The Effect of Digestion and Drug Load on Halofantrine Absorption from Self-nanoemulsifying Drug Delivery System (SNEDDS)
Journal Title: The AAPS Journal - Year 2016, Vol 18, Issue 1
Abstract
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.
Authors and Affiliations
Maria Høtoft Michaelsen, Kishor M. Wasan, Olena Sivak, Anette Müllertz, Thomas Rades
Keywords
Related Articles
- EP ID EP680827
- DOI 10.1208/s12248-015-9832-7
- Views 51
- Downloads 0
Population Pharmacodynamic Modeling of Hyperglycemic Clamp and Meal Tolerance Tests in Patients with Type 2 Diabetes Mellitus
In this study, glucose and insulin concentration–time profiles in subjects with type 2 diabetes mellitus (T2DM) under meal tolerance test (MTT) and hyperglycemic clamp (HGC) conditions were co-modeled simultaneou...
DNA-based therapeutics and DNA delivery systems: A comprehensive review
The past several years have witnessed the evolution of gene medicine from an experimental technology into a viable strategy for developing therapeutics for a wide range of human disorders. Numerous prototype DNA-based bi...
Blocking of JB6 Cell Transformation by Tanshinone IIA: Epigenetic Reactivation of Nrf2 Antioxidative Stress Pathway
Increasing numbers of natural products have been found to possess anticancer effects. Nuclear factor erythroid-2-related factor-2 (Nrf2) is a master regulator of the antioxidative stress response, and our previous studie...
Development of a Method That Eliminates False-Positive Results due to Nerve Growth Factor Interference in the Assessment of Fulranumab Immunogenicity
Fulranumab, a human IgG2 monoclonal antibody that neutralizes nerve growth factor (NGF), is currently in development for the treatment of pain. Our initial immunogenicity test method was found to be prone to NGF interfer...
Recognition of psychostimulants, antidepressants, and other inhibitors of synaptic neurotransmitter uptake by the plasma membrane monoamine transporters
The plasma membrane monoamine transporters terminate neurotransmission by removing dopamine, norepinephrine, or serotonin from the synaptic cleft between neurons. Specific inhibitors for these transporters, including the...