Transition from temporal to biological control in the clinical development of controlled drug delivery systems

Abstract

Controlled release formulations for medications were first designed to provide temporal control over the delivery of the drug substance. These dosage forms allowed less frequent dosing of rapidly metabolized or excreted medications, improving therapeutic use of the drug. The clinical evaluation of controlled release formulations requires an understanding of not only the drug substance but also the delivery system. This has added new objectives and requirements in the development of these products. Three examples of controlled delivery systems which have been or are under development illustrate key concepts which must be incorporated into the drug development planning for controlled delivery systems. A greater appreciation for the circadian changes in biological processes such as absorption and metabolism has arisen with the development of oral controlled release theophylline products. Biological rhythms must be accounted for in the clinical evaluations of new products. In vitro models of drug input also represent an important tool for evaluation and refinement of controlled drug delivery systems. This has been shown to be a valuable tool in the development of a transdermal system for testosterone. Finally, modification of physiological processes, such as distribution and uptake by the reticuloendothelial system, has allowed improved therapeutic use of amphotericin B in a lipid complex form. A collaborative evaluation of clinical trial design, analysis, and interpretation must be undertaken by clinicians and pharmaceutical scientists to achieve optimal therapeutic use of new controlled delivery systems.