在本研究中,我们开发了新型胃滞留双层片剂,有望用于候选药物MT-1207的每日一次口服给药.胃滞留层由亲水和疏水聚合物的组合组成,即聚环氧乙烷和Kollidon®SR。进行了阶乘实验,结果揭示了一个非泡腾的胃滞留层,与文献中报道的大多数胃滞留层不同,很容易准备,并提供即时片剂浮力(平均浮动滞后时间1.5秒),在禁食状态下持续超过24小时模拟胃液(FaSSGF)pH1.6,与药物层无关,从而允许MT-1207从片剂的药物层持续释放24小时。此外,在不同pH值(1.0、3.0、6.0)介质中优化的双层片剂的体外浮力测试期间,显著差异(单向方差分析,在各自的总漂浮时间之间的p<0.001)表明,在非泡腾胃滞留制剂的开发和给药方案的选择过程中,必须考虑胃pH对片剂浮力的影响。据我们所知,这以前没有报道过,在设计给药方案时,它可能应该被考虑在内。最后,在Beagle犬中进行的一项药代动力学研究表明,MT-1207在24小时时间点从优化的胃滞留双层片剂中成功地在体内24小时持续释放,药物血浆浓度保持在估计的最小有效浓度1ng/mL以上,并且还证明了亲水性和疏水性聚合物组合的胃滞留能力.优化的配方将被转发到临床开发。
In the present study, novel gastroretentive bilayer tablets were developed that are promising for the once-a-day oral delivery of the drug candidate MT-1207. The gastroretentive layer consisted of a combination of hydrophilic and hydrophobic polymers, namely polyethylene oxide and Kollidon® SR. A factorial experiment was conducted, and the results revealed a non-effervescent gastroretentive layer that, unlike most gastroretentive layers reported in the literature, was easy to prepare, and provided immediate tablet
buoyancy (mean floating lag time of 1.5 s) that lasted over 24 h in fasted state simulated gastric fluid (FaSSGF) pH 1.6, irrespective of the drug layer, thereby allowing a 24-hour sustained release of MT-1207 from the drug layer of the tablets. Furthermore, during in vitro
buoyancy testing of the optimised bilayer tablets in media of different pH values (1.0, 3.0, 6.0), the significant difference (one-way ANOVA, p < 0.001) between the respective total floating times indicated that stomach pH effects on tablet
buoyancy are important to be considered during the development of non-effervescent gastroretentive formulations and the choice of dosing regimen. To the best of our knowledge, this has not been reported before, and it should probably be factored in when designing dosing regimens. Finally, a pharmacokinetic study in Beagle dogs indicated a successful in vivo 24-hour sustained release of MT-1207 from the optimised gastroretentive bilayer tablet formulations with the drug plasma concentration remaining above the estimated minimum effective concentration of 1 ng/mL at the 24-hour timepoint and also demonstrated the gastroretentive capabilities of the hydrophilic and hydrophobic polymer combination. The optimised formulations will be forwarded to clinical development.