담즙산염과 2-히드록시프로필-β-시클로덱스트린을 이용한 아토르바스타틴칼슘의 용출 및 십이지장 점막 투과 증진

Enhanced Dissolution and Duodenal Permeation of Atorvastatin Calcium Using Bile Salt and 2-Hydroxypropyl-β-Cyclodextrin

This study was aimed to increase the solubility, dissolution and permeation rates of atorvastatin calcium (ATC) using bile salt and/or 2-hydroxypropyl-β-cyclodextrin (HPβCD). From solubility studies, sodium deoxycholate (SDC) among bile salts studied was found to have the highest solubilizing effect on ATC (4.4±0.4 mg/ml), and the order of increasing solubility was SDC>sod. cholate>sod. glycocholate>sod. taurodeoxycholate>sod. taurocholate>conjugated bile acid. ATC solid dispersions were prepared at various ratios of drug to SDC and/or HPβCD, and evaluated by differential scanning calorimetry (DSC), dissolution studies and dissolution-permeation studies. DSC curves showed amorphous state of ATC in the physical mixture and solid dispersion. Dissolution rates of ATC-SDC solid dispersions and physical mixture were markedly increased at pH 6.8, but decreased at pH 1.2 with greater proportions of SDC due to the precipitation of SDC, compared with that of drug alone. On the other hand, dissolution rates of ATC-HPβCD solid dispersion and physical mixture at pH 1.2 were varied with the ratio of drug to carriers. From duodenal permeation studies, it was found that fluxes of ATC (donor dose: 0.5 mg/3.5 ml) in the presence of 25 mM sodium glycocholate, SDC, sod. cholate and sod. taurocholate (5.7±0.9, 5.6±0.9, 4.8±0.7 and 4.6±0.9 μg/cm2/hr, respectively) were enhanced, compared with drug alone (3.4±0.9 μg/cm2/hr). In the dissolution-permeation studies, 1 : 9 : 10 (w/w) ATC-SDC-HPβCD solid dispersion increased the flux 2.2 times, compared with 1 : 5 : 4 (w/w) ATC-lactose-corn starch mixture as control. In conclusion, solid dispersions with bile salt and HPβCD were found to be an effective means for increasing the dissolution and permeation rates of ATC.