Routes of Drug Administration. Topics in Pharmacy

164 Pages·1990·4.29 MB·English

by  A. T. Florence and E. G. Salole (Eds.)

Routes of
Drug Administration
Edited by
A. T. Florence PhD, DSc, FRSC, FRSE, FRPharmS
The School of Pharmacy,
University of London,
London, UK
and
E. G. Salole BSc, PhD, MRPharmS
Department of Pharmacy,
University of Strathclyde,
Glasgow, UK
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First published 1990
© Butterworth & Co. (Publishers) Ltd, 1990
British Library Cataloguing in Publication Data
Routes of drug administration.
1. Medicine. Drug therapy
I. Florence, A. T. (Alexander Taylor) II. Salole, E.G.
(Eugene G) III. Series
615.6
ISBN 0-7236-0922-5
Library of Congress Cataloging-in-Publication Data
Routes of drug administration/edited by A. T. Florence
and E.G. Salole.
p. cm.—(Topics in pharmacy; v. 2)
Includes bibliographical references.
ISBN 0-7236-0922-5
1. Drugs—Administration. I. Florence, A. T.
(Alexander Taylor) II. Salole, E. G. III. Series.
[DNLM: 1. Drug Administration Routes.
QV 785 R869]
RM147.R68 1990
615'.6—dc20
Composition by Genesis Typesetting, Laser Quay, Rochester, Kent
Printed and bound in England by Page Bros. Ltd, Norwich, Norfolk
Series preface
There is, in our view, an important need to draw the attention of
both students and practitioners concerned with drug therapy to
recent and continuing developments in the pharmaceutical
sciences. The purpose of the Topics in Pharmacy series is to fulfil
this need by providing up-to-date, concise, readable accounts of
current aspects of pharmacy - with particular emphasis on those
aspects of the pharmaceutical sciences related to clinical
practice. In this endeavour we have been fortunate in securing
the collaboration of academics and practitioners recognized as
experts in the subjects of their contributions.
Each volume in the series has a theme, and each constituent
chapter provides a concise account of a particular area; the
accounts are intended to be introductions to a topic rather than
comprehensive and complete reviews, and hence, wherever
possible, each chapter is appended with a short bibliography for
further study.
The series is aimed at a readership comprising senior
undergraduate and postgraduate students in pharmacy, medi­
cine, nursing and allied health sciences, and practitioners in
these fields. However, it is our hope that the series will also be
generally useful to other professionals concerned with the
preparation and administration of medicines and the monitor­
ing of drug therapy.
Alexander T. Florence, London
Eugene G. Salole, Glasgow
Preface
Oral administration, the commonest and most convenient route
for delivery of drugs to the systemic circulation, is not always
the most suitable, for example in the elderly or the seriously ill.
Indeed, the oral route may not be an option for systemic action
of a range of drugs which are poorly absorbed from the
gastrointestinal tract, through inappropriate intrinsic physical
properties, degradation or metabolism. This volume, the second
in the Topics in Pharmacy series, describes a number of parenteral
routes of administration, some of which, such as the transder­
mal route, are increasingly finding favour as viable alternatives
to the enterai route. Others such as the nasal and buccal routes
will possibly find a place in therapy with a more limited group of
drugs.
The theme of Volume 1 of this series, the interaction of
formulations with the biological milieu, is continued in this
volume, as individual chapters review the anatomy and
physiology of administration sites, the formulation and design
of delivery systems and other relevant aspects of biopharma-
ceutics. Dosage form behaviour in vivo has to be taken into
account in the design of the delivery system. The success or
failure of a system can depend on the anatomy of the route and
the tailoring of the formulation to it. Nowhere is this better
illustrated than in pulmonary delivery. This route and the nasal,
buccal and transdermal routes of administration for systemic
delivery are considered in this volume, as are a number of
systems for more localized therapy with antibiotics.
