SCSSTRATE PJSD tLmUFACX-mi'JG m^UOQ THEJiSO?
t-SCK!'iIC?..L FIELD
Tile present invention relates to a stibstrace 3ada.s11rta.c1?. modification technology thereof suitably used in a medical fieid.
BACKGBOUKD ART
blood lias properties of beina activated av.d throxnisus beinc! fcrcneri therein when it is brought into contact witb foreign matter. If tliKombiis is forfiied iii s circuit or dialyssr in ail e«r.ra::orpt>XRdl circul-atiuii 'jl blood sucJi as dn srlXiicial kidnevf circulating pressure rises and in addition to bac-onsing iropossitie for &lood to circulata sliortly, cfisre is a risf. of trte blo-od vessel being obstructed if a portion of generated tbroriil>us enters the body, Ttterefcre, it i5 nsce-ssnry.to add a bioc'd ai'iZico^i'julc.iXvii .^cL^i-i'^y ,\-;ni.i-i<:i-T.rk."l^bltity) substance and this is amethod widely used. Inexpensive heparin is generally used as ttie acti-caagulabiZity sobscance. Hovever^ heparin cannot be used for patients of hepariti-indaced throiBhocytopenia (hereinafter, referred to as HIT! and patients wiLh bleeding such as tficse i'lmsdidlely after an operation an-d an i3>:peinsive adticoagislant such as naiainostafc m&silate and gabesate m&silate needs to be ased instead, leading to a problem
1

of rising trisditai e;-ipen.ss5 :Se2 tioii-j?ater.r 2ucuin~nts 1. C/ ana 3).
Research on antt-coagnliibility materials that can xaduce usage of ajiticoagiilants by ijupartinc anti-coagulai^ility to- the surface of Etiaterial or can be usecL under conditions o£ ao added anticoagulant has been conducted. That is, such mate^riala are obtained by iBiaobili^^xn^ anti-coagulahls substances on. the Sr-artaas cf RiaLerial ami. include ^ heparinizei ffi^terial as Lhe most rs&earched jnateEial- The main method of iinniobilisiiig fteparin to a material is iiassd on SD ionic bond using cations of affiiuonium. salt and the like introduced into thg material and anions o^hspsi:in (See'^on-pat-snt liocainei^t i) ■ B<3we:ver, in this case, heparin is likely to elute and thus, this matticd cantiot be used for patients with HIT and aisa has a problem of io-rfered anti-coagulab-ility. Therefore, several raethotis of inunobilising heparin baaed on a covaient tend ha^'e been reported to resolve the. problera of elutinn. First,-an iinmobi H 7:at1on method based on the coualent botid formed organic chetiiiculiy haa been ispocted, but has a problem oi lowering anti-coagulability during ctiefflica.! reaction fSse Patent Docuiasnt ij. second, a method of iramobiliaing heparin on a luatfirial based on the covaient hnnrt whiis preventing anti-coaguiabitity frnra hping lowered by using an ion beasn and laser light has bcaeb repotted^ but since an ion beam, and laser light are used, it is difficult to iyrjnobilize heparin in a portion such as trie surface Inside

a hoilosi-- fiber where s. shado:^ is cast bv ?.n la^ b-osri .(See Patent DoaLirr.cnt 2).
Hspsrii; icseii has very lav; snfii-ccag'jIabiiiLy and expresst^s f^*gh mtL~ccsqulabi'iit%' bv b&ing bcund ts antithroinbiK III ihereinafter, relecired taas ATII'>. Tbatis, there is also a probSem that anti-coagtjlatoility is insufficient in a?UI deficient blood (See Hon-patent DocLsment 21-
Kith respect to the above pircbl-ems of h*;parici immohilizatiori rnstPrial, te^esxcri on Ji^at^rials en wliicb cojtpouncta having aati-cosgulability oLbei than hepaiin are inUTicbilized has been conducted {See Patent "DocuQient 3). Howex'er, there is s proOieid t'nat it is diLtlcalt to suppress platelet attachnierit by a cojnpcimd having anti-coagulability alone, leading to iormatini! of platelet thr_cimbosis. la addition, no proposal has ijeen made iag^rtliuy Liie prubiem of 9lutior> o£a coiipijundhaving anti-coagulability fj:onsubstrate-
In ceuent-V^ar^j tesearcfi on aJri!iiotiilii:dtioa.,oi:aCGmpoUKd . ha-jing anti-coagulability othi=r than hepatin by sadiaiiioj'. has beeiT Conducted (See y^tent DQcn-mPVit: ^}. Sy usriJig this method, a lowering of anti-coaguiability with radiation ixiddialio!: can "bs sLippcessed arid lurfchar, elution of the cornpCiind having anti-coaguiabiiity £roiu the aubstrate can Ce 55lci to be rcdaced to a certain extent. Hos-'cvcr/ accordijig fco the method of iiBJUoDiliziag only the co:npouiici haviag aRti-coaqiilsbil i.ty, an intrinsic blcod-clattin*^ resction can be supptsssed; bu\. il is

dlcfic-jit to suppress plaCsleL aLLacbineEiL so that a SU^liCletlt ie-'si of anti'CoeguLsbiiifcy h-=s lioi: ye^" been achievsd. Moreover.- aon-reactant-T during laijiauion irrsciation are no-c. taken into account heta and fche -iair^riiic of elufcion of the coiripounc3 tiaving snti~no;?g[]:i, pp.36-4^
-Non-PacentXitera-.tiice'l : JournalBicmedicai Materials Researcii. 1596 3S, pp.86-91 DISCLOSURE OF THS IKVEW^IOrT ProbieiTi to be solved &y the invention
In view of the above probleias, an object of the pEasehL invpntjon is to provide a substrate to which anti-coagulability; preferably antittiL-oicibiji ai^tivifcy and platelet attachment soppressive abilltv are imparted and ifhiah is CKCSllent in fclGOd compatibility and a manufactiiixng method such a substrate and

1. A substrate, comprising a conipGuri.d h^virtg blood anticcagi.!lstioii activity and 3 hydrophilic pnl'^nr-sr cnrapounri, s/heivein the dinaujit a£ elation of tjie cain^'CfUj(d havif-q biood antico-ag-Jiatiofi activity-' is iess thart [).& iig/oii-
2. Tfte substrate according co l, wii^reiu 1 n^'/cnt^ or more of the coiiipQuirici Js,ovir.g blood nnticoagnl^tioti activity is
3. Tne substrdLe iicccrcing to 1 oi 2^ -ijheihiin the cojupcand having blood asit.icDaauiatio-n activity has dnrichrorfcin activitv and the airiount nt tJirOKijin adsorption i,.-; i.O nq/c»r ar Toorc,
i. I'he aiibat.ralis acriordiny to any on?, at l to 3, v;h6i:«in
the iiijBiier or alVached platelets is 10/(4.3 " iO'' \m?'ior. less
and 3 blood coagujation tirae is c-^tended by .10 sBcor.d-a or mors
vjhen a blooj coatjulation. test is psrlGin'.etl- . - ■■ ■
6, TJLS substrate according to any anij of 1 to -1, TTiejr:

chaiT^ pDiticn hat h.ydrophiiicity.
S. Thft sobstrace according to ?, v?h.ereia tiiti poijiaex irh^-in portion contains at least otve selected frora a propylene t>lyvJ,nyi pyxolidone rssidue, a pclvprapylene glycol residue, a polyviJiyl alcohol residuej. ami a residue of a copolyiaer of one residue thereof.
"}. Xhe substrate according to .S.. comprisin.^ the polyi/lfiyi 3 Ic.ohal ^fihose sapcnifi-cation der;!-- nf thii Tnventiori
.3\ccording to the present ipLventlon, e'Ali:eiael)f hiyh anti-coagulability can b« iiaparted. tc the substrate surface by introiluclng a ccrapouiiil having anri-coagulabiiity snd a hydrophiiic polymei: compound to the substxats surface- A5 a result, usage o£ anticoaqulsnts added tn hloocJ -diTCinJi eKtrscoi-poreal cirGulatioD can be reduced also for uses in which blood and raatorial are brought irito coatact and atich ^[iticoaq-uiants need not be used in soiae cases and tnereSo^e, rriaks such as adverse reactions to aritico-agulants can t>6 reduced and eventiualiy/ racluccion in radical exgar.ses- can be expectt^d.
Moreovec, according to the manufacturing mGtliod of the prss^'Ot -iiVi/Bnticnr radiation-grafting -po^Xypn&rip.^t'i.on is pecionnf^d uii ctiK substrate surfaoe by ircadiating a compoiiiid, hdvir.g -^nti-coa^-ulafoility and a hydrophilic polyRcr compoiind in contact -with a substrate in the presence ot an organic solvent with radiation and further, by washiiig out non—leactants while nfaifitaining activitv of tJie compound having anti-co-sguiabiiity, so that the riai: oi the compound having anti-coagulability introduced to the substrate siirface being eiuted can also be reduce ci.

