The Effect of Digestion and Drug Load on Halofantrine Absorption from Self-nanoemulsifying Drug Delivery System (SNEDDS)

A super-saturated self-nanoemulsifying drug delivery system ( super- SNEDDS), containing the poorly water- soluble drug halofantrine ( Hf) at 150% of equilibrium solubility ( Seq), was compared in vitro and in vivo with a conventional SNEDDS ( 75% of Seq) with respect to bioavailability and digestibility. Further, the effect of digestion on oral absorption of Hf from SNEDDS and super- SNEDDS was assessed by incorporation of the lipase inhibitor tetrahydrolipstatin ( orlistat) into the SNEDDS. The SNEDDS contained soybean oil/ Maisine 34- I ( 1: 1), Kolliphor RH40, and ethanol at a ratio of 55: 35: 10, w/ w percent. For the dynamic in vitro lipolysis, the precipitation of Hf at 60 min was significantly larger for the super- SNEDDS ( 66.8 +/- 16.4%) than for the SNEDDS ( 18.5 +/- 9.2%). The inhibition of the in vitro digestion by orlistat ( 1% ( w/ w)) lowered drug precipitation significantly for both the super- SNEDDS ( 36.8 +/- 1.7%) and the SNEDDS ( 3.9 +/- 0.7%). In the in vivo studies, the super- SNEDDS concept proved valid in a rat model with a significantly larger Cmax for the super- SNEDDS ( 964 +/- 167 ng/ mL) than for the SNEDDS ( 506 +/- 112 ng/ mL). The bioavailability of Hf dosed in super- SNEDDS ( 32.9 +/- 3.6%) and SNEDDS ( 22.5 +/- 6.3%) did not change significantly with co- administration of orlistat ( 45.5 +/- 7.3% and 21.9 +/- 6.5%, respectively). However, the pharmacokinetic parameters changed; the tmax of the super- SNEDDS ( 1.3 +/- 0.1 h) and SNEDDS ( 2.8 +/- 1.2 h) were significantly lower when dosed with orlistat ( 6.0 +/- 1.3 and 6.3 +/- 1.2 h, respectively). These findings suggest that the role of lipid digestion for the absorption of drugs from SNEDDS may be less important than previously thought.