Brain Targeting of Duloxetine HCL via Intranasal Delivery of Loaded Cubosomal Gel: In vitro Characterization, ex vivo Permeation, and in vivo Biodistribution Studies.
Brain Targeting of Duloxetine HCL via Intranasal Delivery of Loaded Cubosomal Gel: In vitro Characterization, ex vivo Permeation, and in vivo Biodistribution Studies.
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DOI：
10.2147/ijn.s277352
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发表时间：
2020
影响因子：
8
通讯作者：
Fares AR
中科院分区：
文献类型：
--
作者：
Elsenosy FM;Abdelbary GA;Elshafeey AH;Elsayed I;Fares AR
度洛西汀（DLX）是一种双血清素和去甲肾上腺素再摄取抑制剂，由于肝脏代谢广泛，生物利用度有限（≈40%）。本工作旨在制备和评估DLX鼻内热可逆立方体凝胶，以提高其生物利用度并确保有效的脑靶向。采用33中心复合设计，脂质比例（单油酸甘油：三棕榈酸甘油）、Pluronic F127%和Pluronic F68%三个独立因素制备culo -凝胶。对制备的制剂进行粒径（PS）、胶凝温度（GT）、包封效率（EE%）和体外释放度的评价。优选出理想度最高的立方凝胶（0.88）作为优化配方。采用差示扫描量热法、傅里叶变换红外光谱、x射线粉末衍射和透射电镜对DLX立方凝胶进行了评价。通过细胞毒性研究、体外渗透研究和体内生物分布研究来评价脑靶向治疗的安全性和有效性。最佳立方凝胶为脂质比3.76、w/v PF127 20%、w/v PF68 5%。PS为265.13±9.85 nm， GT为32±0.05°C， EE%为98.13±0.50%，具有控释行为，6 h内释放33% DLX。与DLX溶液和负载DLX的原位立方体凝胶相比，普通原位立方体凝胶的IC50显著高于DLX溶液。体外渗透实验显示，DLX原位立方凝胶对药物的渗透增强了1.27。根据血浆和脑内生物分布研究，经鼻注射的DLX原位立方凝胶在脑内的生物利用度比经鼻注射的高1.96倍。其BTE%和DTP%分别为137.77和10.5，表明经鼻给药后有效靶向脑。因此，鼻腔内DLX原位立方凝胶可以被认为是一种创新的纳米载体递送系统，可以提高DLX的生物利用度，并有效地靶向大脑，以最大限度地发挥其作用。
Duloxetine (DLX) is dual serotonin and norepinephrine reuptake inhibitor suffering from limited bioavailability (≈ 40%) due to extensive hepatic metabolism. This work aims to formulate and evaluate DLX intranasal thermoreversible cubosomal gels to enhance its bioavailability and ensure efficient brain targeting. Cubo-gels were prepared by 33 central composite design with three independent factors, lipid ratio (glycerol monooleate: glycerol tripalmitate), Pluronic F127%, and Pluronic F68%. The prepared formulations were evaluated for their particle size (PS), gelling temperature (GT), entrapment efficiency (EE%), and in vitro release. The cubo-gel with the highest desirability (0.88) was chosen as the optimized formulation. DLX cubo-gel was evaluated using differential scanning calorimetry, Fourier-transform infrared spectroscopy, X-ray powder diffraction, and transmission electron microscopy. Cytotoxicity study, ex vivo permeation study and in vivo bio-distribution study were conducted to evaluate the safety and efficacy of brain targeting. The optimum cubo-gel was composed of 3.76 lipid ratio, 20% w/v PF127, and 5% w/v PF68. It had PS of 265.13 ± 9.85 nm, GT of 32 ± 0.05°C, EE% of 98.13 ± 0.50%, and showed controlled release behavior where 33% DLX was released within 6 hrs. The plain in situ cubo-gel had a significantly higher IC50 compared to DLX solution and DLX-loaded in situ cubo-gel. The ex vivo permeation study showed 1.27 enhancement in the drug permeation from DLX in situ cubo-gel. According to the in vivo bio-distribution study in plasma and brain, the intranasal DLX in situ cubo-gel showed a 1.96 fold improvement in brain bioavailability compared to the intranasal solution. Its BTE% and DTP% were 137.77 and 10.5, respectively, indicating efficient brain targeting after intranasal administration. Accordingly, intranasal DLX in situ cubo-gel can be considered as an innovative nano-carrier delivery system for bioavailability enhancement and efficient brain targeting of DLX to maximize its effect.