Enteric-coated tablets improve oral bioavailability of DX-9065, a novel anticoagulant.
Oral bioavailability of DX-9065, a factor Xa inhibitor, was only 3% when it was administered as a conventional capsule formulation in fasted humans, and was further reduced to about one-tenth when it was administered to fed humans. The poor absorption of DX-9065 probably resulted from its low membrane permeability and its electrostatic interaction with bile acid. We designed enteric-coated tablets with the expectation that this pharmaceutical technology will prevent DX-9065 from interacting with bile acid. More than 85% of DX-9065 was released from the tablet coated with hypromellose acetate succinate within 10min in simulated intestinal fluid (pH 6.8). Monkey experiments demonstrated that AUC of DX-9065 after oral administration of its enteric-coated tablet was about 5 times that of its aqueous solution in the fasted state. The food effect on drug absorption was also reduced when DX-9065 was administered as an enteric-coated tablet. The average ratio of AUC in a fed state to that in a fasted state was approximately 0.5, even though the ratio was 0.1 when the enteric-coated tablet was substituted with the drug solution. Enteric coating could be a useful method for improving oral absorption of DX-9065 with reduced food effects on drug absorption.
Analytical & Quality Evaluation Research Laboratories, Pharmaceutical Technology Division, Daiichi Sankyo Co., Ltd., 1-16-13, Kitakasai, Edogawa-ku, Tokyo 134-8630, Japan. fujii.yoshimine.r3@daiichisankyo.co.jp fujii.yoshimine.r3@daiichisankyo.co.jp
Yoshimine
Y
Fujii
Taro
T
Kanamaru
Hiroshi
H
Kikuchi
Shinji
S
Yamashita
Shinji
S
Sakuma
D000284:Administration, Oral; D000818:Animals; D000925:Anticoagulants / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D019540:Area Under Curve; D001682:Biological Availability; D016503:Drug Delivery Systems; D004386:Duodenum / Q000378:metabolism*; D005215:Fasting / Q000378:metabolism; D005260:Female; D018565:Food-Drug Interactions; D000882:Haplorhini; D009281:Naphthalenes / Q000097:blood / Q000493:pharmacokinetics*; D011422:Propionates / Q000097:blood / Q000493:pharmacokinetics*; D012995:Solubility; D013608:Tablets, Enteric-Coated; D013997:Time Factors
C086910:(2S)-2-(4-(((3S)-1-acetimidoyl-3-pyrrolidinyl)oxy)phenyl)-3-(7-amidino-2-naphtyl)propanoic acid; D000925:Anticoagulants; D009281:Naphthalenes; D011422:Propionates; D013608:Tablets, Enteric-Coated