US 20190169224A1 ( 19) United States (12 ) Patent Application Publication (10 ) Pub. No. : US 2019 /0169224 A1 CAVANAGH et al. (43 ) Pub . Date : Jun . 6 . 2019 ( 54 ) PREPARATIONS OF HYDROPHOBIC 487, filed on Aug. 23 , 2012 , provisional application THERAPEUTIC AGENTS , METHODS OF No . 61 /763 ,770 , filed on Feb . 12 , 2013 , provisional MANUFACTURE AND USE THEREOF application No . 61/ 788 ,519 , filed on Mar. 15 , 2013 . (71 ) Applicant: NICOX OPHTHALMICS, INC. , Fort Worth , TX (US ) Publication Classification ( 72 ) Inventors : Thomas CAVANAGH , New Canaan , (51 ) Int. CI. CT (US ) ; Shikha P . Barman , Bedford , C07 ) 7700 (2006 . 01) MA (US ) ; Tian Hao , Acton , MA (US ) ; C07 ) 71 /00 ( 2006 . 01 ) Thomas B . Leland, Bolton , MA (US ) ; C07J 3 /00 ( 2006 .01 ) Ritesh V . Thekkedath , Dombivli ( E ) . C07 ) 31 /00 (2006 . 01) M . S . ( IN ) (52 ) U . S . CI. CPC C07J 77009 ( 2013 .01 ) ; C07J 71 /0031 ( 2013 . 01 ) ; C07J 3 /005 ( 2013 .01 ) ; Y10T ( 21 ) Appl. No. : 16 / 203, 324 428 / 2982 (2015 . 01 ) ; C07J 71/ 0005 ( 2013 .01 ) ; ( 22 ) Filed : Nov . 28 , 2018 CO7B 2200 /13 ( 2013. 01 ) ; C07J 31/ 006 Related U . S . Application Data ( 2013 .01 ) (63 ) Continuation of application No. 15 / 660 ,470 , filed on (57 ) ABSTRACT Jul. 26 , 2017 , now Pat. No . 10 , 174 ,071 , which is a continuation of application No . 14 /399 ,780 , filed on The present invention further provides method of preparing Nov . 7 , 2014 , now Pat . No . 9 , 822, 142, filed as appli nanocrystals of a hydrophobic therapeutic agent such as cation No . PCT/ US2013 /039694 on May 6 , 2013 , fluticasone or triamcinolone , pharmaceutical compositions which is a continuation of application No . 13 / 735 , ( e . g ., topical or intranasal compositions ) thereof and meth 973 , filed on Jan . 7 , 2013 , now Pat. No . 8 , 765 ,725 . ods for treating and / or preventing the signs and / or symptoms (60 ) Provisional application No . 61/ 644 , 105 , filed on May of disorders such as blepharitis , meibomian gland dysfunc 8 , 2012 , provisional application No . 61 /657 ,239 , filed tion or skin inflammation or a respiratory disease ( e . g . , on Jun . 8 , 2012 , provisional application No . 61 /692 , asthma) . Patent Application Publication Jun . 6 , 2019 Sheet 1 of 42 US 2019 / 0169224 A1 . : . 2 . ChemicalStructureofFluticasonePropionate FIG.1 w wwwwwwwwwwwwww .. : Physico-ChemicalCharacteristicsofFluticasonePropionate : 272-273C(DSC/TGA) afterrightDecomposes 7. 7 500.57Daltons : |240nm 14.48 melting NO IandII Case * * * * * * EL * * * * * * * * * * * ATA : : S KINYARWANA VIEWS MeltingPoint PointDecompositionAAA Polymorphicforms MolecularFormula ???? d60 Properties APlimax M.W pka Photolabile Patent Application Publication Jun . 