title: Comparative studies on physicochemical stability of cyclosporine A-loaded amorphous solid dispersions.
abstract: The present study aimed to evaluate the physical stability on amorphous solid dispersion (SD) of cyclosporine A (CsA) employing hydroxypropyl cellulose (HPC). SD formulations (5-30% CsA) of CsA such wet-milled SD (WM/SD) and freeze-dried SD (FD/SD) were prepared, and both SD formulations were stored at 40 °C/75% relative humidity for 8 weeks. Transitions in morphology, dissolution behavior, crystallinity and thermal behavior of CsA were evaluated. There was at least 84-fold improvement in initial dissolution rate of SD formulations compared with that of amorphous CsA powder, although their dissolution rate was gradually decreased under accelerated conditions. In particular, aged FD/SD with a drug load of 30% exhibited highly limited dissolution as evidenced by 40% reduction of solubility after 8 weeks of storage. In contrast, aged WM/SD exhibited less reduction in dissolution rate compared with FD/SD. No significant changes were seen in crystallinity and thermal behavior after aging of SD formulations for 8 weeks; however, electron microscopic observations revealed aggregation of drug molecules/particles in the aged FD/SD, possibly leading to the reduced dissolution. From these findings, stability on CsA-loaded SD might be variable depending on the preparation methodology, and the wet-milling approach could be a viable option for preparing efficacious SD formulations with improved stability.
authors.affiliation: Department of Pharmacokinetics and Pharmacodynamics and Global Center of Excellence (COE) Program, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Sato
authors.affiliation: Department of Pharmacokinetics and Pharmacodynamics and Global Center of Excellence (COE) Program, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan.
authors.forename: Yohei
authors.initials: Y
authors.lastname: Kawabata
authors.affiliation: Department of Pharmaceutical Physicochemistry, Faculty of Pharmaceutical Sciences, Setsunan University, 45-1 Nagaotoge-cho, Hirakata, Osaka 573-0101, Japan.
authors.forename: Kayo
authors.initials: K
authors.lastname: Yuminoki
authors.affiliation: Department of Pharmaceutical Physicochemistry, Faculty of Pharmaceutical Sciences, Setsunan University, 45-1 Nagaotoge-cho, Hirakata, Osaka 573-0101, Japan.
authors.forename: Naofumi
authors.initials: N
authors.lastname: Hashimoto
authors.affiliation: Department of Pharmaceutical Physical Chemistry, College of Pharmaceutical Sciences, Matsuyama University, 4-2 Bunkyo, Matsuyama, Ehime 790-8578, Japan.
authors.forename: Yukinori
authors.initials: Y
authors.lastname: Yamauchi
authors.affiliation: Department of Pharmacokinetics and Pharmacodynamics and Global Center of Excellence (COE) Program, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan.
authors.forename: Kumiko
authors.initials: K
authors.lastname: Ogawa
authors.affiliation: Peptide Business Development Department, ILS Inc., 1-2-1 Kubogaoka, Moriya, Ibaraki 422-8526, Japan; American Peptide Company, 777 East Evelyn Ave., Sunnyvale, CA 94086, USA.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Mizumoto
authors.affiliation: Department of Pharmacokinetics and Pharmacodynamics and Global Center of Excellence (COE) Program, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan.
authors.forename: Shizuo
authors.initials: S
authors.lastname: Yamada
authors.affiliation: Department of Pharmacokinetics and Pharmacodynamics and Global Center of Excellence (COE) Program, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan. Electronic address: onoue@u-shizuoka-ken.ac.jp.
authors.forename: Satomi
authors.initials: S
authors.lastname: Onoue
mesh_terms: D002152:Calorimetry, Differential Scanning; D002482:Cellulose / Q000031:analogs & derivatives / Q000737:chemistry; D002626:Chemistry, Pharmaceutical; D003460:Crystallization; D016572:Cyclosporine / Q000737:chemistry*; D004339:Drug Compounding; D004355:Drug Stability; D004356:Drug Storage; D007700:Kinetics; D008855:Microscopy, Electron, Scanning; D046529:Microscopy, Electron, Transmission; D033362:Powder Diffraction; D011208:Powders; D012995:Solubility; D013499:Surface Properties; D013678:Technology, Pharmaceutical / Q000379:methods; D014961:X-Ray Diffraction
chemical_list: D011208:Powders; D016572:Cyclosporine; D002482:Cellulose; C008079:hydroxypropylcellulose