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(12) Patent Application Publication (10) Pub. No.: US 2015/0258120 A1 Zarnitsyn Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2015/0258120 A1 Zarnitsyn Et Al US 20150258120A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2015/0258120 A1 Zarnitsyn et al. (43) Pub. Date: Sep. 17, 2015 (54) METHODS AND DEVICES FOR THE 3, 2013, provisional application No. 61/873,660, filed TREATMENT OF OCULAR DISEASES IN on Sep. 4, 2013, provisional application No. 61/898, HUMAN SUBJECTS 926, filed on Nov. 1, 2013. (71) Applicant: CLEARSIDE BIOMEDICAL, INC., Publication Classification Alpharetta, GA (US) (51) Int. Cl. (72) Inventors: Vladimir Zarnitsyn, Atlanta, GA (US); A 6LX3/573 (2006.01) Samirkumar Patel, Atlanta, GA (US); A619/00 (2006.01) Daniel White, Suwanee, GA (US); A6M 37/00 (2006.01) Glenn Noronha, Atlanta, GA (US); A619/16 (2006.01) Brian Burke, Cary, NC (US) (52) U.S. Cl. CPC ................. A6 IK3I/573 (2013.01); A61 K9/16 (21) Appl. No.: 14/441,151 (2013.01); A61 K9/0048 (2013.01); A61M 37/0015 (2013.01); A61M 2037/0023 (22) PCT Fled: Nov. 8, 2013 (2013.01); A61M 2037/0061 (2013.01) (86) PCT NO.: PCT/US13A69156 (57) ABSTRACT S371 (c)(1), Methods and devices are provided for targeted non-Surgical (2) Date: May 6, 2015 administration of a drug formulation to the Suprachoroidal space (SCS) of the eye of a human subject for the treatment of a posterior ocular disorder or a choroidal malady. In one Related U.S. Application Data embodiment, the method comprises inserting a hollow (60) Provisional application No. 61/724,144, filed on Nov. microneedle into the eye at an insertion site and infusing a 8, 2012, provisional application No. 61/734,872, filed drug formulation through the inserted microneedle and into on Dec. 7, 2012, provisional application No. 61/745, the Suprachoroidal space of the eye, wherein the infused drug 237, filed on Dec. 21, 2012, provisional application formulation flows within the suprachoroidal space away from No. 61/773,124, filed on Mar. 5, 2013, provisional the insertion site during the infusion. In one embodiment, the application No. 61/785,229, filed on Mar. 14, 2013, fluid drug formulation comprises drug nanoparticles or provisional application No. 61/819.388, filed on May microparticles. ... SSS. S. S. s Patent Application Publication Sep. 17, 2015 Sheet 1 of 40 US 2015/0258120 A1 *******3%ak-a-a-a-we-a-Wasa >>>>>*<>><<s>>>>>>>>>>>>><<s>>>>******** axe. 8-y3.3 Patent Application Publication Sep. 17, 2015 Sheet 2 of 40 US 2015/0258120 A1 Ye: 2: 35. 3.ww. ::ex *%Ya &: *. & s a. Patent Application Publication Sep. 17, 2015 Sheet 3 of 40 US 2015/0258120 A1 ... '-'. ---...----- ea rara ...w Ya a . at . Patent Application Publication Sep. 17, 2015 Sheet 4 of 40 US 2015/0258120 A1 s ---- Patent Application Publication Sep. 17, 2015 Sheet 5 of 40 US 2015/0258120 A1 2x22% al -: ******* : 2. %3: ' ' ' , , ---.''' 3. 