Part A - Dual Solubility Enhancement Approaches For Arteether: Solid Dispersion And Micronization

Abstract

World Health Organization recommended artemisinin and its derivatives for treatment of falciparum malaria 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, the ethyl ether derivative of dihydroartemisinin, is one of the most widely used therapeutics worldwide because of higher lipophilicity of /-arteether as compare to other artemisinin derivatives, which results in its advantageous accumulation in brain tissues of the patient by crossing the blood-brain barrier and therefore ability to control cerebral malaria effectively. It is active against P. falciparum strains by exhibiting effective erythrocytic schizonticidal activity. It is used in the case of chloroquineresistant malaria, as well as in cerebral malaria. The major issue related with α/β-arteether include 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 α/βarteether (≅ 40%) degrades in the stomach after its oral administration. The drug came under the Biopharmaceutical Classification System (BCS) class II representing low solubility and high permeability. Due to such limitations, only intramuscular injection of α/β-arteether is currently available in market, which suffers from disadvantages like patient non-compliance, pain at injection site etc. The present study aimed to develop novel solid dispersions to investigate the potential of various hydrophilic polymers to improve the aqueous solubility of α/β-arteether because solid dispersion appears to be a better approach to improve drug solubility than other techniques, as they are easier to produce and more applicable. Solid dispersions of α/β-arteether were prepared by solvent evaporation and spray drying method using various hydrophilic polymers viz. soluplus, poloxamer 407, PEG-6000. The prepared solid dispersions were further characterized by particle size analysis, Fourier Transform Infrared Spectroscopy, Differential Scanning Calorimetry, X-ray Diffraction, and evaluated for enhancement in saturated solubility, in vitro dissolution performance, and permeability through pig intestine. On the basis of solubility and dissolution studies, spray-dried binary solid dispersion of α/β-arteether (F7) with soluplus in ratio of 1:15 showed enhancement in solubility by 67.31 times and ternary solid dispersions of α/βarteether (F8) with polyethylene glycol 6000, Poloxamer-407 in ratio of 1:4.3:3.7 w/w and (F11) with soluplus, Poloxamer 407 in ratio of 1:15:3.7 w/w exhibited significant

Department ofPharmaceutical Sciences andTechnology, MRSPTU viii improvement in equilibrium solubility by 46.42 times and 80.58 times respectively. The particle size analysis confirmed that the prepared solid dispersions get transformed to submicron size particles with good size distribution. The XRD and DSC analysis confirmed that crystalline form of prepared solid dispersions was changed to the amorphous state. FT-IR analysis did not reveal any physicochemical interactions in the solid dispersion formulations. Permeability of α/β-arteether by ternary solid dispersion (F11) was maximally enhanced up to 9.08-folds, in comparison to the pure drug. The results indicated the potential of these methodologies for significant enhancement in aqueous solubility of α/β-arteether, which may lead to development of various dosage forms with improved bioavailability, low dose requirement and better therapeutic spectrum.