The Effect of Digestion and Drug Load on Halofantrine Absorption from Self-nanoemulsifying Drug Delivery System (SNEDDS)
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The Effect of Digestion and Drug Load on Halofantrine Absorption from Self-nanoemulsifying Drug Delivery System (SNEDDS). / Michaelsen, Maria Hotoft; Wasan, Kishor M.; Sivak, Olena; Mullertz, Anette; Rades, Thomas.
In: The A A P S Journal, Vol. 18, No. 1, 01.2016, p. 180-186.Research output: Contribution to journal › Journal article › peer-review
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TY - JOUR
T1 - The Effect of Digestion and Drug Load on Halofantrine Absorption from Self-nanoemulsifying Drug Delivery System (SNEDDS)
AU - Michaelsen, Maria Hotoft
AU - Wasan, Kishor M.
AU - Sivak, Olena
AU - Mullertz, Anette
AU - Rades, Thomas
PY - 2016/1
Y1 - 2016/1
N2 - 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.
AB - 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.
KW - absorption
KW - digestion
KW - halofantrine
KW - orlistat
KW - SNEDDS
KW - super-SNEDDS
U2 - 10.1208/s12248-015-9832-7
DO - 10.1208/s12248-015-9832-7
M3 - Journal article
C2 - 26486790
VL - 18
SP - 180
EP - 186
JO - A A P S Journal
JF - A A P S Journal
SN - 1550-7416
IS - 1
ER -
ID: 173321376