Mechanical, optical, and physicochemical properties of HPMC-based doxazosin mesylate orodispersible films

Abstract In this study, orodispersible films formed from hydroxypropyl methylcellulose (HPMC) E6 (2, 2.5, and 3%) and plasticizers ((glycerin (Gly), propylene glycol (PP), or polyethylene glycol (PEG)), containing doxazosin mesylate, were prepared by the solvent casting method and characterized. Design of experiments (DoE) was used as a statistical tool to facilitate the interpretation of the experimental data and allow the identification of optimal levels of factors for maximum formulation performance. Differential scanning calorimetry (DSC) curves and X-ray powder diffraction (XRPD) diffractograms showed doxazosin mesylate amorphization, probably due to complexation with the polymer (HPMC E6), and the glass transition temperature of the polymer was reduced by adding a plasticizer. Fourier transformed infrared (FTIR) spectroscopy results showed that the chemical structure of doxazosin mesylate was preserved when introduced into the polymer matrix, and the plasticizers, glycerin and PEG, affected the polymer matrix with high intensity. The addition of plasticizers increased the elongation at break and adhesiveness (Gly > PEG > PP), confirming the greater plasticizer effect of Gly observed in DSC and FTIR studies. Greater transparency was observed for the orodispersible films prepared using PP. The addition of citric acid as a pH modifier was fundamental for the release of doxazosin mesylate, and the desirability formulation had a release profile similar to that of the reference product.

摘要 本研究以羟丙基甲基纤维素（hydroxypropyl methylcellulose, HPMC）E6（质量分数分别为2%、2.5%和3%）为成膜基质，搭配甘油（glycerin, Gly）、丙二醇（propylene glycol, PP）或聚乙二醇（polyethylene glycol, PEG）作为增塑剂，制备载有甲磺酸多沙唑嗪（doxazosin mesylate）的口腔速溶膜，并采用溶剂浇铸法完成制备与表征。本研究引入实验设计（Design of experiments, DoE）作为统计工具，以辅助实验数据解析，并筛选出使制剂综合性能最优的因素水平。差示扫描量热法（Differential scanning calorimetry, DSC）曲线与X射线粉末衍射（X-ray powder diffraction, XRPD）衍射图谱结果显示，甲磺酸多沙唑嗪发生了无定形化，该现象可能源于其与HPMC E6形成了聚合物复合物，同时增塑剂的添加可降低载体聚合物的玻璃化转变温度。傅里叶变换红外光谱法（Fourier transformed infrared spectroscopy, FTIR）分析结果表明，甲磺酸多沙唑嗪载入聚合物基质后其化学结构未发生改变，且甘油与PEG两种增塑剂对聚合物基质的作用强度更为显著。增塑剂的添加可提升口腔速溶膜的断裂伸长率与黏附性，且效果排序为甘油＞PEG＞PP，该结果验证了差示扫描量热法与傅里叶变换红外光谱法研究中观察到的甘油增塑效果更优的结论。采用丙二醇制备的口腔速溶膜透明度表现更佳。添加柠檬酸作为pH调节剂对甲磺酸多沙唑嗪的体外释药行为至关重要，最优处方的药物释放曲线与参比制剂的释药特征高度相似。