Drug nanocrystals of poorly soluble drugs produced by high pressure homogenisation, European Journal of Pharmaceutics and Biopharmaceutics, vol.62, issue.1, pp.3-16, 2006. ,
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Docosahexaenoic acid ingestion inhibits natural killer cell activity and production of inflammatory mediators in young healthy men, Lipids, vol.45, issue.4, pp.317-324, 1999. ,
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The formulation of Halofantrine as either non-solubilizing PEG 6000 or solubilizing lipid based solid dispersions: physical stability and absolute bioavailability assessment, Int. J. Pharm, issue.205, pp.65-78, 2000. ,
Emulsions as drug carriers -possibilities, limitations and future perspectives, Emulsions and Nanosuspensions for the Formulation of Poorly Soluble Drugs, pp.31-60, 1998. ,
A new oral testosterone undecanoate formulation, World J. Urol, issue.21, pp.311-315, 2003. ,
Absorption of fat soluble vitamins Boca Raton, Fat Absorption, pp.65-86, 1987. ,
Kosmetische Emulsionen und Cremes, 2001. ,
Intestinal lymphatic drug transport: an update, Advanced Drug Delivery Reviews, vol.50, issue.1-2, 2001. ,
DOI : 10.1016/S0169-409X(01)00151-X
Lipid-Based Formulations for Oral Administration, J. Recept. Signal Transduct. Res, issue.21, pp.215-257, 2001. ,
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Lipid formulations for oral administration of drugs: non-emulsifying, self-emulsifying and ???self-microemulsifying??? drug delivery systems, European Journal of Pharmaceutical Sciences, vol.11, issue.11 2, pp.93-98, 2000. ,
DOI : 10.1016/S0928-0987(00)00167-6
Grundlegende Untersuchungen zur Arzneistoffinkorporation, -freisetzung und Struktur von SLN und NLC, 2003. ,
Effects of nonionic surfactants on membrane transporters in Caco-2 cell monolayers, European Journal of Pharmaceutical Sciences, vol.16, issue.4-5, pp.237-246, 2002. ,
DOI : 10.1016/S0928-0987(02)00055-6
Feste Lipid-Nanopartikel (SLN) als kolloidaler Arzneistoffträger für Cyclosporin A, 1998. ,
Certificat of Analysis Fish oil 2261 ,
Feste Lipid Nanopartikel: Herstellung, Charakterisierung, Arzneistoffinkorporation und -freisetzung, 1995. ,
Contribution of Lymphatically Transported Testosterone Undecanoate to the Systemic Exposure of Testosterone after Oral Administration of Two Andriol Formulations in Conscious Lymph Duct-Cannulated Dogs, Journal of Pharmacology and Experimental Therapeutics, vol.306, issue.3, pp.925-933, 2003. ,
DOI : 10.1124/jpet.103.052522
lE5 rug/>« in ca« of hig/l <Itctro<tatk, TI>< m<a<· ill<tll<na in ultnpu« ~ ,
li>< ronn.tiOII of. p_.iik< port, 1<0 .tabili.ing li>< '~-'l<rn. Tru. i. ~-<iI oio=ribed rot rug, p.or ,
d PVP in OOO1birul'-on: .tn>o' LIr< ,1>< ~LC~ F ,
ing <>lorim<try (DSC) ..d Fig. 1 <Jlo',<-.'I>< DSC grapll. Corn· F"'r<d 10 lipid O)-..... n Il S b<Iik m.t<ri... li>< p< ,
woy'glF<M O>fl aY'1O<iliiC On 11= dif· r<.d ~ (mo<' tl><nnody1y 'tabl<) Rutirlg rul'l"< ofll><, 1< li>< tIIr«, p.1 ,
mnimum" 72.1'C ~I>< <oeting I<od< 10 <n'talii..tiOII in'o li>< a tmdi'''''';OII (11.1 'C). Furtl><nnot<. li>< «oond "l"<1< <Ilol'-. li>< Wmodo il ~·itII il< m<~ing poin' of 61 ,
di"r.ruOII .p«trum of ,1>< b<Ilk m ,