23 ......:::::::: re- -: - - - - - - - - - - - - - - - - - - w - - - - - - - - - - - - - - - - - - - - - - - : ------------&- 3 Patent Application Publication Sep. 17, 2015 Sheet 6 of 40 US 2015/0258120 A1 Patent Application Publication Sep. 17, 2015 Sheet 7 of 40 US 2015/0258120 A1 Patent Application Publication Sep. 17, 2015 Sheet 8 of 40 US 2015/0258120 A1 Patent Application Publication Sep. 17, 2015 Sheet 9 of 40 US 2015/0258120 A1 Patent Application Publication Sep. 17, 2015 Sheet 10 of 40 US 2015/0258120 A1 FIG. 11A FG. 11B Patent Application Publication Sep. 17, 2015 Sheet 11 of 40 US 2015/0258120 A1 F.G. 11C F.G. 11D Patent Application Publication Sep. 17 2015 Sheet 12 Of 40 US 2015/0258120 A1 Patent Application Publication Sep. 17, 2015 Sheet 13 of 40 US 2015/0258120 A1 FG. 13A FIG. 13B Patent Application Publication Sep. 17, 2015 Sheet 14 of 40 US 2015/0258120 A1 FIG. 14 F.G. 15 Patent Application Publication Sep. 17, 2015 Sheet 15 of 40 US 2015/0258120 A1 Patent Application Publication Sep. 17, 2015 Sheet 16 of 40 US 2015/0258120 A1 al : Y-a- :^eavera-exo-ows: --------------0-8 a -a- rrrrrrrrrrrrrrrr. 'rury rrrrrrrrrrrrrrrrrrrrrrr Patent Application Publication Sep. 17, 2015 Sheet 17 of 40 US 2015/0258120 A1 FIG. 19A FG. 19B intravitreal injection (left to right for each group) Š3S 83ays 8:338ays Siggays suprachoroidal 8:2::ays : t is 33.8 days traita t. S.S. city's Patent Application Publication Sep. 17, 2015 Sheet 18 of 40 US 2015/0258120 A1 FIG. 19C 10 Lens : Choroid Time, days 1. Lens : Retina Time, days Patent Application Publication Sep. 17, 2015 Sheet 19 of 40 US 2015/0258120 A1 FIG. 20A s * x-x Wesle so to 3.2 mg. A Patent Application Publication Sep. 17, 2015 Sheet 21 of 40 US 2015/0258120 A1 FIG. 20O Single Dose GLP Toxicology in Rabbits Systemic Exposure, n=10 rabbits high low dose dose 8: &this sy Patent Application Publication Sep. 17, 2015 Sheet 22 of 40 US 2015/0258120 A1 FG, 2.0D Rabbit Ocular Tissue Levels. After SCS injection of TA Sclera/choroid Patent Application Publication Sep. 17, 2015 Sheet 23 of 40 US 2015/0258120 A1 FG.2OE FIG. 20F Triamcinolone (TA) in the Sclera-Choroid Triamcinolone (TA) in the Retina Patent Application Publication Sep. 17, 2015 Sheet 24 of 40 US 2015/0258120 A1 FIG 21A FIG. 21B Rabbit Uveitis Model: Detailed SCOres (left) s: 8 (middle) : (right) Patent Application Publication Sep. 17, 2015 Sheet 25 of 40 US 2015/0258120 A1 FIG. 21C FIG. 21D 35 S es is .s 9. t 1: . 25 12 iss 5." s E 15 a : 10 «Velicie SCS 4 5 - 4 mg. TA SCS --4 mg. A VI s s A (Control) B (SCSTA) C(VTTA) vs. i S easientire stays Patent Application Publication Sep. 17, 2015 Sheet 26 of 40 US 2015/0258120 A1 FG.22A FIG. 22B Left bars: LPS+ vehicle Acute Pig Uveitis Model: Scores Middle bars: LPS+2mg TA ... ; Right bars: salt solution + vehicle d od SG s a Sl is $8 N25 r. ssŠ O t 3 C g 2 : it is s 2 r O asC & SY s s > s c & Time after treatment (hours) Tme after treatment (hours) Patent Application Publication Sep. 17, 2015 Sheet 27 of 40 US 2015/0258120 A1 FG 23 **************** ~~ **** Study Days Patent Application Publication Sep. 17, 2015 Sheet 28 of 40 US 2015/0258120 A1 FG . 