`
`DRUGSANDTHEPHARMACEUHCALSCENCES
`
`VOLUME123
`
`
`
`Transdeemal
`Ilene Delivery"
`
`Seeded Edilien, devised and Expanded
`
`
`
`Gimme
`
`Eulllcular
`
`edited by
`Richard H. Guy
`Jonathan Hadgraft
`
`0001
`
`

`

`...... m:—
`
`h
`
`Library of Congress Cataloging-in-Puhlieation Data
`A catalog record for this book is available from the Library of Congress.
`
`ISBN: 0-8247-0861-X
`
`The first edition was published as Tranrderimt Drug Delivery.- Developmental Issues and
`Research Initiatives: edited by Jonathan Hadgraft and Richard H. Guy.
`
`This book is printed on acid—free paper.
`
`Headquarters
`Marcel Dekker, Inc.
`270 Madison Avenue, New York, NY 10016
`
`tel: 212-696—9000; fax: 212-685—4540
`
`Eastern Hemisphere Distribution
`Marcel Dekker AG
`Hutgasse 4, Postfaeh 812, Chi—4001 Basel. Switzerland
`tel: 41—61—260—6300; fax: 41—61—260—6333
`
`World Wide Web
`httpn’fwwwdekkeneom
`The publisher offers discounts on U115 book when ordered in bulk qnantilies. For more
`information, write to Special SalesfProfcssionnl Marketing at the headquarters address
`above.
`
`Copyright © 2003 by Marcel Dekker, Inc. All Rights Reserved.
`
`Neither this book nor any part may be reproduced or transmitted in any form or by any
`means, electronic or mechanical. including photocopying, mierofilming, and recording,
`or by any information storage and retrieval system. without permission in writing from
`the publisher.
`
`_
`
`Current printing (last digit):
`10981654321
`
`Pre
`
`The pr
`of acar
`atlmini
`availal".
`
`pl‘ldr'm‘
`transde
`
`13'3“,“
`optima
`absorpl
`Ital age
`propert
`are mu
`
`techniq
`the has
`”:1“an
`vised h
`
`can be
`throng}
`in the U
`include
`viewed
`
`fully e):
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`PRINTED IN THE UNITED STATES OF AMERICA
`
`
`
`
`

`

`Feasibility Assessment in Topical and Transdermal Delivery
`
`tion, which elicits a systemic effect. This route has a number of attractions. anti
`an accurate and predictive model would be invaluable in the selection and evolu-
`tion of appropriate. transdermal drug candidates. Equally, there are also chemi—
`cals, the absorption of which in significant amounts is clearly undesirable. Com—
`pounds such as pesticides are obvious examples, but there. are. other materials,
`present perhaps as forttnilation exeipients, that could also be detrimental. An
`appropriate mathematical model would allow a reliable risk assessment to be
`made before in vivo evaluations are conducted.
`
`There are different considerations to be taken into account depending on
`whether the drug is to be delivered for local action or for systctnic action. Since
`this book concerns primarily transdermal delivery, the major emphasis will be
`how to ensure the transport of drug through the Skin into the underlying dermal
`vasculature and hence the systemic circulation. For a drug to be administered
`tmnsdenrtally, it has to be very potent. as it is unlikely that more than a few tens
`of milligrams per day can be delivered. To a first approximation, feasibility can
`be assessed from the daily dose. But, as will be seen, even for a compound like
`nitroglycerine, which has ideal physicochemieal properties for tt‘ansdcrmul deliv—
`ery from a reasonable patch area, no more than 4-0 to 50 mg per day can be
`delivered.
`
`ll.
`
`FICK’S LAWS OF DIFFUSION
`
`Considering that the skin is such a heterogeneous membrane. it is surprising that
`Simple diffusion laws can be used to describe the pet'eutaneous absorption process
`(3). Since transdermal delivery involves the application of a device over a long
`period of time,
`it is generally assumed that steady—state conditions have been
`reached and that the most relevant law of diffusion is therefore Fick’s first law.
`
`ln some ways. it is more difficult to assess the feasibility of topical drug
`delivery, as the levels required in the skin for therapeutic effect are usually utt—
`known. For transdermal delivery, there is a well-documented and determinable
`end point, the plasma level required for efficacious therapy. Advances in noninva—
`sive monitoring and microdialysis can be helpful in determining the target skin
`concentration for topical therapy, but data are limited, and the reliability of the
`methodologies involved is still in question, as the techniques remain in very much
`a developmental Stage.
`Validated mathematical Itiotlcls represent an economically advantageous
`approach for the assessment of skin permeation, and their use is rectnnmended
`before full—blown in vitro and in vivo experiments are conducted. The purpose
`of this chapter is to examine the limitations of mathematical modeling and to
`consider appropriate in vitro models prior to full clinical testing.
`
`The second law describes non—steady state diffusion and can be used to analyze
`
`:.-
`
`is, Top
`-
`channels. The
`
`in its passage
`-
`lluinr.
`
`nus route and
`
`an lipophilic
`.me character-
`
`. step, and
`tan nzlen he
`
`.IEl diffusion
`tat-curate
`lit. lac ili-
`
`.cit‘rtt drug
`-
`-.-.; concentra—
`
`