Ils (Fig. 4) <Ilol'-. 11I< tIIr« <xp«t<d p<.la NLC ,
of li>< lipid: 16.4 (lO) rot 11I< a modi, 19.1 (20) fot 1\ ..d 1l 1 (20) ....d 14.1 (20) fot ,1>< Wmodi',cation ,
t<o fouoo t1l.I' 11>< l<ngtll oft!>e f.tty.cid dloir" fi. f.tty >cido ~·itII. dI>in l<ngtll of CI4 10 CIS promo« .b<orptiOll 1»" ~-mp/l.ll'" uPU" (Port« >no:! 01>rmoo 1. _ioo ?. it .. bffi<1kilol if 11>< lipid" FJ««.1<d ... n""ly di,p<ru.!" po..iIll<. TI>< ,-"ioI"", in bioly';lJl>itily of 11>< 1"" q"Clo<porirI A produ"-S .ooimmu",~. ~-<r< <xplllin<d 1»" iooil-id.... ,->riaiOll in ,.n.« ",m-< bil< wU, ind«d. 1«, bil< wU. 1«, ..f<c· 'iI--< di'p"'iOll oftlt< cil, 11>< ool<g.l f>lly .cid TI>< 'rig~"«rid< <1IO«tl (0)-...... Il S _ gl~"C<"fl, pp.11-11, 2001. ,
po<,iIll<. 'full m..." in 11><Id lJtO'I"ld<, 111linl-'l1 11>«< ,
c=<t\Hy i. pt<l""'tioo Il could b< o!IO' .I' . t1l.I' tI><r<fullli,m of d<W,r:adlooo. 1><1'01-""" cil dropl<U >no:! lOIle1 lipid f'lrOCl«. Th< ootid tipid f'lrOCl« .r< d<g1:ad<d 1»-" 10p>«<. 11>< d<j.I'lId>oo Compo<itiOll of 11>< port ,
f'lrticl<' <n'« ,fie g", Iipa«._0 1110 ,fie port"'l< ''''. fao< ~~ , tII< >d. promot«! 1»" 11>< p< of "'.lip ElIlymaic d<j.I'lId>tioo of ,fie liplel port"'''' l<ad, ' 0 11>< fonn ,
00 ,orrounding 11>< f'lrOCl<' 1»-" ? poorty dil'iuilll< m<diId no< rotnpl<t<1y <lim ,m<1I. ing' Or>ttg< 1<m0ll-<r< 'l'pli<d in dilf<t<l\, Th< mo<! ..lld<n ot· ? ng< 1'1» ,
11>< moll<tl lipid bl<tld i"" priot 10 OOmOj of ,fie I"Olail< Il>, llomOj.<tlil.lll"" ~'ill ~< plll« in clo«d coo>in n.... "ming .ny r< ........, lb, p.10 ,
cOO«n fot colour· ing ,fie prodl!<t, Food colour )-<1 ZLTl in14% >no:! 0.011% food cclou, r<d ZLT1 1.1. Cily di'p"'ibl< i. Ilulel mali>. TI>< fonnullllOOII r<pt<l<t\U ?? "t<rnai,-< fot p<, bl< fot .b<orptiOll i. 11>< g ~M fl.I>-< prolll<tm ,~-.I1",·ing ",W do<>i< fonn 11>< port"'l< m...h >no:! fonnulaiOll ,
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URL : https://hal.archives-ouvertes.fr/in2p3-00277323
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URL : https://hal.archives-ouvertes.fr/in2p3-00146875
M ('_' EfIo<o or, EqJJ MoJ ,
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~I1 T«bull.,.-be;li~oan;n'_'''6i 19\1" Clutrman,000 Za\:,001). Vitamin. 'Uo<b .. ,-itamin A ..-.:1 [ .r< 1><11<, al>«i<bed in 11>< TO«?? r< quit< ? ouml><, of drull' foo ~'hich an ir.<r<a«d 0001 biOll' aitobility " r<po<t<d ~'1><0 1I><y ... admin"t<r<d in 11><, · rich food Eumf'l« ... 1«10<1«00? ..-.:1 lutIofantrl"" (Clutrman '" Port<" 1_, 1I01rn <t .1.,001, KI>oo. Pon«, 1987. ,
Ih? <am. tim. of high cornm""," inl««[-<. cYCK><porio A D<li ,
19119) ln. cornl'-""ti\". in \"~·o '100)', cy<lo<porin A n ??dmin,· l<r<d ... drull"''''''''l''utl ,u'p<n''''o (10 and inoo'f'O<"'<d inlo IOlid l'I'id. in 0001 bioo,-aitobility r<port<d foo drull, CUMy. 19\1l). In COO""'I'" Ih" liI<u,ur. dala, 11>< ""ulll of 11>< cYCK><porin A "-.. ualO~· ET Al OOug< fü<m< «.g.? tal>1=. 1"11=)" 0 lot of nt both prodoclion pro",..<.-I>om"ll",inlion 000 micro<rnullion m<1l>OO-y"td an idental produ<t IOlio:! hpio:! particl" di<· p««d m on "'1""00' di<p«<ion m<diuln. A, oi«<ril>ed in 11>< pal"'t (M~II Locb. 19%). SU, pr<par<d by hip ,
