Physiological Pharmaceutics
`
`Barriers to drug absorption
`
`Second Edition
`
`Neena Washington, Clive Washington and
`Clive G. Wilson
`
`
`
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`First edition 1989
`Second edition first published 2001 by Taylor and Francis
`11 New Fetter Lane, London EC4P 4EE
`
`Simultaneously published in the USA and Canada
`by Taylor and Francis Inc,
`29 West 35th Street, New York, NY 10001
`Reprinted 2002
`
`Taylor and Francis is an imprint of the Taylor & Francis Group
`Publisher’s Note
`This book has been prepared from camera-ready copy provided by the
`authors.
`
`© 2001 Neena Washington, Clive Washington and Clive G. Wilson
`Printed and bound in Great Britain by TJ International Ltd, Padstow,
`Cornwall
`
`All rights reserved. No part of this book may be reprinted or reproduced or
`utilised in any form or by any electronic, mechanical. or other merrnrt. now
`known or hereafter invented, including photocopying and recording, or in
`any inionnntion storage or retrieval system. without Inn-mission in writing
`from the publishers.
`Every effort has been made to ensure that the advice and information in this
`hook ir. true and nectn-ntc at the lime of going to press. However. neither the
`publishers nor the authors can accept any legal responsibility or liability for
`any error}: or emissions that may he made. in the ease of drug
`administration, tiny medical procedure or the use of teelntical equipment
`mentioned within this hook, you are strongly advised to consult the
`monut‘nclumr's guidelines.
`British Library Cataloguing in Publication Data
`A catalogue record is available for this book from the British Library
`Library of Congress Cataloging in Publication Data
`Washington, Neena, 196l—
`l’liysloiogicul pharmaceutics: barriers to drug absorption/ Neena
`Washington, Clive Washington. and
`Clive George Wilson.—2nd ed.
`p.
`cm.
`Previous ed. Physiological pharmaceutics: biological barriers to drug
`nhsorpliom’tllive George Wilson. Neena Washington.
`“Simultnneousiy published in the USA and Canada."
`Includes bibliographical references and index.
`'3. Dntgo—Plryrtiologicni
`I. Drugs—Bionvniltrbility.
`2, Drugs—Dosage Forms.
`tinneport.
`rl. Absorption (Physiology)
`I. thrthirtglou, Clive,
`I‘JST— .
`Ll. Wilson,
`[Ilive George.
`111'. Wilson. Clive George. Physiological plinmnrccttties: biological
`barriers to drug absorption.
`IV. Title.
`RM301.6.W54 2000
`615 ’.7—chl
`
`ISBN 0-748-40610-7 (hbk)
`ISBN 0-748-40562—3 (pbk)
`
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`Physiological Pharmaceutics
`
`26
`
`however a number of indications for smaller doses, such as myocardial oxygenation during
`coronary angioplasty, show some promise. The field has been recently reviewed by Krafft
`and coworkers (1998)”.
`ii) Haemoglobin-based products. Free haemoglobin resulting frim lysis of erythro-
`cytes is cleared rapidly from the circulation; large amounts of haemoglobin will cause kid-
`ney damage. Two approaches are being studied to prevent renal excretion; modification
`and encapsulation. The modified route uses polymerized or cross-linked haemoglobin,
`usually treated with glutaraldehyde or coated with polyethylene chains”. Rabinovici and
`coworkers'6 and others have studied the possibility of encapsulating haemoglobin in
`liposomes to make an artificial red cell.
`
`INTRAMUSCULAR DELIVERY
`
`Physiology
`Intramuscular delivery involves the injection of the dose form into a muscle, from
`where it is absorbed due to the perfusion of the muscle by blood. The formulation forms a
`local depot which is partly mixed with interstitial fluid, and partly forms a bolus within the
`muscle, particularly if the injected volume is large. As a result it is important to realize that
`the injection is made into abnormal tissue; this may be particularly important if the formu-
`lation is intended to reside in the body for a significant length of time.
`The structure of a typical muscle is shown in Figure 2.3. The muscle is wrapped in a
`connective sheath called the epimysium, within which are bundles of individual fibres,
`each surrounded by a connective membrane termed the perimysium. A finer matrix of
`connective fibrous tissue, the endomysium (omitted from Figure 2.3 for clarity), surrounds
`the muscle fibres, and the blood capillaries run within the endomysium, largely in a longi-
`tudinal manner, with numerous cross-connections. As a result the whole muscle is ex-
`tremely well perfused. There are also numerous lymphatic vessels, but these lie in the
`epimysium and perimysium.