ERXEf DSSCRIPTIOH QF THE JSA^I^i^^?.
FI'T. 1 is'5 sohcmitic side '-"ie:.'e:-:ejn;:'lifying a hoi low fiber inir-i-nsodiile cjf Sxartiples 12 to 14 p.n.d ccmpaiaLiyfe Sj^amples 10 t,o 12 ot ths pi"s£ent invefition.
FIG, 3 is a schEiJiatic sysr&rn aia.gEam sxempliiying 5
ciiicyj.i: used ton a circulation test of B;:amp-les 12 to 14 and
Cnnip.^c^fivP! £.^nfrip!e£ l& to r? of UTS pri^^afit irventioji.
RXPT.ANATION OF S'lT^lBOLS
i s7;d !■". hlazid port
2 and 2' - -Jialysls pore
3, module case
*!. hollow fitiR.r
5. potting a.gcnt
6- rrdni-iTLOduls
'I. ?.ilicon tube
8. pcrlJta pcwip
9. polystyrfine rounn tube or RTKRH hnhp Mo.i"
10. plasma or protein aclucioi;
11. JTrar.ojaetar
i3E5T MODt; FOR CAF1EYK3G OUT THE IHVEHtrOiJ
A siibstrate accorciino co the present irivontion ccntainc

5 cOKpoand Lai'iag anti-coagulability and s hydropr;ilic poiyHier coj-!pc-jtid. If only a CMipound having aaci~CQag'iila:::ilii.y is ir.troduced to the substrata iurf^acSf nctivatiou 01 a biood-clottirig reaction hy cio.ttiing factors can be snppressed, but formation oi thxonibus and sttacb^iect of platelets to the substrate cannot be coiTipieteiy suppress ed in uses in which bloed is broiiyht itito contact becaase agqregdtlon of platelets canfior be suppressed. Ifr on the- other hand,, -cniy a hydEophilic polyiuex compDund is IrEtroducsct to the substrate surface, agotegation of platelets can be suppressed, but activation by clotting factors can he sapprassed and thus, like the above case, i'oiiiidtlan of throifibus and the like cannot l)e completely suppressed. That ia, the subject of the present invention cannot be resolved simply by incrsasing tlie amouat: of one coflspound. In the present invention, Jiot/averf only after a substrate helncj caused to contain both a compound having (inti-coagulability and a hydtophilio polyaier cojapoufid/ a plurality of coagulation reactions can be suppressed and a strona am:i-coagulability inaterial becoines creatabie. Further, in the present invention,, elution of a compound having antl-coag-iilahiiity is taken into consideration because elution of the corcpotind having anfci-coagiElabiiity i.n blood has d,n ef IteoL of delaying tbs coagulation time and riiay cause adverse reactions. By redaciag the amount of eliztion to less than 1 [ig/ira, pr^iferabiy to less than 0.8 pg/ml^ ^ore prefer-ably to less thari

0. & iig/.Tj., iz becomss possiliZ.^ t'.- reduce s^vsr^e reaction.'; 6ns to a ■;C!aipoi:n.d having ciiiti-cc-s.gal cbili-ty «r,d ths STH'T^-jnt -:if intrcxiur-tion into the £uTnstra"f; -and r.o a-"hi3vs saie'v ana lowar cc-^rs; Icadiag to t'nc- HQliif.lDn of tho subject of the- present invention.
~rj the presRnt invention,- a substrate containing a coirvpouiid hA\rinq anSri-coafjulability- and « hy^raphilio- aal'jia.BX cojiipotfjd on ths subs-trate s-urfact; is a suliStraLe on wiich sarf^ce a compouiid baving ariti-coaguld'oilit^- ar.d a h^-'drophilio polvHier coiupcujid are present. K compound having ari-i-coagulability arid a hydrophiiic polymer co:xipound »ay cr may not be directly conpled. Howsverr it is pr<>ferable that th-use coiripoiidds be directvlv' co'Jpled becdtisis accacdifigly Lbeie GOnjpoij-^ds becoma less likely to- be eJlirainatsd to be ^ble to contiij-ue to have an e-ffect ai^d a xecii>ctioTi IB eiution ol tbess coiTipnunds can be expected. I'he cDUpisng In this caas iricli!dt;& 3 chemical bcmd such as-a covslcnt bondr ioni.r- bond, iiydrogan bondj coordinate bond, and hydrophobic interaction and the cova.tfipt". bend Is preferable because the co^alaat bond is s relatively strong i>ori6. Alternativ^elyr the coupling raay £ combination of-a plurality of these bonds. The me-fchod of ^orrriii^g a ■covalffRt n-ond, that i^, performing graftitig ot a conipound having anti-coagulability and a hydrophiiic pol^^er compourid to the BUbstrat& surface includes an organic cheaiieal method b'/auiicleophiliD substitution reaction and the Like and

radiation. AJBCHIJ chese a^.E:!:hc--:JSf i-he radi-^ii^i^n charnieal iristhcd
is prsferable cec^'jss the airiount of reaction bvproducis is
su^diier and al.^o the substrate can b£ .-Jteriliaed h'/ suitably
selGctirtg cho type and doss cf radiation- The cornpound tiavinrj
anti-coaguiabillty and a hydrophilic poiyraei; cOEipouRd ti\B.y he
treatad siraultajieonsiy or separately. A hydrophilic poljuEejr
cDcnpaTind may setve as a [:osponsnt curistttuting the suiistrate
by bE-ing kneaded: together with raw materiai yhcn tt-iS substrate
is produced, but depending" on tba type of substrate, mscMrjlca-l
at cb$inic3i pi-operties [tor examplej strengtiri-j brittleness^
surface ch^ege. and surface wettstaility) of the substrats ntay
be dii'iiidyed, Tiiecijiyre, iij sucli a cat-e, the hydropbilic polyfTier
compound rasy be introduced and iBmobllized on tho substrate
surface, for SK3mpl&, foy directly tfringing an a<3iieGUs solution
containing the hydrophilic polycier cc-iapoond into contact witSi
ths substrate surface. By adopting such-an ■ - ■ ■ - ■
applicability is increased without the need to select the type of siitsstrate. Therefore, it becomes possible not only co mafce use of an effect of the pr&aerit invention in many fields^ but fllsp to easily change the type of h,ydrophilic poiym&r compound £0 ds to optimise the subsC£ate far the use, wiuch is mary suitable in tacpis of fitnctionality and production costs. The method of confirming eiuted substances is not
13

