D-A192 324 EXAMINATION OF XOTOPHORETIC TRANSPORT OF IONIC DRUGS 1/'1ACROSS SKIN(U) UTAH UNIV SALT LAKE CITY DEPT OF

CHEMISTRY S PONS ET AL. 3S JUL 06 TR-51

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0OFFICE OF NAVAL RESEARCH

Contract N00014-83-K-0470-PO003 OT FILETask No. NR 359-718

TECHNICAL REPORT * 51

Examination of Iotophoretic Transportof' Ionic Drugs across Skin

By

Stanley Pons

W. HiguchiT. Masada

U. Rohr

J. Fox

C. Behl

Prepared for Publication in D T ICJournal of Pharmaceutical Science -- LECTE

APR 1 4 1988 U .University of' Utah SAP --D

Department of Chemistry Q -Salt Lake City, Utah 84112 S

July 30, 1986

Reproduction in whole or in part is permitted for

any purpose of the United States Government.

This document has been approved for public release ',

and sale: its distribution is unlimited. Ii

1:,'. ..

SECUNITy CLA r.IFICAYIONi OF TNIS PAC fwt n t... f.0.014)

REPORT DOCUMENTATION PAGE RKAD irs'RCiOSIJCFORE C.OMLpETING Y'OR.I

I. t!.b'iOr/ NUMbEt 2 .r. T ACCCSSIoN io. 3. mCciPln.P vs CATALOG .Uwltfrt

511

- of Ionrophoretic Transport of Ionf 5 TYPE OF REPORT 6 PEleoo COVERED

Durgs across Skin 51

6. PERFORmING O;IG. REPOrT NU m'stR

7. AUToqO(s) a. cONTRACT OA GRANT NU4:§EFf(&)

Stanley Pons, W. Higuchi, T. Masada, U. Rohr, J H00014-83-K-0470-P0003Fox. C. Behl

9. PE.FoWq.dIG ORGANIZATION NAME AND ADAESS 1o. PRO.RAJ. ELC,ENT.PlOjECT, TASKAREA & WORIK UNIT NUMLIRS

University of UtahDepartment of Chemistry Task No.-.NR 359-718Salt Lake City, UT 84112

I. CONTROLLING OFFICE NAME AND ADDRESS 12. REPORT DATE

Office of Naval Research Jul 30-1986Chemistry Program - Chemistry Code 472 3.'NUMBER OF PAGES

Arlington, Virginia 2221714. MONITORING AGENCY NAME A ADORESS(1I ditllrl Iam Cont/rolln4 Oftlie) 15. SECURITY CLASS. (of gMle r.port)

Unclassif fed

ISA. DOECL AS.,$FICATIOh1/OOW4GRAOING

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This document has been approved for public release and sale; its distributionunl imi ted.

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1. SUPPLEMENTARY NOTES

19. KEY W'OAOS (Continue en ,everee aie it nec.eeo ry, and Identify by block nr bwer)

lontophoretics

20. AO.TRACT (Confinu,* , oeo *ld. II nC@C&*.V id Identity by block nutmbt.)

Potential induced transport of ionic drugs across skin is discussed.*

DD 4 1473 EDITION OF I ,,ov 6S IS oRSOLET-

DD ,,,,. " UnclassifiedN OW % .

Aa

4, -. • -- m Jo4 1 QP ilI I .. e. . .r°i .. *. .

F.W*

0?7 IONIC DRUGS ACROCSS SKIN

Authcrs:

. UE- R OiT. j.OFOS

*C-ole~e 04* Phar-acyDepartment of Pharnacetics

TU'vers~ty of UtahS~alt ake C'-.,, U ta

+1P"harmaceutical R-,s earch Pmi Zevelrrment Eerar'm7ents

Nutley, :~Jersey I

Depar-7-ent C- Che7'stry

SUnIetsT-at; o2 tah

-Q -X-r -*.- -- MR.~ -%,Jn rU VWrI T WF-V

S. D" c e s te- evelopment of a

P ouir-elect.rod,,e syste-r fo ;~ ontopphoresls of single charged dru2gs

rcss the skin. It IS :--so a o clexa7-in2.t'on of an eouation which we

hove er~-d and. WhIch 'ecrb lfn da~mentally flux enhancement across a-n

R T]

Is th-e flux enhance-ient ratio, Y is the flux of a drug with an electric

fIeld, Y0 Is the flux for the dzrug with no electric field across the same

me77trane, 6 is the potential drop across the membrane, Z Is the molecular

charge, D is the di'fus-'vity, F is the Faraday constant, RT has the usual

.eP-n'mg.