We are indebted to Professor Lawrence Danziger, Dr Stephen
Farr, Professor Ian Kellaway, Dr Philip Lamey, Dr Michael
Lewis, Dr Graham Parr, Dr Alan Rogerson, Professor Jill
Shwed, Dr Glyn Taylor and Dr Kenneth Walters for their
sustained interest and contributions to this book.
Alexander T. Florence, London
Eugene G. Salole, Glasgow
vi
Contributors
L. H. Danziger, PharmD
Assistant Professor of Pharmacy Practice, The University of
Illinois at Chicago, USA
S. J. Farr, BSc, PhD, MRPharmS
Lecturer in Pharmaceutics, Welsh School of Pharmacy,
University of Wales College of Cardiff, Cardiff, UK
I. W. Kellaway, BPharm, PhD, MRPharmS
Professor of Pharmaceutics, Welsh School of Pharmacy,
University of Wales College of Cardiff, Cardiff, UK
P.-J. Lamey, BSc, BDS, MBChB, DDS, FDS
Senior Lecturer and Honorary Consultant in Oral Medicine &
Pathology, University of Glasgow, Glasgow, UK; Visiting
Professor of Stomatology, Baylor College of Dentistry, Dallas,
Texas, USA
M. A. O. Lewis, BDS, PhD, FDS
Lecturer in Oral Medicine and Pathology, University of
Glasgow, Glasgow, UK
G. D. Parr, BSc, PhD, MRPharmS
Group Head, Pharmaceutical Development, Reckitt & Colman
Products Ltd, Hull, UK
A. Rogerson, BSc, PhD, MRPharmS
Senior Section Manager, Prescription Product Development,
Reckitt & Colman Products Ltd, Hull, UK
J. A. Shwed, PharmD
Assistant Professor of Hospital Pharmacy Practice and
Administration, Medical University of South Carolina,
Charleston, USA
vii
viii Contributors
G. Taylor, BSc, PhD, MRPharmS
Lecturer in Pharmaceutics, Welsh School of Pharmacy,
University of Wales College of Cardiff, Cardiff, UK
K. A. Walters, PhD
Director of Research & Development, Pharmaserve Ltd,
Swinton, Manchester, UK
1
Nasal drug delivery
A. Roger son and G. D. Parr
Introduction
In most mammals the major function of the nose is as an
olfactory organ, and sense of smell has a vital role in activities as
diverse as hunting, and recognizing young. In man, although its
function is no longer vital to survival, the importance of the nose
should not be underestimated: in the seventeenth century Blaise
Pascal noted that 'if Cleopatra's nose had been shorter, the
whole history of the world would have been different'!
In its simplest form the nose is a passage through which air
must pass en route to the lungs, and thus the modification of
inspired air is probably its most important function in man. The
nose consists of three distinguishable regions (Figures 1.1 and
1.2). The nostrils act to gather and direct air. Behind the nostrils
lies the region which contains the convoluted turbinâtes and the
nasal epithelium. This region leads into the nasopharynx, where
the septum (which divides the nasal cavity into two halves) ends
and the cavity becomes one. From the nostrils to the
nasopharynx is generally a distance of c. 12-15 cm. When air is
inspired it travels in an approximately parabolic pattern from
the nostrils, upwards through the middle meatus, generally
bypassing the turbinâtes, then downwards again through the
nasopharynx (Figure 1.1). To pass into the nasal cavity, air must
first be inspired with sufficient linear velocity to pass through
the constriction of the nasal valve just beyond the nostrils.
