• Journal of Pharmaceutical Investigation
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• 제38권2호
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• pp.111-117
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• 2008

To overcome the solubility of poorly water-soluble drug, the formation of solid dispersion using a spray-dryer with polymeric material, that can potentially enhance the dissolution rate extend of drug absorption was considered in this study. $Eudragit^{(R)}$ E100 as carrier for solid dispersion is acrylate copolymer that soluble in acidic buffer solutions (below pH 5.0). It was used to increase dissolution of atorvastatin calcium as a water-insoluble drug in acidic environments. In this study, a spray-dryer was used to prepare solid dispersion of atorvastatin calcium and $Eudragit^{(R)}$ E100 for purpose of improving the solubility of drug. Atorvastatin calcium and $Eudragit^{(R)}$ E100 were dissolved in ethanol and spray-dryed. DSC and XRD were used to analyze the crystallinity of the sample. It was found that atorvastatin calcium is amorphous in the $Eudragit^{(R)}$ E100 solid dispersion. FT-IR was used to analyze the salt formation by interaction between atorvastatin calcium and $Eudragit^{(R)}$ E100. Comparative dissolution study exhibited better dissolution characteristics than the commercial drug ($Lipitor^{(R)}$) as control. The dissolution rate of atorvastatin calcium was markedly increased in solid dispersion system in simulated gastric juice (pH 1.2). This study proposed that this solid dispersion system improved the bioavailability of poorly water-soluble atorvastatin calcium.

• Biomolecules & Therapeutics
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• 제16권1호
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• pp.28-33
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• 2008

Atorvastatin calcium salt (1) was obtained through the preparation of lactone compound (8) from 2-((4R,6R)-6-(2-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)-1H-pyrrol-1-yl)-ethyl)-2-phenyl-1,3,2-dioxaborinan-4-yl)acetic acid tert-butyl ester (9) by hydrolysis in basic condition. Efficient hydrolysis of boronate compound 9 aimed at the viable synthesis for commercial production and purification of Atorvastatin calcium is reported. Detail studies of evaluation procedure are also reported.

• Journal of Pharmaceutical Investigation
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• 제37권6호
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• pp.339-347
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• 2007

SMEDDS is mixture of oils, surfactants, and cosurfactants, which are emulsified in aqueous media under conditions of gentle agitation and digestive motility that would be encountered in the gastro-intestinal(GI) tract. The main purpose of this work is to prepare self-microemulsifying drug delivery system(SMEDDS) for oral bioavailability enhancement of a poorly water soluble drug, atorvastatin calcium. Solubility of atorvastatin calcium was determined in various vehicles. Pseudo-ternary phase diagrams were constructed to identity the efficient self-emulsification region and particle size distributions of the resultant micro emulsions were determined using a laser diffraction sizer. Optimized formulations for in vitro dissolution and bioavailability assessment were $Capryol^{(R)}$ 90(50%), Tetraglycol(16%), and $Cremophor^{(R)}$ EL(32%). The release rate of atorvastatin from SMEDDS was significantly higher than the conventional tablet ($Lipitor^{(R)}$), 2-fold. Our studies illustrated the potential use of SMEDDS for the delivery of hydrophobic compounds, such as atorvastatin calcium by the oral route.

• Journal of Pharmaceutical Investigation
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• 제41권2호
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• pp.103-109
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• 2011

