Chay Sai Kin, Keating Alison V, James Colin, Aliev Abil E, Haider Shozeb, Craig Duncan Q M
University College London School of Pharmacy 29-39 Brunswick Square London WC1N 1AX UK
University College London Department of Chemistry 20 Gordon Street London WC1H 0AJ UK.
RSC Adv. 2018 Jan 17;8(7):3564-3573. doi: 10.1039/c7ra11015d. eCollection 2018 Jan 16.
Taste assessment in an increasingly important aspect of formulation development, particularly for paediatric medications. Electronic taste sensing systems have the potential to offer a rapid, objective and safe method of taste assessment prior to the use of more costly human panels or animal models. In this study, the ability of the TS-5000Z taste sensing system to assess the taste masking efficiency of (2-hydroxypropyl)-β-cyclodextrin (HP-β-CyD) complexes with ranitidine hydrochloride was evaluated in order to explore the potential of the biosensor approach as a means of assessing taste masking by inclusion complexation. Nuclear magnetic resonance (NMR) spectroscopy and molecular docking studies were employed to identify and examine the interaction between ranitidine hydrochloride and HP-β-CyD. Taste-masking efficiencies were determined by the Euclidean distance between taste-masked formulations and the pure drug substance on a PCA score plot. The results showed that with increasing molarity of HP-β-CyD in the formulation, the distance from ranitidine hydrochloride increased, thus indicating a significant difference between the taste of the formulation and that of the pure drug. NMR studies also provided strong supporting evidence for the complexation between HP-β-CyD and ranitidine hydrochloride, with the H3' region of the former identified as the most likely binding site for the drug. Molecular docking studies suggested that the dimethylamino and diamine groups of the drug form direct hydrogen bonds with the hydroxyl oxygen atoms of HP-β-CyD, while the furan ring docks in close proximity to H3'. This study has demonstrated that the biosensor system may provide quantitative data to assess bitterness of inclusion complexes with HP-β-CyD, while spectroscopic and modelling studies may provide a mechanistic explanation for the taste masking process. This in turn suggests that there is a role for biosensor approaches in providing early screening for taste masking using inclusion complexation and that the combination with mechanistic studies may provide insights into the molecular basis of taste and taste masking.
味觉评估在制剂研发中是一个日益重要的方面，尤其是对于儿科药物。在使用成本更高的人体试验小组或动物模型之前，电子味觉传感系统有潜力提供一种快速、客观且安全的味觉评估方法。在本研究中，评估了TS - 5000Z味觉传感系统评估盐酸雷尼替丁与（2 - 羟丙基）-β-环糊精（HP-β-CyD）复合物味觉掩蔽效率的能力，以探索生物传感器方法作为通过包合络合评估味觉掩蔽手段的潜力。采用核磁共振（NMR）光谱和分子对接研究来识别和研究盐酸雷尼替丁与HP-β-CyD之间的相互作用。味觉掩蔽效率通过主成分分析（PCA）得分图上味觉掩蔽制剂与纯药物之间的欧几里得距离来确定。结果表明，随着制剂中HP-β-CyD摩尔浓度的增加，与盐酸雷尼替丁的距离增大，这表明制剂的味道与纯药物的味道之间存在显著差异。NMR研究也为HP-β-CyD与盐酸雷尼替丁之间的络合提供了有力的支持证据，前者的H3'区域被确定为药物最可能的结合位点。分子对接研究表明，药物的二甲氨基和二胺基团与HP-β-CyD的羟基氧原子形成直接氢键，而呋喃环靠近H3'对接。本研究表明，生物传感器系统可以提供定量数据来评估与HP-β-CyD形成的包合物的苦味，而光谱和建模研究可以为味觉掩蔽过程提供机理解释。这反过来表明，生物传感器方法在利用包合络合进行味觉掩蔽的早期筛选中具有作用，并且与机理研究相结合可能有助于深入了解味觉和味觉掩蔽的分子基础。