6 , 2019 Sheet 2 of 42 US 2019 / 0169224 A1 Impurity 12min 11 Impurity 10 eerecer Baselineexpansionofimpurities ranv rei 199.63 9 16.80450098 35.56320:21 *.PASAP 17070. FluticasonePropionateanditsimpuritiesB,CD Impurity mesmo menit u n pocoRin * * whommes h wit . MAU Y 2.FIG 15min .66 0.72 ht ., . .???????????????????????????????????????- 14 1 . 0 13 . .2 8 12 10.4 14. 59. 4 11 HPLCofFluticasonePropionateanditsimpurities 99?."??????07???????>?????????,????????- 10 9 De FPS 8 7 . N O . 2 . 1 . - - . AN . 1 MAU 700 Patent Application Publication Jun . 6 , 2019 Sheet 3 of 42 US 2019 / 0169224 A1 FilingLine Addfinalexcipienis(optional) i ? conc.desiredconcentrateto1933 TangentialFlow NY Purify,addvehicleand . LE FIG.3 febrero (BatchProcess)0000000 Undersecondtemp.,e25°C PhaseII) PhaseIII Erse (Phase 00 Soose min/mi.41-50:rateowH Stenle-filtered Underfirsttemp.,294°C X Generationofnano-crystals 74 % DissolveFPandsterilefilter fpDissolved insterile SVILES w XXXX Patent Application Publication Jun . 6 , 2019 Sheet 4 of 42 US 2019 / 0169224 A1 Addotherexcipients(optional) FillingLinew Por. D W WHAT AW :. x codes Xu MW Rui (8.9,TFForhollowfibercartridge) WON PurificationApparatus ** * CE N 20 - 5 FIG.4 Annealing/HoldTank Undersecondtemp.,6925°C ProcessofNanocrystalProductionandPurification CAD OUT Underfirsttemp. * TI ter 99 % Stenle PATRODAL Patent Application Publication Jun . 6 , 2019 Sheet 5 01of 4242 US 2019 / 0169224 A1 1.' 0.512405913 . )cp15 (MC %25 .A0 /BAK %12 .0 2.91 )cp15 ( MC %25 .0/ BAK %12 .0 X) cm15 ( MC %25 .0 /BAK %12 .0 1.376XD ...% 50 . 0 /PVA %70 .0/ BAKourth Att %13 .0 Tema146 water/)cp 4000 (HPMC %51. 0 /BAK %15 .0 0.641418631 * * * * Water/Tween80 % 86 .1/ PVA %38 .1 doooos Frie water/CMC %5. 0/ 80 Tween %2 FIG.5 water/CMC %5 .0/ Tween80 %2 *water /CMC %5 .0/ 80 Tween %2 ParticlesizeofFPnanocrystalbatches 1113 H * * * * waterwater/CMC/ Gum %9Xanthan. 0/ 80 Tween% 5. 0/ 80 % 2 Tween % 2 soooooo * * ** * water/CMC %9 .0/ 80 Tween %2 Water/CMCBAK %%365 ..01 / Tween60 %9 .0 water/Tween20 %58 .0 water/Tween20 a% 8. 0 microns in Size Patent Application Publication Jun . 6 , 2019 Sheet 6 of 42 US 2019 / 0169224 A1 * . ooo risurrecce . ** * 1992. SYA WN 5000 . * * * AW 9 : 00 * 2. ** CA * V . AVXXXXX YENT XXX LUX IVACY w 123456789101112131415161718192021222324252627282930 Particlesizeofbatchesobtainedby“top-down"particle2 BATCH# FIG.6 reductiontechniques Microfluidization $Ultrasound uopjezusiowohu OS 7 :17 2ML . * 940002 1 CAPSO 25 8 39 Scott ??? Patent Application Publication Jun . 