DP^Jox-.f is ci tp.d .^r, ^.r- ts.vs.Tvple . '•"O'" °\'af pia, ?-ii JiCA—T J.'.i,:' available from KasfiioSys is u^-:eti ^3 a rtid'jLen:. aiidCOS.rROJi'Ml (codft 3lj ;iM flOOl i-^aniuTactured by TclCO Medical InsCzunisnts Pi-oductlon as an apparatus. An atea (for a hoUow iibar, a surface ^rea insS.de t-he fibei" that comes into contact with b-lood} ■ il^ereinafter, referred to as ?.n ares A) thai- r.oTnes into contact witj^ bl;;-odr biogenic sub-itam^e,- or bG<3y tissue is washed v.-itii. ISO jjl o£ huiEan pl.ap.ma psr i c?i' for foui; hours- 30 |il on hiiciar, plssfiia aitec c^.eaning is collected and 20 ui ot" riistl"iled water la added thereto. This sol^jition 1,1 dcfir^ed as a sample solx^tiDn. TTr,;iiefilRti=l!,' after the sample soiotion is prepared, 103 ^1 of eCA prothrorubij) bu/fesv 30 ^1 t.>f .'^am.pla sciutior], and 25 fii of 9.0-'^ .'^ijbstratp axe mixed and spt, a:ftex being iiicubatea at 3?
"C for 60 s, CO the apparatiis . rfisn, 5<; ^i of EC^. ecarir* rsfigeat is addccf foi- measurement. A mi^-ed soXutioD or 20 jiJ of aqueous solution of a compound having atiti-cos-g-jlAbi I ity-or fciank-di&tilled watei and SO nl oC liui:?ian plasma i.s measttred in advance hy thft same technique, the result thereof is usea ^^ ^ calibration curve, and the diiiouut of coaipoan-d having anti-Go-a-gulability calculated fxosi the calibcation curva i,^ defineci as the amount of elation.
The inoLir.t of compCii;nd having anti-coaigtilability on the substrate surtacie changes depending on the strength ol anti-coaguiabii ity.. but if nhfi atiiounL uC coinpuund is too small,
14

Thaa,- with rcrc;:o:ice ti> ~he are?. A,- the ii7r:.G-i;a'; ot ccinpjiind. 1^ preferably €.1 i^^j/'^s^ or r-::ir=, ncrp (Trafsrsblv' (].S nq/csr or raore. stillTTiorftprEfcrarily 1 r,g/CA"r QI. mo^-s,, diiduiojiTiprefierably ^0 ng/cte-ormore. f?, oa the other f;£i(^, the iiniour.t oc ccmpoijnd hdving anLi-^oriqutabilitv is TZ-OO large, tliere is a problem such a& iriGEeaEsd costs and clu'cica. TtaiG-, the aw^^tit at cotv.pG'jnd is prefsfabl 7 10^"; pg/cm^ or Ic-ss, more pcaferably 10 \!g/cnr or 3.ess, arid n.ost prcforahly i ;i3/c:it^ cr less. T)ie sjioUDt or r.an'pQUnd h3v.ir:q snti~ctiagul^biiiry an. t!:e subsirrate s'jrfa<;a is Eieaaured in the foilowitiy jnajuiei: on ttie basis Of leadings of the .■^ompciind having anti-coaqulat>ility with xeapect to the s'Jbscrate, tJis araoLmt of coiapound is dcterrrdiied in a si^bsequeTit: prc-c&ssy for example^ which is iiiaitily a cleaDing process, by autitcactina the aniauat t:i?mci''i5d i3y ths process cc- reir.ov€ ui-.reflcted cciRponents LhaL are JJ'JC iuimobiilKetj on the substrate, but the-ii'L'jth.Oii is net litf.ired-thetsto. Ttlso, t!ie oiiiount of ■ coirponiid can be calciilar_sd from tlis caiibratioa curve or th^ corap'-innd ti.iving -anti-coagulability pxepaicd ir; advance OQd ch^ aJEOUJi" c£ thcoiiiiiin Adsorption fcy measuring the amount of thrcE'biri ddsorpfcion described beiow,
ft compound havirtg anti-coagulability preferably has aiitiuhEoiTibin activity, A compoyr-d havlm) antirhr'oKbin activity in the present invsnticn is a coirpcund ttiat suppresses activity of ctsrojnbiii, which ifi ?. no^^gutatioa related ^ubstsnc^
] s

iri blood.- i'i.e scriO'urit of tbrcistin 5.iii-arpticn is :ueari;r^ii bv enzions-iiiikGd ijEiiraKOSorijenr a.-;ssy .'ELll^A :!:ecJjcdj , :'.'iit i.he raatJicd is r!Ot liirdted thereto. ?t ieti^iJ.ed Q!:pc:7:±rr.c.!it^X method '.ri ;i h-? dP-';nribed later ^uii !;ha ^jECjnt: o' thra.'nijirj adsorii-ad tiy-the substrate in thR pre&ent li^vsntioi; ].5; with reference to the arsa A, pn&fsrahly C.S ng/cni^ oi :!aoxe. and i^are proforably 1.0 "g/cm' or iR-nice.
Also, ii: the asiD-um: of hydfophilic polyraei: compound is. too small, ciiErfi is a problem that zYie effect of suppressing platelet attachrr.ent is low, ft. substrate ici the ptcsent itiver.tion prersrahly has 2Q't by weight or ciore of ."Surface hydroptiilif; fitqTi-raoieculer i^Klght. }t«rt;/ the sucfactj iiydrophilir; high, moiecylaa; weight is defined/ if the weight or Hionoiner unit of hyd.tophiljcpoiyiiiers Utu^riber of- mol^s of monoruer unit ' rnoleculaE weiceht of monomer unit) on the substrate surf 3ce is ik] and thp wfright of monomei: unit of polyTfiera [rimober of itioias ci laonoiuer unit »; molecular weight of. rnonoiivei: unit; constituting tb6> sisbstrate on the subt^trat-fe surface is (B; . as a Tscio ritij'i.-essnce-'i l>y J^/lRi-i:; . 'TT:,-=: ~itLZ3.c'j^ hydrspj!^ Mr. hiph molecvxlar weight is a p&cameter rspzesej^tiiig the degree of JjydrEjphilicity on th(= substrate surface-
The surface hydrophilic high malecular weight is d'3terjriined by mraasHving only ths substrate surface^ that is^ ■dp to Che depth of abO'Jt l.O tm from tlie 5arfaf:e by the X ray photcei^ctiron spectroscopy (HfiCAl {the angle of a detector with
)6

raspecu to the incidence angla of X rays is SO dograes! . 'jh^t is, the- surCecs tiydrophiliQ high giolecular welqtit is uateriaine:! irrcm chiang-cs of arcs Etrongth of Cls- anrf Ols spectra before and after t-.ERitmenr of the substrste . The surface hydrophi lie high, raclecuiar weight is prcfer.±i>iy 20S by wfii9ht or more £.nd raoi;e preferai'ly 32V: by w&igJit- Tf the surface hydrophilic high molecular v^exght,- is les^ than 20? by weiqliL. an eXTect Q£ supprosfiing attachja^-nt of organic matter" .such as proteins and biogenic substar-ces is lowered.
The substirafce- of the pjrese^it inventioji has i0//3.3 >< 10^
Hm^} or less of huraaii p.latelats attached. The numbSEof attacbe^i plaLKleLs !.s a i/iilue tiet-ernxined as the itujiujei: oC platelets attached to the substrate surface per 4.5 « lO-* jim."" on the su&straf-e surface when tile sui>strace and bloofz are maint^inea in coiitact with each, other f-cr one bQur, The raeasuririg traethod of thiS amount of attached platelets to S>e used is as -foliOKS-: ■ after a-asraple-ia shaken in heparin adde.d. lituHan blood at 37°C for one hoiiCr the sample is cleaned f>y physiological saline, blood con&oiicr.ts are iE-Jic^n iT^-i hv s. aXi.it?r5ldfhyde solution., oad a±ter slow eleaning ami drying {drying undec reduceci pTRSfJiirT^ is appLiRd until tht^ rats or change in wniqht. is wlt.hin 2% before a«id after drying for one hour), the surface of the sartiplo is observed ander 1500=t magnitication of a scanning eleccron micxos-cope, the Tumhei: of platelets in or.e field of view {4.3 ■« 20^ pn^J is counted, ^nci the average riuiaber t>r Dumfc&rs
i?

