Insights into synergistic interactions in binary mixtures of chemical permeation enhancers for transdermal drug delivery
Insights into synergistic interactions in binary mixtures of chemical permeation enhancers for transdermal drug delivery
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DOI：
10.1016/j.jconrel.2006.07.001
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发表时间：
2006-09-28
影响因子：
10.8
通讯作者：
Mitragotri, Samir
中科院分区：
文献类型：
--
作者：
Karande, Pankaj;Jain, Amit;Mitragotri, Samir
已知化学渗透增强剂（CPE）增加皮肤对治疗药物的渗透性。然而，单一的化学品对皮肤渗透性的增强作用有限。化学品的混合物可以克服这种限制，因为它们具有协同作用。然而，要确定化学品的强效混合物，需要对大量配方进行筛选。通过识别CPE现有数据中出现的模式，可以显著加快CPE混合物的发现。在这项研究中，我们系统地挖掘了一个巨大的数据库，通过高通量筛选产生的4000多个二元配方的皮肤透化效果，并提取了控制二元化学品组合对皮肤屏障性能的影响的一般原则。分析这些制剂的效力和协同作用，以确定制剂组成和化学性质所起的作用。分析揭示了几个直观的，但在很大程度上非直观的趋势。例如，当参与部分以几乎相等的分数存在时，由增强剂混合物制成的制剂最有效。甲基吡咯烷酮是一种小分子，在形成有效和协同增强剂制剂方面特别有效，两性离子表面活性剂更可能在有效增强剂中发挥作用。像这样简单但宝贵的规则将为设计库提供指导原则，以进一步加快配方发现过程。(c)2006 Elsevier B.V.保留所有权利。
Chemical permeation enhancers (CPEs) are known to increase skin permeability to therapeutic drugs. Single chemicals, however, offer limited enhancements of skin permeability. Mixtures of chemicals can overcome this limitation owing to their synergistic interactions. However, identification of potent mixtures of chemicals requires screening of a large number of formulations. Discovery of CPE mixtures can be significantly accelerated by identifying patterns that occur in the existing data on CPEs. In this study, we systematically mine through a huge database on skin permeabilizing effect of over 4000 binary formulations generated by high throughput screening and extract general principles that govern the effect of binary combinations of chemicals on skin's barrier properties. Potencies and synergies of these formulations are analyzed to identify the role played by the formulation composition and chemistry. The analysis reveals several intuitive but some largely non-intuitive trends. For example, formulations made from enhancer mixtures are most potent when participating moieties are present in nearly equal fractions. Methyl pyrrolidone, a small molecule, is particularly effective in forming potent and synergistic enhancer formulations, and zwitterionic surfactants are more likely to feature in potent enhancers. Simple but invaluable rules like these will provide guiding principles for designing libraries to further speed up the formulation discovery process. (c) 2006 Elsevier B.V. All rights reserved.