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Children are averse to unpalatable medicines. A medicine will only elicit its desired effect if it is taken by the patient, therefore unpalatable medicines threaten the effective treatment of paediatric indications. Regulators thus now require all new medicines to have associated plans for paediatric formulation development; key to which is palatability testing. Therefore, there is a real need to enhance our understanding of the nascent area of pharmaceutical palatability testing. Much of this research has focused on the rat brief access taste aversion (BATA) model, which uses water-deprived rats to evaluate aversiveness of a given sample by counting the number of rat licks relative to water and has the distinct advantage of being used preclinically due to the absence of human participants. The overall aims of this research were to: explore the methodological limitations of promising palatability assessment methodologies; expand the formulation repertoire and push the limits of the BATA model; and leverage the data from the BATA model to minimise animal use. Our understanding of pharmaceutical palatability testing has been enhanced. Key questions such as the number of participants necessary for a human pharmaceutical taste panel are now known. The limits of the BATA model have been explored, and we now know that it can provide information on mouthfeel as well as taste, enabling assessment of more complex liquid oral dosage forms such as suspensions. Furthermore, by leveraging the data from the BATA model, a methodology for assessing solid oral dosage forms and an in silico model for prediction of palatability were developed. This work has both answered and yielded questions and more work is need to improve pharmaceutical palatability assessment and thus children's medicines. However, it is clear we are on a path towards more palatable children's medicines and thus more effective treatment of paediatric diseases.

A medicine will not elicit its desired therapeutic effect if the patient is not able or willing to take it. The specific needs of the target population must be taken into account in the design of medicines. Evaluation of the effect of formulation factors on patient’s acceptability could guide the development of better medicines for children. Flexible solid oral dosage forms, including multiparticulates and (oro)dispersible formulations, offer advantages over conventional solid and liquid dosage forms to meet the needs of paediatric patients. These advantages include favourable stability profile, suitability for taste masking, flexibility of dose titration and convenient administration. The overall aims of this research were to identify barriers for the development of acceptable medicines for children, to explore methodology for palatability and patient’s acceptability testing and to generate evidence of acceptability of flexible solid oral dosage forms. Methodological tools for the assessment of palatability and acceptability were developed and the use of such tools was explored through a series of investigations in healthy volunteers using model placebo formulations. Pharmaceutical formulation work was performed to optimise formulation design and choice of excipients, integrating manufacturability and patient’s acceptability criteria. A direct comparison between palatability and acceptability outcomes in children and adults was performed, which highlighted the value of conducting studies in adults to provide initial guidance on formulation design. Some of the key formulation factors that affect acceptability of flexible solid oral dosage forms were identified, which can be used to guide the development of more palatable and acceptable medicines. This research also evidenced methodological barriers in the assessment of palatability and patient’s acceptability which are thoroughly discussed in this thesis and will need to be overcome in the future. The knowledge generated by this research is applicable not only to the development of medicines for children, but also for other subsets of the population.

The screening and careful selection of excipients is a critical step in paediatric formulation development, as excipients that are commonly used in adult medicines have been associated with elevated toxicological risks and safety issues in children. An evidence-based approach of toxicity assessment of excipients with the least possible amount of testing is the way forward to addressing the issues with excipients in paediatrics. However, the information available on their safety in paediatric age groups is sparse and distributed over various sources Aim: To design and implement the Safety and Toxicity of Excipients for Paediatrics ("STEP") database for quick and reliable access of the safety information of excipient to facilitate paediatric product development. Method: Three-phase framework was developed. Phase 1: The need assessment study was conducted with potential users through a global survey reporting their information needs and interest in the STEP database. Phase 2: The potential users input was employed for designing the STEP database and developing methodologies to retrieve, evaluate and extract the information into the database. Phase 3: Evaluation framework was developed to evaluate the usability of the STEP database. Result: The survey emphasized the need for STEP database. 90% of respondents reported owning the STEP database. The survey helped in identifying needs and potential obstacles in developing the database. In response, the database that provides easy access to the safety and toxicity data of excipients was developed. The methodology adopted provides an in-depth retrieval and evaluation of the safety and toxicity data of excipients. Usability testing revealed design vulnerabilities, and the system was adapted to address the user's needs and preferences accordingly. Conclusions and Implications for Practice: Through a comprehensive development process including user surveys, the freely accessible STEP database was launched. It is used successfully with more than 2500 users.

Evolving regulatory reforms have strengthened the global focus towards developing age- appropriate and acceptable formulations for paediatric patients. The European Medicines Agency (EMA) also mandates that acceptability of paediatric preparations should be evaluated with children as an integral part of pharmaceutical and clinical development. A review of literature highlights the current paucity of evidence to support the development of dosage forms that are suitable for children of different ages and health backgrounds. Important knowledge gaps also exist in the methodological considerations for conducting acceptability studies. The overall aim of this research was to determine the attitudes, preferences and behaviours of children, caregivers and healthcare professionals towards solid oral dosage forms. Age- adapted questionnaires were systematically developed and pre-tested in collaboration with young people, in keeping with the principles of patient and public involvement in research. A diverse sample of 590 school children and adolescents and over 400 caregivers were surveyed in hospitals, community pharmacies and schools. Attitudes towards dosage forms differed primarily based on age and prior use. Precedence for chewable dosage forms and tablets was identified, while capsules and multiparticulates administered with food were less acceptable. Another aspect of the research identified the prevalence of swallowing difficulties in healthy young adults. These participants showed a preference for taking two smaller dosage forms over a larger size, and for capsules over tablets. In an acceptability trial with placebo capsules, over 95% of young adults were able to swallow size #1 capsules. The inclusion of flavour had variable effects on acceptability . Healthcare professionals showed reservations towards solid oral dosage forms and many favoured liquid medicines for paediatrics. This thesis highlights the gap between regulatory expectations, industrial feasibility and clinical ideals. This should be addressed, to ensure that legislative reforms and global initiatives will have a positive impact on paediatric therapeutics in practice.

The prenatal use of medicines and recreational substances is of significant importance because there is insufficient information on the effects of medicines and recreational substances on pregnancy outcomes. In addition, literatures on health beliefs of pregnant women about medicine and recreational substance use are lacking. The aim of this thesis was to investigate medicine and recreational substance use during pregnancy in an antenatal population of London. The study was approved by the ethics committee. The first part of the thesis was a prospective cohort study of medicine and substance use across all trimesters (using survey methods), and the pregnancy outcomes (using the medical records); the second part was a qualitative study of the health beliefs of pregnant women which employed semi-structured telephone interviews and the Health Belief Model as a framework for data collection and analysis. The results of the prospective study demonstrated that the prevalence of use of prescription, over-the-counter and complementary and alternative medicines during at least one trimester were 32.5%, 50.2% and 57.1% respectively. The prevalence of exposure to alcohol, cigarette and illicit substances were 16.0%, 3.5% and 0.9% respectively. However, due to limited sample size, the study could not demonstrate an association between the medicines and substances used and increased risk of congenital anomalies in the baby. The qualitative study indicated that pregnant women’s adherence to medicines could be explained by women’s perception of the severity of a medical condition, risks of non-adherence to the medicine as well as anxiety about the risks of the medicine on the foetus. In the case of substance use, a low risk perception could be used to explain women’s behaviour. Healthcare professionals have a responsibility to counsel pregnant women about the benefits or risks of medicines and substances, informed by the best evidence, and guided by the women’s perceptions.