Al-Heibshy Fawaz N S, Başaran Ebru, Öztürk Naile, Demirel Müzeyyen
Department of Pharmaceutical Technology, Faculty of Pharmacy, Anadolu University, Eskişehir, Turkey.
Department of Pharmaceutical Technology, Faculty of Pharmacy, Aden University, Aden, Yemen.
Drug Dev Ind Pharm. 2020 Sep;46(9):1495-1506. doi: 10.1080/03639045.2020.1810264. Epub 2020 Aug 25.
Despite being the most effective hypolipidemic agent, poor physicochemical properties of Rosuvastatin calcium (RCa) remain challenging obstacles in the development of pharmaceutical dosage forms. Inclusion complexes (ICs) of RCa with cyclodextrin (CD) derivatives; methyl-beta-cyclodextrin (M-β-CD) and sulfobutylether-beta-cyclodextrin (SBE-β-CD; Captisol) were formulated by kneading and freeze-drying (lyophilization) methods. Pysicochemical properties of ICs were evaluated by SEM, DSC, XRD, FT-IR, H-NMR analyses. Entrapment efficiency (EE), water solubility, release analyses were also performed. Safety and efficacy of the ICs were analyzed by cytotoxicity and permeation studies on Caco-2 cell lines. Both CDs indicated A type phase solubility diagrams showing that [1:1] molar ratio. Apparent stability constants (K) were found to be 60.93 M for M-β-CD and 158.07 M for Captisol. High EE in the range of 93.50-105.40% was achieved. Molar solubility of RCa was increased 3.7- and 4.1-fold with M-β-CD and Captisol ICs, respectively. release analyses have indicated the equivalence of dissolution profiles for M-β-CD and Captisol based ICs to that of pure RCa (f > 50). Cytotoxicity studies on Caco-2 cell lines have revealed the safety of ICs for oral use. Permeability studies demonstrated that selected lyophilized F6 formulation has shown the best permeation rate with P value of 3.08 × 10 cm·s. Considering greater water solubility, lower toxicity, high efficiency of complexation as well as, RCa-like permeability and release behavior at pH 6.8; Captisol based lyophilized F6 formulation was selected as the best IC to be used in oral dosage forms of RCa.
尽管瑞舒伐他汀钙（RCa）是最有效的降血脂药物，但其不良的物理化学性质仍是药物剂型开发中具有挑战性的障碍。通过捏合和冷冻干燥（冻干）方法制备了RCa与环糊精（CD）衍生物；甲基-β-环糊精（M-β-CD）和磺丁基醚-β-环糊精（SBE-β-CD；Captisol）的包合物（ICs）。通过扫描电子显微镜（SEM）、差示扫描量热法（DSC）、X射线衍射（XRD）、傅里叶变换红外光谱（FT-IR）、氢核磁共振（H-NMR）分析对ICs的物理化学性质进行了评估。还进行了包封率（EE）、水溶性、释放分析。通过对Caco-2细胞系的细胞毒性和渗透研究分析了ICs的安全性和有效性。两种CD均显示A型相溶解度图，表明摩尔比为[1:1]。发现M-β-CD的表观稳定常数（K）为60.93 M，Captisol的表观稳定常数为158.07 M。实现了93.50-105.40%范围内的高包封率。RCa与M-β-CD和Captisol包合物的摩尔溶解度分别提高了3.7倍和4.1倍。释放分析表明，基于M-β-CD和Captisol的包合物的溶出曲线与纯RCa的溶出曲线等效（f > 50）。对Caco-2细胞系的细胞毒性研究表明ICs口服使用安全。渗透研究表明，所选的冻干F6制剂显示出最佳的渗透速率，P值为3.08×10 cm·s。考虑到更高的水溶性、更低的毒性、更高的络合效率以及在pH 6.8时类似RCa的渗透性和释放行为；基于Captisol的冻干F6制剂被选为用于RCa口服剂型的最佳包合物。
