title: Enteric-coated tablet of risedronate sodium in combination with phytic acid, a natural chelating agent, for improved oral bioavailability.
abstract: The oral bioavailability (BA) of risedronate sodium (RS), an antiresorptive agent, is less than 1% due to its low membrane permeability as well as the formation of non-absorbable complexes with multivalent cations such as calcium ion (Ca(2+)) in the gastrointestinal tract. In the present study, to increase oral BA of the bisphosphonate, a novel enteric-coated tablet (ECT) dosage form of RS in combination with phytic acid (IP6), a natural chelating agent recognized as safe, was formulated. The chelating behavior of IP6 against Ca(2+), including a stability constant for complex formulation was characterized using the continuous variation method. Subsequently, in vitro dissolution profile and in vivo pharmacokinetic profile of the novel ECT were evaluated comparatively with that of the marketed product (Altevia, Sanofi, US), an ECT containing ethylenediaminetetraacetic acid (EDTA) as a chelating agent, in beagle dogs. The logarithm of stability constant for Ca(2+)-IP6 complex, an equilibrium constant approximating the strength of the interaction between two chemicals to form complex, was 19.05, which was 3.9-fold (p<0.05) and 1.7-fold (p<0.05) higher than those of Ca(2+)-RS and Ca(2+)-EDTA complexes. The release profile of RS from both enteric-coated dosage forms was equivalent, regardless of the type of chelating agent. An in vivo absorption study in beagle dogs revealed that the maximum plasma concentration and area under the curve of RS after oral administration of IP6-containing ECT were approximately 7.9- (p<0.05) and 5.0-fold (p<0.05) higher than those of the marketed product at the same dose (35mg as RS). Therefore, our study demonstrates the potential usefulness of the ECT system in combination with IP6 for an oral therapy with the bisphosphonate for improved BA.
authors.affiliation: Dong-A Pharmaceutical Co. Ltd., Giheung-gu, Yongin, Gyeonggi, 446-905, Republic of Korea.
authors.forename: Jeong S
authors.initials: JS
authors.lastname: Kim
authors.affiliation: Dong-A Pharmaceutical Co. Ltd., Giheung-gu, Yongin, Gyeonggi, 446-905, Republic of Korea.
authors.forename: Sun W
authors.initials: SW
authors.lastname: Jang
authors.affiliation: Dong-A Pharmaceutical Co. Ltd., Giheung-gu, Yongin, Gyeonggi, 446-905, Republic of Korea.
authors.forename: Miwon
authors.initials: M
authors.lastname: Son
authors.affiliation: Dong-A Pharmaceutical Co. Ltd., Giheung-gu, Yongin, Gyeonggi, 446-905, Republic of Korea.
authors.forename: Byoung M
authors.initials: BM
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Dankook University, 119 Dandae-ro, Dongnam-gu, Cheonan, Chungnam 330-714, Republic of Korea. Electronic address: kangmj@dankook.ac.kr.
authors.forename: Myung J
authors.initials: MJ
authors.lastname: Kang
mesh_terms: D000180:Acrylic Resins / Q000737:chemistry; D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D002614:Chelating Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D004285:Dogs; D004338:Drug Combinations; D010833:Phytic Acid / Q000008:administration & dosage* / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics; D000068296:Risedronic Acid / Q000008:administration & dosage* / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics; D012995:Solubility; D013608:Tablets, Enteric-Coated
chemical_list: D000180:Acrylic Resins; D002614:Chelating Agents; D004338:Drug Combinations; C446821:Eudragit L100-55; D013608:Tablets, Enteric-Coated; D010833:Phytic Acid; D000068296:Risedronic Acid
keywords: Chelating agent; Enteric-coated; Oral bioavailability; Phytic acid; Risedronate sodium