Biopharmaceutics of 13-cis-retinoic acid (isotretinoin) formulated with modified β-cyclodextrins

Abstract

13-cis-Retinoic acid (13-cis-RA), also known as isotretinoin, is commonly used in the management of severe acne. Its clinical efficacy in oncology has also been documented. As a vitamin A derivative, it is not soluble in water. This solubility barrier not only affects its oral absorption but also makes parenteral delivery difficult. Recently, water-soluble formulations of 13-cis-RA have been attempted with 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) and randomly methylated-β-cyclodextrin (RM-β-CD). In this study, the pharmacokinetic profiles of these two formulations were assessed in Sprague-Dawley rats after single intravenous or oral administration. We found that 13-cis-RA was eliminated from the body through a dose-independent process after intravenous injection of either sodium salt or the HP-β-CD formulation within the tested dosage range (2.0-7.5 mg/kg). Furthermore, HP-β-CD did not alter the kinetic profile of 13-cis-RA after intravenous administration in comparison with 13-cis-RA sodium salt. We also found that RM-β-CD dramatically enhanced the oral absorption of 13-cis-RA. At 10.0 mg/kg, the bioavailability of 13-cis-RA formulated with RM-β-CD was about three-fold higher than that of the control (13-cis-RA suspended in 0.5% carboxymethylcellulose (CMC)). Similarly, the oral absorption of 13-cis-RA was not saturated within our tested range (2.5-10.0 mg/kg) and the bioavailability remained unchanged. These results demonstrated that HP-β-CD and RM-β-CD were suitable excipients for the delivery of 13-cis-RA. © 2007 Elsevier B.V. All rights reserved.