Development of spray dried chitosan-based nanoaggregates containing lipid nanoparticles for oral delivery to brain targeting using bromocriptine and asiatic acid as drug models

Abstract

Development of spray dried powder nanoaggregates chitosan-based containing two lipids-nanoparticles, solid lipid nanoparticles (SLN) and nanostructured lipid carrier (NLC), which using two drug models bromocriptine mesylate (BM and Asiatic acid (AA) is proposed to enhance oral adsorption and brain targeting. Spray drying optimization was successfully developed by response surface methodology using rotatable composite design. Spray drying process lead aggregation of both type lipid nanoparticles (i.e. SLN and NLC) which increase the size of those lipid nanoparticles. Incorporation chitosan into spray drying SLN and NLC did not produce poor flowability powder. WXRD and DCS study showed that spray dried lipid nanoparticles (AASLN and AANLC) were amorphous in micro size which could easily be redispersed into nanoaggregates of SLN and NLC loaded drug models. AA and BM could be well-entrapped in SLN and NLC. BM and AA retention of the obtained spray dried powder was significantly improved with incorporation of chitosan as base on both SLN and NLC systems. Incorporation of chitosan to spray drying AASLN and AANLC resulted slower prolonged AA-released than the uncorporated ones. Compared to water dispersion of AASLN and AANLC, spray dried powder of AASLN and AANLC showed improvement in stability during storage. TEER (Transepithelial Electrical Resistance) study and confocal microscopy study showed that incorporation chitosan on redispersed spray dried powder of AASLN and AASLN could open the tight junction that increased drug transport of 4.9-fold to AASLN and 4.23-folds to AANLC compared to AA free through Caco-2 cells via paracellular pathway. Permeability study of redispersed spray dried powder of AASLN and AANLC on Caco-2 cells also showed 2.1-folds and 1.61-folds faster than its water dispersion (AASLN and AANLC). The TEER study and the confocal microscopy study on bEnd3 cells showed that incorporation chitosan on redispersed spray dried powder of cAASLN and cAASLN after passing Caco-2 cells penetrate the endothelial cells via intracellular pathway. These findings show that the spray dried powder of SLN and NLC chitosan-based formulation can be employed to oral administration for brain delivery.