobulin G, Immunopurine, Immunorell, Imulin, IMO8400, IMP731 antibody, Implanta, Immunocell, Imran, Imrek, Imsafe, Imsporin, Imtrex, IN0701, Inal, INCB03991 , INCB18424, INCB28050, INCB3284, INCB3344, Indexon, Indic, India, India-A, India Bid, India-Bloss, India Cuff, Indocarsil, Indoside, Indosin, Indomehotopas, Indomen, Indomet, Indomethacin, Indomethacin, Indomethacin , Indomethine, Indomine, Indopal, Indolone, Indotroxin, INDUS8 0, INDUS83030, inflammadase, inflammax, inflammasome inhibitor, inflavis, inflixen, inflectra, infliximab, ingaripto, inixox dp, inmesin, imunoartro, innamit, InnoD06006, INO7997, inosine, inotene, inoban, impula, Inside Pap, Insider-P, Instacil, Instacool, Interfenac, Interfram, Inteban, Intevan Spansur, Integrin, α1 Antibody, Integrin, α2 Antibody, Intenas, Interferon α, Interferon β-1a, Interferon γ, Interferon γ Antibody Interking, Interleukin 1Hy1, Interleukin 1 antibody, Interleukin 1 Tone antibody, interleukin 1, β antibody, interleukin 10, interleukin 10 antibody, interleukin 12, interleukin 12 antibody, interleukin 13 antibody, interleukin 15 antibody, interleukin 17 antibody, interleukin 17 receptor C, Interleukin 18, Interleukin 18 binding protein, Interleukin 18 antibody, Interleukin 2 receptor, α antibody, Interleukin 20 antibody, Interleukin 21 mAb, Interleukin 23 aptamer, Interleukin 31 antibody, Interleukin 34, Interleukin 6 Inhibitor, interleukin 6 antibody, interleukin 6 receptor antibody, interleukin 7, interleukin 7 receptor antibody, interleukin 8, interleukin 8 antibody Interleukin-18 antibody, Inchdolol, Intradex, Intragam P, Intragesic, Intraglobin F, Intratect, Insel, Iomab B, IOR-T3, IP751, IPH2201, IPH2301, IPH24, IPH33, IPI145, Ipocoat, IPP201007, I-profen, Iprox, Ipson, Ipton, IRAK4 inhibitor, Ilemod, Ilton Python, IRX3, IRX5183, ISA247, ISIS104838, ISIS2302, ISISCRPRx, Ismaflon, IsoQC inhibitor, Isox, ITF2357, Ivy gum ENB IVIG-SN, IW001, Ijirox, J607Y, J775Y, JAK inhibitor, JAK3 inhibitor, JAK3 kinase inhibitor, JI3292, JI4135, Ginnan Lida, JNJ10329670, JNJ18003414, JNJ26528398, JNJ27390467, JNJ28818017, JNJ310019258, JNJ38518168, JNJ13759527, JNJ4077527, JNJ4077527, JNJ40377527 , JSM10292, JSM7717, JSM8757, JTE051, JTE052, JTE522, JTE607, JASGO, K412, K832, Kahram, KAHR101, KAHR102, KAI9803, Calimine, Campresol, Cameton, KANAb07 , Kappa Procto, KAR2581, KAR3000, KAR3166, KAR4000, KAR4139, KAR4141, KB002, KB003, KD7332, KE298, Kerikimab, Kemanat, Chemlox, Kenacoat, Kenalog, Kenaxil, Kenkebenoglobulin-Ike, Tomatoketo Ketobos, Ketophan, Ketophen, Kettlegan, Kettneral, Ketoplus Kata Plasma, Ketoprofen, Ketres, Ketoline, Ketorolac, Ketolactolomethamine, Ketoselect, Ketotop, Ketovale, Ketricine, Ketolock, Ketam, Kay, Kayben, KF24345, K- Fenac, K-Phenac, K-Gesik, Kifaden, Kill Coat, Killroll, KIM12 , Chymotab, kinase inhibitor 4SC, kinase N, kincoat, kindolase, kinelet, kineto, kitadol, quitex, chytrak, KLK1 inhibitor, clofen-L, crotalene, KLS-40or, KLS-40ra, KM277, navon, codroola base, coxanine , Koide, Koidexa, Corvette, Konak, Chondro, Chondromin, Concien, Contab, Cordexa, Kosa, Kotase, KPE06001, KRP107, KRP203, KRX211, KRX252, KSB302, K-Sep, Kv1.3 blocker, Kv1.34SC, Kv1. 3 inhibitor, KVK702, Kynol, L156602, rabizon, labhydro, labpen, lacoxa, lamin, lamit, lanfetil, laquinimod, acetic acid Larazotide, LAS186323, LAS187247, LAS41002, Lachicoat, LBEC0101, LCP3301, LCP-Shiro, LCP-Tacro, LCsA, LDP392, Leap-S, Redelcoat, Rederfen, Rederon, Redelspan, Refenin, Leflunomid, Reflux, Lefto , Refmid, refnodine, refba, lenalidomide, renercept, lenti RA, LEO15520, rhease, leukine, leukocyte function related antigen-1 antagonist, leukocyte immunoglobulin-like receptor subfamily A member 4 antibody, leucosera, leuprolide acetate, levalbuterol, Levomenthol, LFA-1 antagonist, LFA451, LFA703, LFA878, LG106, LG26 Inhibitor, LG688 inhibitor, LG5552, Relife, Ridamantle, Redex, Lidocaine, Lidocaine hydrochloride, Lignocaine hydrochloride, LIM0723, LIM5310, Rimethasone, Limus, Rimustine, Lindac, Lymphonex, Linolacute, Lipsy, Lysophylline, Risophylline, Liver X Receptor modulator, Lizak, LJP1207, LJP920, Lovafen, Lob, Locafluo, Locarin, Locaceptyl-Neo, Lokuprene, Rosin, Rhodola, Lofezic, Loflam, Lofnack, Lorcam, Ronak, Ronazolac Calcium, Loprofen, Loracote Ferrolcam , Lorindenrotio, Lone Krat, Lornoxicam, Lorox, Rosmapimod, Loteprednol etabonate, Lottepre Nord, rotilac, small molecule Ganoderma Lucidum polysaccharide, loxaphene, roxyphenine, loxicam, loxofen, loxonal, loxonin, loxoprofen sodium, loxolone, LP183A1, LP183A2, N204T1, S194L, S194L, S194L LTZMP001, Rubo, Lumiracoxib, Lumitect, LX2311, LX2931, LX2932, LY2127399, LY2189102, LY2439821, LY294002, LY30009104, LY309987, LY3333013, lymphocyte activation gene 3 antibody, lymphoglobulin, riser, lysine Phosphorus, lysobact, lysofram, lysozyme hydrochloride, M3000, M834, M923, mAbhG-CSF, MABP1, macrophage migration inhibitory factor antibody, mitonguna, majamilprongatum, major histocompatibility complex class IIDR antibody, major histocompatibility gene Complex class II antibody, maridens, marival, mannan-binding lectin, mannan-binding lectin-related serine protease-2 antibody, MapKap kinase 2 inhibitor, maraviroc, marlex, machininib, maso, MASP2 antibody, MAT304, matrix metalloprotease inhibitor, Mabrilimumab, maxifram, maxilase, maximas, maxizona, maxius, maxipro, maxirel, maxislid, maxi 12, maxi 30, maxi 4, maxi Shi 735, Maxi 740, Mayfenamic, MB11040, MBPY003b, MCAF5352A, McCam, Macrophy, MCS18, MD707, MDAM, MD Colt, MDR06155, MDT012, Mevicam, Mebuton, sodium meclofenamic acid, meclofen, mecofen, medacom, medamol, medamol Medeson, MEDI 2070, MEDI 5117, MEDI 541, MEDI 552, MEDI 571, Medicox, Medifen, Medisol, Medixone, Medonisol, Medrol, Medrolone, Medroxyprogesterone acetate, Mefardin, Mefenamic acid, Mefenix, Mefentan, Mefrene, Mefnetra forte, Meftageic-DT, Mephthal, Megakaryocyte Growth and Differentiation Factor, Mega Pass, Megastar, Megestrol Acetate, Meite, Mexon, Melbrex, Melkham, Melkham, Melphram, Merrick, Melica, Merix, Melocam, Melocox, Mel-One, Meloprol, Melosteral, Melox, Meloxan, Meloxicam, Meloxic, Meloxicam , Meloxifene, meloxin, meloxib, melpred, melpros, merulzine, menamine, menisone, mensomketo, mensonewline, mentcin, mepa, mephalene, meprednisone, mepresso, mepsorone, mercaptopurine, mervan, mesadrone, mesalamine, mesasar, mesatec Leaf progenitor cells, mesenchymal stem cells, mesypol, mesulene, meslan, mesulide, methacin, metadaxane, metaflex, metal captor , Metalenzyme inhibitor, metapled, metax, metaz, meted, metedic, methacine, mesadrum, methazone, mesotrax, methotrexate, methotrexate sodium, mespread, methylprednisolone acetate, methyl salicylate, methylsulfonylmethane, methylone, methylpred, methyl Prednisolone, prednisolone methyl acetate, methylprednisolone sodium succinate, methylprednisolone succinate, methylprednisolone, methisole, methindole, metartate, metject, metrate, metral, methocin, mettabine, metracin, metrex, metronidazole methomethorex , Mevin SR, mexical, mexic farm, mexto, mek Stran, MF280, M-FasL, MHC class II β chain peptide, Micah, microphene, microfenac, microphenolatomofetil, mycosone, microdase, microRNA181a-2 oligonucleotide, MIF inhibitor, MIFQb, MIKA-ketoprofen, Micamethane, milodistim , Miltax, Minaphene, Minalfen, Minalfen, Minestrin, Minocoat, Myofrex, Myolocks, Miprofen, Milidacin, Mirlox, Misoclo, Misofenac, MISTB03, MISTB04, Michiro, Mizoribine, MK0359, MK0812, MK083, MK2M inhibitor , MK8808, MKC204, MLN0002, MLN0415, MLN1202, MLN2 3, MLN3126, MLN3701, MLN3897, MLNM002, MM093, MM7XX, MN8001, Mobikku, Mobikamu, Mobikokkusu, Mobi Fen plus, Mobirato, Mobichiru, Mokokkusu, Mojigurafu, Modorason, modulin, Mofe



Septo, mofetil, mofezolac sodium, mofillet, molase, morulamostim, molthride, momequin, momenguele, moment 100, momeson, momesun, mometamed, mometasone, mometasone furoate, monimate, alpha-luminol monosodium, mopic, MOR103, MOR104, MOR105, MOR208 antibody, MORAb022, Moricum, Morniflumate, Mosolito, Motral, Mobaxin, Mover, Movex, Mobix, Moboxicam, Moxforte, Moxene, Moxifloxacin hydrochloride, Mozovir, MP, MP0210, MP0270, MP1000, MP1031, MP196, MP435, MPA, mPGES-1 inhibitor, MPSS, MRX7EAT, MSL, MT203, T204, mTOR inhibitor, MTRX1011A, mucolase, multicoat, multistem, muramidase, muramidase, muramidase hydrochloride, muromonab-CD3, muslux, muspinyl, mutase, muvera, MX68, mycept, mycocell, mycocept, mycophenolate mofetilactavis, Mycophet, mycofit, mycolate, mycordosa, micomun, myconol, mycophenolate mofetil, mycophenolate sodium, mycophenolic acid, mycotil, myeloid progenitor cell, myfenax, myfetyl, mifotic, migraft, myocridine, myoclysin, miprodol, Mison, nab-cyclosporine, naventac, navigoximols, nabton, nabco, nabucox, nabufram, nabme , Nabumeton, Nabton, Nac Plus, Nacta, Nacton, Nadium, Naclofen SR, NAL1207, NAL1216, NAL1219, NAL1268, NAL8202, Narphon, Nargesin S, Namilumab, Namsafe, Nandrolone, Nanocoat, Nanogum, Nanosaw Malta crolimus, Napageln, Naprolac, Naplelan, Napro, Naprodil, Naproxil, Napropal, Naproson, Naprosin, Naproval, Naprox, Naproxen, Naproxen sodium, Naproxen, Naprozen, Narbon, Nalexin, Narryl, Nashida, Natalizumab, Naxidom, Naxene, Naxin, 300 , ND07, NDC01352, Nebumeton, NecLipGCSF, Nexlide, Nexuni , Nelcid-S, Neoclobenato, Neoswifox FC, Neocofuran, Neo-Drol, Neo-Eblimon, Neo-Hydro, Neoplanta, Neoporin, Neopreol, Neoprox, Neoral, Neotrexate, Neozen, Nepra, Nestacoat, Newmega , Newpogen, Newplex, Neurofenac, Neurogesic, Neurolab, Neuroterrador, Neuroxicam, New Tarin, Neutrazumab, Neuteam, New Parazox, New Fence Top, New Gum, New Mafen, New Matar, New Sicum , NEX1285, sFcRIIB, nextumab, NF-κB inhibitor, NF-kB inhibitor, NGD20001, NHP554B, NHP554P, NI0101 anti Body, NI0401, NI0501 antibody, NI0701, NI071, NI1201 antibody, NI1401, Nissip, Niconas, Nickle, Nicode, Nicox, Niflumart, Nigas, Nikham, Nilitis, Nimus, Nimide, Nimark-P, Nimmaz, Nimeset Juicy, Nime, Nimed, Nimespasto, Nimesulide, Nimesrix, Nimesulon, Nimikaplus, Nimukuru, Nimrin, Nimnut, Nimodor, Nimpidase, Nimside-S, Nimsar, Nimsea-SP, Nimpep, Nimsol, Nimtar, Nimwin, Nimbon-S, Nincoat, Niofen, Nipan Nipent, Nize, Nisoron, Nisopred, Nisoplex, Nislid, Nitazoxanide, Nitocon, Nitric Oxide, Nizubisal B, Nizone, NL, NMR1 47, NN8209, NN8210, NN8226, NN8555, NN8765, NN8765, NN8828, NNC014100000100, NNC051869, Noak, Nodevex, Nodia, Nofenac, Nofragma, Nofram, Noflamen, Noflux, Non-antibacterial tetracycline, Nonpyrone, Nopatrino, Norpatrito, Norpatrito , Novacoat, Novagento, Novaline, Novigen, NOXA12, NOXD19, Noxene, Noxon, NPI1302a-3, NPI1342, NPI1387, NPI1390, NPRCS1, NPRCS2, NPRCS3, NPRCS4, NPRCS5, NPRCS6, NPS3, NPS4, NPS3, NPS4, NPS3, NPS4 Sex factor NF-κ-Bp65 subunit oligo Nucleotides, Nuquats, Nulogics, Numed Plus, Nurokindo Ortho, Nuson-H, Nutrichemia, Nubion, NV07α, NX001, Niclobart, Niox, Niisa, Obacote, OC002417, OC2286, Okaratuzumab, OCTSG815, Oedemase D, Oedemase D O, Off Vista, OHR118, OKi, Okifen, Oxamen, Orai, Orokizumab, Omeprouse E, Omnicortyl, Omnide, Omniclo, Omnigel, Omniwell, Onercept, ONO4057, ONS1210, ONS1220, Ontack, ON14 OPN101, OPN201, OPN302, OPN305, O N401, Oprel Bekin, OPT66, Optifer, Optiflue, Optimira, Olabase Hca, Oradexon, Olafrex, Oralfenac, Oralog, Oral Pred, Ora-Sed, Olason, orBec, Orbonforte, Ocher, ORE10002, ORE10002, Orencia, Org 214007, Org 217993, Org 219517, Org 223119, Org 37663, Org 39141, Org 48762, Org 48775, Orgadrone, Ormoxen, Orofen Plus, Oromiraze Biogaran, Orsofol T, Orthofol T -II, Orthomac, Ortho-Pla , Ortinyms, orthophene, olgis, olbeil, OS2, oscat, osmeton, ospain, ossilife, osterox, osterac, osteothelin, osteopontin, osterelizumab, otipax, awning, ovasave, ox40 ligand antibody, oxa, oxagesic CB, oxalgin DP, oxaprozin, OXCQ, oxeno, oxyb MD, oxybut, oxicam, oxychlorin, oximal, oxynal, oxyphenbutazone, oxyphenbutazone, ozoralizumab, P13 peptide, P1639, P21, P2X7 antagonist, p38α inhibitor P38 antagonist, p38 MAP kinase inhibitor, p38αMAP kinase inhibitor, P7 peptide, P7170, P979, PA401, PA517, Pabi-Dexamethasone, PAC, PAC10649, Paclitaxel, Paynoxam, Pardon, Parima, Pamapimod, Pamatase, Panafucote, Panafcoteron, Panewin, Pangraph, Panimum Viral, Panmeson, Panodine SR, Panze Ray, Panzepanme, N , Papain, Papyrdin, Pappen K-Pup, Pappinim-D, Pankynimod, PAR2 antagonist, Paracetanol, Paradic, Parafen TAJ, Paramidin, Paranac, Parapar, Parsi, Parecoxib, Parixam, Parry-S, Partactobusulfan, Pateclizumab, Pax Seed, PBI0032, PBI1101, PBI1308, PBI1393, PBI160 , PBI1737, PBI2856, PBI4419, PBI4419, P-Cam, PCI31523, PCI32765, PCI34051, PCI45261, PCI45292, PCI45308, PD360324, PD360324, PDA001, PDE4 inhibitor, PDL2pe, PDL24 Pegacharistic, Peganics, Peg-interleukin 12, pegsnercept, pegsnercept, pegylated arginine deiminase, perdesin, perbiprofen, penacle, penicillamine, penostop, pentaargine, pentasa, pentaud, pentostatin, peon, peptidase, pepser, peptidase , Percutardin, perio , Peroxisome proliferator-activated receptor gamma modulator, peptidene, PF00344600, PF04171327, PF04236921, PF04308515, PF05230905, PF05280586, PF251802, PF3475952, PF491967, P5249996, P5249996, P5 PG27, PG562, PG760564, PG8395, PGE3935199, PGE527667, PH5, PH79804, PHA408, Farmania gamefenamic acid, Farmania gameroxicam, Ferdin, phenocept, phenylbutazone, PHY702, PI3Kδ Harmful agent, PI3Kγ / δ inhibitor, PI3K inhibitor, picarum, pidothymod, piketoprofen, pile life, pyropyr, pyrobert, pimecrolimus, pipetanen, pyractam, pyrexyl, pyrobet, pyrok, pyrocam, pyrofel, pyrogel, pyromed, pyrosol pirosol , Piroxen, Piroxicam, Piroxicam betadex, Piroxifer, Piroxyl, Piroxime, Pixim, Pixicaine, PKCθ inhibitor, PL3100, PL5100 Diclofenac, Placental polypeptide, Plaquinyl, Plerixafor, Procfen, PLR14, PLR18, Plutin, PL5633 PLX647, PLX-BMT, pms-diclofenac, pms-ibuprofen, pms-leflunomide, pm s-meloxicam, pms-piroxicam, pms-prednisolone, pms-sulfasalazine, pms-thiaprofenic, PMX53, PN0615, PN100, PN951, podophyllox, POL6326, polcortron, polyderm, polygum S / D, polyphlogin, ponsif, ponstan, pon Stilforte, Porin-A Neoral, Potava, Potassium aminobenzoate, Potencoat, Povidone, Povidone iodine, Pralunacasan, Pludin, Prevel, Precodyl, Precortisylforte, Precortil, Predfoam, Pregicoat, Prezicolten, Prezilab, Prezilon, Predmethyl , Predmix, Predna, Prednesol, Predni, Predni Calvert, Predni Coat, Prednijib Prednipharma, Prednisoska, Prednisolone, Deltacortolyl (Prednisolone), Prednisolone Acetate, Prednisolone Sodium Phosphate, Prednisolone Sodium Succinate, Prednisolone Sodium Succinate, Prednisone, Prednisone Acetate, Prednisotop, Prednol-L, Predox Predone, Prednema, Predol, Predsolone, Predson, Predval, Prefram, Prelon, Prenaxol, Prenolone, Preselbex, Preselvin, Presole, Preson, Plexigage, Priliximab, Primacoat, Primno, Primofenac, Plinaverel, Privisum, Proxil, Probyl Prokimal, Procida-EF, Proctocil, Prodase, Pro Le B, Purodento, pro dent Verde, Puroepa, Purofekomu, Purofenaku L, Purofenido, prophenoloxidase, Purofuramu, Pro Flex, Purogeshikku Z, proglumetacin, proglumetacin maleate, Prograf, Puroraze, Purorikisan,