Teexoer!7,ental results in Ta7le 1 show that Por the twAo-elec-.rode

- S,:Ste-. wlth a donor andA a receiver co-martment the flux enhancement ratio

~tthe benzoate !on amd tetraethnylarnionium .-on Is within a factor of two to

* f ur of he heoet~al redictlons (assuming L = 1C volts in several

Instances. Terncaldiflculty w-'th th-e tw,.o-elect-obe svs:em Is that:

---eIsn eas':-,' to ' :now what -the actual -'Is across the mrembraune. Th),er e

:elofc a.r e Lectrl cal resistances at the elec-,ro-;e'solutlon interfaces

arc acro ss the buksolution. hetween the electrodes and trhe -.-mbrane surface

a ter are no simple methods for est177ating, these. The two-electrooe

tlierefcre, o ann:ot 'be erj'oyed ILn the rL gorous study of ecuatlon 1.

z a- e -.....- . eve r tocr de -e7-1 ne and 0 roro the a ctu:.I

arpo ~~c s irfa-e ir-. a Je"Ined! maner Te new t1,wo chamber

.~' :oo~ ~ofcorsect,-ons. wC 9con -= oe onr a-n: wo each-

-~-~'~-ero-or'~nt. A rngshaoe4 alo w~re serv~es as th e

%,

cnerelec!troJe Ln tn e t ucncell. The !Iggz'n ca:z.llary ser-jes as a

r'eference electrode and ccnsi.sts cfP a long thin capillary and is filled with

1solution. T-he KC! sclutioni conducts th'-e potential P'rom the tip of the

Lugg_'i cap-illary across the stcp cock into a reservoir of' KCl solutlon. A4

calom el electrod e -,easi.ures th,-e poten~tial ari ln'-Ilcates It to a Dotentlostat.

:c working compartments -S rlvlm)w1hterLugocpllre

*mounted togeth-er wfth the -etrane '-n b)etween. A block dfagram of the

e_,ectro-nC circuli for t'he four-electrode diffuslor cell Is shown In Fig. 2.

A use generator (G) supplies voltage vs. ground to the working electrode

.- I. T-he same voltage or the opposite sign1 appears at the bontact to 1the

reference electrode PE1, wille the contact to the reference electrode RE2 is

always held at virtual ground. Only negligible current can flow through the

* fe:-ence electrodes. Th-e Dotential drop between the tips of Luggin

capl_!ll es is tnen cortro-lled_ -Ir a def fned_ way,,. T-he current flowingthcF

tone nemrr,-ne is scle,! ty the outzouts of the o-Derational amp11lfler OA! ant

C3w'-th, the -latlniz- w~res of the counter electrodes CEl and CE2.

F~.3and decl'ct flux enhancement ratios for tetraethylamrronlw7

ote~hthe frour-electrode system by using a cellulo-se acetate memtrane

i harless muse sk~In, rescect-4vely. As ca- he seen, low aledvoltages

oem.ween I ad 21 r4 1volts the agreenent. between exper'-7ental ano

the2-etical predicted flux enh-ancement is excellent.

At higher voltages, the experimental flux enh"ancement rises faster ta a

n-. :rnretialpredIct'lons. A~n expla-nation for th1s is tel leved tobeht

tr-e a7;rlleA elc rl'~elP causes chang;es In s'kin pr, Pe--Ies hchallows

*aster dlffuislon of' molecules throuN,,gh the s1k-.n. T-hese res,.l.ts demnst'"I'ng __

th qnlttleapplicab,1l'_ty of equatlon are belleved1 tc b the Itrs of 0

-. st *-P*-- laiio

- - t~t Sj401i&

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