of platelets zr\ J.D diffej-ent i'ielcs :>i .-ie;/ :':i^{\.L- ":iu- -^snter of 33!rir:le is ^.dopt-^d as the number at al-tacheci plarslets-;nUKlJers/4. ? * 10^ y>^^) - J^ ti^s STnonnr: or art^jcnen hi-jiian platelets ■SMceeds 10/(4.3 >= I'LT'UI'X') / blood c-JiEipatil>ij.iLy wiii &e insufficient and also ttif; firfsnt nr ^^upprs^Rsing .TVtAchiaent cjf organic itiattei: such as proteins and biogenic sub&tsnces will be insufEicleni.
F-jLther, tnc sJbstrate ot the prfi-sent invention prefeTabiy extends tho blood coagulation time by 10 seconds ox more v7hen a "blood coagulation expHritnent is p&rfoi-med. Here, the blood coagula-tion tine- is pleasured by using SonocitH, icoagulation s platelet function, analyser manuxactufecj b-y US Sienco Inc.), but the apparatus is not limitea to this- Hexe, physioiogiGal saline is added so that tbc concentration of the tnbstrate. bRcoTnes lOG iig/ml., 34? ^1 oi hurean blDcd sivd 14 . G fil ot caici-un cfiuconate in^ectior!^ solution (available tram DaSnippon SuraitOTHQ Pharms Co., LtdO are added and the Gxtefision tirae is iTiea&ured by uginci a SoiiACT ?^it and an ACT progr-im, wliich is an internal program of Sonoclot. Ti\e eKtension time of islood coagulation tspzeteraDlY 18 seconds oc moxe snd jccre preferably 15 second or mure.
A coi'.povnd having an amino ;?ci-d prjund havinti an ajaino tcid as ft oor.ipo-.c-nfc ii 3. c.i:!\jro'j:ii:f having an .:r-attu.na acid constituting protsins cind iriciUiie;^, £c£ example, a coinpound ct^jupuayd o£ tiniy amiDO acida such as proteins And. peptide and thst i::oMpC'BBd Oi amino ^cids end other componertCs ottier than aKiltio acids such as giycoproteiji, amino-acid CDpiple^j, and 3roinoac^^i adenylate.
Whsrt bloori coties into cor.c<"ct-. with xorei^n matter, t;lotting cofflpanents are acttvaced t^i CoEAi Lliiojabus stiGxtlv'. If thrombus is foxraed in a. ciccult or dialyzer in nn extracorpor[^al circulation of blood siich as a,n artificial hictney, circulating pxesiiisre in blood iris&3 and in addition t,o beciiming impossible for blood to cifnulate shorti\f, thprra is a i-lsX' of the blood vessel being obstructed if a portion of faiKied throiobuii eriters the body, ThorcforSf in sn ©y.tracorpoieal circulation cf bloodf il is iiaCGs-sarY no add a compound Itsving antx-Ccagul-aHi-lxty to blood circulating ejitxacorporaglly. However, if a coiopoutid having t!\e anticoagulation action is added to blood of patients i.iroaec3iftt*ly sftec an operation or ttio&e couiplicateci t^' digestive tract bleeding^ such patients may be accooipaiiied by bleediiiQ, Thus, by icunobilising a componnd having anti-coagulability on thfe substrate surface aaed for extracorporeal circulation, it becoiTLSs po5:o.irjie to au-ppress bl-ood coagulation viithout adding a compound having Rnri-f-cagulabiiity against ibiood to b-lood circulating
IV

h compound :iavin,g anci-'roacislaLiiiLv -.s i compound; thst extGnds tf^Q prcfchrojzbin ciffis by 3C'. or Kara '-.'tierj the cKupourjd is adiif^d r.o blood in such a way thar. eiie i^cac'enuration t'r.exccf
iecnF^ei'; lO jiy/oL, as totiiparad 1.0 Li'.s.t ■.■j]teo :iat belna aci-ded tt b-0!id. The p'rotbrojnbin tiKe can bs measisxed acci^xdinrj fo a methycj de.-;cribed in tbe folicvjiag iiueratiire:
M. Kanai st al. "?.iT>sho Kensaho rsiyo (Clinical Examinaticri Hsthcd HandbooV.) 30tft Ed." K-anebara ^ Co., Ltd., 1593, pp. AlS-Ai^
That i.^.. .^peeiEjCS] ly; iO-i by '.roii^nip nr :^-2% snrjniim ciLxciLe dnd 90^ by voluD.e of blood are nixed, 0.1 mL o£ preparsciveiy isolated citrate plasaia is put ij>to a small tas-t tube linaids dismetar: 3 jriai; length: 7.5 cmK and the test tube is introduced into a constant ".erriperatme batb at 3T "C to beat ■ I'b*^ tesL ti;be Tor &&oi\t thres iniAi:ti>s. 0.2 iaL nt B t-issnr tfsroii'iioplsstxn/calcium cesgent kept .sf, the sarae tejEperatur-c is added theroto and at ths J5an\e tim&, a stop watch is started srid aft^r IHG sr.u'-l test tybc if sb;?.':en sT.lqbr.iy, the tiEie uri-il fibrin i^ deposited I5 measured widlc the sjnail test tube being settled and tilted.
The coiopound having anfci-coagalability -Jsed in che present invGntion includes, fox exan^ple. heparin; nafamostat nesilate, sodiaii citrate, sodiinn oxialate. Hi antitrypsin, a.2 nacroglcbalin, CI inhibitor, throntboiaodulin, and pcoteiri C.
-')

^xliib-iLmn £: slronij bleed cnticcsr/irla-j^o/i %clio:i by sup-^r^ssiiio activity c-f thrcFT.bin,- that is.- a coffipo'and having anti-throrriiirt activity.
As compoanda having ar.tithxojubia -aetivifcy- against
4-methoxy-bsnzeae5uifonyl-asii{PEG2000-Cme) -PJco-'^-aiaidinoben zvlsnldo (fiereinsfter, saaiecimes abbreviated as a coiapound AJ s^o«n by cfie ilollowing general rormulci tChem. 13
twherein, PSG xeprasents a palyethyiene gl^t^ol fliersxnaiter, referred to as PEG) residua of number average molecular weight 2l>l}0 and Me represents a methyl grcupi^ ATIII and Itiradin caa be citsd.
It a compound having anti-coaguiability contains a polyriisr chain portion like the corapcund A, the ccmipomnd can be ■ bound to the substrate in.the .polymer chain portion ao that an. ariti-coaguiabie portion cav, preferably be bound to the substrata to suppryt.3 Lbe icneriiig of dci.i-/i'-; . hp'.:lyi'.iei: chain portion in the prssent invention refers to a ntolscular chain in wbich a lepeating unit having a specific chemical scEucture is bound by the covalent bond an6 uhose molecular ij'eigbt is 300C or more. Such a polymer chain portion, includes a hydxopbilic polyir.er chain such as a PEG residue, polyvinyl pyrolldone fbexei.nafter, re £ erred to as PVP) r&siriu&, polj.'pxopylene glycol
:!

