Inclusion Complex of Artemether with 2-Hydroxypropyl -β-Cyclodextrin for the Treatment of Malaria: Preparation, Characterization and Evaluation

Abstract

Abbreviations: ATM, artemether; DSC, differential scanning calorimetry; FT-IR, fourier transform infrared spectroscopy; AUC, area under curve; MRT, mass rapid transit; CDs, cyclodextrins; HPLC, high performance liquid chromatography; LE, load efficiency IntroductionMalaria has a serious influence on human beings especially on that in tropical and subtropical countries. It is reported that there are approximately 300-500 million in clinical and 1.5-2.7 million in death every year. Among them, Plasmodium falciparum is the main protozoon for fatal cases. 1 With the widespread drug resistance limited by older therapies dominated by quinine, standard therapy for malaria is now artemisinin-based chemotherapy which is genuine and of high quality. 2 Artemether, [3R-(3R,5aS,6S,8aS,9R ,10R,12S,12aR)]- 6,-1,2-benzodioxepin, 3 is one of the lipidsoluble derivative of artemisinin, which has proved to be efficient against malaria especially for malignant malaria. 4 The structural formula is shown in Figure 1A. ATM disturbs the mitochondrial function, influence ultrastructure, and block the nutritional intake of Plasmodium falciparum, making them to lose cytoplasm and nutrients and cannot get replenish and soon died. 5,6 ATM belongs to BCS IV drug with poorly soluble and poorly permeable peculiarity. 7 ATM is only available as a pre-mixed oilbased solution for intramuscular injection. And there is evidence that the intramuscular injection may not be absorbed absolutely and can cause terrible pain to patient. 8,9 The novel delivery system such as liposome 10 and nanostructured lipid 11 of ATM did not achieve its aim of improving anti-malarial therapeutic efficiency. In addition, its poor bioavailability and rapid clearance from the body limits its exploitation and application in clinical study. From the analysis mentioned above, we can realize the importance of improving its solubility and bioavailability. Several formulation approach could be used to improving the solubility along with bio-availability of insoluble drugs. 12 Until now, different formulations are reported such as Solid Dispersion System, 7 nanoparticle, 13 inclusion complex. 1 Among them, inclusion complex is widely elected due to their mass production achieved easily.As a kind of functional excipients, cyclodextrins (CDs) have been used extensively in pharmaceutical formulations to improve the bio- AbstractArtemether (ATM) is being evaluated for use in Malaria at present. However, its poor solubility in water limits its exploitation and application in clinical. The purpose of this work is to develop inclusion complex of ATM with 2-hydroxypropyl-β-cyclodextrin (ATM-2-HP-β-CD inclusion complex) which have the ability to improve the solubility and oral bioavailability of ATM. The ATM-2-HP-β-CD inclusion complex was prepared by Solution mixing method at the mole ratio of 1:36 (ATM: HP-2-β-CD). The average drug entrapment efficiency and loading capacity were 97.66±1.22% and 2.64±0.03%, respectively. The formation of ATM-2-HP-β-CD inclusion complex was verified by ...