Binary and Ternary Complexes of Arteether β-CD - Characterization, Molecular Modeling and in Vivo Studies

Renu Chadha, Sushma Gupta, Natasha Pathak, Geeta Shukla, D.V.S. Jain, Raghuvir R S Pissurlenkar, Evans C Coutinho

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DOI: 10.4236/pp.2011.23030                

Abstract

The purpose of the present work is to improve the antimalarial activity of arteether through enhancing its solubility subsequently bioavailability by incorporating the drug into the cyclodextrins cavity. The effect of hydrophilic polyvinyl propylene (PVP) polymer on the complexation and solubilizing efficiencies of cyclodextrins (CDs) is also elucidated. Inclusion of arteether molecule in solid state was evidenced by Differential scanning calorimeter (DSC), Powder X-ray diffractometery (PXRD), and in solution state by NMR and solution calorimetry. A 1:1 stoichiometry was proposed by the phase solubility studies both in presence and absence of PVP. The most plausibe mode of inclusion of arteether into the CD cavity is revealed by molecular modeling studies utalizing Fast Rigid Exhaustive Docking acronym. Solution calorimetry was used further to confirm 1:1 stiochiometry in presence or absence of PVP by determining the enthalpy of interaction between the drug and cyclodextrins. The inclusion of drug was found to be exothermic process accompanied by small positive value of entropy (ΔSo). The methylated-β-CD showed the best ability to solublize arteether which is approximately at par with β-CD in the presence of PVP. Better complexation efficiency of β-CD in presence of PVP is also reflected by the higher numerical values of stability constant (K). Compelete eradication of the parasite from the blood and highest anti-malarial pharmacological activity was observed in the complexes of arteether with M-?-CD while 83.7% was observed for ternary complexes of β-CD in presence of PVP.

Keywords

Arteether, cyclodextrins, ternary complexes, complexation efficiency, in vivo studies

