US 20180325884A1 ( 19) United States (12 ) Patent Application Publication ( 10) Pub . No. : US 2018 /0325884 A1 ZARNITSYN et al. ( 43 ) Pub . Date: Nov . 15 , 2018 ( 54 ) METHODS AND DEVICES FOR THE A61K 47 /38 ( 2006 .01 ) TREATMENT OF OCULAR DISEASES IN A61K 9 / 00 (2006 .01 ) HUMAN SUBJECTS A61K 9 / 10 ( 2006 .01 ) A61K 9 / 16 ( 2006 .01 ) (71 ) Applicant: CLEARSIDE BIOMEDICAL , INC. , A61K 31 /573 (2006 . 01) Alpharetta , GA (US ) A61M 37 / 00 ( 2006 .01 ) ( 72 ) Inventors : Vladimir ZARNITSYN , Atlanta , GA A61K 47 / 26 ( 2006 .01 ) (US ) ; Samirkumar PATEL , Atlanta , A61K 47 / 12 ( 2006 .01 ) GA (US ) ; Daniel WHITE , Suwanee, A61K 45 /06 ( 2006 . 01 ) GA (US ) ; Glenn NORONHA , Atlanta , A61K 39/ 00 ( 2006 . 01 ) GA (US ) ; Brian BURKE , Cary , NC ( 52) U . S . CI. (US ) CPC . A61K 31/ 4439 ( 2013 . 01 ) ; A61M 2037 /0061 (2013 . 01 ) ; A61K 47/ 38 ( 2013 .01 ) ; A61K (21 ) Appl . No. : 16 / 041, 067 9 /0048 ( 2013 .01 ) ; A61K 9 / 10 (2013 . 01 ) ; A61K 9 / 16 ( 2013 .01 ) ; A61K 31 /573 ( 2013 .01 ) ; ( 22 ) Filed : Jul. 20 , 2018 A61M 37/ 0015 ( 2013 . 01 ) ; A61K 9 /0019 ( 2013 .01 ) ; A61K 47/ 26 ( 2013 .01 ) ; A61K 47/ 12 Related U . S . Application Data ( 2013 .01 ) ; A61K 45 / 06 ( 2013 .01 ) ; A61K (63 ) Continuation of application No . 15 /454 ,636 , filed on 2039 / 54 (2013 .01 ) ; A61K 2300 /00 ( 2013 .01 ) ; Mar. 9 , 2017 , which is a continuation of application A6IK 2039 / 505 ( 2013 .01 ) ; A61M 2037 /0023 No . 14 /441 , 151, filed on May 6 , 2015 , now aban (2013 . 01 ) ; CO7K 16 / 22 ( 2013 . 01 ) doned , filed as application No . PCT /US2013 / 069156 on Nov. 8 , 2013 . (60 ) Provisional application No . 61 /898 ,926 , filed on Nov. (57 ) ABSTRACT 1 , 2013 , provisional application No . 61 / 873 ,660 , filed on Sep . 4 , 2013 , provisional application No . 61 /819 , 388 , filed on May 3 , 2013 , provisional application Methods and devices are provided for targeted non -surgical No . 61/ 785 ,229 , filed on Mar. 14 , 2013 , provisional administration of a drug formulation to the suprachoroidal application No . 61 /773 , 124 , filed on Mar . 5 , 2013 , space (SCS ) of the eye of a human subject for the treatment provisional application No . 61 /745 ,237 , filed on Dec . of a posterior ocular disorder or a choroidal malady . In one 21 , 2012 , provisional application No. 61 /734 , 872 , embodiment, the method comprises inserting a hollow filed on Dec. 7 , 2012 , provisional application No . microneedle into the eye at an insertion site and infusing a 61 / 724 , 144 , filed on Nov . 8 , 2012 . drug formulation through the inserted microneedle and into the suprachoroidal space of the eye, wherein the infused Publication Classification drug formulation flows within the suprachoroidal space (51 ) Int . Ci. away from the insertion site during the infusion . In one A61K 31 /4439 ( 2006 . 01 ) embodiment, the fluid drug formulation comprises drug CO7K 16 /22 ( 2006 .01 ) nanoparticles or microparticles . vedimoni 4 mg TA TAConcentrationinPlasma(ng/mL) per servisserseitepunderie o ninguna cosa estar en e ngele changes Study Day Patent Application Publication Nov . 15 , 2018 Sheet 1 of 40 US 2018 /0325884 A1 . 