Taste masking medicines for children through cocrystal engineering

Lead Research Organisation: University College London
Department Name: Chemistry

Abstract

Unacceptable palatability (i.e. taste) 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 a major goal in paediatric pharmaceutical development and is widely recognized by regulatory authorities as a key aspect in modern paediatric drug development. In fact, legislation in Europe and the USA is currently requiring and rewarding the development of medicines for children at the same time as for adults. Plenty of highly relevant APIs (e.g. abacavir, praziquantel, artemisinin) exhibit unpleasant taste characteristics. The proposed research project aims to develop a crystal-engineering approach to bitter-taste masking of drug molecules commonly used in paediatric oral formulations. 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 that exhibits an intense pleasant taste to obscure the bitter taste of the drug upon dissolution in the mouth, or a molecule that hydrogen-bonds with the drug in a fashion that prohibits any interaction between the drug and the taste receptors. Successful taste masking using cocrystallization will provide a safe and efficient tool for preparation of palatable paediatric medicine. A gold standard taste masking technology will be developed that can be utilized to formulate a broad range of hydrophilic, lipophilic and ionic active pharmaceutical ingredients.

Publications

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Studentship Projects

Project Reference Relationship Related To Start End Student Name
EP/R512400/1 01/10/2017 31/03/2022
1954819 Studentship EP/R512400/1 25/09/2017 30/03/2022 Divya Amin
 
Description Taste governs how food or medicines are perceived when taken. The perception of taste can influence the acceptability of a medicine. Poor patient compliance can often attribute to a wide range compliance related issues. Taste is far too frequently neglected in early phase paediatric pharmaceutical development and is only taken into consideration towards the end of the formulation process. Recent advances in crystal engineering see more focus being placed on how altering the crystalline landscape can impact the taste of an active pharmaceutical ingredient (API). Our ongoing research aims to explore the functionality of cocrystallisation as an alternative route (compared to traditional methods used) to improve taste of APIs.

Caffeine, Praziquantel, Lamotrigine, Ketoprofen and Prednisolone are the medicines currently being investigated. Cocrystallisation is a relatively contemporary approach to solid state medicinal development. It has been proven to improve the physiochemical properties of active pharmaceutical ingredients (APIs). However, taste is an organoleptic property that has often been neglected during commercial development of paediatric APIs. Our research so far has proven that bitter tasting APIs can be made into cocrystals that are appropriate for paediatric formulations.

So far the investigations into the medicines have shown the 3 approaches that we have undertaken can create novel molecular complexes that have been otherwise difficult when it comes to altering solid-state behaviour. The bitter tasting APIs have formed 19 novel molecular complexes with the chosen constituents with the hope that they will exhibit less of a bitter taste than they currently do.

Besides exploring new avenues to improve the palatability of relevant pharmaceuticals, we have also engaged in studies of polymorphic transformations of our target cocrystals, with a particular focus on caffeine. A part of this work was published in a collaborative effort with colleagues at the University of Cambridge and De Montfort University. The reported study (CGD, 2019, 20, 1119-1129) described how caffeine:citric-acid cocrystals are affected by the disappearing polymorph incidents, a phenomenon that has mystified the crystal engineering and solid-state pharmaceutical development community for over 25 years. The work involved compiling a comprehensive report of all disappearing polymorph examples, whilst attempting to rationalise the puzzling occurrence/lack of occurrence.
Exploitation Route The ultimate goal of the research described is to develop novel pharmaceutical materials with applications in paediatric drug formulations. Particular emphasis will be placed on studies that aim to develop strategies that may be employed to alter or mask the taste of APIs by design using cocrystallisation. Whether or not cocrystallisation is a viable approach to taste engineering, has yet to be investigated within scientific circles. The relationship between taste and solid-state behaviour is a bond that requires attention, particularly when developing substances for paediatric patients. Over the next year, focus will be placed on the kinetic release of the substances synthesised within the laboratory. A fit for purpose oral dissolution method will be designed for the ionic cocrystals in collaboration with the Tuleu group (UCL School of Pharmacy), followed by a solubility residue study, where HPLC analyses will be conducted on the material derived from the dissolution studies.

Following the analysis of pharmacokinetic data from the ionic cocrystals, an assessment will be carried out to determine whether or not it will be appropriate to conduct taste sensing measurements on the cocrystals (in collaboration with the Tuleu group). If taste sensing measurements are conducted, the rodent Brief Assessment Taste Aversion (BATA) model for taste assessment of pharmaceutical compounds and formulations will be used. This method of taste assessment provides results that can be comparable to those from a human taste panel, with correlation between the two being observed.
Sectors Healthcare,Pharmaceuticals and Medical Biotechnology