Promethazine hydrochloride, Promostem, Promon, Prona B, Pronase, Pronut, Prongs, Pronison, Prontofram, Propadelm-L, Propodesas, Propolyzol, Proponol, Propylnicotinate, Prostalock, Prostapol, Protacin, Protase, Protease inhibitor , Protectan, proteinase-activated receptor 2 inhibitor, protophene, protorin, proxalioc, proxydol, proxygel, proxyl, proxyum, prozyme, PRT062070, PRT2607, PRTX100, PRTX200, PRX106, PRX167700, Prisolone, PS031291, PS375179 PS386113, PS540446, PS608504, PS826957, PS 73266, Solid, PT, PT17, PTL101, P-transport factor peptide, PTX3, Purminic, Prsonide, Prasen, Pursin, PVS40200, PX101, PX106491, PX114, PXS2000, PXS2076, PYM60001, Pyralbex, Pyranim, Pyrazinotapyram, Pirinobutacamone , Pyrodex, Piroxy-Kid, QAX576, Chiambombyan, QPI1002, QR440, qT3, Kiacoat, Kidophil, R107s, R125224, R1295, R132811, R1487, R1503, R1524, R1628, R333, R348, R548, R7277, R548, R7277 Radik Suisachijisu, Radfen, Leipec, Rambazole, Randazi , Rapacan, rapamune, raptiva, lavax, leios, RDEA119, RDEA436, RDP58, rarectin, leviv, REC200, recartics-DN, receptor for advanced glycation end product antibody, reclass, reclofen, recombinant HSA-TIMP-2, recombination Human alkaline phosphatase, recombinant interferon gamma, recombinant human alkaline phosphatase, leconyl, lectagel HC, rectisin, lectomenadelum, lectos, red bread, redlet, lefastin, regenica, REGN88, rerafen, relaxib, relev, relex, relifen, relicex, relic, Rematov, Remestem Cell-1, Remes Rhythm, Remicade ^{(Registered trademark)} (Infliximab), Remsima, Remsima, Remsima, ReN1869, Renasep, Renfor, Renodaput, Renodaput-S, Renta, Leosan, Repare-AR, Reparixin, Reparixin, Repataxin, Repispurin, Resokin, Resol, Resolvin E1, Rezurgil -Colloid, letoz, leucap, leuconcon, leumadrol, leumadol, leumanisal, leumadine, leumel, leumotec, leukinol, levamilast, revassecol, leviroc, levulinid, levomoxicum, lewalk, lexargan, RG2077, RG3421, RG4934R, RG7416R , Rheoma, Leprox, Rüdenolone, Rüfen, Rügesic, Rheumaside, Re Romatolex, Rheumatrex, Ryumesa, Ryumid, Roymon, Loimox, Ryuoxib, Ryurin, Ryushin, Ludex, Ryuref, Rebox, Ribunal, Ridaura, Rifaximin, Rilonacept, Rimacarib, Rimase, Remate, Rimatil, Limecid, Risedronate Sodium, Ritamin Rito, Rituxan, Rituximab, RNS60, RO1133842, Ro313948, RO3244794, RO5310074, Rob803, Rocamix, Rocas, Rofeb, Rofecoxib, Loffee, Rofewal, Rofiship Plus, Rojepen, Rocam, Lolociquim, Romacox fort Ronaben, Ronacarelet, Ronoxycin, RORγT antagonist, R ORγt inverse agonist, rosecin, rosiglitazone, rosmarinic acid, rotan, rotec, rosacin, loxam, roxib, roxicam, loxopro, roxidine DT, RP54745, RPI78, RPI78M, RPI78MN, RPIMN, RQ00000007, RQ00000008, RTA402, R-Chim , Rubifen, Lumapap, Lumaref, Lumidol, Lumifen, Lunomex, Rusarachid acetate, Loxoritinib, RWJ445380, RX10001, Lycloser MR, Rideol, S1P receptor agonist, S1P receptor modulator, S1P1 agonist, S1P1 receptor agonist, S2474, S3013 , SA237, SA6541, Saazu, S-adenosyl-L-methionine- Rufate-p-toluenesulfonate, sara, salazidin, salazine, salazopyrine, sarcon, salicum, salsalate, samron, SAN300, sanaven, sandymun, sandglobulin, sanexon, sansiya, SAR153191, SAR302503, SAR479746, sarapep, sargramoptim , Savantac, Save, Succinosone, Sazo, SB1578, SB210396, SB217969, SB242235, SB273005, SB281832, SB683698, SB751689, SBI087, SC080036, SC12267, SC409, SCF3, SD46 , Sd- rxRNA, secukinumab, cedase, sedillax, cefden, sezyme, SEL113, cerazine, celecox, selectin P ligand antibody, glucocorticoid receptor agonist, selectfen, selectin, SelK1 antibody, selox, cell spot, cellzen, cellzenta, cellzentry, semapimod , Semapimod hydrochloride, semparatide, semparatide, senaphene, sendipene, centeric, SEP 119249, sepdase, septylose, seractyl, seraphen-P, serase, seratide D, seratiopeptidase, serato-M, seratoforte, cerazyme, cerezon, cello, cellodase , Serpicum, Sera, Serrapeptase, Seratin, Seratathiopeptidase, Serrazyme, Serbizon, Seven EP , SGI1252, SGN30, SGN70, SGX203, Shark cartilage extract, Cheryl, Shield, Sifazen, Schiffazen-Fault, Thincoat, Thincoat, Siozole, ShK186, Schwann Houenshoien, SI615, SI636, Sigmasporin, Sigmasporin, SIM916, Simpon, Simlect, Sinacote, Sinargia, Sinapol, Sinatrol, Cynthia, Siponimod, Sirolim, Sirolimus, Shiropan, Shirota, Shiroba, Sirumab, Sistalforte, SKF105685, SKF105809, SKF106615, SKF86002, Skinner, Skinim Family SL7 Slo-India, SM101, SM201 antibody, SM401, SMAD Lee Member 7 oligonucleotide, SMART anti-IL-12 antibody, SMP114, SNO030908, SNO070131, gold thiomalate, sodium chondroitin sulfate, deoxyribonucleotide sodium, guarenato sodium, naproxen sodium, sodium salicylate, sodixene, sopheo, soleton, solhydrol, Solikam, Soriki, Soliris, Sol Melcourt, Solomet, Solond, Solon, Sol-Cort, Sol-Coeff, Sol-Decortin H, Solfen, Sol-Ket, Solmark, Sol-Medolol, Solpred, Somargen, Somatropin, Sonap, Son Sonepizumab, Sonexa, Sonim, Sonim P, Sunil, Solar, Solenyl, Sotrastaurine Acetate, P-10, SP600125, Spanidine, SP-Cortil, SPD550, Spedes, Sperm adhesion molecule 1, Spiktor, Spleen tyrosine kinase oligonucleotide, Sporin, S-purine, SPWF1501, SQ641, SQ922, SR318B, SR9025, SRT2104, SSR150106, SSR180575 , SSS07 antibody, ST1959, STA5326, stabilin 1 antibody, stacote, stalogetic, stanozolol, stalen, starmelox, stedex IND-SWIFT, stellara, stemin, stenilol, stellapred, steridem S, sterio, sterisone, sterone, stadiotactichira peptide , Stick Zenol A, Chief Coach, Mulan, STNM01, Store Sensitive Calcium Channel (SOCC) Modulator, STP432, STP900, Stratacin, Stridimun, Strigraph, SU Medrol, Subleum, Subton, Succito, Succimed, Sulan, Sulcolone, Sulfasalazine Hale, Sulfasalazine, Sulfasalazine, Sulfid, Suidac , Slid, Sulindac, Slindex, Slington, Sulfafine, Smir, SUN597, Sprafen, Spretic, Spsidine, Sulgam, Sulgamin, Sulgam, Suspen, Stone, Svenir, Sway, SW Dexason, Syk family kinase inhibitor, Syn1002, Sinaclan, Synaxen, Sinara C, Sinara, Shinavib, Shinel Coat, Sipresta, T Cellular cytokine-inducible surface molecule antibody, T cell receptor antibody, T5224, T5226, TA101, TA112, TA383, TA5433, tatalumab, tasedin, tactograph, TACIFc5, taclobell, tacrograph, tacrol, tacrolimus, tadecinig α, tadrac, TAFA93, toffy Roll Altoro, Taizen, TAK603, TAK715, TAK783, Takufa, Takusta, Talarosol, Talphine, Talmine, Talmapimod, Talmere, Tarnif, Talniflumate, Talos, Talpine, Talmat, Tamalgen, Tamseton, Tamaison, Tandorel, Tannin, Tanocinto, Tantam, Tandiceltiv, Tapain-β, Tapoein, Talenac, Talenflurvir, Talimus, Tarproxen, Tau Kib, Tazomusto, TBR652, TC5619, T cell, immune modulator 1, ATPase, H + transport, lysosomal V0 subunit A3 antibody, TCK1, T-coat, T-dexa, teselac, taekwon, teduglutide, tea coat, teguerin, Tementil, Temoporphine, Tencam, Tendron, Tenefuse, Tenfry, Tenidap sodium, Tenocum, Tenofflex, Tenoxan, Tennotyl, Tenoxicam, Tenoxime, Tepadina, Terracoat, Terador, Tetomilast, TG0054, TG1060, TG20, TG20, tgTAH94 Cytokine synthase inhibitor, Th-17 cell inhibitor, thalidomide, thalidomide, salomide, semicera, tenil, terafectin, serapiace, tiarabin, Azolopyrimidine, thioctic acid, thiotepa, THR090717, THR0921, sulinophene, thrombate III, thymus peptide, thymodepressin, thymogam, Thymoglobulin, thyroglobulin, thymojectthymic peptide, thymomodulin, thymopentine, thymopolypeptide, iotaprofenic acid Tibezonium, Ticoflex, Tilmacoxib, Tilua, T-Immun, Thymocon, Thiolase, Tissop, TKB662, TL011, TLR4 antagonist, TLR8 inhibitor, TM120, TM400, TMX302, TNFα inhibitor, TNFα-TNF receptor antagonist, TNF antibody , TNF receptor superfamily antagonist, TNF TWEAK bispecificity, TNF-quinoid, T NFQb, TNFR1 antagonist, TNR001, TNX100, TNX224, TNX336, TNX558, tocilizumab, tofacitinib, tokhonhap, TOL101, TOL102, lectin, trelimumab, trerostem, trinidol, toll-like receptor 4 antibody, tol



l-like receptor antibody, tolmetin sodium, tong keeper, tommex, top frame, topicot, toprocon, topnac, toppin iktamol, tralizumab, tollane, tuxia, tolox, tory, tocerac, totaryl, touch-med, touchlon, toboku , Toxic Apis, Toyolizome, TP4179, TPCA1, TPI526, TR14035, Trasilfort, Trafiset-EN, Tramace, tramadol hydrochloride, tranilast, trancimon, transpolyna, tratul, trexal, triacote, triacote, trialon, triam, triamcinolone , Triamcinolone acetate, triamcinolone acetonide, triamcinolone acetonide acetate, triamcinolone hexaacetonide, Amcourt, Triamcicote, Trianex, Tricine, Tricote, Tricolton, TricOs T, Triderm, Trilac, Trilysate, Trincote, Trinolone, Triolex, Triptolide, Trisphene, Trivaris, TRK170, TRK530, Trocard, Thorolbyl salicylate, Torobol, ToroCera, ToroCera D, Troycoat, TRX1 antibody, TRX4, Trimoto, Trimoto-A, TT301, TT302, TT32, TT32, TT33, TTI314, Tumor necrosis factor, Tumor necrosis factor 2-methoxyethyl phosphorothioate oligonucleotide, Tumor Necrosis factor antibody, tumor necrosis factor quinoid, tumor necrosis factor oligonucleotide, tumor necrosis factor receptor superfamily member 1B antibody, tumor necrosis factor receptor Body superfamily 1B oligonucleotide, tumor necrosis factor superfamily member 12 antibody, tumor necrosis factor superfamily member 4 antibody, tumor protein p53 oligonucleotide, tumor necrosis factor α antibody, TuNEX, TXA127, TX-RAD, TYK2 inhibitor, Thai Sabri , Ubidecarenone, Ucellase, Urodecin, Ultiflam, Ultrafastin, Ultrafen, Ultralan, U-Nice-B, Uniplus, Unitrexate, Unizen, Ufaxicam, UR13870, UR5269, UR67767, Uremol-HC, Urigon, U-Richis, Ustekinumab , V85546, Balsibu, Balcox, Valdecoxib, Valdez, Valdicks, Baldi, Valentuck, Baroxib, Balti Tune, bals AT, bals, balzel, bamide, vantal, vantelin, VAP-1 SSAO inhibitor, bapariximab, valesprazib methyl, varicosin, validase, vascular adhesion protein-1 antibody, VB110, VB120, VB201, VBY285, vector P, vedolizumab, befrene, VEGFR-1 antibody, verdona, veltuzumab, bendexin, benimmum N, benoforte, benoglobulin-IH, benozel, veral, verax, versimon, belo-dexamethasone, belo-clavribine, betazone, VGX1027, VGX750 MTX, Bidofludimus, Bifenac, Bimobo, Bimurchisa, Bincourt, Bingraph, Bioform-HC, Bioxyl, Viox, Virobron, Vizilizumab, Viva Globin, Vivaldeplus, Vivian-A, VLST002, VLST003, VLST004, VLST005, VLST007, Boala, Voclosporin, Bocam, Bokumore, Volmax, Borna-K, Voltadol, Voltagesic, Voltanase, Voltanek, Voltaren, Voltaren, Voltaren , Button-SR, VR909, VRA002, VRP1008, VRS826, VRS826, VT111, VT214, VT224, VT310, VT346, VT362, VTX763, Vurdon, VX30 antibody, VX467, VX5, VX509, VX702, X7, VX702, X7 W54011, Wallacoat, Warix, WC3027, Willgraph, Win Lamb, Winmol, Winred, Winsorb, Wingeno, WIP901, Woncox, WSB711 antibody, WSB712 antibody, WSB735, WSB961, X071NAB, X083NAB, xanthomicin forte, xedenol, xeffo, xejocam, xenal, xepram, x-flame , Xycam, xycotyl, xyfaxane, XL499, XmAb5483, XmAb5485, XmAb5574, XmAb5871, XOMA052, Xpress, XPro1595, XtendTNF, XToll, Xtra, Xylex-H, xinophen SR, Yansh-IVIG, YH14 Yuma, Yumerol, Yuroben, YY Piroxicam Z104657A, Zashi, Zaltokin, Zaltoprofen, Zap70 inhibitor, Jepine, Zeroximfort, Zema-Pak, Zempak, Zempred, Zenapax, Zenas, Zenol, Xenos, Xenoxone, Zerax, Zerocam, Zerospasm, ZFNs, Zinc oxide, Ripoma dipsaw , Ditis, Zix-S, zocoat, zodixium, zoftadex, zoledronic acid, solfin, zolterol, zopyrine, zolarone, solpurin, zoltres, ZP1848, zcapsaicin, zunobate, zwitterionic polysaccharide, ZY1400, dibodies, zysel, dilofen, Dilogen inhibitors, Zysel, Zytrim, and Bitzywin-Forte are included. In addition, the anti-inflammatory agents listed above may be combined with one or more of the agents listed above or herein or other agents known in the art.

  In one embodiment, the drug is a drug that inhibits, decreases or modulates PDGF-receptor (PDGFR) signaling and / or activity. For example, for the treatment of one or more posterior eye disorders such as macular edema associated with uveitis (eg, non-infectious uveitis), macular edema associated with RVO, or wet AMD The PDGF antagonist delivered to the choroidal space is, in one embodiment, an anti-PDGF aptamer, an anti-PDGF antibody or fragment thereof, an anti-PDGFR antibody or fragment thereof, or a small molecule antagonist. In one embodiment, the PDGF antagonist is an antagonist of PDGFRα or PDGFRβ. In one embodiment, the PDGF antagonist is anti-PDGF-β aptamer E10030, dasatinib, sunitinib, axitinib, sorafenib, imatinib, imatinib mesylate, nintedanib, pazopanib HCl, ponatinib, MK-2461, cazopanib, 121, teratinib, imatinib, KRN633, CP673451, TSU-68 (orantinib), Ki8751, ambatinib, tivozanib, masitinib, motesanib diphosphate, dobitinib, dobitinib dilactic acid, FOVISTA, or rifanib 86 (AB-86). As described herein, in one embodiment, a PDGF antagonist, eg, one of the PDGF antagonists described above, is associated with uveitis associated macular edema, RVO, via SCS administration. Can be used in a method for treating macular edema associated with, wet AMD associated with CN, CNV, wet AMD associated with RVO, or wet AMD associated with CNV. Further, in some embodiments, the PDGF antagonist is administered intravitreally in conjunction with SCS-administered aflibercept in a method of treating one of the aforementioned indications.

  In a further embodiment, the PDGF antagonist also has VEGF antagonist activity. For example, anti-VEGF / PDGF-B darpin, dasatinib, dobitinib, Ki8751, teratinib, TSU-68 (orantinib) or motesanib diphosphate are known inhibitors of both VEGF and PDGF, It can be used in the described method. Dual PDGF / VEGF antagonists can also be administered intravitreally in conjunction with non-surgical delivery of aflibercept to the SCS.

Examples of other suitable drugs for use with the devices and methods described herein include, but are not limited to, A0003, A36 peptide, AAV2-sFLT01, ACE041, ACU02, ACU3223, ACU4429, AdPEDF, Aflibercept, AG13958, Aganilsen, AGN150998, AGN745, AL39324, AL78898A, AL8309B, ALN-VEG01, Alprostadil, AM1101, Amyloid β antibody, Anecortab acetate, Anti-VEGFR-2 Alterase, Aptosine, APX003, ARC1905R , ATG3, ATP binding cassette, subfamily A, member 4 gene, ATXS10, visdine-containing Avastin, AVT101, VT2, bertilimumab, verteporfin-containing bevacizumab, bevaciranib sodium, ranibizumab-containing bevaciranib sodium, brimonidine tartrate, BVA301, canakinumab, Cand5, Lucentis-containing Cand5, CERE140, ciliary neurotrophic factor, CLT009, CNTO2476 collagen Monoclonal antibody, complement component 5 aptamer (pegylated), ranibizumab-containing complement component 5 aptamer (pegylated), complement component C3, complement factor B antibody, complement factor D antibody, lutein, vitamin C, vitamin E, And zinc oxide-containing copper oxide, darantelcept, DE109, bevacizumab, ranibizumab, triamcinolone, triamcinolone acetonide, verteporfin-containing triamcinolone acetonide, dexamethasone Dexamethasone containing ranibizumab and verteporfin, dicitertide, DNA damage-inducing transcript 4 oligonucleotide, E10030, Lucentis-containing E10030, EC400, eculizumab, EGP, EHT204, embryonic stem cell, human stem cell, endoglin monoclonal antibody, EphB4 RTK Inhibitor, EphB4 soluble receptor, ESBA1008, ETX6991, Ebison, Iver, iPromisive, Ivi, Eire, F200, FCFD4514S, fenretinide, fluocinolone acetonide, ranibizumab-containing fluocinolone acetonide, fms related tyrosine kinase 1 oligo Nucleotide, kinase insert domain receptor 169-containing fms-related tyrosine kinase 1 oligonucleotide, phos Bretablin tromethamine, gumnex, GEM220, GS101, GSK933737, HC31496, human n-CoDeR, HYB676, ranibizumab-containing IBI-20089 (Lucentis ^{(registered trademark)} ), iCo-008, icon 1, I-gold, Ilaris, Irbien, Lucentis-containing irbiene, immunoglobulin, integrin α5β1 immunoglobulin fragment, integrin inhibitor, IRIS lutein, I-sense occ shield, isonep, isopropyl unoprostone, JPE1375, JSM6427, KH902, Lentiview, LFG316, LP590, LPO1010AM, Lucentis, Bisdyne-containing Lucentis, lutein extra, myrtillus extract-containing lutein, zeaxa Ntin-containing lutein, M200, Lucentis-containing M200, McGen, MC1101, MCT355, mecamylamine, microplasmin, motexafin lutetium, MP0112, NADPH oxidase inhibitor, Eterna shark cartilage extract (Arsulovas ^™ , Neoletna ^™ , Sobascal ^™ ), Neurotrophin 4 genes, Nova21012, Nova21013, NT501, NT503, Nutri-Stulln, Ocriplasmin, OcuXan, Oftanmakula, optrin, bevacizumab-containing ORA102 (Avastin ^{(registered trademark)} ), P144, P17, Paromid 529, PAN90806, Panze, Zeum PARP inhibitor, pazopanib hydrochloride, pegaptanib sodium, PF4523655, PG1 047, pyrivezil, platelet-derived growth factor β polypeptide aptamer (PEGylated), ranibizumab-containing platelet-derived growth factor β polypeptide aptamer (PEGylated), PLG101, PMX20005, PMX53, POT4, PRS055, PTK787, ranibizumab, triamcinolone acetonide Ranibizumab, verteporfin-containing ranibizumab, borociximab-containing ranibizumab, RD27, rescula, retane, retinal pigment epithelial cells, retinostat, RG7417, RN6G, RT101, RTU007, SB267268, serpin peptidase inhibitor, clade F membrane 1 gene, shark cartilage extract 1 , Shef1, SIR1046, SIR1076, Sirna027, Sirolimus, SMTD004, Snellbit, SOD mimic Soliris, Sonepizumab, Squalamine Lactate, ST602, StarGen, T2TrpRS, TA106, Taraporfin Sodium, Tauroursodeoxycholic Acid, TG100801, TKI, TLCx99, TRC093, TRC105, Tribasal Lettered, TT30, Ursa, Ursodiol, Bangiolax , VAR10200, Vascular Endothelial Growth Factor Antibody, Vascular Endothelial Growth Factor B, Vascular Endothelial Growth Factor Quinoid, Vascular Endothelial Growth Factor Oligonucleotide, VAST Compound, Batalanib, VEGF Antagonist (eg, described herein), Verteporfin, Visdyne , Bisdyne containing Lucentis and Dexamethasone, Bisdyne containing triamcinolone acetonide, Bibis, Boroxiximab, Votrient XV615, zeaxanthin, ZFPTF, zinc - mono cysteine, and Zai shake stat. In one embodiment, one or more of the drugs described above is one or more of the agents listed above or herein or other agents known in the art. Combined with.

In one embodiment, the drug, pirfenidone containing interferon gamma lb (activate mu emissions ^{(registered trademark)),} ACUHTR028, αVβ5, potassium aminobenzoate, amyloid P, ANG1122, ANG1170, ANG3062, ANG3281, ANG3298, ANG4011, anti CTGFRNAi, aplidine, Eurasian extract containing salvia and ginseng, atheroma blocker, azole, AZX100, BB3, connective tissue growth factor antibody, CT140, danazol, esbriette, EXC001, EXC002, EXC003, EXC004, EXC005, F647, FG3019, Fibro , Follistatin, FT011, galectin-3 inhibitor, GKT137831, GMCT01, GMCT 2, GRMD01, GRMD02, GRN510, heberon alpha R, interferon alpha-2b, pirfenidone-containing interferon gamma-1b, ITMN520, JKB119, JKB121, JKB122, KRX168, LPA1 receptor antagonist, MGN4220, MIA2, microRNA29a oligonucleotide, MMI0a oligonucleotide , Noscapine, PBI4050, PBI4419, PDGFR inhibitor, PF-066473871, PGN0052, Pirrespa, Pirfenex, Pirfenidone, Plitidepsin, PRM151, Px102, PYN17, PYN17-containing PYN22, Relibergen, rhPTX109 fusion protein RX -Β inhibitor, transforming agent Factor, beta receptor 2 oligonucleotides, VA999260, or XV615. In one embodiment, one or more of the drugs for treating macular edema associated with uveitis described above is one or more of those listed above or herein. In combination with more agents or other agents known in the art.

  In one embodiment, a drug that treats, prevents, and / or ameliorates 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, sodium bevacilanib, Cand5, choline fenofibrate, corject, c-raf2-methoxyethyl phosphorothioate oligonucleotide, DE109, dexamethasone, DNA damage inducing transcript 4 oligo Nucleotide, FOV2304, iCo007, KH902, MP0112, NCX434, Optina, Ozuldex, PF4523655, SAR1118, sirolimus, SK0503, or trilipix. In one embodiment, one or more of the above-described drugs for treating diabetic macular edema is one or more of the agents listed above or herein or in the field In combination with other agents known in the art.

