Drug Delivery and Translational Research ( IF 5.7 ) Pub Date : 2022-05-27 , DOI: 10.1007/s13346-022-01172-z Heba F Salem 1 , Adel A Ali 1 , Yasmine K Rabea 1 , Fatma I Abo El-Ela 2 , Rasha A Khallaf 1
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Duloxetine HCl (DXH) is a reuptake inhibitor of serotonin and norepinephrine used to treat the major depressive disorder. Following its extensive hepatic metabolism, acid-labile nature, and limited aqueous solubility, DXH has poor oral bioavailability (40%). The rectal route has been suggested as another route of administration to surmount such challenges. The present study aimed to prepare DXH-loaded glycerosomal (DXH-GLYS) in situ gel for rectal administration to increase DXH permeability and improve its bioavailability. Box–Behnken design (BBD) was adopted to prepare and optimize nanoglycerosomes. The impact of Phospholipon 90G (PL90G), Tween 80 concentrations, and glycerol percentage on encapsulation efficiency, nanoglycerosomal size, % cumulative DXH released, and the cumulative DXH permeated per unit area after 24 h were studied by the design. The pharmacokinetic and pharmacodynamic behavior of optimized formulation was investigated in rats. The formulated DXH-GLYS had a vesicle size ranging between 135.9 and 430.6 nm and an entrapment efficiency between 69.11 and 98.12%. The permeation experiment revealed that the optimized DXH-GLYS in situ gel increased DXH permeation by 2.62-fold compared to DXH solution. Pharmacokinetics studies disclosed that the DXH-GLYS in situ rectal gel exhibited 2.24-times increment in DXH bioavailability relative to oral DXH solution. The pharmacodynamic study revealed that the DXH-GLYS rectal treatment significantly improved the behavioral analysis parameters and was more efficacious as an antidepressant than the oral DXH solution. Collectively, these findings demonstrate that GLYS can be considered a potentially valuable rectal nanocarrier that could boost the DXH efficacy.
Graphical abstract
中文翻译：
度洛西汀盐酸盐的甘油体热敏原位凝胶作为直肠递送的新型纳米平台：体外优化和体内评价
Duloxetine HCl (DXH) 是一种血清素和去甲肾上腺素再摄取抑制剂，用于治疗重度抑郁症。由于其广泛的肝脏代谢、酸不稳定性质和有限的水溶性，DXH 的口服生物利用度很差 (40%)。直肠途径已被建议作为克服此类挑战的另一种给药途径。本研究旨在制备用于直肠给药的 DXH 负载甘油体 (DXH-GLYS) 原位凝胶，以增加 DXH 渗透性并提高其生物利用度。采用 Box-Behnken 设计 (BBD) 制备和优化纳米甘油体。Phospholipon 90G (PL90G)、吐温 80 浓度和甘油百分比对包封效率、纳米甘油体大小、释放的累积 DXH 百分比的影响，设计研究了 24 h 后单位面积的累积 DXH 渗透量。在大鼠中研究了优化制剂的药代动力学和药效学行为。配制的 DXH-GLYS 的囊泡大小介于 135.9 和 430.6 nm 之间，包封率介于 69.11 和 98.12% 之间。渗透实验表明，与 DXH 溶液相比，优化的 DXH-GLYS 原位凝胶使 DXH 渗透增加了 2.62 倍。药代动力学研究表明，相对于口服 DXH 溶液，DXH-GLYS 原位直肠凝胶的 DXH 生物利用度增加了 2.24 倍。药效学研究表明，DXH-GLYS 直肠治疗显着改善了行为分析参数，并且作为抗抑郁药比口服 DXH 溶液更有效。总的来说，
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