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.

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Materials

Insulin (recombinant human), obtained from Merck KGaA (Germany), was used as a model peptide in this investigation. Sodium decanoate (C10) and salcaprozate sodium (SNAC) were acquired from Merck KGaA (Germany) and BOC Sciences (New York, USA) respectively. Due to the morphology of the C10 material procured being large, flaky and brittle agglomerates, manual grinding was performed using a pestle and mortar to create uniform particles for processing. A representative image of the C10 raw material before and after grinding is shown in Fig. S1 in the Supplementary Information. SNAC material was processed and characterised as received. The solid state of the insulin, C10 and SNAC was characterised by powder X-ray diffraction (PXRD), with experimental details provided in Supplementary Information S1 and representative diffractograms shown in Fig. S2. Microcrystalline cellulose (MCC), Avicel PH102 grade, and polyvinylpyrrolidone (PVP K30), Kollidon 30 LP grade, used for tableting were donated by International Flavors & Fragrances (IFF) Cork, previously FMC Biopolymer (Ireland) and BASF (Germany), respectively. Potassium phosphate monobasic (KH2PO4) and sodium hydroxide (NaOH) used for preparation of SIF-sp buffer were reagent grade and were obtained from Merck KGaA (Germany). Water (H2O), acetonitrile (ACN), formic acid (FA), l-arginine (L-arg), anhydrous sodium phosphate monobasic (NaH2PO4) and anhydrous sodium phosphate dibasic (Na2HPO4) used for chromatography were all reagent or HPLC grade and were obtained from Merck KGaA (Germany).

A. Fagan, L.M. Bateman, M. O’Mahony, A.M. Crean, J.P. O’Shea, Direct compression peptide tablets: insights into the importance of permeation enhancer processibility and peptide stability, International Journal of Pharmaceutics, Volume 685, 2025, 126257, ISSN 0378-5173, https://doi.org/10.1016/j.ijpharm.2025.126257.

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