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L ?JF " ,Floating particle  Q Flow around a particle  u&Comparison of h  !}Contents 'Overview of oral absorption simulation Nernst-Brunner equation Diffusion coefficient Diffusion layer thickness Solid surface pH and solubility Permeation Villi/fold structure and unstirred water layer Effective concentration and Peff of bile micelle solubilised drug Tube shape and fluid volume ?ZPZ ZZ?0  L ?JF " ;Solubility in NBE = S as one of the slope parameters!!(Solubility at the solid surface Dissociable compounds (and their salts) pH gradient exists in the unstirred water layer pKa, Ksp Solid form Free acid, base or salt Don t use the solubility in the bulk as S for slope )04)0        3,yX*Surface pH and dissolution rate  R@Modification of NBE considering its meaning for oral absorption AA("~Contents 'Overview of oral absorption simulation Nernst-Brunner equation Diffusion coefficient Diffusion layer thickness Solid surface pH and solubility Permeation Villi/fold structure and unstirred water layer Effective concentration and Peff of bile micelle solubilised drug Tube shape and fluid volume ?ZPZ ZZ?P L ?JF " G&Calculation scheme for oral absorption''$&  FNLet s look into the permeation equation(((' #Contents 'Overview of oral absorption simulation Nernst-Brunner equation Diffusion coefficient Diffusion layer thickness Solid surface pH and solubility Permeation Villi/fold structure and unstirred water layer Effective concentration and Peff of bile micelle solubilised drug Tube shape and fluid volume ?ZPZ ZZ?P / ?JF " KCUnstirred water layer (UWL) and surface expansion by fold and villiDD$>NEffect of fold and villi (Contents 'Overview of oral absorption simulation Nernst-Brunner equation Diffusion coefficient Diffusion layer thickness Solid surface pH and solubility Permeation Villi/fold structure and unstirred water layer Effective concentration and Peff of bile micelle solubilised drug Tube shape and fluid volume ?ZPZ ZZ?P /"JF " ^What is apparent concentration? (  _Passing through the UWL a Danazol case   )Contents 'Overview of oral absorption simulation Nernst-Brunner equation Diffusion coefficient Diffusion layer thickness Solid surface pH and solubility Permeation Villi/fold structure and unstirred water layer Effective concentration and Peff of bile micelle solubilised drug Tube shape and fluid volume ?ZPZ ZZ?P L"JF " fSAeff/Veff ratio is the key6  gThe intestine is NOT a cylinder2   hAnimal scale down i`Rat Peff is 5  10 fold smaller than Human Peff @1  $   8# \Maybe, due to the lack of fold in rats. Smaller Peff would cancell out the larger S/V ratio.*]1 )80 kFluid volume in humans dDirect measurement 206 mL (14%) Gotch et al., J. Clin. Invest. 1957, 36, 289-296 105 mL (7%) (pocket water) Schiller et al., Aliment Pharmacol Ther, 2005, 22, 971-979 Active transporter saturation study 500 mL (33%) (Ampicillin) Amidon et al, Pharm Res, 1988, 5, 651-654 250 mL (17%) (Gabapentin) The AAPS Journal 2005; 7 (1) Article 21 BCS 250 mL (17%) P P1PP;P$PP*PP(PP PPPP 1 ;  $ * (    $$$$$$  . <D  XContents 'Overview of oral absorption simulation Nernst-Brunner equation Diffusion coefficient Diffusion layer thickness Solid surface pH and solubility Permeation Villi/fold structure and unstirred water layer Effective concentration and Peff of bile micelle solubilised drug Tube shape and fluid volume j?PPP PP?P L?JF " Y My suggestionPlease self-check the software and the previous publications using them. Misconceptions I found were Standard HH equation with FaSSIF solubility?? Monomer diffusion coefficient