Advanced Pharmaceutical Bulletin, 2013, 3(2), doi:

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1 Advnd Phrmutil Bulltin, 2013, 3(2), doi: Prutnous Absorption of Sliyli Aid ftr Administrtion of Trolmin Sliylt Crm in Rts with Trnsutol nd Eulyptus Oil PrTrtd Skin Pniz Sdi 1, Mohmmd Jvd Khodyr 2, Bhzd Shrif Mkhmlzdh 3, Sd Rz 3 * 1 Dprtmnt of Phrmutis, Shool of Phrmy, Ahvz Jundishpur Univrsity of Mdil Sins, Ahvz, Irn. 2 Dprtmnt of Phrmology nd Toxiology, Shool of Phrmy, Ahvz Jundishpur Univrsity of Mdil Sins, Ahvz, Irn. 3 Nnothnology Rsrh Cntr, Ahvz Jundishpur Univrsity of Mdil Sins, Ahvz, Irn. A R T I C L E I N F O Artil Typ: Rsrh Artil Artil History: Rivd: 17 Fbrury 2013 Rvisd: 6 Mrh 2013 Aptd: 7 Mrh 2013 Publishd: 20 August 2013 Kywords: Trolmin sliylt Trnsutol Eulyptus oil Trnsdrml bsorption Rt Nonlinr mixd fft modling A B S T R A C T Purpos: This study ws ondutd to ssss th fft of skin prtrtmnt with Trnsutol nd ulyptus oil on systmi bsorption of topil trolmin sliylt in rt. Mthods: Phrmokinti prmtrs of sliyli id following dministrtion of trolmin sliylt on rt skin prtrtd with ithr Trnsutol or ulyptus oil wr dtrmind using both nonomprtmntl nd nonlinr mixd fft modling pprohs nd omprd with thos of ontrol group. Rsults: Mdin (% of intrqurtil rng/mdin) of sliyli id AUC 08hr (ng/ml/hr) vlus in Trnsutol or ulyptus oil trtd rts wr 2522(139%) nd 58976(141%), rsptivly s omprd to th 3023(327%) of th ontrol group. Skin prtrtmnt with ulyptus oil ould signifintly drs xtrvsulr volum of distribution (V/F) nd limintion rt onstnt (k) of sliyli id. Conlusion: Unlik Trnsutol, ulyptus oil ld to nhnd trnsdrml bsorption of trolmin sliylt through rt skin. Introdution Dlivry of phrmologil gnts vi th skin provids distint bnfits omprd to othr onvntionl routs of dministrtion, suh s minimizing dvrs ffts nd toxiity du to stdy nd optimum blood lvls, bypssing intstinl nd hpti first pss fft, prvntion of gstrointstinl irrittion, t. 13 Howvr, trnsdrml bsorption of most drugs oftn rsults in low biovilbility bus of th brrir ntur of th skin. Th most importnt rson of rsistn to th pssg of drugs through th skin is th strtum ornum, th outrmost lyr of th skin. 1,2,4,5 In ordr to nhn th prmbility of drugs through th skin, mny thniqus hv bn mployd to ovrom strtum ornum imprmbility. A populr pplid thniqu is th us of pntrtion nhnrs whih rvrsibly drs th brrir rsistn of th skin. 35 Ths phrmologilly intiv hmil ompounds tnd to intrt with th strtum ornum onstitunts to s th bsorption of drugs through th skin by tmporrily inrsing in skin prmbility. 5 Trolmin sliylt is topilly pplid sliyli id drivtiv whih is usd for tmporry rlif of pin or inflmmtion in musls, oints nd othr tissus blow th skin. 610 As trolmin sliylt is n odor fr ompound nd hs no skin irritnt proprtis 9, it n b vibl ltrntiv to orl sliylt but is lss prmbl through skin omprd with othr sliyli id drivtivs lik mthyl sliylt. 11 Consquntly, to hiv thrputi onntrtions of sliyli id ftr trnsdrml dministrtion of trolmin sliylt, th pplition of th pntrtion nhnrs is ndd. 12 A numbr of pntrtion nhnrs hv bn usd to vlut thir influn on th in vitro prmtion of trolmin sliylt through th bdominl rt skin. Th rsults showd tht th bst nhnmnt of trolmin sliylt flux, ws obtind from 12 hours skin prtrtmnt with Trnsutol (dithyln glyol monothyl thr) nd ulyptus oil tht wr bl to provid nr 12 nd 10 fold inrs in flux, rsptivly, in omprison with ontrols. 