Design of co-lyophilised ternary insulin-sucrose-polymer systems with enhanced amorphous glass stability

The glass stability of lyophilized amorphous peptide formulations, intended for incorporation into solid oral dosage forms, require stabilisation against the challenges of manufacturing, storage and handling temperature and humidity. High glass transition temperature (Tg) polymers, polyvinylpyrrolidone (PVP) and polyvinylpyrrolidone-vinyl acetate (PVPVA), were added to insulin-sucrose formulations to enhance glass stability when exposed to temperature and humidity. Tg and onset glass transition humidity (RHg) parameters were experimentally determined as indicators of formulation glass stability with respect to temperature and humidity, respectively. A mixture design of experiment approach was employed to determine the influence of insulin, sucrose and polymer composition on formulation Tg and RHg. Statistical regression models were established to evaluate the relationship between formulation composition and the corresponding glass transition parameters, Tg and RHg. Phase separation noted for PVPVA-containing formulations, undermined regression model goodness of fit. Insulin content was shown to have a negative effect on both formulation Tg and RHg. Formulation Tg appeared to be influenced by insulin's dynamical temperature rather than a previously reported insulin Tg value. Insulin-sucrose and insulin-polymer interactive effects resulted in increased Tg and RHg values, indicating enhanced formulation glass stability. Formulation optimization for maximized Tg and RHg identified a formulation composed of 26 % w/w insulin, 40 % w/w sucrose, and 34 % w/w PVP, with a predicted Tg of 82 °C and RHg of 60 % RH. The enhanced glass stability of the ternary insulin-sucrose-polymer formulations offers potential advantages for the manufacture, storage and handling of peptide containing oral dosage forms.