In vivo enhancement of transdermal absorption of ketotifen by supersaturation generated by amorphous form of the drug

The enhancing effect of supersaturation generated by amorphous ketotifen in silicone pressure-sensitive adhesive matrices (PSA) on the transdermal absorption was evaluated in vivo using hairless rats, and it was compared with the increase of drug amount in skin tissues. The duration of the enhancing effect was also investigated in relation to the time how long supersaturation was maintained in PSA. PSA containing crystalline ketotifen (PSA-Crystalline) and that containing amorphous ketotifen (PSA-Amorphous) were prepared by the solvent casting method using n-hexane and dichloromethane, respectively. In vivo transdermal absorption was evaluated by measuring the amount of ketotifen in PSAs, the stratum corneum, and viable skin tissues after administration of PSAs on abdominal sites of hairless rats. The amount of ketotifen absorbed into the systemic circulation was calculated by subtracting the drug amount in whole skin tissues from the amount of the drug released from PSAs, then it was monitored for up to 23 h. In both types of PSA, a constant absorption rate was maintained for up to 23 h after 7-h lag time. The enhancement factor of PSA-Amorphous against PSA-Crystalline was approximately 7, which was in good agreement with the difference of drug amount in viable skin tissues. Time course of the drug amount in PSA-Amorphous suggested that the supersaturated level was gradually decreased after 10 h, but the decline of the driving force from PSAs was supplemented by the drug release from the skin depot resulting in the constant absorption rate up to 23 h. These results suggest the usefulness of amorphous ketotifen to obtain enhanced transdermal absorption.