12 Howvr, fft of skin prtrtmnt with ths nhnrs on in vivo bsorption of trolmin sliylt hs not bn invstigtd. Thrfor, th im of this study ws to ssss th influn of prtrtmnt with Trnsutol nd ulyptus oil on prutnous bsorption of trolmin sliylt in rt. To do this, both nonomprtmntl nd nonlinr mixd fft modling pprohs wr usd to vlut trolmin sliylt phrmokintis ftr its topil dministrtion in rts with Trnsutol nd ulyptus oil prtrtd skin. *Corrsponding uthor: Sd Rz, Dprtmnt of Phrmutis, Shool of Phrmy, Ahvz Jundishpur Univrsity of Mdil Sins, Ahvz, Irn. Tl: +98 (611) , Fx: +98 (611) , Emil: s.rz@ums..ir

2 Sdi t l. Mtrils nd Mthods Chmils Trolmin sliylt, potssium dihydrogn phospht, prhlori id nd tonitril ( HPLCgrd ) wr purhsd from Mrk, Grmny. Eulyptus oil, ontining 70% 1,8 inol ws from Bri Essn Compny, Kshn, Irn. Trnsutol P (dithylnglyol monothyl thr) ws kindly dontd by Gttfoss, Frn. Animl Exprimnts nd Drug Administrtion Th study ws pprovd by th this ommitt of th Vi Chnllor for Rsrh nd Thnology of Ahvz Jundishpur Univrsity of Mdil Sins. In vivo xprimnt ws don on ml wistr rts wighing 235 ± 20 g whih supplid by Animls Cr nd Brding Cntr of Ahvz Jundishpur Univrsity of Mdil Sins. Twlv hours bfor pplition of pntrtion nhnrs (on dy prior to dosing), th hir of th bdominl rgion ws rmovd with ltri hir lipprs. Th rts wr dividd into thr groups. In prtrtd groups Trnsutol (N=10) or ulyptus oil (N=5) in th form of losd drssing wr pplid to th hirlss surf of bdominl skin for 12 hours. Subsquntly, th losd drssing ws rmovd nd th prtrtd sit ws rfully wipd ln 50 tims with otton to rmov th xss solution nd thn 1 grm of 10% trolmin sliylt(perrigo, USA) ws pplid to th prtrtd skin. In ontrol group (N=7), trolmin sliylt ws pplid to th nottrtd skin. Applition r of dpiltd bdominl skin ws 12 m 2 (3 4 m). Rts wr undr slp ondition with 140 mg/kg intrpritonl phnobrbitl during th priod of prtrtmnt, pplition of drug nd blood smpling. Blood smpls wr olltd from hprinizd thtr insrtd into th til vin t 0.5, 1, 2, 4, 6, 8 nd 10 hours (whn it ws possibl) ftr dministrtion of drug. Plsm smpls wr immditly sprtd by ntrifugtion t 13,000 rpm for 5 minuts nd wr stord t 70 C until th tim of nlysis. Anlytil Produr Sliyli id onntrtion in rt plsm following topil dministrtion of trolmin sliylt ws dtrmind using highprformn liquid hromtogrphy (HPLC) with fluorsn dttion s prviously rportd with som modifitions. 13 Th HPLC pprtus onsistd of n Agilnt 1260 Infinity qutrnry pump nd Agilnt 1260 Infinity fluorsn dttor (Agilnt, USA ). An Allth Altim C18 olumn (150 mm 2.1 mm, 5 µm prtil siz) (Gr Dvison Disovry Sins, USA) ws usd for th sprtion. Th mobil phs onsistd of tonitril: phospht buffr (17: 83) (ph 3) dlivrd t flow rt of 0.5 ml/min. Fluorsn dttion ws prformd t 297 nm (xittion) nd 407 nm (mission). Plsm smpls (50 μl) wr trnsfrrd into 1.5ml mirontrifug tubs nd mixd with 296 Advnd Phrmutil Bulltin, 2013, 3(2), μl of prhlori id 35%. Aftr vortx mixing for 1 min, 300 μl of tonitril ws ddd to this solution. Th