Oier^'fU: CL'ii, r^rgrj'fej to r-.~, ??.j] znsiLCJ^, priiyvidil alcoLol Chei-«i!-iaftsr, rfefgrrad to as SVAj i£sic'.';.6, aad s -.siiai;:^ or copCilyiiisr or one of tbiess. A coL'ip-cur.d haviag such a r,y,jraphllic polyniar c:hdin con p^Eticu^:5T:ly preSsrably ba used bscaiiiie waster solubility of a ciOR'.pDun cl hsviTig flriti-coaifulahi ! - ty ii? loss likoly l-C'isred, dt^^ivatives havinq dti dtuLao gioup or carbQ>:yi
havini^ af'tl-coaguiabillty i>j' introiiuclng these derivatives into a poIvTOSr chain portion is zslcti>/'elY easy.
A hydroph.! lie pnli^M^r cnfnpounci in fchR prsse-nt Invp-nr-ioa refers to s pfjlvjnex coEpcuad that is soliihift in wate*:, or net soiuble in water, but can interact ueakii' w:5tli water mclec-ales thruugJi Hn electrostatic inceractioji or hsfdcoger. boriH. A poiytnor compound rafecs to a coip.pound wtiose number average molecular wetgftC is 1000 or ^ors. SKamp-ies of ztie ttydraphilic polymer corapound include, for eKamplS; ?VA, pve, PEG, PPG, material aomposed at polvethsr and poiysiia^ane,- polyerhylene ajiiliiy, pulyailyi aniiier polyvinyl aminy, polyviiivi acst-ate.. Dolyanrylic acidr and poiyacrylainide and also a copolyjGcr ct graft polyizBr ct a monomer oC these pcilyjaers and ajiotSier itionDtisi.-biit are not limited thereto, toiong tti^mr a hydrophilic polyrrier coinpDU-nd containing at least one of the msterial composed of polyethex ajid jjolysiloxane, eVfe, pnlyether- ami PVP is siiitsbly used and paxtioul srly, the material aoaiposed of polyethejc snd polysilnxane and PVH achlsve a fHqh hydrophilic effect ,^,n,i are

poxyBj\.-z>y.&ii&'\:z&d herein int^iudss ^^ cnpulv-p-ar Z'f. pciysthcr gjia polysiioxane,- pcli^ar caii-;pie:-i, atid pol^irifsr toiended maLsnai. Among "r,hem, the copDl>Ta.ex is preiftxable becatiaa the ccpolvTaer IS hinhly solr.bla in iJ3f.fer snd tfiiis, graft tteatxent b'^ 3ft agueoiis solution J.3 pi^ssiiJie stj that risky oX xqni\,i.oa La solvent and coBbuaticn in facilities c;x radiation ii:i:adiatior; caa be reduced, tlie polyettiar/polvsllQxane copoliiKer is ccrepoasici of d polyether unit and a polysiloKiine 'Jnit and ci copol i-wer form nharGOf may be s r^nriom Ciipcil^-riier, bJ-ccl-copoi^.'iner or graft copol^-mex or a jaixfcjre o£ these ccpolymers.
PPG- arid PB<3 ate suitably used as poiysther, but uhen CDir^psred with P2Gj PPG is preferable because it has higher fiy-dropiLoliicity and thus, can have a sirrorigcr Iiy-drophijfaic interdction «i!:J5 the substrate aod if, for sxisg'iple, radiation grafting is performed, a materiai compcsed of polyethet sad ■poiysilo>:an.e oan efficieitcly be grafted to the aabstrate. Htsibin, if content of PPG in p^iyt;t^.er increases toe lEUChr BtlL;'"-~ility yf tbi? capolyjasr ',n 'vater lo'^'era and rhuK, content Of l^fG inpolyether is pieferabiy 5 ttiol^ or mare, mora preferably 10 cT;ol? or more, and still more preferably 20 mol" or more. On the other hand, content of PPG in polyether is preferably 30 v.ial% or less, Jiiore prefetabiy 50 aol% ai less, and' stiii uiors preferably SO rooll or less. Tbe content [molS) of PPG in the present invention is calculated according to the fOEji^uia !i) .

In i-he forniiilur ? is t-he con-ent ir^cl^f a£ ??G^ ■.?,] i/; me niJiiiisr
of PPG cnits in pojy-ether, and [Dj is the number of ether unit.s
m po"iyer_hP.r- A PFC unit in pnLynhnPr rc-tp.rs- tc a .striicriirf.
iiepri^sented hy the following chemical foxrj'-la:
[Chem. 2}
fin BthBr unit in poly^tber lufurs to aot ,ii-jd":rr."ir,^':-::.
Regarding i?Vh aa a pfslymer chain portion o£ a coinpo'jnd having ant-.t-cosgulsbi lity ar W?. as a bydrophilic pnlytT.er compound.. PVfl having a low saponification cegtse is preferable because iz has an affect oi ;fLJr-tJ3trai:£ surface.
Therefc^re, the GgpDDirico tier; dc-gr.ez-- i^ prsisri'biy S-5 so^ls oi
more., nors E>rf fprp.bly V'^ 7iioi% or raoie, and atill risore pvsfevabiy
?D raoife or rioEs. Conversely, IE th= sspcnificetior, decree i.s
too high, 3Diubiiity in water also beccsses Icyer, yhich results
in rKquiriciy heating during dii>SQlutioji aud ieadiaq to lower
productivity, and thua^ a tco high eaponif iaatioti filegree is not
preferable. Therefore; tiie sapc-ni:fication degree is
preferably 99,9raol% or Jess, mere preferably S5 mol^ o^ le^s^
and still mora preferably 90 tno] % or less-
(Chem. 4] fotaula [2fChem. 51 foriayla (35
(k)=CiTii,/((n) + (ni)>XtOI> formula (AJ
SyEnbola in the fcrmula i^J are as follows r (k): Saponification degree
,(jn> : IJimber of. jaonaiaej repeating ..units .represented hy the formula (2) in PVft
Uii : iioTib^r of mcnoiiie?' rcne'itlriq units reprssented by the formula (3) in EVA
ThP TnannSantiiring method of 3 sTibshrate af the presfint iji'/ention uses a method by which a cotnpotmd having anti-coagulability and a hydcophilic pol^fraer compound in. coTAact with a substrate sre irradiatect with radiation. In 3 preferable aspect of the nariufacturing method of a substrate

