Preformulation and Vaginal Film Formulation Development of Microbicide Drug Candidate CSIC for HIV prevention.
Preformulation and Vaginal Film Formulation Development of Microbicide Drug Candidate CSIC for HIV prevention.
复制标题
DOI：
10.1007/s12247-017-9274-0
复制
发表时间：
2017-06
影响因子：
2.6
通讯作者：
Rohan LC
中科院分区：
文献类型：
--
作者：
Gong T;Zhang W;Parniak MA;Graebing PW;Moncla B;Gupta P;Empey KM;Rohan LC
5-氯-3-[苯磺酰基]吲哚-2-甲酰胺 (CSIC) 是一种高效的 HIV-1 非核苷逆转录酶抑制剂 (NNRTI)，已被证明比正在开发的作为 HIV 预防策略的其他 NNRTI 具有更理想的耐药性。这项工作涉及为 CSIC 生成预制剂数据以及系统开发共溶剂系统以有效溶解这种疏水性候选药物。然后将该系统应用于生产用于CSIC阴道给药的聚合物薄膜固体剂型，以用于预防HIV的性传播。进行了广泛的预配方、配方开发和薄膜表征研究。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、稳定性和药物辅料相容性。使用人上皮细胞和小鼠巨噬细胞系评估细胞毒性。使用三元相图方法来确定用于增强 CSIC 溶解度的共溶剂系统。在预配方评估之后，使用溶剂浇铸技术开发和制造了 CSIC 薄膜配方。在 12 个月的稳定性测试期间，对开发的薄膜产品的理化特性、抗 HIV 生物活性和乳酸菌生物相容性进行了评估。预制剂研究表明 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）组成的共溶剂系统，该系统使 CSIC 在薄膜配方中均匀分散。最终的薄膜产品符合为阴道杀菌剂应用制定的目标规格。通过共溶剂系统成功地在阴道膜中配制出具有高负载能力的疏水性候选药物CSIC。所开发的共溶剂策略适用于在薄膜平台中掺入其他疏水性候选药物。
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 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. 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. 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. 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.
登录
查看更多内容
影响因子：
2.2
作者：
Obitte NC;Rohan LC;Adeyeye CM;Parniak MA;Esimone CO
通讯作者：
Esimone CO
DOI：
10.1097/qai.0000000000000897
发表时间：
2016-04-15
影响因子：
3.6
作者：
Bunge, Katherine E.;Dezzutti, Charlene S.;Hillier, Sharon L.
通讯作者：
Hillier, Sharon L.
影响因子：
12.7
作者：
Delaugerre, C;Rohban, R;Calvez, V
通讯作者：
Calvez, V
影响因子：
3.7
作者：
Garg, S;Vermani, K;Zaneveld, LJD
通讯作者：
Zaneveld, LJD
影响因子：
1.6
作者：
Garg, S.;Kumar, G.
通讯作者：
Kumar, G.