with FaSSIF?? Bulk solubility = surface solubility for dissociable compounds and salts?? Large GI fluid volume of 1.5 L (100 % filled)?? Caco-2 Papp pH 7.4 for Peff pH 6.5 Caco-2 permeability (= free fraction permeability) with FaSSIF solubility?? pH partition theory applied for UWL and paracellular?? Extensive colon absorption for many compounds?? Etc,etc So many misconceptions, but good prediction? What was the trick? Fitting?? Compound by compound change of physiological parameter?? We might need  Good Simulation Practice . ePPAPCP*PPe AC*  b2AuuSummary Two important equations Dissolution (Nernst Brunner) Permeation Parameters should be carefully considered Bile micelles Diffusion coefficient Mucus layer pH (solid surface) Hydrodynamics Fold/Villi/Flatness Etc.etc... Z(Z*ZZ"ZAZZ(*"B8   tBack Up  qThree pitfalls of in vitro dataVery thick unstirred water layer (UWL) Could reach 2000 um in 96 well plate In vivo, it is ca. 30-100 um High membrane binding PAMPA logD >1.5 Caco-2 may be logD >2-3 Inadequate paracellular pathway PAMPA has no paracellular pathway Caco-2 has tighter paracellular pathway Transporter and metabolic enzymes are over or under-expressed in Caco-2 and other cells PEPT1 under expression'PBPP*P PJPXPP'B* JX  ,rHigh membrane binding sPermeability logD curve  :4S: Surface area for polydisperse spherical particles55( 3  ACAT/ADAM81Hintz-Johnson (HJ) model Wang-Flanagan (WF) model22( AFluid dynamics theory(B6Asymptotic molecular diffusion term (Curvature effect)77(6  Lka ,Peff and Fa%68 / X Y Z [ \ ^acfhkt$|&*,.39:DFGJMQSWXYZ\_` acd-j.k/l0m1n2o3p4q5rDsEtOxTzZ{[|b~4  0` 33` Sf3f` 33g` f` www3PP` ZXdbmo` \ғ3y`Ӣ` 3f3ff` 3f3FKf` hk]wwwfܹ` ff>>\`Y{ff` R>&- {p_/̴>?" dd@,|?" dd@   " @ ` n?" dd@   @@``PR    @ ` ` p>> vn(    6  `}  N000 0000n0f_-[ n  0h  `  Z000 0000n0f_-[ ,{ 2 000 ,{ 3 000 ,{ 4 000 ,{ 5 000Z  0(  ^ `  X*  0  ^    Z*  0  ^ `   Z*H  0޽h ? 3380___PPT10.a  jn0000\0  l(     0pd  P     P*    0h       \* d  c $ ?   n  0Lb   0   Z000 0000n0f_-[ ,{ 2 000 ,{ 3 000 ,{ 4 000 ,{ 5 000Z  6u  _P    P*    6y  _    R*  H  0޽h ? 3380___PPT10.a(" $(  $ $ 0,  P     X*  $ 0       Z*  $ 6|  _P    X*  $ 6L  _    Z* H $ 0޽h ? 3380___PPT10.ap* 0 P(  r  S ,     H  0޽h ? 33___PPT10i. a9+D=' = @B +j j0 P(  r  S ( 'g     S x z'g<$0   H  0޽h ? 33RJ___PPT10*. ї+=D' = @B D' = @BA?%,( < +O%,( < +D' =%(D' =%(DT' =A@BBB B0B%(D' =1:Bvisible*o3>+B#style.visibility<*'%(D' =-6B'blinds(horizontal)*<3<*'D ' =%(D ' =%(DT' =A@BBB B0B%(D' =1:Bvisible*o3>+B#style.visibility<*'N%(D' =-6B'blinds(horizontal)*<3<*'NDT' =A@BBB B0B%(D' =1:Bvisible*o3>+B#style.visibility<*Nd%(D' =-6B'blinds(horizontal)*<3<*NdDT' =A@BBB B0B%(D' =1:Bvisible*o3>+B#style.visibility<*d~%(D' =-6B'blinds(horizontal)*<3<*d~DT' =A@BBB B0B%(D' =1:Bvisible*o3>+B#style.visibility<*~%(D' =-6B'blinds(horizontal)*<3<*~D ' =%(D ' =%(DT' =A@BBB B0B%(D' =1:Bvisible*o3>+B#style.visibility<*%(D' =-6B'blinds(horizontal)*<3<*DT' =A@BBB B0B%(D' =1:Bvisible*o3>+B#style.visibility<*%(D' =-6B'blinds(horizontal)*<3<*DT' =A@BBB B0B%(D' =1:Bvisible*o3>+B#style.visibility<*%(D' =-6B'blinds(horizontal)*<3<*DT' =A@BBB B0B%(D' =1:Bvisible*o3>+B#style.visibility<*6%(D' =-6B'blinds(horizontal)*<3<*6Dl' =%(D' =%(D' =4@BBBB%())D' =,54*3>!Bstyle.color='`B@BPB<*'+8+0+0 +  0  d(  d~ d s * q}   ~ d s * m' U    d0 \AP ??"?m      d0 TA( !? ? 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Dissolved 0   <s y q M >Absorbed 0 ZB  s *D>'   <w 3C"?