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Designing physicochemical applications for minimally-invasive transdermal drug and vaccine delivery.

机译：设计用于最小侵入性透皮药物和疫苗递送的物理化学应用。

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摘要

Skin presents itself as an attractive portal for delivery of therapeutic molecules for local and systemic effects. A number of needle-free transdermal drug delivery applications have been developed for breaching the skin barrier and deliver pharmaceutics. Despite decades of research and usage history, several of these applications suffer from low acceptance due to limitations in potency and safety. As part of this study, we demonstrate approaches for increasing potency and safety for two of these applications, namely liquid jet injectors and chemical permeation enhancers. Mechanistic understanding of interactions between skin and conventional liquid jet injector was used to design a novel pulsed-microjet injector. The high velocity (nu > 100 m/s) of microjets was coupled with small jet diameters (50-100 mum) and extremely small volumes (2-15 nanoliters) to limit penetration depth inside skin. Microjets showed superficial skin penetration (-200 mum) and minimal tissue damage, thus increasing safety compared to conventional injectors. The pulsed-microjet showed high insulin bioavailability in rat model.;Combinatorial high throughput screening of binary ternary and quaternary chemical formulations was conducted using In vitro Skin Impedance Guided High Throughput (INSIGHT) screening for discovering formulations with high potency. Ternary formulations represented the peak in potency i.e. highest average skin permeation enhancement amongst all orders and highest percentage of potent formulations. Potency screening of ternary formulations via INSIGHT was then coupled with cytotoxicity and adjuvanticity screening for discovery of safe formulations for needle-free transcutaneous immunization. A leading ternary formulation (BDC [1%] PEG [0.5%] SOS [0.5%]) exhibited over 40-fold enhancement in IgG titers against ovalbumin, a model macromolecular vaccine, in mouse model. Finally, the safety of chemical enhancers as microbicides was improved via a combinatorial screening of binary formulations. Lead formulations showed lower toxicity towards epidermal keratinocytes, with LC50 values up to 3.5-fold higher than their component surfactants, while maintaining antibacterial efficacy against B. thailendensis , a model pathogen for melioidosis causing B. pseudomallei .
机译：皮肤本身表现为吸引治疗分子的局部和全身作用的门户。已经开发出许多无针的透皮药物递送应用，以突破皮肤屏障并递送药物。尽管有数十年的研究和使用历史，但由于效能和安全性方面的限制，这些应用中的一些仍无法令人满意。作为这项研究的一部分，我们演示了为其中两个应用程序（即液体喷射注射器和化学渗透促进剂）提高效能和安全性的方法。对皮肤和常规液体喷射注射器之间相互作用的机械理解被用于设计新型脉冲微喷射注射器。微型喷嘴的高速（nu> 100 m / s）与较小的喷嘴直径（50-100微米）和极小的体积（2-15纳升）相结合，以限制皮肤内部的渗透深度。微型喷射器表现出皮肤浅层穿透力（-200毫米），并且组织损伤最小，因此与传统喷射器相比，安全性更高。脉冲微射流在大鼠模型中显示出较高的胰岛素生物利用度；使用体外皮肤阻抗引导高通量（INSIGHT）筛选进行二元三元和四元化学制剂的组合高通量筛选，以发现具有高效力的制剂。三元制剂代表效力的峰值，即在所有订单中平均皮肤渗透性增强最高，而有效制剂的百分比最高。然后通过INSIGHT对三元制剂进行效能筛选，再结合细胞毒性和佐剂筛选，以发现用于无针经皮免疫的安全制剂。在小鼠模型中，领先的三元制剂（BDC [1％] PEG [0.5％] SOS [0.5％]）对卵白蛋白（一种模型大分子疫苗）的IgG滴度显示超过40倍的增强。最后，通过二元制剂的组合筛选提高了化学增强剂作为杀菌剂的安全性。铅制剂对表皮角质形成细胞的毒性较低，其LC50值比其组成成分表面活性剂高3.5倍，同时保持了对B. Thailendensis的抗菌功效，B。Thailendensis是类拟弧菌病的致病性假芽孢杆菌。

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  • 作者

    Arora, Anubhav.;

  • 作者单位

    University of California, Santa Barbara.;

  • 授予单位 University of California, Santa Barbara.;
  • 学科 Biology Molecular.;Engineering Biomedical.;Chemistry Biochemistry.
  • 学位 Ph.D.
  • 年度 2009
  • 页码 135 p.
  • 总页数 135
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

  • 入库时间 2022-08-17 11:38:24

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