2016-07-30, Machado, Alexandra H.E., Kokubo, Tohru, Dujovny, Gabriela, Jones, Brian, Scialdone, Claudio, Bravo, Roberto, Kuentz, Martin

Water is known to exhibit pronounced effects on lipid-based formulations (LBFs) and much research has focused on aqueous dispersion and dilution behavior regarding biopharmaceutical performance. From a product quality perspective, it is also critical to study a range of lower water amounts in formulations with respect to capsule filling. The present work addressed the need for a better understanding of LBF microstructure by taking percolation theory into account. The effects of increasing amounts of water on LBFs were analyzed by conductivity, water activity, time-domain nuclear magnetic resonance, and diffusing wave spectroscopy. Results were interpreted using percolation theory and preliminary mechanical tests were conducted on gelatin and hypromellose (HPMC) capsule shells. For both LBF systems, increasing water amounts led to marked changes in the microstructure of the formulations. Percolation laws could be fitted adequately to the data and thresholds were identified for the formation of continuous water channels (ϕwc~0.02-0.06). A new theoretical model was proposed for water activity. The preliminary shell material studies showed that the threshold for generating water channels in the formulation could be correlated to mechanical changes of the capsule shell that were relatively more pronounced in the case of gelatin. This mechanistic study demonstrated the importance of understanding and monitoring of microstructural changes occurring in LBFs with increasing amounts of water, which will help to design quality into the final dosage form.

2015-10, Kendall de Kruif, Jan, Varum, Felipe, Bravo, Roberto, Kuentz, Martin

The development of novel systems with oral protein delivery as ultimate goal represents an important field of pharmaceutics. Prilling of protein-loaded polymeric solutions into lipid-based hardening baths could provide here an attractive formulating technology. As the obtained microgel dispersion can be directly capsule-filled, no drying step is required and thermal drug degradation is avoided. This study aims to find excipient combinations for the novel prilling process and investigate systematically diverse material and process factors. Bovine serum albumin and mono-N-carboxymethyl chitosan were selected as model protein and prilling polymer, respectively. The prilling suitability of 880 formulations was screened with 60 ternary phase diagrams comprising two co-solvents, 10 different glycerides, and three so-called complementary excipients. Preliminary capsule compatibility was tested for one month on 245 formulations in hard and soft capsules with different shell materials. Ternary phase diagrams' center points were used to evaluate morphology, encapsulation efficiency, and protein stability of the prilled microgels. As result, several formulations proved suitable for prilling and compatible for capsule filling. Statistical analysis using partial least square regression revealed significant factors regarding different quality attributes of microgel dispersions. Therefore, an improved understanding was obtained for this promising drug delivery approach.