Oral formulations for children : the microstructure of functionalized calcium carbonate as key characteristic to develop age-appropriate and compliance enhanced formulations

The development of age-appropriate formulation for children is a challenging task. Children cannot easily swallow a conventional tablet, therefore alternative dosage forms that can be administered orally are required. These are buccal tablets, oral films as well as orally disintegrating tablets or rapid disintegrating tablets. The age-appropriate formulations are contributing enormously to compliance, as such formulations ensure acceptable palatability. Therefore, there is a need of suitable excipients. Functionalized calcium carbonate (FCC) has already been investigated for different applications. It was used to develop orally disintegrating tablets (ODTs) because the tablets were characterized by high physical stability at low compressive stress. To ensure acceptable palatability, a taste masked and mouthfeel enhanced formulation based on FCC-granules was developed and tested for its acceptance in 20 healthy volunteers. This formulation was also analyzed with a novel in vitro model to determine rate constants for liquid sorption and disintegration as well as disintegration time. As a further step, the stability of the FCC-based granules combined with two model drugs were investigated in form of tablets for oral suspension (TOS). The influence of stress conditions on content, disintegration time and hardness was assessed. To understand and describe the distribution of drug in different drug loads, moxidectin containing mini-tablets were analyzed with synchrotron X-rays micro tomography. Moreover, a mineral polymer composite material (FCC-PCL) was developed and investigated for the use in geometry constrained sustained release formulation in form of a tablet-in-cup (TIC) device. The results show that the FCC-based ODTs with enhanced mouthfeel and taste-masking show good acceptability in vivo and the analysis with the in vitro model showed, that the ODTs do not need more liquid to completely disintegrate than available in the human mouth. The additional excipient in the formulation did not change the characteristics of the FCC under pressure. TOS were found to be stable in stress conditions and there was no chemical degradation detected. Humidity and temperature affected disintegration time, highlighting the importance of correct storage conditions. It was possible to analyze content distribution based on the data obtained from synchrotron X-ray micro tomography. The composite material was successfully used in the TIC device providing higher drug load than a commercial product by ensuring the same sustained release kinetic. The FCC, with the unique lamellar structure on its surface, is able to provide a novel formulation platform based on a ready-to-use granule that ensures fast disintegration times, whether formulated in ODTs, TOS or mini-tablets. It was also possible to compact mini-tablets with different drug loads. The composite material showed to have plastic flow under pressure which is based on the fact that the FCC particles are embedded in the PCL. Even though they were exposed to shear stress the lamellae stayed intact and resulted in stable compacts, whereas the pure polymer PCL is not compactable. It can therefore be concluded, that the microstructure is the key characteristic to the development of age-appropriate as well as compliance enhanced formulations.