Enhanced bioavailability of poorly water-soluble clotrimazole by inclusion with beta-cyclodextrin.
Clotrimazole, a poorly water-soluble antimycotic agent, is a promising agent for various diseases including cancer and sickle cell anemia. To improve the oral bioavailability of clotrimazole, the inclusion compound of clotrimazole with beta-cyclodextrin was prepared by spray-drying method and characterized by phase solubility, differential scanning calorimetry and dissolution. Furthermore, the pharmacokinetics after oral administration in rats was then performed compared with clotrimazole powder. The solubility of clotrimazole increased linearly as a function of beta-cyclodextrin concentration, resulting in A(L) type phase solubility diagram which revealed a formation of inclusion compound in a molar ratio of 1:2, with the apparent association constant of 230.2 M(-1). The dissolution rate of clotrimazole in the inclusion compound increased greatly compared to clotrimazole powder in pH 7.4 phosphate buffer solution. The inclusion compound gave significantly higher initial plasma concentrations, Cmax and AUC of clotrimazole than did clotrimazole powder when they were administered as suspension form, indicating that the drug from inclusion compound could be more orally absorbed in rats. Thus, the oral bioavailability of clotrimazole could be improved markedly by inclusion complexation, possibly due to an increased dissolution rate.
Prabagar
Balakrishnan
B
College of Pharmacy, Yeungnam University, Gyongsan 712-749, Korea.
Yoo
Bong-Kyu
BK
Woo
Jong-Soo
JS
Kim
Jung-Ae
JA
Rhee
Jong-Dal
JD
Piao
Ming Guan
MG
Choi
Han-Gon
HG
Yong
Chul Soon
CS
D000284:Administration, Oral; D000818:Animals; D000935:Antifungal Agents / Q000097:blood / Q000737:chemistry* / Q000493:pharmacokinetics*; D001682:Biological Availability; D003022:Clotrimazole / Q000097:blood / Q000737:chemistry* / Q000493:pharmacokinetics*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility; D014867:Water / Q000737:chemistry*; D047392:beta-Cyclodextrins / Q000737:chemistry*
D000935:Antifungal Agents; D047392:beta-Cyclodextrins; D014867:Water; D003022:Clotrimazole; C031215:betadex