`The preferred sites for injection are the gluteal, deltoid, triceps, pectoral and vastus
`lateralis. The deltoid muscle is preferred due to its greater perfusion rate compared to the
`other muscles, although the vastus lateralis has the advantage of having fewer major blood
`vessels into which the injection might accidentally be placed. When an intramuscular in-
`jection is administered, it is normal practice to withdraw the syringe plunger briefly to see
`if blood can be withdrawn. Blood indicates that the needle may be in a vessel, and the
`injection should be repositioned. There is also a minor danger of damaging a nerve fibre
`during the injection.
`
`Pharmacokinetics
`
`The most significant advantage of intramuscular delivery is the ease with which a
`wide range of drugs can be administered in a variety of dosage forms, which not only
`provide rapid absorption, but can also be used for sustained therapy. Intramuscular delivery
`involves a number of steps (Figure 2.4); i) release of the drug from the dose form into the
`intercellular fluid (ICF), ii) absorption from the ICF into the blood and lymphatics, iii)
`transport from the local blood volume into the general circulation, and iv) metabolism. The
`concentration of drug and kinetic profile are determined by the relative rates of these proc-
`esses, and we should note that the capillary membrane is highly permeable and in general
`will not be rate-limiting, but perfusion of the muscle by the blood may be significantly
`slower. We can distinguish two particular limiting cases of interest:
`i). Injection of a bolus of soluble drug. In this case the drug is immediately available
`in the ICF and is rapidly absorbed into the capillaries. In this case the rate-limiting absorp-
`tion step is the perfusion of the muscle by the blood. Any factor which influences muscle
`perfusion (such as movement or exercise) will change the rate of absorption. In particular,
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`Parenteral drug delively
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`27
`
`Perimysium
`Muscle fibres
`
`Fibre bundle
`
`
`
`
`
`Capillaries
`Figure 2.3 Schematic structure ofmuscle
`
`if cardiac failure has occurred, absorption will be extremely low since the muscle perfusion
`rate will be small. For this reason intramuscular delivery is contra-indicated if cardiac
`function is poor.
`ii) Injection of the drug in sustained-release form (e. g a solid depot or crystal suspen-
`sion). In this case release from the formulation is slower than absorption or perfusion, and
`so the behaviour of the device becomes the rate-limiting step, and the effects of muscle
`perfusion are not evident. Under these conditions the concentration of drug in the plasma
`remains approximately constant until the delivery device is exhausted, a period which can
`be designed to last from several hours to several months.
`
`Pharmacokinetics limited by device
`_
`Capillary blood flow
`
`-
`
`Figure 2.4 Absorption ofdrugs from intramuscular injections
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`28
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`Physiological Pharmaceutics
`
`Formulation considerations
`
`Since the formulation does not have to be miscible with water, it is possible to inject
`a much wider range of materials than those which can be administered intravenously. The
`possible formulations include aqueous solutions, aqueous suspensions, oily solutions, oil in
`water emulsions, water in oil emulsions, oily suspensions, and dispersions in polymer or
`solid implants. These are listed approximately in order of release rate, as aqueous solutions
`can be absorbed in minutes, while implants can deliver drugs for several months.
`In addition a range of other factors can influence the absorption rate. If the drug is
`extremely hydrophobic it will not dissolve in the ICF, while if it is strongly ionized or
`extremely water soluble it will not be able to cross the capillary membrane. Drugs which
`are strongly protein-bound will also be slowly absorbed since their activity in solution will
`be reduced. A number of drugs administered in solutions may be absorbed anomalously
`slowly if the composition of the formulation changes after injection. For example, pheny-
`toin is formulated as an injection at pH 12 due to its low solubility. On injection the ICF
`quickly reduces the pH to normal levels, and the drug precipitates. As a result it may then
`take several days for the dose to be fully absorbed.
`
`SUBCUTANEOUS DELIVERY
`
`Physiology
`A subcutaneous inj ection (SC) is made into the connective tissue beneath the dermis,
`and should be contrasted with an intradermal injection which is made into the dermal layer,
`often between the dermis and the epidermis (Figure 2.5). This is a critical distinction be-
`cause the subcutaneous tissues have a significant volume of interstitial fluid into which the
`drug can diffuse, while the epidermal tissue has relatively little available fluid, nor is it well
`perfused by blood. As a result an intradermal injection persists at the site for a long period
`and the available volume for injection is small; it is normally used for antigens (e.g. tuber-
`culin) and vaccines (smallpox).
