Purpose: Isoliquiritigenin (ILQ), an important component of Anti-Asthma Herbal Medicine Intervention (ASHMI), had shown potent anti-asthma effect in vitro in our previous study. However, poor solubility and low bioavailability hindered in vivo application to treat asthma. This study was to develop a novel ILQ loaded self-nanoemulsifying drug delivery system (ILQ-SMEDDS) with enhanced bioavailability.
Methods: The optimized SMEDDS formulation was composed of ethyl oleate (oil phase), Tween 80 (surfactant) and PEG400 (co-surfactant) at a mass ratio of 3:6:1. The physiochemical properties of ILQ-SMEDDS, including drug content, globule size, zeta potential, scanning electron microscopy (SEM), Fourier transform infrared (FTIR) spectroscopy, were characterized. And the in vitro release profile, in situ intestinal absorption, in vivo pharmacokinetic parameters and the anti-asthma effect of ILQ suspension and ILQ-SMEDDS were evaluated.
Results: The ILQ-SMEDDS had an average globule size of 20.63 ± 1.95 nm with a polydispersity index (PDI) of 0.11 ± 0.03, and its zeta potential was − 12.64 ± 2.12 mV. The cumulative release rate of ILQ from ILQ-SMEDDS to the simulated gastrointestinal tract was significantly higher than that of free ILQ suspension. And area under curve with ILQ-SMEDDS was found to be 3.95 times higher than that of ILQ suspension indicating improved bioavailability by SMEDDS. Although ILQ-SMEDDS showed a slight less effective inhibitory effect on eotaxin-1 in human lung fibroblast (HFL-1) cells than free ILQ, in an ovalbumin-induced asthma model, ILQ-SMEDDS exhibited more efficacy than ILQ suspension in improving asthma-associated inflammation, including eosinophil production, ovalbumin-specific immunoglobulin E (OVA-sIgE), interleukin 4 (IL 4), interleukin 5 (IL 5) and interferon-γ (IFN-γ). Even the low dose of ILQ-SMEDDS group (10 mg/kg) showed better anti-asthma effect than that of the ILQ suspension group (20 mg/kg).
Conclusion: Compared with ILQ suspension, ILQ-SMEDDS showed significantly improved bioavailability and anti-asthma effect, revealing its potential as a favorable pharmaceutical agent for treating asthma.

Keywords: isoliquiritigenin, self-nanoemulsifying drug delivery system, SMEDDS, ovalbumin-induced asthma, eotaxin-1, increased bioavailability


中文翻译：

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开发一种口服生物可利用的异甘草素自纳米乳化给药系统，以有效治疗卵清蛋白诱导的哮喘

目的：异甘草素 (ILQ) 是抗哮喘草药干预 (ASHMI) 的重要组成部分，在我们之前的研究中已在体外显示出有效的抗哮喘作用。然而，溶解度差和生物利用度低阻碍了体内应用于治疗哮喘。本研究旨在开发一种新型负载 ILQ 的自纳米乳化药物递送系统 (ILQ-SMEDDS)，该系统具有增强的生物利用度。
方法：优化的 SMEDDS 配方由油酸乙酯（油相）、吐温 80（表面活性剂）和 PEG400（助表面活性剂）组成，质量比为 3:6:1。对ILQ-SMEDDS的理化性质，包括药物含量、球大小、zeta电位、扫描电子显微镜（SEM）、傅里叶变换红外（FTIR）光谱进行了表征。并对 ILQ 混悬剂和 ILQ-SMEDDS 的体外释放曲线、原位肠道吸收、体内药代动力学参数和抗哮喘作用进行了评价。
结果：ILQ-SMEDDS 的平均球大小为 20.63 ± 1.95 nm，多分散指数 (PDI) 为 0.11 ± 0.03，其 zeta 电位为 - 12.64 ± 2.12 mV。ILQ 从 ILQ-SMEDDS 到模拟胃肠道的累积释放率显着高于游离 ILQ 悬浮液。并且发现 ILQ-SMEDDS 的曲线下面积比 ILQ 悬浮液高 3.95 倍，表明 SMEDDS 提高了生物利用度。尽管 ILQ-SMEDDS 对人肺成纤维细胞 (HFL-1) 中 eotaxin-1 的抑制作用略低于游离 ILQ，但在卵清蛋白诱导的哮喘模型中，ILQ-SMEDDS 在改善哮喘方面比 ILQ 悬浮液更有效。相关炎症，包括嗜酸性粒细胞生成、卵清蛋白特异性免疫球蛋白 E (OVA-sIgE)、白细胞介素 4 (IL 4)、白细胞介素 5 (IL 5) 和干扰素-γ (IFN-γ)。即使是低剂量的ILQ-SMEDDS组（10 mg/kg）也显示出比ILQ混悬剂组（20 mg/kg）更好的抗哮喘作用。
结论：与ILQ混悬剂相比，ILQ-SMEDDS具有显着提高的生物利用度和抗哮喘作用，显示出其作为治疗哮喘的有利药剂的潜力。

关键词：异甘草素，自纳米乳化给药系统，SMEDDS，卵清蛋白诱导的哮喘，eotaxin-1，增加的生物利用度