_  JDissolution rate0CT    # '  ZB   s *D) ZB   s *D)  ZB   s *D) T   # 6  E ZB  s *D) ZB  s *D)  ZB  s *D) T   # *PZB  s *D) ZB  s *D)  ZB  s *D) ZB B s *D)l ZB B s *D z  <~  y n D Solubility 0 CZB B s *Djj>   < 8 ~ IPermeation rate0C  < iy= 5Solidl A C <A"$MCj01992480000[1]jl C C <A"$MCj01992480000[1] &  G <\ J1 XXsolid H < z a WXsolu I < j1   VXabs P <   (A)`B S 0D TB TB c $DP U <   2Senser (Sbulk  Cbulk(t))P6`B ZB 0DJj [ <H $H@8___PPT9  _Dissolution rate limited absorption (Slope of NBE determines oral absorption) Permeability limited absorption (PE determines oral absorption) Solubility limited absorption (Ceiling of NBE and PE determine oral absorption)4/ 8X ] B4 3 o#Sugano et al, DMPK 2007 (4) 225-254$$ # H  0޽h ? ̙33  ___PPT10u +'wKDY ' = @B D ' = @BA?%,( < +O%,( < +D' =%(D' =%(Dh' =4@BB BB%(E5' =1B B`BPB,54*3>B ppt_c='`B@BPB<*aD' =1:Bvisible*o3>+B#style.visibility<*a%(D' =-g6B fade*<3<*aDH' =%(D' =%(D' =4@BB BB%()))E5' =1B B`BPB,54*3>B ppt_c='`B@BPB<*_D' =1:Bvisible*o3>+B#style.visibility<*_%(D' =-g6B fade*<3<*_D' =%(D' =%(D+' =4@BB BB%(D' =1:Bvisible*o3>+B#style.visibility<*`%(D' =-g6B fade*<3<*`+ k0 0(  x  c $  `}   x  c $  `   H  0޽h ? 33___PPT10i. ї+D=' = @B +  30   ((  x  c $ 'gt   ^  6j  S AM ??"?' 2  TfdS" ?   H fdfS" ?   <    6   %Solid Surface (S)^  6Z     <   h ! <X ~  Cs " <, i _P  C # B: F  @Conc. grad. Cs-C $ <t S :  FDiff. Coeff. (D)X2 % 06  ^2 & 6 ={ ^" ' 6 A ` RB ( s *Df>  H  0޽h ? 33___PPT10i.B+D=' = @B +d   0  lG(  lx l c $ 'gt   ^ l 6j l S A ??"?kp l l 0A ? ? \  XB l 0D ==XB l 0D9?$ l # BqCQDEFf>Qkq@  S" < 9 ,$D 0XB l 0D6 == XB l 0D\ Cl l 0A ? ?A    l B`  +u time l H (  Conc.H l 0޽h ? 33IA___PPT10!.B+V8g.D' = @B D' = @BA?%,( < +O%,( < +D' =%(D' =%(D7' =4@BBBB%(D' =1:Bvisible*o3>+B#style.visibility<*l%(D'  =-s6Bwipe(down)*<3<*l+   0 [S p(  p p0 TA= ? ?'h    x p c $` T   z 7]C  p IU ,$D02 p 633C"?j p < 7]C  w7Diffusion coefficient Q1: How should we calculate this?$8"&z D   p  ,$D0  p 0% D  fThickness of the stagnant unstirred water layer Q2: How about the effect of agitation in the GI tract?$g072  p 633C"? ? Rz  '  p 0 6,$D0: p <+  9 ' dS has two meanings. Maximum concentration One of the slope parameters Q3: What value should we use?F222 p 633C"?+  H p 0޽h ? 33W O ___PPT10/ .q++a(D ' = @B D ' = @BA?%,( < +O%,( < +D' =%(D' =%(DG' =4@BBB B%(D' =1:Bvisible*o3>+B#style.visibility<*p%(D' =-6B'blinds(horizontal)*<3<*pD' =%(D' =%(DG' =4@BBB B%(D' =1:Bvisible*o3>+B#style.visibility<* p%(D' =-6B'blinds(horizontal)*<3<* pD' =%(D' =%(DG' =4@BBB B%(D' =1:Bvisible*o3>+B#style.visibility<* p%(D' =-6B'blinds(horizontal)*<3<* p+ l0 0(  x  c $L{  `}   x  c $?  `   H  0޽h ? 33___PPT10i. ї+D=' = @B ++- 0 ""8:t*"(  tx t c $ T 'gt   X t 0zwg x2 t 0C"?j7g t <W G [Dmono    t <[ z ZDmic   ^ t 6%%z `  t Jg ,$D0T  @F   t# ` 2  t 0S"`?    t 0S"`? ; k 2  t 6RS"`?    t 6RS"`?  2 t 6!S"`? O `  t 6!S"`? 2 t 6v4S"`?N   t Hv4c S"`? 0 p  <  2 t 6պCS"`? Z>  t 6պCS"`?T  P 2 t 6ZS"`? @  t 6ZS"`?  H 2 t 6RhS"`?% F  t 6RhS"`? + E 2 t 6{S"`?  t 6{S"`?8 h [ 2 t 6vS"`?u>  t Hvj S"`? P  <  2 t 6պS"`?Vn   t 6պS"`? p 2 t 6S"`?R!   t 6S"`? 6 Zf 2  t 6RS"`?L   !t 6RS"`? ] 2 "t 6S"`?@ s  #t 6S"`? G 2 $t 6vS"`?   %t Hv p S"`?2 0 b  <  2 &t 6պS"`?$ F  't 6պS"`? P  2 (t 6S"`? B  )t 6S"`? : 2 *t 6RS"`? P <  +t 6RS"`?J = z 2 ,t 6/S"`?e   -t 6/S"`? ' = 2 .t 6vBS"`? D `  /t BvB8v S"`?%  <  2 0t 6պQS"`?    1t 6պQS"`? n `2 2t 0`2 3t 0`2 4t 0Pp 5t B@z  |Naylor LJ, Bakatselou V, Dressman JB 1993. Pharm. Res. 10(6):865-870. Balakrishnan A, Rege BD, Amidon GL, Polli JE 2004. J. Pharm. Sci. 93(8):2064-2075.      F  E 6t   Er 7t S A   ??"?    = 8t <  E Kfmono: fraction of free monomer drug fmic: fraction of aggregate bound drug6L!#$ #H t 0޽h ? 339 1 ___PPT10 .@,+UD ' = @B D ' = @BA?