Assessing the need for dissolution testing for inhaled drugs
For solid oral dosage forms, such as tablets and capsules, dissolution testing is standardised and routine. The dissolution
profile of a product guides formulation and development, and is a widelyused QC tool. Dissolution data may also be used to
support claims of parity in a generic product and/or to demonstrate equivalence following a formulation change since it is
sufficiently sensitive to identify outofspecification manufactured batches.
With orally inhaled products (OIPs), the efficiency of drug delivery is linked with the extent of deposition in the respiratory
tract. A particle size of less than 5 µm is usually regarded as optimal for penetration to the deep lung, so the focus is
to develop device/formulation combinations that deliver a high proportion of the dose in this size range: a high fine particle
dose (FPD).1
As with solid dosage forms, the therapeutic effect of an inhaled powder is realised via dissolution and subsequent absorption. Powders delivered to the lung are, of necessity, extremely fine, so there may be an
assumption that dissolution rates are rapid enough to have little impact on the overall process of drug delivery. Within a
recent USP Pharmacopeial Forum review,2 however, it was recognised that dissolution testing may expand our understanding of inhaled drug delivery and support the
development of new OIPs. This view is reinforced by industrial interest in the topic, as exemplified by recent work presented
by GlaxoSmithKline contrasting the dissolution profile of a longacting beta agonist with that of an inhaled corticosteroid.3 If inhalation technologies follow the same development trajectory as tablets, there is no reason why the modification of
particle properties, such as size, shape or crystal habit, to control in vivo release rate should not become routine. Formulations based on liposome, micelle and microsphere technologies also provide
for more closely tailored delivery profiles.4,5 The trend towards the pulmonary route for the delivery of systemic drugs strengthens the impetus for refining OIP performance
in this way.
Understanding the requirements for OIP dissolution testing
From a practical viewpoint, in vitro dissolution testing for inhalable products should be able to distinguish between samples in a way that replicates trends
found
in vivo
. This suggests that test conditions should reflect the pulmonary environment. Perfectly designed for absorption, the lungs
are not ideal from the point of view of dissolution, with fluid levels in the region of 10 to 20 mL/100 m2 of surface. Such small amounts of liquid are likely to be stagnant, inhibiting dissolution. Also, the exact composition
of the aqueous fluids and surfactants lining the respiratory tract is not accurately known,6 which complicates the selection of a test medium.
Equally importantly, testing must also consider the delivery characteristics of OIPs. Just a portion of the emitted dose,
the FPD, enters the lung so dissolution testing of the whole dose is inappropriate. A better aim is to access the dissolution
profile of only those particles that will deposit in the lung.
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