Wits Advanced Drug Delivery Platform Research Unit, Department of Pharmacy and Pharmacology,School of Therapeutic Sciences, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, 7 York Road, Parktown, 2193, South Africa.
Department of Chemistry, Faculty of Natural and Agricultural Sciences, University of Pretoria, Pretoria, 0002, South Africa.
AAPS J. 2017 Nov;19(6):1745-1759. doi: 10.1208/s12248-017-0130-4. Epub 2017 Aug 4.
In this study, an intravaginal delivery system able to deliver an anti-HIV-1 agent for the purpose of potentially reducing HIV-1 transmission acting over an extended duration was successfully formulated. This delivery system was a composite polymeric caplet comprising zidovudine-loaded polyethylene glycol enclatherated pectin-mucin submicron matrices embedded within a poly (D,L-lactide), magnesium stearate, Kollidon® SR, and Carbopol® 974P NF-based polymeric caplet matrix. A three-factor and three-level Box-Behnken statistical design was utilized to optimize the polymeric caplet. The optimized directly compressed composite polymeric caplet hardness was 22.1 ± 0.3 N and the matrix resilience was 62.4 ± 0.6%. The swelling- and diffusion-controlled fractional zidovudine (AZT) release from the optimized caplet was 0.74 ± 0.01 in simulated vaginal fluid (SVF), which increased to 0.81 ± 0.21 in phosphate-buffered saline (PBS) simulating seminal fluid, over 30 days. Caplet matrix swelling was directly related to the percentage Carbopol 974P NF composition. An intravaginal system for AZT delivery was tested in the pig model over 28 days. X-ray analysis depicted delivery system swelling with matrix contrast fading over time as vaginal fluid permeated the matrix core. Plasma, vaginal fluid swab eluates, and tissue AZT concentrations were measured by gradient ultra-performance liquid chromatography (UPLC)-tandem photodiode array detection. Vaginal tissue and vaginal fluid swab eluate AZT concentrations remained above effective levels over 28 days and were higher than plasma AZT concentrations, availing a system with reduced systemic toxicity and more effective inhibition of viral replication at the site of entry.
在这项研究中，成功地制备了一种能够递送达抗 HIV-1 药物的阴道内递药系统，该递药系统可延长作用时间，从而潜在降低 HIV-1 的传播。该递药系统是一种复合聚合物帽片，包含负载齐多夫定的聚乙二醇包封的果胶 - 粘蛋白亚微米基质，嵌入在聚（D，L-丙交酯）、硬脂酸镁、Kollidon® SR 和 Carbopol® 974P NF 聚合物帽片基质中。利用三因素三水平 Box-Behnken 统计设计对聚合物帽片进行优化。优化后的直接压缩复合聚合物帽片硬度为 22.1±0.3N，基质弹性为 62.4±0.6%。优化后的帽片中，齐多夫定（AZT）的溶胀和扩散控制的分数释放率在模拟阴道液（SVF）中为 0.74±0.01，在模拟精液的磷酸盐缓冲盐水（PBS）中增加至 0.81±0.21，持续 30 天以上。帽片基质的溶胀与 Carbopol 974P NF 成分的百分比直接相关。在猪模型中对 AZT 阴道递药系统进行了 28 天的测试。X 射线分析显示，随着阴道液渗透到基质核心，递药系统随着基质对比度的减弱而肿胀。通过梯度超高效液相色谱（UPLC）-串联光电二极管阵列检测法测定血浆、阴道液拭子洗脱液和组织 AZT 浓度。阴道组织和阴道液拭子洗脱液中的 AZT 浓度在 28 天内保持在有效水平以上，且高于血浆中的 AZT 浓度，为降低系统的全身毒性和更有效地抑制病毒在进入部位的复制提供了一种可能性。