%,( < +O%,( < +D' =%(D' =%(D7' =4@BB?BB%())?))Dk' =.37 BBBBBEM 0 4.78834E-6 L 0.26319 0.00023 *3>*B ppt_xB ppt_y=@0BBAApBBl>B<*tD' =%(D' =%(DG' =4@BBB B%(D' =1:Bvisible*o3>+B#style.visibility<*t%(D' =-6B'blinds(horizontal)*<3<*tD' =%(D' =%(D9' =4@BB?BB%())?)D}' =.E7 BBBBBWM -3.33333E-6 -4.5177E-6 L 0.22448 0.0007 *3>*B ppt_xB ppt_y=@0BBAApBB[=Br9<*t+p $0 ` X(  Xx X c $  `    X TA ?   X < M m n.A. Okazaki, T. Mano, K. Sugano, JPS 2008, 1843$'   X" X 0/] ? X <̟ @ S h With Dmono  X" X 0 ]  X <  m w  g With Deff  j  X < "q  rDanazol d50 ca. 25 um (real particle size data used) (h = r range) FaSSIF Mini vessel (50 mL) 50 rpm 1 mg dose 0s  g8E H X 0޽h ? 33___PPT10i.`Bo+D=' = @B +# :0 #")20"(  0x 0 c $ T    7 8 20 #"" 78   0 < ?"`l R g1  @` 0 <8 ?"`l R g1  @` 0 <8  ?"` l R i100  @` 0 <  ?"` l R i100  @` 0 < ?"`l R g1  @`  0 <P  ?"`l R q 33.9 +-15.2     @`  0 <D  ?"`7l R nsolution    @`  0 < ?"` l  xDeff$   @`  0 < ?"` l  Dmono.   @`  0 <  ?"` l  xDeff$   @` 0 <)  ?"` l  yDmono$   @` 0 <l3  ?"` R 8 h47  @`  0 <>  ?"`   Sim. Fa%  0  @` 0 <G  ?"` R8 g7  @` 0 <P ?R8 j0.07  @` 0 <,B ?R8 j0.47  @` 0 <(c ?R 8 j0.05  @` 0 <e ?R8 p 1.7 +- 0.5     @` 0 <W +  2 *a  00 <  7  S#Observed AUC and simulation results#  10 <  ,  *Scholz, A., Abrahamsson, B., Diebold, S.M., Kostewicz, E., Polentarutti, B.I., Ungell, A.-L. and Dressman, J.B., Pharm. Res., 19: 42-46 (2002).                     H 0 0޽h ? 33___PPT10i.A+D=' = @B +B 90 AA{|8_A(  8x 8 c $X I'g    8 0  < S#Sugano et al, DMPK 2007 (4) 225-254# '5Z / 8# "zT 8 c $X99?/j 8 3     < 8 # g$ < 8 # g$ <B  8 # g <B  8 #   <B  8 #   <B  8 #   <B  8 # ef<B 8 # !"<B 8 # <B 8 # <B 8 # gh<B 8 #  $ <B 8 #   <B 8 #   <B 8 #   <B 8 #    <B 8 #   <B 8 #   <B 8 # $ %  8 BC:DEF 5%H    #&(*+,-./00 1"2$2%2'3)3+3,4.4042435557595:5<6>6?6A6C6E6F6H6J7L7M7O7Q7S7T7V7X7Z7[7]7_8a8b8d8f8h8i8k8m8o8p8r8t8v8w8y8{8}8~8888899999999999999999999999999999999999999999999999999999999::::::::::::::::::: : : ::::::::::: :":$:&:':):+:-:.:0:2:4:5:7:9:;:<:>:@:B:C:E:G:H:J:L:N:O:Q:S:U:V:X:Z:\:]:_:a:c:d:f:h:j:k:m:o:q:r:t:v:x:y:{:}::::::::::::::::::::::::::::::::::::::::::: @i$  8 zB C DEF   @`  B 8 3    8 zB C DEF   @`   8 zB C DEF   @`* 6  8 zB C DEF   @`H T   8 zB C DEF   @`fu r  !8 zB C DEF   @`~Q ]  "8 zB C DEF   @`K W  #8 zB C DEF   @`- 9  $8 zB C DEF   @`  B %8 3    &8 zB C DEF   @`   '8 zB C DEF   @`   (8 zB C DEF   @`  B )8 3   B *8 3 y  B +8 3 [ a B ,8 3 U [ B -8 3 7 = B .8 3 1 7  /8 zB C DEF   @`  B 08 3 B 18 3  B 28 3  & 38 zB C DEF   @`&}2 48 zB C DEF   @`,Y8e 58 zB C DEF   @`25>AB 68 3 8>B 78 3 >D 88 zB C DEF   @`>JB 98 3 DJB :8 3 JPB ;8 3 JPB <8 3 P]ViB =8 3 P9VEB >8 3 V\!B ?8 3 V\ @8 zB C DEF   @`VbB A8 3 \bB B8 3 bhB C8 3 bhB D8 3 bahmB E8 3 h=nIB F8 3 hn%B G8 3 hnB H8 3 hnB I8 3 hnB J8 3 ntB K8 3 nt L8 zB C DEF   @`nezqB M8 3 tAzM<2 N8 # *u ` <2 O8 #  3 <2 P8 #   <2 Q8 # 2<2 R8 # 2Wh<2 S8 # h<2 T8 #   <2 U8 #   <2 V8 # / e <2 W8 #  <2 X8 #   <2 Y8 #   <2 Z8 #  <  [8 6 L y  ?0" \8 6  ;  @20" ]8 64 m   @40" ^8 6 / @60" _8 6 { @80" `8 6 = A100" a8 6\ o A120" b8 6X 1 A140" c8 6    ?0" d8 6    ?5" e8 6  2   @10" f8 6%  B   @15" g8 6*  L  @20" h8 6/  V  @25" i8 64  `  @30" j8 6\9 * ? S  VConcentration of TC (mM)" k8 <> %v=  K Diameter (nm)" RB l8 s *D V  m8 <C a  i FeSSIFhuman$ 33 33  RB n8 s *DR  o8 <xI > i FaSSIFhuman$ 33 33  RB p8 s *D  q8 <O ~ g FaSSIFdog$ 33 33  RB r8 s *D  s8 <$U 2 V  g FaSSIFrat$ 33 33  j w8 S A# ??"?"0 j v8 S A, ??"?2 j u8 S AI ??"?"  j t8 S AJ ??"? k  ^ x8 6HH8 y8 B\ V~v0___PPT106___PPT9 @ "#  7 {8 Bb  o ~v0___PPT106___PPT9 ? "#  8 |8 B`f   ~v0___PPT106___PPT9 @ "#  H 8 0޽h ? 33___PPT10i.bPٟ+D=' = @B +' ~0 M E  (    N))?C"?p ``x  c $`00   X  0A?q ^  6j  S AU |??"? pu  |j  S AV }??"