A silica-based pH-sensitive nanomatrix system improves the oral absorption and efficacy of incretin hormone glucagon-like peptide-1

Wei Qu,^1,2 Yong Li,^2,* Lars Hovgaard,³ Song Li,¹ Wenbin Dai,¹ Jiancheng Wang,¹ Xuan Zhang,¹ Qiang Zhang<sup>1,*

1</sup>State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, PR China; ²Department of Nutrition and Food Hygiene, Peking University Health Science Center, Beijing 100191, PR China; ³Oral Formulation Development, Novo Nordisk A/S, Maalov, Denmark

^*Both authors contributed equally to this work

Background: Glucagon-like peptide-1 (GLP-1) (7–36) is a peptide incretin hormone released from the endocrine L-cells of the intestinal mucosa with unique antidiabetic potential. Due to low absorption efficiency and instability in the gastrointestinal tract, the introduction of orally active GLP-1 is a large challenge. Here we developed a novel silica-based pH-sensitive nanomatrix of GLP-1 (SPN-GLP-1) in order to provide a strategy for oral peptide delivery.
Methods: SPN-GLP-1 composed of silica nanoparticles and pH-sensitive Eudragit^® was prepared and characterized by dynamic light scattering, scanning electron microscope, transmission electron microscope, high-performance liquid chromatography, surface analysis, drug release, and so on. Its permeability across the Caco-2 cell monolayer and intestinal mucosa, proteolytic stability against the intestinal enzymes, pharmacokinetics, hypoglycemic effect in the intraperitoneal glucose tolerance test (IPGTT), and primary toxicity were then evaluated.
Results: It was indicated that the nanomatrix system obtained had a unique nanoscale structure and pH-sensitivity in drug release. It displayed a five-fold intestinal mucosa permeability and significantly higher proteolytic stability compared to native GLP-1 (P < 0.001). A longer half-life was observed after oral administration of SPN-GLP-1, and its relative bioavailability was 35.67% in comparison to intraperitoneal GLP-1. Oral delivery of SPN-GLP-1 significantly reduced the blood glucose level and its hypoglycemic effect over intraperitoneal GLP-1 reached 77%. There was no evident toxicity of SPN-GLP-1 found from both animal status and histochemical analysis of gastrointestinal tissues.
Conclusion: The silica-based pH-sensitive nanomatrix designed and prepared here might be considered as a potential oral delivery system not only for GLP-1, but also for other peptide or macromolecular drugs.

Keywords: nanomatrix, oral peptide delivery, silicon nanoparticles, pH-sensitive, GLP-1