Rivastigmine-DHA ion-pair complex improved loading in hybrid nanoparticles for better amyloid inhibition and nose-to-brain targeting in Alzheimer’s

Abstract

Rivastigmine hydrogen tartrate (RIV-HT) is given orally for Alzheimer's disease. However, oral therapy shows low brain bioavailability, short half-life and gastrointestinal-mediated adverse effects. RIV-HT intranasal delivery can avoid these side effects, but its low brain bioavailability remains challenging. These issues could be solved with hybrid lipid nanoparticles with enough drug loading to enhance RIV-HT brain bioavailability while avoiding oral route side effects. The RIV-HT and docosahexaenoic acid (DHA) ion-pair complex (RIV:DHA) was prepared to improve drug loading into lipid-polymer hybrid (LPH) nanoparticles. Two types of LPH, i.e., cationic (RIV:DHA LPH(+ve)) and anionic LPH (RIV:DHA LPH(-ve)) were developed. The effect of LPH surface charge on in-vitro amyloid inhibition, in-vivo brain concentrations and nose-to-brain drug targeting efficiency were investigated. LPH nanoparticles showed concentration dependant amyloid inhibition. RIV:DHA LPH(+ve) demonstrated relatively enhanced Aβ1-42 peptide inhibition. The thermoresponsive gel embedded with LPH nanoparticles improved nasal drug retention. LPH nanoparticles gel significantly improved pharmacokinetic parameters compared to RIV-HT gel. RIV:DHA LPH(+ve) gel showed better brain concentrations than RIV:DHA LPH(-ve) gel. The histological examination of nasal mucosa treated with LPH nanoparticles gel showed that the delivery system was safe. In conclusion, the LPH nanoparticle gel was safe and efficient in improving the nose-to-brain targeting of RIV, which can potentially be utilized in managing Alzheimer's.