A novel nasal powder formulation of glucagon: toxicology studies in animal models

摘要: Glucagon nasal powder (GNP), a novel intranasal formulation of glucagon being developed to treat insulin-induced severe hypoglycemia, contains synthetic (10 % w/w), beta-cyclodextrin, and dodecylphosphocholine. The safety this was evaluated in four studies animal models. first study 28-day sub-chronic toxicology rats treated intranasally with 1 2 mg GNP/day (0.1 0.2 mg glucagon/rat/day). second dogs administered 20 40 mg formulation/dog/day (2 4 mg glucagon/dog/day) intranasally. A pulmonary insufflation assessed acute following intra-tracheal administration 0.5 mg GNP (0.05 mg glucagon) rats. Local tolerance 30 mg (equivalent 3 mg glucagon, the final dose for humans) tested through direct into eyes rabbits. There were no test article-related adverse effects on body weight and/or food consumption, ophthalmology, electrocardiography, hematology, coagulation parameters, clinical chemistry, urinalysis, or organ weights, macroscopic findings at necropsy any study. In rats, GNP/rat glucagon/rat) did not result clinical, macroscopic, microscopic effects. dogs, only use transient (<30 s) salivation sneezing immediately post-treatment mild moderate reversible histological changes mucosa. Daily dosing over 28 days resulted moderate, unilateral bilateral erosion/ulceration olfactory epithelium, frequently minimal mild, sub-acute inflammation lamina propria dorsal turbinates cavity 2/10 males 3/10 females high-dose group (0.2 mg glucagon/day). These lesions resolved completely 14 days. Histological examination tissues from both revealed findings. rabbits, observations noted GNP-treated eye surrounding areas included ≥1 following: clear discharge, red conjunctiva, partial closure, swelling peri-orbital area, which correlated erythema edema during ocular grading. reported here concerns associated Studies published earlier have highlighted local profile cyclodextrins (a component GNP). choline group, phosphate saturated 12-carbon aliphatic chain that are present dodecylphosphocholine excipient used all phospholipids lecithins seen ubiquitously mammalian cell membranes unlikely pose concerns; notion is supported by several conducted authors concerns. Taken together, these results suggest delivery holds promise as future rescue medication caregivers hypoglycemic episodes patients type 2 diabetes. This drug product well tolerated