ontnts wr vortx mixd thoroughly for 2 minuts nd ntrifugd t 1500 g for 5 minuts. Twnty μl of th lr suprntnt ws intd onto th olumn. Phrmokinti Anlysis NonComprtmntl Anlysis Ar undr th sliyli id plsm onntrtion tim urv btwn 0 nd 8 hours post dministrtion of trolmin sliylt (AUC 08 hr ) ws lultd using trpzoidl rul to ompr th xtnt of bsorption in rts with Trnsutol or ulyptus oil prtrtd skin with tht of th ontrol group. KrusklWllis tst followd by pirwis multipl omprisons (SPSS Sttistis 20, IBM, USA) ws usd to hk ny signifint diffrn of AUC vlus btwn trtmnt groups. Nonlinr mixd fft modling: Sliyli id plsm onntrtion tim dt wr modld by onomprtmnt modl with zroordr bsorption input. Th intrniml rror trms for ll struturl modl prmtrs inluding Tk0 (durtion of zro ordr bsorption), k (first ordr limintion onstnt) nd V/F (xtrvsulr pprnt volum of distribution) wr ssumd to b indpndntly nd lognormlly distributd with mn zro nd vrin ω 2. A onstnt rror modl ws usd for th rsidul rndom vribility. Covrit nlysis ws lso don to ssss th fft of skin prtrtmnt on trolmin sliylt phrmokintis. Influn of prtrtmnt on th phrmokinti prmtrs wr modld using th following gnrl qution: 14 in whih P i, prtrtd nd P i, ontrol r th popultion vlus of phrmokinti prmtr i in h of prtrtd groups nd ontrol group, rsptivly. β i is th prtrtmnt fft for prmtr i. Nonlinr mixd fft nlysis ws rrid out using Monolix (Lixoft, Frn). Modl sltion ws bsd on th signifint rdution in minimum obtiv funtion(mof) tht is qul to 2 log liklihood vlu; prmtr prision(xprssd s rltiv stndrd rrors of th stimtd prmtrs) nd visul insption of goodnssoffit plots inluding th prdition distribution grph. Disrimintion btwn two nstd modls (.g. with nd without ovrit fft) ws rrid out using logliklihood rtio tst ssuming hisqurd distribution for th diffrn btwn minimum obtiv funtion vlus. A signifin lvl of orrsponding to drs of (1 dgr of frdom) in minimum obtiv funtion ws onsidrd. Rsults nd Disussion Sliyli Aid Anlysis Mthod Th linr dynmi quntittion rng of th mployd HPLC mthod ws btwn 25(limit of quntittion)

3 Prutnous systmi bsorption of trolmin sliylt nd 5000 ng/ml in rt plsm with orrltion offiint of Th intr nd intrdy ury for sliyli id ovr th bov onntrtion rng fll in th rngs of % nd %, rsptivly with th nlytil rovry of grtr thn 85%. Th intr nd intrdy prision wr 56% nd 313%, rsptivly. NonComprtmntl Anlysis Plsm onntrtion tim profils of sliyli id following topil dministrtion of trolmin sliylt in diffrnt groups of rts with Trnsutol or ulyptus oil prtrtd skin in omprison to ontrol group( without ny skin prtrtmnt) is prsntd in Figur 1. Mdin vlus of AUC 08 hr (% of intrqurtil rng/mdin) wr 2522(139%), 58976(141%), 3023(327%) ng/ml/hr for Trnsutol, ulyptus oil nd ontrol groups, rsptivly. As ould b sn from Figur 2, signifint diffrns wr obsrvd btwn mdin vlu of AUC 08 hr in rts whih thir skins wr prtrtd with ulyptus oil with thos of Trnsutol (p =0.030) nd ontrol ( p=0.004)groups. Howvr, no sttistilly signifint diffrn ws dttd btwn th mdin of AUC 08 hr in ontrol nd Trnsutol prtrtd rts. Furthrmor, th intrniml vribility in AUC 08 hr ws lowr in rts with ithr Trnsutol or ulyptus oil prtrtd skin s omprd to ontrol group. with th sm rng of g nd wight. 