24 Study Time Patent Application Publication Sep. 17, 2015 Sheet 29 of 40 US 2015/0258120 A1 § ( : Patent Application Publication Sep. 17, 2015 Sheet 30 of 40 US 2015/0258120 A1 3. Patent Application Publication Sep. 17, 2015 Sheet 31 of 40 US 2015/0258120 A1 2: Patent Application Publication Sep. 17, 2015 Sheet 32 of 40 US 2015/0258120 A1 Patent Application Publication Sep. 17, 2015 Sheet 33 of 40 US 2015/0258120 A1 § § §§ Pate nt Application Publication Sep. 17, 2015 Sheet 34 of 40 US 2015/0258120 A1 FIG. 27 Anterior Segment Posterior Segment Patent Application Publication Sep. 17, 2015 Sheet 35 of 40 US 2015/0258120 A1 FIG. 28 Aqueous Humor Vitreous Humor Patent Application Publication Sep. 17, 2015 Sheet 36 of 40 US 2015/0258120 A1 FIG. 29 S. as ^ Ss.^ ----------------------------------------------------s-N-mŠ^s. *::::: Si Sis g Stady lay Patent Application Publication Sep. 17, 2015 Sheet 37 of 40 US 2015/0258120 A1 Patent Application Publication Sep. 17, 2015 Sheet 38 of 40 US 2015/0258120 A1 FIG. 31 xas. s s ^x was ^x.1. ^ss Vehicle Study Day Patent Application Publication Sep. 17, 2015 Sheet 39 of 40 US 2015/0258120 A1 FIG. 32 O Study Day 9 Patent Application Publication Sep. 17, 2015 Sheet 40 of 40 US 2015/0258120 A1 FG. 33 Study Day US 2015/0258120 A1 Sep. 17, 2015 METHODS AND DEVICES FOR THE SUMMARY OF THE INVENTION TREATMENT OF OCULAR DISEASES IN 0007. In one aspect, the present invention relates to non HUMAN SUBJECTS Surgical ophthalmic therapies in human patients in need of Such treatment, and more particularly to the infusion of a drug CROSS REFERENCE TO RELATED formulation into the suprachoroidal space of the eye for tar APPLICATIONS geted, local drug delivery, for the treatment of posterior ocu 0001. This application claims priority from U.S. Provi lar disorders, choroidal maladies and other diseases associ sional Application Ser. Nos. 61/724,144, filed Nov. 8, 2012: ated with vascular abnormalities. 61/734,872, filed Dec. 7, 2012: 61/745,237, filed Dec. 21, 0008. In one aspect of the invention, a method is provided 2012: 61/773,124, filed Mar. 5, 2013: 61/785,229, filed Mar. for treating a posterior ocular disorder in a human Subject in 14, 2013: 61/819,388, filed May 3, 2013: 61/873,660, filed need of treatment. In one embodiment, the method comprises Sep. 4, 2013, and 61/898,926, filed Nov. 1, 2013, all of which non-Surgically administering an effective amount of a drug are incorporated herein by reference in their entireties for all formulation to the suprachoroidal space (SCS) of the eye of purposes. the subject in need of treatment of the posterior ocular disor der or choroidal malady. In a further embodiment, upon administration, the drug formulation flows away from the BACKGROUND OF THE INVENTION insertion site and is substantially localized to the posterior 0002 This invention is generally in the field of ophthalmic segment of the eye. In one embodiment, the posterior ocular therapies, and more particularly to the use of a microneedle disorder is an ocular inflammatory condition Such as uveitis, for infusion of a fluid drug formulation into ocular tissues for Scleritis, glaucoma, ocular sarcoidosis, optic neuritis, macu targeted, local drug delivery. lar edema, diabetic retinopathy, macular degeneration, a cor 0003. The delivery of drug to the eye is extremely difficult, neal ulcer, an autoimmune disorder, ophthalmic manifesta particularly delivery of macromolecules and delivery to the tions of AIDS, optic nerve degeneration, geographic atrophy, posterior segment.
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