title: In vitro-in vivo correlation for wet-milled tablet of poorly water-soluble cilostazol.
abstract: The purpose of the present study was to investigate oral bioavailability of an immediate release tablet containing wet-milled crystals of a poorly water-soluble drug, cilostazol, and to establish in vitro-in vivo correlation. Sub-micron sized cilostazol (median diameter: 0.26 microm) was successfully prepared using a beads-mill in water in the presence of a hydrophilic polymer and an anionic surfactant. The milled suspension was solidified with a sugar alcohol as a water-soluble carrier by spray-drying method. The co-precipitate was compressed into an immediate release tablet with common excipients. Oral bioavailability of the wet-milled cilostazol tablet in male beagle dogs was 13-fold higher than the hammer-milled commercial tablet in fasted condition. Food did not increase the oral bioavailability of the wet-milled tablet, while 4-fold increase was found for the commercial tablet. Irrespective to the bioavailability enhancement, in vitro dissolution rate of the wet-milled tablet was even slower than the commercial tablet by the compendial method (USP Apparatus 2). On the other hand, a good correlation was found between the dissolution profiles obtained by a flow-through cell method (USP Apparatus 4, closed-loop system without outlet filter) using a large volume of water and sodium lauryl sulfate (SLS) solution at the concentration lower than the critical micellar concentration (cmc) as dissolution media corresponding to the fasted and fed conditions, respectively.
authors.affiliation: Otsuka Pharmaceutical Co., Ltd., 224-18 Ebisuno Hiraishi Kawauchi-cho, Tokushima 771-0182, Japan.
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Jinno
authors.forename: Naoki
authors.initials: N
authors.lastname: Kamada
authors.forename: Masateru
authors.initials: M
authors.lastname: Miyake
authors.forename: Keigo
authors.initials: K
authors.lastname: Yamada
authors.forename: Tadashi
authors.initials: T
authors.lastname: Mukai
authors.forename: Masaaki
authors.initials: M
authors.lastname: Odomi
authors.forename: Hajime
authors.initials: H
authors.lastname: Toguchi
authors.forename: Gary G
authors.initials: GG
authors.lastname: Liversidge
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Higaki
authors.forename: Toshikiro
authors.initials: T
authors.lastname: Kimura
mesh_terms: D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D001682:Biological Availability; D002851:Chromatography, High Pressure Liquid; D000077407:Cilostazol; D004285:Dogs; D004339:Drug Compounding; D016503:Drug Delivery Systems / Q000379:methods*; D004353:Drug Evaluation, Preclinical / Q000295:instrumentation / Q000379:methods; D008297:Male; D010316:Particle Size; D012995:Solubility; D013607:Tablets; D013777:Tetrazoles / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics
chemical_list: D013607:Tablets; D013777:Tetrazoles; D000077407:Cilostazol