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1]	D. L. Klaymann, “Qinghaosu, an Antimalarial from China,” Science, Vol. 228, No. 4703, 1985, pp. 1049- 1055. doi:10.1126/science.3887571
[2]	R. G. Patel, A. C. Shah and J. H. Patel, “An Arteether Injection for Treatment of Malaria,” WIPO Patent Application WO/2010/082219, IN2009/000757, 22 July 2010.
[3]	G. A. Balint, “Artemisnin and Its Derivatives an Important New Class of Antimalarial Agents,” Pharmacology & Therapeutics, Vol. 90, No. 2-3, May-June 2001, pp. 261- 265. doi:10.1016/S0163-7258(01)00140-1
[4]	Report of a Joint CTD/DMP/TDR, “The Use of Artemis- inin and Its Derivatives as Antimalarial Drugs,” World Q3 Health Organization, Malaria Unit Division of Con- trol of Tropical Diseases, World Health Organization 1998, Geneva. (WHO, WHO/MAL/98/1086). http://www.doh.gov.za/issues/malaria/red_reference/case_management/cm2.PDF.
[5]	R. Ferone, “Folate Metabolism in Malaria,” Bulletin - World Health Organization, Vol. 55, 1977, pp. 291-298. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2366725/pdf/bullwho00446-0156.pdf
[6]	A. K. Krishna, D. R. Flanagan, “Micellar Solubilisation of a New Antimalarial Drug, β-Arteether,” Journal of Pharmaceutical Sciences, Vol. 78, No. 7, July 1989, pp. 574-576. doi:10.1002/jps.2600780713
[7]	A. J. Lin, R.E. Miller, “Antimalarial Activity of New di- Hydroartemisinin Derivatives. 6. Alpha-Alkylbenzyic Ethers,” Journal of Medicinal Chemistry, Vol. 38, No. 5, March 1995, pp. 764-770. doi:10.1021/jm00005a004
[8]	Li QG, P. J., Fleckenstein LL, K. Masonic, M. H. Heiffer, T. G. Brewer, “The Pharmacokinetics and Bioavailability of Dihydroartemisinin, Arteether, Artemether, Artesunic Acid and Artelinic Acid in Rats,” Journal of Pharmacy and Pharmacology, Vol. 50, No. 2, February 1998, pp. 173-182. doi:10.1111/j.2042-7158.1998.tb06173.x
[9]	B. J. Aungst, “Novel Formulation Strategies for Improving oral Bioavailability of Drugs with Poor Membrane Permeation or Presystemic Metabolism,” Journal of Pharmaceutical Sciences, Vol. 82, No. 10, October 1993, pp. 979-987. doi:10.1002/jps.2600821002
[10]	H. Fridriksdottir, T. Loftsson and E. Stefansson, “Formu- lation and Testing of Methazolamide Cyclodextrin Eye Drop Solutions,” Journal of Controlled Release, Vol. 44, No. 1, February 1997, pp. 95-99. doi:10.1016/S0168-3659(96)01506-4
[11]	D. Duchene, D. Wouessidjewe,” Pharmaceutical and Medicinal Applications of Cyclodextrins,” In: S. Dumi- triu, Ed., Polysaccharides in Medical Applications, Marcel Dekker, New York, 1996, pp. 575-602.
[12]	K. Uekama, F. Hirayama, T. Irie, “Cyclodextrin Drug Carrier Systems,” Chemical Reviews, Vol. 98, No. 5, July 1998, pp. 2045-2076.
[13]	T. Loftsson, M. E. Brewster, “Pharmaceutical Applica- tions of Cyclodextrins, I: Drug Solubilization and Stabilization,” Journal of Pharmaceutical Sciences, Vol. 85, No. 10, 1996, pp. 1017-1025. doi:10.1021/js950534b
[14]	R. A. Rajewski, V.J. Stella, “Pharmaceutical Applications of Cyclodextrins, II: in Vivo Drug Delivery,” Journal of Pharmaceutical Sciences, Vol. 85, No. 11, 1996, pp. 1142- 1169. doi:10.1021/js960075u
[15]	Del Valle EM.Martin, “Cyclodextrins and Their Uses: A Review,” Process Biochemistry, Vol. 39, No. 9, 2004, pp. 1033-1046. doi:10.1016/S0032-9592(03)00258-9
[16]	T. Loftsson, H. Fridriksdottir, B. J. Olafsdottir, “Solubi- lization and Stabilization of Drugs through Cyclodextrin Complexation,” Acta Pharmaceuitca Nordica, Vol. 3, 1991, pp. 215-217.
[17]	T. Loftsson, H. Fridriksdottir, A.M. Sigurdadottir and H. Ueda, “The Effect of Water Soluble Polymers on Drug Cyclodextrin Complexation,” International Journal of Pharmaceutics, Vol. 110, 1994, pp. 169-177. doi:10.1016/0378-5173(94)90155-4
