MECHANISM AND ENHANCEMENT OF TRANSDERMAL ABSORPTION

这项研究的长期目标是了解交通 透皮吸收机制使更可靠和更 可以设计出可预测的药物输送系统。因为一个 继续需要安全有效的药物来调节生育能力， 调查的重点是避孕药具的发放。 毒品。该项目的具体目标是：(1)评估 药物结构与化学性质的关系 人体经皮吸收；(2)测定- 药物对皮肤渗透的限制过程 结构和属性；(3)定义级别 利用渗透性可增加体内的透皮吸收 ‘促进剂’；(4)理解皮肤的作用机制(S) 渗透“促进剂”的作用。实验在以下地点进行 利用整形手术切除的人皮肤进行人体活体和体外实验 做手术。在存在和不存在的情况下的渗透率测量 “增强剂”利用新的质量平衡和表面消失 局部应用放射性标记药物后的技术。 在咬合状态下的局部“增强器”效应由 经皮失水和激光多普勒测速仪。药效 皮肤的穿透和定位是通过以下方式测量的 反射傅里叶变换红外光谱(FTIR)。状态 以及对角质层脂质的扰动(由“促进剂”引起) 用FTIR和差示扫描量热法对结构进行了表征 量热法。为了在分子水平上探索 角质层脂质的组成和组织，一种气液 角质形成细胞培养的建立、操作和试验 体能技术考试。使用Closed的模型试验 由角质层脂质制备的囊泡同时存在 为加强文化研究而采取的措施。总的来说， 因此，本项目旨在建立透皮吸收机制。 通过合理地应用生物物理吸收， 生物工程和生化技术来解释 药物在体内对人体皮肤的渗透及其增强作用。

The long term goal of this research is to understand the transport mechanisms of transdermal absorption such that more reliable and predictable drug delivery systems may be designed. Because of a continued need for safe and effective agents to regulate fertility, the investigation is focussed on the delivery of contraceptive drugs. The specific aims of the project are: (1) to evaluate the relationship between drug structure and chemical properties and percutaneous absorption in humans; (2) to determine the rate- limiting process in skin penetration as a function of drug structure and properties; (3) to define the level by which transdermal absorption in vivo may be increased using penetration `enhancers'; (4) to comprehend the mechanism(s) by which skin penetration `enhancers' function. Experiments are performed in vivo in man and in vitro using human skin excised during plastic surgery. Penetration measurements in the presence and absence of `enhancers' utilize novel mass balance and surface disappearance techniques following topical application of radiolabeled drug. Local `enhancer' effects under occlusion are monitored by transepidermal water loss and laser Doppler velocimetry. Drug passage across and localization within the skin is measured by reflectance Fourier-transform infrared spectroscopy (FTIR). Status and perturbations (by the `enhancers') to stratum corneum lipid structure are assessed by FTIR and differential scanning calorimetry. To probe, at a molecular level, the significance of stratum corneum lipid composition and organization, an air-liquid keratinocyte culture is established, manipulated and subjected to examination by physical techniques. Model experiments using closed vesicles prepared from stratum corneum lipids are concurrently undertaken to reinforce the studies in culture. Overall, therefore, the project aims to establish mechanisms of transdermal absorption by the judicious application of biophysical, bioengineering and biochemical techniques to the interpretation of drug penetration and its enhancement through human skin in vivo.