Development of a Vaginal Fast-Dissolving Insert Combining Griffithsin and Carrageenan for Potential Use Against Sexually Transmitted Infections
Development of a Vaginal Fast-Dissolving Insert Combining Griffithsin and Carrageenan for Potential Use Against Sexually Transmitted Infections
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DOI：
10.1016/j.xphs.2018.06.002
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发表时间：
2018-10-01
影响因子：
3.8
通讯作者：
Zydowsky, Thomas
中科院分区：
文献类型：
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作者：
Lal, Manjari;Lai, Manshun;Zydowsky, Thomas
用于降低女性性传播感染风险的性交前、按需局部杀微生物剂已经开发了近30年，但由于可接受性问题和临床试验依从性差，没有产品获得批准。我们着手开发一种通过冷冻干燥生产的自我管理的阴道快速溶解插入物（FDI），该插入物将提供安全有效量的抗病毒剂griffithsin（GRFT）和角叉菜胶（CG），并且具有女性及其伴侣可以接受的特性。我们评估了FDI物理标准、溶解后产生的凝胶的属性和GRFT稳定性。主要制剂FDI-024选自13种候选制剂，含有4 mg GRFT、15 mg CG和辅料（冷冻保护剂蔗糖和填充剂葡聚糖40和甘露醇）。FDI表现出良好的脆碎度和硬度，在高达40摄氏度/75%相对湿度下稳定至少6个月。它在生理相关体积（类似于1 mL）的模拟阴道液中在不到60 s内崩解，形成具有良好粘膜粘附和扩散特性的粘性半固体凝胶。在基于细胞的测定中，该制剂分别保留了GRFT和CG对HIV 1型和人乳头瘤病毒的抗病毒活性。(c)2018年美国药学协会（R）。爱思唯尔公司出版All rights reserved.
Precoital, on-demand topical microbicides to reduce a woman's risk of sexually transmitted infections have been in development for nearly 3 decades, but no product has been approved due to acceptability issues and poor adherence in clinical trials. We set out to develop a self-administered vaginal fast-dissolving insert (FDI) produced by freeze-drying that would deliver safe and effective amounts of the antiviral agents griffithsin (GRFT) and carrageenan (CG) and would have properties women and their partners find acceptable. We evaluated FDI physical criteria, attributes of the gel produced upon dissolving, and GRFT stability. The lead formulation, FDI-024, was selected from 13 candidates and contains 4 mg of GRFT, 15 mg of CG, and excipients (the cryoprotectant sucrose and bulking agents dextran 40 and mannitol). The FDI exhibits good friability and hardness and is stable for at least 6 months at up to 40 degrees C/75% relative humidity. It disintegrates in less than 60 s in a physiologically relevant volume (similar to 1 mL) of simulated vaginal fluid, forming a viscous semi-solid gel with favorable mucoadhesive and spreading properties. The formulation retains the antiviral activity of GRFT and CG against HIV type 1 and human papillomavirus, respectively, in cell-based assays. (c) 2018 American Pharmacists Association (R). Published by Elsevier Inc. All rights reserved.