  In one embodiment, the methods and devices provided herein are associated with uveitis (eg, non-infectious uveitis), macular edema associated with uveitis, wet AMD, CNV, RVO To treat wet AMD, or wet AMD associated with CNV, triamcinolone or triamcinolone acetonide is used to deliver to the choroidal space of the eye of a human subject in need of treatment. In another embodiment, triamcinolone or triamcinolone acetonide is delivered via one of the methods described herein.

  In one embodiment, the therapeutic formulation comprises a suspension of cells, eg, a suspension of retinal stem cells. In one embodiment, a suspension of neural stem cells (NSC) is administered to the SCS via one of the devices and / or methods provided herein. NSCs are self-replicating pluripotent cells that can differentiate into the major cellular phenotypes of the nervous system. They have been isolated from adult mammalian brain tissue, including humans. In one embodiment, a suspension of retinal stem cells (RSC) is administered to the SCS via one of the devices and / or methods provided herein. Early in development, retinal stem cells (RSCs) are a potent donor source that produces all retinal cell types. These cells can be isolated, expanded, and differentiated into retinal neurons by culturing these cells in the presence of growth factors such as epidermal growth factor and fibroblast growth factor. In yet another embodiment, a suspension of adult stem cells or mesenchymal stem cells (MSCs) of a patient in need thereof via one of the devices and / or methods provided herein. Administered to SCS. Other cell types adapted for administration via the devices and methods provided herein include, but are not limited to, hematopoietic stem cells (HSC), human embryonic stem cells (hESC), retinal progenitor cells, endothelial progenitor cells Cells or combinations thereof are included.

  In one embodiment, Arch Ophthalmol. 2004; 122 (4): 621-627 (for all purposes, one or more of the stem cells described herein is incorporated herein by reference in its entirety). Delivered to the patient via the device or method described in the document.

  A “therapeutic formulation” delivered via the methods and devices provided herein, in one embodiment, is an aqueous solution or suspension, which is an effective amount of a drug or therapeutic agent, eg, a cell. Provide suspension. In some embodiments, the therapeutic formulation is a fluid drug formulation. A “drug formulation” is a drug formulation, which typically includes one or more pharmaceutically acceptable excipient materials known in the art. The term “excipient” refers to any inactive ingredient of the formulation intended to facilitate handling, stability, dispersibility, wettability, release rate, and / or drug injection. In one embodiment, the excipient may comprise or consist of water or saline.

  Uveitis (eg, non-infectious uveitis), macular edema associated with uveitis (eg, non-infectious uveitis), wet AMD, CNV, wet AMD associated with RVO, or CNV A therapeutic formulation delivered to the suprachoroidal space of a human subject's eye for treatment of associated wet AMD is a liquid drug, a solution containing the drug or therapeutic agent in an appropriate solvent, or a liquid suspension It can be in form. Liquid suspensions may include microparticles or nanoparticles dispersed in a suitable liquid vehicle for injection. In various embodiments, the drug is contained within a liquid vehicle, microparticle or nanoparticle, or both vehicle and particle. The drug formulation is sufficient fluid to flow into and within the suprachoroidal space and into the surrounding posterior ocular tissue. In one embodiment, the viscosity of the fluid drug formulation is about 1 cP at 37 ° C.

In one embodiment, the drug formulation (eg, fluid drug formulation) includes microparticles or nanoparticles, either of which includes at least one drug. Desirably, the microparticles or nanoparticles provide controlled release of the drug into the suprachoroidal space and surrounding posterior ocular tissue. As used herein, the term “microparticle” includes microspheres, microcapsules, microparticles, and beads, from about 1 μm to about 100 μm, such as from about 1 to about 25 μm or from about 1 μm to about It has a number average diameter of 7 μm. A “nanoparticle” is a particle having an average diameter of about 1 nm to about 1000 nm. The microparticles, in one embodiment, have a D ₅₀ of about 3 μm or less. In a further embodiment, D ₅₀ is about 2 μm. In another embodiment, the D ₅₀ of the particles in the drug formulation is about 2 μm or less. In another embodiment, the D ₅₀ of the particles in the drug formulation is about 1000 nm or less. In one embodiment, the drug formulation comprises microparticles having a D ₉₉ of about 10 μm or less. The microparticles, in one embodiment, have a D ₅₀ of about 3 μm or less. In a further embodiment, D ₅₀ is about 2 μm. In another embodiment, the D ₅₀ of the particles in the drug formulation is about 2 μm or less. In another embodiment, the D ₅₀ of the particles in the drug formulation is about 1000 nm or less. In one embodiment, the drug formulation comprises microparticles having a D ₉₉ of about 10 μm or less. The microparticles, in one embodiment, have a D ₅₀ of about 3 μm or less. In a further embodiment, D ₅₀ is about 2 μm. In another embodiment, the D ₅₀ of the particles in the drug formulation is about 2 μm or less. In another embodiment, _{D 50} of the particles in the drug formulation is about 100nm~ about 1000 nm. In one embodiment, the drug formulation comprises microparticles having a D ₉₉ of about 1000 nm to about 10 μm. The microparticles, in one embodiment, have a D ₅₀ of about 1 μm to about 5 μm or less. In another embodiment, the drug formulation comprises particles having a D ₉₉ of about 10 μm. In another embodiment, _{D 99} of the particles in the formulation is less than about 10 [mu] m, or less than about 9 .mu.m, or less than about 7 [mu] m, or less than about 3 [mu] m. In a further embodiment, the microparticle or nanoparticle comprises an anti-inflammatory agent. In a further embodiment, the anti-inflammatory drug is triamcinolone.

  Microparticles and nanoparticles may or may not be spherical. “Microcapsules” and “nanocapsules” are defined as microparticles and nanoparticles whose outer shell surrounds a core of another material. The core can be a liquid, gel, solid, gas, or a combination thereof. In some cases, a microcapsule or nanocapsule has a “microbubble” or “wherein the outer shell surrounds a gas core and the drug is placed on the surface of the shell, within the shell itself, or in the core. (Microbubbles and nanobubbles are responsive to acoustic vibrations known in the art for diagnostics, or rupture the microbubbles to load it into / in the selected ocular tissue site "Microspheres" and "nanospheres" are porous, sponge or honeycomb structures formed by pores or voids in a matrix material or shell, which can be solid spheres. A plurality of discrete voids can be included in the matrix material or shell. The microparticle or nanoparticle may further comprise a matrix material. The shell or matrix material may be a polymer, amino acid, saccharide, or other material known in the art of microencapsulation.

  Drug-containing microparticles or nanoparticles may be suspended in an aqueous or non-aqueous liquid vehicle. The liquid vehicle may be a pharmaceutically acceptable aqueous solution and optionally further comprise a surfactant. The microparticles or nanoparticles of the drug itself may include excipient materials such as polymers, polysaccharides, surfactants, etc. that are known in the art to control the rate of drug release from the particles.

  In one embodiment, the drug formulation further comprises an agent effective to degrade collagen or GAG fibers in the sclera, which may improve drug penetration / release into the ocular tissue. The agent may be an enzyme such as, for example, hyaluronidase, collagenase, or combinations thereof. In a variation of the method, the enzyme is administered to the ocular tissue in a separate step before or after drug injection. The enzyme and drug are administered at the same site.

  In another embodiment, the drug formulation undergoes a phase change upon administration. For example, a liquid drug formulation may be injected through the hollow microneedle into the suprachoroidal space, which then gels and the drug diffuses out of the gel for controlled release.

  The therapeutic agent is, in one embodiment, formulated with one or more polymer excipients to limit therapeutic agent transfer and / or increase the viscosity of the formulation. The polymer excipient may be selected and formulated to act as a viscous gel-like material in situ, thereby diffusing into the region of the suprachoroidal space and uniformly dispersing and retaining the drug. The polymer excipient is, in one embodiment, selected and formulated to provide appropriate viscosity, flow, and solubility properties. For example, carboxymethylcellulose is used in one embodiment to form a gel material in the superior choroidal space. The viscosity of the polymer, in one embodiment, is improved by appropriate chemical modifications to the polymer that increase association properties such as the addition of hydrophobic moieties, selection of higher molecular weight polymers, or formulations with appropriate surfactants. Is done.

  The solubility properties of the therapeutic formulation, in one embodiment, allow the water solubility, molecular weight, and concentration of the polymer excipient to be adequately tuned to allow both delivery through a small gauge needle and localization in the suprachoroidal space. It is adjusted by adjusting to the denaturation range. The polymeric excipient may be formulated to increase viscosity or crosslink after delivery to further limit the migration or dissolution of the material and the incorporated drug.

  An aqueous solution that is physiologically compatible and suitable for use as a polymeric excipient in the therapeutic formulations described herein and for delivery via the methods and devices described herein. Examples of the functional polymer include, but are not limited to, synthetic polymers (such as polyvinyl alcohol, polyvinyl pyrrolidone, polyethylene glycol, polyethylene oxide, polyhydroxyethyl methacrylate, polypropylene glycol, and propylene oxide), and biopolymers (cellulose derivatives, chitin derivatives). , Alginates, gelatin, starch derivatives, hyaluronic acid, chondroitin sulfate, dermatan sulfate, and other glycosaminoglycans), and mixtures or copolymers of such polymers. The polymer excipient is, in one embodiment, selected so that it can dissolve for a long period of time at a rate controlled by the concentration, molecular weight, water solubility, crosslinking, enzyme instability, and tissue adhesion of the polymer.

  In one embodiment, the viscosity modifier is present in a therapeutic formulation delivered by one of the methods and / or devices described herein. In further embodiments, the viscosity modifier is polyvinyl alcohol, polyvinyl pyrrolidone, methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose, or hydroxypropyl cellulose. In another embodiment, the formulation comprises a gelling agent such as poly (hydroxymethyl methacrylate), poly (N-vinyl pyrrolidone), polyvinyl alcohol, or an acrylic acid polymer such as carbopol.

  In one embodiment, the therapeutic formulation is delivered as a liposomal formulation via one of the methods and / or devices described herein.

  Liposomes can be produced by a variety of methods. Bangham's procedure (J. Mol. Biol., J Mol Biol. 13 (1): 238-52, 1965) produces normal multilamellar vesicles (MLV). Lenk et al. (US Pat. Nos. 4,522,803, 5,030,453, and 5,169,637), Fountain et al. (US Pat. No. 4,588,578), and Cullis et al. (US Pat. No. 4,975,282) discloses a method for producing multilamellar liposomes in which the distribution of interlaminar solutes in each aqueous compartment is substantially equal. Paphadjopoulos et al. U.S. Pat. No. 4,235,871 discloses the preparation of oligolamellar liposomes by reverse phase evaporation. Each patent reference in this paragraph is incorporated herein by reference in its entirety for all purposes.

  In one embodiment, the liposomal formulation comprises a phospholipid. In a further embodiment, the liposomal formulation comprises a sterol, such as cholesterol.

  In another embodiment, the liposomal formulation comprises a single lamellar vesicle. Single lamellar vesicles have been described in several techniques, for example, Cullis et al. (US Pat. No. 5,008,050) and Loughley et al. (US Pat. No. 5,059,421) can be produced from MLV by extrusion. Sonication and homogenization can be used to generate smaller unilamellar liposomes from larger liposomes (eg, Paphadjopoulos et al., Biochim. Biophys. Acta., 135: 624-638, 1967). Deamer, U.S. Pat. No. 4,515,736; and Chapman et al., Liposome Technol., 1984, pp. 1-18). A review of these and other methods of liposome production can be found in the literature Liposomes, Marc Ostro, ed. , Marcel Dekker, Inc. , New York, 1983, Chapter 1, the relevant portions of which are incorporated herein by reference. In addition, Szoka, Jr. et al. (1980, Ann. Rev. Biophys. Bioeng., 9: 467). Each document in this paragraph is hereby incorporated by reference in its entirety for all purposes.

  As described above, for example, drugs delivered to the suprachoroidal space via the methods described herein to treat macular edema associated with uveitis or macular edema associated with RVO The formulation can be administered with one or more additional drugs. One or more additional drugs, in one embodiment, are present in the same formulation as the initial drug formulation. In another embodiment, one or more additional drugs are present in the second formulation. In further embodiments, the second drug formulation is delivered to a patient in need thereof via the non-surgical SCS delivery method described herein. Alternatively, the second drug formulation is associated with macular edema or RVO associated with uveitis in the vitreous, in the anterior chamber, subtenon, orally, locally, or parenterally. Delivered to a human subject in need of treatment for macular edema. In one embodiment, the VEGF antagonist is associated with macular edema or RVO associated with uveitis via one of the methods and / or devices disclosed herein in combination with an anti-inflammatory compound. Delivered to the upper choroidal space of the eye of a human subject in need of treatment for macular edema. In some embodiments, the drug formulation comprises aflibercept.

As explained above, in addition to suprachoroidal delivery, one or more additional drugs delivered to a human subject may be administered intravitreally (IVT) (eg, intravitreal injection, intravitreal implants, or eye drops). Drug). Methods of IVT administration are well known in the art. Examples of classes of drugs that can be administered via IVT include, but are not limited to, VEGF modulators, PDGF modulators, anti-inflammatory drugs. Examples of drugs that can be administered via IVT include, but are not limited to, A0003, A0006, acedron, AdPEDF, aflibercept, AG13958, aganylsen, AGN208397, AKB9778, AL78898A, amyloid P, angiogenesis inhibition Drug gene therapy, ARC1905, Aurocoat, sodium bevacilanib, brimonidine, brimonidine, brimonidine tartrate, sodium bromfenac, Cand5, CRE140, ciganclo, CLT001, CLT003, CLT004, CLT005, complement component 5 aptamer (pegylated), Complement factor D antibody, cortiject, c-raf2-methoxyethyl phosphorothioate oligonucleotide, cyclosporine, triamcinolone, DE109, denufoso Tetrasodium, dexamethasone, dexamethasone phosphate, dicitertide, DNA damage-inducing transcript 4 oligonucleotide, E10030, ecarantide, EG3306, Eos013, ESBA1008, ESBA105, Eirea, FCFD4514S, fluocinolone acetonide, fms-related tyrosine kinase 1 oligo nucleotides, Homi building Sen sodium phosphate blur tab phosphorus tromethamine, FOV2301, FOV2501, ganciclovir, ganciclovir sodium, GS101, GS156, hyaluronidase, IBI20089, iCo007, Irubien, INS37217, Isonepu, JSM6427, Karubita, KH902, Reruderimumabu, LFG316, Lucentis ^{( registered trademark),} M200, Macugen Macueid, microplasmin, MK0140, MP0112, NCX434, neurotrophin 4 gene, OC10X, ocriplasmin, ORA102, ozuldex, P144, P17, paromido 529, pazopanib hydrochloride, pegaptanib sodium, plasma kallikrein inhibitor, platelet derived growth factor β polypeptide aptamer (pegylated), POT4, PRM167, PRS055, QPI1007, ranibizumab, resveratrol, retilon, retinal pigment epithelium-specific protein 65 kDa gene, retisate, rod-derived complex survival factor, RPE65 gene therapy, RPGR gene therapy , RTP801, Sd-rxRNA, serpin peptidase inhibitor clade F membrane 1 gene, Sirna027, sirolimus, sonepizumab, SRT 01, STP601, TG10088, Trabio, Triamcinolone, Triamcinolone acetonide, Trivaris, Tumor necrosis factor antibody, VEGF / rGel-Op, Verteporfin, Bisdyne, Vitorase, Vitrasart, Vitraben, Vitrials, Borociximab, Votrient, XG102, Xibrome , And Zybrestat. Thus, the methods of the present invention can be used in combination with one or more drugs disclosed herein that are administered into the suprachoroidal space using the microneedle device described herein. Administering one or more of the drugs listed in I.V. via IVT.

  In some embodiments, the methods provided herein include administering one or more drugs via IVT and one or more drugs via SCS. The inventors have surprisingly found that the SCS administration of a drug formulation is effective for drugs administered IVT to treat one or more of the ocular disorders disclosed herein. Found to improve the sex. For example, in some embodiments, SCS administration of an anti-inflammatory agent associated with IVT administration of a biological agent significantly improves the effectiveness of the biological treatment. In some embodiments, the drug administered via IVT and the drug administered to the SCS act synergistically. Two or more compounds acting synergistically interact such that the combined effect of the two compounds exceeds the sum of the individual effects of each compound when administered alone. For example, in some embodiments, an IVT administered biological agent (eg, aflibercept) combined with a drug (eg, TA) administered by SCS administration acts synergistically and causes ocular disorders (eg, Treat macular edema).

  The invention is further illustrated with reference to the following examples. However, it should be noted that these examples, like the embodiments described above, are illustrative and should not be construed as limiting the scope of the invention in any way.

Example 1 Triamcinolone Formulation for Delivery to the suprachoroidal space Triamcinolone is delivered to the suprachoroidal space using the methods and devices provided herein. The triamcinolone formulation, in one embodiment, is selected from one of the seven formulations in Table 2 below.

Example 2 Phase 1/2 Open Label Safety and Tolerability Study of Triamcinolone Acetonide Administered into the Suprachoroidal Cavity in Patients with Non-Infectious Uveitis SCS in Patients Diagnosed with Non-Infectious Uveitis A clinical trial was designed to evaluate the safety and tolerability of a single injection of TA into it (triamcinolone acetonide administered as Triesence ^™ ).

From each mL of sterile aqueous suspension of Triesense ^™ 4 mg of triamcinolone acetonide was obtained, which was sodium chloride for isotonicity, 0.5% (w / v) sodium carboxymethylcellulose, and 0.015% polysorbate 80 is added. This suspension is composed of potassium chloride, calcium chloride (dihydrate), magnesium chloride (hexahydrate), sodium acetate (trihydrate), sodium citrate (dihydrate), and distilled for injection. Includes water. Sodium hydroxide and hydrochloric acid may be present to adjust to the target value pH 6-7.5.

  The primary purpose of this study was to treat patients with uveitis due to triamcinolone administration into the SCS via a single suprachoroidal injection (non-infectious uveitis-intermediate uveitis, posterior uveitis, or panuvea) To assess the overall safety and tolerability of the treatment). Eligibility criteria include adult patients with non-infectious uveitis who experienced either macular edema or vitreous turbidity (a common complication of uveitis). This was to determine if TA SCS administration could improve patient vision by reducing the effects of either condition. As a study participation condition, the patient's IOP (intraocular pressure) must be 22 mmHg or less.

Specifically, the characteristics of the research group were as follows.
・ Men and non-pregnant women (over 18 years old)
・ Non-infectious middle uveitis, posterior uveitis, or panuveitis ・ No damage caused by glaucoma and does not respond to “steroids” ・ Both eyes with BCVA 20/200 or higher registered Cystic macular edema (CME) 310μ or more, or vitreous turbidity 1.5+ or more

In addition, the following participation / exclusion criteria were applied.
• Stable 6 months of systemic immunosuppressive therapy (IMT), stable 1 month of prednisone • 6 months of no intravitreal triamcinolone or dexamethasone implantation • 2 months of no anti-VEGF intravitreal treatment • 1 month No difluprednate eye drops • 3 years Retisate® ⁽ intravitreal graft of fluocinolone acetonide) None • No ophthalmic surgery within 6 months.

  Eight patients (6 women, 2 men) were enrolled and treated. The average age of the patient population was 56.0 years and the patient age range was 42-78 years. Seven patients met the study requirements based on the CME criteria, and four patients met the study requirements based on the vitreous turbidity criteria of 1.5 or higher.

  Each enrolled patient was microinjected into the SCS once with 4.0 mg (100 μL) of triamcinolone acetonide on day 1. Patients visited for follow-up on the day after injection and visited 1, 2, 4, 8, 12, 16, 20, and 26 weeks after treatment for a further 8 evaluations. Based on the physician's best medical judgment, if the patient's condition worsens or otherwise determined by the physician, the patient may Other treatments with acceptable therapy can be received. If the patient received other treatments, he was followed for the duration of the study for safety purposes, but efficacy measurements were no longer considered.

  A single SCS injection was made 4 mm behind the patient's edge and an ultrasonic assessment of the scleral thickness was made immediately after the injection.

  end point. The primary safety endpoint was a change from baseline in intraocular pressure (IOP). Efficacy endpoints for changes in maximum corrected visual acuity (ie, BCVA) and excessive changes in retinal thickness were also evaluated.

  Safety result. All subjects had at least one adverse event (AE) and a total of 37 AEs were reported. Most AEs were mild or moderate in severity (95%). The most commonly reported AE was pain. Specifically, eye pain was reported in 4 subjects. However, all pain AEs were reported as mild and were not associated with TA SCS injections. One serious event (irrelevant pulmonary embolism; SAE) occurred. No deaths were reported. Approximately half (57%) of reported AEs were ocular adverse events. Nine ocular AEs in 4 subjects were considered likely to be related to SCS injections of TA.

  Eight patients did not have a significant increase in IOP, and no patient needed an IOP-lowering drug.

  The graph in FIG. 22 shows the average change in the patient's IOP during the study, measured at different time points after treatment. The number of patients included in the results at the following various time points has fluctuated, because 4 patients were treated on different days and only 2 patients had completed the 26 week observation period at the present time. It is.

  In addition to these IOP findings, the drug was generally well tolerated. One patient with a history of pulmonary embolism was hospitalized for embolism after 10 weeks of treatment. This serious adverse event was considered unrelated to treatment and recovered after 3 days.

  Sight. BCVA (best corrected visual acuity) was measured for all eight patients. BCVA is a general measurement of a patient's visual acuity at a fixed distance, and the change is measured as a difference in the number of characters read on a standard visual acuity table. FIG. 23 summarizes the average BCVA improvement observed. Four out of eight patients had a significant improvement in BCVA (approximately 3 line increase) 26 weeks after a single suprachoroidal injection of TA on day 1.

  Retinal thickness. Seven patients with macular edema were enrolled. Changes in macular edema were evaluated by measuring changes in retinal thickness. The retinal thickness of macular edema patients decreases with the removal of excess fluid from the retina, which reflects a decrease in macular and other parts of the retina that develop edema.

  The graph in FIG. 24 summarizes the average change in retinal thickness observed on the test day. The average reduction in macular edema at 26 weeks exceeded 100 microns in observations over 26 weeks after treatment with a single TA injection into SCS, with a range of reductions of 76-154 microns. Seven patients were found to have an average reduction of about 20 percent in CME.

