Artemether/hydroxypropyl-β-cyclodextrin host–guest system: Characterization, phase-solubility and inclusion mode
Introduction
Malaria has a devastating effect throughout tropical regions. There are approximately 300–500 million clinical cases each year resulting in 1.5–2.7 million deaths. Nearly all fatal cases are caused by Plasmodium falciparum.1 The problem is compounded by the spread of drug resistant strains of the parasite. As a result, traditional alkaloid drugs such as chloroquine and quinine are now largely ineffective.2 The spread of parasite resistance has led the World Health Organization (WHO) to predict that without new antimalarial drug intervention, the number of cases of malaria will have doubled by the year 2010.3 Artemisinin (Qinghaosu) is a sesquiterpene 1,2,4-trioxane (sesquiterpene lactone endoperoxide) isolated from the Chinese medicinal herb qinghao (Artemisia annua L.). In 1979 it was shown to be an effective antimalarial against chloroquine-resistant strains of P. falciparum.4 This compound and its derivatives, such as artemether (ATM), dihydroartemisinin, arteether, and artesunate, are effective against both chloroquine-resistant and chloroquine-sensitive strains of P. falciparum, as well as against cerebral malaria.5, 6 Most countries where malaria is endemic have adopted the WHO recommendation of artemisinin combination therapy (ACT) for fast and reliable malaria treatment.7 However, artemisinin’s poor solubility in both oil and water, and hydrolytic instability of the lactone function, have led scientists to prepare a series of semisynthetic first generation analogues, such as ATM (Chart 1).8 Although ATM is a potent antimalarial, poor bioavailability and rapid clearance are observed with it and the other derivatives in both human and animal models.9
Cyclodextrins (CDs) are truncated-cone polysaccharides mainly composed of six to eight d-glucose monomers linked by α-1,4-glucose bonds. They have a hydrophobic central cavity and hydrophilic outer surface and can encapsulate model substrates to form host–guest complexes or supramolecular species. This usually enhances drug solubility in aqueous solution and affects the chemical characteristics of the encapsulated drug.10, 11, 12, 13 Hydroxypropyl-β-cyclodextrin (HPβCD, Chart 2) is a hydroxyalkylated βCD derivative that combines relatively high water solubility with low toxicity and satisfactory inclusion ability.14, 15 Several commercial formulations are composed of cyclodextrin inclusion complexes, illustrating the usefulness of this approach.16, 17, 18, 19
The latest research indicates that HPβCD complexation with dihydroartemisinin increases dihydroartemisinin solubility and stability.20 In this work we studied the formation of an inclusion complex of ATM with HPβCD. We utilized phase-solubility techniques, molecular modeling by 1H NMR and 2D NMR spectroscopy (Rotating-frame Overhauser effect spectroscopy, ROESY) and characterized the complex by Powder X-ray diffraction and thermal analysis. We focused on the binding behaviors of hydroxypropyl-β-cyclodextrin with ATM and the solubilization effect of HPβCD toward ATM, as these may provide a useful approach to produce novel ATM formulations with high bioavailability.
Section snippets
Phase-solubility
The phase-solubility diagram of the HPβCD/ATM system (Fig. 1) showed drug solubility increased linearly with increasing HPβCD concentration.
This diagram can be classified as AL type according to the model proposed by Higuchi and Connors.21 It can be related to the formation of a soluble inclusion complex. The apparent stability constant (K1:1), was calculated from the linear fit of the curve according to the following equation:where Slope is the value found in the linear
Conclusion
In summary, the complexation behavior, characterization and bioavailability of an inclusion complex of ATM with HPβCD were investigated. Results showed that HPβCD could enhance the watersolubility and bioavailability of ATM. Considering the lack of ATM applications, the complex could prove useful in the design of novel medicinal ATM formulations.
Materials
ATM (FW = 298, PC >99%) was obtained from Kunming Pharmaceutical Corporation (Yunnan Province, P R China). Hydroxypropyl-β-cyclodextrin (average FW = 1380) was purchased from Sigma–Aldrich Chemical Corporation (Shanghai, P R China) and used as received. Other reagents and chemicals were of analytical reagent grade. All experiments were carried out using ultrapure water.
HPLC assay
An Agilent 1100 HPLC system was used to determine the amount of ATM. The Agilent HPLC system was equipped with G1311A pump and
Acknowledgments
Support for this work from the Opening Foundation of State Key Laboratory of Elemento-Organic Chemistry of Nankai University (0704 and 0815) and NSFC 30860342 are gratefully acknowledged, and we thank Zhao-Xiang Yang at Kunming Pharmaceutical Corporation, for his help on the bioavailability studies in the rats.
References and notes (28)
- et al.
J. Pharm. Sci.
(1996) - et al.
Food Chem. Toxicol.
(2005) - et al.
Bioorg. Med. Chem.
(2006) - et al.
J. Controlled Release
(1999) - et al.
J. Pharm. Sci.
(1997) - et al.
Int. J. Pharm.
(2005) - et al.
Bioorg. Med. Chem.
(2005) - et al.
Bioorg. Med. Chem.
(2008) - et al.
Eur. J. Pharm. Sci.
(2006) - et al.
Science
(1999)