Preparation and evaluation of oral controlled-release cilostazol formulation: pharmacokinetics and antithrombotic efficacy in dogs and healthy male Korean participants.
OBJECTIVE
To prepare oral controlled-release cilostazol formulations and evaluate their pharmacokinetics and pharmacodynamics in dogs and humans compared with a commercial twice-daily immediate-release formulation (Pletal), thereby showing the potential for the development of an improved once-daily cilostazol formulation.


METHODS
Six different controlled-release preparations were formulated using a micronized cilostazol, solubilizer/absorption enhancer and erodible hydrogel. In-vitro drug release profiles were tailored by varying hydrogel viscosity. Pharmacokinetics and pharmacodynamic (antithrombotic) efficacy were evaluated in beagle dog model of arterial thrombosis. Finally, their pharmacokinetics and pharmacodynamics were also evaluated in healthy human volunteers after single and multiple oral administrations.


RESULTS
Hydrogel viscosity-dependent sustained drug release profiles were observed with zero-order release kinetics during 8-12 h. In dogs and humans, compared with Pletal, prolonged drug absorption profiles were observed in the two controlled-release formulations studied. In dogs, the controlled-release formulations showed greater antithrombotic efficacy than twice-daily Pletal. In humans, the antithrombotic efficacy of the selected once-daily cilostazol formulation was equivalent to that of twice-daily Pletal after single and multiple administrations.


CONCLUSIONS
The prepared oral controlled-release cilostazol formulation may provide prolonged drug absorption and sufficient therapeutic efficacy, potentially serving as an oral once-daily cilostazol formulation to improve patient compliance.
College of Pharmacy, Chungnam National University, Daejeon, Republic of Korea; R&D Team, Pacificpharma Co., Yongin-si, Republic of Korea.
Kwang-Hyun
KH
Shin
Goo
G
Yoon
In-Soo
IS
Yoon
Jin Woo
JW
Park
D000284:Administration, Oral; D000818:Animals; D000077407:Cilostazol; D003692:Delayed-Action Preparations; D004195:Disease Models, Animal; D004285:Dogs; D004337:Drug Carriers / Q000737:chemistry; D005343:Fibrinolytic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D005782:Gels; D006801:Humans; D007408:Intestinal Absorption; D008297:Male; D012995:Solubility; D013777:Tetrazoles / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D013927:Thrombosis / Q000188:drug therapy*; D014783:Viscosity
D003692:Delayed-Action Preparations; D004337:Drug Carriers; D005343:Fibrinolytic Agents; D005782:Gels; D013777:Tetrazoles; D000077407:Cilostazol
antithrombotic efficacy; cilostazol; controlled-release; oral delivery; pharmacokinetics