Orally disintegrating mini-tablets for children: Using interactive mixtures to obtain mini-tablets of high dose-homogeneity

Abstract

Administration of drugs in children presents several challenges and requires appropriate dosage forms in order to achieve the correct pharmacotherapy. Today, most dosage forms are developed for adults, not children, and therefore new dosage forms are required to improve the administration of drugs in children of all ages. One new and promising system is the orally disintegrating mini-tablets. Using this system, the number of units taken can be personalized in accordance to weight or age. Studies have shown that orally disintegrating mini-tablets can be administered safely in children down to 6 months of age. These systems require high dose-homogeneity because of their small size. In this project, the use of interactive mixtures, where micronized drug particles adhere to the surface of larger carrier particles, is investigated as means to obtain high dose-homogeneity. The effect of different factors on the homogeneity of the interactive mixtures were investigated such as mixing time, mixing method, sampling size and particle size of the carrier particles, using granulated mannitol (Pearlitol® 100SD, Roquette Pharma, France) of three different particle size fractions (63-90 μm, 90-125 μm and 125-180 μm) as carrier particles and 1 % (w/w) micronized sodium salicylate (< 10 μm) as active substance. The results showed that longer mixing times (24 hours or more), use of a tumbling mixer with diffusive mixing as main mixing mechanism and use of the largest investigated particle size fraction (125-180 μm) gave the highest homogeneity in the interactive mixtures. The interactive mixtures were used to prepare orally disintegrating mini-tablets, using a custom-made compaction simulator. The mini-tablets were characterized according to set criteria by the European Pharmacopoeia. Uniformity of mass and content, mechanical strength and disintegration time of the mini-tablets were tested. The prepared orally disintegrating mini-tablets showed high uniformity of mass and content, sufficient mechanical strength and a short disintegration time.

In conclusion, several factors are important for preparation of interactive mixtures. The interactive mixtures gave mini-tablets with high dose-homogeneity, and were suitable for preparation of orally disintegrating mini-tablets for use in children.