시클로덱스트린류와의 복합체 형성에 의한 벤즈이미다졸계 구충 약물의 용해성 및 용출 증가

Solubilization and Dissolution Enhancement of Benzimidazole Antnelmintic Drugs by Cyclodextrin Complexation

Complex formations of practically insoluble antelmintic drugs such as mebendazole (MBZ), albendazole (ABZ) and flubendazole (FBZ) with dimethyl-beta-cyclodextrin (DM-beta-CyD) and 2-hydroxypropyl-beta-cyclodextrin (HP-beta-CyD) together with alpha-, beta- and gammar-cyclodextrins (CyDs) in buffered solutions were investigated by solubility method. AL type phase solubility diagrams were obtained in all cases except for the complexation (BS type) of FBZ with gammar-CyD. The highest stability constants were obtained with DM-P-CyD, followed by allpha-CyD > beta-CYD > HP-beta-CyD > gammar-CyD for ABZ, and HP-beta-CyD > gammar-CyD > beta-CyD > alpha-CyD for FBZ at pH 1.2. On the other hand, solid dispersion systems of ABZ and FBZ with beta- and DM-beta-CyDs were prepared by solvent evaporation method and evaluated by dissolution, differential thermal analysis and powder x-ray diffractometry. The dissolution rates of ABZ- and FBZ-DM-P-CyD solid dispersions were much faster than those of drugs alone, corresponding physical mixtures and tablets on market both at pH 1.2 and 6.8. Although dissolution rates of all samples at pH 6.8 were by far lower than those obtained at pH 1.2, as explained by pH-solubility profiles for ABZ and FBZ, the dissolution rates at pH 6.8 of ABZ from beta- and DM-beta-CyD solid dispersions exceeded the respective equilibrium solubility (23.9mcg/ml). Fast dissolution of ABZ from solid dispersions with CyDs was attributed to the reduction of drug crystallinity and particle size which was supported by DTA and powder x-ray diffractometry. Consequently these results suggest that solid dispersion systems with CyDs may provide useful means to markedly enhance the solubility and dissolution of benzimidazole antelmintic drugs.