Release Rate of Peptides From Formulations Containing Permeation Enhancers

Title: Release Rate of Peptides From Formulations Containing Permeation Enhancers
Abstract: Several oral dosage forms containing beyond rule of five peptide drugs have been commercialized in recent years. Due to challenges with permeability and/or solubility, enabling excipients, such as permeation enhancers, are added to the formulation. Common permeation enhancers of current interest include sodium decanoate (C10) and salcaprozate sodium (SNAC), which have surfactant-like properties. Permeation enhancers temporarily disrupt the gastrointestinal membrane, enhancing the absorption of large, hydrophilic molecules, and relatively high concentrations of the PE are required for membrane disruption. Furthermore, permeation enhancers such as C10 are absorbed very rapidly, so the concentration rapidly diminishes. As a result, it is critical that the appropriate concentration of the permeation enhancer is achieved at the membrane surface, and that the peptide is also present as the membrane becomes disrupted. Consequently, it is of interest to understand the release performance of common permeation enhancers from solid formulations and compare to the release of peptides. We have used two peptides to bookend peptide hydrophilicity variations; octreotide, a highly hydrophilic peptide with a molecular weight of 1019 D and a log P of ~ -1, and cyclosporine, a lipophilic peptide with a molecular weight of 1203 D and a log P of ~4. C10 and SNAC were evaluated as typical permeation enhancers. Using Wood's dissolution apparatus, the intrinsic dissolution of neat components can be determined and compared. These are expected to predict the relative release rates from physical mixtures of the permeation enhancer and the peptide, assuming no interactions occur between the components. We also consider formulation strategies to synchronize release of the permeation enhancer and the peptide. As peptide oral solid dosage forms become increasingly utilized, release studies such as those described in this talk will play increasingly important roles in formulation optimization.