title: Inhalable sustained-release formulation of glucagon: in vitro amyloidogenic and inhalation properties, and in vivo absorption and bioactivity.
abstract: OBJECTIVE
  The present study aimed to develop novel glucagon-loaded PLGA nanospheres without cytotoxic fibril formation for chronic glucagon replacement therapy.
  
  
  METHODS
  Glucagon-loaded nanospheres (GLG/NS) were prepared by an emulsion solvent diffusion method in oil, and a respirable powder formulation (GLG/NS-RP) was prepared with a jet mill. Physicochemical and inhalation properties of GLG/NS-RP were characterized, and pharmacokinetic behavior and hyperglycemic effect of intratracheally instilled GLG/NS-RP were evaluated in rats.
  
  
  RESULTS
  Although preparation of GLG/NS using glucagon solution at concentrations over 10 mg/mL led to significant formation of cytotoxic glucagon aggregates, glucagon solution at less than 5 mg/mL did not cause structural changes. Drug release behavior of GLG/NS showed a biphasic pattern with an initial burst and slow diffusion. Laser diffraction and cascade impactor analyses of GLG/NS-RP suggested high dispersion and deposition in the respiratory organs with a fine particle fraction of 20.5%. After the intratracheal administration of the GLG/NS-RP (200 μg glucagon/kg) in rats, glucagon was released in a sustained manner, leading to sustained hyperglycemic effects compared with those of normal glucagon powder.
  
  
  CONCLUSIONS
  These data would suggest a therapeutic benefit of the newly developed GLG/NS-RP as an alternative to the injection form of glucagon currently used.
authors.affiliation: Department of Pharmacokinetics and Pharmacodynamics and Global Center of Excellence (COE) 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: Kazuki
authors.initials: K
authors.lastname: Kuriyama
authors.forename: Atsushi
authors.initials: A
authors.lastname: Uchida
authors.forename: Takahiro
authors.initials: T
authors.lastname: Mizumoto
authors.forename: Shizuo
authors.initials: S
authors.lastname: Yamada
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D003692:Delayed-Action Preparations / Q000737:chemistry*; D058995:Dry Powder Inhalers / Q000379:methods*; D005934:Glucagon / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology; D006801:Humans; D019344:Lactic Acid / Q000737:chemistry*; D008297:Male; D054118:Nanospheres / Q000737:chemistry*; D011100:Polyglycolic Acid / Q000737:chemistry*; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D051381:Rats; D017208:Rats, Wistar
chemical_list: D003692:Delayed-Action Preparations; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D005934:Glucagon