Dry Powder Inhalation of Glucagon-like Peptide-1 for Management of Type-2 Diabetes Mellitus

Sanketkumar Pandya^1,2, Durgesh Kumar^1,2, Swati Gupta¹, Kalyan Mitra¹, Anil N Gaikwad¹ & Amit Misra¹

¹CSIR-Central Drug Research Institute, Sector 10, Jankipuram Extension, Lucknow, 226031, India

²Academy of Scientific and Innovative Research, New Delhi – 110025, India

Summary

Background: Glucagon-like peptide 1 (7-36) amide (GLP-1) is a bioactive peptide that regulates glucose homeostasis through multiple actions. The present study aims to develop a particulate delivery system for administration of the prototype incretin GLP-1 fragment for the management of Type 2 diabetes mellitus. Methods: Particles incorporating 5% and 10% GLP-1 were engineered using spray freeze drying (SFD) employing L-leucine and trehalose as cryoprotectants. The particles were extensively characterized for physicochemical properties such as mean particle size, surface morphology, mass median aerodynamic diameter (MMAD), specific surface area (SS_BET) and porosity. Circular Dichroism (CD) spectroscopy was done to assess the structure integrity of peptide. Pharmacokinetic and pharmacodynamic studies with GLP-1 particles were performed on C57/BL6 mice. Results: Particles prepared by SFD in high yield (>90 %) exhibited good aerodynamic performance (MMAD=1.1 ± 0.35 µm, FPF=60.5±0.5%). Particles were porous and possessed high SS_BET of 195 m²/g and low density (0.03 g/ml). In-vitro MTT assay on A549 cell-line showed that the particles did not exert any significant lung toxicity. CD analysis indicated that the secondary structure of GLP-1 fragment in particulate formulation was intact. Maximum circulating GLP-1 levels in mice were achieved in 20-30 min. Intraperitoneal glucose tolerance test revealed that a dose dependent response in terms of plasma glucose concentration was achieved following pulmonary administration of GLP-1 particles. Particles with 10% GLP-1 provided good control over glucose homeostasis. Conclusion: A suitable inhalable formulation of GLP-1 was developed for its feasible use in management of type 2 diabetes mellitus.