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Hitta Denna Unutrition Adult Clio HITTA DENNAUS UNUTRITION 20180042989A1 ADULT CLIO III ( 19) United States (12 ) Patent Application Publication (10 ) Pub. No. : US 2018/ 0042989 A1 Aversa et al. ( 43 ) Pub . Date : Feb . 15 , 2018 ( 54 ) IMMUNOMODULATORY COMPOSITIONS Publication Classification (51 ) Int. Cl. ( 71 ) Applicant : Sigmoid Pharma Limited , Dublin ( IE ) A61K 38 / 13 ( 2006 .01 ) (72 ) Inventors : Vincenzo Aversa , Ridgewood Swords A61K 31 / 502 ( 2006 . 01) ( IE ) ; Ivan Coulter, Mount Merrion A61K 31/ 436 (2006 . 01 ) ( IE ) ; Mónica Torres Rosa , Dublin (IE ) ; A61K 45 / 06 ( 2006 .01 ) Bernard Francis McDonald , A61K 9 / 16 ( 2006 . 01 ) Castleblayney (IE ) A61K 9 /50 ( 2006 .01 ) (52 ) U . S . CI. ( 73) Assignee : Sigmoid Pharma Limited , Dublin ( IE ) CPC . .. .. .. A61K 38 / 13 ( 2013 .01 ) ; A6IK 9 / 167 (2013 .01 ) ; A61K 9 / 16 (2013 . 01 ) ; A61K 9 /5036 (21 ) Appl . No. : 15 /791 , 104 ( 2013 .01 ) ; A61K 31 / 436 ( 2013 .01 ) ; A61K 9 /5084 ( 2013 .01 ) ; A61K 9 / 1658 ( 2013 .01 ) ; (22 ) Filed : Oct . 23, 2017 A61K 45 / 06 ( 2013 .01 ) ; A61K 31/ 502 ( 2013 .01 ) ; A61K 9 / 5042 (2013 . 01 ) ; A61K Related U . S . Application Data 2300 / 00 (2013 .01 ) (63 ) Continuation of application No . 13 /989 , 372 , filed on May 23 , 2013 , now Pat . No . 9 ,821 ,024 , filed as ( 57 ) ABSTRACT application No. PCT /EP2011 /071088 on Nov . 25 , 2011. Immunomodulator formulations for use in the treatment of disease of the GI tract. The formulations comprise a Foreign Application Priority Data hydroxylase inhibitor and /or an immunosuppressant. Exem (30 ) plary formulations comprise hydralazine as a hydroxylase Nov . 25 , 2010 (GB ) . .. 1020032 .7 inhibitor and / or cyclosporin A as an immunosuppressant. Patent Application Publication Feb . 15, 2018 Sheet 1 of 43 US 2018 / 0042989 A1 . .. .. ... from house mething from interim Em FIG.1 K olmayan -DSS2.5% wyfuumDSS+C .DSS+A .DSS*B -NoDSS YYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYY 105 100 Patent Application Publication Feb . 15, 2018 Sheet 2 of 43 US 2018 / 0042989 A1 brandfang memberi manual *.** .*. * . * * * . * . *- *. .* * .*.* . * . * . * . * . .* * ** * * * HEY RH ABA FIG.2 N s' DSS2.5% DSS+A 8+SSO NoDSS *DSS+C - ITTO O O ~ N promo o Patent Application Publication Feb . 15, 2018 Sheet 3 of 43 US 2018 / 0042989 A1 DSS2.5%+C DSS2.5% DSS2.5%+B FIG.3 NoDSS CODDSS2.5%+A Patent Application Publication Feb . 15, 2018 Sheet 4 of 43 US 2018 / 0042989 A1 DSS2.5%+A 8+%97SS3 DSS2.5%+C -DSS2.5%+F11 .DSS25%+E -DSS2.5%+D amefanNoDSS .DSS25% www - I KH 6 - food A . * * * tnt ty 5 . .. .. .. ** . .. 4 * * FIG.4 * ... Hay W 3 .. Days 2 1 ?- 1 - 1 - 1 - 1 - 1 - 1 - 1 - 1 - 1 - 1 - 1 - 1 -colegio 1 - 1 - 1 - 1 - 1 - 1 - 1 - 1 - 1 - 1 - 1 - 1 - 1 - 1 - 1 - 1 - 1 - 1 - 1 - 1 - 1 - I - - I - - I - - I - - I - 1 - - I - - I - - I - - I - - I - - I - - I - - I 0 change Weight % Patent Application Publication Feb . 15, 2018 Sheet 5 of 43 US 2018 / 0042989 A1 DSS2.5%+A DSS2.5%+D maximeDSS2.5%+c westonDSS2.5%+E DSS2.5% .DSS25%+B -DSS2.5%+F offeeNoDSS 6 ***. .. .. ... .. Auto 5 .... of los de al i famil 4 FIG.5 3 .. Days 10 ... .. .. 