ABSTRACT
Most oral modified-or controlled-release drug delivery systems (DDS) are based on single unit or multiple unit reservoir-or matrix-type systems with constant-or variable drug-release rates. These dosage forms offer many advantages when compared to immediate-release delivery systems, such as
Nearly constant drug levels at the site of action Minimization of peak-trough fluctuations of the drug concentration Avoidance of undesirable side effects Reduced dose Reduced frequency of administration, and Improved patient compliance Many approaches to achieve controlled-release of drugs have been developed in
recent years. However, in a number of cases, a continuous drug release and consequently a nearly constant drug concentration at the targeted site of action is not optimal for the therapy. Many efforts have been made during recent years to optimize drug delivery (1). In this context, an approach of fluctuating drug levels may mimic physiological conditions in a better way. The dependence of several diseases and body function on circadian rhythms is well-known. A number of hormones, such as renin, aldosterone, or cortisol, show distinct daily fluctuations (Fig. 1) (3). The onset and extent of symptoms often vary with circadian rhythms with respect to diseases such as the following:
Angina pectoris Bronchial asthma Hypertension Myocardial infarction
Rheumatic disease Ulcer disease Chronopharmacological aspects have to be considered also for the treatment of
tumors (4,5). Blood flow to tumor tissue and cancer growth have a chronobiological behavior. Optimal circadian timing of 5-fluorouracil (5-FU)/leukovorin and oxyplatin can double the objective response frequency of this combination in patients with metastatic colo-rectal cancer (6). In addition, the toxicity of 5-FU can be reduced by chronomodulated therapy (7).
