Introduction

A number of elegant devices have been developed in recent years that can deliver an aerosol to the deep lungs with high efficiency, but what can be influenced after deposition has occurred? Presently, there is little flexibility in aerosol formulations that will allow for manipulation of in vivo performance, and there remains an inadequate body of literature discussing the concept [1]. Despite this situation there is certainly more than ample justification for pursuing the topic, as specified in Table 1.

In a previous incarnation of this chapter, emphasis was placed on the feasibility of modulating pulmonary drug delivery. This version looks beyond feasibility and critically examines several formulation strategies that have been pursued since the early 1990s. Before proceeding, however, it is beneficial to mention topics that will be neglected. Clearance mechanisms and kinetics will not be mentioned, for they were covered at length in the first edition. The mathematics certainly hasn't changed, and, although our understanding of lung

Table 1 Reasons for Modulating Release of Drug in the Lungs

Optimization of drug combinations

Life cycle management of existing therapeutics

Limiting acute toxicity caused by the actions of the drug or in response to it Minimizing toxicity arising from high initial levels of drug in the circulation Limiting irritation due to the chemical action of a specific drug Reducing the clearance rate of a drug of short pulmonary half-life Taste-masking of drug deposited in the oral cavity Improved targeting of drug load to macrophages

Tendency of some drugs to intrinsically exhibit extended "release" due to limited solubility

Improving in vivo stability due to chemical or biological degradation mechanisms Influencing the potential for an immune response to the drug or components biology has evolved, no earth-shattering developments in the way we analyze drug clearance have emerged. There is also the emergence of gene therapy, and many studies have aerosolized lipid-DNA complexes with the objective of sustaining the expression and "release" of protein therapeutics in the lungs. However, gene therapy is hardly a "classical" controlled delivery system and is beyond the scope of this chapter. Finally, the use of absorption enhancers to promote uptake will also be avoided because the vast majority, if not all, appear to exert their action by causing varying degrees of damage to the surrounding tissue.

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