2 au - -- - -- - -- 0 0 1 0 0 A Nwod DAI Patent Application Publication Feb. 15, 2018 Sheet 6 of 43 US 2018/ 0042989 Al DSS+B ?????Dss+F DSS+A Dss+E FIG.6 DSSonly DSS+D NoDSS ??DSS+C Patent Application Publication Feb . 15, 2018 Sheet 7 of 43 US 2018 / 0042989 A1 Att ** .*.-* * -* - *. .. .* .* . **. * 6 **. DSS+HydralazineOral50mg/kg kg25mg/I.P)Hydralazine(DSS+. %DSS.52 Ratih 55 * SSGONmennes * : -* * . www * ?? 4 -~ FIG.7 formal -3 - finned 2 -* . ? www - \ ? Patent Application Publication Feb . 15, 2018 Sheet 8 of 43 US 2018 / 0042989 A1 nunnunt compania panna 7 *.* *. * * .. ... .. * FR wa 6 ***** . .. *. * .* .* .* . .. *** .** ** * * ** * * * * 5 4 FIG.8 ty 3w .. DSS+HydralazineOral50mg/kg 2 .DSS+HydralazineIP25mg./kg 1 muffwnNoDSS .DSS25% O Ñ Õ 0 0 A N O ? Patent Application Publication Feb . 15, 2018 Sheet 9 of 43 US 2018 / 0042989 A1 - + 1 H 1 Hydralazine300M+DSS4% 450 DSS%4150M+Hydralazineouin .Hydralazine600M+DSS4% 400 NoDSScontrol DSS4% + 350 300 250Time FIG.9 200 ..* . 150 *** * Hostel 100 * bontott 50 fa 0 1501 50 Patent Application Publication Feb . 15 , 2018 Sheet 10 of 43 US 2018 /0042989 A1 HIF-1a B-Actin 50um FIG.10 Hydralazinedose 51025 0 Patent Application Publication Feb . 15, 2018 Sheet 11 of 43 US 2018 / 0042989 A1 VehicleSmPill)( ??????????????????????????????????????????????????? IIIIIIIIIIIIIIIIIIIIIIIIIIIIIII SmPillCyA)( ????????????????????????????. .. .. .. .. .?????????????? .': oral)CyA( FIG.11 )CyA(ip ?????????????????????????????????????????????????????? Untreated ?? ? ? ? ? ? 8 0 M - ? ?????Numbers Patent Application Publication Feb . 15 , 2018 Sheet 12 of 43 US 2018 /0042989 A1 SmPill(Vehicle) -SmPill(CyA) CyA(ip) wehetCYA(oral) noUntreated u . it : tillillit family membering | mati FIG.12 me 01 JUAWILOSOM binnen 2 on ) % ( change Weight Patent Application Publication Feb . 15 , 2018 Sheet 13 of 43 US 2018 /0042989 A1 Vehi P<0.001 SmPill(CyA)Vehicle CyA(oral) P<0.001 FIG.13 CyA(ip) P<0.01 P<0.001 Untreated 5 90when wana 110 Tili) % ( change Weight Patent Application Publication Feb . 15 , 2018 Sheet 14 of 43 US 2018 /0042989 A1 P<0.05 SmPill(CYA)Vehicle CyA(oral) FIG.14 P<0.05 CYA(ip) LH Untreated ? ? ?? LILIIndex Activity Disease Patent Application Publication Feb . 15 , 2018 Sheet 15 of 43 US 2018 /0042989 A1 SmPill(Cya)Vehicle CyA(oral) FIG.15 P<0.001 CyA(ip) P<0.01 44 Untreated Patent Application Publication Feb . 15, 2018 Sheet 16 of 43 US 2018 / 0042989 A1 SmPill(CyA)SmPilVehicle CyA(oral) FIG.16 .liCyA(ip) Untreated * * ? ; ; ; ; ? 7 Numbers Patent Application Publication Feb . 15, 2018 Sheet 17 of 43 US 2018 / 0042989 A1 SmPil(CyA)Vehicle ? P>0.05 CyA(oral) |..l FIG.17 CyA(ip) p<0.05 Untreated {} ) protein colon mg / U ( Activity Enzymatic Patent Application Publication Feb . 15, 2018 Sheet 18 of 43 US 2018 / 0042989 A1 SmPill{Vehicle) SmPili(CyA) P<{}.05 IL-16 CyA(oral) .?1FIG.18A CyA{ip) P<0},5 Untreated 5{}• ?{}2 *{} ? und Patent Application Publication Feb . 15, 2018 Sheet 19 of 43 US 2018 / 0042989 A1 SimPill(CyA)SimPiliVehicle CyA(oral) TNFa 1?.FIG,18B p<0.05. CyA(ip) Untreated ?(475 {5} {250 4000 7504 500 2504 au/ ad Patent Application Publication Feb . 