Design and evaluation of Lumefantrine – Oleic acid self nanoemulsifying ionic complex for enhanced dissolution

Abstract

BackgroundLumefantrine, an antimalarial molecule has very low and variable bioavailability owing to its extremely poor solubility in water. It is recommended to be taken with milk to enhance its solubility and bioavailability. The aim of present study was to develop a Self Nanoemulsifying Delivery system (SNEDs) of lumefantrine (LF) to achieve rapid and complete dissolution independent of food-fat and surfactant in dissolution media.MethodsSolubility of LF in oil, co-solvent/co-surfactant and surfactant solution and emulsification efficiency of surfactant were analyzed to optimize the LF loaded self nanoemulsifying preconcentrate. Effect of LF-oleic acid complexation on emulsification, droplet size, zeta potential and dissolution were investigated. Effect of milk concentration and fat content on saturation solubility and dissolution of LF was investigated. Dissolution of marketed formulation and LF-SNEDs was carried out in pH 1.2 and pH 6.8 phosphate buffer.ResultsLF exhibited very high solubility in oleic acid owing to complexation between tertiary amine of LF and carboxyl group of oleic acid (OA). Cremophore EL and medium chain monoglyceride were selected surfactant and co-surfactant, respectively. Significantly smaller droplet size (37 nm), shift in zeta potential from negative to positive value, very high drug loading in lipid based system (> 10%), no precipitation after dissolution are the major distinguish characteristics contributed by LF-OA complex in the SNED system. Saturation solubility and dissolution study in milk containing media pointed the significant increment in solubility of LF in the presence of milk-food fat. LF-SNEDs showed > 90% LF release within 30 min in pH 1.2 while marketed tablet showed almost 0% drug release.ConclusionSelf nanoemulsification promoting ionic complexation between basic drug and oleic acid hold great promise in enhancing solubility of hydrophobic drugs.

Optimization of self-nanoemulsifying formulations for weakly basic lipophilic drugs: role of acidification and experimental design

“…Most of the tested formulations showed excellent self-emulsification in water, at pH 1.2, and even at pH 6.8. This observation is in agreement with recent studies (Larsen et al, 2012;Patel, Sarma, Vavia, 2013) where OL self-emulsifying formulations have exhibited excellent self-emulsification in all tested media. This promising OL characteristic might be explained by the low acid value of OL compared with other fatty acids ( Figure 5) leading to a decreased precipitation tendency at pH 6.8.…”

“…Some articles showed droplet size increases upon drug incorporation (Kommuru et al, 2001;Kang et al, 2004), while a few articles showed no droplet size difference upon drug incorporation (Nielsen et al, 2007). However, one recent publication showed significant droplet size decrease upon drug incorporation (Patel, Sarma, Vavia, 2013). This last publication may be in agreement with the current work because it has also investigated a very similar formulation composition (OL/ medium chain monoglycerides/Cr-El) with a weakly basic drug (lumefantrine).…”

“…This last publication may be in agreement with the current work because it has also investigated a very similar formulation composition (OL/ medium chain monoglycerides/Cr-El) with a weakly basic drug (lumefantrine). According to that recent publication (Patel, Sarma, Vavia, 2013), this phenomenon might be due to the interaction between the drug amine group and the OL carboxylic group, which leads to the formation of an ion-pairing complex. The formed complex presented more efficient self-emulsification and lower droplet sizes than the drug-free formulation.…”

New lumefantrine self nanoemulsifying delivery system – will it by-pass lymphatic transport mechanisms?

“…The recently published article in the esteemed journal entitled “Design and evaluation of Lumefantrine – Oleic acid self nanoemulsifying ionic complex for enhanced dissolution” [1], describes an in-depth research pertaining to the formulation attributes of lumefantrine, an important ani-malarial drug, to enhance its in vitro dissolution and thereby improving its bioavailability upon oral administration. As discussed by authors’ poor solubility of novel chemical entities (NCEs) leads to lack of in vivo translation of the promising in vitro attributes of NCEs because they fail to achieve adequate exposure needed to modulate the target or receptors under in vivo conditions [1].…”

“…As discussed by authors’ poor solubility of novel chemical entities (NCEs) leads to lack of in vivo translation of the promising in vitro attributes of NCEs because they fail to achieve adequate exposure needed to modulate the target or receptors under in vivo conditions [1]. Since lumefantrine has a low and variable bioavailability dependent on the food intake, it is extremely challenging to maintain the threshold levels of the drug needed to combat malarial infections [2].…”