Membrane-controlled transdermal therapeutic system containing clonazepam and anticonvulsant activity after its application.

Abstract

A trial transdermal dosage form designed to sustain a suitable plasma concentration of clonazepam (CZP) was produced using a porous membrane (Hipore 2100 or 4050) and applied to rabbits and rats for pharmacokinetic and pharmacodynamic evaluations. The release rate constants for the drug through the porous membranes were significantly smaller than that without any membrane. The transdermal system (Hipore 4050 system, ointment 0.25 g, 2.25 cm2) provided a well sustained plasma concentration of CZP and the therapeutic plasma concentration range was maintained for about 26 h. When the Hipore 4050 system with an increased amount of ointment and enlarged absorption area (0.5 g, 4.0 cm2) was applied, the therapeutic range was sustained for about 40 h, and slightly higher plasma levels over the whole application period and much higher bioavailability (37%) were obtained compared with those after the 2.25 cm2-Hipore 4050 system. The transdermal system exerted an excellent anticonvulsant activity in rats, with the best (3+ or 4+) protective score. The plasma concentrations of CZP when the activity was estimated were in the therapeutic range. Thus, the transdermal system has the potential to be an efficient drug delivery system.