The ability of two in vitro lipolysis models reflecting the human and rat gastro-intestinal conditions to predict the in vivo performance of SNEDDS dosing regimens.

In this work, the influence of drug load and physical state of R3040 in self-nanoemulsifying drug delivery systems (SNEDDS) on R3040 absorption in rats was assessed. Furthermore, an in vitro lipolysis model simulating rat conditions (rat lipolysis model) was compared to a human lipolysis model in regard to the prediction of the in vivo data. The formulations were SNEDDS 80%, containing R3040 at 80% of its equilibrium solubility in SNEDDS (Seq); super-SNEDDS solution with R3040 supersaturated at 200% Seq; super-SNEDDS suspension containing R3040 at 200% Seq; Chasing principle (drug-free SNEDDS followed by R3040 aqueous suspension) and R3040 aqueous suspension. The pharmacokinetic profiles of R3040 in SNEDDS 80% and super-SNEDDS solution 200% were superimposed and higher than for super-SNEDDS suspension 200%, Chasing principle and aqueous suspension. Therefore, dosing R3040 dissolved in SNEDDS increased R3040 absorption irrespective of the drug load. While the human lipolysis model could not predict the rank order of absorption of the formulations, the rat lipolysis model predicted the similar absorption of R3040 in SNEDDS 80% and super-SNEDDS solution 200%. Thus, the rat lipolysis model showed to be an important step towards predictive in vitro models for rat studies.

Siqueira Jørgensen SD ，Al Sawaf M ，Graeser K ，Mu H ，Müllertz A ，Rades T ... -  《-》

Influence of drug load and physical form of cinnarizine in new SNEDDS dosing regimens: in vivo and in vitro evaluations.

Siqueira SD ，Müllertz A ，Gräeser K ，Kasten G ，Mu H ，Rades T ... -  《AAPS Journal》

In vitro and in vivo performance of novel supersaturated self-nanoemulsifying drug delivery systems (super-SNEDDS).

Novel supersaturated self-nanoemulsifying drug delivery systems (super-SNEDDS) containing the poorly water-soluble drug halofantrine above equilibrium solubility (150% S(eq)) were compared in vitro and in vivo with conventional SNEDDS containing the drug below equilibrium solubility (75% S(eq)). Pre-concentrates comprising of either medium chain lipids (Captex 300/Capmul MCM) or long chain lipids (soybean oil/Maisine), Cremophor RH40 and ethanol were formulated maintaining the lipid-to-surfactant-to-cosolvent ratio constant (55:35:10, w/w %). The ability of super-SNEDDS to increase the absorption of halofantrine in dogs, as well as the predictivity of the dynamic in vitro lipolysis model was studied. In vitro lipolysis of SNEDDS and super-SNEDDS showed rapid drug precipitation from all formulations while the same drug concentrations in the digestion medium were found during digestion of equal amounts of SNEDDS and super-SNEDDS. Elevated halofantrine solubilisation during in vitro lipolysis was observed only when multiple capsules of conventional SNEDDS were subjected to in vitro digestion. After lipolysis the isolated super-SNEDDS pellets were characterised by XRPD revealing no crystalline halofantrine from any of the investigated formulations. Subsequent dissolution studies of the super-SNEDDS pellet in the lipolysis medium demonstrated enhanced dissolution of halofantrine suggesting that halofantrine in the pellet was amorphous. The enhanced dissolution of the amorphous halofantrine was also reflected in vivo since two capsules of conventional SNEDDS were needed to achieve similar AUC and C(max) as obtained after dosing of a single capsule of super-SNEDDS. The study demonstrated that the absorption of halofantrine was not hampered by drug precipitation. Super-SNEDDS lead to precipitation of halofantrine in an amorphous form, which can be the driving force for enhanced absorption. Since super-SNEDDS were also physically stable for at least 6 months they represent a potential novel oral lipid-based drug delivery system for low aqueous soluble compounds.

Thomas N ，Holm R ，Müllertz A ，Rades T ... -  《-》

Fenofibrate oral absorption from SNEDDS and super-SNEDDS is not significantly affected by lipase inhibition in rats.

The effect of drug load and digestion on the solubilization and absorption of fenofibrate in self-nanoemulsifying drug delivery system (SNEDDS) was assessed in a pharmacokinetic study in rats and in an in vitro lipolysis model. SNEDDS containing fenofibrate at 75% of equilibrium solubility (Seq), a super-saturated SNEDDS (super-SNEDDS) containing fenofibrate at 150% of Seq and a super-SNEDDS suspension containing fenofibrate at 100% of Seq and an additional 50% Seq fenofibrate suspended (150% of Seq in total) were used. To assess the effect of lipid digestion on fenofibrate absorption in rats and fenofibrate solubilization during in vitro lipolysis, the lipase inhibitor orlistat was added at 1% (w/w) to the SNEDDS, resulting in six different SNEDDS: SNEDDS, super-SNEDDS and super-SNEDDS suspension with and without orlistat 1% (w/w). In vivo, super-SNEDDS had a higher Cmax and AUC0-30h compared to SNEDDS and super-SNEDDS suspension, both with and without orlistat. While orlistat did not affect fenofibrate absorption in SNEDDS and super-SNEDDS, an increase of Tmax and AUC0-30h for super-SNEDDS suspension was found when orlistat was present. During in vitro lipolysis, the addition of orlistat decreased digestion and lowered drug precipitation. Super-SNEDDS showed significantly increased absorption in rats compared to SNEDDS and super-SNEDDS suspension and the inhibition of digestion resulted in prolonged and increased absorption for the super-SNEDDS suspension.

Michaelsen MH ，Siqueira Jørgensen SD ，Abdi IM ，Wasan KM ，Rades T ，Müllertz A ... -  《-》

Fed and fasted state gastro-intestinal in vitro lipolysis: In vitro in vivo relations of a conventional tablet, a SNEDDS and a solidified SNEDDS.

The present study aims at evaluating the ability of a gastro-intestinal in vitro lipolysis model to predict the performance of two lipid formulations and a conventional tablet containing a poorly soluble drug, cinnarizine, in dogs, both in the fasted and fed state. A self-nano-emulsifying drug delivery system (SNEDDS) was either dosed in a hard gelatin capsule (SNEDDS-C) or loaded onto a porous tablet core (SNEDDS-T) and compared to a marketed conventional tablet (Conv) in an in vitro lipolysis model. The model simulates the digestion in the stomach and intestine during either the fasted or the fed state. Whole fat milk (3.5%) was used in the fed state model to mimic the dynamic lipolysis events after ingestion of food. The results were compared to a dog study published in this issue. In the fasted state in vitro lipolysis model, the amount of solubilized cinnarizine decreased in the order SNEDDS-C>SNEDDS-T>Conv, which correlated well with the in vivo bioavailability. In the fed state in vitro lipolysis model, cinnarizine was solubilized to the same degree for all formulations. Compared to the fasted state model, only the performance of the conventional tablet was improved, indicating food effect. This correlated with the in vivo study, where the tablet was the only formulation with a significant food effect. The fasted state model correlated well with the in vivo results and although the fed state model did not accurately predict the fed state in vivo results, it could predict which formulation that would exhibit a food effect.

Christophersen PC ，Christiansen ML ，Holm R ，Kristensen J ，Jacobsen J ，Abrahamsson B ，Müllertz A ... -  《-》