title: Novel dry powder inhaler formulation of glucagon with addition of citric acid for enhanced pulmonary delivery.
abstract: Glucagon, a gut hormone, is one of the key regulatory elements in glucose homeostasis, and is clinically used for treatment of hypoglycemia and premedication in peroral endoscopy. Dry powder inhaler (DPI) form of glucagon is believed to be a promising new dosage form, and the present study aimed to develop a novel glucagon-DPI using absorption enhancer for improved pharmacological effects. The cytotoxicity of citric and capric acids, the potential absorption enhancers, at 1 and 10 mM was assessed by monitoring extracellular LDH levels in rat alveolar L2 cells, and a concentration- and time-dependent release of LDH was observed in capric acid, but not in citric acid-treated cells. DPI form of glucagon containing citric acid was prepared with a jet mill, and laser diffraction and cascade impactor analyses of the newly developed glucagon-DPI suggested high dispersion and deposition in the respiratory organs with an emitted dose and fine particle fraction of 99.5 and 25%, respectively. Addition of citric acid in glucagon-DPI improved the dissolution behavior, and did not impair the solid-state stability of glucagon-DPI. Intratracheal administration of glucagon-DPI (50 microg-glucagon/kg body weight of rat) containing citric acid led to 2.9-fold more potent hyperglycemic effect in rats, as compared to inhaled glucagon-DPI without citric acid. Based on these physicochemical and pharmacological characterization, the dry powder inhaler of glucagon with addition of citric acid would be of use as an alternative to injection form.
authors.affiliation: Department of Pharmacokinetics and Pharmacodynamics and Global Center of Excellence Program, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan. onoue@u-shizuoka-ken.ac.jp
authors.forename: Satomi
authors.initials: S
authors.lastname: Onoue
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Yamamoto
authors.forename: Yohei
authors.initials: Y
authors.lastname: Kawabata
authors.forename: Mariko
authors.initials: M
authors.lastname: Hirose
authors.forename: Takahiro
authors.initials: T
authors.lastname: Mizumoto
authors.forename: Shizuo
authors.initials: S
authors.lastname: Yamada
mesh_terms: D000280:Administration, Inhalation; D000818:Animals; D001692:Biological Transport; D001786:Blood Glucose / Q000187:drug effects; D002460:Cell Line; D002626:Chemistry, Pharmaceutical; D019343:Citric Acid / Q000737:chemistry* / Q000633:toxicity; D003652:Decanoic Acids / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D004337:Drug Carriers; D004339:Drug Compounding; D004355:Drug Stability; D005934:Glucagon / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D007834:Lasers; D008297:Male; D008855:Microscopy, Electron, Scanning; D009330:Nebulizers and Vaporizers; D010316:Particle Size; D011208:Powders; D011650:Pulmonary Alveoli / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility; D013499:Surface Properties; D013678:Technology, Pharmaceutical / Q000379:methods; D013997:Time Factors
chemical_list: D001786:Blood Glucose; D003652:Decanoic Acids; D004337:Drug Carriers; D007004:Hypoglycemic Agents; D011208:Powders; D019343:Citric Acid; C031071:decanoic acid; D005934:Glucagon; D007770:L-Lactate Dehydrogenase