Taste masking medicines for children through crystal engineering

不可接受的适口性是婴幼儿药物开发的主要障碍，因为它经常阻碍患者的依从性。因此，掩盖不良味道被监管当局广泛认为是现代儿科药物开发的一个关键方面。欧洲和美国的立法目前要求并奖励开发可口的儿科药物。拟议的博士研究项目旨在开发一种晶体工程方法来掩盖儿科口服制剂中常用的药物分子（例如氟氯西林和强的松）的苦味。该方法依赖于多组分晶体的构建，其中包括苦味药物和味道掩蔽剂，其中分子通过氢键结合在一起。味道掩蔽剂是一种药学上可接受的化合物味道阻滞剂，或者是一种与药物以一种阻止药物与味觉受体之间任何相互作用的方式形成氢键的分子。所描述的多组分晶体（即共晶体）的形成可以快速（<1h）实现，使用少量的溶剂（甚至没有）和大量（bbb1kg），而无需使用专门的设备。共晶的味道将在体内进行评估，包括使用Brief Access taste Aversion模型。此外，药物研究将评估共晶是否可以增强与处理、可制造性和潜在临床性能相关的材料特性（例如，可食用性），以确保本研究的结果完全转化。该研究计划将探索晶体工程策略在儿科药物配方中的应用，并旨在开发用于可口药物的药物共晶体。该研究计划将包括以下内容：-选择与儿科保健相关的活性药物成分（API），并使用数据库调查和化学信息学确定一组合适的共晶形成物-完成每种API的共晶筛选并完成所制备的共晶的固态表征-评估相关共晶的药代动力学特性并使用大鼠短暂接触厌恶（BATA）模型评估其味道-开发结构-性质关系，这将使使用晶体工程原理设计可口共晶的指导方针得以发展。

Unacceptable palatability is a major obstacle in the development of medicines for infants and toddlers, as it often impedes patient adherence. The masking of bad taste is therefore widely recognized by regulatory authorities as a key aspect in modern paediatric drug development. and legislation in Europe and USA is currently requiring and rewarding the development of palatable paediatric medicines. The proposed PhD research project aims to develop a crystal-engineering approach to bitter-taste masking of drug molecules commonly used in paediatric oral formulations (e.g. flucloxacillin and prednisone). The approach relies on the construction of multi-component crystals involving a bitter-tasting drug and a taste-masking agent, whereby the molecules are held together by hydrogen bonds. The taste-masking agent is either a pharmaceutically acceptable compound taste blocker, or a molecule that hydrogen-bonds with the drug in a fashion that prohibits any interaction between the drug and the taste receptors. The formation of the described multi-component crystals (i.e. cocrystals) can be achieved fast (<1h), with the use of minimal amounts of solvents (or even without) and in large quantities (>1kg) without the use of specialised equipment. The taste of the cocrystals will be assessed in vivo, including using the Brief Access Taste Aversion model. Moreover, pharmaceutical studies will assess if cocrystals could enhance material properties (e.g. tabletability) in relation with handling, manufacturability and potentially clinical performance ensuring that the outcomes of this research are fully translational.The research programme will explore the use of crystal engineering tactics in paediatric drug formulation, and aim to develop pharmaceutical cocrystals for palatable medicines. The research programme will involve the following:- Selection of active pharmaceutical ingredients (APIs) relevant to paediatric health care and identify a set of suitable cocrystal formers using data base surveys and cheminformatics- Completion of cocrystal screens for each API and finish the solid-state characterisation of the prepared cocrystals- Evaluation pharmacokinetic properties of relevant cocrystals and assess their taste using the rat brief-access taste aversion (BATA) model - Develop structure-property relationships that will enable development of guidelines for the design of palatable cocrystal using principles of crystal engineering.