Impact of Permeation Enhancers on the Release of Insulin from Tablets in Biorelevant Media.

The use of chemical permeation enhancers (PEs) to improve the permeation of peptides across gastric and intestinal epithelia has proven an effective strategy in the development of oral dosage forms of peptides. However, there remains a poor understanding of how the presence of PEs impacts the dissolution characteristics of oral formulations containing peptides, nor is it known how the complex composition of biological media can influence their behavior in vivo. This investigation sought to examine the effect of two widely studied PEs, sodium caprate (C10) and salcaprozate sodium (SNAC), on the release behavior of a model peptide, insulin, from minitablets in a variety of biorelevant media. First, the equilibrium solubilities of insulin, C10, and SNAC were determined in simulated gastric and intestinal media. Insulin, C10, and SNAC all displayed pH-dependent solubility across a physiologically relevant range of pH conditions. Moreover, at high concentrations, C10 was found to overwhelm the buffer capacity of the simulated media, increasing the pH of fasted state simulated intestinal fluid (FaSSIF) from 6.5 to 9.0, fed state simulated intestinal fluid (FeSSIF) from pH 5.0 to 8.8 and fasted state simulated gastric fluid (FaSSGF) from pH 1.6 to 9.2. Similarly, SNAC caused an increase in the pH of FaSSIF from 6.5 to 7.9, FeSSIF from pH 5.0 to 7.7, and FaSSGF from pH 1.6 to 7.6. Relative to in simulated intestinal media, the solubility of insulin was found to increase significantly in media at pH representative of saturated C10 and SNAC solutions, increasing from 0.1 mg/mL in blank FaSSIF to 14.0 mg/mL in phosphate buffer at pH 7.6 and to 23.7 mg/mL in phosphate buffer at pH 9.2, suggesting that the presence of C10 and SNAC at high concentrations could have a considerable favorable impact on insulin solubility. Furthermore, the release profiles of insulin from minitablets containing C10 and SNAC were investigated in each of the biorelevant media and compared with the release profiles of insulin from blank minitablets in the absence of PEs. Insulin release from the blank minitablets was found to be media dependent, following an apparent solubility trend. Complete release of insulin was observed in simulated gastric media; however, only between 67 and 82% release was observed in the simulated intestinal media. On the other hand, on the addition of C10 and SNAC to the formulation, greater than 90% release was observed across all media investigated. This difference in release behavior was determined to be caused by an increase in pH at the surface of the minitablets due to the presence of high local concentrations of C10 and SNAC, respectively, as confirmed by a change in color of a universal indicator solution. These findings offer a key insight into the influence that C10 and SNAC have on the dissolution characteristics of insulin from an oral dosage form in a variety of simulated gastric and intestinal media.