`Drugs injected subcutaneously dissolve in the interstitial fluid and gain entry to the
`bloodstream by two routes. They may be absorbed directly into blood vessels, but the
`subcutaneous tissues are often adipose and poorly perfused. Alternatively the interstitial
`
`lntradermal
`
`_,.r'
`
`”5”
`. Q:\
`
`Epidermis
`Dermis
`
` Subcutaneous
`
`Subcutaneous
`Tissue
`
`
`
`Adipose
`Tissue
`
`Muscle
`
`Figure 2.5. Physiology ofparenteral administration routes
`
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`29
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`r p
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`arenteral drug delivery
`
`fluid is collected by lymphatic capillaries and these drain into the regional lymph nodes and
`then into the bloodstream. These pathways are both relatively slow and depend on the local
`vasculature, so absorption from subcutaneous sites can be slow and unpredictable. To some
`extent this allows a sustained release effect to be obtained; however it is not particularly
`satisfactory to design a dose form in this way because of the inherent variability of the
`pharmacokiueties. A better strategy is to make the release from the dose form rate~limiting
`{as is the case for intramuscular depot delivery systems) so that biological variation then
`has little influence on the drug pharmacokinetics. A large number ofdelivery systems have
`been devised which work in this way; probably the best known being Zoladex® (AstraZeneca)
`which releases the hormone goserelin, a chemical castrating agent used in the treatment of
`androgen-dependent tumours. The hormone is incorporated into a small rod of biodegrad—
`able poly (D,L lactide) polymer about 5mm long and implanted subcutaneously in the ab-
`domen. A single injection lasts for 28 days; the cost (over £100 per injection at the time of
`writing) reflects the difficulty of manufacturing the device in a totally aseptic environment.
`Technology of this type is particularly suited to peptide hormones in which the dose is small
`and the size of the device can be minimized. A number of other interesting examples of this
`depot technique can be found in the literature, including the use of emulsion depots for
`methotrexate”, hydrogelsl8 and block copolymer gels”.
`
`Subcutaneous colloidal delivery systems
`It has already been indicated that materials injected subcutaneously may be carried
`by the lymphatic flow into the regional lymph nodes and then into the blood. Colloidal
`particles which are injected subcutaneously can follow the same route, although their large
`size (tens to hundreds of nanometres) relative to drug molecules will reduce their diffusion
`rate considerably. On reaching the lymph nodes they will be taken up by macrophages
`rather than passing to the bloodstream.
`Most of the work in this area has been performed in rats, with the foot and footpad
`being the most closely studied injection sites. Ousseren and Storm20 used this technique to
`study the lymphatic uptake of liposomes from SC injection, and found relatively high lym-
`phatic localization (60% of injected dose). However, injections into the flank produced
`only a slight uptake, and the suspicion is that footpad injections cause a large increase in
`local interstitial pressure due to the small volume of the site, and that this drives the injec-
`tion into the lymphatic vessels. Consequently the targeting effect may not be so pronounced
`if the technique were used in man. The same study showed that the liposomes needed to be
`small (> 0.2 um) or they could not be moved from the injection site, and that highly charged
`liposomes were taken up more efficiently than weakly charged ones. Interestingly, liposomes
`made from the ‘stealth phospholipid’ with grafted PEG-chains were taken up to a similar
`extent to normal liposomes of the same size. Although this study was performed exclu-
`sively with liposomes there seems to be no reason why the results should not broadly apply
`to other colloidal particles.
`
`TISSUE DAMAGE AND BIOCOMPATABILITY
`
`With any injected formulation damage occurs to the surrounding tissues. In the case
`of an intravenous injection, this usually has little consequence for drug absorption, but in
`the case of intramuscular and subcutaneous systems the drug or device is inherently present
`in a wound site and the body will react accordingly. The reaction depends on the size and
`composition of the device. Small isolated particles less than 10 um will be engulfed by
`macrophages without any major reaction occurring, but larger objects in a microsphere
`form will gather a layer of macrophages and giant cells adhering to the surface of the parti-
`cles. Larger devices with large surface areas will elicit a foreign body reaction which be—
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