Gong Tiantian, Zhang Wei, Parniak Michael A, Graebing Phillip W, Moncla Bernard, Gupta Phalguni, Empey Kerry M, Rohan Lisa C
Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA.
Magee-Womens Research Institute, Pittsburgh, PA.
J Pharm Innov. 2017 Jun;12(2):142-154. doi: 10.1007/s12247-017-9274-0. Epub 2017 Mar 3.
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 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, ) 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.
5-氯-3-[苯磺酰基]吲哚-2-甲酰胺（CSIC）是一种高效的HIV-1非核苷类逆转录酶抑制剂（NNRTI），已证明其耐药性比其他正在开发用于HIV预防策略的NNRTI更理想。这项工作涉及生成CSIC的制剂前数据，并系统开发一种助溶剂体系以有效溶解这种疏水性候选药物。然后将该体系应用于制备用于阴道给药的CSIC聚合物薄膜固体剂型，以预防通过性行为感染HIV。
进行了广泛的制剂前研究、制剂开发和薄膜表征研究。开发了一种用于CSIC定量的HPLC方法。制剂前测试包括溶解度、晶体性质、稳定性和药物-辅料相容性。使用人上皮细胞系和小鼠巨噬细胞系评估细胞毒性。采用三元相图方法确定用于提高CSIC溶解度的助溶剂体系。在制剂前评估之后，使用溶剂浇铸技术开发并制造了CSIC薄膜制剂。在12个月的稳定性测试期间，对所开发的薄膜产品进行了物理化学性质、抗HIV生物活性和生物相容性评估。
制剂前研究表明CSIC非常稳定。由于其疏水性，开发了一种由聚乙二醇400、丙二醇和甘油（5:2:1）组成的助溶剂体系，该体系使CSIC在薄膜制剂中均匀分散。最终的薄膜产品符合为阴道杀微生物剂应用设定的目标规格。
通过助溶剂体系成功地将疏水性候选药物CSIC高载量地制成了阴道薄膜制剂。所开发的助溶剂策略适用于将其他疏水性候选药物纳入薄膜平台。
