Influence of bile on the absorption of halofantrine from lipid-based formulations.

The bioavailability of the poorly soluble model drug halofantrine, dosed in a soy bean oil solution or in a self-nanoemulsifying drug delivery system (SNEDDS), at two levels of lipid, was assessed in rats. Three rat models were used: intact rats, sham-operated rats and bile duct cannulated rats. The study showed no difference in the pharmacokinetic parameters between intact and sham-operated rats. T(max) increased with lipid load for both oil solution and SNEDDS, whereas C(max) and the absolute bioavailability were significantly higher for the SNEDDS at both lipid dosing levels. Bile duct cannulation of the rats reduced the C(max) and the absolute bioavailability of halofantrine significantly, by a factor of 2, for all 4 treatments. These data clearly demonstrate that bile has an importance for the absorption of drugs from lipid-based formulations independent of the type.

Holm R ，Tønsberg H ，Jørgensen EB ，Abedinpour P ，Farsad S ，Müllertz A ... -  《-》

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 ... -  《-》

Effect of bile on the oral absorption of halofantrine in polyethylene glycol 400 and polysorbate 80 formulations dosed to bile duct cannulated rats.

The aim of this study was to examine the effects of bile on the oral absorption of the poorly water-soluble compound, halofantrine, when administered to rats in vehicles consisting of the co-solvent polyethylene glycol 400 (PEG 400) alone or in mixtures with the surfactant polysorbate 80 (PS 80) (95:5; 85:15; 75:25 PEG 400:PS 80). Halofantrine (17.5 mg/kg) was administered to bile duct cannulated (BDC) and sham-operated rats in a fixed vehicle volume of 5 ml/kg. The bioavailability of halofantrine was significantly lower in BDC rats when dosed with 0-5% PS 80 in PEG 400 compared with BDC rats dosed with >15% PS 80. Increasing the concentration of PS 80 to 15-100% eliminated this difference. A possible explanation for the lower bioavailability of halofantrine in BDC rats when dosed in pure PEG 400 could be the dilution of the vehicle by intestinal fluids, decreased transit time and precipitation in the gastrointestinal tract upon dilution of PEG 400. The addition of PS 80 to the formulation increased its solubilising power upon dilution and may have inhibited precipitation and substituted the absence of bile above a certain level. Adjusting the level of surfactant in drug formulations could therefore be used to minimise variability in the bioavailability from co-solvent systems based upon differences in bile concentration between individuals.

Tønsberg H ，Holm R ，Mu H ，Boll JB ，Jacobsen J ，Müllertz A ... -  《-》

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

Michaelsen MH ，Wasan KM ，Sivak O ，Müllertz A ，Rades T ... -  《-》

Intestinal lymphatic transport of halofantrine in rats assessed using a chylomicron flow blocking approach: the influence of polysorbate 60 and 80.

Lind ML ，Jacobsen J ，Holm R ，Müllertz A ... -  《EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES》