Percutaneous absorption of acemetacin from a membrane controlled transdermal system and prediction of the disposition of the drug in rats.

To avoid development of a lesion on the small intestine by acemetacin (ACM) following oral administration of the drug, we developed a new device for its percutaneous application. The device for transdermal application of ACM consisted of a silicon O-ring, a backing of aluminum foil and adhesive tape, and rate-controlling membranes with three different pore sizes (HP-1100, 2100 and 4050). Two percent ACM gel ointment was contained in the device. In the in vitro release experiment, the ACM release from the device was limited by these membranes with release rate constants of 0.630 +/- 0.052, 0.289 +/- 0.012, 0.098 +/- 0.11 and 0.083 +/- 0.011 h-1 for no membrane, HP-4050, HP-2100 and HP-1100 membranes, respectively. In the in vitro penetration experiment, the ACM penetrating through the skin appeared in the reservoir cell without the metabolic conversion to indomethacin (IM). After the application of the ACM device with the HP-2100 rate-controlling membrane on the rat abdominal skin, ACM was not detected in the plasma but the therapeutic plasma concentration of IM could be maintained over a 54 h period. These results indicate that the device with a rate-controlling membrane may be useful for the percutaneous application of ACM as an anti-inflammatory drug and its clinical application. For the percutaneous absorption of ACM after application of the ACM devices, the values estimated by the proposed model which consisted of 6 compartments well fit to the data obtained from this in vivo experiment.(ABSTRACT TRUNCATED AT 250 WORDS)