TRANSITION FROM TEMPORAL TO BIOLOGICAL-CONTROL IN THE CLINICAL DEVELOPMENT OF CONTROLLED DRUG-DELIVERY SYSTEMS

Controlled release formulations for medications were first designed to provide temporal control over the delivery of the drug substance. The se dosage forms allowed less frequent dosing of rapidly metabolized or excreted medications, improving therapeutic use of the drug. The clin ical evaluation of controlled release formulations requires an underst anding of not only the drug substance but also the delivery system. Th is has added new objectives and requirements in the development of the se products. Three examples of controlled delivery systems which have been or are under development illustrate key concepts which must be in corporated into the drug development planning for controlled delivery systems. A greater appreciation for the circadian changes in biologica l processes such as absorption and metabolism has arisen with the deve lopment of oral controlled release theophylline products. Biological r hythms must be accounted for in the clinical evaluations of new produc ts. In vitro models of drug input also represent an important tool for evaluation and refinement of controlled drug delivery systems. This h as been shown to be a valuable tool in the development of a transderma l system for testosterone. Finally, modification of physiological proc esses, such as distribution and uptake by the reticuloendothelial syst em, has allowed improved therapeutic use of amphotericin B in a lipid complex form. A collaborative evaluation of clinical trial design, ana lysis, and interpretation must be undertaken by clinicians and pharmac eutical scientists to achieve optimal therapeutic use of new controlle d delivery systems.