Enhanced Antimalarial Activity by a Novel Artemether-Lumefantrine Lipid Emulsion for Parenteral Administration

Abstract

dArtemether and lumefantrine (also known as benflumetol) are difficult to formulate for parenteral administration because of their low aqueous solubility. Cremophor EL as an emulsion excipient has been shown to cause serious side effects. This study reports a method of preparation and the therapeutic efficacies of novel lipid emulsion (LE) delivery systems with artemether, lumefantrine, or artemether in combination with lumefantrine, for parenteral administration. Their physical and chemical stabilities were also evaluated. Furthermore, the in vivo antimalarial activities of the lipid emulsions developed were tested in Plasmodium berghei-infected mice. Artemether, lumefantrine, or artemether in combination with lumefantrine was encapsulated in an oil phase, and the in vivo performance was assessed by comparison with artesunate for injection. It was found that the lumefantrine lipid emulsion (LUM-LE) and artemether-lumefantrine lipid emulsion (ARM-LUM-LE-3) (1:6) began to decrease the parasitemia levels after only 3 days, and the parasitemia inhibition was 90% at doses of 0.32 and 0.27 mg/kg, respectively, with immediate antimalarial effects greater than those of the positive-control group and constant antimalarial effects over 30 days. LUM-LE and ARM-LUM-LE-3 demonstrated the best performance in terms of chemical and physical stabilities and antiplasmodial efficacy, with a mean particle size of 150 nm, and they have many favorable properties for parenteral administration, such as biocompatibility, physical stability, and ease of preparation. Malaria is one of the most significant causes of morbidity and death worldwide. Every year, nearly one million deaths result from malaria infection, with about 85% occurring among children under 5 years of age. Indeed, one patient dies from malaria every 36 s (1).Artemisinin and its derivatives are the most important antimalarial drugs; the chemical structures of the four artemisinin compounds and lumefantrine (also known as benflumetol) are presented in Fig. 1. Artemisinin is an effective antimalarial drug isolated from the Chinese herbal medicine Artemisia annua L. It has a special sesquiterpene lactone with a peroxy group. In malaria parasites, artemisinin can be activated by intraparasitic heme iron, which catalyzes cleavage of the endoperoxide (2). Due to its unique structure and antimalarial mechanism, artemisinin has excellent antimalarial activity with low toxicity; therefore, artemisinin-based combination therapy (ACT) is recommended as the first-line strategy to treat malaria (3). After the introduction of ACT interventions, morbidity and mortality rates associated with malaria were decreased in several parts of the world (4). However, antimalarial resistance would probably be increased after longterm application of artemisinin alone. WHO reformed the malaria treatment policy in February 2004, proposing to stop the use of single antimalarial drugs (e.g., artemisinin and quinine) and promoting the use of ACTs. Recently, combination therapies such as artemether in co...

Improved antimalarial activity of caprol-based nanostructured lipid carriers encapsulating artemether-lumefantrine for oral administration

“…It shows that the NLC is fairly polydispersed and indicates a broad particle size distribution 28 . This is in agreement with the findings of other workers [29][30][31][32][33][34][35] . The results of thermal analysis are as shown in Table 2 and Figures 2a-d.…”

“…With all the major peaks which were seen in each of these components still showing even after the drug incorporation is an indication that the drug and the excipients are compatible since no major interaction occurred between the functional groups of the various components hence the appearance of the major peaks in the FT-IR spectrum. The overall FT-IR spectra of the drugs and all the excipient used in the formulation suggested absence of any incompatibility between the drug and the excipients 31 .…”

“…The coartem ® and chloroquine were more drastic in the reduction of parasitemia, restoration of normal hemoglobin level (12.0-17.5g/dl) after 14 days post-treatment and restoration of normal packed cell volume but at a point after days post treat-ment, recrudescence set in and both the hemoglobin and packed cell volume started to decrease after day 7 post-treatment and the parasitemia level in the group treated with coartem ® and chloroquine started to increase, while the level in the group treated with Mo group continued to decrease. This may be as a result of NLC formulation being able to sustain the release of the drugs in the body much more than the other two drug formulations, which is an advantage over the standard, as has been demonstrated in previous studies, where Plasmodium berghei-infected mice treated with artemether and lumefantrine co-loaded NLCs showed better antimalarial activity with respect to parasitemia progression 17,[29][30][31] . Table 5 is a summary of the histopathological study carried out on groups treated with the NLC formulation Mo (A), coartem ® (B), chloroquine phosphate (C), distilled water (D) and group with no parasite inoculation (E).…”

Solidification of Self-Emulsifying Drug Delivery Systems as a Novel Approach to the Management of Uncomplicated Malaria

“…Firstly, due to the highly lipophilic properties and poor aqueous solubility of the said drugs, for example, the ART-LUM combination, absorption thereof is variable and food-dependent. Indeed, treatment failure has been associated with incomplete drug absorption [39,40]. In addition, a "fatty meal" is predominantly required to invoke the "food effect" [39,[41][42][43][44].…”

Nanoparticles Formulations of Artemisinin and Derivatives as Potential Therapeutics for the Treatment of Cancer, Leishmaniasis and Malaria

“…In vivo studies in Plasmodium berghei -infected mice revealed a decrease in the parasitemia levels after 3 days with a parasitemia inhibition rate of 90% at doses of 0.32 and 0.27 mg/kg, respectively for lumefantrine lipid emulsion and artemether-lumefantrine lipid emulsion. An antimalarial effect was observed for 30 days after the administration of the formulation [ 172 ]. Ibrahim et al prepared a nanoformulation of human serum albumin-bound artemisinin for intravenous injection and for the targeting of infected erythrocytes.…”