Metered Dose Inhalers and Nebulized Drugs

In general, and with a few rare exceptions (see below), the inhaled route of administration is the most difficult that is commonly encountered. Metered dose inhalers and nebulizers are considered together here because they have many features in common. These formulations, in both cases, are administered as aerosols of drug solution.

It is customary, in textbooks for a general audience, to insert at this point a graph that relates aerosol particle size to the various levels of the airway where drugs can impact. Particles > 10 pm are stated to be commonly impacted in the pharynx; < 5 pm particles are assumed to be ideal for alveolar delivery, and < 0.05 pm particles are said not to impact at all, being liable to be exhaled. This is an oversimplification. Particle deposition is dependent on a large number of other factors, attested to by a vast literature that has accumulated over at least the last 25 years, straddling the border with the disciplines of pulmonol-ogy and industrial hygiene. Other factors governing particle deposition (and example studies) include:

• Mucociliary action (Lippmann et al 1980)

• Exercise and minute ventilation (Bennett et al 1985)

• Mucous production and ability to expectorate (Agnew et al 1985)

• Apnoeic pause at the end of inhalation (Legath et al 1988)

• Whether a patient is actually having an asthma attack (Patel et al 1990)

• Breathing pattern, airway calibre, spacers and reservoirs (Bennett 1991)

• The physicochemical properties of the drug(s) (Zanen et al 1996)

• Lung morphometry (Hofmann 1996)

• Sampling techniques, on which exposure calculations are based (Cherrie and Aitken 1999).

The truth is that it is practically impossible to measure the lung deposition of inhaled drugs in man. Furthermore, in vitro studies use apparati that do not model the anatomy of the human respiratory tree, let alone the diseased respiratory tree. The British Association for Lung Research have recognized this complexity and issued a consensus statement (Snell and Ganderton 1999) which recommends, at a minimum, a five-stage collection apparatus, examination of a range of particle sizes (0.05 — 5 pm), a range of flow rates and patterns to mimic the various physiological states, the development of an apparatus modeled on the shape of the human pharynx, the concomitant use of swallowed activated charcoal in clinical studies to minimize absorption by swallowing drug impacting on the oropharynx, regional lung assessments in three dimensions, and further development of useful statistics to describe such findings.

The metered dose inhaler has been in use for about 50 years and doubtless forms the mainstay for the treatment of asthma, as well as for patients with chronic bronchitis with a reversible component. Great technical challenge has been experienced in the last few years, due to the need to change their propellants into non-fluorohydrocarbon materials, as part of the global effort to protect the atmospheric ozone layer. The contribution of metered dose inhalers to this problem, in comparison to vapour escaping from refrigerators and car air conditioners, must have been negligible. Nonetheless, indirectly, these huge costs are now being borne by healthcare systems worldwide. The clinical studies had to rely on efficacy parameters because of the inability to quantitate lung deposition and the general aim of avoiding systemic drug absorption.

A wide variety of nebulizers are now available. They all have their own physicochemical properties. In the absence of the ability to quantitate lung deposition, the Food and Drug Agency (FDA) has now said that it will approve only combinations of new drugs with specified nebulizers; labeling for adornase is the first to exhibit this change in policy. This requires that the clinical development plan be implemented, as early as possible, with the nebulizer that is intended to be marketed.

Inhalational toxicology is generally required to support inhalational clinical trials and product approvals. This highly specialized field requires the validation of the nebulizing system for each drug and species separately. The scaling from animals to man in the selection of initial doses is something of an imponderable, given the complexities in measuring lung deposition described above.

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