15, 2018 Sheet 20 of 43 US 2018 / 0042989 A1 ? SmPill(CyA)Vehicle 17-IL CyA(oral) FIG,18C CyA(ip) Untreated {}7 9{} au/ ad Patent Application Publication Feb . 15 , 2018 Sheet 21 of 43 US 2018 /0042989 A1 SmPill(CyA)Vehicle 1- P<0.01 FIG.19 II. II. II. II. CyA(oral) P<0.01 CyA(ip) Untreated pasangan0 Scores Patent Application Publication Feb . 15 , 2018 Sheet 22 of 43 US 2018 /0042989 A1 SmPill(CyA)Vehicle Medium _ IL-16 CyA(oral) PMAI FIG.20A CYA(ip) Untreated 600 ITITml/ pg Patent Application Publication Feb . 15, 2018 Sheet 23 of 43 US 2018 / 0042989 A1 SnFiltyA)StaPill(ehicle ? ) F ral) FIG.20B TNF A ? (in) «().{} Intrated }{?? {} 3{} ???till Patent Application Publication Feb . 15, 2018 Sheet 24 of 43 US 2018 / 0042989 A1 ???? SmFill(CyA)SnFiltVehicle F().f5 CyA(oral) IL-17 FIG.20c CyA(in) -(.33 Untreatect } {} ?????HLE, Patent Application Publication Feb . 15 , 2018 Sheet 25 of 43 US 2018 /0042989 A1 famento @ . 91 recewomess . e . 86 emotor 91 mormancecom. sammenmed et commodoet 2 . 1 . 000 sáro FIG.21 . 8 . 9 **** * * ** * * * *** * * * * * .. buying for ** **** **** paddos$50 *** ** ** * ** ** ** * * * * ** * * * ** * ** K * 7 23- - **** 2H* ** * * * *** * * * ** * * * * * MY 11 **54 : ** * 58;KNO 23212530) 2 ** SSO-9Z exe OveH. ZSSCI-* WZSSO -- - - -- -- -- - - - - 0 house a in house enter you so abueyo jubiOM % . Patent Application Publication Feb . 15 , 2018 Sheet 26 of 43 US 2018 /0042989 A1 * 19 k *** * ** 18 * ?!** ** g-K*59ZSS Connef 17 16 Canal2930. minHART49290 S50mod.X3NX092 RAUCeznimotor .€2850 VI 15 14 13 WIII. for entertainment 12 *** ** * * * * * * * * **** * framan *** af france 11 **" " ?iiiiii * 10 * * * ***** * * * * *789 **** FIG.22 * SABO - - - 9 487*** * * * * Foto te molting wanamme 8 matemat 7 faunajua utang 6 *** * * * 5 ** e pasurivesarias 0$stopped 4 *** 3 2 1 score } DA Patent Application Publication Feb . 15 , 2018 Sheet 27 of 43 US 2018 /0042989 A1 Hya/Cya +DSS Cya+DSS Hya+DSS 11| FIG.23 RecoveryDSS recoveryNo DSS DSSNo minnanonowanaa nãomainonnanamwamandamananana não ä o length Colon/ weight Colon Patent Application Publication Feb . 15 , 2018 Sheet 28 of 43 US 2018 /0042989 A1 Hasiera 4 (jakejmodekoekid*S80 (@nayubIH)eleihSSO. *.,4 *. * . 3697SSO * SSOON ** t 9S . fungsanleitung woman . FIG.24 funktion to the forest Days ***** ** , www ** ,, Ammin 2 ** * . * * 1 . w 105 100 SSOI J?blan % Patent Application Publication Feb . 15 , 2018 Sheet 29 of 43 US 2018 /0042989 A1 Bumbled bugtong tante . Bw *** * * *** * .. frowning :. ... .. FIG.25 hartanen nopting the ming Days * SSOONwildfires KGZSSO . ndenkinemannément i m memnuninn namundan your poco o Nowa wi O DAI Patent Application Publication Feb . 15 , 2018 Sheet 30 of 43 US 2018 /0042989 A1 - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - 4 . 4 . 4 . 4 . 4 . 4 . 4 . 4 . 4 . 4 . 4 . 4 . 4 4 . 4 . 4 . 4 . 4 . 4 . 4 . 4 . 4 . 4 . 4 . 4 . 4 . 4 . 4 . 4 . 4 . 4 . 4 . 4 . 4 . 4 . 4 . 4 . 4 . 4 4 . 4 . 4 . 4 . 4 . 4 . 4 . 4 . 4 . 4 . 4 . 4 . 4 . 4 . 4 . 4 . 4 . 4 . 4 . 4 . 4 . 4 . 4 . 4 . 4. 4 4 . 4 . 4 . 4 . 4 . 4 . 4 . 4 . 4 . 4 . 4 . 4 . 4 . 4 . 4 .44 * * * * * * * * * *
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