  One patient (a 52-year-old female) had bilateral uveitis with macular edema in both eyes. The woman was treated with one eye with TA via SCS injection (4 mg TA) and the other eye with subtenon TA injection (20 mg TA). FIG. 25 provides OCT images of this patient's eye before and after the dosing session. Results for this patient (Figure 25). Eyes treated with TA via superior choroidal injection have a greater decrease in retinal thickness compared to subtenon injection (FIG. 25).

  A 25-year-old male patient suffered from bilateral uveitis with macular edema in both eyes. The patient's left eye was treated with ozuldex and the right eye was treated with TA. After 4-6 weeks of treatment, eyes treated with TA via suprachoroidal injection appeared better than eyes treated with intravitreal ozuldex (FIG. 26).

Example 3 Randomized masked multicenter study to assess the safety and efficacy of CLS-TA (Triamcinolone Acetonide Injection Suspension) in the treatment of subjects with macular edema after uveitis The study described in this example is a phase II randomized masked multicenter to assess the safety and efficacy of CLS-TA in the treatment of subjects with ME after non-infectious uveitis Research. The purpose of this study is to evaluate the safety and efficacy of CLS-TA in subjects with ME after non-infectious uveitis. Two different doses (4 mg and 0.8 mg) of CLS-TA are evaluated for safety and efficacy, respectively.

  Oral corticosteroids are the primary first choice for the treatment of patients with uveitis that still do not respond to topical treatment, but their chronic use can be particularly toxic to bone (including osteoporosis or growth retardation). Non-steroidal immunosuppressive drugs can be used directly to treat uveitis, i.e. used as corticosteroid-sparing therapy or control refractory uveitis if condition threatens vision Use as a drug for. Commonly used drugs are cyclosporin A, methotrexate, azathioprine, cyclophosphamide, and chlorambucil. Cyclosporine is effective but is nephrotoxic, especially in elderly patients. Cyclosporine is rarely effective as a monotherapy and is rarely used in the treatment of uveitis. Methotrexate is a well-tolerated first-line steroid sparing agent that has been useful for many years. Methotrexate is very effective in many patients, but its onset of action is very slow (months) and is associated with the risk of liver toxicity and white blood cell count reduction (Kalinina 2011). Similarly, methotrexate causes significant fatigue and nausea and is difficult to tolerate in some patients. Methotrexate is also absolutely contraindicated for use during pregnancy (fetal risk classification category X). Azathioprine is another drug in the same class as methotrexate. Azathioprine also has a slow onset of action and may not be well tolerated. Mycophenolate mofetil is another steroid sparing agent. Mycophenolate mofetil is somewhat faster onset of action than the other two drugs, but can result in decreased white blood cell count and increased blood pressure. Similarly, mycophenolate mofetil has significant gastrointestinal side effects. Cyclophosphamide and intravenous steroids are useful for first aid. Chlorambucil is toxic and carcinogenic, but increases the rate of remission and may be useful for short-term treatment. In short, all of the above systemic drugs carry a risk of significant systemic side effects.

  This clinical study will be conducted in accordance with protocols, International Harmonization Conference (ICH), GCP guidelines, and other applicable regulatory requirements. The study population comprises approximately 20 adult subjects (18 years of age or older) who have been diagnosed with post-infectious uveitis macular edema (ME) who meet all participation criteria and do not meet the exclusion criteria. Including. All subjects receive a single injection of study reagent in one eye. Subjects from this study will be recruited at approximately 11 US facilities.

The subjects enrolled in the study, as determined by SD-OCT using Heidelberg Spectra squirrel ^{(registered trademark),} when it is confirmed by the Central Reading Center, retinal thickness of the central窩亜region of 1mm at least 310 microns (center The average retinal thickness) is selected from subjects with ME in the study eye.

The formulation of triamcinolone used in this study (CLS-TA, triamcinolone acetonide injection suspension) was made up to 4 mg in 100 microliters (μL) or in 100 microliters (μL) using a microinjector. Final sterile aqueous suspension with no preservative treatment formulated for administration in SCS as a single injection of up to 0.8 mg. The drug product is intended for single use. CLS-TA is supplied as 2mL / 13mmTopLyo ^(R) single use vials with rubber stoppers and aluminum seal 40 mg / mL or 8 mg / mL sterile TA suspension 1.3mL filled.

  The study has 2 treatment groups randomized 4: 1. See the table below. Subjects are randomized in a 4: 1 ratio to make a single injection of 4 mg CLS-TA in a 100 μL volume or 0.8 mg CLS-TA in a 100 μL volume. Mask researchers, target patients, sponsors, and contract research organization (CRO) project teams involved in the study against treatment assignments. Enroll approximately 20 subjects across approximately 11 US facilities. The study design includes 5 visits over approximately 2 months. Subject studies are 70 days or less. Subjects are treated on day 1 (Visit 2) (approximately 1-10 days after the first screening visit (Visit 1)). Subjects will continue to be monitored for safety and efficacy for 2 months after injection.

  Establish eligibility at Visit 1 (Visit for Screening). Subjects are qualified with SD-OCT readings confirmed with a Central Reading Center prior to treatment. Depending on the treatment treatment group to which the subject is assigned, subjects will receive a single suprachoroidal injection of up to 4 mg CLS-TA in 100 μL or a single suprachoroidal injection of CLS-TA up to 0.8 mg in 100 μL. Do either one eye. Injection as described in FIG.

  If both eyes are eligible (see below for participation and exclusion criteria), select an eye with worse edema (higher macular thickening by SD-OCT). If the ME is equivalent for both eyes, the right eye is selected.

Subjects stay in the clinic for at least 30 minutes after treatment for evaluation. Follow-up is performed approximately 7-10 days after the injection procedure (Visit 3). All subjects return to the clinic every month for Visits 4-5 (1 and 2 months). Visit 4 is 28 days ± 3 days after treatment in Visit 2, and Visit 5 is 28 days ± 3 days after Visit 3. The final assessment will be performed at Visit 5-End of Study (2 months). Treatment treatment groups for the study are shown in Table 3 below.

Endpoints The primary objective of this study was the retina from baseline in foveal thickness (CST) in subjects with non-infectious uveitis ME as measured by spectral domain optical coherence tomography (SD-OCT) The determination of the change in thickness is to determine the safety and efficacy of CLS-TA at doses up to 4 mg and 0.8 mg (volumes up to 100 μL, respectively). Thus, the primary endpoint was absolute from baseline in CST as measured by SD-OCT after 2 months of treatment with CLS-TA (4 mg and 0.8 mg) in eyes with ME after uveitis. Average of change.
・ The safety endpoints of this study are as follows.
• Occurrence of adverse events (TEAE) and serious adverse events (SAE) that occurred during treatment, grouped by organ system, association with study drug, and severity • Subjects with increased IOP> 30 mmHg Percentage of subjects whose IOP increases by more than 10 mmHg from the subject's baseline IOP

The secondary research endpoints are:
The percentage of subjects whose CST decreased by 20% or more at 1 month and 2 months after treatment with CLS-TA (4 mg and 0.8 mg). Subjects whose CST was 310 μm or less at 1 month and 2 months Percentage of body • Mean change from baseline in BCVA at 1 and 2 months after treatment with CLS-TA (4 mg and 0.8 mg) • Baseline [diabetic retina assessed at 4 meter starting distance Percentage of subjects who increased by 5 characters or more in BCVA at baseline and baseline at 1 month and 2 months compared to the BCVA score based on the Evidence Early Treatment Study (ETDRS) vision chart] 10 characters in BCVA at 1 month and 2 months compared to the BCVA score based on the ETDRS vision chart evaluated) Subjects who have increased by more than 15 characters in BCVA at 1 and 2 months compared to the percent increase in baseline and baseline (BCVA score based on ETDRS vision chart evaluated at 4 meter starting distance) Percentage of subjects who lost less than 15 characters in BCVA at 1 and 2 months compared to baseline (BCVA score based on ETDRS vision chart evaluated at 4 meter starting distance)

General participation criteria . Individuals are eligible to participate in this study if they meet the following criteria:
・ Understanding informed consent language and being able to voluntarily provide written informed consent before any research procedure.
・ At least 18 years old.
• Voluntarily follow instructions and attend all planned research visits.
• For women, the subject must not be pregnant, breastfeeding, or scheduled to become pregnant. Women who are likely to become pregnant must agree to use acceptable contraceptive methods while participating in the study. Acceptable contraceptive methods include double barrier methods (condoms containing spermicides or pessaries containing spermicides), hormonal methods (oral contraceptives, implantable, transdermal, or injectable contraceptives), or uterus Included are contraceptive devices (IUCD) (annual failure rates reported to be less than 1%). Although abstinence can be viewed as a contraceptive method that can be tolerated at the discretion of the investigator, the subject agrees to use one conception adjustment method that is acceptable when the subject becomes active in sexuality. There must be.

Ophthalmic Participation Criteria . Only one eye can be treated under this protocol. If both eyes are eligible, the eye with the worse measurement of ME associated with uveitis is designated as the study eye. A subject is eligible if the study eye has the following:
• History of non-infectious uveitis, including all uveitis, middle uveitis, posterior uveitis, or panuveitis.
ME with or without subretinal fluid associated with non-infectious uveitis.
When measured by SD-OCT (using Heidelberg Spectraris ^{(registered trademark))} and confirmed by Central Reading Center, the retinal thickness of the subfoveal region (average retinal thickness in the ring 1 mm from the center) is 310 microns. That's it.

Exclusion criteria . An individual is not eligible for participation in this study if it meets any of the following criteria:
• Have any uncontrollable systemic disease (eg, uncontrollable blood pressure increase, cardiovascular disease, and unstable medical conditions including glycemic control) that would be excluded from participation in this study in the investigator's opinion Or the subject is at risk from a research treatment or procedure.
• There is a high probability that hospitalization or surgery (including planned elective surgery or hospitalization that cannot be postponed) will be required within the study period.
Having a known human immunodeficiency virus infection, other immunodeficiency disease, or other medical condition that is considered contraindicated to corticosteroid therapy in the opinion of the investigator.
Have a known hypersensitivity to any component of the TA formulation, fluorescein, or local anesthetic.
• Have a systemic infection for which anti-infective pharmacological therapy requiring prescription is indicated.
• You are currently participating in a study drug or device study or have been using the study drug or device within 30 days of this study registration.
-You are a worker of a facility that is directly involved in the management, management, and support of this research, or you are a close relative of the facility.
A history of any serious or active psychosis that, in the opinion of the investigator, would interfere with subject's treatment, evaluation, or protocol compliance.
- two weeks before the study on the treatment acetazolamide (Diamox ^(R)) that you were using.
• Systemic administration of corticosteroids at doses exceeding 20 mg / day instead of oral prednisone (or other corticosteroid equivalents) required to maintain subject care 2 weeks prior to study treatment is being done.
・ Currently prescribed non-steroidal anti-inflammatory drugs (excluding use of over-the-counter drugs) or prescribed unless the dose is stable for at least 2 weeks and dosing is not expected to remain unchanged during the study period Using immunomodulatory therapy • 6 weeks prior to study treatment, the drug had been administered any interferon / fingolimod or any other drug known to induce or exacerbate ME .
• Having uncontrollable diabetes.

Ophthalmic exclusion criteria . A subject is not eligible to participate if the subject is:
・ Must be one eye.
・ Having uveitis caused by infection.
• Having significant intermediate translucency that interferes with the evaluation of the retina and vitreous in the study eye.
• Have chronic ME, macular scars, or significant ischemia that is unlikely to improve vision using treatment at the discretion of the investigator.
・ Having ME caused by other than uveitis.
• In the investigator's opinion, the subject has an ophthalmic condition (ie, active eye infection, history of suprachoroidal hemorrhage, etc.) that is considered to be at risk due to the study treatment or procedure.
Had uveitis unresponsive to previous systemic corticosteroid treatment in either eye.
・ Active eye disease other than uveitis in the eye under study or infection in any eye (conjunctivitis, herpes infection, chalazion, or significant external eye infections such as blepharitis) Having.
• Having ocular hypertension (IOP> 22 mmHg) unrelated to local treatment or evidence of glaucomatous optic nerve damage in the study eye. Also excluded are those who have a clinically significant history of elevated IOP in response to corticosteroid treatment ("steroid responders") in the study eye.
• The IOP-lowering drug had changed 30 days before the study treatment.
-Any vitreous retinal surgery in the study eye (scleral buckle, ciliary vitrectomy, nuclear loss or intraocular lens repair; prior photocoagulation and IVT injections are acceptable) Having a medical history of Prior cataract extraction or yttrium-aluminum-garnet (YAG) laser capsulotomy is acceptable but must have been performed at least 3 months prior to treatment.
• Have a history of ciliary destruction procedures and multiple filtration operations (two or more) in the study eye.
• In the investigator's opinion, have evidence of epiretinal membrane affected by macular traction or vitreous macular traction in the study eye, which may hinder vision improvement.
-The presence of staphylococci in the study eye.
• The presence of a toxoplasmosis scar in the study eye.
• Have eye diseases other than uveitis (eg, clinically significant diabetic retinopathy, scleritis, ischemic optic neuropathy, or retinitis pigmentosa) that can impair central vision in the study eye.
• Have an intense myopia defined as an equivalent spherical power greater than −6 diopters or an axial length of 26 mm or greater in the eye under study.
・ In the opinion of the investigator, have any condition in the eye of the study that can predispose to scleral thinning
• Have any eye trauma in the study eye within 6 months immediately prior to study treatment.
• Photocoagulation or cryotherapy was performed within 6 months prior to study treatment in the study eye.
• Any IVT injection of an anti-VEGF treatment (bevacizumab, aflibercept, pegaptanib, or ranibizumab) was given in the study eye 2 months prior to the study treatment.
- Any ophthalmic topical corticosteroids within 10 days of study treatment, corticosteroid injections in periocular or intraocular within 60 days of study treatment, implantation of the previous 120 days study treatment Ozurudekkusu ^® or Research, There has been any prior use of Retissert ^TM or Irbien ^TM implantation in the study eye for the past year prior to treatment.
• A previous TA epichoroidal injection in the study eye in the past 30 days.

Randomization criteria . Subjects are eligible for randomization at Visit 2 if they meet the following criteria:
・ The ME (with or without subretinal fluid) caused by non-infectious uveitis (according to the investigator's judgment) in the subject eye is SD-OCT (derived from OCT data from Visit 1) at the Central Reading Center ) To be confirmed.
The central reading center has a retinal thickness of the subfoveal region (average retinal thickness in an annulus 1 mm from the center as measured by SD-OCT using Heidelberg Spectraris ^{(registered trademark)} ) of 310 microns or more. Confirmation from OCT data at Visit 1
• Subject continues to meet participation / exclusion criteria.

Post injection procedure . The following evaluations must be made after the injection (Visit 2).
• Evaluate AE.
• Review changes to concomitant medications.
・ Measure heart rate and blood pressure at rest while sitting.
・ Evaluate ophthalmology only for the eyes to be studied.
○ Perform slit lamp biomicroscopy.
O Assess IOP 30 minutes after injection (± 5).
• If the IOP remains elevated, the subject must remain in the facility until the investigator's best judgment controls the IOP.
○ Perform an indirect ophthalmoscopic examination.
• Schedule a return visit for Visit 3 of the subject.

Visit 3 is performed 7-10 days after Visit 2 (Randomization / Treatment). During Visit 3, do the following:
• Evaluate AE.
• Review changes to concomitant medications.
・ Measure heart rate and blood pressure at rest while sitting.
・ Evaluate ophthalmology only for the eyes to be studied.
○ Authorized facility personnel conduct BCVA testing using the ETDRS protocol.
○ Perform slit lamp biomicroscopy.
O Evaluate IOP.
○ Perform mydriatic inversion ophthalmoscopic examination.
○ Obtain a FP-4W visual field fundus photo and upload it to the Central Reading Center.
○ Obtain SD-OCT images and upload them to the Central Reading Center.
• Schedule a return visit for Visit 4 of the subject.

Visit 4 is performed approximately one month after injection. Visits should be 28 ± 3 days from Visit 2. The following procedure is performed during Visit 4.
• Evaluate AE.
• Review changes to concomitant medications.
・ Measure heart rate and blood pressure at rest while sitting.
・ Evaluate ophthalmology only for the eyes to be studied.
○ Authorized facility personnel conduct BCVA testing using the ETDRS protocol.
○ Perform slit lamp biomicroscopy.
O Evaluate IOP.
○ Perform an indirect ophthalmoscopic examination.
○ Obtain SD-OCT images and upload them to the Central Reading Center.
• Schedule a return visit for the subject's next visit.

Visit 5 is the final evaluation visit and is the end of the study. Visit 5 will take place within 56 ± 4 days from Visit 2. Perform the following procedure.
• Evaluate AE.
• Review changes to concomitant medications.
・ Measure heart rate and blood pressure at rest while sitting.
・ Perform urine pregnancy tests on women who can give birth.
• Ophthalmic evaluation is performed on both eyes (excluding FA; only the eye to be studied).
○ Authorized facility personnel conduct BCVA testing using the ETDRS protocol.
○ Perform slit lamp biomicroscopy.
O Evaluate IOP.
○ Perform mydriatic inversion ophthalmoscopic examination.
○ Obtain a FP-4W visual field fundus photo and upload it to the Central Reading Center.
○ Obtain SD-OCT images and upload them to the Central Reading Center.
○ Perform an FA using the eye of the initial series of research subjects and upload it to the Central Reading Center.

Evaluation of efficacy The fovea thickness measured by SD-OCT is evaluated as a measure of efficacy. Each facility will be provided with an imaging protocol and submission procedure from the Central Reading Center. SD-OCT instruments and technicians must be certified before submitting research data. Technicians are trained on imaging for this particular protocol and uploading images to EyeKor's Excelsior system. Reticular thickness and disease characteristics are assessed by SD-OCT (Heidelberg Spectraris® ^{) at} each visit. OCT is performed on both eyes in Visits 1 and 5, and on Visits 2, 3, and 4 only on the study eye.

  The Central Reading Center masks and evaluates the image under study in an independent manner. At screening (Visit 1), the Central Reading Center confirms the subject's eligibility based on the retinal thickness criteria prior to subject registration. Upon confirmation from the Central Reading Center via email, the facility can proceed with subject qualification for randomization / treatment to be performed at Visit 2.

  The SD-OCT submission includes a volume (cube) scan consisting of 49B-scan 6 mm long from the center of the fovea. A further depth-enhanced imaging (EDI) scan is obtained that passes horizontally through the fovea. SD-OCT scans are evaluated for quality and any segmentation affecting the measurement of retinal thickness in the foveal subregion is corrected. Further assessment outputs include assessment of macular grid volume and retinal and choroidal anatomy.

  BCVA evaluated using the ETDRS protocol is also evaluated. Each facility has at least one accredited test lane that contains all the equipment needed to assess BCVA by one or more accredited vision testers. Training / certification in the ETDRS protocol is completed prior to patient enrollment. In addition, ETDRS training / certification documents will be maintained at the facility and shared with the sponsor. Facility staff should be masked for treatment. BCVA is assessed at each visit. BCVA is measured for both eyes in Visits 1 and 5, and in Visits 2, 3, and 4 only for the study eye.

  Safety and tolerability are assessed using the following endpoints:

  Intraocular pressure. IOP is measured with a Tonopen or Goldmann applanation tonometer, but the average of three measurements should be used. The average IOP value should be rounded up to the next integer if the value is greater than or equal to 0.5 mmHg, and should be rounded down if it is less than 0.5 mmHg. All instruments used for IOP measurements must be calibrated according to the manufacturer's specifications and documentation (ie calibration log). The same IOP measurement tool should be used for each visit. IOP is measured at every visit. IOP is measured for both eyes in Visits 1 and 5, and in Visits 2, 3, and 4 only for the study eye.

  Slit lamp biomicroscopy. Slit lamp biomicroscopy is performed by the investigator using standard slit lamp equipment and procedures. This procedure should be the same for all subjects observed at the investigator's facility. Each eye should be observed for the following items, including but not limited to: conjunctiva, cornea, lens, anterior chamber, iris, and pupil. Slit lamp biomicroscopy is assessed at each visit. Slit lamp biomicroscopy is measured for both eyes in Visits 1 and 5, and in Visits 2, 3, and 4 only for the study eye.

  Inversion ophthalmoscope examination. Mydriatic ophthalmoscopic examination should be performed according to the investigator's standard mydriatic procedures. This procedure should be the same for all subjects observed at the investigator's facility. The fundus should be fully tested for the following items (including but not limited to): vitreous cloudiness, vitreous, retina, choroid, and optic nerve / disc. Evaluate mydriasis ophthalmoscopic examination at each visit. Mydriatic inversion ophthalmoscopic examination is measured for both eyes at Visits 1 and 5, and only for the study eye at Visits 2, 3, and 4.

  Fluorescein angiogram. If both fundus photography and FA are performed at the same visit, it is recommended that fundus photography be taken first. The digital device is registered and the photographer will be certified for the imaging procedure. The same equipment should be used throughout the study. All tests should be performed by the same operator for all subjects per laboratory when possible. The designated person must be recorded in the facility business commission log. It is recommended that you also specify a backup. Upload all data / images to EyeKor's Excelsior system. As a reminder, all images should be unspecified before uploading. FA is performed only for the study eye in Visits 1 and 5. Anatomical evaluation includes the presence of fluorescein leakage areas, non-capillary perfusion areas, retinal vascular and optic disc staining, and retinal pigment epithelial abnormalities.

  Fundus photo. FP-4W field of view (4 standard wide angle fields of view). The same camera should be used throughout the study. All photographs should be taken by the same photographer for all subjects per research facility when possible. Upload unspecified images to EyeKor's Excelsior system. Fundus photographs are taken at Visits 1 and 5, and both eyes are photographed at Visit 3 only. Features categorized from fundus photographs include vitreous turbidity scores, lesions consistent with posterior uveitis, optic disc swelling, and vascular abnormalities.

Vitreous turbidity. Vitreous turbidity on photographs is clinically assessed on a visit-by-visit basis using a standard photographic scale ranging from 0 to 4 (0 to 4 defined in Table 4 below) via inversion ophthalmoscopic examination. (Nussenblatt 1985, modified in Lower 2011). Vitreous turbidity is also classified from color fundus photographs according to a similar scale. Vitreous turbidity is assessed for both eyes at Visits 1 and 5, and only for the study eye at Visits 2, 3, and 4.

