Papakyriakopoulou Paraskevi, Rekkas Dimitrios M, Colombo Gaia, Valsami Georgia
Department of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens, 15784 Athens, Greece.
Department of Life Sciences and Biotechnology, University of Ferrara, 44121 Ferrara, Italy.
Pharmaceutics. 2022 Aug 21;14(8):1742. doi: 10.3390/pharmaceutics14081742.
The objective and novelty of the present study is the development and optimization of innovative nasal film of Donepezil hydrochloride (DH) for potential use in Alzheimer’s disease. Hydroxypropyl-methyl-cellulose E50 (factor A) nasal films, with Polyethylene glycol 400 as plasticizer (factor B), and Methyl-β-Cyclodextrin, as permeation enhancer (factor C), were prepared and characterized in vitro and ex vivo. An experimental design was used to determine the effects of the selected factors on permeation profile of DH through rabbit nasal mucosa (response 1), and on film flexibility/foldability (response 2). A face centered central composite design with three levels was applied and 17 experiments were performed in triplicate. The prepared films exhibited good uniformity of DH content (90.0 ± 1.6%−99.8 ± 4.9%) and thickness (19.6 ± 1.9−170.8 ± 11.5 μm), storage stability characteristics, and % residual humidity (<3%), as well as favourable swelling and mucoadhesive properties. Response surface methodology determined the optimum composition for flexible nasal film with maximized DH permeation. All selected factors interacted with each other and the effect of these interactions on responses is strongly related to the factor’s concentration ratios. Based on these encouraging results, in vivo serum and brain pharmacokinetic study of the optimized nasal film, in comparison to DH oral administration, is ongoing in an animal model.
本研究的目的和创新之处在于开发和优化用于阿尔茨海默病的新型盐酸多奈哌齐（DH）鼻用薄膜。制备了以羟丙基甲基纤维素E50（因素A）为基质、聚乙二醇400为增塑剂（因素B）、甲基-β-环糊精为渗透促进剂（因素C）的鼻用薄膜，并进行了体外和离体表征。采用实验设计来确定所选因素对DH透过兔鼻黏膜的渗透曲线（响应1）以及对薄膜柔韧性/可折叠性（响应2）的影响。应用了具有三个水平的面心中央复合设计，并进行了17次实验，每次实验重复三次。所制备的薄膜显示出良好的DH含量均匀性（90.0±1.6% - 99.8±4.9%）和厚度均匀性（19.6±1.9 - 170.8±11.5μm）、储存稳定性特征以及残余湿度百分比（<3%），还具有良好的溶胀和黏膜粘附性能。响应面法确定了具有最大DH渗透的柔性鼻用薄膜的最佳组成。所有所选因素相互作用，这些相互作用对响应的影响与因素的浓度比密切相关。基于这些令人鼓舞的结果，正在动物模型中进行优化鼻用薄膜与DH口服给药相比的体内血清和脑药代动力学研究。
