Direct compression peptide tablets: insights into the importance of permeation enhancer processibility and peptide stability.

Abstract

Much of the remarkable advancements in oral peptide delivery have been achieved through the use of chemical permeation enhancers, such as sodium caprate (C10) and salcaprozate sodium (SNAC). However, co-formulation of peptides with permeation enhancers in an oral product introduces several processing and formulation challenges which require further investigation. This investigation sought to rationalise the development of direct compression insulin compacts, using C10 and SNAC as model permeation enhancers, respectively. The physical and mechanical properties of C10 and SNAC were first assessed to evaluate their suitability for processing via direct compression. Overall, C10 displayed passable flow character, however, poor tabletability, compactibility and compressibility profiles were obtained. SNAC, on the other hand, exhibited superior compaction properties, though its flow character was poor. Improvement in the compaction properties of both materials were observed on addition of commonly used direct compression excipients microcrystalline cellulose (MCC) and polyvinylpyrrolidone (PVP) K30, and formulations consisting of 72 % C10/ SNAC, 20 % MCC, 5 % PVP and 3 % insulin were selected for production of direct compression compacts at compaction pressures of 100 and 200 MPa. The compacts produced exhibited complete release within 30 min, and this release behaviour was not significantly affected by the compaction pressure used. Furthermore, the stability of insulin after compaction at 200 MPa, and on storage of the compacts at 40°C/ 75 % RH for 1 month was assessed. Insulin displayed excellent physical stability to mechanical stress, where no evidence of unfolding or aggregation was identified. Moreover, on storage of the formulations at accelerated stability conditions for 1 month, a significant reduction in overall deamidation and aggregation tendency was observed on blending of insulin within the direct compression formulations in comparison to raw insulin material stored under the same conditions, independent of the permeation enhancer used. These results offer a key insight into the influence that formulation components have on the manufacturability of direct compression peptide formulations and the stability of the peptide during compaction and storage.