title: Encapsulation of an antivasospastic drug, fasudil, into liposomes, and in vitro stability of the fasudil-loaded liposomes.
abstract: The objectives of this work were to develop a liposomal fasudil, an antivasospastic drug, as a possible means to deliver the encapsulated drug to the brain, and to characterize the stability of the liposomal formulation in vitro. Transmembrane electrochemical gradients of H+ or ammonium sulfate were created, and their effect on the uptake of fasudil into preformed hydrogenated soy phosphatidylcholine/cholesterol (HSPC/CHOL) liposomes were examined. Fasudil was successfully loaded into preformed liposomes in response to sulfate ion (SO4(2-)) and, in part, by H+. Encapsulation levels approaching 100% could be achieved up to a drug to lipid ratio of 0.364 (mol/mol). A stability study of the fasudil-loaded liposomes was performed by storage at 4 degrees C in 4-(2-hydroxyethyl)-1-piperazineethanesulphonic acid (HEPES)-buffer (pH 7.4) and by incubation in human cerebrospinal fluid (CSF) at 37 degrees C. The formulations were stable with respect to drug retention as well as size alteration, for the period studied. A leakage study clearly showed the sustained release properties of the fasudil-loaded liposomes in human CSF. We recently reported that the intrathecal administration of liposomal fasudil significantly decreased ischemia, with no obvious adverse effect in a rat model [Neurol. Med. Chir. 41 (2001) 109]. Taken together, efficient encapsulation of fasudil into preformed liposomes, their long-term stability at 4 degrees C and the sustained release characteristics in CSF indicate that fasudil-loaded liposomes could be potential candidates for further clinical evaluation.
authors.affiliation: Department of Pharmacokinetics and Biopharmaceutics, Faculty of Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, The University of Tokushima, 1-78-1 Sho-Machi, 770-8505, Tokushima, Japan. ishida@ph.tokushima-u.ac.jp
authors.forename: Tatsuhiro
authors.initials: T
authors.lastname: Ishida
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Takanashi
authors.forename: Hisako
authors.initials: H
authors.lastname: Doi
authors.forename: Isao
authors.initials: I
authors.lastname: Yamamoto
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kiwada
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D004355:Drug Stability; D006801:Humans; D008081:Liposomes; D014665:Vasodilator Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics
chemical_list: D008081:Liposomes; D014665:Vasodilator Agents; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; C049347:fasudil