1:<. E'p<<<oUl' SL~' J""I"rOO from on< hiihly J>llrifIiz< m 0 0< l«, p<rl«t «)'''''1''' l''oc<. Soch 0 p<rf«t «.,-.alli .. '1N<I"'" 1"'"<5 lit· tI< room fo< 11\< it><0fl"I<aIi0n of drui'. U'ually. drui' arr it><0fl'0<"I<d 1>«...<", tl>< fonl' acio:! <1ta~"1y in !>«~-«n lipio:!IO) f«lion?. Tl>< mot< p<rl<ct d<".. 1y pa<~al tl>< «)-~tal ". 11>< f<...« drui Cln 1>< i and ~ Ouri"i 'lOfai<. 11\< l'l'id, 0< in _"'l'hou. <lu, p.0 ,
p<rf«t l'l'id «)-~t"l"" <tno<t"'" teod, to, 1997. ,
po<,ibl<. T0 ach<1)' diff<""'1 mol<<raJ 0 IOlio:! lipid " mix<d ~·ith 0 Iiquio:! l'l'id (oil). Th.. bl<rol " u"d 10 prodoc< tl>< l'l'io:! part"'l" tlu< arr <tililOlid, 10 abo<!l 4<J'c Il Cln 1>< ,ummoriz<d that SL~' or< parti<l« prodlJC<d from 0 IOlio:!l'l'io:! only rol ~LC'" arr part ,
Thi< of 11>< part"'l< motrix i Clpaci1y 000 minimizi"i 0< ,-oidi"i drui "'J'lIll"'" duritli '1""1:< wc Ba«d on 1I><it hPOl'hil'" <!tara<I«. SL~' 000 ~LC'" ha,.. onll' 0 Itmital loooli"i Clpaci1y fo< h.,-drophili< drui'. Th Mt 0 prol>l<m m CI" of hiihll' po1<"t h)-drophil'" drui EPO: 11><)-' <an 1>< IOlubiliz<d m 11>< m<ltal lipio:! motrix u""i .macta"t mixt 000 diil)--oerid« l'''''nI m tl>< l'l'io:! 0")"-0)' «.i.? Im~·itot 900) 110 Mt ach",-abl< ~·i1l\ th.. 'ind of lipio:!lUoopart, drui" tfOf"fonn<d 10 0 mot< lip"l'hil"'. inlOlubl< ,
Z<n< of abo<!t JJ% fonnuw<d .. diminadia«lura_acid ra_acid <onlUP1< ~·ith palmioc acio:! .1..rie acio:! (Olbrich M~II1« <an 1>< mal!< from 11>< <ooluPI<d drui onty 0< IOlio:! Ilpio:!. <an 1>< additio!wly admtX<d 10 fonn 0 mixal mallix of LOC'" 000 lipio:! rROOUCTIOI" 01" UR >CALE Th< prodUoction m<ll>o<l of f"'t <110",< for 11>< th«< t)'p<. of l'I'id I\II\opart 1'>om"ll",inoon. In <a« of SL~·. 11>< drui i. di<· 101\"<01 0< di<p<r«d m 11\< m<ll of 0 IOlio:! lipid. 'Yl'i<>lly ol'l'fO"itnll<I)-' l-IO'C _ ,.. tl>< lipio:!'. m<ltini point. In <a« of ~LC"'. 11>< drui .. di<lOh"<ol in 0 m<ll<d bl<OO of 0 IOlio:! l'l'io:! ~·i1l\ 0 I",uid lipid (oil). 'Pm .Iiihtty 01>0,.. tl>< m<tl"'i point of 11>< lipio:! bl<OO. LOC'" I\II\opart"'l" .< <on-.nonty l"oolJC<d" room 1<, 11>< "'"t pro<! Uoction ,1<1'. tl>< à1.Ji-rotl ,
Il<"ization J'fOC«'. it " "'romm<r.led 10 u" di<p<l diffu''''i. <I<e- 1ll' .taI>ilizini. 10,· mol«ular ~-<iiht .urfoctanu ('.i.? lOdiLltn _l'~ulf Th<)' diffu" ''''l' f..t i"1O "~.Iy fotm<d in1<rfmoll dr"l'I<.. <mcl"'tll' minimiz"'i .Ub«qu.<fil ro'-«>« ph, 1SI). SI",i< 'ab~ lization .. I.tl< 0< 1", tmpa;ml by 11>< Jl ,
ur<-<onIroIl<d hiih-J'f«'u", 1'>om"ll",iHrIl>« from tl>< p..too- Pl' typ< (ArV Gallim. M'V D<uu<ltl..-.l GI>"i>II< (mi<rolluio:!iLll, 0< from tl>< j<l prin<'l'I?? Mi<rofluio:!iHr ,
Il-.:I ~LC..z .. ai"'" t),I'''''11)' al>o<ll l'C _ ,.. 11>< m<lti"1l fIO"'l of 11>< l'l'id l'ha« aro:l room l<mfl'<'" 1"'" fOf LOC..z 1" pri"'''l'~ fOf SL~·..-.:I ~LC..z prodoctioo, on< 1>o""'ll<"",tion c)'c~ al Joo!lM .. ,ufflci<flt 10 y;'te1 a 1>o<0ilwa ,
fIO<t<d in 11>< litera· 1"'" are 100 bar aro:l ul' to tltr« hom"ll<fliz.alion c)'d"?. Th< IWO aOditional C)'d.. leao:IlO a furù><, .Iight ,edoctioo '" 11>< l""icl" .iz" to _ima"l)' "0 nm ..-.:1 a tam:lw"'ll of 11>< ~·idIh of 11>< dizuiblltion ("'doction '" 11>< fIOl)'dizfl"'<ity o..l<x of fIl>o<on, PCS). Ilow ,