15 Prmtrs of th bs popultion modl (modl without inluding ny ovrits) r prsntd in Tbl 1. Bysin individul rts stimts of phrmokinti prmtrs wr usd for ovrit srning. As ould b sn from Figur 3, sttistilly signifint diffrns wr obsrvd btwn th mdin of individul stimts of th phrmokinti prmtrs in ulyptus oil prtrtd rts with both Trnsutol prtrtd nd ontrol groups. So, th influn of prtrtmnt on th phrmokinti prmtrs of sliyli id ws furthr ssssd by inluding it s tgoril ovrit in th popultion modl. Rsults of ovrit nlysis r shown in Tbl 2. Although, inlusion of both prtrtmnts(with Trnsutol nd ulyptus oil) s n influntil ovrit on ll phrmokinti prmtrs ld to sttistilly signifint rdutions in MOF vlus, th stimtd β offiints wr not nough pris(pvlus grtr thn 0.05). In s of modl with prtrtmnt fft on Tk0 lon (sond modl in Tbl 2), th stimtd vlus of Tk0 did not mk sns (4 hour for ontrol group). Figur 2. Comprison of r undr th sliyli id plsm onntrtiontim urv up to 8 hours (AUC 08hr ) post dministrtion of 100 mg trolmin sliylt (1g of 10% rm) in rts with untrtd, Trnsutol or ulyptus oil prtrtd skin. Figur 1. Mdin plsm onntrtiontim profil of sliyli id following topil dministrtion of trolmin sliylt in diffrnt groups of rts with Trnsutol or ulyptus oil prtrtd skin in omprison to ontrol group (dshd lins with th sm olor rprsnt 95 % onfidn round th mdin vlus). NonLinr Mixd Efft Modling Any ttmpt to stimt sliyli id limintion rt onstnt (k) with nough prision ws unsussful tht ould b rltd to insuffiint plsm onntrtiontim dt of th limintion phs in th mority of th rts undr invstigtion. Thrfor, th popultion vlu of k ws fixd to hr 1 whih hs bn rportd by Vrm t l in group of ml rts Tbl 1. Phrmokinti prmtrs of sliyli id bs popultion modl (modl without prtrtmnt fft s tgoril ovrit) following topil dministrtion of trolmin sliylt in rts with Trnsutol or ulyptus oil prtrtd skin nd ontrol group. Prmtr Vlu SE Rltiv SE (%) Tk0(hr) V/F(mL) b k(hr 1 ) ω Tk ω V ω k Rsidul rror(ng/ml) Stndrd rror of stimt b Not stimtd Intrindividul vribility of phrmokinti prmtrs in lognorml domin Advnd Phrmutil Bulltin, 2013, 3(2),

4 Sdi t l. Figur 3. Comprison of bs modl (without prtrtmnt fft s ovrit) individul stimts of sliyli id phrmokinti prmtrs ftr topil dministrtion of trolmin sliylt btwn diffrnt groups of rts with nd without skin prtrtmnt. Box nd horizontl lin insid it rprsnts prntil rng nd mdin, rsptivly. Nonoutlir minimum nd mximum obsrvd vlus r shown by whiskrs. As ould b sn from Tbl 2, fft of skin prtrtmnt with Trnsutol on phrmokinti prmtrs of sliyli id ws not sttistilly signifint. Thrfor, in th nxt stp of ovrit nlysis, Trnsutol nd ontrol group rts wr poold into on group s nottrtd with ulyptus oil. Th finl sltd ovrit modl (shown in itli lttrs) ws th on tht ssums signifint fft of skin prtrtmnt with ulyptus oil on xtrvsulr volum of distribution nd limintion rt onstnt of sliyli id. Considring ovrin btwn Tk0 nd V/F rsultd in bttr stimts of ll prmtrs. Prdition distribution of sliyli id plsm onntrtion by th finl popultion modl long with th obsrvd dt r shown in Figur 4. Th mority of th obsrvd onntrtion dt li within th 90 prnt onfidn intrvl of th modl prdition. Tbl 2. Comprison of diffrnt modls with skin prtrtmnt s ovrit (lvls of signifint diffrn of th β prmtrs r givn in prnthsis). 