Paediatric patient centric development of novel processes for the formulation of orally disintegrating tablets

Abstract

Following the European regulation for paediatric formulations, the demand for the production of paediatric dosage forms has escalated. Managing the clinical needs of children is challenging, especially as this must often be accomplished using adult medicine formulations. For this reason, further paediatric dosage forms need to be developed to address their clinical needs. There are various formulations which can be administered via the oral route including tablets, capsules, liquids and chewable tablets. It is essential to mention orally disintegrating tablets (ODTs) which have been a popular area of research for scientists in the last decade. The overarching aim of this thesis was to develop novel oral dosage forms for children and young adults aged 6 to 18 years. The principal theme of this thesis is sub divided into two main areas of research: the first area evaluated dosage form preferences in children and young adults and assessed the key pragmatic dosage form characteristics that would enable formulation of patient centred ODTs; the second area focused on a wide range of laboratory-based investigations for development of low dose blends and pre-blends of ODT formulations using various blending techniques. The results of clinical investigations revealed that ODTs are a preferred dosage form among children because they combine the advantages of both solid and liquid dosage forms, without incorporating their disadvantages such as difficulty in swallowing and lack of stability respectively. Healthcare professionals indicated that taste and disintegration time were the most important factors to provide both suitable dose units and acceptable medicines for paediatric patients. Results from powder blending indicated that the dry particle coater provided a robust platform for obtaining content uniformities at 1% and 0.5%w/w API using non-sieved carriers. Micro crystalline cellulose as a carrier showed superior flow properties and better drug content uniformity for both geometric and ordered blending techniques. Furthermore, the co-processed excipients containing 86.5% w/w of milled-mannitol, 12% w/w pregelatinised starch and 1.5% w/w silica using Aston Particle Technology (APT’s) new coating technique can be utilised as a potential multifunctional directly compressible ODT pre-blend. An investigation into the role of moisture content on micro/macro properties of ODTs illustrated that moisture considerably affects the consolidation characteristics of blended powders; and the extent of consolidation and the bonding of particles depend, not exclusively on moisture content, but also on the powder processing conditions. In conclusion this work supports the World Health Organisation (WHO)’s claim for a paradigm shift from liquid towards ODT dosage forms for drug administration to young children older than 6 years. Data from this study will equip formulators to prioritise development of key physical/performance attributes within the delivery system.