?  ? }j  S AW ~??"?p / ~^   6 @    <H^ @ E PBase    BXN@ 5 ^Acid"`    0п``f +Glomme, A.; Mrz, J.; Dressman, J.,. In Pharmacokinetic Profiling in Drug Research, Testa, B.; Krmer, S.; Wunderli-Allenspach, H.; Folkers, G., Eds. Wiley-VCH: Zurich, 2006; pp 259-280. Avdeef, A.; Box, K. J.; Comer, J. E.; Hibbert, C.; Tam, K. Y.,. Pharmaceutical Research 1998, 15, (2), 209-215. ,,b      A      V  D    <0 P   Y Dipyridamol     BG H C"? ` ,$D0 7If FaSSIF solubility (at pH 6.5) was used to calculate the pH solubility profile using the standard HH equation, solubility at low pHs would be over estimated. Please check your program simulation.(b& H  0޽h ? 33z___PPT10Z.@ܸ-+UD' = @B D' = @BA?%,( < +O%,( < +D' =%(D' =%(D8' =A@BB BB0B%(D' =1:Bvisible*o3>+B#style.visibility<*%(D' =-g6B fade*<3<*+8+0+0 + m0 00(  x  c $  `}   x  c $  `   H  0޽h ? 33___PPT10i. ї+D=' = @B + .0 p(  2  fA!$Blue tissue paper"  Ir  S   `}   X  0  c 8 g  A `2  0 `2  0qS `2   0& 7 `2   0GC`2   0c  `2   0t  `2   0s  `2  0 ' `2  0T  `2  0G g `2  0:c  `2  0W  `2  0W F `2  0S   <   B V&The relative velocity is not so large.& H  0޽h ? 33]U___PPT105.gbp\x+D ' = @B D' = @BA?%,( < +O%,( < +D' =%(D' =%(DI' =4@BBBB%()D'  =/u8CC*Q3> Br<*D' =%(D' =%(DI' =4@BBBB%()D'  =/u8CC*Q3> Br<*D' =%(D' =%(DI' =4@BBBB%()D'  =/u8CC*Q3> Br<*+0  P(  x2  0C"??}RB  s *D=  <+ {  (A) Terminal velocity (vt)> ( `& x2  0C"? f|  C .BChDE|F4f SQ(73'TTx#x#o+TBj8MA4[ah^fG4@          S"  3|  C .BCDE|F4fR6l ) "x.O8W;R9K=FJ5a)u%? ;TZx~aC& @          S" mn,   # RBCDEF@f((/-,)g&O8,Vjz &X%o)@Wa<`nh@dM>'|| @             S" x  < 4  d (B) Microeddy effect (vm)> ( `8   ^B  6cdB  <}f  <t; nk ]G$ `   <|@ : `Drag$ ` `  c $A% ?? k  r  S XC Tt     <G S :  @Particle density   <K [ eB  9 Agitation  Z  0N ,tL Levins, D. M.; Glastonbury, J. R., Particle-liquid hydrodynamics and mass transfer in a stirred vessel. 2. Mass transfer. Trans. Inst. Chem. Eng. 1972, 50, (2), 132-46.   H  0޽h ? 33___PPT10i.Cך+D=' = @B +  &0 H@ d(  dr d S \  `}   4 d # A l (`  d(`,$D0ZB d s *Dm@ ` d 0` @ (C n>HJ model with 30 um approximate terminal velocity of 1.1 g/cm3> l  p  dp ,$D0ZB d s *D p  d 0f  s  tDWF model with 30 um is close to fluid dynamic model in < 75 um rangeD   d <j  EFluid dynamics theory   d <4o / GSugano, IJP, early view H d 0޽h ? 33 ___PPT10.a+D' = @B D' = @BA?%,( < +O%,( < +D' =%(D' =%(D+' =4@BB BB%(D' =1:Bvisible*o3>+B#style.visibility<* d%(D' =-g6B fade*<3<* dD' =%(D' =%(D+' =4@BB BB%(D' =1:Bvisible*o3>+B#style.visibility<* d%(D' =-g6B fade*<3<* d+ n0 @0(  x  c $`{  `}   x  c $8|  `   H  0޽h ? 33___PPT10i. ї+D=' = @B + 0 m e " (  ~  s *(  `}   RB  s *D>cRB  s *D>   0 TAS ? ?   f  s *A? ? ?e RB  s *DRB  s *D $  # BqCQDEFf>Qkq@  S"   ,$D 0RB  s *D  RB  s *Dn f  s *AT ? ? u    < Q  time  B   Conc.RB  s *D>P   < C"? 'I 5Slope  H C"?% 6  EMaximum concentration ! 0 (-i E1Important for dissolution rate limited absorption " 0,    ?+Important for solubility limited absorptionH  0޽h ? 33IA___PPT10!.H+TID' = @B D' = @BA?%,( < +O%,( < +D' =%(D' =%(D7' =4@BBBB%(D' =1:Bvisible*o3>+B#style.visibility<*%(D' =-s6Bwipe(down)*<3<*+G 0 ^V0 (  x  c $  `}   x  c $H ]     H fdfS" ?)  <    6 F-  ! Solid Surface  <  z  C  B7 T}  @Conc. grad. Cs-CRB  s *Df>8    B1CDEFA>D>dy1@  S" 8i   <4 Pi7 PpH H  0޽h ? 33___PPT10i.p+D=' = @B +  *0 # (    TA ?'N   r  S   `}   y  <` V  Surface pH and dissolution rate ratio. Calculated based Mooney-Stella equation. Compound: MW = 350, D = 610-6 cm2/sec. Buffer: HCO3-, 6.7 mM. 4x&   B | e rBMooney et al, JPS, 1981, 13-22 Sugano et al, DMPK 2007 (4) 225-254B H  0޽h ? 33___PPT10i.o@vOC+D=' = @B +6 z0 ME` (  r  S   `}    0 TAK ? ?!    