Formulation and Evaluation of Some in Vitro and in Vivo Properties of Artemether-Loaded Self Emulsifying Drug Delivery System

Abstract

The aims of this research work were to formulate artemether-loaded self emulsifying drug delivery system (SEDDS), evaluate some of its in vitro and in vivo properties, and prevent drug precipitation through supersaturation approach. The solubility of artemether (ARM) in various oils, surfactants and cosurfactants was determined using the equilibrium solubility method. Vehicles such as Triacetin®, Labrasol® and Transcutol P® were selected as components of the formulation due to their high solubilising capacities. Pseudoternary phase diagrams were constructed in order to select the optimized batches. SEDDS containing 40 mg, 50 mg and 55 mg of ARM respectively were formulated and called non-hydroxypropylmethylcellulose batches (non-HPMC batches) while those containing 5 % hydroxypropylmethylcellulose (HPMC), a precipitation inhibitor, were called HPMC batches. The melting point of artemether was determined. The following evaluation tests: droplet size, preformulation and postformulation visual isotropicity, emulsification time, refrigeration cycle, centrifugation, aqueous dilution, viscosity, pH, drug content, and crystallization/precipitation studies were carried out. In vitro release studies of the formulations were carried out in simulated gastric fluid (SGF) without pepsin (pH, 1.2) and stimulated intestinal fluid (SIF) without pancreatin (pH, 6.8) respectively. Finally, the antimalarial activity of the ARM was evaluated using 25 mice grouped into five groups: SEDDS-treated group, chloroquine-treated group, placebo-treated group, untreated group (negative control) and aqueous ARM dispersion-treated group (positive control). The melting point range was obtained as 86-88 oC. Results showed that ARM has high solubility in Triacetin® (136.00 ± 0.09 mg/ml), Labrasol® (156.00 ± 0.01 mg/ml), and Transcutol P® (166.00 ± 0.02 mg/ml). From the pseudoternary phase diagrams, the optimized batches of Smix (1:0.5, and 3:1) were selected. The preformulation visual isotropicity test carried out on the optimized batches showed that the oil: Smix ratios; 1:2.0, 1:2.5, 1:3.5 and 1:4 were isotropically stable, while the postformulation visual isotropicity test showed that the SEDDS remained thermodynamically stable after 72 h. There was no significant difference in the emulsification times of the HPMC and non-HPMC batches. The result of refrigeration cycle and centrifugation test showed no variation in the physical properties such as colour, odour change or phase separation. Phase separation was not noticed after dilution of the SEDDS to 1 L with 0.1N HCl. There was no significant difference in the loading efficiency (%) between HPMC and non-HPMC batches. Also, there was no significant change in the pH of the HPMC and non-HPMC batches. There was, however, significant difference (p < 0.05) in the viscosity of the HPMC and non-HPMC batches. After three hours of the SEDDS formulation in aqueous phase, the photomicrographs revealed the presence of some drug crystals in the non-HPMC batches, while no crystal was observed in the HPMC batches. The drug release profiles of non-HPMC batches showed T50 (time to release 50 % of the drug) and T85 (time to release 85 % of the drug) values that ranged between 3-8 min and 14-22 min respectively in SIF, and 3-4 min and 5-18 min respectively in SGF. On the other hand, the drug release profiles of HPMC batches showed T50 and T85 values that ranged between 8-35 min, and 53-153 min in SGF and T50 and T85 values that ranged between 4-13 min and 92-213 min respectively in SIF. Results of antimalarial studies showed the following percent activities: SEDDS-treated group (94.00 ± 0.57 %), chloroquine-treated group (59.00 ± 0.85 %), placebo-treated group (16.0 ± 4.1 %), and aqueous ARM-treated group (47.0 ± 1.8 %). The SEDDS-treated group had a significantly (p < 0.05) higher antimalarial activity than the rest.