Formulation design and bioavailability assessment of lipidic self-emulsifying formulations of halofantrine

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Abstract

The potential for lipidic self-emulsifying drug delivery systems (SEDDS) and self-microemulsifying drug delivery systems (SMEDDS) to improve the oral bioavailability of a poorly absorbed, antimalarial drug (Halofantrine, Hf) was investigated in fasted beagles. Hf free base, rather than the commercially available hydrochloride salt (Hf.HCl), was studied due to its much higher solubility in lipidic triglyceride solvents. The multi-component delivery systems were optimised by evaluating their ability to self-emulsify when introduced to an aqueous medium under gentle agitation, and by determination of particle size of the resulting emulsion. Optimised formulations selected for bioavailability assessment were medium-chain triglyceride SEDDS and SMEDDS, and a long-chain triglyceride SMEDDS. The relevant pharmacokinetic parameters of Hf, and its desbutyl metabolite, were determined relative to an intravenous formulation. The lipid-based formulations of Hf base afforded a six- to eight-fold improvement in absolute oral bioavailability relative to previous data of the solid Hf.HCl tablet formulation. These data indicate the utility of dispersed lipid-based formulations for the oral delivery of Hf free base, and potentially other lipophilic drugs.

Introduction

Halofantrine (Hf) is a highly lipophilic phenanthrenemethanol antimalarial (Fig. 1) which is an important agent in the treatment of malaria due to its activity against multi-drug resistant Plas-modium falciparum (Watkins et al., 1988, ter Kuile et al., 1993). Hf is orally active and well-tolerated, however, the resulting plasma concentrations are highly variable and often low following oral administration of the commercially available tablet formulation (Halfan®, 250 mg Hf.HCl). Sub-therapeutic Hf plasma concentrations, due to incomplete drug absorption, are a major concern as they can result in treatment failures and facilitate development of drug resistance (Bryson and Goa, 1992, Karbwang and Na Bangchang, 1994). Although a number of studies have shown that the absorption of Hf.HCl can be substantially increased when co-administered with a fatty meal (Milton et al., 1989, Humberstone et al., 1996), this practice is now contraindicated due to the uncontrolled increase in Hf plasma levels which can result in prolongation of the QTc interval of the ECG (Karbwang and Na Bangchang, 1994).

In this study, the potential of lipidic self-emulsifying drug delivery systems (SEDDS) and self-microemulsifying drug delivery systems (SMEDDS) for improving the extent and reproducibility of the oral absorption of Hf was investigated as such formulations have been reported to improve the rate and extent of absorption of lipophilic drugs (Charman et al., 1992, Constantinides et al., 1994, Kovarik et al., 1994, Shah et al., 1994, Matuszewska et al., 1996). These formulations are isotropic mixtures of an oil and a surfactant which form fine oil-in-water emulsions (i.e. SEDDS) or microemulsions (i.e. SMEDDS) when exposed to aqueous media under conditions of gentle agitation (Constantinides, 1995). Whilst SEDDS typically produce emulsions with particle sizes between 100 and 300 nm, SMEDDS form transparent microemulsions with a particle size of less than 100 nm. The spontaneous formation of an emulsion upon drug release in the GI tract advantageously presents the drug in a solubilised form, and the small droplet size provides a large interfacial surface area for drug absorption (Charman et al., 1992, Shah et al., 1994).

The SEDDS and SMEDDS developed in this study are multi-component systems comprising a triglyceride, mono-/diglyceride, nonionic surfactant, a hydrophilic phase and Hf drug substance. In this study, the effect of altering the chain length of the lipid component was also investigated as literature reports describe either enhanced or decreased absorption when using medium chain triglycerides (MCT) compared with long chain triglycerides (LCT) (Palin and Wilson, 1984, Myers and Stella, 1992, Behrens et al., 1996).

The optimised formulations subject to bioavailability assessment were a MCT SEDDS, a MCT SMEDDS and a LCT SMEDDS and this study design also provided for assessment of the effect of glyceride chain length and particle size on Hf absorption. To maximise drug loading in a unit dose lipid formulation, Hf free base was utilised as its solubility in triglyceride lipidic solvents was at least 100-fold greater than Hf.HCl.

Section snippets

Materials

Hf free base (SmithKline Beecham Pharmaceuticals, India), Captex 355 and Capmul MCM (Abitec Corporation, Janesville, WI), soybean oil BP (R.P. Scherer, Australia), Maisine 35-1 (Gattefossé s.a., Saint-Priest, France), Cremophor EL (BASF, Germany), and absolute ethanol (CSR, Australia) were used as received. One ml air-filled oblong soft gelatin capsules were supplied by R.P. Scherer (Australia). Ten percent Intralipid® (Kabi Pharmacia, Sweden) and AR grade N,N-dimethylformamide (Ajax Chemicals,

Formulation and in vitro assessment of the SEDDS and SMEDDS

Excipients with a definite regulatory status were chosen to formulate the lipid-based formulations, and the triglyceride component of the formulations was either a MCT or a LCT lipid. Medium-chain glycerides (mono-, di- and triglycerides) are commonly used in lipid-based formulations, (Charman et al., 1992, Constantinides et al., 1994, Shah et al., 1994, Matuszewska et al., 1996) and those employed in this study were Captex 355 (C8/C10 triglyceride) and Capmul MCM (C8/C10 mono-/diglyceride).

Acknowledgements

The authors wish to thank SmithKline Beecham Pharmaceuticals (UK) for funding, and Dr John Horton for his project support.

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