title: Improved dissolution and pharmacokinetic behavior of cyclosporine A using high-energy amorphous solid dispersion approach.
abstract: The aim of the present investigation is to develop solid dispersion (SD) formulations of cyclosporine A (CsA) for improving the oral bioavailability of CsA. Amorphous SDs of CsA with eight hydrophilic polymers were prepared with wet-mill employing zirconia beads. The physicochemical properties were characterized with a focus on morphology, crystallinity, thermal behavior, dissolution, and interaction of CsA with co-existing polymer. Although CsA molecules were found to be amorphous in all wet-milled formulations, some SD formulations failed to improve the dissolution. Of all CsA formulations, SD using polymer with HPC(SSL) exhibited the largest improvement in dissolution behavior. Pharmacokinetic profiling of orally dosed CsA in rats was carried out using UPLC/ESI-MS. After the oral administration of HPC(SSL)-based SD, enhanced CsA exposure was observed with increases in C(max) and AUC of ca. 5-fold, and the variation in AUC was ca. 40% less than that of amorphous CsA. Infrared spectroscopic studies suggested an interaction between CsA and HPC(SSL), as evidenced by the conformational transition of CsA. From the improved dissolution and pharmacokinetic data, the amorphous SD approach using wet-milling technology should lead to consistent and enhanced bioavailability, leading to an improved therapeutic potential of CsA.
authors: Department of Pharmacokinetics and Pharmacodynamics, School of Pharmaceutical Sciences, University of Shizuoka, Suruga-ku, Shizuoka, Japan. onoue@u-shizuoka-ken.ac.jp
authors: Satomi
authors: S
authors: Onoue
authors: Hideyuki
authors: H
authors: Sato
authors: Kumiko
authors: K
authors: Ogawa
authors: Yohei
authors: Y
authors: Kawabata
authors: Takahiro
authors: T
authors: Mizumoto
authors: Kayo
authors: K
authors: Yuminoki
authors: Naofumi
authors: N
authors: Hashimoto
authors: Shizuo
authors: S
authors: Yamada
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D055598:Chemical Phenomena; D002626:Chemistry, Pharmaceutical; D002851:Chromatography, High Pressure Liquid; D016572:Cyclosporine / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D004337:Drug Carriers / Q000737:chemistry*; D004339:Drug Compounding / Q000379:methods*; D057927:Hydrophobic and Hydrophilic Interactions; D008297:Male; D008855:Microscopy, Electron, Scanning; D011108:Polymers / Q000737:chemistry*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility; D021241:Spectrometry, Mass, Electrospray Ionization; D017550:Spectroscopy, Fourier Transform Infrared; D013499:Surface Properties
chemical_list: D004337:Drug Carriers; D011108:Polymers; D016572:Cyclosporine