Small intestine-permeable cyclic peptides enable foundational advances toward oral insulin development

A research group led by Associate Professor Shingo Ito from the Faculty of Life Sciences at Kumamoto University has established groundbreaking foundational technology toward realizing oral insulin. Their work is expected to accelerate the development of new diabetes treatment drugs. The findings were published in Molecular Pharmaceutics.

Insulin injections are essential for blood glucose control in diabetes patients. However, the physical and psychological burden of daily injections significantly reduces patient quality of life. This is why making insulin available as an oral medication has been a long-standing goal.

However, insulin is easily broken down by digestive enzymes in the gastrointestinal tract, including the stomach and intestines, and there is no transport mechanism in the small intestine to absorb insulin. For these reasons, oral insulin had not been achieved before.

The research group had previously made an original discovery of a small intestine-permeable cyclic peptide (DNP peptide) that promotes intestinal absorption of macromolecular drugs. They reported that mixing this DNP peptide with zinc-stabilized insulin hexamers for oral administration could lower blood glucose levels in mice. However, the pharmacological effect was weaker than subcutaneous injection, requiring high doses of insulin.

Led by Doctoral Student Shoma Chikamatsu, the researchers developed two methods for attaching their original DNP peptide to insulin, successfully achieving a dramatic improvement in oral insulin absorption.

First, the team synthesized D-DNP-V peptide by linking an insulin-binding peptide to a DNP peptide composed of D-amino acids. Simply mixing this peptide with zinc-stabilized insulin hexamers used in injectable formulations and allowing them to interact resulted in significant improvements in oral absorption. As a result, blood glucose levels in diabetic model mice dropped to normal ranges.

Furthermore, stable blood glucose-lowering effects were observed even with once-daily oral administration continued over three days. Next, the group synthesized a DNP-insulin conjugate by directly linking the DNP peptide to insulin through covalent bonding using click chemistry. When this covalently bonded insulin was combined with zinc and administered orally, it showed blood glucose-lowering effects comparable to the mixing method.

These results established foundational technology for oral insulin drug development using two approaches: mixing (interaction) and conjugation (covalent bonding).

Moving forward, the researchers aim to apply these findings to actual treatment. They will verify the safety and sustained efficacy of the formulation through long-term administration experiments in large animals such as dogs. Additionally, they will conduct pharmacokinetic analysis using in vitro models of human intestinal permeability, and the development of oral insulin formulation technology will be advanced to ensure reliable delivery and absorption in the small intestine. Through these efforts, they will accelerate research toward realizing innovative therapies that significantly improve patient quality of life.

Journal Information
Publication: Molecular Pharmaceutics
Title: Small Intestine-Permeable Cyclic Peptide-Based Technology Enables Efficient Oral Delivery and Glycemic Efficacy of Zinc-Stabilized Insulin Hexamer and Its Analogs in Diabetic Mice
DOI: 10.1021/acs.molpharmaceut.5c00902