Self-micellizing solid dispersion of cyclosporine A with improved dissolution and oral bioavailability.
The present study aimed to develop a self-micellizing solid dispersion (SMSD) of cyclosporine A (CsA) using an amphiphilic block copolymer, poly[MPC-co-BMA], to improve the biopharmaceutical properties of CsA. The cytotoxicity of poly[MPC-co-BMA] was assessed in rat intestinal IEC-6 cells, and the pMB was less cytotoxic than polysorbate 80, a non-ionic surfactant with a wide safety margin. SMSD/CsA was prepared using a wet-milling system, and its physicochemical properties were characterized in terms of morphology, crystallinity, dissolution, particle size distribution, and stability. The SMSD/CsA exhibited immediate formation of fine micelles with a mean diameter of ca. 180 nm when introduced into aqueous media. There was marked improvement in the dissolution behavior of the SMSD/CsA compared with amorphous CsA. Even after storage at 40°C/75% relative humidity, the dissolution behavior of aged SMSD/CsA seemed to be almost identical to that of its freshly prepared equivalent, and CsA in aged SMSD/CsA was still in amorphous form. After oral administration of SMSD/CsA (10 mg CsA/kg) in rats, enhanced CsA exposure was observed with increases of Cmax and BA by ca. 11- and 42-fold, respectively, compared with those of amorphous CsA. The poly[MPC-co-BMA]-based SMSD formulation system might be an efficacious dosage option for CsA to achieve improvements in oral bioavailability.
Department of Pharmacokinetics and Pharmacodynamics, School of Pharmaceutical Sciences, University of Shizuoka, 52-1, Yada, Suruga-ku, Shizuoka 422-8526, Japan. Electronic address: onoue@u-shizuoka-ken.ac.jp.
Satomi
S
Onoue
Department of Pharmacokinetics and Pharmacodynamics, School of Pharmaceutical Sciences, University of Shizuoka, 52-1, Yada, Suruga-ku, Shizuoka 422-8526, Japan.
Hiroki
H
Suzuki
Department of Pharmacokinetics and Pharmacodynamics, School of Pharmaceutical Sciences, University of Shizuoka, 52-1, Yada, Suruga-ku, Shizuoka 422-8526, Japan.
Yoshiki
Y
Kojo
Department of Pharmacokinetics and Pharmacodynamics, School of Pharmaceutical Sciences, University of Shizuoka, 52-1, Yada, Suruga-ku, Shizuoka 422-8526, Japan.
Saori
S
Matsunaga
Department of Pharmacokinetics and Pharmacodynamics, School of Pharmaceutical Sciences, University of Shizuoka, 52-1, Yada, Suruga-ku, Shizuoka 422-8526, Japan.
Hideyuki
H
Sato
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.
Takahiro
T
Mizumoto
Department of Pharmaceutical Physical Chemistry, Faculty of Pharmaceutical Sciences, Setsunan University, 45-1, Nagaotoge-cho, Hirakata, Osaka 573-0101, Japan.
Kayo
K
Yuminoki
Department of Pharmaceutical Physical Chemistry, Faculty of Pharmaceutical Sciences, Setsunan University, 45-1, Nagaotoge-cho, Hirakata, Osaka 573-0101, Japan.
Naofumi
N
Hashimoto
Department of Pharmacokinetics and Pharmacodynamics, School of Pharmaceutical Sciences, University of Shizuoka, 52-1, Yada, Suruga-ku, Shizuoka 422-8526, Japan.
Shizuo
S
Yamada
D000818:Animals; D001682:Biological Availability; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002626:Chemistry, Pharmaceutical; D016572:Cyclosporine / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics; D004355:Drug Stability; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics; D008297:Male; D008689:Methacrylates / Q000737:chemistry*; D008823:Micelles; D010767:Phosphorylcholine / Q000031:analogs & derivatives* / Q000737:chemistry; D017207:Rats, Sprague-Dawley; D012995:Solubility
D007166:Immunosuppressive Agents; D008689:Methacrylates; D008823:Micelles; D010767:Phosphorylcholine; C079200:poly(2-methacryloyloxyethyl phosphorylcholine-co-n-butyl methacrylate); D016572:Cyclosporine
Cyclosporine A; Dissolution; Self-micellization; Solid dispersion; Stability