of xh= prasoiii: iin/entIcn, a icethr^d ot iL-radiating thsss
organic solvcut with raciauion is ns^d.
i''.ad:a"i:iOTi ysed in the prijss.nv. inyention is a parincls bsazi or an f^iectrocidgnetic ME-V'^ of high energy and sach radiation includes, for eKaciple, ff rav, ^ ray, V ray.- S ray, iiitravioiei; ray, eleccron heaiS: and neutron bea^.. RTUong Chera, V t^y and electron besm are-preferably iissd in thai: energy is paEticularly hiyh anrl l."^e substrata 3an effacisntiy b& iiiod:;fied. y ray, X ray, and electron beam are suitable for modification -of the substrate such as s rfiedical Trsarerial because the substrats caii be sterilized at the sawe time by controlling the dose.
iih'Sn the substrate is irzadiated with radiati-on, if the dose ct radiation is too s-mall, it becoses difticult to- conrrci rim dose s^ach as variability in absorbed dose in t)i& substrate. Thus, tile dose of radiation is prefsr^biij 1 \G'^ or rr\ore and more pxelerably S );Gy. -.if steiilizotion i& perforsiied simultaneously with modificstiQn for 3. substKsfce such as a KeaicdJ inntirial, tt-i dc--^ -i^ r/'.distion is preferabiy 10 KGy oi: more and more preferably 2resent xnventioa liicludes a solvent coJicsining a {lydro^yJ group, the tiydroxyi group Jias a qrecft etabiiizing <:ffoct en r,2diCwis generated by TSd.ia.zi.ofi irradiation, is .^ Donicnic fnnctioiis.! group, has a. veak inteiiaction with compoimds having strong surface charges, h^s sioall oxidiiing/redLic^iiig posisr, and, causes litrle deiialjrallzdtioii of comp^jumis. Pdrticularly secondajry and tertiary hydl^oKyl groups ha-vc a great stabiliEing effect on radicals andtUus^ in the present ir.vention, anorganic solyent having at -iesat one secondary or tertiary hydrosyl group, fot oxarapie, gl^cetift, propylene glycol (hereinafter, referrad to &s PG) , iiopropaaoi {bereijiaiier, - rfcit:ri:er,iirat;icrt at" i zoTtipc\ino. in sn oroafiic SQiven!.. sclu-:ioiL '.s arererebiv bO'-,'-. cv :;slgnr or "^ess,. i?or>s preferably 30£ by weicht or i.css, ^rid st.iii moiie preiyiicbiy IG?. by we-ighE Of." less.
The- moisturs content in the prtii^eiit iiiveation is defined by the fQiiowing formiilai
(\^oiume of water contained in £ coKpcund uitstabie with respect to zadiation and an organic aolverjt aqaaons solution that dissolves aiid/or disperses, th*; corepcund)/4Voi.uine oz a compound uristsiJlsi witti xyspt^ct to xadlaticn and an organic solvent solution thsfc dissolves and/or disperses the coffipcundj
■^ ir>c ii)
Tde msthod that brings a ci^iriDcuud having antl-cnaguJ.ahiiity into conta.ct with the substrate in. the presejtce of ^li or-j'i".-i h-avirig aiit^i-coagulibiiity !>-rir:a ovc'c^h' in~o ;c:M,ac;t with 'ilsf subsirrgre. riio £olv^nt say ij'^ rre^^lscsd by the i^srgt-t orGSTiic 5C'lvc-r>t. lii "his castt, tht; solvent it: whicb tlieconipo^rxj rid vine ADti-coagulshilizy is dissolved ra^y ba an ij^crgaiiic solvent sLJCh as watsr. That is, alcei the 3ufcsr.rar.c- bsiao drouqlii. into Gijntr:~-!-ivith s sciiution obtained by diaaolvir.g a ccrsp&urid having ant i-cosgulabillF.y in water, the wviifr-- is teplaCedby ar. or.-janLc soJve.nc dr.d the subsziats 13 iri.^rjisted w:i£h rsdialitj/i.
Iri the present Ijivsntion, ^ compound naving anti-r.Daguiabllity rnay b& applied or acisorbed uo a su&scrate in. adyrincs; and ths aubatirate to vr-ich tht compound is attached ma;? bs dipped iJi an fijganir, sol'jfir-f,
A bufisr used for a cofripound f'laving anfci-coagulability '^.nd a hydEophilic pcjlv'oiei" ccmpcund in the pressnL invention is d soiuLiuii sjiepdred in suuU a way tbat pJl tii&reot does-noC.cltangs even if a sKall aitount of acid as bi^ce is added and the concentration thereof changes, and Lnciur,f^ buifsr^, thepflDsphatebuffer, Trisbuffer, -;uiBi3-Ttisbufrer

aire 2-aii:abiy iii-rG bscause rhna-s bctrsrs havs s fcu-ijrer act-iors in riputr^i. ^n.i ^cidici reyions and isrc xL-^^CiH:ntI'/ addcct ?.B. SDlvenCs of cojf.poufj'ds iitvinq p'i.vsiolG-jical acCiviC.y, J^ereiD/ the buffer range is pH 3 or iHQre and piiBfijr.afciy 5 or siDro because ander strong acid condiltlons of pH 5 OJ: less or stroTig alkali condj'tions of" pH 10 or more, 5 portion of moieciiiar structure of r.LimpCiunds hsTing physiotagica"! acti'^'ity clisnqeti leacfina to changes in the ptiysXcdl fuucfcionT chacnical t-jiiction, or piiysio-logical function, and wJ^'^tij for sjiample, a graft JKunobilizing material is creaced, performance of t2i-e inateriai itself 25 cons±d.sred to deti3fl"er used ia the present InvivrstiOQ means an aqueous ooiuticn -of the buffer or a solution containing othef- sai«er,t:s or solutions, bnc does nnt mffflr^- ^. SGlutrion that ohanges beyond ttie pH rangH of the buffer as a whole solution containing the buffer and is prefeirably a soictiOQ wilose pK due^a iiot L;hsmie.
m the present inveatiorjj an anti-oxidizing agent may be used in coiabiaation «hen 5 compound having blood anticoagulation activity and a hydiophi lie polymer corr;poand are brought into continct with the substrate. Tbis is because an Qxtiid to capture Kydio.nyi ra.dii;ai:j qetit^rated by radiation

arit-i-CGagulaoi; ity can bs o;-:pectoa frx.i the snt-:-osiai ,zir,g ager.t. The anti-OKidizir.g agi^nt usisd hernir. is 3 coracouad tiavisiy niL>le'^i.il,t;a v:it)i proparties iRon- ?, iki^ly uc dciiats electrons to other ^aoleciTiles atidaisc'ias properties t:p sogprsss-densturation. or t^e substrate, and also a compound iiavlng jn-oiecuies «ith properties to prevent the substrate, tl^.e compci-jnd hsviiiq blcod anticoagviiation activity, and the hydrophilic polyiner compouna Exois. qytLicy dfeiiatureii due zo
Examples cf ariti-oxirfizing aqent include water soluble vitainins such as vifeaiain C; polyphenols; mineral salts such as soiiitira hydrnj;i)lfite, sadivim pyrosuLfite, and spdium dithionste; ur.to aoidi cyst-einr and glutrfLl»iune, but ijot lijciitecl tbe^^eto, Tbss^ an^i-onidising aaaTits arc used alon© ex two or more kinds thereof are used In coiribination-
Sincc it ia iiccessQty to consider safety when the . substratfi according to tha prssenc in-rren-rinn is trsed TU meafc^.i devices,, an anti--oxidiEittg agent «itfi lower toi^icity is asad. The ccncentraticm of an anti-ci>;idizing agent depends on the ryptj of the contained anti-oxtdizing aqeiit and the dose of ra-iiation irrsdiatior. and thus, an optiifial concentration may be used according Co cii'cunistance^.
Iri ordeE to reduce the aBoun?; of ijlution of the compouti'^i having anti-coaguiabijity aifid hydrophilic pol^.'sier compoand.

3irt-e'" th'ss^ r^oispotinds, bamg i'^iOErced to zt.^, ft-.ibstra"::3 surface, the c-ubstrsi^s iiisy ba washed Sefoce, -.Iter, or i;uc.^L tcfare iij-iri sftsr radiatic-i: iirradisfeioji. Since the coTT-pound leaving anti-coagulability 5nd hydropUillc poVjm-e.z compourLd. are linKe^ fco tl\c aiibstrate surface through coviiient bonds ptjrtlculairiy after radiation Irrarii^Ttion, there Is Little risk ttiat the compound having antl-coagulabillty and hydroplillic poiyiijei; compound axs exeessivclv r^axovsd sven by exceseive ale^ii-ilng. Furtner, unrsactpci coiripoTtents and byprocincts can ba tertioved by cleanifig and thao^ the sybatrats; can be uaad particuiai:ly tQc medical uses wxthoat anxiety. Water, pitysiolnginal saline, fiK buffer, or an organic solvent can bt- used Ear cleaning. ^ sclvLicfn a£ a suirface active a^n^at achie'/os a Jfiyli cleanirig-eliect.
The suriacG active agent in the present invention mo^no a general, surface active a^jent and is a aulistance that exhibits. StEoftg aurface activity with, reapcct to.wat.er and has both a
its iiiolecule. >!h«!ia aubstratr^ aaviiiq d.ii ionic functional group or s hydrophiiic: polymer coRpound is used, i£ an ionic surface active agent among surface active agents is used, the possibility of physical properties of surface being chancjed by linkage of ths surface active agsnt d^j.e to a.n slecttcscattc interaction cdiiiiot bs denied, Thua, a ncnloiiit:. .surface active agent is pjcef exably used. Aisong nonior:ic. surface active agcnta ,
3.^

