`
`DRUGS AND THE PHARMACEUTICAL SCIENCES
`
`ORO)
`
`ONSITE
`WR
`SHRUTI RTCAADHMeUT eT
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`eccrine
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`follicular
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`Crete OY
`Richard H. Guy
`Jonathan Hadgraft
`
`
`
`————
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`Library of Congress Cataloging-in-Publication 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 Transdermal Drug Delivery: Developmental Issues and
`Research Initiatives, edited by Jonathan Hadgraft and Richard H. Guy.
`
`This book is printed on acid-free paper.
`
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`Copyright © 2003 by Marcel Dekker, Inc, All Rights Reserved.
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`Neither this book nor any part may be reproduced or transmitted in any form or by any
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`the publisher.
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`Feasibility Assessment in Topical and Transdermal Delivery
`
`tion, whichelicits a systemic effect. This route has a numberofattractions, and
`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 whichin significant amounts is clearly undesirable. Com-
`pounds such as pesticides are obvious examples, but there are other materials,
`present perhaps as formulation excipients, that could also be detrimental. An
`appropriate mathematical model would allowa 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 systemic action. Since
`this book concerns primarily transdermal delivery, the major emphasis will be
`how to ensure the transport of drug throughthe skin into the underlying dermal
`vasculature and hence the systemic circulation. For a drug to be administered
`transdermally, it has to be very potent, as it is unlikely that more than a few tens
`of milligrams per day can be delivered. Toa first approximation, feasibility can
`be assessed from the daily dose. But, as will be seen, even for a compoundlike
`nitroglycerine, which has ideal physicochemical properties for transdermal deliv-
`ery from a reasonable patch area, no more than 40 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 percutaneous absorption process
`(3). Since transdermal delivery involves the application of a device overa long
`period of time,
`it is generally assumed that steady-state conditions have been
`reached and that the most relevant lawof diffusion is therefore Fick’s first law.
`
`The secondlaw describes non-steady state diffusion and can be used to analyze
`
`In 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 un-
`known. Fortransdermal delivery, there is a well-documented and determinable
`end point, the plasmalevel required forefficacious therapy. Advancesin 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 models represent an economically advantageous
`approach for the assessment of skin permeation, and their use is recommended
`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.
`
`dermis. Top
`faz
`channels. The
`
`fous route and
`
`pnd lipophilic
`me character-
`pt that mathe-
`ie a term to
`
`al step, and
`
`Milations are
`
`he absorption
`
`pid diffusion
`accurate
`nd facili-
`
`aficient drug
`maconcentra-
`
`
`
`the rates of release from matrix type transdermal patches, to evaluate the lag
`phasepriorto the establishmentof steady-state conditions, and to describe con-
`centration profiles across the skin as they evolve towardslinearity.
`The most quoted formof Fick’s first lawof diffusion describes steady-state
`diffusion through a membrane:
`
`j= BD oe —«)
`h
`
`(1)
`
`Input rate = A X k, X cy
`
`(3)
`
`The output orelimination rate from the systemic circulation equals the clearance
`(Cl) multiplied by the plasma concentration at steady state (c,..)
`
`Output rate = C/ X c,..
`
`(4)
`
`Hence Eggs.(3) and (4) may be combinedto predict the drug’s plasma concentra-
`tion following transdermal delivery:
`
`Ak,Cy
`Cl
`
`Coss =
`
`“
`(3)
`
`The plasma concentration achieved therefore dependsdirectly on the area of the
`device, the skin permeability, and the applied concentration and is inversely re-
`lated to the drug’s clearance (4).
`For a given drug, the clearance and the target plasmalevel 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
`physicochemicalproperties, which are typically measured during preformulation.
`
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`4
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`Hadgraft and Guy
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`Feasib
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`where J is the flux per unit area, K is the stratum corneum-formulationpartition
`coefficient of the drug, and D is its diffusion coefficient in the stratum corneum
`of path length A; c, is the concentration of drug applied to the skin surface, and
`c; is the concentration inside the skin. In mostpractical situations, c, = c,, and
`Eq. (1) simplifies to
`(2)
`J = kee
`where k, (= DK/h) is the permeability coefficient, which has units of velocity
`(often quoted as cm h™'),
`i.e.,
`it is a heterogeneous rate constant and encodes
`both partition and diffusional characteristics. The input rate ofthe drug into the
`systemic circulation, from a patch of area A, is therefore given by the product
`
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