1O 11>< total drull ad<l<d. Il 'l''<<f... 1>ow m..)' J'<"'<fIl of drull are "'clL>d<Il '" th< l''mel''? ..-.:I1>ow m..y J'<"'<fIl of rr.. drulla'" ,tilll""«flt '" th< dizfl"'<ion m<dium LotJJf'g oepadJy 10 th< J'<=lIi< of drull i10 th< lipid10 th< total ~-<ight of 11>< l'l'Odic fIlw' (i.<.,lil'Od. drull)· To IlUm< a 10% lil'id lU'ion (i.<., 10% l'l'id, al>o<ll 1% In th~ Ca«" th< l''rtie~ mao, .. <qu~-al<nt 10 IO%, th< particl< mao If th< drull had a lotJJ"g _dJy of 10%, :I!9% ~-_) def....d .. 11>< ,um of lil'id..-.:l drull ( ? 100%)mc~ dizfl"'<ion E.rr_"" _ff1"'bUÙ' in th< il ,
10 th< total lil'Odic m... of th< parocl« Th< laod",city d<p<M' on th<ILlbihty of th< drull '" th< ",Iid lil'Od ('" ca« of SL~'l Of th< lipid b~oo ('" cao< of ~LC..z) In ca .. of LOC' lUicl«, th< IoaJ"g <apadty i. d<I«mtro<d from 11>< of th< mol<cutal fraction, '" th< coojupl< «.ll., drullaOO coojui=d fany acid) Exampl« of laodinll oep_ll. "'fIO<I<d fOf SL~' are 1% fOf p«dr.i",lon< (Sch~-arz, 19\11), 10% fOf "1ta<ai .. (Sch~-.,. ?? 19\11), aOO ,0% fOf <)ü"j>O<'ir. ,\ by Ru"S< (R U"ll<, 19\II!), aOO1% for <)"<lo>5j>O<'ir. ,\ by RadIl;< (RadIl;<,00)). 1" cao< of ,
ul' 10 JO% can 1>< ><h GaMa, 199\1) V'-hat are th< m<<ha"~m< of ~ it>ro<fIOOIlion Th<r< a Th< _je>< ~-O<I: ha< 1>«" <lot>< by 11>< 19\II!). Baoicall)', th<r< are tltr«, fIO<"tion moO<tl Ilom"ll<ro<l' m.,rlx of ",lOI ",IUlion Co«>-.h<1I model ~·ith drull <nrich<d '" th< .h<1I (. drull«>ri<l><d .h<II) C.""...h<1I moO<l ~·ith drull <nri<h<d '" th< rot< ( . drull«>ri<l><d <0"') ,
Iid lipid mm <nrich<d in th< .h<II. 70.. <a" 1>< <>pwr.<d by a lil'O:! l"""l'iation m«hani.m occurri"ll duritlll pamc~ prodoction. Ml<'ll<nizOlion, th<r< .. a mixt"'" of drull roll'l'id", <><h drap~t Il .. th<fl I><"'ll 0001«1. D<p<OOUlIl on th< TX "'Iubility dÙlgram, th< l'l'id ca" l""''l'ia", ..ri;', than th< drull to form a drull-fr« cO« or" I<..t HO« ~·ith r<doc<d dnJll ""n1<flt (TX dÙlgram' a lwo..:l"""n.ional ll"'I'hicai "'pr«<fllatlon, ~·i1hI1<m). R~h'"ll th< <tit«oc 1<rnJ Exampl« are ""<fIl)'nl< QI 0 SL~ Th<, of th< t<ooaric l'ha«1y '" th< 0ll1<r .h<1I of th< lAFM) (OUlll ,
Iubilrty fOf m..y dnJll' '" th< OU"" l'ha« (.urf><taltl ",1"· tion) ., <I<\ ...d 1<m)'< Coolinll of th< oi~w"<r FlGUlE 1 -'-I 139UrnDlI' ET Al "üU, II" .. do R Of ,
J>Ol<"ti ,
1(~ttl< OEÙlion ,
<On-- lra11 10. i" bioo"oil>l>itity t<poned for a "umb« of drull'.1»' 11>< 1ci"'1"" of 11>< < 11>< bioo"oil>l>tiit)' of danazol ""uld 1>< inaeo«d from 1 10 !:1% b)' ""o,f<l'li"ll m< drulllO a IU CUr.d)'. 19\11). Th< "' aIOO' fo< 11>< 10... bioo"aitab'lrty of l')'<lo<porin, 11>< pl' '",inl..tinal fLuid. Il i, kMwo th., IUOOctyl1" aggr<pl"" <an 'lGUo.E' fil ,
Il<, 19\II!) A. m"'tion<d lUM<mutlioo ",doc« th. dNg wiubilay in 11>< "' 1"""' " f'l\>«, drull tri«'" f<I'Irtition inlO Il>< l'l'id lding 10 <Mch! in 11>< J"'lk~ .1><11 in ca« th. J'lrticl< co« oIreodl' Itl""d to wlidify (Fill"" lI. Soch f""licl«.r< <rown 10 l<od 10 ? !>U 19\11) In th. ca« of th. onI cyclo><porin'\ f, 01 ..phroloxi< 1<,..,1 ?. In ca« of o<h« "1'l'liation., it miih' Il<, 1999. ,
.d by ,atyi"ll Ù\< pro<!IJoctll 11>< f'lrtiçl< pro M<!u><rt, IWIl) Soch roro:litiom"", 10"" pro<!IJoction ,
11>< IIi"ll, 0 ,uP<' I.oluration..-.:l 'U!>«qLJ.<fil drulll""cip'lItion.d 1»' lh.. mod<l (zur M~"I M<hr.<r!, 19\II!) rN FLlrÙI<rmo«, it might 1>< tlu< tl>< d"",lutioo r'l< of <y<lo<pori" A frorn tl><, <t>1< n. Ml a< high a< frorn 11>< hl'id lur'II,..ti ,
