whether or not the patient is actually having an
asthma attack (Patelet al., 1990);
breathing pattern, airway calibre, device spacers
and reservoirs (Bennett, 1991);
the physicochemical properties of the drug(s)
(Zanenet al., 1996);
lung morphometry (Hoffmann, 1996);
sampling techniques on which exposure calcula-
tions are based (Cherrie and Aitken, 1999).
The reality is that it is impossible to measure
accurately the lung deposition of inhaled drugs in
humans.
Much vauntedin vitrostudies actually use appa-
ratuses that do not model well the anatomy of the
human respiratory tree, let alone one with disease.
The British Association for Lung Research has
recognized this complexity and issued a consensus
statement (Snell and Ganderton, 1998) which
recommends, at a minimum, a five-stage collection
apparatus, examination of a range of particle sizes
0.05–5mm, a range of flow rates and patterns to
mimic the various physiological states, the devel-
opmentof anapparatusmodeledon theshapeofthe
human pharynx, regional lung assessments in three
dimensions, the concomitant use of swallowed
activated charcoal in to minimize systemic absorp-
tion of drug that was swallowed after affecting the
oropharynx and further development of better sta-
tistics for analyzing the data.
The metered-dose inhaler has been in use for
about 50 years and forms the mainstay for the
treatment of asthma, as well as chronic bronchitis
with a reversible component. Great technical chal-
lenge has been experienced in the last few years
due to the need to change excipients (propellants)
in metered-dose inhalers, so as to avoid non-fluor-
ohydrocarbon materials. In comparison with
domestic refrigerators, industrial refrigeration
plants and cattle-generated methane, this contribu-
tion to protecting the atmospheric ozone layer must
be negligible. Nonetheless, these huge drug re-
development costs are now being borne by health-
care systems worldwide. In this case, although a
bioequivalence approach has been taken when
changing the propellant, clinical studies have
mostly relied on efficacy parameters, again
because of the inability to quantitate lung deposi-
tion, while avoiding systemic drug absorption.
Inhaled insulin is studied on the basis of
both pharmacodynamic and pharmacokinetic
parameters.
A wide variety of nebulizers are now available.
They all have their own physicochemical proper-
ties. In the absence of the ability to quantitate lung
deposition, most modern labels specify the combi-
nation of a new drug with particular nebulizer
device (the labeling for alpha-dornase was the
first to exhibit this change in regulatory policy).
The corollary is that product development plans
should decide, as early as possible, which nebulizer
is intended for the marketplace, and that device
should be used in all inhalational toxicology stu-
dies and subsequent clinical trials.Intranasal formulations
The absorptive capacity of the nasal mucosa has
been known for centuries: nicotine (Victorians
using snuff) and cocaine (aboriginal peoples
since time immemorial) are the two historical
examples of systemic drug absorption via the
nose. The opposite pharmacokinetic aspiration is
illustrated by anti-allergy and decongestant drugs
which are now administered via the noses in the
developed world literally by the tonne: here, the
intent is to treat local symptoms and avoid signifi-
cant systemic exposure of drugs with varied phar-
macology such as alpha-adrenergic agonists,
antihistamines and corticosteroids. These products
also contain buffers and preservatives.
There is particular interest in the nasal mucosa
because it can provide systemic absorption of
drugs that otherwise must be administered by
injection. These are often polypeptide drugs. Cal-
citonin and vasopressin-like drugs (nonapeptides)
for diabetes insipidus in patients with panhypopi-
tuitarism are examples.
There is a specific guidance document from the
International Conference on Harmonization which
discusses the demonstration of bioequivalence for5.4 SPECIFIC FORMULATIONS 57