Kinetic Aspects for Local and Systemic Delivery

Increasing the duration of action of inhaled drugs is an area of great interest for the short-acting substances, because, generally speaking, the less frequent the need for dosing, the better the patient's compliance. Therapeutic efficacy may be improved if the drug levels in the respiratory tract are relatively constant, as shown by the improved therapeutic effects achieved with a corticosteroid inhaled four times a day compared to two times a day [121].

The regional differences in the mucociliary clearance rate provide opportunities to increase the duration of residence of drugs in the respiratory tract by depositing the drug initially in the regions with the slow clearance rates [36,37]. This suggests that deposition in the peripheral regions is desirable. However, the very slow clearance component, presumably representing mainly the material deposited on the nonciliated parts of the peripheral lung, may never get transported to the more central parts, where the receptors could be located. Furthermore, the drug may disappear by absorption. The latter can be prevented by placing the drug in a carrier that either is absorbed slowly or is nonabsorbable. The release rate of the drug from the carrier is critical to achieve adequate levels of the free drug in the lung for therapy, because drug still present in its delivery system is usually incapable of causing the desired therapeutic effect [37]. The sustained-release effect may be achieved in a number of ways. Four methods have been described in the literature: (1) magnesium hydroxide precipitates as a model for sustained release [122], (2) entrapment of drugs in liposomes and other hydrophobic microcarriers [123131], (3) sparingly soluble drugs [25,132,133], and (4) the use of poorly soluble, porous carrier particles, with the view also to minimize the digestion of the drug-loaded material by phagocytosis [105].

Drug entrapment in liposomes has been most extensively investigated, and evidence has been presented both in experimental animals and in humans that the drug residence time in the lung can be substantially extended [123129,131].

To increase the residence times of drugs in the conducting airways served by the mucociliary escalator, mucoadhesive formulations were investigated [134]. This approach can be effective, but safety consequences of slowing down this natural clearance mechanism will need to be investigated.

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