The objective of the study was to prepare self-microeulsifying drug delivery system (SMEDDS) incorporating atorvastatin calcium and evaluate its properties and oral bioavailability. Solubility of atorvastatin in various vehicles was determined. Pseudo-ternary phase diagrams were constructed to identify the good self-emulsification region. The droplet size distributions of the resultant emulsions were determined by dynamic light scattering measurement. The mean droplet size of chosen formulation (20% ethyl oleate, 40% tween-80, 40% Carbitol$^{(R)}$) was $23.4{\pm}1.3$ nm. The SMEDDS incorporating atorvastatin calcium appeared to be associated with better performance in dissolution and pharmacokinetic studies, compared with raw atorvastatin calcium. In dissolution test, the release percentage of atorvastatin from SMEDDS mixture could rapidly reach more than 95% within 3 min. Oral $AUC_{0{\rightarrow}8hr}$ values in SD rats was $1994{\pm}335\;ng{\cdot}hr/mL$, which significantly increased (P<0.05) compared with raw atorvastatin calcium. The SMEDDS formulation was relatively stable when stored at $4^{\circ}C$ during 3 months. Our studies illustrated the potential use of SMEDDS for the delivery of hydrophobic compounds, such as atorvastatin, by the oral route.

• Journal of Pharmaceutical Investigation
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• 제38권4호
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• pp.249-254
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• 2008

Solid dispersions of poorly water-soluble drug, atorvastatin, were prepared with Eudragit L100 to improve the solubility by spray dryer. To investigate the correlation between physicochemical properties and dissolution rate of solid dispersions, the samples were characterized by scanning electron microscopy (SEM), differential scanning calorimeter (DSC) and fourier transform infrared spectroscopy (FT-IR). SEM and DSC were found that atorvastatin is amorphous in the Eudragit L100 solid dispersion. FT-IR was used to analyze the salt formation by interaction between atorvastatin and Eudragit L100. The dissolution rate of solid dispersed atorvastatin was markedly increased compared to drug powder in stimulated intestinal juice (pH 6.8). Thus, the solid dispersed atorvastatin using the spray drying method with Eudragit L100 may be effective for the bioavailability.

• 폴리머
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• 제38권5호
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• pp.656-663
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• 2014

생분해성 고분자인 폴리옥살레이트(POX)를 이용하여 아토르바스타틴 칼슘을 함유한 미립구를 $O_1/O_2/W$ 에멀젼용매증발법으로 제조하였다. 약물의 함량, POX의 분자량과 농도 그리고 유화제인 PVA의 농도를 달리하여 아토르바스타틴 칼슘이 함유된 미립구의 형태학적 특성, 방출거동, 분해거동 등을 평가하였다. 아토르바스타틴 칼슘이 함유된 미립구에 대한 물리화학적 성질 및 형태를 X선 회절분석법과 시차주사열량계, 적외선 분광분석기, 그리고 주사 전자 현미경을 이용하여 분석하였다. 또한 미립구의 방출거동과 포접률을 분석하기 위하여 고성능 액체 크로마토그래피를 이용하였으며 분해성을 분석하기 위하여 10일 동안 in vitro 실험을 통해 관찰하였다. 본 연구를 통하여 제조 조건에 따라 아토르바스타틴 칼슘을 함유한 POX 미립구의 약물방출과 형태 제어를 확인할 수 있었으며, 이를 통해 아토르바스타틴 뿐만 아니라 유사 약물의 약물 방출과 형태 제어에 도움이 될 것으로 기대된다.

• 약학회지
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• 제56권3호
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• pp.164-172
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• 2012

This study was aimed to increase the solubility, dissolution and permeation rates of atorvastatin calcium (ATC) using bile salt and/or 2-hydroxypropyl-${\beta}$-cyclodextrin ($HP{\beta}CD$). From solubility studies, sodium deoxycholate (SDC) among bile salts studied was found to have the highest solubilizing effect on ATC ($4.4{\pm}0.4$ 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 $HP{\beta}CD$, 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-$HP{\beta}CD$ 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 $(5.7{\pm}0.9$, $5.6{\pm}0.9$, $4.8{\pm}0.7$ and $4.6{\pm}0.9\;{\mu}g/cm^2/hr$, respectively) were enhanced, compared with drug alone ($3.4{\pm}0.9\;{\mu}g/cm^2/hr$). In the dissolution-permeation studies, 1 : 9 : 10 (w/w) ATC-SDC-$HP{\beta}CD$ 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 $HP{\beta}CD$ were found to be an effective means for increasing the dissolution and permeation rates of ATC.