Rizatriptan loaded Bilosomes for Nose to Brain Delivery: Fabrication, Statistical Optimization, and Biological Evaluation

Abstract

Rizatriptan (RTP) is an anti-migraine drug and after oral administration, it exhibits low bioavailability (45%) due to high first-pass hepatic metabolism. Therefore, to resolve this issue, RTP-loaded bilosomes (BLSs) for brain delivery through the intranasal route were developed. RTP-BLSs were prepared by the thin-film hydration technique and optimized by the L9 Taguchi model. Bile salt (sodium glycocholate, mg), surfactant (Span 40, mg), and edge activator (Cremophor RH 40, mg) were selected as independent factors and their influence was observed on vesicle size (nm) and entrapment efficiency (%). Selected optimized RTP-BLSs (F5) have low vesicle size (204.70 ± 5.8 nm) and polydispersity index (0.260 ± 0.022), good entrapment efficiency (78.32 ± 3.1%), and high zeta potential (-27.6 ± 1.67 mV). The optimized RTP-BLSs exhibited a more sustained released profile (96.41 ± 4.48 % in 24 h) than RTP-Sol (98.65 ± 3.46 % RTP released in 4 h). The flux and apparent permeability coefficient for optimized RTP-BLSs were calculated and found to be 1.069 ± 0.026 μg.cm-2.h1 and 10.690×10-4 ± 0.262×10-4 cm.h-1) and comparatively (P<0.05) better than RTP-Sol (0.548 ± 0.148 μg.cm-2.h-1 and 5.481×10-4 ± 1.476 ×10-4 cm.h-1). The relative bioavailability of RTP formulated within the optimized RTP-BLSs administered intranasally was 2.94 ± 0.78-fold higher than the one obtained with RTP-Sol. The optimized RTP-BLSs showed 1.91 ± 0.15-fold higher absolute bioavailability as compared to intravenous administration RTP-BLSs. The optimized RTP-BLSs showed 64.18 ± 2.34% nose-to-brain drug transport, while RTP-Sol exhibited 20.72 ± 1.46% after intranasal administration. The optimized RTP-BLSs showed a significantly higher brain drug targeting efficiency (279.16 ± 6.37%) as compared to RTP-Sol (126.15 ± 4.79%) given intranasally. From our findings, it can be concluded that the developed BLSs are novel alternative RTP carriers for direct nose-to-brain delivery for the improvement of brain drug targeting.