Thomson, Sarah Angela; (2009) An investigation into the compaction and clinical potential of mini-tablets for paediatric drug delivery. Doctoral thesis (Ph.D.), University College London (United Kingdom).

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Abstract

There are ongoing problems with administration of medicines to young children due to the lack of choice of formulation. Oral liquids are regarded as the gold standard due to dosing flexibility and ease of swallowing. Nevertheless, liquid formulations have their own limitations (e.g., taste, bulkiness, limited modified release and stability). Tablets are the most popular adult dosage form; however their use is limited in paediatrics because of swallowing issues. New regulations are requesting the development of age appropriate paediatric dosage forms. One approach showing particular promise is that of mini-tablets. This thesis investigated the development of mini-tablets for paediatric use. The main objectives were: o Evaluate the manufacturing potential of mini-tablets by comparing the differences in compaction behaviour and the effects of process variables when compressed into mini-tablets and standard size tablets. o Assess the current prescribing trends of oral liquids and solids to observe how medicines are currently prescribed to paediatrics. o Assess of the acceptability of placebo mini-tablets in children aged 2-6. An initial assessment of various pharmaceutical excipients demonstrated the potential to compact a range of materials with varying deformation mechanisms into mini-tablets. The compaction behaviour of mini-tablets was further evaluated by varying aspect ratio, tabletting speed and state of lubrication. The compaction properties were assessed by tabletability, compressibility and compactability profiles and Weibull analysis. The investigations showed that in general material response was the same when compressed into mini-tablets or standard size compacts. When internally lubricated, solid fraction normalised the data and could be used to estimate the tensile strength regardless of compact size or tabletting speed. Under varying states of lubrication the compaction profiles of mini-tablets may vary compared to standard sized tablets due to differences in frictional forces, flaw distributions and force transmission. Mini-tablets were intrinsically more varied than standard size compacts and differences in density distributions were observed. The general perception is that oral solids are suitable for children of six years and above. A review of the current prescribing trends showed that in practice a cross over between oral liquid and oral solid prescriptions was observed between the ages of 12-13 years for erythromycin (acute). This was reduced to 9-10 years for carbamazepine (chronic). Clinical investigations were carried out to assess the acceptability of 3 mm mini-tablets in children aged 2-6 (n=100). The safety of mini-tablets in this age range was demonstrated. Children aged 4 and above can swallow safely mini-tablets. Between the ages 2-4 years, children could generally swallow the mini-tablet. They were also likely to chew the mini-tablet and therefore may require training or experience before they can routinely swallow without chewing.

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