11>< 001I of1l>< SL~' a< ir.:!i00 in in ,-itro «1<....100... (Ru"ll', IWIl) ln 'UIn, drull 1UOO. fonwl>tioo _ < I I fo< pooriy ",Iubl< drull', do Ml "-0<'< in '"Y <a«. Fo<. "um!><r of drull', it, 10 1>< I><,...r~ ci.. to""" lipoli p««rtt durinll tl>< >b<otption J>ro«<'. Thi oel<ril>i"ll ÙI' J'O"I~" .ff.ct of lipid. 00 0001 drull .!><o<ptioo, p.0 ,
Th<<<fo<<, ÙI' r"'l <!>ok, Porter ...1.? 1_Il might 1>< drull IUOO<ry'w., bIll lipid _rti<~. ... 11>< .... "ti.. !»<k up fonnutalioo, 1997. ,
It leao:I 10'" >b<orp!ioot.ro:! ilio todoclbl< bi<>ly.i~ >bility (Iinl< """'00" in bi<>lYoitabilily) TI>«< m«lWt"m. ? i"'<r>I ,
Ml .p.cifL< fo< lipid lU ,
:1 fa! <t.ol... ron.i_ .. y.. id fo< ÙI' hl'id tunOj>.olli<l... Tl>< low Y>ri.olioo in bi<>lY.i~ >bility ol>«r\'«1 "·ith <y<lo<porin A· Optonoll<'0001 mi<ro<mul<ioo (Ru"Il',IWIl) Il i< koown th 19I!7). Th<!>o<Iy >b«i<!>'I1I>< f.ol, r< lipidoch a< yia· 1>< <Xpl.....d ma« "'«LH""11y by 11>< ,100'" ptrfonna! by W. Chlormon..-.:l <0- "-0<\, 1991. ,
in 11>< llUI ~dinll 10 tl>< fro:! dill~"«rid« 00 11>< .urf"" of tl>< lipid drofIl<u a: ",Iid lipid p"oc Durinll tl>< oet><lun<flt..-.:l mic<l~ fonninll proc«&, 11>< drull d..",II'OO in tl>< lipid" 1.1 Solubili""ioo .. ? w.l~koown pri"",pl. fo< "'Iubility ..wn«m<nt in plu<, 11.. ·· In 11>< 'U!>«q ,
iÙI of tl>< f.olty ><id <Ja.n. ur tl>< primo'Y pta.,. of >b<orp!ioo. F.tty ><id GI! <!aUI. J"û"l"l< Iy"l'hloti< >I>!ofption, C1IlIln'aM Th" .. of in1<",1 fo< drull' ,och a< 1<'1 ,
« _ « 1 Ùlrough 11>< llUI nll _ pa< , l)mplu<'" >b<o<ptioo .,-oid, th" rt<'ll_pa<. m<taI>oli<m '" ? <<ri.." oegr«..-.:I """ 1>< u<al 10 i""", tl>< 0001 >I>!<Ifl>tioo of 1<.10'1«I<f<In< uOO« 1<. A rom""r",.1 fonnutaoon "'plo""'ll th.. <oooept" Aro:I<iol' ""p'ul« "·iÙl 1..10'1«, 1< d..",~..d in o~i< ..,id (SIt><'~fool <t .1.,00)). O~'" ><id a<. GI! f.olly .cid il ioeolly .uil<d a< <ril rompoot>:! in <'l"ul< ?. Th< b".Y.il>bility of I<'ItO'lI<fOO ,
Aro:I<iol T<'ItOCllp<' "-.« IlIllocl><d Il)' tl>< < 1>< .tor<d >t room t.l><"", tl>< -rt<'llll], to 1>< 'tor<d I><low !'C. Aro:I<iol T<lto<'l'" rontom ? b _ of 01<1< .cio:! _ <..lOf <ril (whi<ll m.;or rom tl>< GI! f,"y .cio:! ri<""I"'" .cio:!) a< <ril <""lI"""'I..-.:I >dditiO<»lIy' .ur· f''''''"1 tallroll~"olFCC (-propy~"" ll~"ooi moootae) (S"cl:~fotd.I<ifyinll drull oel~, Th. IlYoitabilily r<J'O'l<d i< >l>oot ,.!! " O.!II% (SIt><'~fotd ...1.SEDDS) (Chlonn... <t .... 199" POOIOO, p.0 ,
of al>o<ll ,10 Ml ( . 0.21~m). Solubiliz.alion CO" ta\;< pla'ty dLJ< 10 11>< la'll' ,un",. or.. ofl1>< ;>arti<l« ln cal< ? ?"w" deWadalion, fo< prolool:.d «1....)?? fraction of 11>< 11« CO" Il< .Ulliliz<d ~·ith ,
I.own tlu< 10 «>m< <xt<"' 11>< ,
11>< 1)1'< of <tll>iliur .ff"", 11>< 'I\Z)-" m.,i< deWadalion,bilintion of 11>< lipO:l ;>art"'''' ~·ith ? mlxlur< of <Odium <!>ola, Otbrich. M<!u><rt, vol.001, issue.11 ,
M~II«, 1999) Th< u'" of high mo~'" ulor ~-<ighl <tll>iliz«< ,och .. Poloxam<r 407~, 10. '1«i< hirodran"" of 11>< an<l>o<i"1: of 11>< <00>1'1<>:, mu. d<tayi"1: 11>< I1: mlxll"« of deWadalion, teratinl: ..-.:1 d<w>dalion d<la)"itll: .abili..... (Otll<i<h '" M~tl«, 1999. ,