`

`4
`
`Hadgraft and Guy
`
`the rates of release from matrix type transdermal patches, to evaluate the lag
`phase prior to the establishment of steady—state conditions. and to describe con-
`centration profiles across the skin as they evolve towards linearity.
`The most quoted form of Fick’s first law of diffusion describes steady-state
`diffusion through a membrane:
`
`J- : Etc; _ Ci)
`it
`
`(1}
`
`where J is the flux per unit area, K is the stratum cerneum-forrnulation partition
`coefficient of the drug, and D is its diffusion coefficient in the. stratum comcum
`of path length it; cc. is the concentration of drug applied to the skin surface, and
`ft is the concentration inside the skin In most practical situations, (:0 3) ch and
`Eq. (1) simplifies to
`
`J 2 kn“
`
`{2.)
`
`where kp (2 IJK/lt) is the permeability coefficient. which has units of velocity
`{often quoted as cm h"}. i.e._.
`it is a heterogeneous rate constant and encodes
`bnth partition and diffusional characteristics. The input rate of the drug into the
`systemic circulation. front a patch of area A, is therefore given by the product
`
`Input rate = A X k“ X c0
`
`(3)
`
`The output or elimination rate from the systemic circulation equals the clearance
`(Cl) multiplied by the plasma concentration at steady state (€th
`
`Output rate = Cl x Cu.»
`
`(4)
`
`The plasma concentration achieved therefore depends directly on the area of the
`device. the skin permeability, and the applied concentration and is inversely ref
`lated to the drug‘s clearaHCe (4).
`For a given drug, the clearance and the target plasma level are likely to
`be known, so to examine the feasibility of delivery, one needs the drug‘s skin
`permeability and its solubility, as this will give an indication of the. maximum
`concentration that can be applied. These parameters can be estimated from basic
`physicochemical properties which are typically measured (luring preformulation.
`
`Feasil:
`
`"l-
`
`E
`F
`F
`
`Over t'
`(e.g., F
`from at
`other v
`the bar
`
`Guy Lo
`tics oft
`lar wei
`
`l‘
`
`If log i
`by con
`and ac:
`F-
`wherea
`be“ at:
`often g
`
`COCITIL‘
`ery. Re
`eoeffic
`sion er
`aehiev:
`
`this ya
`mated
`
`I
`
`where
`mp 15 11
`
`It 5 in
`“33335
`I‘elleeti
`be 53“
`emploj
`coeflie
`the d1"
`in Fig.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Hence Eqs. (3) and {4] may be combined to predict the drug‘s plasma concentra—
`tion following transderrnal delivery:
`
`Alene“
`Cl.
`
`(-‘pss :
`
`_
`[3)
`
`
`
`
`