Bioactive Permethrin/-Cyclodextrin Inclusion Complex Guang-Fu Yang,* ,²,‡ Hong-Bo Wang, ² Wen-Chao Yang, ²,‡ Daquan Gao, ‡ and Chang-Guo Zhan* ,‡ Key Laboratory of Pesticide and Chemical Biology of the Ministry of Education, College of Chemistry, Central China Normal UniVersity, Wuhan 430079, People’s Republic of China, and Department of Pharmaceutical Sciences, College of Pharmacy, UniVersity of Kentucky, 725 Rose Street, Lexington, Kentucky 40536 ReceiVed: NoVember 23, 2005; In Final Form: January 15, 2006 Permethrin is popularly used in a variety of therapeutic areas. However, the poor water solubility of permethrin seriously limits its wider clinical applications. The present study demonstrates that solubility of permethrin in aqueous solution can considerably increase in the presence of -cyclodextrin (-CD). Extensive experimental data along with computational modeling reveal the formation of stable permethrin/-CD inclusion complexes, including permethrin(-CD) and permethrin(-CD) 2 , through hydrophobic binding. Both permethrin(-CD) and permethrin(-CD) 2 complexes coexisted in aqueous solution, and the ratio of the concentration of permethrin(-CD) complex to that of permethrin(-CD) 2 complex was dependent on the concentration of -CD. The complexation of permethrin with -CD significantly improved the bioavailability of permethrin and, therefore, increased the bioactivity. The significant increase of the bioactivity of permethrin in the presence of -CD provides an effective approach to improve the practical use of permethrin in public health and agriculture. Introduction Permethrin, a synthetic pyrethroid, is one of the two currently available “over-the-counter” agents for the treatment of head lice, one of the most common diseases in the U.S. and in most of the developed world. 1 Recently, the increase of opportunistic infections in HIV-infected patients, like scabies, has developed an increasing interest in formulation of this substance for therapy. 2 The use of permethrin has also been extended for the prevention of malaria in tropical areas. In addition, permethrin is also recommended by the World Health Organization to be used as the active ingredient of public hygiene insecticidal products for treatment of mosquitos, fleas, flies, mites, and cockroaches. 3 However, the poor water solubility of permethrin seriously limits its practical clinical applications. In efforts to overcome the limitation, some approaches, including the use of cosolvents, solubilizers, and surfactants, have been considered to improve the water solubility of permethrin, although all of these existing approaches have their own limitations. A promis- ing approach for the solubilization of synthetic pyrethroids could be the use a cyclodextrin (CD), which imparts its beneficial physicochemical properties through formation of an inclusion complex, as CDs have been used for delivery of other pharmaceutical agents. 4,5 CDs are cyclic oligosaccharides composed of six (R-), seven (-), or eight (γ-) D-glucopyranose residues linked by R-(1,4) bonds. 6 As important host compounds, CDs have high molecular recognition ability toward guest molecules with a suitable polarity and dimension because of their hydrophobic internal cavity and hydrophilic external surface. This ability has been widely used in pharmaceutical applications with the aim to enhance water solubility, chemical stability, and bioavailability of insoluble or poorly soluble drugs, to reduce toxicity, and to control the rate of release. 7 Here we report the preparation and characterization of a new type of inclusion complexes formed from permethrin and -cyclodextrin, with an aim to improve the water solubility and bioavailability of permethrin. The obtained inclusion complexes were found to significantly improve the water solubility of permethrin and demonstrated a 4-fold increase of the insecticidal activity. The work described in this report is based on an integrated experimental-computational approach. Compared to the previously used pure experimental approaches, the integrated experimental-computational approach not only demonstrates some macroscopic information about the solubility and possible intermolecular interactions through wet experimental measure- ments but also provides valuable information about the micro- scopic binding through the computational modeling. Materials and Methods Materials. All materials were obtained from commercial sources and were used as received unless stated otherwise. Specially, -cyclodextrin (g99%) was obtained from Shanghai Boao Life Science and Technology Corp. (China). trans- (1R,3R)-Permethrin was recrystallized from ethanol and dried in low temperature. Preparation and Experimental Characterization of the Permethrin/-Cyclodextrin Inclusion Complexes. An ethanol solution of permethrin (0.l mM, 0.0391 g) was added to aqueous solution of -CD (0.2 mM, 0.227 g) in 80 mL of water. The resulting mixture was stirred at 30 °C for 3 days. After removal of 20 mL of a mixture of ethanol-water under vacuum, the reaction mixture was cooled at 2 °C overnight. The precipitate was filtered and washed by a little hot water in order to remove unreacted -CD. The obtained residue was dried overnight at 30 °C under high vacuum. Phase solubility studies were carried out according to Higuchi and Connors’ method. 8 An excess amount of permethrin was added to 10 mL aqueous solutions containing different concen- trations of -CDs (0-14 mM). Flasks were sealed to avoid * To whom correspondence should be addressed. Telephone: 859-323- 3943. Fax: 859-323-7585. E-mail: zhan@uky.edu. ² Central China Normal University. ‡ University of Kentucky. 7044 J. Phys. Chem. B 2006, 110, 7044-7048 10.1021/jp056809l CCC: $33.50 © 2006 American Chemical Society Published on Web 03/10/2006