1: l"ll" «>~ _h Mt« qu.alrty of 11>< 1"00"" ~·ith «ganllO ??ImI'" meon J'lrtk~ .i l . and it5 !>o<lY (widIh of 11>< .i.. d"trib<ltion) Bal' " ad\-.nal:' .. thal high-pr«,«lI"''' iMUi1r)' fo< 11>< 1"oo""ion of <mut<ion. for J'lf<n, ilalion ... pro<!OCOO" t<cl\niqLJ< ~·id<ty u«<l food pro<!""ion, ~.1><<< !>o""'I ,
fot tal>-"",I< prodoction _ th< Micron L\B 4<) (bal<h .il<: ,0-40 mL,\PV D<uu<htaM GI>"i>Il) andtin Cl (balch .," 7 mL to 1 l,capa«ty_ tin E""'f'<) In ca« ofl-..y <>:l'''''~'' drull' ot if1l><rc ... hm· ital ,u1'l'Iy «.ll., n<w ch<mi<aI "'Hti..), it il f,-otaI>l< to rNoc< the balch .il< (ICalinll down ''''l''biltty). Bal<h .ize rNoction con 1>< do!>< by utin E""'I'<) Th< bateh mlum< il O.~J.' mL A f, ion of th< Mi<ron L\B 4<). Il Ul« 11>< <am< h ,
:I ll<Om<"'y of 11>< hom"ll ,
Il ~·ith 4<) ml <a<h .rc rcqu<!<d). 1" ca .. of 11>< coot0 , ion, 11>< 1>omoll"'iZllion tower.oo 11>< two prodlJCl cootlu,1'fI<d ~·ith I<mfl'<"lur< co", Irol jacbu. 1" 1I>eot)', on< could "'tarj:< 11>< prodlJCl COOl OOll""'lly 00< dc,igned 10 N" tarj:<r mlume< in COOlxt ICaI"'ll ul' 'l<fl ~·ith. min.mum bateh .ize of, 'll ..-.:1 ? muArV D<uu<htand GI>"i>Il). Th< L\B 60 ha<. hom"ll",izotio" cal""it)' of 60 Uh Th< two prodoct conta 10 pr<fI"< 11>< pt<-<twl.ion in it Fot th< production of, um of 10 'li ~-.. a<h....·ed u,inll th< L\B 60ll bateh, th< pt<-<twllion" fI&l«<l throllgh the hom"ll",izotioo un'l, and 11><" it ci"",I.,.. bac. 10 11>< f«dinll coot""",. Il ... contin""", l>omo:Ig"'''alion pro ,
1\ min 10ti<tically-99.'/% of 11>< drofIl<Il ha,.. 1"'«<1 11>< 1>omoll",iZllion ,-al,.. al a.l oncc (l<'.-iton '" rallanlch, 19\9, M~II<" Wil.inll ,
ur< that 99.9% of th< dr"l'i«' ha'... 1"'«<1 11>< 1>omoll",iZllion Pl' al l<Olt ,
,er, il ~·ill 1>< fed bac.< from 11>< ..roM cootvity via ? teure-controlled lUI>< to 11>< fI 11>< «co<>:! 1>omollI, t~-o 1>omoll",iZllion cycl.. al \00 bar.rc fully .uff";"'l 10 y"ld. rc",~"1y moood~p«« prodoc~ 11>< total l>omo:Ig<n"ation t.m< fot 10 "ll .. only ,0 min (10 min 1'" cycl<) A?? Ireody m"'tion<d, fot otally '_"t<r<d lipid _.'" on< ''''lll< hom"ll",izotioo cycl< il coo.i_ 10 1>< .ulf"'''nt ln tlW Cal<, it dot Ml mal:uny diff ,60ot nOnm Th< L\B 60 un" n. d..ign<d fot. pharma<cutical coml''n ,-. thal .. ~·hy it ca 1>< u«<l in. GMr _. fot clinical batch 1"oduction. A, JIOinted 0111 _ ,.., 11>< l>omo:Ig<n"ation.d ~·ith largc--<eal< tYl'ical1y I><TIer than ~·ith th< 1. raI rea<on. fot thfer ofti>< proc«' from ??maller capa«ty mach .... to. larger capacity of th< idcntical ot .imital ll<om<uy of 11>< l>omo:Ig<n"ation v I<adinll 10 1«. fLoctu.ation in 11>< a<nlal l>omo:Ig<n"ation pr«'ur<. Th< L\B 4<) ha< onl)-' on< plunll<c. 1I><rcfore, th< fI'«'ur< """d. 10 bIliO:l up, the f"'l .maIl fraction of th< 1"c-- <twllioo .. 1«. cff";"'tly hom"ll<nized than th<inll ~·ith thr« plunll.....moothinll th< fI'«.urc fLlJClu.alion prof.l< Furth<rnlOrc, 11>< COOlO}l of th< talller can 1>< ool<rN "lui1'fl<d ~·ith 1>< ool<rN _bic-wall<d fot t, 11>< f«dur< conIroI Utl<! fotioo Utl<! it«lf Allo, ail rcquir<d lUl>«..-.:I <ontaiur< control with. t<mfl'<"tur< controllinll l''uid. In .ddition, ù>«< l>omo:IJl<n".... _ <qu,1'fI<d ~·ith IWO hom"ll th< fI"t hom"ll1y high l ....tic <I><fJlj-'. Tl>N ,urf.cc might tIO! )"1 1>< fully co,-.rcd ~·ith\« al on< tenth of th< fI'«.ur< of th< f"'l ,-.h.. , <.ll., \00 bar fo< th< f"'l ,-.h.. and \0 bar fot th< «co<>:! ,-.h ,
ty of 1\0 l"h (_1\0 "li) Th< pt<-<twllion .. fl'<l'""'d in tarj:er fI'l"Iuct coot. and h"""'ll<n"er.r< 1>100<1< from m.,.rial of pharma<cuticalll"dc. Th< prodlJCl cootai""" can 1>< lt<ril"ed by .!locl.Yinll' fI'<I'''''''ion of the pr<-<twllion ur.l<, l""'<e"'.. i " il fIOl"bl<. Th<y al", ha'... the f<alur.. of deln'"ll·i"1'tacc «(Ir)..-.:I «<riI"atioo-,"1'iac< (Sir). Fot th< prodoctioo,1I>< l'I'id con 1>< _lied in 11>< f<edinll cont,"cr Surf, idinll'teril< ~-.,., of SO'C, ~·hich ,
ny of fI"l"IlJClion lcod?? Ilo 10 ? '''''y low microbiol"llical load. Fot otal admitl"motioo, on< hom"ll, Th< product .. coll<ctcd in th< ..roM prodoct con"' .... , ..-.:1 cool<d in ? conIroIl<d ~-O). UMer lt.mno:. A balch.il< of ._t half. too I-W, "-..VOIOW ET Al ,
'll<nization tim< with 11>< G...I., 1.1. Fo< many prodoct< ,
Th~ ny of prodoction n. u«<l by 11>< company "Ch<ClR)-in B<riin to prodoc< 11>< f"'l ta'll<-""'~ balch of ~lC'" fo< oo<m<l'" indu,1t)' 10 f<ali", 11>< f"'t oo<m<oc ~lC'" prodOCIl (M~tl«, oro:! Sdlw-ab<, p.70 ,
ta'll« <aI«, an A,"«tin EIWI ..F~x C1000 (A,"«tin E""'I"') 0< 0 Ra ,
<<ty io 1,00012,000 Uh al 11>< 10..- pt«'ur<d fo< iol'id _"iç~ prodoction ln Ihi. <aI<, it ~ no! ...,..b~ any mot< 10 J"<I"f< 0 '·ton balch in 0 diooontinL>O<l' ny, i.<., P«pari"ll 11>< ~utoion in 0 oontain«. Th<!>eIt <xchanll< ti Of< too loolllliyittll0 100 high I<~""uf<!>urd<n on 11>< oct~ Fo< production lit>« of th, 0< drull) ,
Th< hom"ll",iZ«! prodOCl """d, 10 1>< 000100' 11>< =l'<<''tur<oonlfOllOO oont...... w'ili Ih<n 1>< r<fIlaoed by 0 1><ot =olunll'" 10 f<mo,.. al I..-t tnO<l of'h< h<al. Fillur< 6 .how. 0 oe.illn fo< ,och on, Of< mo« <ff<cti,.. in dio· p«<i"IlOrol mof< '''l'h..tal<d f<gaNinll 11><~ f"",ur« to <<Jn ,
A. 0 ""ult, 11>< product qLalrt)-· ~ in Il ,
<an 1>< u<al .. on 0001 OOull< fonn, f<J'O"<d (M~I,",« al., 19\11) Uo.uOd doug< fonn. miiht 1>< <oo,..,""t fo< ""rWn llfO'lP' of l""'nll «.ll., <hil<!r<n _ <to<,ty 11 <hoi« fo< d<liY«y Of< dry fonm, tllb"'., ""l'oul«, 0< f..t..:liooolyittil drull d<1~"«y ')-<1 Of< 0100 "''''1'100. p<I~1I w·itl\ I><<n produ«d by pittto _ M~II« (1_) Th< oq Sl~' di.p«<"" w-.. u«<l .. w-«tinll 'Il"" in th< pr0- duction J"O"«' of1l>< »<1, FDDS) il< th< 0001 <oyi1y. In .on.. <oontri«~I<ty ond W'ithollt Of '"«Y litll< 'Ill:"" ption. Soch »<1"" ClIn 1>< foIlal ittto ltalU 1l<loti <on"",..<d 10 'aIll<lI (?.mita, 10 »<1~I.çonwn"'ll ta/>. 1<11 .och .. B<loc ZOK') ,
M~I 19\II!) orol 11>< ol>tlo ined l'''wd<< _ 10 th< ubl<tti"ll I<d'lIOlogy) (M~I A, m",tioo<d _''', w'h<n prodocittll 0001 doug< fonm,1I>< Ioodinll < ,
<ory 10 prodlJ« »<11eu 0< tallieu miiht 1<0<1 10 an wU<'''I''· obI< larg< I"Olum<. In ,och <a«<, it miiht 1>< """,id««! 10 prodlJ« 0 'l',.y..:lried l'''wd<< fo< oooIodmlMIration, Il, issue.1 ,
_(obi ,
'l'«'i« of lipid _artic"" cootd 1>< <xploaal fo, d<1~.. ,)' 10 ÙI< tnO<llh c"'ity. Ir\10 ,LJOCl\ an FDDS ~'oold 1>< I)'ophilizinll ÙI< lipO:! n"""f"rticl< ,u'1'<",ioo UM<r additioo of ~<c' ti,.. all<rta ,och B ,
