Abstract：
BX795 is an emerging drug candidate that has shown a lot of promise as a next-generation non-nucleoside antiviral agent for the topical treatment of herpes simplex virus type-1 (HSV-1) and herpes simplex virus type-2 (HSV-2) infections. Our studies indicated that BX795 has limited oral bioavailability, which could be attributed to its low and pH-dependent solubility. Lipid-based formulations such as self-nanoemulsifying systems (SNESs) can improve the solubility and oral bioavailability of BX795, but the poor lipid solubility of BX795 further limits the development of SNES. To improve the loading of BX795 into SNES, we evaluated the ability of various bulky and biocompatible anions to transform BX795 into an ionic liquid (IL) with higher lipid solubility. Our studies showed that sodium lauryl sulfate and docusate sodium were able to transform BX795 into IL. Compared to pure BX795, the developed BX795 ILs showed differential in vitro cytocompatibility to HeLa cells but exhibited similar in vitro antiviral activity against HSV-2. Interestingly, BX795 docusate (BX795-Doc), an IL of BX795 with ∼135-fold higher lipid solubility than pure BX795, could be successfully incorporated into an SNES, and the developed BX795-Doc-SNES could readily form nanoemulsions of size ≤200 nm irrespective of the pH of the buffer used for dilution. Our in vitro studies showed that BX795-Doc-SNES retained the inherent antiviral activity against HSV-2 and showed similar in vitro cytocompatibility, indicating the availability of BX795 from the SNES in vitro. Finally, orally delivered SNES containing BX795-Doc showed a significant reduction in HSV-2 infection in mice compared to the untreated control. Thus, the transformation of BX795 into IL and the subsequent incorporation of the BX795 IL into the SNES are an effective strategy to improve oral therapy of genital herpes infection.
摘要：
BX795是一种新兴的候选药物，已显示出很大的希望作为下一代非核苷抗病毒剂，用于局部治疗1型单纯疱疹病毒（HSV-1）和2型单纯疱疹病毒（HSV-2）感染。我们的研究表明，BX795具有有限的口服生物利用度，这可能归因于其低和pH依赖性的溶解度。基于脂质的制剂如自纳米乳化系统（SNESs）可以提高BX795的溶解度和口服生物利用度，但BX795较差的脂溶性进一步限制了SNES的发展。为了提高将BX795加载到SNES中，我们评估了各种大体积和生物相容性阴离子将BX795转化为具有较高脂溶性的离子液体（IL）的能力。我们的研究表明，十二烷基硫酸钠和多库酯钠能够将BX795转化为IL。与纯BX795相比，开发的BX795IL显示出与HeLa细胞的体外细胞相容性差异，但对HSV-2的体外抗病毒活性相似。有趣的是,BX795文档（BX795-Doc），BX795的IL具有比纯BX795高135倍的脂溶性，可以成功地掺入SNES，并且开发的BX795-Doc-SNES可以容易地形成尺寸≤200nm的纳米乳液，而与用于稀释的缓冲液的pH无关。我们的体外研究表明，BX795-Doc-SNES保留了针对HSV-2的固有抗病毒活性，并显示出相似的体外细胞相容性，表明体外SNES中BX795的可用性。最后,与未处理的对照相比,口服递送的含有BX795-Doc的SNES显示小鼠中HSV-2感染的显著减少。因此，将BX795转化为IL以及随后将BX795IL掺入SNES是改善生殖器疱疹感染口服治疗的有效策略。