[18]	T. Loftsson, H. Fridriksdottir, A. M. Sigurdadottir and T. K. Gudmundsdottir, “The Effect of Water Soluble Polymers on the Aqueous Solubility of Drugs,” International Journal of Pharmaceutics, Vol. 127, 1996, pp. 293-296. doi:10.1016/0378-5173(95)04207-5
[19]	T. Loftsson, “Increasing the Cyclodextrin Complexation of Drugs and Drug Bioavailability through Addition of Watersoluble Polymers,” Pharmazie, Vol. 53, No. 1, 1998, pp. 733-740.
[20]	A. C. C. Asbahr, L. Franco, A. Barison, C. W. P. Silva, and L. N. C. Rodrigues, H. G. Ferraz, “Binary and Ternary Inclusion Complexes of Finasteride in HPbCD and Polymers: Preparation and Characterization,” Bioorganic & Medicinal Chemistry, Vol. 17, No. 7, April, 2009, pp. 2718-2723. doi:10.1016/j.bmc.2009.02.044
[21]	M. Bayomi, “Characterisation of Arteether Interactions with β-Cyclodextrin and Hydroxy- β — Cyclodextrin,” Saudi Pharmaceutical Journal, Saudi Pharmaceutical Society, Vol. 10, No. 1/2, 2002, pp. 36-43.
[22]	A. C. Illapakurthy, Y. A. Sabins, B. A. Avery, M. A. Avery, C. M. Wyandt, “Interaction of Artemisnin and Its Related Compounds with Hydroxypropyl-β-Cyclodextrin in Solution State: Experimental and Molecular-Modeling Studies,” Journal of Pharmaceutical Science, Vol. 92, No. 3, March 2003, pp. 649-655. doi:10.1002/jps.10319
[23]	P-V. Jacqueline, G. Margriet, “Inclusion Complexes of Artemisinin or Derivatives with Cyclodextrins,” Patent No. WO/2004075921, International Application No. PCT/ EP2004/001851, September 2004.
[24]	M. McGann, H. Almond, A. Nicholls, J. A. Grant, F. Brown, “Gaussian. Docking Functions,” Biopolymers, Vol. 68, No. 1, January 2003, pp. 76-90. doi:10.1002/bip.10207
[25]	G. B. McGaughey, R. P. Sheridan, C. I. Bayly, J. C. Cul- berson, C. Kreatsoulas, S. Lindsley, V. Maiorov, J.-F. Truchon, W. D. Cornell, “Comparison of Topological, Shape, and Docking Methods in Virtual Screening,” Journal of Chemical Information and Modeling, Vol. 47, No. 4, June 2007, pp. 1504-1519. doi:10.1021/ci700052x
[26]	H. M. Berman, J. Westbrook, Z. Feng, G. Gilliland, T. N. Bhat, H. Weissig, I. N. Shindyalov, P. E. Bourne, “The Protein Data Bank,” Nucleic Acids Research, Vol. 28, 2000, pp. 235-242. doi:10.1093/nar/28.1.235
[27]	P Mark, L. Nilsson, “Structure and Dynamics of the TIP3P, SPC, and SPC/E Water Models at 298 K,” Journal of Physical Chemistry A, Vol. 105, No. 43, October 2001, pp. 9954-9960. doi:10.1021/jp003020w
[28]	D. Quigley, M. I. J, “Probert, “Constant Pressure Lange- vin Dynamics,” Theory and Application, Vol. 169, September 2004, pp. 322-325.
[29]	J. P. Ryckaert, G. Ciccotti, H. J. C. Berendsen, “Numeri- cal Integration of the Cartesian Equations of Motion of a System with Constraints: Molecular Dynamics of n-al- kanes,” Journal of Computational Physics, Vol. 23, No. 3, March 1977, pp. 327-341. doi:10.1016/0021-9991(77)90098-5
[30]	T. Higuchi, K. A. Connors, “Phase Solubility Techniques,” Advanced Analytical Chemistry of Instrumentation, Vol. 4, 1965, pp. 117-212.
[31]	M. Valero, J. Tejedor, L. J. Rodriguez, “Encapsulation of Nabumetone by Means of -Drug: (β-Cyclodextrin)2: Polyvinylpyrrolidone Ternary Complex Formation,” Journal of luminescence, Vol. 126, No. 2, October 2007, pp. 297-302. doi:10.1016/j.jlumin.2006.07.028
[32]	P. Job, “Recherches sur la formation de complexes min- eraux en solution et sur leur stabilite,” Annual Chemistry, Vol. 9, 1928, pp. 1132-114.
[33]	A. R. Patel, P. R. Vavia, “Effect of Hydrophilic Polymers on Solubilization of Fenofibrate by Cyclodextrin Com- plexation,” Journal of Inclusion Phenomenon and Mac- rocyclic Chemistry, Vol. 56, 2006, pp. 247-251. doi:10.1007/s10847-006-9091-4
[34]	L. Ribeiro, T. Loftsson, D. Ferreira and F. Veiga, “Inves- tigation and Physicochemical Characterization of Vinpo- cetine-Sulfobutyl Ether β-Cyclodextrin Binary and Ternary Complexes,” Chemistry Pharmaceutical Bulletin, Vol. 51, 2003, p. 914. doi:10.1248/cpb.51.914