基于苦味成分“隐形修饰”的中药儿童药剂抑苦掩味机理研究

Bitterness is the key to restrict the children's use of traditional Chinese medicine (TCM) liquid preparation. The bitter taste of TCM is complex and diverse, and children's taste buds have high sensitive ability of catching bitterness information. Therefore, there are some deficiencies to mask bitterness only using receptor inhibitors or sweeteners. As we know, the combination of the electrophilic group, the hydrophobic group of components with the receptors is the key to stimulate the bitterness. Inspired by the design of the stealth aircraft, can we shield the signal of bitterness components in solution and finally inhibit bitterness? Based on the above thinking and analysis, our research group first proposes a theoretical hypothesis of bitterness components steal modification. According to it, the bitterness can be suppressed by using strong dipole substances to affect the electrophilic groups or by adding nonionic surfactants to shield the hydrophobic groups..On the basis of the former Nation Science Foundation Project of astringent masking, the water extract of Forsythia forsythia, Coptis chinensis and Andrographis paniculata with outstanding bitterness are selected as the models. During the study, this project focuses on the main bitterness components, including lignin, alkaloids, diterpene lactones, and so on. Then, the evaluation methods of bitterness, precise identification of bitter substances, regulation of electron density, shielding law of hydrophobic group, inhibition bitterness and systematic evaluation of three water extracts will be carried out. Furthermore, the structure-activity relationship, the dose-effect relationship, and the application law of steal modification of different bitter substances will be revealed. The study results can be used to inhibit the bitterness of formula granules and Chinese patent medicines. It will be of great significance to develop a new form of masking bitterness for children preparations.

苦味是儿童畏惧中药汤剂的关键。中药苦味刺激复杂多样，儿童味蕾具有高灵敏度的苦味感知能力，单纯依赖受体抑制剂、甜味剂等均有其局限。苦味成分的亲电性基团、疏水基团与受体结合是激发苦味的关键。受隐形飞机设计的启发，能否在溶液中实现对苦味基团的信号屏蔽，达到抑苦目的？为此，课题组提出采用强偶极力作用物质改变亲电性基团供电子能力、表面活性剂屏蔽疏水基团的中药苦味成分“隐形修饰”理论假说。.以课题组承担的自然基金中药涩味掩蔽技术与方法研究为基础，选取典型苦味药物连翘、黄连、穿心莲水煎液为研究对象，聚焦其中木质素、生物碱、二萜内酯等苦味成分，从“儿童苦味评价模型-苦味物质精准辨识-电子密度调控规律-疏水基团屏蔽规律-汤剂抑苦效果评价”5个环节开展系统研究，揭示不同结构苦味成分隐形修饰的构效关系、量效关系与应用规律。研究结果可用于配方颗粒与中成药抑苦，对于探寻中药儿童药剂掩味新模式具有重要意义。

苦味是儿童畏惧中药汤剂的关键。中药苦味刺激复杂多样，苦味物质高度分散，瞬间形成广泛刺激，产生强烈苦味。除添加甜味剂外，缺少有效的应对方法。基于苦味形成的三点接触理论，提出两亲性嵌段共聚物（Amphiphilic block copolymers , ABCs）通过改变苦味成分电荷分布与屏蔽疏水基团，用于汤剂抑苦掩味的理论假说。本项目围绕黄连、穿心莲、黄连解毒汤等经典苦味中药，从苦味成分-单味药-复方多层次系统研究ABCs的抑苦效果与作用机制，探索ABCs与其他辅料联合应用的开发前景。.发现ABCs对于盐酸小檗碱（BER）、龙胆苦苷、苦参碱、硫酸奎宁等苦味成分均具有一定抑苦效果，证明其抑苦作用的广谱性。以BER为例，阐明了ABCs通过使苦味成分从真溶液转移到胶体相，促进BER嵌入PLLA螺旋腔，使苦味基团的静电势减弱，形成相对稳定的超分子结构，避免苦味受体识别的"隐形修饰"抑苦原理。进一步研究mPEG-PLLA与黄连中巴马汀、药根碱、小檗碱、表小檗碱及黄连碱等5种苦味生物碱的相互作用，发现抑苦效果与生物碱结构参数，如苦味成分供氢体、表面静电势正值、亲电性等密切相关。针对儿童敏感的感官特点与穿心莲水煎液、黄连解毒汤的极苦特征，借鉴“咖啡伴侣”形式，提出中药汤剂伴侣新形式，揭示ABCs、环糊精类、合成甜味剂通过改变苦味成分的相态分布、屏蔽苦味信号特征、竞争抑制苦味信号传导，达到1+1+1>3的协同抑苦组方原理，实现汤剂从极苦到微苦或几乎不苦的转变，证实了伴侣剂不影响药效、不增加毒副作用、不干扰肠道菌群的作用特点。.该研究证明了项目的理论假说，拓展了ABCs的抑苦新用途，推动了中药伴侣新产品开发。发表研究论文7篇，其中SCI论文2篇；申请发明专利1项，入选成都市中医药高价值专利培育对象；培养毕业硕、博士研究生2名，指导学生获第七届四川省国际“互联网+”大学生创新创业大赛银奖。