title: Development of novel prasugrel base microsphere-loaded tablet with enhanced stability: Physicochemical characterization and in vivo evaluation in beagle dogs.
abstract: The objective of this study was to develop a novel prasugrel base microsphere-loaded tablet (PBMST) with enhanced stability as a bioequivalent to the commercial prasugrel hydrochloride-loaded tablet. Numerous prasugrel base-loaded microspheres were prepared with hydroxypropylmethyl cellulose (HPMC), colloidal silica and various acidifying agents using a spray-drying process, and the physicochemical properties, solubility and stability were investigated. The PBMSTs were prepared and their dissolution, pharmacokinetics in beagle dogs and stability were evaluated compared to commercial prasugrel hydrochloride-loaded tablets. Among the acidifying agents tested, phosphoric acid provided the greatest increase in drug solubility, by as much as 110-fold. The prasugrel base-loaded microspheres composed of prasugrel base, HPMC, colloidal silica and phosphoric acid at a weight ratio of 10/10/5/2.5 provided an amorphous drug and reduced particle size of about 11.3μm. Moreover, it exhibited excellent solubility and improved stability compared to prasugrel base and hydrochloride. Moreover, PBMST drug dissolution was improved in comparison to the prasugrel base-loaded tablet (PBT), with similar dissolution to the commercial prasugrel hydrochloride-loaded tablet at pH 1.2 and 4.0. PBMST provided significantly higher plasma concentrations of AUC and Cmax in beagle dogs compared to PBT. In particular, the AUC of PBMST was approximately four times greater than PBT, leading to improved oral bioavailability. There were no significant differences observed for all pharmacokinetic parameters between PBMST and the commercial prasugrel hydrochloride-loaded tablet, suggesting their bioequivalence in beagle dogs. Furthermore, the prepared PBMSTs were stable for at least six months. Therefore, this novel prasugrel base microsphere-loaded tablet could be a potential alternative for enhancing the stability and bioavailability of prasugrel.
authors.affiliation: College of Pharmacy & Institute of Pharmaceutical Science and Technology, Hanyang University, 55 Hanyangdaehak-ro, Sangnok-gu, Ansan 426-791, Republic of Korea; Pharmaceutical Research Centre, Hanmi Pharm. Co., Paltan-myeon, 893-5 Hwaseong, Gyeonggi-Do 445-913, Republic of Korea.
authors.forename: Kyeong Soo
authors.initials: KS
authors.lastname: Kim
authors.affiliation: College of Pharmacy & Institute of Pharmaceutical Science and Technology, Hanyang University, 55 Hanyangdaehak-ro, Sangnok-gu, Ansan 426-791, Republic of Korea; Pharmaceutical Research Centre, Hanmi Pharm. Co., Paltan-myeon, 893-5 Hwaseong, Gyeonggi-Do 445-913, Republic of Korea.
authors.forename: Jin Cheul
authors.initials: JC
authors.lastname: Kim
authors.affiliation: College of Pharmacy & Institute of Pharmaceutical Science and Technology, Hanyang University, 55 Hanyangdaehak-ro, Sangnok-gu, Ansan 426-791, Republic of Korea.
authors.forename: Sung Giu
authors.initials: SG
authors.lastname: Jin
authors.affiliation: College of Pharmacy & Institute of Pharmaceutical Science and Technology, Hanyang University, 55 Hanyangdaehak-ro, Sangnok-gu, Ansan 426-791, Republic of Korea.
authors.forename: Dong Wuk
authors.initials: DW
authors.lastname: Kim
authors.affiliation: College of Pharmacy & Institute of Pharmaceutical Science and Technology, Hanyang University, 55 Hanyangdaehak-ro, Sangnok-gu, Ansan 426-791, Republic of Korea.
authors.forename: Dong Shik
authors.initials: DS
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Yeungnam University, 214-1, Dae-Dong, Gyongsan 712-749, Republic of Korea.
authors.forename: Chul Soon
authors.initials: CS
authors.lastname: Yong
authors.affiliation: College of Pharmacy, Yeungnam University, 214-1, Dae-Dong, Gyongsan 712-749, Republic of Korea.
authors.forename: Jong Oh
authors.initials: JO
authors.lastname: Kim
authors.affiliation: School of Pharmacy, Sungkyunkwan University, 300 Cheoncheon-dong, Jangan-gu, Suwon 440-746, Republic of Korea.
authors.forename: Yu Seok
authors.initials: YS
authors.lastname: Youn
authors.affiliation: College of Pharmacy, Chung-Ang University, 221 Heuksuk-dong Dongjak-gu, Seoul 156-756, Republic of Korea.
authors.forename: Kyung Taek
authors.initials: KT
authors.lastname: Oh
authors.affiliation: Pharmaceutical Research Centre, Hanmi Pharm. Co., Paltan-myeon, 893-5 Hwaseong, Gyeonggi-Do 445-913, Republic of Korea. Electronic address: jswoo@hanmi.co.kr.
authors.forename: Jong Soo
authors.initials: JS
authors.lastname: Woo
authors.affiliation: College of Pharmacy & Institute of Pharmaceutical Science and Technology, Hanyang University, 55 Hanyangdaehak-ro, Sangnok-gu, Ansan 426-791, Republic of Korea. Electronic address: hangon@hanyang.ac.kr.
authors.forename: Han-Gon
authors.initials: HG
authors.lastname: Choi
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D004355:Drug Stability; D008297:Male; D008863:Microspheres; D000068799:Prasugrel Hydrochloride / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D013607:Tablets / Q000737:chemistry*; D053719:Tandem Mass Spectrometry; D014018:Tissue Distribution
chemical_list: D013607:Tablets; D000068799:Prasugrel Hydrochloride
keywords: Bioavailability; Bioequivalence; Microsphere; Phosphoric acid; Prasugrel base; Solubility; Stability