Inam Sana, Irfan Muhammad, Lali Noor Ul Ain, Khalid Syed Haroon, Asghar Sajid, Khan Ikram Ullah, Khan Salah-Ud-Din, Iqbal Muhammad Shahid, Zaheer Imran, Khames Ahmed, Abou-Taleb Heba A, Abourehab Mohammad A S
Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Government College University, Faisalabad 38000, Pakistan.
Department of Medicine, Fatima Jinnah Medical University, Lahore 42000, Pakistan.
Pharmaceuticals (Basel). 2022 Apr 18;15(4):492. doi: 10.3390/ph15040492.
Poor solubility is the major challenge involved in the formulation development of new chemical entities (NCEs), as more than 40% of NCEs are practically insoluble in water. Solid dispersion (SD) is a promising technology for improving dissolution and, thereby, the bioavailability of poorly soluble drugs. This study investigates the influence of a pH-sensitive acrylate polymer, EPO, on the physicochemical properties of rosuvastatin calcium, an antihyperlipidemic drug. In silico docking was conducted with numerous polymers to predict drug polymer miscibility. The screened-out polymer was used to fabricate the binary SD of RoC in variable ratios using the co-grinding and solvent evaporation methods. The prepared formulations were assessed for physiochemical parameters such as saturation solubility, drug content and in vitro drug release. The optimized formulations were further ruled out using solid-state characterization (FTIR, DSC, XRD and SEM) and in vitro cytotoxicity. The results revealed that all SDs profoundly increased solubility as well as drug release. However, the formulation RSE-2, with a remarkable 71.88-fold increase in solubility, presented 92% of drug release in the initial 5 min. The molecular interaction studied using FTIR, XRD, DSC and SEM analysis evidenced the improvement of in vitro dissolution. The enhancement in solubility of RoC may be important for the modulation of the dyslipidemia response. Therefore, pharmacodynamic activity was conducted for optimized formulations. Our findings suggested an ameliorative effect of RSE-2 in dyslipidemia and its associated complications. Moreover, RSE-2 exhibited nonexistence of cytotoxicity against human liver cell lines. Convincingly, this study demonstrates that SD of RoC can be successfully fabricated by EPO, and have all the characteristics that are favourable for superior dissolution and better therapeutic response to the drug.
低溶解度是新化学实体（NCEs）制剂开发中面临的主要挑战，因为超过40%的NCEs在水中几乎不溶。固体分散体（SD）是一种很有前景的技术，可用于改善难溶性药物的溶出度，从而提高其生物利用度。本研究考察了pH敏感型丙烯酸酯聚合物EPO对降血脂药物瑞舒伐他汀钙理化性质的影响。通过与多种聚合物进行计算机对接来预测药物与聚合物的相容性。筛选出的聚合物用于采用共研磨和溶剂蒸发法制备不同比例的瑞舒伐他汀钙二元固体分散体。对制备的制剂进行了饱和溶解度、药物含量和体外药物释放等理化参数的评估。使用固态表征（傅里叶变换红外光谱、差示扫描量热法、X射线衍射和扫描电子显微镜）和体外细胞毒性对优化后的制剂进行了进一步筛选。结果表明，所有固体分散体均显著提高了溶解度和药物释放。然而，制剂RSE-2的溶解度显著增加了71.88倍，在最初5分钟内药物释放率达92%。通过傅里叶变换红外光谱、X射线衍射、差示扫描量热法和扫描电子显微镜分析研究的分子相互作用证明了体外溶出度的提高。瑞舒伐他汀钙溶解度的提高可能对血脂异常反应的调节具有重要意义。因此，对优化后的制剂进行了药效学活性研究。我们的研究结果表明RSE-2对血脂异常及其相关并发症具有改善作用。此外，RSE-2对人肝癌细胞系无细胞毒性。令人信服的是，本研究表明EPO可以成功制备瑞舒伐他汀钙固体分散体，且具有所有有利于优异溶出度和更好药物治疗反应的特性。
