Development of lipid matrix tablets containing a double fixed dose combination of artemisone and lumefantrine
Malaria is one of the most important parasitic diseases as well as one of the most life-threatening diseases known to man. This vector-borne disease caused by Plasmodium spp., is responsible for over 438 000 deaths globally, of which 90% of these deaths occur in Africa (WHO, 2017; Sokhna et al., 2013; Rosenthal, 2012). The intricate life cycle of the malaria parasite offers numerous attack-points for antimalarial drugs. Rapidly spreading resistance against antimalarial drugs, especially chloroquine, mefloquine, and pyrimethamine-sulphadoxine, emphasises the necessity for new alternatives or alteration of existing antimalarial drugs (Nosten & Brasseur, 2002). Artemisone, an artemisinin derivative, signifies a new class of antimalarial drugs that is an effective blood schizontocide against strains of drug-resistant Plasmodium falciparum malaria. On the other hand, lumefantrine is an antimalarial drug active against the asexual stages of the parasitic reproduction (Nostem et al., 2012). Artemisinin-based combination therapies (ACTs) have been recommended as first-line treatment for uncomplicated P. falciparum in countries where malaria is endemic. ACT allows for simultaneous administration of longer- and shorter-acting drugs that have different mechanisms of action, subsequently preventing, or delaying the development of resistance (Basu & Sahi, 2017; Nosten & Brasseur, 2002). By incorporating 80 mg artemisone and 120 mg lumefantrine in a fixed-dose combination, a new ACT may be formulated. Lumefantrine was chosen as the long acting drug that has poor aqueous solubility, is highly lipophilic and depicts erratic absorption, leading to poor bioavailability (Garg et al., 2017). Artemisone, the short acting drug in this study, also depicts insufficient aqueous solubility as well as poor bioavailability (Pawar et al., 2016; White, 2008). To overcome these drawbacks, lipid-matrix tablets were formulated by means of the hot-melt method. Lipid matrix formulations attracted significant attention over the past years, especially in cases where drugs with high lipophilicity are to be incorporated into various dosage forms. Lipid based formulations have proven useful in increasing the absorption, and consequently enhancing the bioavailability (Xia et al., 2014). Modified release of the drugs from the lipid-matrices is another advantage of incorporating drugs into a lipid-matrix (Nisha et al., 2012). Drug releases from lipid-matrices occur by means of erosion and/or pore diffusion — in this study pore diffusion is more prevalent. The lipid forms a coating around the drug particles and subsequently, pores are formed. These pores aid in the modified release of the drugs included in lipid-matrices (Abd-Elbary et al., 2013; Nisha et al., 2012). Modified release drugs will reduce the blood concentration fluctuations and subsequently frequent dosing (Rajabi-Siahboomi et al., 2013; Abdul et al., 2010; Ishida et al., 2008). In this study, lipid-matrices were formed by utilising hot-melt to incorporate a fixed-dose combination of artemisone and lumefantrine into two selected lipids, i.e. stearic acid (SA) and glycerol monostearate (GM), respectively. Hot-melt can be described as a process where a polymer is melted with continuous stirring in a porcelain mortar on heated water. The chosen drugs are homogenously mixed into the melted polymer and allowed to cool. After the mass solidifies, it is grounded and sieved until the appropriate particle size is achieved (Nikghalb et al., 2012; Kalaiselvan et al., 2006; Obaidat & Obaidat, 2001). The various formulations were developed in three stages: basic formulation development, employing a factorial design to procure optimised formulations, and assessing the optimised formulations. First, differential weight loss thermograms (DTG) and thermal activity monitor (TAM) analysis were conducted to identify any possible interactions between the active pharmaceutical ingredients (drugs); and the drugs' and excipients. Following, the flow properties of the two drugs, the selected fillers (MicroceLac® 100, RetaLac® and CombiLac®), along with the lipid dispersions were characterised by means of bulk- and tapped density; critical orifice diameter (COD); angle of repose; and flow rate. Furthermore, all formulations were tableted by means of direct compression. The lipid-matrix tablets were assessed and characterised in terms of friability, crushing strength, weight variation and disintegration. A full factorial design was utilised to identify the optimal formulations in terms of their physical properties. Dissolution tests, as well as swelling and erosion experiments, were performed on the optimised formulations and analysed by means of high performance liquid chromatography (HPLC). Results indicated that the type of lipid, the drug:lipid ratio, the type of filler as well as the concentration (%w/w) in which the lubricant was incorporated into the formulations, influenced the friability, weight variation, crushing strength and disintegration of the lipid-matrix tablets. CombiLac® produced the hardest tablets, followed by MicroceLac® 100, then RetaLac®. MicroceLac® 100 formulations, conversely, depicted the most ideal friability results but illustrated a relatively high average weight variation. RetaLac® displayed the least weight variation, indicating the formulations comprising RetaLac® are the most uniform concerning average weight. The formulations that incorporated stearic acid (1:0.5 ratio) and CombiLac®, was the only formulation that disintegrated in 15 min, thus did not portray modified release, Formulations containing 0.5% w/w magnesium stearate proofed more acceptable compared to formulations that included 1% w/w lubricant, however, the 0.5% w/w lubricant formulations were aesthetically undesirable. Thus, only the formulations comprising 1% w/w magnesium stearate were included in the optimised formulations. Artemisone exhibited a delayed release profile from all of the lipid matrix tablet formulations. CombiLac® was deemed unacceptable as artemisone did not display any dissolution from the formulations S1C1, G0.5C1 and G1C1. The formulation S0.5C1 disintegrated in 15 min, thus did not depict modified release. Lumefantrine, conversely, displayed burst release profiles from all of the optimised formulations. Stearic acid illustrated slightly higher percentage dissolution for lumefantrine in comparison with glycerol monostearate, but unfortunately no modified release, whilst the fillers did not play a significant role in the different formulations. In conclusion, the formulations need further work to be perfected. Formulations comprised MicroceLac® 100 and stearic acid displayed the most delayed release for artremisone and release lumefantrine to a slightly higher extent comparative to the other formulations.
- Health Sciences