Within the central region of the nasal cavity lie the ciliated
nasal epithelial cells. This region presents a barrier to the
absorption of drugs and contaminants that is relatively thin (and
unkeratinized, despite its continuity with the exterior) and well
perfused by nasal blood vessels. However, any drug substance
applied nasally would rarely come into prolonged intimate
contact with the epithelial cell surface owing to the presence of
mucus glands and goblet cells (Figure 1.3). Mucus is a
glycoprotein which is stored within goblet cells in its dehy­
drated form (containing c. 5% water), and is then hydrated as it
1
Figure 1.1 A side view of the upper respiratory tract. In the diagram, the
left-hand dashed line (just behind the nostrils) indicates the region of the nasal
valve; the intermediate dashed line indicates the approximate region of the
ciliated epithelial mucosa, which ends near the termination of the nasal septum
at the pharynx (indicated by the right-hand dashed line)
Figure 1.2 A frontal view of the nasal tract. The upper olfactory region (stippled
area) is generally free from inspired air. The clear areas either side of the central
nasal septum indicate the zone which is lined with absorptive epithelial cells and
most accessible to inspired air
Nasal drug delivery 3
Mucus
Figure 1.3 Schematic representation of ciliated epithelium overlaid with
discontinuous mucus and periciliary fluid. The cilia beat in periciliary fluid, with
a velocity gradient which is greatest at their apex
is released, swelling rapidly to form a layer (which may or may
not be continuous) on top of the ciliated epithelial cells. Thus,
mucus, which contains 95% water when fully hydra ted, is
responsible for the protection of the nasal epithelium, as it
normally prevents intimate contact of epithelial cells with
inspired material. The upper layers of mucus are propelled by
the tips of the beating cUia, so that any airborne contaminants
that may become associated with the periciliary fluid are forced
backwards into the nasopharynx and swallowed. Clearance
from the nasal cavity by means of ciliary expulsion proceeds at a
rate of c. 5-6mm/min. However, if contaminants penetrate the
mucus layer, or if mucus is absent in certain regions, then it
becomes almost impossible for the cilia to clear material from the
nasal cavity. The degree of continuity of the mucus layer within
the nasal cavity is not known, although particles appear to be
transported at a relatively uniform rate irrespective of their size,
density or composition. In addition, the viscosity of mucus is
believed not to affect this expulsion of material, and poor
transport is probably a consequence of inadequate cilia density,
poor beating coordination or alterations in the composition of
mucus [1].
It is impossible to avoid inspiration of contaminating particles.
The atmosphere contains materials that range from metallur­
gical dusts and fumes (some particles of which may be c. 1 nm in
diameter), tobacco smoke, bacteria and viruses (0.1-10 μπι) to
dusts and sand (^ 1mm diameter). Thus, many disorders,
which may include both local irritation and inflammation (e.g.
4 Routes of drug administration
allergic rhinitis), and systemic bacterial and viral infections, are
mediated by nasal inspiration of atmospheric contaminants.
Nasally administered dosage forms generally deliver most of
the drug to the ciliated region and, consequently, residence time
is unlikely to be longer than a few minutes. The expulsion of
drug by the cilia may be reduced (at least to some extent) by
utilizing formulations that contain mucoadhesive materials (e.g.
polyacrylic acid). These attach themselves to the mucus layer
allowing a relatively long and intimate contact with the
epithelial cell surface. Generally, pharmaceutical nasal dosage
forms do not rely on adhesion to the mucus layer.
For a given aerosol the most important criteria in determining
the site of deposition are particle diameter and size distribution,
and the velocity of the aerosol particles [2]. The three most
common mechanisms of deposition are shown in Figure 1.4.
(a) (b)
(0
Figure 1.4 Schematic representation of the different mechanisms for particle
deposition within the nasal cavity: a, gravity; b, inertial impaction; c, Brownian
movement
Inspired particles are prone to the downward pull of gravity:
those that are particularly large and dense do not penetrate far
into the nasal cavity. Impaction is most likely to take place when
an airstream carrying an aerosol particle rapidly changes
direction: therefore, because of the shape of the nasal cavity, it is
unlikely that a large number of particles will be deposited in the
deeper regions. Other criteria, such as random diffusion and
electrical effects, are mainly of only theoretical interest.
The presence of the nasal valve, and the sharp bend in the
pathway taken by inspired air just beyond it, are responsible for
the deposition of many aerosol particles within the anterior