2logliklihood Modl ( b d f g h ΔMOF β MOF) 1 β 2 β 3 β 4 β 5 β 6 Bs modl(noovrit fft) Efft of prtrtmnt on Tk (0.0019) 0.74 Efft of prtrtmnt on V/F (0.75) Efft of prtrtmnt on k (0.53) 1.73 (0.0014) Efft of prtrtmnt on Tk0 nd V/F ( i ) (0.87) (0.69) Efft of prtrtmnt on Tk0 nd k (0.0520) (0.11) (0.77) (0.0001) Efft of prtrtmnt on V/F nd k (0.21) (0.65) Efft of prtrtmnt on Tk0, V/F nd k (1) (0.71) (0.63) (0.63) Efft of ulyptus oil on Tk (0.021) Efft of ulyptus oil on V/F Efft of ulyptus oil on k (0.0005) Efft of ulyptus oil on V/F nd k (0.012) Efft of ulyptus oil on Tk0 nd V/F (0.84) Efft of ulyptus oil on Tk0 nd k (0.007) Efft of ulyptus oil on Tk0, V/F nd k (0.42) (0.0001), k Efft of ulyptus oil on V/F nd k ssuming ovrin btwn Tk0 nd V/F (0.0015) Minimum obtiv funtion; b in omprison to th bs modl; offiint of th fft of Trnsutol prtrtmnt on Tk0; d offiint of th fft of ulyptus oil prtrtmnt on Tk0; offiint of th fft of Trnsutol prtrtmnt on V/F; f offiint of th fft of ulyptus oil prtrtmnt on V/F; g offiint of th fft of Trnsutol prtrtmnt on k; h offiint of th fft of ulyptus oil prtrtmnt on k; i ould not b lultd; ssuming no diffrn btwn phrmokinti prmtrs of rts in Trnsutol nd ontrol groups nd putting thm into on group s not0trtd with ulyptus oil; k finl sltd modl 298 Advnd Phrmutil Bulltin, 2013, 3(2),

5 Prutnous systmi bsorption of trolmin sliylt On th othr hnd, onsidrbl drs in limintion rt onstnt of th ulyptus oil group rts, ould b ttributd to th sturtion of sliyli id limintion pthwys du to th high plsm onntrtion of sliyli id hivd following pplition of ulyptus oil s trnsdrml pntrtion nhnr. 16,17 Tk0 is not fftd by prtrtmnt, thrfor th zro ordr bsorption rt is not diffrnt mong thr groups of rts. Figur 4. Prdition distribution of sliyli id plsm onntrtion following dministrtion of trolmin sliylt to rts by th finl popultion modl inluding skin prtrtmnt with ulyptus oil s n influntil ovrit (olor bnds rprsnt diffrnt prdition prntils) Prmtrs of th finl sltd modl r prsntd in Tbl 3. Rsults inditd tht inlusion of prtrtmnt with ulyptus oil ould ld to substntil rdution in intrniml vribility of phrmokinti prmtrs. Tbl 3. Phrmokinti prmtrs of sliyli id finl popultion modl (modl inluding prtrtmnt with ulyptus oil s tgoril ovrit) following topil dministrtion of trolmin sliylt in rts with Trnsutol or ulyptus oil prtrtd skin nd ontrol group. Prmtr Vlu SE Rltiv SE (%) Tk0(hr) V/F(mL) b β ulyptus oil fft on V/F k(hr 1 ) d β ulyptus oil fft on k ω Tk ω V/F ω k orrltion btwn Tk0 nd V/F V/F ulyptus oil group (ml) V/F othr groups (ml) k ulyptus oil group (hr 1 ) k othr groups (hr 1 ) Rsidul rror(ng/ml) Stndrd rror of stimt b Signifint t p < Not stimtd d Signifint t p = Intrniml vribility of phrmokinti prmtrs in lognorml domin Lowr xtrvsulr pprnt volum of distribution in rts with ulyptus oil prtrtd skin s omprd to othr groups, might b du to th nhnd biovilbility (inrs in F) of trolmin sliylt. Prmtion Enhning Efft of Trnsutol nd Eulyptus Oil Th rsults of th prsnt study show tht ulyptus oil rtd n ppribl inrs in trnsdrml bsorption of trolmin sliylt through rt skin omprd with th ontrol