polyoy-V^tnyiane alkyipbe^-iyletntr and po.Lyc.\y=; L/, ,^l&ne alf.ylfe'L-fifcix are patLictildi ■.v exc^I^^nr iri ci'^aainc: effect.
li"! !:r:s presenL invenf.ioii, thf? surf.^cc? actdys aa^stit la frecuently a solid or n viscous IJ.qaid anri vrnen >i3ed. tnr --l^s^inirLg, the surfscii aati'-re agent: Is pretecably a li-quid in terjss of handling properties. If the com^sititration of solution iii toe lew, d stiCricieiil cieafiinq eCfecL cannot be achievecf and oon'^-^eiselv/ i I: th^! concentration OE S%->'1 tit:ion i? too high, thi; suUstrate could t« rfftnature-d gs viell as heightening proQUctiori E;G3ta, Iherefore, the-concentrEtion of a SMuface active ag^int snliifcion ir, prpf eratil y C , 01H% by weight or more, moirs pxefsrably i>.0O[f£ by weight or oinrc,- da^J sLili Jtore preft-ralily 0,OI£ oy weight or jtore. Qr, ths otViSr hand, th.^ upper concpnfexatlcn is preferably 20^ by weigMt or Isss, mere preferably 10* by weignt or Xcsc, ,-ir.d still raore preferably S% by --ie'-gfit oi; les&-
'flisre mav bs (.iseci .-iny cJearf.ing m^thnrt cf a substroite by which a cleaning agont EUch as a surface active, dyer;t an4 .d solutiori to whi.ch a surface active agent is added is branght iuucj contact with the substrate so that sn excessive compound having anti-congulability and hydropiij lie poiyiaeJ: conpok^rjd are leaciiad. P.->r fty.ampiR, s methad ot ci&arilng by wiiich a cleaning agent is passed at a predetetiainwd flcjw rate in a predeleiuain^d dirsctior! is most «f,ficiei3t -and can clean tne substrate wel-Z. ftlEoaJ3tthud af dipping the substrate in a sutlace active agan^ may "be adopted as rhe cleaning mothod.. For eiiajr.plG, a s'Jrf^c-e
;u

active ager-it GX a soiutiian obtained b^ ad^jlncs a 3'drfEce active agsm: can bs used as a fiilirig iiqul;? or a bi..-;';d pu^i f i.ostion modyie. t>'h?^rt.a siiiiface active Agent or 5 30i»n;icr: cbtaiii^d bv addin-g a surface activii =g'Jr.t is- pa<;,?Gd to th'^ substrate in a predetermined dixeatiou, the .surface active agent cr the solution may bs circulated around the substtatc, but reuse of a surface active agent ?.o which a compound Having anti-coagLilabilityj a hydropjiillcpolyiaar ccmpourtd and the like hsvfi pfut.ed may lead tD deterioration ir. cisariing efi;ici.^nc-^. If the flow rdte when a cleaning liquid Is passed at; a prefdetermined flow rate £or cleaning is too low, 3 sufticisrtt cleaning effect may not ije obtainable. if the Xlow xaCB is too high, the cleaning tame will be longer^ leadirig to- lower p-roductivity. Therefnte, the? tl.nvj raf.p. per surface area of the substrate is preferably 0.5 LM^ or more, nore preferably 1 Wni^ or more, and still more preferable? 3 L/m'^ or »ore. On th.e othsr hand, the upper liait of the floH rate Is- preferably 300- li/si^ or less, more preferably ?flu;i'J haviliq hloa:i diitLCOaCUl^tion activity and hydrophilic pol^Tnar c.CinpQund that are aofe grafted can be ir&duced so chat cieanirL^- sicer radiation i^radia-ioQ csn be reduced.
A pCilyiTierif:: tTisturial is preferably used as a siibstratc-uMed for the present inveation. 2xampis£ of polymeric i-ojiipound constituting a poli'raeric raa-deri.il includss, fot e^:aIlIple. poiymethacrylste fiucti a*pcil.ymethyl usethaorviate {iiexeinaftyr, referred to as ei'RfK) , polyacrylate, polypropylene, polS'ethvlene, pOii.T;ir.^), ahiaride, piyi\tvinylidsne: chlorirfft, polyvijiyiidene fluoride, polvvinyl acetate, polycarborfite-, cellaicsSj cellulose acetate, cellaloso triHcetate^ polyacryionitriie, polyamidej pDlystilfQiie fhereinafter, referred to as PSi], polyether suifone. polystyrene, polysster, p.nd pQlyuret.^aiiej r>ut not iiaiitftd tlierfito,
A substrate o£ the.prersent invention can suitably ba u^Gd as a medical substrate, gxemple^ of raarfidaZ subsf^ratg lacltms an arr\f;ciai ves-S*^!, catheter.- blood bag, contacf- lens, intraocular lens, and auxlli iry deviccrs for opcratiorij afidalso s separation filiri anfl adsorbent contained and used by a biogenic substance separation modale and blood puri ftcatian iTiodale are included. In the present invention, the biogenic substance sepiardtiun inuOule ia a module tliat KeparataB bioqs^uic substariCGS by Filtr^tionj dialysis, adsorption and the like to
3(1

38


.■''•)


4i)

iiiaaonictei -nns provided in a ci,rcuit betwsb:); the hlac'd pu.'j-p and. the bleed port on the bicod incorainj ^Ids,. and pressure vjas recoriiPd at eacn paint oi 1, 5< 15, 30. eo, 12G^ ISO.- and 240 tTiinufces after starting circulat-l&n in [3) . (PtieparatidTs of a hollow fiber jmoduls (motJiile iO.iJ
5 parts by weight of iso-proSA and 20 parts by weight of aya--PldJIS of weight section 20 were added ro "JS part-i by ijsight OI diaetbyl suljfoxidB tc obtaix» an u/idiluEed solut-iun for filin pEDduction aftex stirring dt 110 °C for eight hours. The lindiiuted solution for film production, was dischargeQ front an orifice typs doiible cyliz;dxical mouthpiece and led to a ooagulstion bath of 100% water aftat being passed, t-iirough the air for 300 mia to ubtaiti a liollovf ITilJex. Dry nitrogen was used as s.n ifitsxrnal injection gss. The inside diiSreetar of the Obtained hollow fiber- was 0 .2 inm and ctia .thickriess Llieteof was a.03 rnm.
FT*?. 1 is a schematic side vipiwexsmplitvingri boIItU'jiibfir BiDdute. 11000 E^a■lA hollow fibers.'! prepared as described above. ware bundled, and both ends fchersof were- fixed to a module case 3 by using a urachsne potzing a-geat 5 in such a way that a Jioilow portion'.jas not blocked off to create a hoilow fiber module ^iith ^ sti-ye:t.Hte Shown in PIG. 1, hn eifective areatheraof was 1.3 ra^. Lilce a general hnlioi'J fiber type dialyzer, the module has


42

dropping fir; hydiochlcric acid- ^available tzoj:-. Signaa Aldrlch; . The same TiiC-'cl'itd as 'ch&t foir th^ bafiar cf pK S i/as '-ised for (tieasureinant of pH. f-j: a reauit, pH of each buffer was 7.8 and 30.0.
A soiu-tion [aolution h} obtsinsd by disiiolving the ccjFipound A and 3 cnmgannd R, losing s copoiyraeT- (F--3031 {lafc. 41010^1 avallatoie jTrora Siiin-Etsu Chemical Co., itd.) ot polyether and polys-T-loxaris, in a Tris buffer of pH 7 .S in such, a wa^- that the concencratlons ttiereoi; were as listed in xabie i way prepared and 0.5 L of the solution A entered at =5 flow rate o-f 160 mT/fflin from tbe (IHR hiood port 1 insidfi th€i hoiiow fibers 4 of the module (B) and exited f rear, the other blood port 1 aftar passing through the hollow fibers A, and entered to the dialyp.ing riuld port ?' on tjte blood port I' side via a tube (not 3ho-Kn) and exited,, to the other .dialyzing-fiuiressu.re. Ho pressure rise was observed In 2*iO


