Design of oral insulin tablet formulations to enable manufacture and storage under ambient conditions

The development of oral peptide therapeutics is significantly limited by poor gastrointestinal bioavailability and instability during manufacturing and storage. Insulin, a peptide prone to enzymatic degradation, aggregation, and chemical modification, serves as an exemplary model for addressing these challenges in peptide oral solid dosage forms. While parenteral administration remains the clinical standard, oral delivery is highly desirable for its advantages in patient preference, improved compliance, and more physiologically relevant absorption. Conventional tablet manufacturing techniques, such as direct compression, expose peptides to mechanical, thermal, and hygroscopic stresses with the potential to accelerate degradation. In contrast, lyophilisation (freeze-drying), a low-stress process commonly used in parenteral formulations, enables the formation of amorphous matrices that immobilise peptides, restricting molecular mobility and mitigating degradation pathways. This thesis investigates lyophilisation as a core stabilisation strategy for oral insulin tablets capable of withstanding ambient manufacturing and storage conditions. The overarching aim was to design robust oral insulin tablet formulations that preserve peptide integrity under room temperature and moderate humidity. The research systematically examined excipient selection and processing approaches to enhance the stability of amorphous glasses. Initial studies focused on binary sugar–polymer systems to establish principles of glass stability. Sucrose proved superior to trehalose (which recrystallised under humidity stress), while high-Tg polymers polyvinylpyrrolidone (PVP) and poly(vinylpyrrolidone-vinyl acetate) (PVPVA) provided complementary benefits: PVP facilitated strong hydrogen bonding for enhanced chemical protection, whereas PVPVA offered lower hygroscopicity and greater resistance to humidity-induced plasticisation. These findings were extended to ternary insulin–sucrose–polymer systems. Optimisation via mixture design of experiments targeted elevated glass transition temperature (Tg) and onset glass transition humidity (RHg) as key stability indicators. Synergistic interactions, particularly between insulin and PVP, produced non-additive improvements, yielding optimised blends with Tg exceeding 80 °C and RHg around 60% RH. The optimised amorphous matrices were incorporated into oral tablets and compared with direct compression formulations. Both approaches maintained insulin integrity immediately after compaction, indicating resilience to mechanical stress. However, under accelerated humidity conditions, lyophilised tablets showed greater degradation attributable to sucrose hygroscopicity and the porous structure of freeze-dried material. In contrast, PVPVA-containing direct compression blends exhibited superior mechanical robustness and the highest long-term insulin stability. This thesis demonstrates that glass stability for oral peptides can be systematically enhanced through rational excipient selection and formulation design. Lyophilisation effectively generates protective amorphous matrices and supports favourable processing, yet direct compression with humidity-resistant polymers such as PVPVA provides better overall performance under ambient conditions. The identified trade-offs between chemical stabilisation, mechanical properties, and humidity sensitivity guide tailored excipient choices based on desired stability profiles. These insights offer a practical guide for developing stable, manufacturable oral peptide formulations suitable for ambient storage, thereby advancing the development of clinically viable, patient-friendly oral therapies as alternatives to injections.

Grantor dc:publisher

University College Cork

Year dc:date.issued

2025

Author dc:creator

• Giannachi, Claudia

Advisors dc:contributor.advisor

• Crean, Abina
• Allen, Evin
• Vucen, Sonja

• Lyophilisation
• Mixture design of experiments
• Humidity
• Polymer
• Dynamic vapour sorption
• Amorphous solid dispersions

Statement dc:rights

• © 2025, Claudia Giannachi.

Licence dc:rights.uri

• https://creativecommons.org/licenses/by-nc/4.0/

Language dc:language.iso

en

Handle dc:identifier.uri

https://hdl.handle.net/10468/18947

OAI identifier oai:identifier

oai:cora.ucc.ie:10468/18947