1B.FIG **** * $ . Ninh www TV #eatrjvar *** * ** ietim **** * * ** * * * 141010FIC www. N iis*** ** ** or h *** * ** r * : * **** * * * * * * * * *** ** * * * * * * ** * * * * Site *** * * * * ** berkes ** went ** Huvirinimo FIG.1A Patent Application Publication Nov . 15 , 2018 Sheet 2 of 40 US 2018 /0325884 A1 wwwwwwww FIG.1D emis sis . 7 . turistes FIG.10 Patent Application Publication Nov . 15 , 2018 Sheet 3 of 40 US 2018 /0325884 A1 FIG.3 FIG.2 ?????????????????????????????????????????????????????????????????????????????????????????????????? Patent Application Publication Nov . 15 , 2018 Sheet 4 of 40 US 2018 /0325884 A1 FIG.5 FIG.4 va Patent Application Publication Nov . 15 , 2018 Sheet 5 of 40 US 2018 / 0325884 A1 ???? :** FIG.6B :: ** * * * : .. :: : :: *** * ** * * * * * * EMTV *** FIG.6A Patent Application Publication Nov . 15 , 2018 Sheet 6 of 40 US 2018 /0325884 A1 Suction tohold intes . FIG.7B Insert Microneedle ** ** * SEN Sclera Choroid Retina Cannulato induce intraocular pressure FIG.7A Patent Application Publication Nov . 15 , 2018 Sheet 7 of 40 US 2018 /0325884 A1 w wwww ws w FIG.8B SuprachoidalSpace Choroid Retina FIG.8A *** * Sclera Choroid Vitreous Patent Application Publication Nov . 15 , 2018 Sheet 8 of 40 US 2018 /0325884 A1 .4 FIG.9C FIG.9D FIG.9A FIG.9B Patent Application Publication Nov . 15 , 2018 Sheet 9 of 40 US 2018 /0325884 A1 *. FIG.10B FIG.10A w Patent Application Publication Nov . 15 , 2018 Sheet 10 of 40 US 2018 /0325884 A1 350 . InfusionPressure(kPa) FIG.11B 100nmParticles 150200250300 IM moeten700um wayto800um A900um -1000um ) %( InjectionsSO Successful 350 InfusionPressure(kPa) FIG.11A 20nmParticles 150200250300 many700um wyth800um 900um 1000um ) %( Injections Successful Patent Application Publication Nov . 15 , 2018 Sheet 11 of 40 US 2018 /0325884 A1 350 InfusionPressure(kPa) FIG.11D 1000nmParticles 150200250300 700um way800um metu900um nogiu1000um * ) %( 8 Injections Successful * 350 InfusionPressure(kPa) 11C.FIG 500nmParticles 150200250300 morethan700um modernen800um vanons900um inon1000um ) % ( Injections. Successful ??00 Patent Application Publication Nov. 15, 2018 Sheet 12 of 40 US 2018 / 0325884 A1 FIG.12B FIG.12A wo Patent Application Publication Nov . 15 , 2018 Sheet 13 of 40 US 2018 /0325884 A1 southeast800um 1000uminwat wetmomentin700um 300 continue.ww FIG.13B t 250 InfusionPressure(kPa) 36mmHgIOP ist!: : : : ** *!* 4 ! ! T art + 14 200 . 150 ) %( Injections Successful unooormeer *** * * ** 300 **** * * * * * * * * ** * * FIG.13A *** * * * ** * * * * * * * * * * * * * erritin 250 18mmHgIOP **** * * ** : InfusionPressure(kPa) 11** *rd * 150200 22 ) %( Injections*0000 Successfulcom Patent Application Publication Nov . 15 , 2018 Sheet 14 of 40 US 2018 /0325884 A1 30 25 20 3 Time(hr) Sinis 15 FIG,15 SCSFluoresceinInjection 0510 *Mid-Vitreous 10000 )OMml / ng( ConcentrationA 160 5min 140 120 Lens 100 80 FIG.14 S: Vitreous 60 Position 40 iRetina 20 0 1400 1300 book Hook Intensity FluorescentDooOo Patent Application Publication Nov . 15 , 2018 Sheet 15 of 40 US 2018 /0325884 A1 30 25 101520 FIG.17 SCS500nmInjection 28 )days(TimeSCS . Mid-Vitreous 5 - 10000 0 Intensity13 : Fluorescence 40 * 35 * * 30 days)Time(SCS SCS20nmInjection 510152025 Mid-Vitreous 0 10000 Intensity Fluorescence Patent Application Publication Nov . 