Investigating In Vitro and Ex Vivo Properties of Artemether/Lumefantrine Double-Fixed Dose Combination Lipid Matrix Tablets Prepared by Hot Fusion.

Christi A Wilkins,Joe M Viljoen,Lissinda H Du Plessis

doi:10.3390/pharmaceutics13070922

Abstract

Highly lipophilic antimalarial drugs, artemether and lumefantrine, whilst an effective fixed-dose combination treatment to lower the malarial disease burden, are therapeutically hindered by low aqueous solubility and varied bioavailability. This work investigates the plausibility of directly compressed lipid matrix tablets, their role as lipid-based formulations and their future standing as drug delivery systems. Lipid matrix tablets were manufactured from solid lipid dispersions in various lipid:drug ratios employing hot fusion—the melt mixing of highly lipophilic drugs with polymer(s). Sequential biorelevant dissolution media, multiple mathematical models and ex vivo analysis utilizing porcine tissue samples were employed to assess drug release kinetics and more accurately predict in vitro performance. Directly compressed stearic acid tablets in a 0.5:1 lipid:drug ratio were deemed optimal within investigated parameters. Biorelevant media was of immense value for artemether release analysis, with formulation SA0.5C1 (Stearic Acid:double fixed dose in a 0.5:1 ratio (i.e., Stearic acid 70 mg + Lumefantrine 120 mg + Artemether 20 mg); CombiLac® as filler (q.s.); and 1% w/w magnesium stearate) yielding a higher percentage of artemether release (97.21%) than the commercially available product, Coartem® (86.12%). However, dissolution media lacked the specificity to detect lumefantrine. Nonetheless, stearic acid lipid:drug ratios governed drug release mechanisms. This work demonstrates the successful utilization of lipids as pharmaceutical excipients, particularly in the formulation of lipid matrix tablets to augment the dissolution of highly lipophilic drugs, and could thus potentially improve current malarial treatment regimens.

Highlights

This study focused on investigating the effect of hot fusion on augmenting dissolution, together with the significance of biorelevant media for these tested active pharmaceutical ingredients
This study found that whilst simulated gastric media is recommended, specific method development is still required for extremely lipophilic compounds such as lumefantrine as lumefantrine release could not be detected in the dissolution media and no dissolution profiles could be drawn
This study validates the feasibility of manufacturing lipid matrix tablets from solid lipid dispersions prepared by means of hot fusion

Summary

Introduction

The World Health Organization has called for the use of artemisinin-based combination therapy in the fight against malaria, which accounted for an estimated 405,000 deaths globally in 2018 [1]. The Biopharmaceutics Classification System (BSC) has categorized the highly lipophilic antimalarial drugs, artemether and lumefantrine, in Class II (drugs having high permeability but low solubility). These drugs are employed as a double-fixed dose combination in a 6:1 ratio (lumefantrine:artemether) for first-line antimalarial therapy in commercial products such as Coartem® [2,3,4]. The therapeutic potential of highly lipophilic drugs is considerably hindered due to their low and inconsistent bioavailability arising from poor aqueous solubility. The primary challenge remains to design a dosage form capable of enhancing the solubility of these active pharmaceutical ingredients

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