Aziz Anam, Zaman Muhammad, Khan Mahtab Ahmad, Jamshaid Talha, Butt Muhammad Hammad, Hameed Huma, Rahman Muhammad Shafeeq Ur, Shoaib Qurat-Ul-Ain
Faculty of Pharmaceutical Sciences, University of Central Punjab, Lahore 54000, Pakistan.
Faculty of Pharmacy and Alternative Medicine, The Islamia University Bahawalpur, Bahawalpur 63100, Pakistan.
ACS Omega. 2024 Feb 21;9(9):10522-10538. doi: 10.1021/acsomega.3c08700. eCollection 2024 Mar 5.
Ticagrelor (TCG) is a BCS class IV antiplatelet drug used to prevent platelet aggregation in patients with acute coronary syndrome, having poor solubility and permeability. The goal of this study was to develop a self-nanoemulsifying drug delivery system (SNEDDS) of TCG to improve its solubility and permeability. The excipients were selected based on the maximum solubility of TCG and observed by UV spectrophotometer. Different combinations of oil, surfactant, and co-surfactant (1:1, 2:1, and 3:1) were used to prepare TCG-SNEDDS formulations, and pseudo-ternary phase diagrams were plotted. The nanoemulsion region was observed. Clove oil (10-20%), Tween-80 (45-70%), and PEG-400 (20-45%) were used as an oil, surfactant, and co-surfactant, respectively. The selected formulations (F1, F2, F3, F4, F5, and F6) were analyzed for ζ potential, polydispersity index (PDI), ζ size, self-emulsification test, cloud point determination, thermodynamic studies, entrapment efficiency, Fourier transform infrared (FTIR) spectroscopy, X-ray diffraction (XRD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), scanning electron microscopy (SEM), dissolution, permeation, and pharmacodynamic study. The TCG-SNEDDS formulations exhibited ζ potential from -9.92 to -6.23 mV, a ζ average of 11.85-260.4 nm, and good PDI. The drug release in phosphate buffer pH 6.8 from selected TCG-SNEDDS F4 was about 98.45%, and F6 was about 97.86%, displaying improved dissolution of TCG in 0.1 N HCl and phosphate buffer pH 6.8, in comparison to 28.05% of pure TCG suspension after 12 h. While the drug release in 0.1 N HCl from F4 was about 62.03%, F6 was about 73.57%, which is higher than 10.35% of the pure TCG suspension. In permeability studies, F4 also exhibited an improved apparent permeability of 2.7 × 10 0.6708 × 10 cm/s of pure drug suspension. The pharmacodynamic study in rabbits demonstrated enhanced antiplatelet activity from TCG-SNEDDS F4 compared to that from pure TCG suspension. These outcomes imply that the TCG-SNEDDS may serve as an effective means of enhancing TCG's antiplatelet activity by improving the solubility and permeability of TCG.
替格瑞洛（TCG）是一种生物药剂学分类系统（BCS）IV类抗血小板药物，用于预防急性冠脉综合征患者的血小板聚集，其溶解性和渗透性较差。本研究的目的是开发一种替格瑞洛的自纳米乳化药物递送系统（SNEDDS），以提高其溶解性和渗透性。根据替格瑞洛的最大溶解度选择辅料，并通过紫外分光光度计进行观察。使用油、表面活性剂和助表面活性剂的不同组合（1:1、2:1和3:1）制备替格瑞洛-SNEDDS制剂，并绘制伪三元相图。观察纳米乳区域。分别使用丁香油（10 - 20%）、吐温80（45 - 70%）和聚乙二醇400（20 - 45%）作为油、表面活性剂和助表面活性剂。对所选制剂（F1、F2、F3、F4、F5和F6）进行ζ电位、多分散指数（PDI）、ζ粒径、自乳化试验、浊点测定、热力学研究、包封率、傅里叶变换红外光谱（FTIR）、X射线衍射（XRD）、差示扫描量热法（DSC）、热重分析（TGA）、扫描电子显微镜（SEM）、溶出度、渗透率和药效学研究。替格瑞洛-SNEDDS制剂的ζ电位为-9.92至-6.23 mV，ζ平均粒径为11.85 - 260.4 nm，且具有良好的PDI。所选替格瑞洛-SNEDDS F4在pH 6.8磷酸盐缓冲液中的药物释放率约为98.45%，F6约为97.86%，与12小时后纯替格瑞洛混悬液的28.05%相比，替格瑞洛在0.1 N盐酸和pH 6.8磷酸盐缓冲液中的溶出度有所提高。而F4在0.1 N盐酸中的药物释放率约为62.03%，F6约为73.57%，高于纯替格瑞洛混悬液的10.35%。在渗透率研究中，F4的表观渗透率也有所提高，为2.7×10⁻⁶ cm/s，而纯药物混悬液为0.6708×10⁻⁶ cm/s。家兔体内的药效学研究表明，与纯替格瑞洛混悬液相比，替格瑞洛-SNEDDS F4的抗血小板活性增强。这些结果表明，替格瑞洛-SNEDDS可能是通过提高替格瑞洛的溶解性和渗透性来增强其抗血小板活性的有效手段。
