Insulin-loaded PLGA/cyclodextrin large porous particles with improved aerosolization properties: In vivo deposition and hypoglycaemic activity after delivery to rat lungs

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 (MMAD exp) 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. Novel 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. ▪