Example 4: Safety and efficacy of suprachoroidal CLS-TA in combination with intravitreal aflibercept in subjects with macular edema after retinal vein occlusion This phase 2, multicenter, randomized, active drug A controlled, masked, parallel treatment group study found that an IVT of CLS-TA administered simultaneously with intravitreal (IVT) injection of aflibercept in subjects with macular edema (ME) after retinal vein occlusion (RVO) We attempt to evaluate the safety and efficacy of a single superior choroidal injection compared to aflibercept alone. RVO is a condition that affects vision and results from the obstruction of one vein that returns blood from the retina. RVO is the second most common cause of vision loss due to retinal vascular disease.

  This study shows the safety of suprachoroidal injection of CLS-TA + IVT aflibercept compared to subjects who received a simulated suprachoroidal procedure + IVT aflibercept in the treatment of subjects with ME after retinal vein occlusion (RVO) Evaluate effectiveness. Each subject will receive at least one IVT aflibercept injection and approximately half of the subjects will receive a single suprachoroidal injection of CLS-TA. Subjects enrolled in this study are RVO subjects (HRVO, CRVO, and BRVO) with treated naive ME in the study eye. All eligible subjects are randomized (Day 1) to receive an anti-VEGF-treated (Aflibercept) IVT injection + CLS-TA suprachoroidal injection or an aflibercept IVT injection + simulated suprachoroidal procedure . Subjects will be followed for approximately 3 months after randomization. The subject, sponsor, vision technician, and optical coherence tomography (OCT) reading center are masked for treatment.

  Enroll approximately 40 subjects in approximately 10 US facilities. The study design includes 5 clinic visits and 1 safety confirmation phone call over approximately 3 months. The subject's eligibility is established during the screening process at Visit 1 (Days -14 to -1), where the subject is identified by the Central Reading Center (CRC) prior to treatment. Must be eligible for optical coherence tomography (SD-OCT) reading. Eligible subjects return to the clinic for Visit 2-Randomization (Day 1), at which time subjects are randomized via the Web Automatic Response System (IWRS). Subjects are randomized to receive either IVT aflibercept injection followed by suprachoroidal CLS-TA injection or IVT aflibercept injection followed by suprachoroidal simulation procedure. The subject stays in the clinic for approximately 30 minutes for evaluation after suprachoroidal CLS-TA injection or mock injection. A follow-up call for safety confirmation is required on the second day (24-48 hours after treatment). The subject is then given an IVT aflibercept injection at Visits 3 (Month 1) and 4 (Month 2) only if additional treatment criteria are met. If the subject is not eligible for AFT injection of aflibercept, the subject is subjected to a simulated IVT aflibercept procedure. Visit 5-At the end of the study (month 3), subject will undergo final assessment. Visit 5 will not be injected for research.

Endpoint The primary endpoint is the total number of times that the subject has met eligibility for IVT aflibercept in each treatment group over a three month period.

Occurrence of TEAEs and SAEs grouped by safety endpoint / organ system, association with study drug, and severity.
• The occurrence of changes in safety parameters as described in Section 8.1, including: IOP, slit lamp biomicroscopy, inverse ophthalmoscopic examination, imaging parameters, and vital signs.

Secondary endpoints: Total number of treatments with aflibercept in each treatment group at 1 month, 2 months, and 3 months.
• Percentage of subjects with a CST of 310 μm or less at 1, 2, and 3 months.
Average of change from baseline in CST at 1, 2, and 3 months.
• Mean reduction in macular edema at 1, 2, and 3 months.
• Average change in BCVA from baseline at 1, 2, and 3 months.
• Percentage of subjects who increased by 15 characters or more in BCVA at 1, 2, and 3 months compared to baseline.
• Percentage of subjects who lost less than 15 characters in BCVA at 1, 2, and 3 months compared to baseline.

Trial treatment

CLS-TA (triamcinolone acetonide injection suspension) is a sterile aqueous suspension formulated for intraocular administration. The drug product is terminally sterilized and intended for single use. CLS-TA is supplied as 2mL / 13mmTopLyo ^(R) single use vials with rubber stoppers and aluminum seal 40 mg / mL sterile CLS-TA suspension 1.3mL filled. CLS-TA must be stored at about 20 ° C. to 25 ° C. (68 ° F. to 77 ° F.) under ambient temperature conditions and should not be frozen. Protect from light by storing in the kit.

  A dose of 4 mg CLS-TA contains 40 mg / mL TA. Subjects are randomized 1: 1 and given a single suprachoroidal injection (active treatment group) or simulated suprachoroidal procedure (control treatment group) of 40 mg / mL (4 mg in 100 μL) CLS-TA. This is based on randomization code and assignment via IWRS.

Ilea® ⁽ Aflibercept) injection is an FDA-approved prescription drug for RVO treatment. In this study, dosage of Airia ^(R) is 2 mg (0.05 mL) was administered by intravitreal injection. Afribercept is purchased by the clinical facility.

  All eligible subjects are randomized on day 1 into one of the following treatment groups and the following are performed:

  Active drug treatment group: IFT injection of aflibercept [2 mg (0.05 mL)] + suprachoroidal injection of CLS-TA [4 mg (100 μL)] or

  Control treatment group: IFT injection of aflibercept [2 mg (0.05 mL)] + simulated suprachoroidal procedure.

  Subjects randomized to the active treatment group (the treatment group receiving CLS-TA) or the control treatment group only in Visits 3 (1 month) and 4 (2 month) if additional treatment criteria are met Treat with AVT injection of aflibercept. If the subject is not eligible for AFT injection of aflibercept, the subject is subjected to a simulated IVT aflibercept procedure. The Clearside microinjector is designed for the suprachoroidal administration of drugs through the SCS. The micro-injector used for intra-SCS injection is supplied to the facility.

Retreatment criteria. If the study eye at month 1 and month 2 (Visits 3 and 4) meets any of the following criteria, retreatment with aflibercept IVT injection is required. Dosage according to the latest package insert.
Macular edema or subretinal fluid combined with CST below 340 microns measured by SD-OCT (new or persistent)
-Decrease in BCVA by 10 characters (ETDRS) or more between this visit and BCVA readings from previous visits.
A decrease in BCVA of 10 letters (ETDRS) or more from the best measurement (under study) with an increase in CST> 50 microns from a previous visit related to a new fluid.
• At 1 month and 2 months (Visits 3 and 4), if the subject is not eligible for retreatment with an IVT injection of aflibercept, perform the IVT aflibercept simulation procedure.

Registration criteria General participation criteria. Individuals are eligible to participate in this study if they meet the following criteria: (1) be able to understand informed consent language and voluntarily provide written informed consent prior to any study procedure; (2) be at least 18 years of age; (3) voluntarily follow all directions and attend all planned study visits; (4) in the case of women, subjects will be pregnant, breastfeeding, and scheduled to become pregnant There must not be. Women who are likely to become pregnant must agree to use acceptable contraceptive methods while participating in the study.

Ophthalmology participation criteria. Individuals are eligible to participate in this study if they meet the following criteria: (1) received clinical diagnosis with ME after RVO in the study eye; (2) SD with or without subretinal fluid -When measured by OCT (using Heidelberg Spectraris® ⁾ and confirmed by CRC, CST of 310 microns or more (average retinal thickness in the ring 1 mm from the center) in the studied eye; (3) each ETDRS BCVA score with readings in the eye of 20 characters or more (Snellen equivalent visual acuity 20/400) and readings in the study eye of 70 characters or less (Snellen equivalent visual acuity 20/40); (4) macular edema with the following characteristics: a. Including a fovea, b. Due to RVO but not to other causes of ME, c. A history of ME of 12 months or less, d. Vision loss due to edema.

  General exclusion criteria. An individual is ineligible to participate in the study if it meets the following criteria: (1) Any uncontrollable systemic disease that is excluded from study participation (eg, infection, uncontrollable) Have increased blood pressure, cardiovascular disease, and glycemic control), or subject is at risk from a research treatment or procedure; (2) myocardial infarction or stroke within 90 days of treatment; 3) Any new prescription or modification of existing prescription within 30 days of randomization; (4) Maintenance of stable and non-excluded medical care of subjects 30 days prior to study treatment Had received systemic doses of corticosteroids in excess of 10 mg / day instead of oral prednisone (or other corticosteroid equivalents) required for; (5) hospitalization or surgery (planned) within the study period Waiting hands (6) considered to be contraindicated for corticosteroid therapy due to known human immunodeficiency virus infection, other immunodeficiency diseases, or best medical judgment (7) have a known hypersensitivity to any component of the TA formulation, aflibercept, fluorescein, or local anesthetic; (8) currently investigational drug Or participated in device research, used a clinical drug within 30 days of study registration, or participated in ophthalmic device research for the last 90 days; (9) management of this study; You are a worker of a facility that is directly involved in management or support, or a close relative of the facility.

Ophthalmic exclusion criteria. An individual is not eligible for this study if the individual meets the following criteria: (1) Any IVT injection of anti-VEGF (bevacizumab, aflibercept, pegaptanib, or ranibizumab) for RVO in the study eye it had received; (2) in the eye of the study, corticosteroid injections any intraocular or periocular 3 months prior to treatment, implantation of 6 months prior to Ozurudekkusu treatment ^(TM), treated 1 years ago Rechisato ^TM implantation or treatment 3 years ago Irubien ^® implantation; (3) any eye condition in a study of the eye other than RVO which can impair vision in opinion of investigator (e.g. Evidence, or history of AMD, diabetic retinopathy, retinal detachment, central severe chorioretinopathy, scleritis, optic neuropathy, or retinitis pigmentosa; (4) Any previous vitreal retinal surgery (scleral buckle replacement, ciliary vitrectomy, intraocular lens repair, epivascular sheath incision) in the study eye 3 months prior to randomization or History of any eye surgery. A history of IVT injection is acceptable; (5) Ophthalmic procedures or conditions within 3 months prior to randomization, or conditions that may impair the integrity of the eyeball or retina in the study eye in the opinion of the investigator (Eg, staphyloma, cryotherapy, intensity myopia [defined as equivalent sphere power above -8 diopters), sclera thinning predisposition, etc.]; (6) the eye of the subject in the investigator's opinion Conditions of the eye that are considered to be at risk due to research treatments or procedures in (eg, history of active eye infection, suprachoroidal hemorrhage, chalazion, significant blepharitis); (7) study subject More than 3 macular laser photocoagulation treatments in the eye. Previous macular laser photocoagulation must be more than 60 days prior to injection. Panretinal photocoagulation is tolerated; (8) Significant intermediate translucency hindering assessment of the retina and vitreous of the eye under study. This includes significant bleeding or cataracts that are thought to be the main cause of vision loss; (9) In the investigator's opinion, the eye of the study that may not benefit from the recovery of ME (Eg foveal atrophy, dense pigment changes, chronic ME over 12 months, or eyes with dense subfoveal hard vitiligo); (10) unrelated to local treatment or evidence of glaucomatous optic nerve damage in the study eye Uncontrolled ocular hypertension (IOP> 22 mmHg); (11) History of glaucoma surgery (filtered surgery / travelectomy or tube shunt) in the study eye; (12) In response to corticosteroid treatment ("steroids" Responder ") having a clinically significant history of elevated IOP; (13) any systemic or local to treat ocular conditions one month prior to treatment. Family nonsteroidal anti-inflammatory drug (NSAID) that were using the; (14) before it had received on choroidal injection TA in the eye of the study.

  Randomization criteria. A subject is eligible for randomization at Visit 2 if the following criteria are met: (1) The ME (with or without subretinal fluid) caused by RVO in the study eye is CRC-SD- Confirmed by OCT (derived from OCT data at Visit 1); (2) From the SD-OCT data at Visit 1, the retinal thickness of the foveal subregion is confirmed to be 310 microns or more by CRC; (3) Study subjects Eyes improved by 10 characters or less between the screening visit and randomization (Visit 2) in the study eye; (4) Subjects continually meet all participation criteria Satisfies and does not meet exclusion criteria.

  General procedure. The study consists of five study visits and one safety confirmation phone call over a maximum of 101 days (14 weeks). Subjects will attend visits for all studies. All eye assessments at Visit 1 and Visit 5 are performed on both eyes, except for fluorescein angiography (FA), which is performed only on the study eye. Eye assessments at all other visits (Visits 2-4) are performed only on the study eye. Subjects are screened for entry (Visit 1) and then returned to the clinic within 14 for randomization / treatment (Visit 2). At randomization, subjects received a single IVT injection of aflibercept into the study eye (following the package insert) and subsequent CLS-TA in the study eye, depending on the randomization code assigned to the subject. Perform single unilateral suprachoroidal injection or suprachoroidal simulation procedure. Subjects stay in the clinic for approximately 30 minutes after suprachoroidal or sham injection and are evaluated for safety. Subjects will receive a phone call for safety confirmation from the facility 24 to 48 hours after injection, and then will return for one month after the injection for evaluation (Visit 3). Visit 2 and 3 months later for further follow-up (Visits 4 and 5).

Visit 1-Screening (Days -14 to -1). At Visit 1, subjects are screened for eligibility. Written informed consent is obtained from each subject prior to conducting a specific assessment for any study. During Visit 1, perform the following assessments:
• Obtain written informed consent.
• Assign a subject number.
Collect population, medical history, and eye medical history.
• Review current and past concomitant medications.
・ Measure heart rate and blood pressure at rest while sitting.
• Collect blood and urine at a central laboratory before FA.
• Ophthalmic evaluation is performed on both eyes (excluding FA; only the eye to be studied).
○ Authorized facility personnel conduct BCVA testing using the ETDRS protocol.
○ Perform slit lamp biomicroscopy.
O Evaluate IOP.
○ Perform mydriatic inversion ophthalmoscopic examination.
○ Obtain SD-OCT images and upload them to the CRC.
○ Obtain four wide-view color fundus photographs (FP-4W) and upload them to the CRC.
○ Perform FA using the initial series of research subjects and upload to CRC.
O Verify subject eligibility based on participation / exclusion requirements.
○ Determine the target eye based on eligibility criteria. If both eyes are eligible, select an eye with worse edema (higher macular thickening by SD-OCT). If the ME is equivalent for both eyes, the right eye is selected.
○ Perform a simple physical examination. Schedule a return visit for Subject Visit 2 (Randomization / Treatment).

  Visit 2-Randomization / Treatment (Day 1). Visit 2 must occur within 14 days of Visit 1 (Screening), and Visit 2 can only be performed when the subject becomes eligible for treatment. This eligibility includes the CRC receiving and reviewing the results of the central laboratory and confirming eligibility. If disease eligibility and CST greater than 310 microns are not confirmed by CRC, the subject cannot be treated. Once qualified, subjects will be randomized via IWRS. All eligible subjects will be randomized (Day 1) to receive:

  Active drug: IFT injection of aflibercept [2 mg (0.05 mL)] + suprachoroidal injection of CLS-TA [4 mg (100 μL)] or control: IVT injection of aflibercept [2 mg (0.05 mL)] + mock Choroidal procedure.

  Only if further treatment criteria are met, subjects randomized to the active treatment group (subjects receiving CLS-TA) or control treatment group will be referred to Visits 3 (1 month) and 4 (2 months) Re-treat with an IVT injection of aflibercept. If the subject is not eligible for an AVT injection of aflibercept, the subject is given a simulated IVT aflibercept injection.

Pre-injection procedure. The following must be done immediately prior to the IVT aflibercept injection.
• Evaluate AE.
• Review changes to concomitant medications.
• Review the results of any significant abnormalities that would exclude subjects from the central laboratory from entry.
• Review the results received from the CRC to confirm that the subject is eligible based on disease and CST.
• Review eligibility based on participation / exclusion criteria and randomization criteria.
・ Measure heart rate and blood pressure at rest while sitting.
・ Perform urine pregnancy tests on women who can give birth.
・ Evaluate ophthalmology only for the eye to be studied
O Authorized facility personnel conduct BCVA testing using the ETDRS protocol (with BCVA technicians masked against treatment assignments).
○ Perform slit lamp biomicroscopy.
O Evaluate IOP.
○ Perform an indirect ophthalmoscopic examination.
O Obtain SD-OCT images and upload to Central Reading Center (Visit 1 image is used for qualification; Visit 2 pre-dose image is used as baseline).
• Record in the IWRS system and randomize subjects. Assign a kit number.

  IFT injection of aflibercept: Prepare the study eye for IFT injection of aflibercept. Aflibercept IVT injection is performed according to the package insert. It is recommended that intravitreal and suprachoroidal injections be performed at approximately 2 hours apart. The superior lateral quadrant is the recommended location for superior choroidal injection.

  CLS-TA suprachoroidal injection (active drug kit): As determined by the investigator, suprachoroidal injection is performed after IVT injection of aflibercept when the IOP of the study eye is less than 30 mmHg either voluntarily or by treatment Should be done. A Clearside microinjector is used to inject 100 μL of CLS-TA into the SCS, preferably the upper and outer quadrants of the eye under study, approximately 2 hours away from the location where IVT aflibercept was administered. See FIG. 21 for the method.

  Superior Choroidal Simulated Procedure (Control Kit): A simulated procedure is performed after IVT injection of aflibercept when the IOP of the study eye is less than 30 mm Hg voluntarily or by treatment, as determined by the investigator. Eyes are prepared as in the suprachoroidal CLS-TA injection. Perform pseudoupchoidal injections into the study eye.

  Post injection procedure. Subjects will remain in the facility for approximately 30 minutes after injection for observation. The following assessments are made after IVT injection and suprachoroidal injection or simulated procedure: (1) Evaluate retinal artery for perfusion; (2) Evaluate AE; (3) Review changes to concomitant medications; (4 ) Measure sitting heart rate and blood pressure; (5) Perform ophthalmic evaluation only on study eye (a. Slit lamp biomicroscopy; b. Evaluate IOP 10-30 minutes after injection; c. Perform an indirect ophthalmoscope examination). If the IOP remains elevated, the subject must remain in the facility until the investigator's best judgment controls the IOP. If the IOP is less than 30 mmHg, the subject can exit the clinic.

Visit 3 (Follow-up after 1 month injection (Day 28 ± 3)) Visit 4 (Follow-up after 2 month injection (Day 56 ± 3)) Visit 3 occurs approximately 1 month after Visit 2 (Randomization / Treatment). This visit is 28 ± 3 days from Visit 2. Visit 4 occurs approximately 2 months after Visit 2 (Randomization / Treatment). Visit 4 is 56 ± 3 days from Visit 2. During Visits 3 and 4, perform the following procedure:
• Evaluate AE.
• Review changes to concomitant medications.
・ Measure heart rate and blood pressure at rest while sitting.
・ Evaluate ophthalmology only for the eyes to be studied.
○ Authorized facility personnel conduct BCVA testing using the ETDRS protocol.
○ Perform slit lamp biomicroscopy.
O Evaluate IOP.
○ Perform mydriatic inversion ophthalmoscopic examination.
○ Obtain SD-OCT images and upload them to the CRC.
○ Optional: Only if the investigator feels that medical judgment is necessary, perform an FA using the initial series of study eyes and upload to the CRC.
• Administer IVT aflibercept to a subject only if the subject is eligible for further treatment. If the subject is not eligible for further treatment, an IVT simulation procedure is performed.

Visit 5-3 months; end of study visit (84 ± 4 days). Visit 5 is a final evaluation visit, and this study is completed. Visit 5 is within 84 ± 4 days from Visit 2. The following procedure is performed during Visit 5.
• Evaluate AE.
• Review changes to concomitant medications.
・ Measure heart rate and blood pressure at rest while sitting.
・ Evaluate ophthalmology only for the eyes to be studied.
○ Authorized facility personnel conduct BCVA testing using the ETDRS protocol.
○ Perform slit lamp biomicroscopy.
O Evaluate IOP.
○ Perform mydriatic inversion ophthalmoscopic examination.
○ Obtain SD-OCT images and upload them to the CRC.
○ Optional: Only if the investigator feels that medical judgment is necessary, perform an FA using the eye of the initial series of research subjects and upload it to the CRC.

  The evaluation of effectiveness is as follows.

Foveal thickness measured by SD-OCT. Reticular thickness and disease characteristics are assessed by SD-OCT (Heidelberg Spectraris® ^{) at} each visit. OCT is performed on both eyes in Visits 1 and 5, and on Visits 2, 3, and 4 only on the study eye. The CRC evaluates the image under study in a masked and independent manner. At screening (Visit 1), the CRC verifies the subject's eligibility based on the retinal thickness criteria prior to subject registration. Upon confirmation from the CRC via email, the facility may proceed with subject certification for randomization / treatment to be performed at Visit 2. The SD-OCT submission includes a volume (cube) scan consisting of 49B-scan 6 mm long from the center of the fovea. Further depth-enhanced imaging scans are obtained that have passed horizontally through the fovea. SD-OCT scans are evaluated for quality and any segmentation affecting the measurement of retinal thickness in the foveal subregion is corrected. Further assessment outputs include assessment of macular grid volume and retinal and choroidal anatomy.

  BCVA evaluated using the ETDRS protocol. BCVA is assessed at each visit. BCVA is measured for both eyes in Visits 1 and 5, and in Visits 2, 3, and 4 only for the study eye.

  Safety and tolerability are assessed using the following endpoints:

  Intraocular pressure. IOP is measured with a Tonopen or Goldmann applanation tonometer. The average IOP value is rounded up to the next integer if the value is greater than or equal to 0.5 mmHg, and rounded down if less than 0.5 mmHg. All instruments used for IOP measurements are calibrated according to the manufacturer's specifications and documents (ie calibration log). The same IOP measurement tool should be used for each visit. IOP is measured at every visit. IOP is measured for both eyes in Visits 1 and 5, and in Visits 2, 3, and 4 only for the study eye.

  Slit lamp biomicroscopy. Slit lamp biomicroscopy is performed by the investigator using standard slit lamp equipment and procedures. Each eye is observed for the following items, including but not limited to: conjunctiva, cornea, lens, anterior chamber, iris, and pupil. Slit lamp biomicroscopy is assessed at each visit. Slit lamp biomicroscopy is measured for both eyes in Visits 1 and 5, and in Visits 2, 3, and 4 only for the study eye.

  Inversion ophthalmoscope examination. The fundus is thoroughly tested for the following items, including but not limited to: the vitreous, retina, choroid, and optic nerve / disc. Evaluate mydriasis ophthalmoscopic examination at each visit. Mydriatic inversion ophthalmoscopic examination is measured for both eyes at Visits 1 and 5, and only for the study eye at Visits 2, 3, and 4.