0 TAL ? ?% )j    XB   0DԔ XB   0DԔ5 5 XB   0DԔ5 5   <| p W  S#Dissolution rate limited absorption$$  <    MSolubility limited absorptionf  s *AO ? ?    B |  S#Sugano et al, DMPK 2007 (4) 225-254# H  0޽h ? 33___PPT10i.$pų+D=' = @B + o0 P0(  x  c $,  `}   x  c $T-  `   H  0޽h ? 33___PPT10i. ї+D=' = @B +G G0 ^VP  (  x  c $hA  `}     <B d2 s'in vitro data (Caco-2, MDCK, PAMPA etc)(('   <H w  ^Peff     <L b w  Zka     <Q    o#Plasma concentration - time profile$$# ^2  6}Z^2  6 Z ^2   6 Z   <W } q'Villi and Fold structure, Free fraction((#  <D\    ISurface area/volume ratioH  0޽h ? 33___PPT10i.g+D=' = @B + F0 Z R @  (  x  c $i  `}    0 TA( ? ?    &z "|s   "|s ,$D02  633C"? |s   0tl "  2Q1: How can we obtain Peff for humans and animals?63 z ` PY5   P` Y5 ,$D02  633C"?b5    0t ` PY7 :Q2: What  solubilized mean?   z J   J,$D02   6333C"?- E 2   6333C"?66     0y J  :Q3: How can we know the effective surface area and volume?4;3633J  "B C DEF:AA""RL|bbRHBv+?Si2 %  ;  !   C '   P %<@           `ls LB  c $D9 LB  c $D V    0   Jka,C6K6H  0޽h ? 33  ___PPT10 .$@+J62D ' = @B Dj ' = @BA?%,( < +O%,( < +D' =%(D' =%(D+' =4@BB BB%(D' =1:Bvisible*o3>+B#style.visibility<*%(D' =-g6B fade*<3<*D' =%(D' =%(D+' =4@BB BB%(D' =1:Bvisible*o3>+B#style.visibility<*%(D' =-g6B fade*<3<*D' =%(D' =%(D+' =4@BB BB%(D' =1:Bvisible*o3>+B#style.visibility<* %(D' =-g6B fade*<3<* + p0 `0(  x  c $  `}   x  c $h  `   H  0޽h ? 33___PPT10i. ї+D=' = @B + J0  ++F(  ~  s *| ,   F  Pp  a T `$  #  PN nk2   `$ l  <d0 Z  s *k    BCDE(F"|o 00p@  `n    BCDE(F"|o 00p@  `P    BCDE(F"|o 00p@  `    BCDE(F"|o 00p@  `M     BCDE(F"|o 00p@  ` 2 TB   c $D l2  <:@PbT @b  #   pN @b   @b l  <d Z  s *@ P    BCDE(F"|o 00p@  `     BCDE(F"|o 00p@  `@     BCDE(F"|o 00p@  `     BCDE(F"|o 00p@  `}    BCDE(F"|o 00p@  `" b TB  c $DP P l2  <: p@ l2  <:p p l2  <: p` l2  <: p $F  S   S ] l  <nd S ZB  s *Do    T( ?;a H 0C   ! TD ?  v UWL 30  100 mm:0CCCpB " HD?s s # T ?hS  H 0C   $ Tx ?W ]  z$UWL 1500  4000 mm:0CCC % T ? :+ AIn vivo0C & T ?S h s @Caco-20C ' <x zCa    ( < d *High permeability comp ) <@  D  )Low permeability comp * < 4  Human Peff ~ 10-4 order6&   + < ] K Papp, Caco-2 ~ 10-6 order6  H  0޽h ? f3y___PPT10Y+D=' = @B +h" M0 6. K(  x  c $  `}   d  <dT5 R  s *T5,   BCDE(F"|o 00p@  `b*R    BCDE(F"|o 00p@  `b( d2  <:V d  <d T5 R   s * T5     BCDE(F"|o 00p@  `3 *R     BCDE(F"|o 00p@  `3 ( d2   <:B x d2   <:  d2  <:  d2  <:6 m  0  `A ? ?y#H $D0    B  n ^Fa% = 95     B4    ]Fa% = 5  RB  s *DTTRB  s *DB B _z J/:  t1,$D0  B 3f+/vS" `?9  <    N$ +/vS" `?  <    H Zm <    < : BIn vitro UWL range   HZ I) <    B( J/1C  AIn vivo UWL range  K < Lw# tCalculated based on Oliver et al, JPS, 1998, 634-639 Sugano et al, Hit to lead optimization (book chapter), in pressul H  0޽h ? 33___PPT10.0 +EDV' = @B D' = @BA?%,( < +O%,( < +DA' =%(D' =%(D' =A@BBBB0B%(D' =1:Bvisible*o3>+B#style.visibility<*%(DA' =%(D' =%(D' =A@BBBB0B%(D' =1:Bvisible*o3>+B#style.visibility<*%(DA' =%(D' =%(D' =A@BBBB0B%(D' =1:Bvisible*o3>+B#style.visibility<*%(DA' =%(D' =%(D' =A@BBBB0B%(D' =1:Bvisible*o3>+B#style.visibility<*%(DA' =%(D' =%(D' =A@BBBB0B%(D' =1:Bvisible*o3>+B#style.visibility<*%(D' =%(D' =%(D+' =4@BB BB%(D' =1:Bvisible*o3>+B#style.visibility<*%(D' =-g6B fade*<3<*+0+(+0+   q0 (0(  (x ( c $\*  `}    x ( c $4+  `   H ( 0޽h ? 33___PPT10i. ї+D=' = @B +5 Q0 ss es(  x  c $H? 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I NDF Se  B } 2 C 0C"?S2 D 0C"?2 E 0C"?S@p2 F 0C"?@p2 G 0C"? 92 H 0C"?d2 I 0C"? @9p2 J 0C"?d@p2 K 0C"?S2 L 0C"?2 M 0C"?S&2 N 0C"?&2 O 0C"? 92 P 0C"?d2 Q 0C"? 9&2 R 0C"?d&2 S 0C"?2 T 0C"?I2 U 0C"?@p2 V 0C"?@Ip2 W 0C"?t2 X 0C"?2 Y 0C"?t@p2 Z 0C"?