title: Modulation of microenvironmental pH for dual release and reduced in vivo gastrointestinal bleeding of aceclofenac using hydroxypropyl methylcellulose-based bilayered matrix tablet.
abstract: This study was designed to develop a once-daily controlled-release matrix tablet of aceclofenac 200mg (AFC-CR) with dual release characteristics and to investigate the role of an alkalizer in enhancing drug solubility and reducing the occurrence of gastroduodenal mucosal lesions. Two formulation approaches were employed, namely a monolithic matrix tablet and a bilayered tablet. In vitro dissolution studies of AFC-CR tablets were carried out in simulated intestinal fluid (pH6.8 buffer). The in vivo pharmacokinetic studies and drug safety of the immediate-release reference tablet Airtal® 100mg (Daewoong Co., Korea) and the optimized AFC-CR tablet were compared in beagle dogs under fasted condition. The optimally selected AFC-CR formulation displayed the desired dual release characteristics in simulated intestinal fluid with satisfactory micromeritic properties. The swelling action of the optimal matrix tablet, which was visualized by near-infrared (NIR) chemical imaging, occurred rapidly following hydration. Incorporation of sodium carbonate (Na2CO3) was found to enhance the release rate of the AFC-CR bilayered tablets at early stages and increase the microenvironmental pH (pHM). A pharmacokinetic study in beagle dogs indicated a higher drug plasma concentration and a sustained-release pattern for the AFC-CR tablet compared to the Airtal® tablet. AFC-CR was also superior to Airtal® in terms of in vivo drug safety, since no beagle dog receiving AFC-CR experienced gastrointestinal bleeding. The significant enhancement of drug safety was attributed to the size reduction and the increase of pHMof drug particles by means of incorporation of the alkalizer. These findings provide a scientific rationale for developing a novel controlled-release matrix tablet with enhanced patient compliance and better pain control.
authors.affiliation: College of Pharmacy, Ajou University, Suwon 16499, Republic of Korea; Korea United Pharm Inc., Seoul 135010, Republic of Korea.
authors.forename: Won-Ho
authors.initials: WH
authors.lastname: Kang
authors.affiliation: College of Pharmacy, Ajou University, Suwon 16499, Republic of Korea.
authors.forename: Hien Van
authors.initials: HV
authors.lastname: Nguyen
authors.affiliation: College of Pharmacy, Ajou University, Suwon 16499, Republic of Korea.
authors.forename: Chulhun
authors.initials: C
authors.lastname: Park
authors.affiliation: Korea United Pharm Inc., Seoul 135010, Republic of Korea.
authors.forename: Youn-Woong
authors.initials: YW
authors.lastname: Choi
authors.affiliation: College of Pharmacy, Ajou University, Suwon 16499, Republic of Korea; Institute of Pharmaceutical Science and Technology, Ajou University, Suwon 16499, Republic of Korea. Electronic address: bjl@ajou.ac.kr.
authors.forename: Beom-Jin
authors.initials: BJ
authors.lastname: Lee
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry* / Q000493:pharmacokinetics; D003692:Delayed-Action Preparations / Q000737:chemistry / Q000493:pharmacokinetics; D004008:Diclofenac / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics; D004285:Dogs; D016503:Drug Delivery Systems; D065546:Drug Liberation; D006471:Gastrointestinal Hemorrhage / Q000517:prevention & control; D006863:Hydrogen-Ion Concentration; D065347:Hypromellose Derivatives / Q000737:chemistry* / Q000493:pharmacokinetics; D007419:Intestinal Secretions / Q000737:chemistry; D008297:Male; D012995:Solubility; D013607:Tablets
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D003692:Delayed-Action Preparations; D013607:Tablets; D004008:Diclofenac; D065347:Hypromellose Derivatives; C056498:aceclofenac
keywords: Aceclofenac; Bilayered tablet; Dual release; In vivo drug safety; Microenvironmental pH; Monolithic matrix tablet