Finding Optimal Leuprorelin-Permeability Enhancer Complexes for Extended Release

Deborah Shalev, Department of Pharmaceutical Engineering, Azrieli College of Engineering Jerusalem, Jerusalem, Israel (debbie@jce.ac.il)
Adel Penhasi, Department Of Research And Development, Polycaps Holdings Ltd, Tel Aviv, Israel
Zeina Zaatari, Department Of Pharmaceutical Engineering, Azrieli College Of Engineering Jerusalem, Jerusalem, Israel

Leuprorelin is a peptide drug analog of the gonadotropin releasing hormone (GnRH) that is used in clinical applications including treating prostate cancer, endometriosis, and precocious puberty. It is currently administered via injection, warranting the development of an oral formulation. Peptide drugs must be protected during their passage through the gastrointestinal tract due to their metabolic and chemical instability. The large size of peptide drugs necessitates using permeability enhancers (PEs) to facilitate peptide transit through the tight junctions of the intestinal membrane.

Optimal PEs will bind peptide drugs such that: (1) The PEs will reach the intestinal membrane together with the drug to increase absorption and decrease side effects; (2) LogP of the peptide will increase upon complexation, thereby increasing the affinity of the complex to the intestinal membrane; and (3) The peptide will be stabilized in a conformation that is less susceptible to degradation by proteases.

NMR was used to determine the degree of complexation of leuprorelin with several PEs, and the structure of the bound peptide. The peptide structure was compared to the calculated structures of GnRH bound to protease receptors and was found to differ significantly, suggesting that the complexed peptide would be less susceptible to metabolic degradation. The complexes showed less polar surface area, potentially enhancing absorption. Leuprorelin-PE complexes were formulated in calcium-crosslinked alginate microspheres with high encapsulation efficiencies. FTIR and DSC showed that some of the PEs complexed the drug, some did not, and some also affected the stability of the microsphere itself. Dissolution release profiles of the stronger PE-complexed drugs from the microsphere formulations showed significant extended release compared to leuprorelin alone.

This analytic methodology is broadly applicable to peptide drugs, which are likely to become more prevalent as advances in AI continue to identify new protein-protein interactions that can be targeted by peptide drugs.

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Short Biography of Presenting Author

Deborah Shalev did her undergraduate degree, MSc in organic chemistry and PhD in NMR all at Tel Aviv University. She has been working in the area of structural biology, drug design and analysis using nuclear magnetic resonance (NMR), for over three decades. She has published almost 70 articles in peer-reviewed journals and has advised and co-advised tens of graduate and engineering-project students. Deborah’s research interests include structural biology on systems involving peptides and proteins by NMR and pharmaceutical polymer release systems studied by NMR, infrared spectroscopy, mechanical testing and differential scanning calorimetry.  She is currently conducting working on oral formulations for peptide drugs.