title: Biopharmaceutics of 13-cis-retinoic acid (isotretinoin) formulated with modified beta-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-beta-cyclodextrin (HP-beta-CD) and randomly methylated-beta-cyclodextrin (RM-beta-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-beta-CD formulation within the tested dosage range (2.0-7.5mg/kg). Furthermore, HP-beta-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-beta-CD dramatically enhanced the oral absorption of 13-cis-RA. At 10.0mg/kg, the bioavailability of 13-cis-RA formulated with RM-beta-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 (2.5-10.0mg/kg) and the bioavailability remained unchanged. These results demonstrated that HP-beta-CD and RM-beta-CD were suitable excipients for the delivery of 13-cis-RA.
authors.affiliation: Department of Pharmacy, Faculty of Science, National University of Singapore, 10 Kent Ridge Crescent, Singapore 119260, Singapore.
authors.forename: Hai-Shu
authors.initials: HS
authors.lastname: Lin
authors.forename: Wendy Wen Yi
authors.initials: WW
authors.lastname: Leong
authors.forename: Jie An
authors.initials: JA
authors.lastname: Yang
authors.forename: Pei
authors.initials: P
authors.lastname: Lee
authors.forename: Sui Yung
authors.initials: SY
authors.lastname: Chan
authors.forename: Paul C
authors.initials: PC
authors.lastname: Ho
mesh_terms: D000073738:2-Hydroxypropyl-beta-cyclodextrin; D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D002266:Carboxymethylcellulose Sodium / Q000737:chemistry; D002626:Chemistry, Pharmaceutical; D003879:Dermatologic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D004337:Drug Carriers; D004339:Drug Compounding; D005079:Excipients / Q000737:chemistry*; D007275:Injections, Intravenous; D015474:Isotretinoin / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D008297:Male; D008745:Methylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility; D014867:Water / Q000737:chemistry; D047392:beta-Cyclodextrins / Q000737:chemistry*
chemical_list: D003879:Dermatologic Agents; D004337:Drug Carriers; D005079:Excipients; D047392:beta-Cyclodextrins; D014867:Water; D000073738:2-Hydroxypropyl-beta-cyclodextrin; D015474:Isotretinoin; D002266:Carboxymethylcellulose Sodium