whil Trnsutol did not hv ny signifint nhning fft on trolmin sliylt prmtion. Th inbility of Trnsutol to promot trnsdrml prmtion of trolmin sliylt in th prsnt study is inonsistnt with th finding of in vitro study of Shrif Mkhmlzd nd Hsni. 12 In thir xprimnts Trnsutol ws found to us th bst nhnmnt of trolmin sliylt flux (12 fold) followd by ulyptus oil (10 fold) in omprison to ontrol. Suh lk of orrltion btwn in vitro nd in vivo prmbility of trithnolmin sliylt ws lso rportd by Cross t l during thir study on topil pntrtion of sliylt strs nd slts using humn isoltd skin nd linil mirodilysis thniqu. Thy suggstd tht thr is possibility tht in vivo sliylt in th pidrmis ould not b rlsd s quikly s in vitro bus of diffrns in sink ondition or som sorts of strong binding to tissu onstitunts. 18 Aording to th ontrditory rsults tht hv bn publishd in th litrtur, Trnsutol n inrs or drs trnsdrml dlivry of topilly pplid ompounds. It hs bn rportd tht prostglndin 19 nd thophyllin 20 in vitro skin prmbility ws inrsd by th prsn of Trnsutol du to its solubilizing fft tht inrss th solubility of drug in th skin, thus provids rising in drug prtitioning. 21 Howvr, othr rsrhrs found tht Trnsutol ws not bl to show ny signifint nhning fft on th prutnous bsorption of morphin, 22 sliyli id 23 nd mltonin. 24 It hs bn suggstd tht Trnsutol n ld to formtion of utnous dpot of drugs du to its bility to us intrllulr lipids swlling, thrby ssoitd with drug ntrpmnt in th skin In ddition, high molulr wight of som drugs hv bn suggstd to b on of th rstritions for Trnsutol fftivnss. 28 1, 8 Cinol (ulyptol) is th prinipl hmil omponnt of ulyptus oil. Cinol is yli thr nd tnd to b mor fftiv on hydrophili drug (lik sliylts) prmtion. This pntrtion nhnr Advnd Phrmutil Bulltin, 2013, 3(2),

6 Sdi t l. ffts th lipid bilyr strutur by forming liquid pools in thos rgion. Thus inol inrss skin prmbility by disrupting th lipid strutur of th strtum ornum. 5,29,30 Conlusion Unlik ulyptus oil, skin prtrtmnt with Trnsutol ould not ld to nhnmnt of trolmin sliylt trnsdrml bsorption in rt. Eulyptus oil ould rsult in mor thn 20 fold inrs in systmi bsorption of trolmin sliylt through rt skin s omprd to ontrol group. Aknowldgmnts This ppr ws xtrtd from Phrm.D thsis no. 812 tht submittd in Shool of Phrmy of Ahvz Jundishpur Univrsity of Mdil Sins nd finnilly supportd by grnt no. N27 from Nnothnology Rsrh Cntr of th sm univrsity. Th uthors lso would lik to thnk Frtin Co.S.K for supplying Trnsutol from Gttfoss ompny. Conflit of Intrst Thr is no onflit of intrst to b rportd. Rfrns 1. Hdgrft J. Skin, th finl frontir. Int J Phrm 2001;224(12): Prusnitz MR, Lngr R. Trnsdrml drug dlivry. Nt Biothnol 2008;26(11): Brry BW. Drmtologil formultions: Prutnous bsorption. Nw York: M. Dkkr; Finnin BC, Morgn TM. Trnsdrml pntrtion nhnrs: Applitions, limittions, nd potntil. J Phrm Si 1999;88(10): Willims AC, Brry BW. Essntil oils s novl humn skin pntrtion nhnrs. Int J Phrmut 1989;57(2):R7R9. 