Department of Pharmaceutics, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia; Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Al-Azhar University, Cairo 11651, Egypt.
Department of Pharmaceutics, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia; Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Al-Azhar University, Cairo 11651, Egypt.
Int J Pharm. 2021 Oct 25;608:121057. doi: 10.1016/j.ijpharm.2021.121057. Epub 2021 Aug 28.
To enhance the poor bioavailability and extensive liver metabolism of atorvastatin calcium (ATC), we have developed an oleic acid-reinforced PEGylated polymethacrylate (OLA-PEG-E-RLPO) transdermal film as a convenient and alternative delivery system. The effect of varying levels of Eudragit RLPO, PEG 400, and oleic acid on the target product profile was optimized through Quality by Design (QbD) approach. The ATC-loaded OLA-PEG-E-RLPO transdermal films were evaluated in ex-vivo experiments using full thickness skin, utilizing Franz cell studies, and undergone in-vivo pharmacokinetics/pharmacodynamics (PK/PD) assessment, using poloxamer-induced dyslipidemic Sprague-Dawley rats. At 2 and 12 h, the optimized ATC films with a thickness of 0.79 mm showed permeation of 37.34% and 97.23% into the receptor compartment, respectively. Steady-state flux was 0.172 mg/cmh, with 7.01 × 10 cm/h permeability coefficient, and 0.713 × 10 cm/h diffusion coefficient. In-vivo PK results indicated that the absorption profiles (AUC) of the optimized film in pre-treated group of animals were 8.6-fold and 2.8-fold greater than controls pre-treated with non-PEGylated non-oleic acid film and orally administered ATC, respectively. PD assessment of the lipid panel indicated that the lipid profile of the optimized film pre-treated group reached normal levels after 12 h, along with the significant enhancement over the non-PEGylated non-oleic acid film and the oral marketed tablet groups. The histopathological findings revealed near-normal hepatocyte structure for the optimized film pre-treated animal group. Our results further indicate that transdermal delivery films based on an optimized ATC-loaded OLA-PEG-E-RLPO were successfully developed and their assessment in both ex-vivo and in-vivo suggests enhanced permeability and improvement in bioavailability and antidyslipidemic activity of ATC. This approach can provide several advantages, especially during chronic administration of ATC, including improvement in patient compliance, therapeutic benefits, bioavailability, and feasibility for commercialization and as a platform for other drug classes.
为了提高阿托伐他汀钙（ATC）的生物利用度和广泛的肝脏代谢，我们开发了一种油酸增强的聚甲基丙烯酸酯（OLA-PEG-E-RLPO）透皮膜，作为一种方便的替代给药系统。通过质量源于设计（QbD）方法优化了 Eudragit RLPO、PEG 400 和油酸的不同水平对目标产品特性的影响。使用 Franz 细胞研究对载有 ATC 的 OLA-PEG-E-RLPO 透皮膜进行了离体实验评估，并使用泊洛沙姆诱导的血脂异常 Sprague-Dawley 大鼠进行了体内药代动力学/药效学（PK/PD）评估。在 2 小时和 12 小时时，厚度为 0.79 毫米的优化 ATC 膜分别显示出 37.34%和 97.23%的渗透到受体隔室中。稳态通量为 0.172mg/cmh，渗透率为 7.01×10cm/h，扩散系数为 0.713×10cm/h。体内 PK 结果表明，在预处理动物组中，优化膜的吸收曲线（AUC）分别比用非 PEG 化非油酸膜预处理的对照组和口服给予 ATC 的对照组高 8.6 倍和 2.8 倍。脂质谱的 PD 评估表明，优化膜预处理组的脂质谱在 12 小时后达到正常水平，与非 PEG 化非油酸膜和口服市售片剂组相比有显著提高。组织病理学检查结果显示，优化膜预处理动物组的肝细胞结构接近正常。我们的结果进一步表明，基于优化的载有 ATC 的 OLA-PEG-E-RLPO 的透皮给药膜已成功开发，并且在离体和体内评估中均表明其渗透性增强，提高了 ATC 的生物利用度和抗血脂异常活性。这种方法可以提供多种优势，特别是在慢性给予 ATC 期间，包括提高患者依从性、治疗效果、生物利用度以及商业化的可行性，并且可以作为其他药物类别的平台。