@p2 [ 0C"?2 \ 0C"?I2 ] 0C"?&2 ^ 0C"?I&2 _ 0C"?t2 ` 0C"?2 a 0C"?t&2 b 0C"?&2 c 0C"?SP2 d 0C"?P2 e 0C"?S2 f 0C"?2 g 0C"? P92 h 0C"?dP2 i 0C"? 92 j 0C"?d2 k 0C"?S62 l 0C"?62 m 0C"?S`2 n 0C"?`2 o 0C"? 962 p 0C"?d62 q 0C"? `92 r 0C"?d`2 s 0C"?P2 t 0C"?PI2 u 0C"?2 v 0C"?I2 w 0C"?tP2 x 0C"?P2 y 0C"?t2 z 0C"?2 { 0C"?62 | 0C"?I62 } 0C"?`2 ~ 0C"?`I2  0C"?t62  0C"?62  0C"?t`2  0C"?`2  0C"?S2  0C"?2  0C"?SE2  0C"?E2  0C"? 92  0C"?d2  0C"? 9E2  0C"?dE2  0C"?Sq2  0C"?q2  0C"?S2  0C"?2  0C"? q92  0C"?dq2  0C"? 92  0C"?d2  0C"?2  0C"?I2  0C"?E2  0C"?IE2  0C"?t2  0C"?2  0C"?tE2  0C"?E2  0C"?q2  0C"?qI2  0C"?2  0C"?I2  0C"?tq2  0C"?q2  0C"?t2  0C"?2  0C"?S% U 2  0C"?% U 2  0C"?S  2  0C"?  2  0C"? % 9U 2  0C"?d% U 2  0C"?  9 2  0C"?d  2  0C"?S  2  0C"?  2  0C"?S5 e 2  0C"?5 e 2  0C"?  9 2  0C"?d  2  0C"? 5 9e 2  0C"?d5 e 2  0C"?% U 2  0C"?% IU 2  0C"?  2  0C"? I 2  0C"?t% U 2  0C"?% U 2  0C"?t  2  0C"?  2  0C"?  2  0C"? I 2  0C"?5 e 2  0C"?5 Ie 2  0C"?t  2  0C"?  2  0C"?t5 e 2  0C"?5 e   < s :~Z  @Nano?    < :f  ZMicelles (FaSSIF, SEDDS)&    <T mJ T 7Monomer rF  I   wI2  0C"?f  2  0C"?- ITB B c $D [9 TB  c $D [ITB  c $D9    < Ya @ E CyD complex RB  s *D)z\RB  s *D)"RB  s *D)   < j 7Q ?Filter membrane   N ))? 8,$D0 m=We should pay attention which solubility value we are using. =   <  3API RB  s *D}RB  s *DRB  s *D RB  s *D RB  s *D)  H  0޽h ? 33___PPT10 .G+Ȩ>D| '  = @B D7 ' = @BA?%,( < +O%,( < +D~ ' =%(D& ' =%(D/' =4@BB?BB%()?)?D' =.K7 BBBBB]M 3.88889E-6 1.48148E-6 L 0.44895 1.48148E-6 *3>*B ppt_xB ppt_y=@0BBAApBBe>B<*D+' =4@BB?BB%()?)?D' =.G7 BBBBBYM 3.33333E-6 -2.96296E-6 L 0.44479 0.00486 *3>*B ppt_xB ppt_y=@0BBAApBBc>B&;<*1D+' =4@BB?BB%()?)?D' =.G7 BBBBBYM -3.05556E-6 4.44444E-6 L 0.44497 0.00509 *3>*B ppt_xB ppt_y=@0BBAApBBc>B&;<*D1' =4@BB?BB%()?)?D' =.M7 BBBBB_M -3.61111E-6 2.22222E-6 L 0.44688 2.22222E-6 *3>*B ppt_xB ppt_y=@0BBAApBBd>B<*D' =%(D' =%(D8' =A@BB BB0B%(D' =1:Bvisible*o3>+B#style.visibility<*%(D' =-g6B fade*<3<*+8+0+0 +Q D0 w;o; KK;(    dd zzA3ShingleS"`?j6  <  x  c $\ 'gt      6̿ C"? <  x2  0C"? G  <  a) [Dmono     < \  ZDmic   ^  6%%z `     ] & ,$D0T  @F   # ` 2   0S"`?     0S"`? ; k 2   6RS"`?    6RS"`?  2  6!S"`? O `   6!S"`? 2  6v4S"`?N    Hv4$ S"`? 0 p  <  2  6պCS"`? Z>   6պCS"`?T  P 2  6ZS"`? @   6ZS"`?  H 2  6RhS"`?% F   6RhS"`? + E 2  6{S"`?   6{S"`?8 h [ 2  6vS"`?u>   Hvd S"`? P  <  2  6պS"`?Vn    6պS"`? p 2  6S"`?R!     6S"`? 6 Zf 2 ! 6RS"`?L   " 6RS"`? ] 2 # 6S"`?@ s  $ 6S"`? G 2 % 6vS"`?   & Hv| S"`?2 0 b  <  2 ' 6պS"`?$ F  ( 6պS"`? P  2 ) 6S"`? B  * 6S"`? : 2 + 6RS"`? P <  , 6RS"`?J = z 2 - 6/S"`?e   . 6/S"`? ' = 2 / 6vBS"`? D `  0 BvB S"`?%  <  2 1 6պQS"`?    2 6պQS"`? n `2 3 0`2 4 0`2 5 0Pp 6 <    MUnstirred water layer (mucus) B 7 0DԔ,$D0B 8 0DԔSS,$@02 9 0C"?#S,$D0JF q[  : @   N qu[  ; qu[  < @BCDEF@3f((>"c(o w vz!4GZB/1=+@qG\ht+Ezz @             S" W+  = BZCDEF`3f@@} 2pj80w*/'B%U%g!E)elv[;(XGA[<p=;Yp~#~).4_G2T9XAWIYO[Z_Z_-0@                     S" &  > pBCDEFL3f11 mda4/ &h*)1!62FJ{'`&N{jdvZ}JB"@  1JVDZfo#$@                S" u  ?  FBCDEF@3f((>"c(o w vz!4GZB/1=+@qG\ht+Ezz @             S" T?~ @  F)BCDEF@3f((>"c(o w vz!4GZB/1=+@qG\ht+Ezz @             S" dp8[  A pBCDEFL3f11 mda4/ &h*)1!62FJ{'`&N{jdvZ}JB"@  1JVDZfo#$@                S" q6 H-  N qu[  B H  C @BCDEF@3f((>"c(o w vz!4GZB/1=+@qG\ht+Ezz @             S" W+  D BZCDEF`3f@@} 2pj80w*/'B%U%g!E)elv[;(XGA[<p=;Yp~#~).4_G2T9XAWIYO[Z_Z_-0@                     S" &  E pBCDEFL3f11 mda4/ &h*)1!62FJ{'`&N{jdvZ}JB"@  1JVDZfo#$@                S" u  F  FBCDEF@3f((>"c(o w vz!4GZB/1=+@qG\ht+Ezz @             S" T?