Development and evaluation of a self-emulsifying drug delivery system for artemether and lumefantrine

Abstract

Malaria is a grave concern globally, however, in sub-Saharan Africa it remains an even more severe problem due to the fact that more than 90% of all malaria cases caused by Plasmodium falciparum reside in this region. The World Health Organisation (WHO) set an international goal to eliminate malaria by 2018, however, even though a steady decline in the amount of deaths was noticed, the number of reported cases still increase at an alarming rate. The fight against malaria is disadvantaged by the limit in drug availability, nonetheless, this is not the only concern. Resistance against malaria treatment by the parasite is slowly becoming a more serious issue compared to drug availability. The WHO recommended Coartem®, a fixed-dose combination of artemether and lumefantrine, as first line treatment. However, there have been cases reported of treatment failure which is possibly due to sub-optimal lumefantrine levels available in the systemic circulation, indicating that attention needs to be focussed on attempting to rectify increase the bioavailability of Coartem®. Artemether and lumefantrine are both classified as poorly aqueous soluble drugs and lumefantrine was found more effective when provided with a highly fatty meal. For this reason, formulating highly lipophilic antimalarial drugs into lipid dosage forms has become a topic of interest as it is postulated that the additional lipophilic delivery system properties may assist in enhancing drug absorption even more. One such formulation being investigated is self-emulsifying drug delivery systems (SEDDSs), which have proven to be physically stable emulsions that are able to be distributed in the gastrointestinal tract. The digestive motility of the stomach and small intestine initiates the self-emulsifying mechanisms, which in turn solubilise the drug(s) incorporated; and this will consequently have a positive effect on the bioavailability of the incorporated drug(s) due to improved absorption. The main objective of this study is to investigate the effect that the fixed-dose combination of artemether and lumefantrine has on the stability of SEDDS formulations as well as to establish the extent to which artemether and lumefantrine are released from this particular dosage form. The effect of the use of natural oils (avocado-, castor-, coconut-, olive-, and peanut oil) in combination with a surfactant (Sodium lauryl sulphate (SLS) and Tween® 80) and co-surfactant (Span® 60 and Span® 80) was also investigated. Solubility of both artemether and lumefantrine was tested in the selected oils, after which pseudo-ternary phase diagrams were constructed to identify the most optimum ratio of oil to surfactant and co-surfactant in order to produce the most ideal SEDDS formulations. Subsequently, certain SEDDS formulations were chosen due to their emulsion range characteristics and these formulations were tested to determine the physical stability of each of the selected SEDDS formulations together with the incorporated fixed-dose combination of artemether and lumefantrine. Following, dissolution experiments were conducted to conclude the rate and extent of release of the artemether and lumefantrine from the selected SEDDS formulations. In this study it was identified that the oils improved the solubility of both artemether and lumefantrine exponentially when compared to their individual solubility in water. The combination with the selected oils chosen, the surfactant Tween® 80 in conjunction with the co-surfactant Span® 80 produced the most stable SEDDS formulations. Moreover, the surfactant and co-surfactant combinations that contained SLS either formed no emulsion area, or formed a very small emulsion area that could not be used for further studies. Consequently, the SEDDS formulations that were considered optimal are: avocado oil (4:6) (4 being the surfactant and 6 being the co-surfactant used), castor oil (2:8) S80, castor oil (3:7) S60, coconut oil (6:4), olive oil (3:7), and peanut oil (6:4). Furthermore, these selected SEDDS formulations were subjected to physical stability testing and all of these formulations displayed adequate stability. Droplet size measurements of the selected SEDDS formulations indicated that avocado oil (4:6), castor oil (2:8) S80, castor oil (3:7) S60, coconut oil (6:4), and olive oil (3:7) could be deemed as being in the nano-range, whereas peanut oil (6:4) portrayed an average droplet size that classifies it as being in the micro-range. Both artemether and lumefantrine were satisfactorily released from the SEDDS formulations; though release was only observed when the pH of the dissolution media was increased. The release of artemether was noted when the pH was increased to 6.8 and lumefantrine was released only when the pH was increased to 7.4. Artemether displayed a superior release from the SEDDS formulations compared to lumefantrine that displayed only moderate release. Both active ingredients displayed Fickian diffusion when released from the SEDDS formulations, as all of their drug release profiles could be fitted to the Peppas Sahlin 2 equation. Due to the abovementioned results obtained, it could be concluded that the SEDDS formulations: avocado oil (4:6), castor oil (2:8) S80, castor oil (3:7) S60, coconut oil (6:4), olive oil (3:7), and peanut oil (6:4), which comprised the surfactant Tween® 80and the co-surfactant Span 80®, produced physically stable SEDDS formulations that displayed adequate release of both artemether and lumefantrine. Considering the physical stability and the SEDDS formulations that displayed superior release of both artemether and lumefantrine, the avocado oil (4:6) and olive oil (3:7) SEDDS are regarded as being the most optimal SEDDS formulations for the fixed-dose combination of artemether and lumefantrine. However, these dosage forms will need to be investigated further in order to determine the bioavailability of both artemether and lumefantrine from these drug delivery systems.