Sutar Yogesh, Yadavalli Tejabhiram, Paul Sagar Kumar, Mallick Sudipta, Koganti Raghuram, Chauhan Harsh, Date Abhijit A, Shukla Deepak
Department of Pharmaceutical Sciences, The Daniel K. Inouye College of Pharmacy, University of Hawaii Hilo, Hilo, HI 96720, USA.
Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL 60612, USA.
Pharmaceutics. 2021 Nov 12;13(11):1920. doi: 10.3390/pharmaceutics13111920.
BX795 is a TANK binding kinase-1 inhibitor that has shown excellent therapeutic activity in murine models of genital and ocular herpes infections on topical delivery. Currently, only the BX795 free base and its hydrochloride salt are available commercially. Here, we evaluate the ability of various organic acids suitable for vaginal and/or ocular delivery to form BX795 salts/cocrystals/co-amorphous systems with the aim of facilitating pharmaceutical development of BX795. We characterized BX795-organic acid coevaporates using powder X-ray diffractometry, Fourier-transform infrared spectroscopy (FT-IR), Raman spectroscopy, H-nuclear magnetic resonance spectroscopy, thermogravimetric analysis (TGA), and differential scanning calorimetry (DSC) to elucidate the interaction between BX795 and various organic acids such as taurine, maleic acid, fumaric acid, tartaric acid, and citric acid. Furthermore, using human corneal epithelial cells and HeLa cells, we evaluated BX795-organic acid coevaporates for in vitro cytocompatibility and in vitro antiviral activity against herpes simplex virus-type 1 (HSV-1) and type-2 (HSV-2). Our studies indicate that BX795 forms co-amorphous systems with tartaric acid and citric acid. Interestingly, the association of organic acids with BX795 improved its thermal stability. Our in vitro cytocompatibility and in vitro antiviral studies to screen suitable BX795-organic acid coevaporates for further development show that all BX795-organic acid systems, at a concentration equivalent to 10 µM BX795, retained antiviral activity against HSV-1 and HSV-2 but showed differential cytocompatibility. Further, dose-dependent in vitro cytocompatibility and antiviral activity studies on the BX795-fumaric acid system, BX795-tartaric acid co-amorphous system, and BX795-citric acid co-amorphous system show similar antiviral activity against HSV-1 and HSV-2 compared to BX795, whereas only the BX795-citric acid co-amorphous system showed higher in vitro cytocompatibility compared to BX795.
BX795是一种TANK结合激酶-1抑制剂，在局部给药的生殖器和眼部疱疹感染小鼠模型中显示出优异的治疗活性。目前，只有BX795游离碱及其盐酸盐可商购获得。在此，我们评估了各种适用于阴道和/或眼部给药的有机酸与BX795形成盐/共晶体/共无定形体系的能力，旨在促进BX795的药物研发。我们使用粉末X射线衍射、傅里叶变换红外光谱（FT-IR）、拉曼光谱、氢核磁共振光谱、热重分析（TGA）和差示扫描量热法（DSC）对BX795-有机酸共蒸发物进行表征，以阐明BX795与各种有机酸（如牛磺酸、马来酸、富马酸、酒石酸和柠檬酸）之间的相互作用。此外，我们使用人角膜上皮细胞和HeLa细胞，评估了BX795-有机酸共蒸发物的体外细胞相容性以及对1型单纯疱疹病毒（HSV-1）和2型单纯疱疹病毒（HSV-2）的体外抗病毒活性。我们的研究表明，BX795与酒石酸和柠檬酸形成共无定形体系。有趣的是，有机酸与BX795的结合提高了其热稳定性。我们为筛选适合进一步开发的BX795-有机酸共蒸发物而进行的体外细胞相容性和体外抗病毒研究表明，所有BX795-有机酸体系在相当于10 µM BX795的浓度下，均保留了对HSV-1和HSV-2的抗病毒活性，但显示出不同的细胞相容性。此外，对BX795-富马酸体系、BX795-酒石酸共无定形体系和BX795-柠檬酸共无定形体系进行的剂量依赖性体外细胞相容性和抗病毒活性研究表明，与BX795相比，它们对HSV-1和HSV-2具有相似的抗病毒活性，而只有BX795-柠檬酸共无定形体系与BX795相比显示出更高的体外细胞相容性。
