Purpose

5-Chloro-3-[phenylsulfonyl] indole-2-carboxamide (CSIC) is a highly potent non-nucleoside reverse transcriptase inhibitor (NNRTI) of HIV-1 which has been shown to have a more desirable resistance profile than other NNRTIs in the development as HIV prevention strategies. This work involves generation of preformulation data for CSIC and systematic development of a cosolvent system to effectively solubilize this hydrophobic drug candidate. This system was then applied to produce a polymeric thin film solid dosage form for vaginal administration of CSIC for use in prevention of sexual acquisition of HIV.

Methods

Extensive preformulation, formulation development, and film characterization studies were conducted. An HPLC method was developed for CSIC quantification. Preformulation tests included solubility, crystal properties, stability, and drug-excipient compatibility. Cytotoxicity was evaluated using both human epithelial and mouse macrophage cell lines. Ternary phase diagram methodology was used to identify a cosolvent system for CSIC solubility enhancement. Following preformulation evaluation, a CSIC film formulation was developed and manufactured using solvent casting technique. The developed film product was assessed for physicochemical properties, anti-HIV bioactivity, and Lactobacillus biocompatibility during 12-month stability testing period.

Results

Preformulation studies showed CSIC to be very stable. Due to its hydrophobicity, a cosolvent system consisting of polyethylene glycol 400, propylene glycol, and glycerin (5:2:1, w/w/w) was developed, which provided a uniform dispersion of CSIC in the film formulation. The final film product met target specifications established for vaginal microbicide application.

Conclusions

The hydrophobic drug candidate CSIC was successfully formulated with high loading capacity in a vaginal film by means of a cosolvent system. The developed cosolvent strategy is applicable for incorporation of other hydrophobic drug candidates in the film platform.

中文翻译：

---

用于HIV预防的杀菌剂候选CSIC的预配制和阴道膜配方开发。

目的

5-氯-3- [苯磺酰基]吲哚-2-羧酰胺（CSIC）是HIV-1的高效非核苷逆转录酶抑制剂（NNRTI），已被证明具有比其他NNRTIs更理想的耐药性。发展作为预防艾滋病毒的战略。这项工作涉及为CSIC生成配方前数据，以及系统开发可有效溶解该疏水性候选药物的助溶剂系统。然后将该系统应用于制备用于阴道给药的CSIC的聚合物薄膜固体剂型，用于预防HIV的性获取。

方法

进行了广泛的预配方，配方开发和膜表征研究。开发了一种用于CSIC定量的HPLC方法。预制剂测试包括溶解度，晶体性质，稳定性和药物赋形剂相容性。使用人上皮细胞和小鼠巨噬细胞系评估细胞毒性。三元相图方法学被用于识别用于CSIC溶解度增强的助溶剂系统。在进行预配方评估后，使用溶剂流延技术开发并制造了CSIC薄膜配方。在12个月的稳定性测试期间，对开发的薄膜产品进行了理化性质，抗HIV生物活性和乳杆菌生物相容性的评估。

结果

配制前研究表明CSIC非常稳定。由于其疏水性，开发了由聚乙二醇400，丙二醇和甘油（5：2：1，w / w / w）组成的助溶剂体系，该体系在薄膜配方中提供了CSIC的均匀分散。最终的薄膜产品符合阴道杀菌剂应用的目标指标。

结论

疏水性候选药物CSIC通过助溶剂系统成功地在阴道膜中高载量配制。所开发的助溶剂策略适用于在膜平台中掺入其他疏水性候选药物。