Release-modulating mechanism and comparative pharmacokinetics in beagle dogs of bethanechol-loaded oral dosage forms.

Autor: Jeong HM; Department of Pharmacy, College of Pharmacy, Ajou University, Suwon 16499, Republic of Korea; Central Research Institute, IL-YANG Pharmaceutical Co., Ltd., Yongin 17096, Republic of Korea., Kim H; Central Research Institute, IL-YANG Pharmaceutical Co., Ltd., Yongin 17096, Republic of Korea., Jang T; Central Research Institute, IL-YANG Pharmaceutical Co., Ltd., Yongin 17096, Republic of Korea., Choi A; Central Research Institute, IL-YANG Pharmaceutical Co., Ltd., Yongin 17096, Republic of Korea., Park JB; College of Pharmacy, Sahmyook University, Seoul 01795, Republic of Korea., Park C; College of Pharmacy, Jeju National University, Jeju 63243, Republic of Korea. Electronic address: chpark@jejunu.ac.kr., Lee BJ; Department of Pharmacy, 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.
Jazyk: angličtina
Zdroj: International journal of pharmaceutics [Int J Pharm] 2024 Dec 17; Vol. 669, pp. 125091. Date of Electronic Publication: 2024 Dec 17.
DOI: 10.1016/j.ijpharm.2024.125091
Abstrakt: Bethanechol chloride (BTC), a quaternary ammonium compound used in bladder dysfunction treatment, requires challenges in developing optimal oral dosage forms due to its high water-solubility, short half-life, rapid elimination and four times a day administration. The aim of this study was to develop optimal BTC-loaded oral dosage forms that could provide both rapid onset and sustained therapeutic effects while reducing the frequency of conventional four-times-daily dosing (Mytonin® tablets). Four different BTC-loaded oral dosage forms were designed including gastro-retentive tablet (GRT), controlled-release tablet (CRT), bilayer tablet (BLT), and tablet-in-tablet (TIT). Then, release-modulating mechanism and in vivo pharmacokinetics in beagle dogs were compared. The release profiles of the four BTC-loaded dosage forms varied according to system design and formulation composition. The optimized GRT F-5 showed rapid buoyancy within 15 s and floated for 12 h, while continuously releasing the drug. CRT showed Fickian diffusion release, whereas BLT and TIT exhibited biphasic immediate and sustained release profiles. Polymer swelling behavior was analyzed using the Vergnaud model, where GRT F-5 and CRT showed n values < 0.5, confirming diffusion-controlled polymer hydration mechanism. In the instrumental analysis, the hydrogen bonding formation of BTC with release-modulating polymers, such as hydroxypropyl methylcellulose and polyethylene oxide and loosening of the polymer structure was crucial as the water influx increased. In pharmacokinetic studies in beagle dogs, the area under the plasma concentration-time curve (AUC) by normalizing dose for 48 h for GRT, CRT, BLT, and TIT were 90.2 %, 108.6 %, 83.8 %, and 76.4 %, respectively, compared with that of the reference drug (Mytonin® tablets, immediate release, four times a day). Interestingly, the plasma maximum concentration (C max ) and AUC) 0-12h of GRT F-5 and and Mytonin® tablets for the first 12-h period were much higher compared with that of other BTC-loaded CRT, BLT, and TIT. BTC was absorbed throughout the gastrointestinal tract, but is preferably absorbed in the stomach and upper intestinal sites. However, the GRT F-5 could provide more therapeutic potential for improving patient compliance in bladder dysfunction treatment by achieving both rapid onset and sustained drug release with reduced dosing frequency.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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