Article ID Journal Published Year Pages File Type
1426377 Journal of Controlled Release 2009 10 Pages PDF
Abstract

The aim of the present work is to develop large porous particles (LPP) of poly (lactide-co-glycolide) (PLGA) containing insulin with optimal aerodynamic properties and to test their in vivo potential, in pulmonary delivery. Insulin-loaded LPP were fabricated by a double emulsion method by aid of hydroxypropyl-β-cyclodextrin (HPβCD). Conceiving this system for the controlled release of insulin to the lungs, the aerosolization properties and the release features in simulated lung fluids of PLGA/HPβCD/insulin LPP were investigated in depth. The technological results show that the combination of appropriate amounts of insulin and HPβCD plays a crucial role to achieve PLGA/HPβCD/insulin LPP with the desired bulk and aerodynamic properties, that is a highly porous structure, a very low density (0.1 g/ml), an experimental mass mean aerodynamic diameter (MMADexp) ranging from 4.01 to 7.00 and a fine particle fraction (FPF) estimated to be 26.9–89.6% at the different airflow rates tested (i.e. 30–90 l/min). Confocal microscopy studies, performed after administration of labeled PLGA/HPβCD/insulin LPP to the rat lung by means of a low-scale dry powder inhaler (DPI), suggest that particles reach alveoli and remain in situ after delivery. The pharmacological effect of PLGA/HPβCD/insulin LPP was confirmed by dose–response studies performed on both normoglycaemic and streptozotocin-induced diabetic rats. While insulin solutions administered via pulmonary route are unable to cause a significant hypoglycaemic effect, insulin delivered through PLGA/HPβCD/insulin LPP at the same doses (0.5–4.0 IU/kg) significantly reduces blood glucose level as a function of the administered dose in both animal models. The developed LPP, tested in hyperglycaemic rats at evident pathological conditions, exerts a very significant and longer hypoglycaemic effect even at insulin doses as low as 0.5 IU/kg (about 0.5 mg of PLGA/HPβCD/insulin LPP per rat) as compared to a insulin solution. Taken together, our results support the viability of a dry powder formulation based on biodegradable LPP for the controlled release of insulin to the lungs. In vivo data show that PLGA/HPβCD/insulin LPP are able to reach alveoli, release insulin, which is absorbed in its bioactive form.

Graphical abstractNovel dry powders for insulin inhalation based on PLGA/cyclodextrin hybrid particles were developed. The powders are able to reach alveoli, allowing a significant and prolonged systematic effect.Figure optionsDownload full-size imageDownload as PowerPoint slide

Related Topics
Physical Sciences and Engineering Materials Science Biomaterials
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