  Fluorescein angiogram (FA). Upload all data / images to EyeKor's Excelsior system. As a reminder, all images should be unspecified before uploading. FA is performed only for the study eye in Visits 1 and 5. FAs can be performed at Visits 3 and 4 only if the investigator feels that medical judgment is necessary (optional). Anatomical evaluation includes the presence of fluorescein leakage areas, non-capillary perfusion areas, retinal vascular and optic disc staining, and retinal pigment epithelial abnormalities.

  Fundus photo. FP-4W (4 wide-field color fundus photography). Take fundus photos of both eyes in Visits 1 and 5. Features categorized from fundus photographs include optic disc swelling and vascular abnormalities.

Results Forty-six subjects were randomized into the trial (23 were the control treatment group and 23 were the active treatment group). All 46 people completed the trial. Patient populations are provided in Table 5 below.

  As shown in FIG. 41, the primary endpoint has been satisfied. In the control treatment group (ie, the group that received IFT injection of aflibercept and did not receive CLS-TA), 23 received a further IVT injection of aflibercept while the translation treatment treatment group (ie In the group that received 2 mg aflibercept IVT injection and received 4 mg CLS-TA SCS injection, only 9 people received additional IVT injection. Thus, in the active treatment group, the number of injections was 60% less compared to the control treatment group, and when the IVT injection of the biological agent was combined with the SCS administration of the anti-inflammatory drug, the treatment was more effective, and Indicates lasting longer. The p-value for the difference in the number of people required for treatment is p = 0.013 (negative binomial distribution; Wald-chi square test) and p = 0.002 (Wilcoxon test used to assess sensitivity). there were.

  From the viewpoint of BCVA change at the third month, subjects in the active drug group increased by 18.9 characters, while subjects in the control group increased by 11.3 characters, compared to the control group (FIG. 42). A further increase in 7.6 letter BCVA is shown for the active group. BCVA also improved early in the first and second months, with an increase of 4.7 letters in the active group compared to the control group in the first month, and in the active group the control group at the second month Compared with, 8.5 characters increased. (FIG. 43).

  Macular edema was also improved in the active group compared to the control group. Subjects in the active group exhibited a 446 micron foveal subregion thickness (CST) reduction, while subjects in the control group exhibited a 343 micron CST reduction and at 3 months the active group In FIG. 44, the retinal thickness decreased by 103 microns compared to the control group. Macular edema likewise improved early in the 21st and 21st months. At month 1, subjects in the active group exhibited a 446 CST decrease compared to a 405 CST decrease (FIG. 45). At 2 months, subjects in the active group exhibited a 459 CST decrease compared to a 344 CST decrease in the control group (FIG. 45).

  From a safety perspective, the active group was generally safe and well tolerated. There were no serious adverse events in the trial, and there were no adverse events in any subject that could have led to study termination.

  Therefore, the results of the trial show that SCS administration of the CLS-TA formulation improved the treatment of macular edema associated with RVO compared to aflibercept treatment alone. SCS administration of CSS-TA significantly improved outcome in patients compared to patients receiving IVT biologics without SCS administration.

Example 5 Study comparing the effect between SCS injection and intravitreal injection of triesence in rabbits Distribution of triesence through different ocular tissues and drug levels in plasma using our microinjector A study was conducted in rabbits to compare the results of SCS injections with commercially available TA (Triessence) with the results of intravitreal injections for the measurement of.

  In this study, each rabbit was injected with a single dose of 4.0 mg of triesense, either intravitreally or in SCS, on study day 1. The rabbits were then observed for up to 90 days, and the concentration of triessence in various eye sites was measured on days 14, 28, 56, and 91.

  Figures 27, 28A-28F illustrate the results of this study. The values shown in FIG. 28 for various parts of the eye show the ratio of total drugs over a 91-day study period when comparing the two injection routes. The measurements in FIGS. 28A-28F show the amount of drug found in a particular tissue or region after SCS injection as a ratio of the amount found in the same tissue or region after intravitreal injection. . For example, a ratio of 1.0 indicates that the amount of drug found in a particular tissue after both injection routes is equal, while a ratio of 10 indicates that the amount of drug present in the tissue after SCS administration is It is 10 times compared with intravitreal administration. A ratio of 0.03 indicates that the drug in a particular area after intravitreal injection is approximately 33 times compared to SCS injection.

  In the case of intravitreal injection, the highest concentration of triessence was present in the iris, ciliary body, and lens, all of which were present in the front of the eye throughout 91 days. Throughout the period, significantly lower concentrations of triesence were present in the choroid and outer retina, and until day 91 there was little triesence in the choroid or outer retina. In contrast, in the case of SCS injection, a significantly higher concentration of triessence was present in the choroid and outer retina during 91 days, with only minimal levels in the iris, ciliary body, and lens. These results indicate that drugs administered through the SCS can remain localized away from the rest of the eye, and that SCS injection is significantly more in target retinal and choroidal tissues than intravitreal injection. Suggests providing good bioavailability.

Example 6: A study comparing the efficacy of SCS administration of CLS-TA and triesence in rabbits Aspects of the present invention are triamcinolone acetonide formulations having the characteristics provided in Table 6 below. Product ("CLS-TA").

  Pharmacokinetic studies in rabbits were performed by comparing the pharmacokinetic profile of CLS-TA, each administered during SCS, with the triessence profile. Pharmacokinetics refers to the process by which a drug is distributed and metabolized in the body, and this process provides information about the drug levels in a particular tissue and how these levels change over time. Each rabbit received a single dose of either 4.0 mg CLS-TA or triessence on study day 1 and was administered through SCS. The rabbits were then observed for up to 90 days and the concentration of the two respective TA formulations in the various parts of the resulting eye was measured on days 15, 29, 58, 63, and 91.

  In this study, CLS-TA and triessence were similarly distributed throughout the eye over 90 days. As shown in FIGS. 29-30, both CLS-TA and triessence administered during SCS remained present in the retina and choroid at high concentration levels throughout 90 days after injection.

Example 7 Animal Toxicity Studies Toxicity studies in rabbits have shown that both CLS-TA and triessence are well tolerated when injected into SCS. In one study, a single injection of triessence was given in rabbit SCS and then evaluated for 17 weeks. In the other study, CLS-TA was injected into rabbit SCS and then evaluated for 13 weeks. A second injection of CLS-TA was then given in the SCS of the rabbit subgroup and the rabbits were evaluated for an additional 13 weeks. Both studies were generally well tolerated and safe after single and repeated dosing, supporting CLS-TA and triessence administration in clinical studies.

Example 8 Evaluation of suprachoroidal triamcinolone injection and oral prednisone in a porcine model of uveitis In this experiment, the anti-inflammatory effect after oral administration of high daily and maintenance daily oral steroids was evaluated and acute posterior uveitis Compared with the anti-inflammatory effect of suprachoroidal steroid injection in a porcine model of inflammation. The questionnaire included whether triamcinolone administration to the SCS demonstrated anti-inflammatory properties in a porcine model of acute uveitis, and this effect is derived from the most commonly used oral high daily dosage regimen in uveitis And whether the anti-inflammatory effect of triamcinolone was comparable to an oral low daily maintenance dose regimen frequently used for long-term control of intraocular inflammation. The study design is shown in Table 6 below.

  24 hours after induction of acute uveitis by intraocular lipopolysaccharide (LPS) injection (day 0) into the vitreous, 50 μL of balanced salt solution (BSS, group 1) or triamcinolone (CLS-TA) (2 mg Group 3) was injected into the suprachoroidal space (SCS). In groups 2 and 4, oral prednisone (1 mg / kg / day, group 2 or 0.1 mg / kg / day, group 4) was dosed on day 0 and repeated every 24 hours until euthanasia on day 3. . Eyes are tested every 24 hours, which includes measurement of inflammation scores (modified Hackett-McDonald) and intraocular pressure (IOP) until euthanasia 3 days after the start of treatment. Safety assessment and histopathology were performed on all eyes. Electroretinography and wide field fundus photography were performed at -24 hours, time 0 (before treatment), and 3 days. Histopathology was performed on eyes after euthanasia.

  The oral dose selected for this study reflects the dose typically used to treat patients with uveitis, the dose being the initial dose (1 mg / kg / day) and the maintenance dose (0 .1 mg / kg / day). In this study, only the right eye of each animal was used, and the left eye was not changed (n = 4 / group).

Uveitis model. SCS injection of CLS-TA or vehicle or oral administration of prednisone and anesthetize pig with (intramuscular terazole-ketamine-xylazine and oxygenated isoflurane via mask) 24 hours before (time -24) 100 ng of Lipopolysaccharide (LPS; E. coli 055: B55; Sigma, Inc. St. Louis, MO) with 100 uLBSS (Alcon Laboratories, Inc, Forth Worth, TX) using a 27 gauge needle in the middle rear glass Injection into the body. All injections were performed aseptically. Prior to all eye injections, the eyes were prepared using a sterile 5% betadine solution and then washed with a sterile eye wash. Immediately after injection, a drop of moxifloxacin eyedrops (Vigamox ^(TM), Alcon Laboratories, Fort Worth, TX) was applied topically, restored the pig from anesthesia.

  treatment. Twenty-four hours after LPS injection (time 0), either 50 uL of CLS-TA (2 mg) (Group 3) or BSS (Group 1) was used aseptically prepared ocular SCS (30 gauge, approximately 1100 μM microneedle). ). Sterile microneedles were used to inject into pig SCS. All injections were made upward (12:00) (approximately 5-6 mm behind the edge). In Groups 2 and 4, oral prednisone (Roxane Laboratories, Columbias, Ohio) (1 mg / kg / day PO [Group 2] or 0.1 mg / kg / day PO [Group 4]) was administered from Day 0 anesthesia. Medication was given at recovery and repeated every 24 hours until euthanasia.

  Eye inflammation score. A modified Hackett-McDonald microscopic eye inflammation scoring system was used to evaluate the anterior eye, lens and anterior vitreous. Specifically, each animal's eyes were examined by a veterinary ophthalmologist using a hand-held slit lamp and an inverted ophthalmoscope as follows. Lens test: Approximately 1 drop of short-acting mydriatic fluid was injected into each eye to dilate the pupil. After acceptable dilation occurred, the lens of each eye was examined using a slit lamp biomicroscope. Hackett, R.A. B. and McDonald, T .; O. Ophthalmic Toxicology and Assessing Ocular Irritation. Dermatotoxicology, 5th edition. Ed. F. N. Marzulli and H.M. I. Maibach. Washington, D.C. C. : Hemisphere Publishing Corporation. 1996; 299-305 and 557-566 (incorporated herein by reference in their entirety).

  Using a portable slit lamp biomicroscope (Zeiss HSO-10, Carl Zeiss Meditec, Inc. USA), the ocular inflammation score was measured at time -24 (before LPS injection), time 0 (vehicle or CLS-TA injection). Prior, then evaluated 24, 48, and 72 hours after injection, the scores were combined to give a single inflammation score for each animal in each study.

  Intraocular pressure. Intraocular pressure (IOP) in conscious pigs restrained by hand was measured after -144, -96, -24, 0, 24, 48, and 72 hours using a TonoVet tonometer (iCare, Finland) (Fig. 1). Measurements were made in awake pigs without local anesthesia. Measurements were made six times sequentially with the tip of the probe in contact with the center of the cornea. After 6 measurements, the average IOP was displayed on the display and the IOP was recorded.

  Dark-adapted electroretinogram (ERG). All animals were dark adapted for 15 minutes prior to ERG. Using anesthetized pigs at times -24, 0, and 72 hours, the pupils were dilated with 1% tropicamide HCl, and whole-field dark-adapted ERGs were recorded from the right eye prior to injection. A monopolar contact lens electrode (ERG-jet, La Chaux des Funds, Switzerland) was placed on the cornea for use as an active electrode. A subcutaneous electrode at the external eye angle was used as the indifferent electrode. A barraque opener was placed to keep the eyelid open, and the hypodermic needle electrode was inserted as the ground electrode on the dorsal side. ERG was induced by a short flash at 0.33 Hz delivered at maximum intensity with a mini-Ganzfeld photostimulator (Roland Instruments, Wiesbaden, Germany). Twenty responses were amplified, filtered and averaged (Relipto Electrophysical Diagnostic Systems, Rolland Instruments, Wiesbaden, Germany). B wave amplitude was recorded from each pig at the specified time.

  Wide-field fundus digital photo. Fundus photographs were taken using a pig anesthetized at times -24, 0, and 72 hours and dilated with 1% tropicamide, and a wide-field digital imaging system (Retcam II, Clarity Medical Systems, Pleasanton, CA). Was taken at standard illumination and focal length.

  Ocular histopathology. Pigs were euthanized at 72 hours of study after completion of clinical scoring, ERG, and wide-field fundus photography. After euthanasia using intravenous barbiturate overdose, the right eye was removed. Aqueous humor (AH) was aspirated and then the eyeball was fixed in Davidson's solution for 24 hours and then treated with alcohol. The median sagittal plane of each eyeball containing the optic nerve was stained with hematoxylin and eosin and examined by light microscopy. Two observers masked for the study group rated the degree of inflammatory infiltration in the front and back of the eye, with the final grade being the average of the two scores. The rating scale used is Tilton, et al. (IOVS 1994) was a modified form.

Anterior chamber tissues including the iris, ciliary body, ciliary process, corneal endothelium, and anterior chamber were scored for the following inflammation severity.
0 = normal tissue 1 = expanded iris vessels and thickened iris parenchyma with exudates, proteins and / or few scattered inflammatory cells in the anterior chamber 2 = moderate number of inflammatory cells in the anterior chamber Infiltration of inflammatory cells into the iris and / or ciliary parenchyma with 3 = severe infiltration of inflammatory cells in the iris parenchyma and ciliary body and severe infiltration of inflammatory cells in the anterior chamber 4 = previous Severe exudation of cells during dense protein aggregation in the chamber and deposition of inflammatory cells on the corneal endothelium.

The retina and posterior histological classification system was as follows.
0 = normal tissue 1 = minimal infiltration of inflammatory cells in the vitreous cavity and / or retina 2 = moderate infiltration of inflammatory cells in the vitreous cavity and / or retina 3 = of inflammatory cells in the vitreous cavity and / or retina Severe infiltration

  Data and statistical analysis. Parametric normal distribution data (ie, IOP, ERG, retinal thickness) were compared by time for each group using a one-way ANOVA model with Tukey-Kramer post hoc analysis. For non-parametric data (ie, clinical score, histological rating), Wilcoxon test per animal was performed at each time point. Differences were considered significant at P <0.05. Results and probabilities were calculated using computer statistical software (JMP10, SAS Inc. Cary, NC).

Results Findings of injection procedure. Injection of CLS-TA or BSS into the SCS (Groups 1 and 3) was performed using microneedles without difficulty or adverse effects. Eyes were examined via slit lamp biomicroscopy and inversion ophthalmoscopic examination after each injection. There was no evidence of reverse leakage of treatment material due to scleral perforation with microneedles or drug leakage into the vitreous. Furthermore, there was no evidence of bleeding at the injection site or vitreous after any injection (SCS).

  Eye inflammation score. The mean cumulative inflammation score assessed by -24-hour ophthalmoscopic examination ranged between 0 and 1 in all groups and was not significantly different. After intravitreal injection of LPS, up to time 0, the mean cumulative inflammation score increased between 5.5 and 6.25 in all groups (FIG. 31) and no significant difference was observed between treatment groups . After treatment, mean inflammation scores generally decreased over the next 3 days in all groups. On days 1 and 2 (24 hours and 48 hours after the start of treatment, respectively), group 3 (CLS-TA) alone had a significantly lower mean cumulative inflammation score than group 1 (BSS treatment; P = 0.04 and P = 0.023 for day 1 and 2). After 72 hours of treatment, Group 2 (high dose prednisone) and Group 3 (CLS-TA) had significantly lower mean cumulative inflammation scores than Group 1 (P <0.034). The mean cumulative inflammation score for group 4 (low dose oral prednisone) was not significantly different from saline treated eyes at any treatment time. These results indicate that in this uveitis model, 2 mg CLS-TA injection into SCS is more rapid in reducing inflammation than high dose oral prednisone (1 vs. 3 days), CLS-TA and high dose It is suggested that both of the prednisone were more effective in reducing ocular inflammation than the low dose prednisone.

  Intraocular pressure. The mean intraocular pressure during habituation was in the range of 14.24-17 mmHg and decreased slightly as the pigs became accustomed to handling. At the same time that uveitis was induced, the mean IOP decreased between 11.5 and 14.25 mmHg by time 0 in all groups and was not significantly different. After treatment, IOP returned to baseline by day 1 in all groups. On day 3, the eyes of group 4 (low dose oral prednisone) have significantly lower IOP than all other groups (P <0.0065), and these eyes are more in comparison to the other groups. It was suggested to have inflammation. The IOP for Group 3 eyes was substantially constant throughout the study period (Figure 32).

  Electroretinogram. At -24 hours, the mean dark-adapted B wave amplitude was not significantly different between groups, ranging from 121.9 +/- 58.7 uV to 220 +/- 16.04 uV. There was no significant difference in mean dark-adapted B-wave amplitude at time 0 (after inducing uveitis) between the groups, ranging from 92.2 +/− 15.3 uV to 204 +/− 62.0 uV. Up to the third day of treatment, ranges of 262.7 +/− 26.5 uV and 91.2 uV +/− 24.5 uV were measured. On day 3, the mean dark-adapted B-wave amplitude in group 3 (CLS-TA) was significantly lower than the other groups (P = 0.034). This decrease in B-wave amplitude was interpreted as biological variability and not toxicologically significant as no correlated abnormalities were observed in fundus studies or retinal histology.

  Wide-field fundus digital photo. A wide field fundus image revealed substantial opacity of the posterior eye 24 hours after LPS injection. The turbidity observed in day 0 eyes was mainly the result of cell infiltration into the vitreous humor and some changes in the retina. In BSS treated eyes (Group 1), turbidity appeared to worsen after 24-72 hours. Treatment with high-dose prednisone (Group 2) and CLS-TA (Group 3) produced a fundus image close to the pre-treatment appearance at 72 hours. However, treatment with low dose prednisone (Group 4) resulted in images that were only slightly improved over vehicle treated eyes.

  Ocular histopathology. No signs of inflammation or degeneration associated with SCS injection in group 3 animals were observed by ocular histopathology. Each eye in this group had evidence of TA crystals during SCS. There was no evidence of toxicity associated with the test article in the front or back of the eye in any group. The mean histological score of the anterior part of the eye with CLS-TA (group 3) was significantly lower than that of saline treated eyes (group 1) (P = 0.018), whereas oral prednisone The mean anterior score of eyes treated with (Groups 2 and 4) was not significantly different from Group 1 (FIG. 33). The mean histological score of the back of eyes treated with CLS-TA was significantly lower than eyes treated with saline (Group 1) and treated with high dose prednisone (Group 2) and CLS-TA (Group 3). The eyes treated were lower than the average score of eyes treated with low dose oral prednisone (Group 4) (P <0.013) (FIG. 33). These results suggest that the effectiveness of CLS-TA in reducing histological inflammation is comparable to high dose oral prednisone and higher than low dose oral prednisone compared to saline treated eyes. ing.

Example 8 Efficacy of suprachoroidal aflibercept in a laser-induced choroidal neovascularization (CNV) model Treatment of chronic retinal diseases such as angiogenesis (wet type) age-related macular degeneration (AMD) is often visual acuity To prevent loss, requires intravitreal injection of biological drugs such as Lucentis, Eilea (Afribercept), or Avastin. The disease shows new blood vessel formation from the choroid. The disease affects the choroid and retina, and specific targeting of these tissues may be more beneficial in modulating disease progression. Specific tissue can be targeted by administering the drug directly into the choroid rather than the current method of injecting into the vitreous. Disclosed herein is a method of targeting the choroid and retina via the suprachoroidal injection technique. This example demonstrates that Eire's superior choroidal injection can lead to a reduction in angiogenic area in a validated animal disease model. This experiment demonstrates that this anti-VEGF agent can provide potential for a useful alternative treatment approach. In addition, there is the potential for accessing new blood vessels in the choroid, which may reduce the frequency of treatment required. If the results of this experiment can be transferred to clinical practice, this may provide a unique option for the treatment of books and other visually threatening diseases.

  We examined the effectiveness of acholine administration of aflibercept in reducing the angiogenic area in the rat laser-induced choroidal neovascularization (CNV) model. Reduction of the angiogenic area in this model may provide evidence for treating retinal diseases such as wet age-related macular degeneration.

  Method. Approximately 8 weeks old Brown Norway rats (4 / group) were used for this study. On the first day, three laser spots / eyes were opened using both eyes for each rat. On the third day, rats were treated using microneedles for a superior choroidal injection. A microneedle was inserted 1-2 mm after the rim and 5 microliters of test drug was injected into the suprachoroidal space. Rats were treated with either saline or aflibercept (Eire 40 mg / mL, Regeneron Pharmaceuticals). Three weeks after laser treatment, the eyes were examined using fluorescein angiography and images were obtained for quantitative analysis. The area of neovascularization was quantified for each laser spot using computer software. Statistical analysis was performed using the Mann Whitneyt-test. The day after fluorescein angiography was performed and CNV lesion area was assessed, the rats were euthanized.

result. As illustrated in FIGS. 34A-34B, based on assessment of angiogenic leakage area, animals treated with saline exhibited approximately 4,862 ± 192 pixels ² while treated with aflibercept. The animals showed approximately 3,318 ± 353 pixels ² . The difference between these measurements represents a statistically significant (p <0.001) decrease in angiogenesis in the comparison between the aflibercept treated group and the saline treated group.

  Conclusion. The suprachoroidal injection of aflibercept leads to a significant reduction of the angiogenic area in this 21-day model of the laser-induced choroidal neovascular model in rats. This three-week treatment effect with a favorable reduction in angiogenic area is the first reported evidence provided over the duration of treatment after suprachoroidal administration with a soluble biological agent (Eirea). Furthermore, these results indicate that top choroidal injection of anti-VEGF agonists can provide another treatment option for diseases such as wet age-related macular degeneration.

Example 9: A method for demonstrating the effectiveness of Eilea administered during SCS in the CNV model . About 8 weeks old Brown Norway rats (4 / group, 4 groups) were used for this study, as illustrated in FIGS. 35-36. On the first day, 3 laser spots / eyes were opened using both eyes for each rat. On the third day, rats were treated using microneedles for a superior choroidal injection. A microneedle was inserted 1-2 mm after the rim and 5 microliters of test drug was injected into the suprachoroidal space. Rats were treated with either saline or aflibercept (Iriea (Aflibercept) 40 mg / mL, Regeneron Pharmaceuticals). On day 10, the rats were treated with microneedles again for a superior choroidal injection. A microneedle was inserted 1-2 mm after the rim and 5 microliters of test drug was injected into the suprachoroidal space. Rats were treated with either saline or aflibercept (Eire 40 mg / mL, Regeneron Pharmaceuticals).

  Three weeks after laser treatment, the eyes were examined using fluorescein angiography and images were obtained for quantitative analysis. The area of neovascularization was quantified for each laser spot using computer software. Statistical analysis was performed using the Mann Whitney t-test. The day after fluorescein angiography was performed and CNV lesion area was assessed, the rats were euthanized.

result. As illustrated in FIGS. 37A-37B (also including the results of single injection saline from Example 8 and Eire treated animals), double injection saline based on assessment of angiogenic leakage area Treated animals exhibited approximately 4898 ± 254 pixels ² while double-injected aflibercept treated animals exhibited approximately 3485 ± 280 pixels ² . The difference between these measurements represents a statistically significant (p <0.001) reduction in angiogenesis in the comparison between the double injection aflibercept treatment group and the double injection saline treatment group.

  Figures 38-40 illustrate that there is little statistically significant difference in lesion area between single injection saline treated animals and double injection saline treated animals. FIGS. 38-40 also illustrate the difference in lesion area between single-injected Ilia (Aflibercept) treated animals (200 μg) and double-injected Ilia (Aflibercept) treated animals (400 μg). Lesion area values for saline (intravitreal administration) and Ilea (200 μg, intravitreal administration) are also shown for comparison. FIG. 39 illustrates in more detail the comparison between a single injection Ilea treatment (200 μg, suprachoroidal administration), saline treatment (intravitreal administration), and Ilea (Aflibercept) (200 μg, intravitreal administration). .

Example 10 Efficacy of suprachoroidal CLS-TA in combination with intravitreal aflibercept in a subject with BRVO or CRVO The data collected in the study described in Example 4 above was further analyzed, and the subject In the treatment of subjects with macular edema (ME) following retinal venous occlusion (RVO) by stratified by RVO type and perfusion type, and subjects who received the simulated suprachoroidal procedure plus IVT aflibercept In comparison, the efficacy of superior choroidal injection of CLS-TA + IVT aflibercept was further evaluated. As discussed in Example 4, each subject received at least one IVT aflibercept injection and half of the subjects received a single suprachoroidal injection of CLS-TA. Subjects enrolled in this study were untreated RVO subjects (HRVO, CRVO, and BRVO) for ME in the study eye. All eligible subjects were randomized (Day 1) and received an anti-VEGF-treated (Aflibercept) IVT injection + CLS-TA suprachoroidal injection or aflibercept IVT injection + simulated suprachoroidal procedure . Subjects were followed for approximately 3 months after randomization. Subjects, sponsors, vision technicians, and optical coherence tomography (OCT) reading centers were masked for treatment.

  The scheduled visit design for all 46 enrolled subjects is described in Example 4. The following assessments were made: total number of times a subject was eligible for IVT aflibercept administration within each treatment group over 3 months; mean foveal subregion thickness (CST) at 1, 2, and 3 months; Mean change in foveal subregion thickness (CST) at 1, 2, and 3 months; mean best corrected visual acuity (BCVA) at 1, 2, and 3 months; and best correction at 1, 2, and 3 months Average change in visual acuity (BCVA). As explained above, subjects are stratified based on RVO type (BRVO or CRVO) and perfusion type (ischemic or non-ischemic), with any difference between the control treatment (IVT aflibercept + mock) It was determined whether it could be detected in the efficacy of the active treatment group treatment (IVT aflibercept + SCS supra) compared to SCS).

Study treatment, re-treatment criteria, enrollment criteria, visit schedule, injection procedure, and efficacy assessment were described in Example 4.
result

Patients were stratified by type of RVO and perfusion type (ischemic versus non-ischemic) as described in Table 7.

  The purpose of this study was to determine the number of doses of CST, BVCA, and the required aflibercept in subjects within each group category (BRVO vs. CRVO; and ischemic vs. non-ischemic) (as described in Example 4 above). Based on CST or BCVA criteria, as determined by subjects eligible for re-treatment with IVT aflibercept). FIG. 46 shows the retreatment eligibility of enrolled patients from both treatment groups with aflibercept. As shown in the figure, the percentage of patients in the active treatment group (IVT aflibercept + SCS TA) eligible for retreatment with aflibercept in both BRVO and CRVO groups (21% and 22%, respectively) was It was lower compared to the percentages eligible for further aflibercept (aflibercept alone) in the control treatment group in patients with BRVO and CRVO (67% and 71%, respectively). Thus, the combination of aflibercept + zuplater (SCS TA) represented an effective treatment by both BRVO and CRVO patients.

  As shown in FIG. 47, at baseline, the mean foveal subregion thickness (CST) was 638 μm in BRVO subjects treated with aflibercept + suplater (active group) and within the control group In the BRVO subject, 586 μm. In the first month, the average CST decreased by about 300 μm in both treatment groups. At 2 months, the average CST increased to 455 μm in the control group, but the average CST in subjects treated in the active group remained at 295 μm. At 3 months, the average CST was about 300 μm for subjects in both groups. The active group was consistently effective with a reduction in CST.

  From the point of view of mean change in CST, at 2 months, BRVO subjects in Aflibercept + Zuplater (active drug group) showed a decrease of 347 μm, while BRVO subjects in the control group only showed a decrease of 130 μm. The difference between the 217 μm groups was shown. In addition, in both month 1 and month 3, the average CST is lower in subjects treated in the active group compared to the average CST in the control group, and combined with SCS injection of anti-inflammatory drugs Shown that the IVT injection of aflibercept administered was more effective to reduce CST (FIG. 48).

  As shown in FIG. 49, mean best corrected visual acuity (BCVA) in BRVO subjects improved in both active and control groups from baseline to 3 months. From the perspective of changes in BCVA (FIG. 50), subjects in the BRVO active group had consistently increased BCVA from month 1 to month 3 (13-16-17), but within the control group BCVA also increased in the first month, decreased in the second month, and increased again in the third month), and the active group was more consistently effective in improving BCVA in BRVO subjects. It shows that.

  For CRVO patients, aflibercept + Zuplater (active group) treatment also resulted in more CST reduction compared to the control group (1 month from baseline: 778 μm to 326 μm) (eg, from baseline (Month 1: 876 μm to 268 μm) (FIG. 51), Aflibercept + Zuprata is also a more effective treatment for CRVO patients. In terms of CST change, subjects in the active group exhibited a 607 μm decrease at month 1 while subjects in the control group exhibited a 452 μm decrease, with a 156 μm CST relative to the active group compared to the control group. Shows a further decrease in (Figure 52). Similarly, the active drug group showed a further 212 μm decrease in CST at 2 months than the control group, and a further 238 μm decrease in CST at 3 months.

  In addition, as shown in FIG. 53, aflibercept + zuplater (active drug group) also increased the average BCVA score in CRVO patients from baseline to 3 months compared to subjects in the control group. Further improved. From the perspective of changes in BCVA, subjects in the active group increased by 21 scores, while subjects in the control group increased by 10 scores, and in the first month, 11 scores for the active group over the control group. A further increase in BCVA is shown (Figure 54). Similarly, BCVA is also improved at 2 and 3 months, with an 18-score increase in the active group compared to the control group at 2 months, and the active drug at 3 months compared to the control group. There was an increase of 16 scores within the group.

  The data was also evaluated to determine the effect of perfusion type (ischemic versus non-ischemic patients) on eligibility for aflibercept, BVCA, and CST. Patients were stratified to ischemic RVO or non-ischemic RVO and further stratified to BRVO or CRVO. Eligibility for further aflibercept administration, BVCA, and CST were evaluated for each subgroup of patients.

  A higher proportion of non-ischemic patients were eligible for aflibercept retreatment independent of the control versus active group (Figure 55). Within the ischemic group (independent of RVO type), active treatment patients were not eligible for aflibercept retreatment, whereas 40% of control patients were eligible for aflibercept retreatment (Figure 56). Within the non-ischemic group (independent of RVO type), more patients in the control treatment group required aflibercept retreatment compared to the active treatment group (of the total number of patients in each group). Of these, 13 (72%) vs. 5 (29%) people; FIG. 57).

  58A-D show BVCA and CST data for ischemic versus non-ischemic patients independent of treatment at 1, 2, and 3 months of the study. FIG. 58A shows BVCA in ischemic versus non-ischemic patients. There was little difference in BVCA between the non-ischemic group and the ischemic group. FIG. 58B shows that BVCA changes remained the same in the non-ischemic group (13 or 14), but increased in the ischemic group (16, 21 at 1, 2, and 3 months, respectively). , And 20). FIG. 58C shows that CST in non-ischemic patients decreased from 715 μm at baseline to 352 μm at 3 months and CST in ischemic patients decreased from 773 μm at baseline to 280 μm at 3 months. . FIG. 58D shows changes in CST, showing that ischemic patients exhibited a consistent decrease with CST over a 3 month study period.

  Patients were then stratified into treatment groups to evaluate any differences in BVCA and CST data in the ischemic versus non-ischemic subgroup.

  FIGS. 59A-D show BVCA and CST data for non-ischemic patients within each treatment group at months 1, 2, and 3 of the study. FIG. 59A shows that for non-ischemic patients, BVCA increased from about 52 at baseline to about 69 at month 3 in the drug treatment group, while in the control group BVCA increased from about 48 to about baseline at baseline. It shows that it increased only to 58. The change in BVCA over time in these patients is about a 3 letter increase in the active versus control group at month 1 and about 8 in the active versus control group at months 2 and 3. There was an increase in letters (FIG. 59B). FIG. 59C shows that CST decreased in the active treatment group until 2 months compared to the control treatment group and remained reduced compared to the control at 3 months. Similarly, FIG. 59D shows that in the second and third months, the active treatment group showed a much smaller decrease in CST compared to the control treatment group.

  Figures 60A-D show BVCA and CST data for ischemic patients within each treatment group at months 1, 2, and 3 of the study. FIG. 60A shows that for ischemic patients, the group BVCA was similar in each group for each month of study. However, FIG. 60B shows that changes in BVCA in ischemic patients in the control treatment group were reduced compared to changes in BVCA in the active treatment group. Patients in the active treatment group increased about 9 letters in the first and second months and about 7 letters in the third month compared to control patients. FIG. 60C shows that CST decreased in the active treatment group compared to the control treatment group up to month 1. FIG. 60D shows the change in CST, showing that the active treatment group patients exhibited a more consistent decrease in CST over the 3 month study period.

  Patients were further categorized into BRVO or CRVO and ischemic or non-ischemic subgroups. Figures 61A-D show BVCA data by treatment group stratified into ischemic or non-ischemic BRVO or CRVO groups at 1, 2, and 3 months of the study. FIG. 61A shows BVCA in ischemic BRVO patients within the control treatment group (Aflibercept + Simulation) versus the active treatment group, with patients within the active treatment group exhibiting an increase in BVCE each month of the study. It shows that. In contrast, FIG. 61B shows that patients within the active treatment group exhibited a consistent increase in BVCA, while patients within the control treatment group were active treatment patients at both month 1 and month 3. Shows a higher BVCA. Surprisingly, in both ischemic CRVO patients and non-ischemic CRVO groups, the active treatment group patients exhibited even higher BVCA compared to the control treatment group patients at 1, 2, and 3 months. (FIGS. 61C and 61D). In particular, patients with ischemic CRVO unexpectedly show a high increase of about 27 characters in the first month, about 36 characters in the second month, about 33 characters in the third month, which is higher than the control treatment group. Was also a significant improvement (increases of about 13, about 19, and about 21 characters at months 1, 2, and 3, respectively; FIG. 61D). In summary, the data show that the combination of aflibercept and zuplata provided superior clinical benefits in CRVO patients, particularly in ischemic CRVO patients. FIG. 62 provides an overview of the data provided in FIGS. 61A-D.

  Publications, patents, and patent applications cited herein are specifically incorporated by reference in their entirety. Although the described invention has been described with reference to specific embodiments thereof, those skilled in the art can obtain various modifications and substitute equivalents without departing from the spirit and scope of the invention. It should be understood that it can. In addition, many modifications may be made to adopt a particular situation, material, composition of matter, process, process step, or step within the objective spirit and scope of the present invention. All such modifications are intended to be within the scope of the claims appended hereto.

Claims (75)

A method of treating wet age-related macular degeneration (AMD), choroidal neovascularization (CNV), CNV-related wet AMD, or RVO-related wet AMD in a human subject in need thereof, comprising:
Non-surgically administering in a dosing session an effective amount of aflibercept drug formulation into the suprachoroidal space (SCS) of the eye of said human subject in need of treatment;
Upon administration, the aflibercept drug formulation flows out of the insertion site and is substantially localized to the back of the eye.   The method of claim 1, further comprising non-surgically administering a second drug to the patient's eye.   3. The method of claim 2, wherein the second drug is present in the aflibercept drug formulation.   3. The method of claim 2, wherein the second drug is present in a second drug formulation and is administered intravitreally.   5. The method of any one of claims 2-4, wherein the second drug is a VEGF modulator.   6. The method of claim 5, wherein the VEGF modulator is a VEGF antagonist.   The second drug is from a VEGF-receptor kinase antagonist, anti-VEGF antibody or fragment thereof, anti-VEGF receptor antibody, anti-VEGF aptamer, small molecule VEGF antagonist, thiazolidinedione, quinoline, or design ankyrin repeat protein (DARPin) 7. The method of claim 6, which is a VEGF antagonist selected. The VEGF antagonist is aflibercept, dibu-aflibercept, bevacizumab, sonepizumab, VEGF sticky trap, cabozantinib, foletinib, vandetanib, nintedanib, regorafenib, cediranib, ranibizumab, lapatinib, sultinib, sunitib Bucillamine, axitinib, pazopanib, fluocinolone acetonide, nintedanib, AL8326, 2C3 antibody, AT001 antibody, XtendVEGF antibody, HuMax-VEGF antibody, R3 antibody, AT001 / r84 antibody, HyBEV, ANG3070, APX003 antibody, APX004 antibody, APX004 antibody BDM-E, VGX100 antibody, VGX200, VGX300, COSMIX, D X903 / 1008 antibody, ENMD2076, INDUS815C, R84 antibody, KD019, NM3, MGCD265, MG516, MP0260, NT503, anti-DLL4 / VEGF bispecific antibody, PAN90806, paromid 529, BD0801 antibody, XV615, lucitanib mote Salt, AAV2-sFLT01, soluble Flt1 receptor, AV-951, boraseltib, CEP11981, KH903, lenvatinib, lenvatinib mesylate, terameprocol, PF00337210, PRS050, SP01, carboxyamidotriazole orotic acid, hydroxychloroquine, linifanib ALG1001, AGN150998, MP0112, AMG386, ponatinib, PD173074, AVA 01, BMS690514, KH902, Gorbatinib (E7050), Dobitinib, Dobitinib lactate (TKI258, CHIR258), ORA101, ORA102, Axitinib (Inwriter, AG013736), PTC299, Pegaptanib sodium, Tropona, EG3306B, Tropona, EG3306G, Anti-VEGFR Arterase, Avila, CEP7055, CLT009, ESBA903, GW6544652, HMPL010, GEM220, HYB676, JNJ17029259, TAK593, Nova21012, Nova21013, CP564959, Smart Anti-VEGF antibody, AG028262P, AG1395S , PG545, PTI101, TG100948, ICS283, XL647, enzastaurin hydrochloride, BC194, COT601M06.1, COT604M06.2, mabion VEGF, apatinib, RAF265 (CHIR-265), motesanib diphosphate (AMG-706) Lenvatinib (E7080), TSU-68 (SU6668, orantinib), Brivanib (BMS-540215), MGCD-265, AEE788 (NVP-AEE788), ENMD-2076, OSI-930, CYC116, Ki8751, Terratinib, AR13633S, AR13633S Dobitinib (TKI-258) dilactic acid, apatinib, BMS-794833, brivanib alaninato (BMS-582664), golvatinib (E 050), semaxanib (SU5416), ZM323881HCl, Kabozanchinibu malic acid (XL184), ZM306416, AL3818, AL8326,2C3 antibody, AT001 antibody, HyBEV, bevacizumab (Avastin ^(TM)), ANG3070, APX003 antibody, APX004 antibody, Ponachinibu ( AP24534), BDM-E, VGX100 antibody (VGX100CIRCADIAN), VGX200 (c-fos induced growth factor monoclonal antibody), VGX300, COSMIX, DLX903 / 1008 antibody, ENMD2076, sunitinib malate (Sutent ^{(registered trademark)} ), INDUS815C, Allogeneic mesenchymal progenitor cells combined with R84 antibody, KD019, NM3, anti-VEGF antagonist (Eg, anti-VEGF antibody), MGCD265, MG516, VEGF-receptor kinase inhibitor, MP0260, NT503, anti-DLL4 / VEGF bispecific antibody, PAN90806, paromid 529, BD0801 antibody, XV615, lucitanib (AL3810, E3810) , AMG 706 (motesanib diphosphate), AAV2-sFLT01, soluble Flt1 receptor, cediranib (Recentin ^TM), AV-951, Chibozanibu (KRN-951), REGORAFENIB (Suchibaga ^{(registered trademark)),} Boraseruchibu (BI6727), CEP11981, KH903, lenvatinib (E7080), Ren bee nibs mesylate, Terra Mepuro call (EM1421), ranibizumab (Lucentis ^(TM)), hydrochloric pazopanib (Votori Cement ^{TM), PF00337210, PRS050, SP01} ( curcumin), orotic acid carboxyamidotriazole, hydroxychloroquine, Rinifanibu (ABT 869, RG3635), fluocinolone acetonide (Irubien ^{(registered trademark)),} ALG1001, AGN150998, DARPin MP0112, AMG386 , Ponachinibu (AP24534), AVA101, nintedanib (Barugatefu ^TM), BMS690514, KH902, Gorubachinibu (E7050), everolimus (Afinitor ^®), Dobichinibu lactate (TKI258, CHIR258), ORA101, ORA102, axitinib (Inraita ^{(registered trademark),} AG013736), Purichidepushin (Aplidine ^{(registered trademark)),} P C299, aflibercept (monkey trap ^{(registered trademark),} Airia ^{(registered trademark)),} pegaptanib sodium (Macugen ^TM, LI900015), verteporfin (Visudyne ^(TM)), bucillamine (Rimachiru, lamin, Burimani, Ramitto , Boomik), R3 antibody, AT001 / r84 antibody, troponin (BLS0597), EG3306, batalanib (PTK787), Bmab100, GSK2136773, anti-VEGFR alterase, Ávila, CEP7055, CLT009, ESBA903, HuMax-WEMH, HEMEM-65MP , HYB676, JNJ17029259, TAK593, XtendVEGF antibody, Nova21012, Nova21013, CP 64959, Smart anti-VEGF antibody, AG0282262, AG13958, CVX241, SU14813, PRS055, PG501, PG545, PTI101, TG10088, ICS283, XL647, Enzastaurine hydrochloride (LY317615), BC194, quinoline, COT601T0. 7. The method of claim 6, which is SIR sphere, apatinib (YN968D1), or AL3818 conjugated to mabion VEGF, anti-VEGF or VEGF-R antibody.   7. The method of claim 6, wherein the VEGF antagonist is aflibercept. A method of treating wet age-related macular degeneration (AMD) in a human subject in need thereof comprising:
In a dosing session, an effective amount of aflibercept drug formulation comprising a first drug is non-surgically administered to the suprachoroidal space (SCS) of the eye of the human subject in need of treatment for the wet AMD Including steps,
Upon administration, the aflibercept drug formulation flows out of the insertion site and is substantially localized to the back of the eye.   11. The method of claim 10, wherein the wet AMD is associated with choroidal neovascularization (CNV) in the human subject.   114. The method of any one of claims 10-11, further comprising non-surgically administering a second drug to the patient's eye.   13. The method of claim 12, wherein the second drug is present in the aflibercept drug formulation.   13. The method of claim 12, wherein the second drug is present in a second drug formulation and is administered intravitreally.   15. The method of any one of claims 12-14, wherein the second drug is a VEGF modulator.   16. The method of claim 15, wherein the VEGF modulator is a VEGF antagonist.   The second drug is from a VEGF-receptor kinase antagonist, anti-VEGF antibody or fragment thereof, anti-VEGF receptor antibody, anti-VEGF aptamer, small molecule VEGF antagonist, thiazolidinedione, quinoline, or design ankyrin repeat protein (DARPin) 17. A method according to claim 16 which is a VEGF antagonist selected. The VEGF antagonist is aflibercept, dibu-aflibercept, bevacizumab, sonepizumab, VEGF sticky trap, cabozantinib, foletinib, vandetanib, nintedanib, regorafenib, cediranib, ranibizumab, lapatinib, sultinib, sunitib Bucillamine, axitinib, pazopanib, fluocinolone acetonide, nintedanib, AL8326, 2C3 antibody, AT001 antibody, XtendVEGF antibody, HuMax-VEGF antibody, R3 antibody, AT001 / r84 antibody, HyBEV, ANG3070, APX003 antibody, APX004 antibody, APX004 antibody BDM-E, VGX100 antibody, VGX200, VGX300, COSMIX, D X903 / 1008 antibody, ENMD2076, INDUS815C, R84 antibody, KD019, NM3, MGCD265, MG516, MP0260, NT503, anti-DLL4 / VEGF bispecific antibody, PAN90806, paromid 529, BD0801 antibody, XV615, lucitanib mote Salt, AAV2-sFLT01, soluble Flt1 receptor, AV-951, boraseltib, CEP11981, KH903, lenvatinib, lenvatinib mesylate, terameprocol, PF00337210, PRS050, SP01, carboxyamidotriazole orotic acid, hydroxychloroquine, linifanib ALG1001, AGN150998, MP0112, AMG386, ponatinib, PD173074, AVA 01, BMS690514, KH902, Gorbatinib (E7050), Dobitinib, Dobitinib lactate (TKI258, CHIR258), ORA101, ORA102, Axitinib (Inwriter, AG013736), PTC299, Pegaptanib sodium, Tropona, EG3306B, Tropona, EG3306G, Anti-VEGFR Arterase, Avila, CEP7055, CLT009, ESBA903, GW6544652, HMPL010, GEM220, HYB676, JNJ17029259, TAK593, Nova21012, Nova21013, CP564959, Smart Anti-VEGF antibody, AG028262P, AG1395S , PG545, PTI101, TG100948, ICS283, XL647, enzastaurin hydrochloride, BC194, COT601M06.1, COT604M06.2, mabion VEGF, apatinib, RAF265 (CHIR-265), motesanib diphosphate (AMG-706) Lenvatinib (E7080), TSU-68 (SU6668, orantinib), Brivanib (BMS-540215), MGCD-265, AEE788 (NVP-AEE788), ENMD-2076, OSI-930, CYC116, Ki8751, Terratinib, AR13633S, AR13633S Dobitinib (TKI-258) dilactic acid, apatinib, BMS-794833, brivanib alaninato (BMS-582664), golvatinib (E 050), semaxanib (SU5416), ZM323881HCl, Kabozanchinibu malic acid (XL184), ZM306416, AL3818, AL8326,2C3 antibody, AT001 antibody, HyBEV, bevacizumab (Avastin ^(TM)), ANG3070, APX003 antibody, APX004 antibody, Ponachinibu ( AP24534), BDM-E, VGX100 antibody (VGX100CIRCADIAN), VGX200 (c-fos induced growth factor monoclonal antibody), VGX300, COSMIX, DLX903 / 1008 antibody, ENMD2076, sunitinib malate (Sutent ^{(registered trademark)} ), INDUS815C, Allogeneic mesenchymal progenitor cells combined with R84 antibody, KD019, NM3, anti-VEGF antagonist (Eg, anti-VEGF antibody), MGCD265, MG516, VEGF-receptor kinase inhibitor, MP0260, NT503, anti-DLL4 / VEGF bispecific antibody, PAN90806, paromid 529, BD0801 antibody, XV615, lucitanib (AL3810, E3810) , AMG 706 (motesanib diphosphate), AAV2-sFLT01, soluble Flt1 receptor, cediranib (Recentin ^TM), AV-951, Chibozanibu (KRN-951), REGORAFENIB (Suchibaga ^{(registered trademark)),} Boraseruchibu (BI6727), CEP11981, KH903, lenvatinib (E7080), Ren bee nibs mesylate, Terra Mepuro call (EM1421), ranibizumab (Lucentis ^(TM)), hydrochloric pazopanib (Votori Cement ^{TM), PF00337210, PRS050, SP01} ( curcumin), orotic acid carboxyamidotriazole, hydroxychloroquine, Rinifanibu (ABT 869, RG3635), fluocinolone acetonide (Irubien ^{(registered trademark)),} ALG1001, AGN150998, DARPin MP0112, AMG386 , Ponachinibu (AP24534), AVA101, nintedanib (Barugatefu ^TM), BMS690514, KH902, Gorubachinibu (E7050), everolimus (Afinitor ^®), Dobichinibu lactate (TKI258, CHIR258), ORA101, ORA102, axitinib (Inraita ^{(registered trademark),} AG013736), Purichidepushin (Aplidine ^{(registered trademark)),} P C299, aflibercept (monkey trap ^{(registered trademark),} Airia ^{(registered trademark)),} pegaptanib sodium (Macugen ^TM, LI900015), verteporfin (Visudyne ^(TM)), bucillamine (Rimachiru, lamin, Burimani, Ramitto , Boomik), R3 antibody, AT001 / r84 antibody, troponin (BLS0597), EG3306, batalanib (PTK787), Bmab100, GSK2136773, anti-VEGFR alterase, Ávila, CEP7055, CLT009, ESBA903, HuMax-WEMH, HEMEM-65MP , HYB676, JNJ17029259, TAK593, XtendVEGF antibody, Nova21012, Nova21013, CP 64959, Smart anti-VEGF antibody, AG0282262, AG13958, CVX241, SU14813, PRS055, PG501, PG545, PTI101, TG10088, ICS283, XL647, Enzastaurine hydrochloride (LY317615), BC194, quinoline, COT601T0. 17. The method of claim 16, which is SIR sphere, apatinib (YN968D1), or AL3818 conjugated to mabion VEGF, anti-VEGF or VEGF-R antibody.   17. The method of claim 16, wherein the VEGF antagonist is aflibercept. A method of treating macular edema associated with retinal vein occlusion (RVO) in a human subject in need thereof comprising:
(I) administering an effective amount of a VEGF modulator to the human subject;
(Ii) non-surgically administering an effective amount of an anti-inflammatory agent to the suprachoroidal space (SCS) of the eye of the human subject;
Including a method.   21. The method of claim 20, wherein the anti-inflammatory drug is a steroid or a non-steroidal inflammatory drug (NSAID).   24. The method of claim 21, wherein the steroid is triamcinolone acetonide (TA).   24. The method of claim 22, wherein the TA is administered to the SCS of the human subject at a dose level of about 2 mg to about 10 mg.   24. The method of claim 23, wherein the TA is administered to the SCS of the human subject at a dose level of about 4 mg.   21. The method of claim 20, wherein the VEGF modulator is administered intravitreally to the subject.   21. The method of claim 20, wherein the VEGF modulator is a VEGF antagonist.   The VEGF antagonist is selected from 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, thiazolidinedione, quinoline, or design ankyrin repeat protein (DARPin). 27. The method of claim 26. The VEGF antagonist is aflibercept, dibu-aflibercept, bevacizumab, sonepizumab, VEGF sticky trap, cabozantinib, foletinib, vandetanib, nintedanib, regorafenib, cediranib, ranibizumab, lapatinib, sultinib, sunitib Bucillamine, axitinib, pazopanib, fluocinolone acetonide, nintedanib, AL8326, 2C3 antibody, AT001 antibody, XtendVEGF antibody, HuMax-VEGF antibody, R3 antibody, AT001 / r84 antibody, HyBEV, ANG3070, APX003 antibody, APX004 antibody, APX004 antibody BDM-E, VGX100 antibody, VGX200, VGX300, COSMIX, D X903 / 1008 antibody, ENMD2076, INDUS815C, R84 antibody, KD019, NM3, MGCD265, MG516, MP0260, NT503, anti-DLL4 / VEGF bispecific antibody, PAN90806, paromid 529, BD0801 antibody, XV615, lucitanib mote Salt, AAV2-sFLT01, soluble Flt1 receptor, AV-951, boraseltib, CEP11981, KH903, lenvatinib, lenvatinib mesylate, terameprocol, PF00337210, PRS050, SP01, carboxyamidotriazole orotic acid, hydroxychloroquine, linifanib ALG1001, AGN150998, MP0112, AMG386, ponatinib, PD173074, AVA 01, BMS690514, KH902, Gorbatinib (E7050), Dobitinib, Dobitinib lactate (TKI258, CHIR258), ORA101, ORA102, Axitinib (Inwriter, AG013736), PTC299, Pegaptanib sodium, Tropona, EG3306B, Tropona, EG3306G, Anti-VEGFR Arterase, Avila, CEP7055, CLT009, ESBA903, GW6544652, HMPL010, GEM220, HYB676, JNJ17029259, TAK593, Nova21012, Nova21013, CP564959, Smart Anti-VEGF antibody, AG028262P, AG1395S , PG545, PTI101, TG100948, ICS283, XL647, enzastaurin hydrochloride, BC194, COT601M06.1, COT604M06.2, mabion VEGF, apatinib, RAF265 (CHIR-265), motesanib diphosphate (AMG-706) Lenvatinib (E7080), TSU-68 (SU6668, orantinib), Brivanib (BMS-540215), MGCD-265, AEE788 (NVP-AEE788), ENMD-2076, OSI-930, CYC116, Ki8751, Terratinib, AR13633S, AR13633S Dobitinib (TKI-258) dilactic acid, apatinib, BMS-794833, brivanib alaninato (BMS-582664), golvatinib (E 050), semaxanib (SU5416), ZM323881HCl, Kabozanchinibu malic acid (XL184), ZM306416, AL3818, AL8326,2C3 antibody, AT001 antibody, HyBEV, bevacizumab (Avastin ^(TM)), ANG3070, APX003 antibody, APX004 antibody, Ponachinibu ( AP24534), BDM-E, VGX100 antibody (VGX100CIRCADIAN), VGX200 (c-fos induced growth factor monoclonal antibody), VGX300, COSMIX, DLX903 / 1008 antibody, ENMD2076, sunitinib malate (Sutent ^{(registered trademark)} ), INDUS815C, Allogeneic mesenchymal progenitor cells combined with R84 antibody, KD019, NM3, anti-VEGF antagonist (Eg, anti-VEGF antibody), MGCD265, MG516, VEGF-receptor kinase inhibitor, MP0260, NT503, anti-DLL4 / VEGF bispecific antibody, PAN90806, paromid 529, BD0801 antibody, XV615, lucitanib (AL3810, E3810) , AMG 706 (motesanib diphosphate), AAV2-sFLT01, soluble Flt1 receptor, cediranib (Recentin ^TM), AV-951, Chibozanibu (KRN-951), REGORAFENIB (Suchibaga ^{(registered trademark)),} Boraseruchibu (BI6727), CEP11981, KH903, lenvatinib (E7080), Ren bee nibs mesylate, Terra Mepuro call (EM1421), ranibizumab (Lucentis ^(TM)), hydrochloric pazopanib (Votori Cement ^{TM), PF00337210, PRS050, SP01} ( curcumin), orotic acid carboxyamidotriazole, hydroxychloroquine, Rinifanibu (ABT 869, RG3635), fluocinolone acetonide (Irubien ^{(registered trademark)),} ALG1001, AGN150998, DARPin MP0112, AMG386 , Ponachinibu (AP24534), AVA101, nintedanib (Barugatefu ^TM), BMS690514, KH902, Gorubachinibu (E7050), everolimus (Afinitor ^®), Dobichinibu lactate (TKI258, CHIR258), ORA101, ORA102, axitinib (Inraita ^{(registered trademark),} AG013736), Purichidepushin (Aplidine ^{(registered trademark)),} P C299, aflibercept (monkey trap ^{(registered trademark),} Airia ^{(registered trademark)),} pegaptanib sodium (Macugen ^TM, LI900015), verteporfin (Visudyne ^(TM)), bucillamine (Rimachiru, lamin, Burimani, Ramitto , Boomik), R3 antibody, AT001 / r84 antibody, troponin (BLS0597), EG3306, batalanib (PTK787), Bmab100, GSK2136773, anti-VEGFR alterase, Ávila, CEP7055, CLT009, ESBA903, HuMax-WEMH, HEMEM-65MP , HYB676, JNJ17029259, TAK593, XtendVEGF antibody, Nova21012, Nova21013, CP 64959, Smart anti-VEGF antibody, AG0282262, AG13958, CVX241, SU14813, PRS055, PG501, PG545, PTI101, TG10088, ICS283, XL647, Enzastaurine hydrochloride (LY317615), BC194, quinoline, COT601T0. 27. The method of claim 26, wherein the method is SIR sphere, apatinib (YN968D1), or AL3818 conjugated to mabion VEGF, anti-VEGF or VEGF-R antibody.   30. The method of claim 28, wherein the VEGF antagonist is aflibercept.   30. The method of claim 29, wherein the aflibercept is administered intravitreally to the human subject at a dose level of about 0.5 mg to about 10 mg.   32. The method of claim 30, wherein the aflibercept is administered intravitreally to the human subject at a dose level of about 2 mg.   21. The method of claim 20, wherein the VEGF modulator and the anti-inflammatory agent are administered to the human subject concomitantly or sequentially.   21. The method of claim 20, wherein the method reduces retinal thickness and / or macular thickness relative to baseline measurements prior to treatment of the subject with the VEGF modulator or anti-inflammatory agent.   21. The method of claim 20, wherein the method reduces retinal thickness and / or macular thickness as compared to a subject that has received the VEGF modulator administered to the SCS but has not received the anti-inflammatory agent. The method described.   35. The method of claim 33 or 34, wherein the retinal thickness is a foveal subregion thickness (CST).   36. The method of claim 35, wherein the CST is measured by spectral domain optical coherence tomography (SD-OCT).   36. The method of claim 35, wherein the CST is reduced by at least about 20 μm, at least about 40 μm, at least about 50 μm, at least about 100 μm, at least about 150 μm, or at least about 200 μm.   21. The method of claim 20, wherein the method increases the subject's best corrected visual acuity (BCVA) compared to a baseline measurement prior to treatment of the subject with the VEGF modulator or anti-inflammatory agent. the method of.   21. The method of claim 20, wherein the method increases BCVA in the subject as compared to a subject that has received the VEGF modulator administered to the SCS but has not received the anti-inflammatory agent. Method.   40. The method of claim 38 or 39, wherein the BCVA is assessed using an early treatment study for diabetic retinopathy (ETDRS) vision chart protocol.   40. The method of claim 38 or 39, wherein the increase in BVCA is an increase in the number of characters of about 5, about 6, about 7, about 8, about 9, about 10, or more. A method for improving anti-VEGF therapy in the treatment of ocular disease in a human subject comprising:
(I) administering an effective amount of a VEGF modulator to the human subject;
(Ii) non-surgically administering an effective amount of an anti-inflammatory agent to the suprachoroidal space (SCS) of the eye of the human subject;
Including a method.   43. The method of claim 42, wherein the anti-inflammatory drug is a steroid or a non-steroidal inflammatory drug (NSAID).   44. The method of claim 43, wherein the steroid is triamcinolone acetonide (TA).   45. The method of claim 44, wherein the TA is administered to the SCS of the human subject at a dose level of about 2 mg to about 10 mg.   46. The method of claim 45, wherein the TA is administered to the SCS of the human subject at a dose level of about 4 mg.   43. The method of claim 42, wherein the VEGF modulator is administered intravitreally to the subject.   43. The method of claim 42, wherein the VEGF modulator is a VEGF antagonist.   The VEGF antagonist is selected from 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, thiazolidinedione, quinoline, or design ankyrin repeat protein (DARPin). 49. The method of claim 48. The VEGF antagonist is aflibercept, dibu-aflibercept, bevacizumab, sonepizumab, VEGF sticky trap, cabozantinib, foletinib, vandetanib, nintedanib, regorafenib, cediranib, ranibizumab, lapatinib, sultinib, sunitib Bucillamine, axitinib, pazopanib, fluocinolone acetonide, nintedanib, AL8326, 2C3 antibody, AT001 antibody, XtendVEGF antibody, HuMax-VEGF antibody, R3 antibody, AT001 / r84 antibody, HyBEV, ANG3070, APX003 antibody, APX004 antibody, APX004 antibody BDM-E, VGX100 antibody, VGX200, VGX300, COSMIX, D X903 / 1008 antibody, ENMD2076, INDUS815C, R84 antibody, KD019, NM3, MGCD265, MG516, MP0260, NT503, anti-DLL4 / VEGF bispecific antibody, PAN90806, paromid 529, BD0801 antibody, XV615, lucitanib mote Salt, AAV2-sFLT01, soluble Flt1 receptor, AV-951, boraseltib, CEP11981, KH903, lenvatinib, lenvatinib mesylate, terameprocol, PF00337210, PRS050, SP01, carboxyamidotriazole orotic acid, hydroxychloroquine, linifanib ALG1001, AGN150998, MP0112, AMG386, ponatinib, PD173074, AVA 01, BMS690514, KH902, Gorbatinib (E7050), Dobitinib, Dobitinib lactate (TKI258, CHIR258), ORA101, ORA102, Axitinib (Inwriter, AG013736), PTC299, Pegaptanib sodium, Tropona, EG3306B, Tropona, EG3306G, Anti-VEGFR Arterase, Avila, CEP7055, CLT009, ESBA903, GW6544652, HMPL010, GEM220, HYB676, JNJ17029259, TAK593, Nova21012, Nova21013, CP564959, Smart Anti-VEGF antibody, AG028262P, AG1395S , PG545, PTI101, TG100948, ICS283, XL647, enzastaurin hydrochloride, BC194, COT601M06.1, COT604M06.2, mabion VEGF, apatinib, RAF265 (CHIR-265), motesanib diphosphate (AMG-706) Lenvatinib (E7080), TSU-68 (SU6668, orantinib), Brivanib (BMS-540215), MGCD-265, AEE788 (NVP-AEE788), ENMD-2076, OSI-930, CYC116, Ki8751, Terratinib, AR13633S, AR13633S Dobitinib (TKI-258) dilactic acid, apatinib, BMS-794833, brivanib alaninato (BMS-582664), golvatinib (E 050), semaxanib (SU5416), ZM323881HCl, Kabozanchinibu malic acid (XL184), ZM306416, AL3818, AL8326,2C3 antibody, AT001 antibody, HyBEV, bevacizumab (Avastin ^(TM)), ANG3070, APX003 antibody, APX004 antibody, Ponachinibu ( AP24534), BDM-E, VGX100 antibody (VGX100CIRCADIAN), VGX200 (c-fos induced growth factor monoclonal antibody), VGX300, COSMIX, DLX903 / 1008 antibody, ENMD2076, sunitinib malate (Sutent ^{(registered trademark)} ), INDUS815C, Allogeneic mesenchymal progenitor cells combined with R84 antibody, KD019, NM3, anti-VEGF antagonist (Eg, anti-VEGF antibody), MGCD265, MG516, VEGF-receptor kinase inhibitor, MP0260, NT503, anti-DLL4 / VEGF bispecific antibody, PAN90806, paromid 529, BD0801 antibody, XV615, lucitanib (AL3810, E3810) , AMG 706 (motesanib diphosphate), AAV2-sFLT01, soluble Flt1 receptor, cediranib (Recentin ^TM), AV-951, Chibozanibu (KRN-951), REGORAFENIB (Suchibaga ^{(registered trademark)),} Boraseruchibu (BI6727), CEP11981, KH903, lenvatinib (E7080), Ren bee nibs mesylate, Terra Mepuro call (EM1421), ranibizumab (Lucentis ^(TM)), hydrochloric pazopanib (Votori Cement ^{TM), PF00337210, PRS050, SP01} ( curcumin), orotic acid carboxyamidotriazole, hydroxychloroquine, Rinifanibu (ABT 869, RG3635), fluocinolone acetonide (Irubien ^{(registered trademark)),} ALG1001, AGN150998, DARPin MP0112, AMG386 , Ponachinibu (AP24534), AVA101, nintedanib (Barugatefu ^TM), BMS690514, KH902, Gorubachinibu (E7050), everolimus (Afinitor ^®), Dobichinibu lactate (TKI258, CHIR258), ORA101, ORA102, axitinib (Inraita ^{(registered trademark),} AG013736), Purichidepushin (Aplidine ^{(registered trademark)),} P C299, aflibercept (monkey trap ^{(registered trademark),} Airia ^{(registered trademark)),} pegaptanib sodium (Macugen ^TM, LI900015), verteporfin (Visudyne ^(TM)), bucillamine (Rimachiru, lamin, Burimani, Ramitto , Boomik), R3 antibody, AT001 / r84 antibody, troponin (BLS0597), EG3306, batalanib (PTK787), Bmab100, GSK2136773, anti-VEGFR alterase, Ávila, CEP7055, CLT009, ESBA903, HuMax-WEMH, HEMEM-65MP , HYB676, JNJ17029259, TAK593, XtendVEGF antibody, Nova21012, Nova21013, CP 64959, Smart anti-VEGF antibody, AG0282262, AG13958, CVX241, SU14813, PRS055, PG501, PG545, PTI101, TG10088, ICS283, XL647, Enzastaurine hydrochloride (LY317615), BC194, quinoline, COT601T0. 49. The method of claim 48, wherein the method is SIR sphere, apatinib (YN968D1), or AL3818 conjugated to mabion VEGF, anti-VEGF or VEGF-R antibody.   51. The method of claim 50, wherein the VEGF antagonist is aflibercept.   52. The method of claim 51, wherein the aflibercept is administered intravitreally to the human subject at a dose level of about 0.5 mg to about 10 mg.   53. The method of claim 52, wherein the aflibercept is administered intravitreally to the human subject at a dose level of about 2 mg.   43. The method of claim 42, wherein the VEGF modulator and the anti-inflammatory agent are administered to the human subject concomitantly or sequentially.   43. The method of claim 42, wherein the method reduces retinal thickness and / or macular thickness compared to baseline measurements prior to treatment of the subject with the VEGF modulator or anti-inflammatory agent.   43. The method of claim 42, wherein the method reduces retinal thickness and / or macular thickness compared to a subject that has received the VEGF modulator administered to the SCS but has not received the anti-inflammatory agent. The method described.   57. The method of claim 55 or 56, wherein the retinal thickness is a foveal subregion thickness (CST).   58. The method of claim 57, wherein the CST is measured by spectral domain optical coherence tomography (SD-OCT).   58. The method of claim 57, wherein the CST is reduced by at least about 20 μm, at least about 40 μm, at least about 50 μm, at least about 100 μm, at least about 150 μm, or at least about 200 μm.   43. The method of claim 42, wherein the method increases the subject's best corrected visual acuity (BCVA) relative to a baseline measurement prior to treatment of the subject with the VEGF modulator or anti-inflammatory agent. the method of.   43. The method of claim 42, wherein the method increases the BCVA of the subject compared to a subject that has received the VEGF modulator administered to the SCS but has not received the anti-inflammatory agent. Method.   62. The method of claim 60 or 61, wherein the BCVA is assessed using an early treatment study of diabetic retinopathy (ETDRS) vision chart protocol.   62. The method of claim 60 or 61, wherein the increase in BVCA is an increase in the number of characters of about 5, about 6, about 7, about 8, about 9, about 10, or more.   43. The method of claim 42, wherein the ocular disease is macular edema.   65. The method of claim 64, wherein the macular edema is associated with retinal vein occlusion (RVO).   43. The method of claim 42, wherein administration of the anti-inflammatory drug reduces the number of VEGF modulator drug treatments required to treat the ocular disease.   43. The method of claim 20 or 42, wherein the RVO is retinal vein branch occlusion (BRVO) or central retinal vein occlusion (CRVO).   43. The method of claim 20 or 42, wherein the RVO is an ischemic or non-ischemic RVO.   68. The method of claim 67, wherein the CRVO is ischemic CRVO.   70. The method of claim 69, wherein the method increases the subject's BVCA by more than 20 characters.   71. The method of claim 70, wherein the method increases the subject's BVCA by more than 25 characters.   72. The method of claim 71, wherein the method increases the subject's BVCA by more than 30 characters.   43. The method of claim 20 or 42, wherein the anti-inflammatory agent is TA and the VEGF modulator is aflibercept.   74. The method of claim 73, wherein the method increases BCVA in the subject as compared to a control subject that has received aflibercept but no anti-inflammatory agent has been administered to the SCS.   74. The method of claim 73, wherein the method reduces the need to re-treat the subject with an additional dose of aflibercept.