6 , 2019 Sheet 7 of 42 US 2019 / 0169224 A1 ;2. i i 277.vrrrrrrr . E.L T +7/111 . S 6.5/006%FP 11 " . 117411122 rriii 22 . 2 wir : oots % 0.25%MC/12BAK,PH * .55FFEE i DJ/ VW b& * + 1 . 22 po . 1 :.III 360Bongo . Rrrrr!.1177rrmVrrrrrrr- FIG.7 ww . 5./01%FP . W r . EffectofpHonparticlesize ilF.FE M 22 rirrrrrrr.'-rrrrrrrr1 rrrrrrrr. rururawrrrrrrrrrrrrrrrrrrrr EE . T . T : . -2222, - #xILLIOZY Phosphate0.1%/25 MC10.12%BAK,PH7/01 .-11222222222 CY 122222.:-222222222 1222271:27 rerirrrrrrrrrrrrrrr Hécrittrrrrrr Patent Application Publication Jun . 6 , 2019 Sheet 8 of 42 US 2019 / 0169224 A1 SYYYSYLLTY : . : ' S ' YY 714 * * * * * )cp4000 (MC r+11877- . UFRIR /2142. )cp50 ( MC ! Frrr 177. 427 -. ????????? )cp15 (MC " ??????????????? FIG.8 .us EffectofstabilizerinphaseIIonparticlesize40 )cp45 ( HPMC ooooooo walan errrrr )cp000 , 100( HPMC st *** * * * vreerreen ? ? ?? ? ? ? ? ?- - - ???? ? ? ?? ??? ?????? . ? ? ? ? ? )cp4000 (HPMC $ $ 1999 )microns ( Size Particle Patent Application Publication Jun . 6 , 2019 Sheet 9 of 42 US 2019 / 0169224 A1 30 . X A NXXXXXX MUUTTOV* * * * * * * A LA2222222222222* XXXXXXXXXX 24124222223 * * T22WXXXXXXX* * * * * * * * * * * * * * * 2 1922 * 22222 XLIXL2411 22222222222222222222 . 111 22222 2 2222 LILL21222 , 3" LYWELYYYYYAX122X122X2 LLLLLLLLLLLLLL122222XXXXXX LL22 WAMWWW 11MNIA122 * 1423 1214224242424242242 . 2 * * 3 2323 err/4' 2 ALLY. MALESRh212121 irr-.777 522222222 YUYULA 2 22222 24 12. 2012. 2222222 22292 .44111117/7W Daysat25C FIG.9 2 2222222. 22 2 . 7 * L 012LLLLLLLL 1411172241222222222222012 022 2 1912922222222322 EffectofpHphaseIII(I+II)onparticlesize in1.2rrt' %pH7.5 2441442444919421211211 2X41421194LIKE1922- .? 242212. 2011 222222 * 49 , ' * ' * ' * * ' * ' YYN Y , 34 , 922399 , 99 * .-224/ V ILLE KAT T ' AKLA RE 24X14X 112 22 * * 24 * * * 4III PH5, .-22411 MLXLXX X* . 112 L110 1111111111 11111 . tum 2211. LLLLLLLLS 9222242 11 - 19 ELEO oped Patent Application Publication Jun . 6 , 2019 Sheet 10 of 42 US 2019 /0169224 A1 Batch2 46 14 VANVANKAw doo of 2 -._ PurifiedFluticasonePropionatenanoparticlesdonotdisplay 2345 particlesizegrowthovertime TimeinDays(25degreesC) FIG.10 oooooo 1 *.14 0 AZ CAT TiffSTRANI 900004 microns in Size Particle Patent Application Publication Jun . 6 , 2019 Sheet 11 of 42 US 2019 /0169224 A1 ULAWESI M FIG.12 * * 55F 17 ) d90( Size Particle . .ix .-', . .-' .: FIG.11 : '.- .,'Y: . 26CC .'-: .:;' : 2.80 ,.': '.-: : . : ) microns( Size Particle Patent Application Publication Jun . 6 , 2019 Sheet 12 of 42 US 2019 / 0169224 A1 44444444444444444444444444+. - ', . 14:.siirrr11rrrrrrrrterr+10-, . 2 . FIG.14 .4 Loss+777 Percent ?? 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