Oral insulin dosage forms: assessment of solid-state stability, compaction behaviour and permeation enhancers’ impact on dissolution performance
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Date
2025
Authors
Fagan, Andrew
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Publisher
University College Cork
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Abstract
Since the isolation of insulin in the 1920’s, there has been significant interest in developing oral peptide dosage forms given their numerous advantages, including non-invasive administration and improved patient compliance. Despite recent progress, as evidenced by the approval of products such as Rybelsus® and Mycapssa®, the poor stability of peptides and their limited permeability continue to restrict oral bioavailability and hinder widespread adoption of this approach. Among the approaches developed to address the oral bioavailability challenge, the use of permeation enhancers (PEs) has proven the most successful. However, from a formulation development perspective, the co-formulation of peptides and PEs presents a number of technical challenges that remain poorly investigated. Furthermore, the stability of peptides to storage and processing conditions is a primary concern during oral dosage form development and manufacture. Accordingly, this thesis aimed to assess the importance of stability and permeation enhancers in the development of peptide tablets, using insulin as a model peptide and sodium decanoate (C10) and salcaprozate sodium (SNAC) as model PEs.
In the first part of this thesis, we sought to investigate the impact that storage and processing conditions have on the solid-state stability of insulin. Insulin was observed to degrade similarly in the solid-state as in solution, where the primary chemical degradation pathway was observed to be deamidation, while aggregation proceeded via a disulfide exchange mechanism. Interestingly, there was no evidence of unfolding occurring in the solid-state. The rates at which the different physical and chemical degradation pathways occurred appeared to follow Arrhenius-like kinetics. Overall, temperature had the largest effect on degradation, with reaction rates increasing as storage temperature increased. Humidity, on the other hand, was found to have a temperature dependent effect, where moisture had minimal impact on degradation rates at 25°C and 40°C, but had an important effect at 60°C. This temperature-dependent effect of humidity was determined to be due to a change in moisture sorption characteristics at 60°C relative to 25°C and 40°C, which increased the overall reactivity of the material. In addition to temperature and humidity, the effect of high compaction pressures on the stability of insulin was also assessed. Compaction pressure was found to have no significant impact on the conformational stability of insulin in the solid-state or on reconstitution, nor was there any evidence of aggregation occurring during compaction.
In the next part of the thesis, the role of PEs in the development of insulin compacts was examined. We firstly assessed the suitability of C10 and SNAC for processing via direct compression. Overall, SNAC displayed superior tabletability, compactibility and compressibility profiles, due to its greater tendency to deform plastically and its greater capacity for strong interparticulate bonding. SNAC did, however, display poor flow character. C10, on the other hand, possessed passable flow character but demonstrated an inability to form strong compacts at suitable porosities, as exhibited by its poor tabletability, compactibility and compressibility profiles. The compaction properties of both C10 and SNAC were found to be substantially improved on addition of MCC and PVP as commonly used direct compression excipients, and formulations consisting of 72% C10 or SNAC, 20% MCC/ 5% PVP and 3% insulin enabled acceptable direct compression compacts to be produced. Next, we sought to explore the influence of having such high C10 and SNAC contents present in the formulations on the release characteristics of insulin from the compacts produced. Overall, C10 and SNAC were found to have a profound impact on insulin release behaviour, demonstrating an ability to elevate the pH at the surface of the minitablets, thereby increasing insulin solubility at the dissolution interface in comparison to the bulk media and increasing its total release from the compacts.
In conclusion, in this thesis we have demonstrated the important role that insulin stability and PEs have on the successful development of an oral insulin product. From a stability perspective, our results indicate that the insulin raw material used would be suitable for handling for short periods of time in the controlled environmental conditions typically used during tableting. Furthermore, we have highlighted the impact that PEs have on the performance of insulin compacts, and it is clear that careful formulation design will be key for optimising the manufacturability and release kinetics of an oral peptide dosage form containing PEs.
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Keywords
Oral peptide delivery
Citation
Fagan, A. 2025. Oral insulin dosage forms: assessment of solid-state stability, compaction behaviour and permeation enhancers’ impact on dissolution performance. PhD Thesis, University College Cork.