Hydrodispersions For Solubility Enhancement And Development Of Oral Suspension Containing Arteether Using Formulation By Design

Abstract

World Health Organization recommended artemisinin and its derivatives for treatment of falciparum and chloroquine resistance malaria. The most important artemisinin derivatives are artesunate, artemether, arteether and dihydroartemisinin. Among the extensive armamentarium available to treat drug resistant malaria, arteether, is the ethyl ether derivative of dihydroartemisinin is one of the most widely used therapeutics worldwide because of higher lipophilicity than artemether, results in its advantages that it accumulates in brain tissues of the patient by crossing the blood-brain barrier and effectively control cerebral malaria. It is active against P. falciparum strains by exhibiting effective erythrocytic schizonticidal activity. The major issue related with arteether includes its poor aqueous solubility (≅17 μg/mL) and low stability in the gastric medium as it degrades at the gastric pH 1.2 resulting in its poor bioavailability. Majority of arteether (≅ 40%) degrades in the stomach after its oral administration. The drug falls under the Biopharmaceutical Classification System (BCS) class II exhibiting low solubility and high permeability. Due to such limitations, only intramuscular injection of arteether is currently available in market, which suffers from disadvantages like patient non-compliance, pain at injection site etc. The aim of the present study was to improve the aqueous solubility of arteether and develope the reconstituted oral suspension by employing hydrotropic solubilization technique by using various hydrotropic agents at various concentrations of sodium benzoate, sodium citrate, urea, mannitol, sodium saccharin and nicotinamide Maximum solubility enhancement of 39.0 times was observed with 10% blend of sodium saccharin and 18.0 times with 10% blend of mannitol as hydrotropic agent. For further characterization solution was freeze dried using hydrotropic technique to form powder and analyzed through FTIR, XRD, DSC, in vitro dissolution. The freeze dried hydrotropic solid dispersion containing arteether was further employed for the formulation of reconstituted powder for development of oral suspension and characterized on the basis of in process (angle of repose, particle size, bulk density, tapped density) and finished product quality evaluation (drug release, sedimentation volume, particle size, pH, viscosity). The results reflected formation of non-interactive and stabe suspension with desired quality attributes. This study had shown successful approach of solubility enhancement of arteether and further development and optimization of oral reconstituted suspension of arteether, which Abstract 2022 Department of Pharmaceutical Sciences & Technology, MRSPTU VII may eventually lead to increased bioavailability of this poorly water soluble drug. However dose determination and scale up studies are required for development of industry acceptable oral formulation of arteether with improved bioavilability.