15 , 2018 Sheet 16 of 40 US 2018 /0325884 A1 Repositioningof insertedmicroneedle No Yes FIG.18 microneedleintothe scleraoftheeye Applyingapressuretoinduce Continuedinfusionof selectedvolumeoffluid fromtheeye Insertingahollow infusionofadrugformulation throughthehollowmicroneedle Evaluating whetherthere hasbeensuccessfuldelivery intosuprachoroidalspace andawayfromisertion siteofhollow microneedle drugformulationbefore removingpressure Retractingofmicroneedle Patent Application Publication Nov . 15 , 2018 Sheet 17 of 40 US 2018 /0325884 A1 *120days NeryOptic (lefttorightforeachgroup) Lens NervOptic aut Lens Suprachoroidalinjection segAnt : segAnt P FIG.19B Intravitrealinjection STE Retina p101040 Choroid2 Sclera TAPO pg. TA 120 90 t1/2=39.8days days3.13=/21 FIG.19A intravitreal 60 Time,days 30 0 0.5 Patent Application Publication Nov . 15 , 2018 Sheet 18 of 40 US 2018 /0325884 A1 IVT SCS 120 120 - SOOOOAAAAAA!. 6090 Lens:Choroid 306090 Lens:Retina Time,days FIG.190 Time,days NATYTOSEDI . 1AAAA. 30 . vy AAAA 0 concentration TA concentration TA Patent Application Publication Nov . 15 , 2018 Sheet 19 of 40 US 2018 /0325884 A1 . Vehicle *3.2mgTA. -5.2mgTA 89 28 FIG.20A 17 . StudyDay * *** ** 0 -1 iiiiiiiiiii 266 ) mmHg( IOP Patent Application Publication Nov . 15 , 2018 Sheet 20 of 40 US 2018 /0325884 A1 . ? ?????+ tte FIG.20B ???? Patent Application Publication Nov . 15 , 2018 Sheet 21 of 40 US 2018 /0325884 A1 highdose(5.2mgTA) lowdose(3.2mgTA) SystemicExposure,n=10rabbits FIG.200 SingleDoseGLPToxicologyinRabbits highlow dosedose highlow dose Day1142860 lowdose highdose lowdose highdose Patent Application Publication Nov . 15 , 2018 Sheet 22 of 40 US 2018 /0325884 A1 30 .. : :. ! Sclera/choroid .. ! .! :.. 25 . Roo . :8 . 20 og .. Lens . Retina iiiiii. .. como . Time(days) . 15 . wwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwww RabbitOcularTissueLevelsAfterSCSInjectionofTA . FIG.200 co w .. opers . 10 . ICB. Vitreous 40000000. 5 wiiiiiiii 100 10000 1000 0.001 tissue & / TA ug Concentration Patent Application Publication Nov . 15 , 2018 Sheet 23 of 40 US 2018 /0325884 A1 30 25 HighDoseTA LowDoseTA 20 ww oooooooooooooo 15 Time(days) FIG.20F Triamcinolone(TA)intheRetina W highdose MAMERTEMAMAN 10 1lowdosessoramento 5 0 ] ug( TA of Mass # halflife# days12 30 # 9days 25 WO TADoseHigh* hetLowDoseTA NhighdoseSongs 20 Triamcinolone(TA)intheSclera-Choroid 15 Time(days) FIG.20E lowdose 10 5 MAAAAAAAAAAAAAAAAAAAAAAAAAA 0 ) ug( TA of MassAU Patent Application Publication Nov . 15 , 2018 Sheet 24 of 40 US 2018 /0325884 A1 ) days are s ' #( images fundus Rabbit **** * * * FIG.21B . Vehicle SCS SCS *VehicleScs(left) middle)SCS(TAmg4* *4mgTAIVT(right) eyesgroup FIG.21A RabbitUveitisModel:DetailedScores ? 1 maammanaman iamman mimni Daysaftertoxin: Scores Daysaftertreatment Shadduck - McDonald Cumulative Patent Application Publication Nov . 15 , 2018 Sheet 25 of 40 US 2018 /0325884 A1 viviu VehicleSCS *4mgTASCSIVTTA mg4 TreatmentTime(days) w FIG.21D . [6Hww ) ) IOP ( Pressure Intraocular TAIVT)C(SCSControl)B(A FIG.210 33 4. Inflammatory Cumulative Patent Application