Development of formulations and drug delivery strategies for paediatrics use is scientifically challenging due the broad age ranges presented within this population, resulting in varying requirements in achieving optimised patient outcomes. Though the oral route of drug delivery remains the preferred option for patients due to its convenience, there are a number of problematic issues such as difficulty in swallowing and palatability of the oral medicine that are specific to this population. On the other hand, parenteral route of drug administration is not well accepted in this population due to needle-related fear and pain. For these reasons, a plethora of alternative routes of drug administration have been investigated. One of such approaches is via transdermal route. The readily accessible and large surface area of the skin provides a promising site for delivery of drugs into the body. However, the stratum corneum (SC) offers a formidable barrier to transdermal transport due to its lipophilicity and highly complex cellular architecture. Microneedle (MN) delivery has been proposed as a strategy to breach the SC barrier function in order to facilitate effective transport of molecules across the skin. This strategy involves the use of micron-sized needles fabricated from different materials and using different geometries to create transient aqueous conduits across the skin. In this present study, . poly(methyl vinyl ether/maleic acid) (PMVE/MA)-based polymeric MNs, namely soluble MN and hydrogel forming MN, were fabricated using a micromoulding technique and incorporating two model drugs commonly used in paediatric patients, i.e. caffeine and lidocaine hydochloride. The feasibility and efficacy of these MNs for potential paediatric dosing were investigated in a series of in vitro and in vivo studies, by employing. The views pertaining MN technology were sought among school children in Northern Ireland (via focus groups discussion), members of UK general public and UK paediatrician (through online surveys), in order to determine the perceived perceptions, acceptance, barriers and concerns for future adoption of this technology. In this thesis, polymeric MNs have been shown to dramatically enhance the skin permeability of the model therapeutic molecules either in vitro or in vivo. Furthermore, this thesis also highlighted a large consensus on the opinions of MN technology among schoolchildren, UK paediatricians and the general public, with respect to its potential usefulness of delivering various types of therapeutic substances for the benefit of paediatric population

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La population néonatale est la population pédiatrique la plus vulnérable car immature et celle ayant probablement les besoins en médicaments les plus importants, compte tenu de la spécificité des pathologies néonatales. Pour autant, un grand nombre de médicaments sont prescrits en dehors des conditions de leur AMM, ne permettant pas leur utilisation optimale. Cela est lié notamment aux difficultés de la recherche clinique chez le nouveau-né. L’objectif de cette thèse est d’analyser les différentes étapes de l’évaluation des médicaments chez le nouveau-né et de discuter les méthodes permettant de les optimiser, en centrant la réflexion sur la classe des médicaments anti-infectieux. En effet, ces médicaments sont parmi les plus prescrits hors AMM chez le nouveau-né, prématuré et à terme, bien qu’ils soient commercialisés depuis de nombreuses années. Nos travaux ont porté sur les différentes étapes de leur évaluation, illustrées chacune par un exemple. 1) Analyse des spécificités de la population néonatale et des pratiques d’utilisation des médicaments, illustrées par l’enquête Européenne sur l’utilisation de la ciprofloxacine et du fluconazole dans les unités de soins intensifs néonatales. Cette enquête a mis en évidence la grande variabilité des pratiques entre les pays mais aussi entre les centres d’un même pays, 2) Recueil et analyse des données disponibles, illustrés par la revue exhaustive de la littérature sur l’utilisation de la ciprofloxacine pour le traitement d’infections néonatales à germes Gram négatif, 3) Détermination de la posologie adéquate. L’implémentation d’outils de modélisation et de simulation de données est particulièrement préconisée chez le nouveau-né. La validation de ces modèles est importante, illustrée ici par une étude d’évaluation externe des modèles pharmacocinétiques de population de la vancomycine chez le nouveau-né. 4) Conception et réalisation des essais cliniques illustrées par l’exemple du développement clinique de la ciprofloxacine en néonatologie. La revue de la littérature sur les essais contrôlés randomisés évaluant les antibiotiques chez le nouveau-né a montré que la qualité des résultats de ces essais était globalement faible. L’analyse des obstacles à leur réalisation a permis de discuter les alternatives méthodologiques afin de contourner les difficultés pratiques, cliniques et éthiques sous-jacentes. / Neonates represent the most vulnerable paediatric population and probably the one with the greatest needs in medicines with regard to the specificities of neonatal diseases. Nevertheless, the off-label prescribing of drugs with no marketing authorisation, consequentlywithout information for their proper use, is widespread in neonatology. This situation is related to the difficulties of clinical research encountered in this population. The objective of this thesis is to analyse the different steps of drug development in neonates and to discuss the possible methods to optimize drug evaluation. To illustrate this development, we expose examples from the evaluation of anti-infective agents in neonatology. These drugs are very often concerned by a use outside their product licence in term and preterm neonates, despite the fact that they have been marketed for many years. This thesis includes studies concerning the different steps of their development illustrated by examples. 1) Evaluation of the specificities of the neonatal population and of drug prescribing. This was demonstrated by the results of a European survey on the use of ciprofloxacin and fluconazole in neonatal intensive care units. The surveys’ results underline the considerable variability in drug prescribing observed between different countries but also between units in the same country. 2) Analysis of available data, illustrated by the systematic review of the literature on ciprofloxacin use for the treatment of Gram negative neonatal infections, 3) Definition of optimal dosing. Use of modelling and data simulation approaches should be particularly favoured in neonatal drug research. Correct validation of models should be performed as illustrated by the external validation of vancomycin population pharmacokinetic models. 4) Design and implementation of clinical trials. This step has been illustrated by the clinical development of ciprofloxacin in neonatology. The review of all randomised controlled trials evaluating the therapeutic and prophylactic use of antibiotics in neonates showed that these trials are poorly designed, conducted and reported. Different methods of evaluation should be considered and further developed to circumvent the difficulties in drug evaluation and ensure the efficient and safe use of antibiotics.