6. Algozzin GJ, Stin GH, Doring PL, Aruo OE, Akin KC. Trolmin sliylt rm in ostorthritis of th kn. JAMA 1982;247(9): Bldwin JR, Crrno RA, Imondi AR. Pntrtion of trolmin sliylt into th skltl musl of th pig. J Phrm Si 1984;73(7): Hill DW, Rihrdson JD. Efftivnss of 10% trolmin sliylt rm on musulr sornss indud by rproduibl progrm of wight trining. J Orthop Sports Phys Thr 1989;11(1): Rothkr D, Difigilo C, L I. A linil tril of topil 10% trolmin sliylt in ostorthritis. Curr Thrp Rs 1994;55(5): Rothkr DQ, L I, Littlohn TW, 3rd. Efftivnss of singl topil pplition of 10 x% trolmin sliylt rm in th symptomti trtmnt of ostorthritis. J Clin Rhumtol 1998;4(1): Bldwin J, Crrno R, Imondi A. Pntrtion of trolmin sliylt into th skltl musl of th pig. J Phrm Si 1984;73(7): Mkhml Zdh BS, Hsni MH. Th fft of hmil nd physil nhnrs on trolmin sliylt prmtion through rt skin. Trop J Phrm Rs 2010;9(6): Mgw SA, Bnson HA, Robrts MS. Prutnous bsorption of sliylts from som ommrilly vilbl topil produts ontining mthyl sliylt or sliylt slts in rts. J Phrm Phrmol 1995;47(11): Lvill M. Monolix usr's guid. 4.2 d: Th monolix tm; Vrm DR, Yu TL. Influn of g, sx, prgnny nd protinlori mlnutrition on th phrmokintis of sliylt in rts. Br J Phrmol 1984;82(1): Co Y, Dubois DC, Almon RR, Jusko WJ. Phrmokintis of slslt nd sliyli id in norml nd dibti rts. Biophrm Drug Dispos 2012;33(6): Ptl DK, Notrinni LJ, Bnntt PN. Comprtiv mtbolism of high doss of spirin in mn nd rt. Xnobioti 1990;20(8): Cross SE, Andrson C, Robrts MS. Topil pntrtion of ommril sliylt strs nd slts using humn isoltd skin nd linil mirodilysis studis. Br J Clin Phrmol 1998;46(1): Wtkinson AC, Hdgrft J, By A. Aspts of th trnsdrml dlivry of prostglndins. Int J Phrm 1991;74(23): Touitou E, LviShffr F, ShoEzr N, Bn Yossf R, Fbin B. Enhnd prmtion of thophyllin through th skin nd its fft on fibroblst prolifrtion. Int J Phrm 1991;70(1 2): Hrrison JE, Wtkinson AC, Grn DM, Hdgrft J, Brin K. Th rltiv fft of Azon nd Trnsutol on prmnt diffusivity nd solubility in humn strtum ornum. Phrm Rs 1996;13(4): Ros J, Flson F, Courrz G, Frnis A, Puisiux F. Optimiztion of binry nd trnry solvnt systms in th prutnous bsorption of morphin bs. STP Phrm Si 1991;1(1): Smith JC, Irwin WJ. Ionistion nd th fft of bsorption nhnrs on trnsport of sliyli id through silsti rubbr nd humn skin. Int J Phrm 2000;210(12): Kikwi L, Knikknnn N, Bbu RJ, Singh M. Efft of vhils on th trnsdrml dlivry of mltonin ross porin skin in vitro. J Control Rls 2002;83(2): Pnhgnul R, Ritshl WA. Dvlopmnt nd vlution of n intrutnous dpot formultion of ortiostroids using trnsutol s osolvnt: 300 Advnd Phrmutil Bulltin, 2013, 3(2),

7 Prutnous systmi bsorption of trolmin sliylt Invitro, xvivo nd invivo rt studis. J Phrm Phrmol 1991;43(9): Du Plssis J, Winr N, Müllr DG. Th influn of in vivo trtmnt of skin with liposoms on th topil bsorption of hydrophili nd hydrophobi drug in vitro. Int J Phrmut 1994;103(2):R Godwin DA, Kim NH, Flton LA. Influn of trnsutol CG on th skin umultion nd trnsdrml prmtion of ultrviolt bsorbrs. Eur J Phrm Biophrm 2002;53(1): Bonin FP, Montngro L. Effts of som nontoxi pntrtion nhnrs on in vitro hprin skin prmtion from gl vhils. Int J Phrmut 1994;111(2): Moghimi HR, Willims AC, Brry BW. Enhnmnt by trpns of 5fluorouril prmtion through th strtum ornum: Modl solvnt pproh. J Phrm Phrmol 1998;50(9): Willims AC, Brry BW. Pntrtion nhnrs. Adv Drug Dliv Rv 2004;56(5): Advnd Phrmutil Bulltin, 2013, 3(2),