Microneedle-Assisted Percutaneous Delivery of Naltrexone Hydrochloride in Yucatan Minipig: In Vitro-In Vivo Correlation
Microneedle-Assisted Percutaneous Delivery of Naltrexone Hydrochloride in Yucatan Minipig: In Vitro-In Vivo Correlation
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DOI：
10.1021/mp400227e
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发表时间：
2013-10-01
影响因子：
4.9
通讯作者：
Stinchcomb, Audra L.
中科院分区：
文献类型：
--
作者：
Milewski, Mikolaj;Paudel, Kalpana S.;Stinchcomb, Audra L.
尽管微针辅助经皮给药已经成为多项科学研究的主题，但很少有人尝试定量地将体外和体内渗透联系起来。盐酸纳洛酮也不例外。在本研究中，报告了尤卡坦小型猪“戳和贴片”微针应用方法后获得的药代动力学特征。该曲线表明快速达到最大盐酸纳洛酮血药浓度，随后出现相对突然的浓度下降。在体内未达到稳态。为了将目前的体内研究结果与以前发表的体外稳态渗透数据相关联，开发了一种扩散房室数学模型。该模型结合了两个平行的渗透途径，屏障厚度依赖的扩散阻力，微通道封闭动力学，和一个药代动力学模块。药代动力学数据的回归分析表明与独立计算的微通道闭合率和体外渗透数据具有良好的一致性。有趣的是，在体外扩散实验中采用的全层皮肤而不是分层皮肤提供了与体内数据的最佳相关性。用本文提出的模型进行的数据分析提供了新的机理见解，并允许预测与改变的微通道闭合速率相结合的药代动力学。
Although microneedle-assisted transdermal drug delivery has been the subject of multiple scientific investigations, very few attempts have been made to quantitatively relate in vitro and in vivo permeation. The case of naltrexone hydrochloride is not an exception. In the present study, a pharmacokinetic profile obtained following a "poke and patch" microneedle application method in the Yucatan minipig is reported. The profile demonstrates a rapid achievement of maximum naltrexone hydrochloride plasma concentration followed by a relatively abrupt concentration decline. No steady state was achieved in vivo. In an attempt to correlate the present in vivo findings with formerly published in vitro steady-state permeation data, a diffusion-compartmental mathematical model was developed. The model incorporates two parallel permeation pathways, barrier-thickness-dependent diffusional resistance, microchannel closure kinetics, and a pharmacokinetic module. The regression analysis of the pharmacokinetic data demonstrated good agreement with an independently calculated microchannel closure rate and in vitro permeation data. Interestingly, full-thickness rather than split-thickness skin employed in in vitro diffusion experiments provided the best correlation with the in vivo data. Data analysis carried out with the model presented herein provides new mechanistic insight and permits predictions with respect to pharmacokinetics coupled with altered microchannel closure rates.