44


45


4h


47


4,S


■49


>ii

those Of Re.r8renca Sxan-^ile i -except tnat 5 i-G solucicn -.■lii'i pzs-pa.-::■•■a by using PG (ave-iiablii ir.-u'. '^.3.'-:si --.:-e Chemical
Inciu.-jt.jjas^ Ltd.) instead of IP.%, >n.'i t:hp rp.^idjjrfT .^.afric <7f the antltbroiPiJin acCivicy vslys ■■.•as cajculdtisd dccorditig to tj^e above formula (ij. ft. result: cl vhich is shown in FIG. 3.
Comporijtlve RererencG Ewampic i
ha eKpecirnent was perfoxiped Dr.rii:-r zhe: .satuft contiitlons -as those Ox Reference Examplf; 1 e-^-ctspt: that a coiapoiind A solution with R concsntration of 50C0 ppm by weight wa.s prepared by dissolving the compound ft. used in ExHGipltj l^ ajid the residLiai iratio of the antithrombin activity value uas- calculated according r.o th-t: above fDrinula ;i] . A result, of which 1^3 shown in FIG. 3.
Compaxatlve Reference EKa/nplti 2
Jin'experiment vtas performed undar the same conditions as tJiose of Ktaference Example 1 except that an EG solution vtas-prep^ied by using EG {available froai Sigma Aldrich) instead of IPA, and thi? residual ratio a± che ant^ithirOiub^ri aci;-. v; !■>■ 'J^i^a waa cidlculated according Co the- above foimula {!) . A result of vjhich was shoHn in FIG, 3.
Corapar&tive RsferEiice EKampie 3
ATI fixperLmenL was performed iinrter ti^e- "i^.me conditions ;is

those r>? RfiteraDiis 'F.y.RmclS: i excapt r.'-^.s!; a PEG solLJitior. w^s pzepajied cy usino- 2rEG (avaxlabl^^ ^aos^i Na'zul&i Z-s,^■qae., Ir:c, ; instead of IPA, and the residu^.l v-^t:in of tb? =ntitnronibir! activity vdlue war, calcalatid ^ccoidJ-iLij to ins above fori'^uia !,!] . A xesu.lt OJ: which was shoi^Ti in PIG. 3. [Table 3]
Exaiap le ^
A cciDpOund riaquaou^ Kolution with a c-oncontration of 5OQ0 ppiTi by ■.leight iias prepared by dissolving ths coEipound A in uJCrapare vater. The compound h aqueous solution, ultt-tiput:e vJaterj IPAr and s Tii a-fiiia baffer -of ptl 5 in double concen-tratinj^ WGra rcixsd in sijch a way that the conrrer.tr.^tions iiecams as iisted in Table 4. The compounci A h^itfer vjas irrsdiated vith y rdv. The abaocbed dose of v ^^y "^^ v?5 kCy. The antithromb-in activity values of the coffipound A buffer betore and after xadiati-on irradjatiori were incasurcd and the rasiciual ratio of the iii-iti thTfimhiTi arA.±v±ty valufts was calculated according to the iibove ioiniiula !!] . As o. resLiit, the xesio'ual ratio of" the antithcDmbin activity values when ttie IPA Eractions are L'.i, 1- 10, and 5i> vol% are as listed In Table i.
E>:ainp^p T
A compound A agueoys solutiofs was prepared in the aame
manner as in Eviample 4. The iiTompound A aqueoi'.-s solution.

'^on-^icntratiart were mlnad in snch ~ way trhst the coacerLtr^i^ic-ns bacamr- as listed in Tablfe 4. The coripo-uad A buffer was iiradlaLed with y ray by the S'^is method as in Ei;aF;iple 4. The antithrombin aorivity values of ttsH conipoHn.d h butter iietare and aXLsr xddlation irradiation were Jaeasujredand the residual ra1:io of ths antithrotnbin activity values was calculated according to tise c&ove formtiia (1} . As a result^ tiie residual i-atio of tbe antithroKibin activity values v?hcn the ISA fcaotions are 0.1, 1, in,- snci ^U voi^ are aa listed in Table 4.
E^acnpltt 5
A compound A aqueoLjs solution was prepared in the same manner as in Example '1. The compound A aqrieous Eolution, ■uJ.trspurs watftr, IPA, and a Tris buffer of pH, 7.6 in double concentration were nixed in such a way that the concentrations beca»-GE as listed in Table 4. The coEipGiind A buffer was
irradiated witri 7 ray hy tHe same method as in Esample 4. The anti thrombin activity value-:; or! liiB ■^ujr'poaaci iS Cizzi^L ^•■^'ior.'^ and after radiation lEcadiation wete aeasurad and the >:esiduai ratio of the antithronibin activity values wa-3 calculated 3Ccoi:ding to the above forinula {!) , As a res-ult, the residual ratio or the antitiiroi-ibXJi dutivity values when the 12ji. fractions are 0.1, 1, 10, and SO volk aie as listed in Tabis 'I-


54

passirig to the outside. 1I0II0-.7 Jib-^ris •:;■; tM-~ T.i:*i-inodi;j.e azd the msidp nf rne VLini-irtccij].-?-. wsre ciaaiiad using distiilod Till utj r >
[Prep^isratiark method of a PSt hoi:.oi,' xibej-: mini-ir^odulfij
16 psrts by i^elght of ESf (Udel [registered, tradesarki £"-3500 available from Solvsy) ar.d 5 parts by weigh.t of EVP [K30 aijaiiabie froa BASFt were addsrl to ;a mixed solvent of 72 parts by weight of" DMAc an-d 1 psrt by i^eicihl: of water LO abtaiii an undiluted solution for lilm praducticn after heating at 9& ^C lor 14 hours for dissolution. The undiluled sol'Jtion far film producitiori was discharged fxom -an outer pipe of an orifice type double cyiindEical mouthpiece (outaidedismfiter: 0.3inni; inside diametsr; 0,2 rnmj in an annular slit. A solution including 59 parts by weight of DSi^lAc and '12 part£3 by weight of ■■later vjas dischajrqed from ajiicHier pipe in the same maRTior as a core liquid. The discharged undiluted solution for film production passed the distance, for,350 mm fr-om the cnonthpiece to thn .■surface of a caagtjlatiun bath tftrougfi this air before beincf led to the -nsi!'-- ' .\t j nn bath of ICO^ w^iv^r. ri^siiltijiq in obtaining a hollovr fiber film, li& SSf hollow fibers prHjjared in this manner were bundis propylDitG glycol residue, a pclyvinyl pyrolidone Kssidue, h pLilvpi-"«e>yleiie ylynol residue r a eolyvinvl aXcobol rs-sidue, anci d xesid'at of a copo-lyii'tsr ijC CIIK residua thereof.
9- The substrate accord-ing Co claim 'a, cnuipri 5I ng rhea polyvinyl alcohol Vihcse saponification degree is SSiPolS or jnorfs and 99.5 pioi?; or les.".
10, The £ubsti:ate accoxding to any one of claia'.s 7 tc> Qj ^'jhei-Siji si ccjiupoutiu having tiic! olooa auLiOiji-^iiin-,. Lori acnvi ;:■/ is 4-tnethoxy-benaeneaulf;onyl—Asii [PBG20Otj~Oniel -£'ro-Jj-arQidiTioben7,ylaniido.
11 . Th9 substrate according to sny one of cl.iainc i to IG, whoiein Llie liydrcphilic poliTnet ccnpoiind contains at lea.'^t. one sali^cte-d from a group consisting of polyvinyl alcohol.

polyether, pc)v'-'iii.yl pyrcZ,iGor.ej arid 2 ~atez"ial corripoesd ^f poiyethex and poiyEiio-;-:an5.
-2. Iha siibsl,j:ate occcr