Modification of Peptide and Permeation Enhancer In Vitro Release Rates by Dispersion with a Gel-Forming Polymer

Purpose: Herein, we evaluated the release properties of peptides when combined with a permeation enhancer (PE) as well as a gel-forming polymer.

Methods: Octreotide was selected as a model hydrophilic peptide, while cyclosporine was chosen as a lipophilic peptide. The PEs studied were sodium decanoate (SD) and salcaprozate sodium (SNAC). To achieve synchronous release of the peptide and the PE, copovidone, a gel-forming polymer, was also included. Solid dispersions containing peptide, PE and polymer were prepared by dissolving all components in methanol followed by solvent removal. Dispersions were evaluated using powder X-ray diffraction. Surface normalized release rates of peptide, SNAC and copovidone alone and in combination were measured using Wood's intrinsic dissolution rate apparatus.

Results: Octreotide dissolved rapidly while amorphous cyclosporine release rate was essentially undetectable. The PEs and neat polymer also dissolved rapidly. However, the intrinsic dissolution rates of octreotide and SNAC differed by a factor of two. Addition of copovidone to the formulation led to synchronous release of octreotide and SNAC, controlling their release. Furthermore, both SNAC and SD enhanced the dissolution rate of the polymer, leading to very rapid release of the components from the ternary dispersion. Cyclosporine released well from dispersions when present at a very low concentration, with a deterioration in release performance being observed at higher drug loadings.

Conclusions: Based on the findings of this study, inclusion of a gel-forming polymer may help synchronize the release of a hydrophilic peptide and a PE, which in turn may improve co-localization at the epithelial membrane.

copovidone; peptide; permeation enhancer; release rate.