School of Pharmacy, University of Nottingham, Nottingham NG7 2RD, UK.
Pfizer Drug Product Design, WRD Pharmaceutical Sciences, Sandwich, UK.
Eur J Pharm Biopharm. 2021 Mar;160:125-133. doi: 10.1016/j.ejpb.2021.01.017. Epub 2021 Jan 30.
Drug release within the oral cavity can be of paramount importance for formulations that are designed for specific purposes such as taste-masking, faster onset of therapeutic action, localization of treatment or avoidance of first-pass metabolism. Preclinical methods for assessment of dissolution in the oral cavity are necessary for design and development of these formulation but currently there is no consensus on what variables should be defined to achieve biorelevance in these tests. In this study, biorelevant simulated salivary fluids (SSFs) that can be uniformly applied for oral cavity dissolution testing were developed. Unstimulated saliva (US) SSF and stimulated saliva (SS) SSF were separately developed since the two states significantly differ. Physicochemical properties including pH, buffer capacity, surface tension and viscosity were assessed during development and optimised to mimic human saliva (HS). In order to account for the salivary proteins in HS, use of bovine submaxillary mucin (BSM) and porcine gastric mucin (PGM) in SSFs was evaluated. Following optimisation of the SSFs, biorelevance of the developed SSFs to HS was assessed by their comparative physicochemical properties as well as dissolution profiles of three diverse model compounds (sildenafil citrate, efavirenz, and caffeine) which showed comparable profiles between the SSFs and HS. This work addresses the lack of uniformed biorelevant dissolution media for oral cavity dissolution studies and provides a basis for standardised dissolution tests that provide consistency and harmonisation in future oral cavity dissolution studies. We envisage that this will have a positive impact on the development of new medicines that require functionality in the oral cavity.
口腔内的药物释放对于特定用途的制剂非常重要，例如掩味、更快地发挥治疗作用、治疗部位定位或避免首过代谢。评估口腔内溶解的临床前方法对于这些制剂的设计和开发是必要的，但目前对于应定义哪些变量以实现这些测试的生物相关性尚无共识。在这项研究中，开发了可用于口腔内溶解测试的生物相关模拟唾液（SSF）。由于两种状态有很大的不同，因此分别开发了未刺激唾液（US）SSF 和刺激唾液（SS）SSF。在开发过程中评估了包括 pH、缓冲能力、表面张力和粘度在内的物理化学性质，并进行了优化以模拟人唾液（HS）。为了考虑 HS 中的唾液蛋白，评估了 SSF 中牛颌下腺粘蛋白（BSM）和猪胃粘蛋白（PGM）的使用情况。对 SSF 进行优化后，通过比较三种不同模型化合物（枸橼酸西地那非、依非韦伦和咖啡因）的物理化学性质和溶解曲线来评估所开发的 SSF 对 HS 的生物相关性，结果表明 SSF 与 HS 之间具有相似的溶解曲线。这项工作解决了口腔内溶解研究中缺乏统一的生物相关溶解介质的问题，并为标准化溶解试验提供了基础，为未来的口腔内溶解研究提供了一致性和协调性。我们预计，这将对需要在口腔内发挥功能的新药的开发产生积极影响。
