Inhalable Sustained-Release Formulation of Glucagon: In Vitro Amyloidogenic and Inhalation Properties, and In Vivo Absorption and Bioactivity
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The present study aimed to develop novel glucagon-loaded PLGA nanospheres without cytotoxic fibril formation for chronic glucagon replacement therapy.
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.
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.
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.
KEY WORDScytotoxic fibril dry powder inhaler glucagon PLGA sustained release
This work was supported in part by a Grant-in-Aid for Young Scientists (B) (No.22790043; S. Onoue) from the Ministry of Education, Culture, Sports, Science and Technology, and Project of Shizuoka Prefecture and Shizuoka City Collaboration of Regional Entities for the Advancement of Technological Excellence, Japan Science and Technology Agency (JST).
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