w proooc" to th< ma_ i. m'<linll "'llula. tO<)' "'quir<m..", not ooly with "'i"d to .xcipi.." bIlt ail() qwolifLcatioo and ,'alidatioo of prodoction li ,
,d in prOOOCll on th< pharma<.utical maMI. 10 th< tatt<r cal<, th<,d in th<i, commooly 'l'l'Ii.d, "'llulatOOly ac«ptI"'tioo?. If d"tioctly high<' c""".m"'tioo. a", uO«1, a limit<d toxicity 'IUdy millht 1>< ""«''''y to pro,.. th< .. f<ly of th< .xcipi.m in thi. c""""I"'tioo. Ali lipid., .urractaoll, and "abili<11'11, aM tabl<lI cao lle fully Hploit<d f"" th< prodoction of<", .ioo?. TI><", i. d<f'O'I.ly no ~ck of acc.pt.d .xcipi"lI. 10 _itioo, ail lipid.,urractaoll, aM pol u",d in food ioou"'y can b?? mpIO)-..d. 1I0w<l'<r, th<y "".d a "'lli'l"'tioo fo, pharma«utical PW'flO«'. Or.< cao r<f<r to ÙI< toxicity dall coll«l.d f T0 ,um up, a rich lao<ly of .xcipiIlipid 1U"'l"~icl<l AMth<, imJ>O<llol poilu i. ÙI< qwolifl<atioo of prodoctioo i"". within th< jl< TI>< prodoctioo lial to 1>< mad< 001 of mal.tilis aM comJ'O'lM' allowinlla q.alifl<atioo of th< prodoctioo li Ail() ..ch rompouM of ÙI< li 1- 'f"d in acad<mic, xampl<, a clinical balch prodoction UM i. ,'ailabl. r-1~1l<" Diolll<rabli.h<d and H"tioll in th< jtlarma<<utical iooU'I'Y. TI>< ~ulatO<)' acc.pl.d prodoctioo i"". f"" .mulsioo. can 1>< u, p.0, 2010. ,
ay Th<r<fOf<, it i. »O<,ibl. to u'" th< li"", of par<01.,.1 <mul· "00' f"" th< prodoctioo of lipid J'Orncl< ,u,)'<n.ioo?. Th< mil' "d"'dyaollll'--i. thot a «rtaio min""um balch " .. ~·iII lle "'quir<d, ~·hich i. 'l'\'=itml<lyhalfa ton CONCLUSION AND rERSrEOIVES Th< tht« ditf<r<m 'l"l'" of lipO:! n ,
1 oral doui' fonn ?. Lipid IUOOf'Irncl<' fulfoll «1 pr<utalion. Soch pr<r<qU 0051 prodoclion, clin-.:1 aC<<p1al "alu. of <xetpi<rttl. In COO!nll to Iipo- 1Om«, th<y Mt ooly a 10,· 0051 ','I<m bill ?0???o ph,·.ically mOf< "abl?. I romm<rcial .xplortalioo .. th. .xclu,iYity of th. ,'ariou. lipid partiel. t«hool"ll"" th<y ar< 1.d pIl<n by p>t<m ai'\'licalioo, in th< majo' COllOW,. By acqu"itioo of ÙI< SL1<' t<choolOjly by s,)..rharmo nc in 1999 th< t<ehoolOjly of SL1<' hao Th< 005m<tiC produ"" l''''Y<d th< f'Bibility of 1<LC' prod"", in Il'''''aI. Allo larg<--lCaI< prodoctioo 1..... ~.<r. «tabl"l>ed f"" ÙI«< prod, l<ChoolOjly of 1<LC" .. m<an~·hil. pr«<nt 00 th< 005m<tiC m.....l in mot< thoo ,0 prodOCtl ~·otId ~·id< (M~II<r <1 al. indu,rty ('.ll., R~1er G,mll, ~·w,·.rimpler.d<), ~·hich <an a!Jo 1>< uO«1 1<0\"<m"" ,007. th< US pharma<<utical cotwid< .xclu,i,.. righa f"" th< 1<LC' t<choolOjly frorn rharm...,11O 1W'n 1<LC" inlO pharm.. c<utical producu. Th< futur< ~·ill .how if thful ACKI"OWlEDGMENT Th" ~.ot1< ~'B ,uPl""'1<d by Gawot1< of th< EU l'roj<ct "TowaN' a E""'f'<an l'hD in Ad,'....,al Orull D<liv<ry: Mari< curi< COO1ta<t MEST CT ·,()().l-1<).<99', p.p in th< ,
?. ??l i, 2000. ,
1< '_'1, V (2OOOo1, ft.'" L _ ._J'l.'~"I-I ,
_'1'-'. e.111 Ai, E ?, 20001. ,
A. 0;'1 ,
URL : https://hal.archives-ouvertes.fr/ujm-00617603
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URL : https://hal.archives-ouvertes.fr/in2p3-00319758
L (lOO"I ,
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nd part of the pre-registration year: Dr st part of the pre-registration year: Faculté de Pharmacie, PhD studies, Prof. Rainer H. Müller, p.148, 1974. ,
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