Dang Nhung T T, Sivakumaran Haran, Harrich David, Shaw Paul N, Davis-Poynter Nicholas, Coombes Allan G A
The University of Queensland, School of Pharmacy, St Lucia, Australia.
Queensland Institute of Medical Research, Molecular Virology Laboratory, Brisbane, Australia.
Eur J Pharm Biopharm. 2014 Oct;88(2):406-14. doi: 10.1016/j.ejpb.2014.05.018. Epub 2014 Jun 2.
Polycaprolactone (PCL) matrices were simultaneously loaded with the antiviral agents, tenofovir (TFV) and nevirapine (NVP), in combination to provide synergistic activity in the prevention of HIV transmission through the vaginal route. TFV and NVP were incorporated in PCL matrices at theoretical loadings of 10%TFV-10% NVP, 5%TFV-5%NVP and 5%TFV-10%NVP, measured with respect to the PCL content of the matrices. Actual TFV loadings ranged from 2.1% to 4.2% equating to loading efficiencies of about 41-42%. The actual loadings of NVP were around half those of TFV (1.2-1.9%), resulting in loading efficiencies ranging from 17.2% to 23.5%. Approximately 80% of the initial content of TFV was released from the PCL matrices into simulated vaginal fluid (SVF) over a period of 30 days, which was almost double the cumulative release of NVP (40-45%). The release kinetics of both antivirals over 30 days were found to be described most satisfactorily by the Higuchi model. In vitro assay of release media containing combinations of TFV and NVP released from PCL matrices confirmed a potential synergistic/additive effect of the released antivirals on HIV-1 infection of HeLa cells. These findings indicate that PCL matrices loaded with combinations of TFV and NVP provide an effective strategy for the sustained vaginal delivery of antivirals with synergistic/additive activity.
聚己内酯(PCL)基质同时负载了抗病毒药物替诺福韦(TFV)和奈韦拉平(NVP),二者联合使用可在预防经阴道途径传播HIV方面发挥协同作用。TFV和NVP按理论负载量10%TFV - 10%NVP、5%TFV - 5%NVP和5%TFV - 10%NVP掺入PCL基质中,该负载量是相对于基质中PCL含量测定的。实际TFV负载量在2.1%至4.2%之间,相当于负载效率约为41 - 42%。NVP的实际负载量约为TFV的一半(1.2 - 1.9%),负载效率在17.2%至23.5%之间。在30天的时间里,约80%的TFV初始含量从PCL基质释放到模拟阴道液(SVF)中,这几乎是NVP累积释放量(40 - 45%)的两倍。发现两种抗病毒药物在30天内的释放动力学最适合用Higuchi模型描述。对含有从PCL基质释放的TFV和NVP组合的释放介质进行体外测定,证实了释放的抗病毒药物对HeLa细胞HIV - 1感染具有潜在的协同/相加作用。这些发现表明,负载TFV和NVP组合的PCL基质为持续经阴道递送具有协同/相加活性的抗病毒药物提供了一种有效策略。