caa a22 4500 445313773 CHVBK 20180317142639.0 cr unu---uuuuu 170323e20110501xx s 000 0 eng 10.1007/s11095-011-0379-8 doi (NATIONALLICENCE)springer-10.1007/s11095-011-0379-8 Inhalable Sustained-Release Formulation of Glucagon: In Vitro Amyloidogenic and Inhalation Properties, and In Vivo Absorption and Bioactivity [Elektronische Daten] [Satomi Onoue, Kazuki Kuriyama, Atsushi Uchida, Takahiro Mizumoto, Shizuo Yamada] ABSTRACT: Purpose: 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 10mg/mL led to significant formation of cytotoxic glucagon aggregates, glucagon solution at less than 5mg/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 (200μg glucagon/kg) in rats, glucagon was released in a sustained manner, leading to sustained hyperglycemic effects compared with those of normal glucagon powder. Conclusion: 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. Springer Science+Business Media, LLC, 2011 cytotoxic fibril nationallicence dry powder inhaler nationallicence glucagon nationallicence PLGA nationallicence sustained release nationallicence Onoue Satomi Department of Pharmacokinetics and Pharmacodynamics and Global Center of Excellence (COE) Program, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, 422-8526, Shizuoka, Japan aut Kuriyama Kazuki Department of Pharmacokinetics and Pharmacodynamics and Global Center of Excellence (COE) Program, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, 422-8526, Shizuoka, Japan aut Uchida Atsushi Department of Pharmacokinetics and Pharmacodynamics and Global Center of Excellence (COE) Program, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, 422-8526, Shizuoka, Japan aut Mizumoto Takahiro Department of Product Development, Ito Life Sciences Inc., 1-2-1, Kubogaoka, 302-0104, Moriya, Ibaraki, Japan aut Yamada Shizuo Department of Pharmacokinetics and Pharmacodynamics and Global Center of Excellence (COE) Program, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, 422-8526, Shizuoka, Japan aut Pharmaceutical Research Springer US; http://www.springer-ny.com 28/5(2011-05-01), 1157-1166 0724-8741 28:5<1157 2011 28 11095 https://doi.org/10.1007/s11095-011-0379-8 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s11095-011-0379-8 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Onoue Satomi Department of Pharmacokinetics and Pharmacodynamics and Global Center of Excellence (COE) Program, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, 422-8526, Shizuoka, Japan aut NATIONALLICENCE 700 1- Kuriyama Kazuki Department of Pharmacokinetics and Pharmacodynamics and Global Center of Excellence (COE) Program, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, 422-8526, Shizuoka, Japan aut NATIONALLICENCE 700 1- Uchida Atsushi Department of Pharmacokinetics and Pharmacodynamics and Global Center of Excellence (COE) Program, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, 422-8526, Shizuoka, Japan aut NATIONALLICENCE 700 1- Mizumoto Takahiro Department of Product Development, Ito Life Sciences Inc., 1-2-1, Kubogaoka, 302-0104, Moriya, Ibaraki, Japan aut NATIONALLICENCE 700 1- Yamada Shizuo Department of Pharmacokinetics and Pharmacodynamics and Global Center of Excellence (COE) Program, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, 422-8526, Shizuoka, Japan aut NATIONALLICENCE 773 0- Pharmaceutical Research Springer US; http://www.springer-ny.com 28/5(2011-05-01), 1157-1166 0724-8741 28:5<1157 2011 28 11095 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer