The efficacy and safety of clopidogrel resinate as a novel polymeric salt form of clopidogrel.
A novel polymeric salt of clopidogrel, clopidogrel resinate, was prepared as a anticoagulant drug. To prove the feasibility as a new active substance, clopidogrel resinate was evaluated for its efficacy and safety. In accelerated stability tests, the clopidogrel resinate tablet (Pregrel) showed less brown discoloration and fewer impurities than the clopidogrel bisulfate tablets under open and closed conditions. In toxicity tests, no deaths occurred after a single dose of up to 2000 mg/kg/day and 13-week repeated doses of up to 625 mg/kg/day in rats without abnormal symptoms compared to clopidogrel bisulfate. When clopidogrel resinate was treated onto Caco-2 cell monolayers, clopidogrel, but not the resin, permeated across the cells with a hight permeation coefficient (Papp) of 13.5 +/- 1.13 x 10(-6) cm/sec. Clopidogrel resinate and clopidogrel bisulfate showed similar pharmacokinetics following oral administration to beagle dogs. A single oral administration of clopidogrel resinate dose-dependently inhibited ADP-induced ex vivo aggregation up to 30 mg/kg in rats. In conclusion, clopidogrel resinate was proved to be an efficient and safe polymeric salt as a candidate for a new clopidogrel salt.
Ki
Min-Hyo
MH
DDS Research Lab, CKD Research Institute, CKD Pharmaceutical Corp., Chonan 330-831, Korea.
Choi
Mee-Hwa
MH
Ahn
Kwang-Bok
KB
Kim
Byoung-Su
BS
Im
Dai Sig
DS
Ahn
Soon-Kil
SK
Shin
Hee-Jong
HJ
D000818:Animals; D001760:Bleeding Time; D018938:Caco-2 Cells; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D000077144:Clopidogrel; D004285:Dogs; D004355:Drug Stability; D041981:Gastrointestinal Tract / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007408:Intestinal Absorption / Q000187:drug effects; D008297:Male; D051379:Mice; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D011108:Polymers; D051381:Rats; D017207:Rats, Sprague-Dawley; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity
D010975:Platelet Aggregation Inhibitors; D011108:Polymers; C528439:clopidogrel resinate; D000077144:Clopidogrel; D013988:Ticlopidine