A range of options exists to increase or decrease the fraction of dose deposited in different parts of the respiratory tract and to control the concentration-time profiles of the drug at these sites. New techniques are being developed that enable noninvasive monitoring of the drug [12] or monitoring of a labeled marker compound [16-18,39-41,87] in the respiratory tract in vivo so that the degree of achievement of spatial and temporal selectivity can be investigated. Better spatial resolution is now possible with the greater availability of tomographic technique, such as single-photon emission computerized tomography (SPECT) and positron emission tomography (PET) [154,155].

The primary objective for the development of targeting strategies is to improve the safety and efficacy of therapy. This requires intrasubject reproducibility of delivery within the margins of therapeutic and toxic responses to the drug. In the first instance, the aerosol generators should give adequately reproducible output in terms of drug mass and its aerodynamic size distribution. It is now possible to incorporate features into the aerosol delivery systems that minimize the dependence on patient factors. In particular, the management of the patient's inspiratory flow rate and the volume of air inhaled at the time of actuation of the aerosol delivery reduces the variability of the dose to the lung and its distribution [98]. In aerosol administration to subjects with poor respiratory function, the most frequent dominant source of variability is the state of the patient's airways. For patients with reversible obstructive airway disease, this may be controlled with appropriate therapy. Interestingly, the greatest advances in pulmonary targeting have been obtained in recent years with "deep lung" delivery. Complete pulmonary absorption of small molecules in human volunteer studies has been found with these specially developed aerosol delivery systems, resulting in blood levels that are practically indistinguishable in terms of the pharmacokinetics and variability from intravenous administration [146].

Systems producing fine-particle insulin aerosols have been tested extensively in humans [156]. A clear dose response of glucose reduction and reproducibilities comparable to subcutaneous injections were obtained with an inhaler that combines almost monodisperse insulin particles (MMAD ~ 2-3 mm)

with electronic control of inspiratory flow rate and delivery of the aerosol bolus early in the inspiration, followed by a chase volume ("deep breath") [157].

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