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

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

Sanketkumar Pandya1,2, Durgesh Kumar1,2, 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 (SSBET) 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 SSBET 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.