title: Improved oral absorption of cilostazol via sulfonate salt formation with mesylate and besylate.
abstract: OBJECTIVE
  Cilostazol is a Biopharmaceutical Classification System class II drug with low solubility and high permeability, so its oral absorption is variable and incomplete. The aim of this study was to prepare two sulfonate salts of cilostazol to increase the dissolution and hence the oral bioavailability of cilostazol.
  
  
  METHODS
  Cilostazol mesylate and cilostazol besylate were synthesized from cilostazol by acid addition reaction with methane sulfonic acid and benzene sulfonic acid, respectively. The salt preparations were characterized by nuclear magnetic resonance spectroscopy. The water contents, hygroscopicity, stress stability, and photostability of the two cilostazol salts were also determined. The dissolution profiles in various pH conditions and pharmacokinetic studies in rats were compared with those of cilostazol-free base.
  
  
  RESULTS
  The two cilostazol salts exhibited good physicochemical properties, such as nonhygroscopicity, stress stability, and photostability, which make it suitable for the preparation of pharmaceutical formulations. Both cilostazol mesylate and cilostazol besylate showed significantly improved dissolution rate and extent of drug release in the pH range 1.2-6.8 compared to the cilostazol-free base. In addition, after oral administration to rats, cilostazol mesylate and cilostazol besylate showed increases in C max and AUC t of approximately 3.65- and 2.87-fold and 3.88- and 2.94-fold, respectively, compared to cilostazol-free base.
  
  
  CONCLUSIONS
  This study showed that two novel salts of cilostazol, such as cilostazol mesylate and cilostazol besylate, could be used to enhance its oral absorption. The findings warrant further preclinical and clinical studies on cilostazol mesylate and cilostazol besylate at doses lower than the usually recommended dosage, so that it can be established as an alternative to the marketed cilostazol tablet.
authors.affiliation: College of Pharmacy and Integrated Research Institute of Pharmaceutical Sciences, The Catholic University of Korea, Bucheon, South Korea.
authors.forename: Jae Hong
authors.initials: JH
authors.lastname: Seo
authors.affiliation: College of Pharmacy and Integrated Research Institute of Pharmaceutical Sciences, The Catholic University of Korea, Bucheon, South Korea.
authors.forename: Jung Bae
authors.initials: JB
authors.lastname: Park
authors.affiliation: College of Pharmacy and Integrated Research Institute of Pharmaceutical Sciences, The Catholic University of Korea, Bucheon, South Korea.
authors.forename: Woong-Kee
authors.initials: WK
authors.lastname: Choi
authors.affiliation: College of Pharmacy and Integrated Research Institute of Pharmaceutical Sciences, The Catholic University of Korea, Bucheon, South Korea.
authors.forename: Sunhwa
authors.initials: S
authors.lastname: Park
authors.affiliation: College of Pharmacy and Integrated Research Institute of Pharmaceutical Sciences, The Catholic University of Korea, Bucheon, South Korea.
authors.forename: Yun Jin
authors.initials: YJ
authors.lastname: Sung
authors.affiliation: College of Pharmacy and Integrated Research Institute of Pharmaceutical Sciences, The Catholic University of Korea, Bucheon, South Korea.
authors.forename: Euichaul
authors.initials: E
authors.lastname: Oh
authors.affiliation: College of Pharmacy and Integrated Research Institute of Pharmaceutical Sciences, The Catholic University of Korea, Bucheon, South Korea.
authors.forename: Soo Kyung
authors.initials: SK
authors.lastname: Bae
mesh_terms: D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D001557:Benzenesulfonates / Q000008:administration & dosage / Q000097:blood / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D001682:Biological Availability; D002317:Cardiovascular Agents / Q000008:administration & dosage / Q000097:blood / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D002626:Chemistry, Pharmaceutical; D000077407:Cilostazol; D004355:Drug Stability; D065569:Gastrointestinal Absorption; D008297:Male; D008698:Mesylates / Q000008:administration & dosage / Q000097:blood / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D017207:Rats, Sprague-Dawley; D012995:Solubility; D013678:Technology, Pharmaceutical / Q000379:methods; D013777:Tetrazoles / Q000008:administration & dosage / Q000097:blood / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D017155:Wettability
chemical_list: D001557:Benzenesulfonates; D002317:Cardiovascular Agents; D008698:Mesylates; D013777:Tetrazoles; C045880:methanesulfonic acid; C032365:benzenesulfonic acid; D000077407:Cilostazol
keywords: BCS class II; acid addition reaction; besylate; cilostazol; dissolution; mesylate