~ G  F)BCDEF@3f((>"c(o w vz!4GZB/1=+@qG\ht+Ezz @             S" dp8[  H pBCDEFL3f11 mda4/ &h*)1!62FJ{'`&N{jdvZ}JB"@  1JVDZfo#$@                S" q6 H-  I 6T C"?q <   J 6 C"?7  <   K 08 F W  eMucus layer permeability would be the rate-limiting step when the membrane permeability in very fast.e H  0޽h ? 33 ___PPT10.@,+D'  = @B DB' = @BA?%,( < +O%,( < +D' =%(D' =%(D7' =4@BB?BB%())?))Dk' =.37 BBBBBEM 0 4.78834E-6 L 0.26319 0.00023 *3>*B ppt_xB ppt_y=@0BBAApBBl>B<*D' =%(D' =%(DG' =4@BBB B%(D' =1:Bvisible*o3>+B#style.visibility<* %(D' =-6B'blinds(horizontal)*<3<* D' =%(D' =%(D9' =4@BB?BB%())?)D}'  =.E7 BBBBBWM -3.33333E-6 -4.5177E-6 L 0.22448 0.0007 *3>*B ppt_xB ppt_y=@0BBAApBB[=Br9<* D' =%(Dh' =%(D' =4@BBBB%(D' =1:Bvisible*o3>+B#style.visibility<*8%(D' =4@BBBB%(D' =1:Bvisible*o3>+B#style.visibility<*7%(D4' =%(D' =%(D' =4@BBBB%(D' =1:Bvisible*o3>+B#style.visibility<*9%(D' =%(D' =%(DC' =4@BB?BB%()?)?))Dw' =.?7 BBBBBQM -0.00243 -0.00255 L 0.08212 -0.00255 *3>*B ppt_xB ppt_y=@0BBAApBB,=B<*9D' =%(DC' =%(D' =A@BB?BB0B%()?)?)D"' =.7 BBBBB'M 0 0 L 0.25 0 E*3>*B ppt_xB ppt_y=0BB<*+8+0+0 +U S0 TT ~mT(  x  c $$ T      6  M 3Simulation results for danazol absorption in humans$43G$     6  M U $G    60 M6 [Fasted/$G    6   WFed$G    6`#  U $G    6 ( M fFa% $G     6- x Vob$G      61 t Us$G      6D6 M U $G     6; M  \Scenario$ G     6T? M  U $G    6D M -  UP$G    6H . t  eff, pred$ G 4      6O e} U $G     62  U $G   0 6 U2  U2$G   1 6 2  U $G  : 2 3 S: 3 3 : 4 3 : 5 3 : 6 3  : 7 3  : 8 3  : 9 3 : : 3 D ; 6X - t  U $G   < 6 -   U $G   = 6x -   UB$G   > 6 -   U $G   ? 6 - N  V0.$G   @ 6 - =  X44& G   A 6 -   U $G   B 6 - U  a8$G   C 6 -   U $G   D 6  tn  U $G   E 6D  n  U $G   F 6  n  UC$G   G 6    n  U $G   I 6   3  O1.1    J 6  >n  U $G   K 6  3n  V17$G   L 6`  n  U $G   M 6$ i t  U $G   N 6x  i   U $G   O 6$ i   U $G   P 6) i  U $G   Q 6. i x  U $G   R 62    WFed$G   S 67    U $G   T 6<  )  V44$G   U 6@    U-$G   V 6  U $G   \ 6Ta  U  U2$G   ] 6e    U $G   ^ 6  U $G   m 6  B 3  X60& G   n 6 B   U $G  : o 3  K : p 3   : q 3   : r 3   : s 3   : t 3  : u 3   : v 3   : w 3  H  x 6T    U $G  $ y <l l7 A) Only free monomer transfers across the mucus layer. B) Both free and bile micelles bound molecule diffuse. C) (B) plus water convection  2 z <,    @  2 { < ( {  @  2 | <0 pR  @  2 } <  {  @   ~ < < FSugano, IJP, submitted   NX ))? , sPlease remind that even in the case of solubility limited absorption, Peff affects the absorption (cf. absorption equation). Two fold difference of Peff could results in two fold change of ka and Fa%. HGK& >FJ,H  0޽h ? 33___PPT10i.l"2+D=' = @B + r0 ,0(  ,x , c $  `}    x , c $  `   H , 0޽h ? 33___PPT10i. ї+D=' = @B +s W0 `  (  x  c $8  `}    ~  BA> ? ?2C    <!   g-Tsi: small intestine transit time (3.5 hours)* X  0A@?    <!    jSA/V = 2.4-2.8$ `    < ! `  6Humans    <!   'Fagerholm et al., Pharm Res, 1995, 1336.(  4      H  0޽h ? 33___PPT10i.&) +D=' = @B +$ X0 ;3p (  ~2  6oC"?=!~  6CC"?`q&x  c $D 'g  !   0 TAA ? ?6    0 TAB ? ?     2  <od"! `0 D` F P@0   d `2   0@0`2   0P@@0   <`'! @0 D`    <*!  z ^2a$ `    <.!  4H  ^2b$ ` X  0 0 ^r  69 f ~2  6C"?P@`   <,4! H  @Circumference remains same. Adjust a and b to make S/V = 2.4-2.8$A@ `@ X2  0 0    <(:!  $g ^2a$ ` ^r  6P 0  LB  c $Dp`p  <?! @d' ]r$ `   <D! 0 @T  ^2b$ ` X  0H <  0 TAC ? ? Z  !   <J! "7  nCf. 2rL is used as surface value for Peff calculation.>8 !F  H  0޽h ? 33___PPT10i._RH+D=' = @B +<% Y0 b Z ** (   x   c $\!  `}  !   D'   # #""   CD'  !    <^!  ?"`  '  f0.07  @`   <p`!  ?"`   f0.17  @`   <hx!  ?"` U  f0.50  @`   <؀!  ?"`  U hb (cm)  @`   <dz! ? S'  j18.1  @`   <! ? S j7.23  @`   <T! ? US j2.41  @`   <\! ? SU jSA/V  @`   <