Department of Pharmaceutical Technology, College of Pharmacy, University of Tanta, Tanta, Egypt.
School of Pharmacy, University College of Cork, Cork, Ireland.
AAPS PharmSciTech. 2021 Jan 31;22(2):59. doi: 10.1208/s12249-021-01925-y.
Development of fixed dose combinations is growing and many of these drug combinations are being legally marketed. However, the development of these requires careful investigation of possible physicochemical changes during co-processing. This requires investigation of the effect of co-processing of drug combination in absence of excipients to maximize the chance of interaction (if any). Accordingly, the aim was to investigate the effect of co-processing of ezetimibe and atorvastatin on drugs dissolution rate. The objective was extended to in vitro in vivo correlation. Drugs were subjected to wet co-processing in presence of ethanol after being mixed at different ratios. The prepared formulations were characterized using FTIR spectroscopy, X-ray powder diffraction, differential scanning calorimetry, scanning electron microscopy, and in vitro dissolution testing. These investigations proved the possibility of eutectic system formation after drugs co-processing. This was reflected on drugs dissolution rate which was significantly enhanced at dose ratio and 2:1 atorvastatin:ezetimibe molar ratio compared to the corresponding pure drugs. In vivo antihyperlipidemic effects of the co-processed drugs were monitored in albino mice which were subjected to hyperlipidemia induction using poloxamer 407. The results showed significant enhancement in pharmacological activity as revealed from pronounced reduction in cholesterol level in mice administering the co-processed form of both drugs. Besides, histopathological examinations of the liver showed marked decrease in hepatic vacuolation. In conclusion, co-processing of atorvastatin with ezetimibe resulted in beneficial eutexia which hastened the dissolution rate and pharmacological effects of both drugs.Graphical abstract.
固定剂量组合的开发正在增长，其中许多药物组合正在合法上市。然而，这些药物的开发需要仔细研究在共加工过程中可能发生的物理化学变化。这需要调查在没有赋形剂的情况下药物组合共加工对药物溶解速率的影响，以最大限度地提高可能的相互作用的机会（如果有）。因此，目的是研究依折麦布和阿托伐他汀共加工对药物溶解速率的影响。目的是扩展到体外体内相关性。在不同比例混合后，在存在乙醇的情况下对药物进行湿共加工。使用傅里叶变换红外光谱法、X 射线粉末衍射、差示扫描量热法、扫描电子显微镜和体外溶解试验对制备的制剂进行了表征。这些研究证明了药物共加工后形成共晶体系的可能性。这反映在药物的溶解速率上，与相应的纯药物相比，在剂量比和阿托伐他汀：依折麦布摩尔比为 2:1 时，药物的溶解速率显著提高。用泊洛沙姆 407 诱导白化小鼠高脂血症，监测共加工药物的体内抗高血脂作用。结果表明，从给药两种药物共加工形式的小鼠胆固醇水平显著降低，可以看出药理活性显著增强。此外，肝脏组织病理学检查显示肝空泡形成明显减少。总之，阿托伐他汀与依折麦布共加工导致有益的共晶形成，加速了两种药物的溶解速率和药理作用。
