Abstract
The object of this study was to prepare binary and ternary solid dispersions of atorvastatin (ATR) by the melting method using PEGs and poloxamer 188 (P188) as the carriers, singly and in combination with each other. Dissolution behavior, solubility studies, X-ray diffractometry, differential scanning calorimetry, and Fourier transform infrared spectroscopy were studied. Furthermore, antihyperlipidemic activities of formulations were compared to each other by serum lipid analyses in hyperlipidemic rats. Based on the results, the highest dissolution efficiency (DE30 = 83%) was obtained by binary systems consisted of ATR and P188. Also, no additional improvement was observed in dissolution properties of ternary solid dispersion formulations. Solubility studies showed enhancement of ATR phase solubility in water and a buffer solution containing P188 or PEG 10000. Furthermore, saturated solubility of ATR in the buffer solution improved more than twofold in the optimized ternary dispersion system. No crystalline changes occurred in PEG-based formulations; meanwhile, partial amorphization happened in the ATR-P188 combination. Finally, the in vivo study in hyperlipidemic rats exhibited a rapid decrease in the lipid profile of all formulations compared to ATR (after 7 days). Moreover, reduction of serum triglycerides and total cholesterol on the 14th day in the ATR group (p value < 0.01) was less than solid dispersion or physical mixing preparations (p value < 0.001). These findings proved the appropriate influence of using PEG and P188 in solid dispersion systems for the improvement of the therapeutic efficiency of ATR.
Highlights
Hyperlipidemia or dyslipidemia is a chronic condition that refers to an abnormality in total cholesterol (TC), triglyceride (TG), high-density lipoprotein (HDL), and low-density lipoprotein (LDL) concentration in the blood and usually can be diagnosed by isolated elevation of TG, TC, or both
Results showed that the dissolution rate of ATR from PMB7 was significantly higher than that of the intact drug but lower than that of the same ratio of solid dispersion (SD) (BS7), which could be seen within 10 min (Figure 1)
The SD process had an extra effect on dissolution enhancement, maybe due to drug recrystallization during SD preparation and molecularly dispersion of the drug in the carrier (PEG 10000), which can cause particle size reduction and surface area elevation that results in better wettability of drug particles [12]
Summary
Hyperlipidemia or dyslipidemia is a chronic condition that refers to an abnormality in total cholesterol (TC), triglyceride (TG), high-density lipoprotein (HDL), and low-density lipoprotein (LDL) concentration in the blood and usually can be diagnosed by isolated elevation of TG, TC, or both. The relationship between the blood lipid level and the risk of cardiovascular diseases (CVD) such as myocardial infarction and stroke, as the leading cause of death in adults, is well established. Those with dyslipidemia are at a twofold risk for CVD comparing to those with standard conditions. Atorvastatin (ATR), the most prescribed statin, is a selective inhibitor of the HMG-CoA reductase and is currently used as calcium salt to treat hyperlipidemia [4]. The negative point of ATR is low oral bioavailability (12%), due to its poor solubility, that results in high dose administration and more adverse effects [5]
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