Higaki K, Nakayama K, Suyama T, Amnuaikit Chomchan, Ogawara K, Kimura T
Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Okayama University, Okayama 700-8530, Japan.
Int J Pharm. 2005 Jan 20;288(2):227-33. doi: 10.1016/j.ijpharm.2004.09.025. Epub 2004 Dec 1.
The purpose of this work was to investigate the effect of blood flow in the skin on the direct penetration of topically applied drugs into the muscular layer, and to show that the skin blood flow could also be one of the important factors determining the direct penetration of drugs to the muscular layer. In vivo percutaneous absorption study was performed for antipyrine, salicylic acid or diclofenac by using rats with tape-stripped skin. Phenylephrine, which is well known to reduce the local blood flow by vasoconstrictor action, was topically applied to decrease the local blood flow in the skin. The concentrations of drugs in viable skin and muscle, and the local blood flow in the skin under the applied and the contralateral sites were determined to evaluate the effect of the local blood flow on the delivery of topically applied drugs into the muscular layer. Dose dependency for the effect of phenylephrine was, first of all, investigated for antipyrine in the range from 0.4 to 10 micromol. The distribution of antipyrine into the viable skin and muscular layer 2 h after topical application significantly increased, but the effect of phenylephrine was saturated around 2 micromol and the dose-dependent profiles for both tissues were almost superimposed. On the other hand, the fraction dose absorbed, plasma concentration and concentrations in viable skin and muscular layer under the contralateral site showed the decreasing tendency and the saturation of the effect around 2 micromol. To confirm the effect of phenylephrine on the local blood flow in the skin, the skin blood flow was measured 2 h after topical application of 2 micromol phenylephrine, and the significant decrease in the blood flow was recognized. In vivo percutaneous absorption studies were performed for salicylic acid and diclofenac, too. Extensive enhancement of penetration into the viable skin and muscular layer was observed for both drugs, although total absorption from the donor cell showed the decreasing tendency. In conclusion, direct penetration of drugs applied topically is enhanced by reducing the local blood flow in the skin, which would be a possible approach to improve the local delivery of drugs applied topically.
本研究旨在探讨皮肤血流对局部应用药物直接渗透至肌肉层的影响，并表明皮肤血流也可能是决定药物直接渗透至肌肉层的重要因素之一。采用皮肤去角质大鼠对安替比林、水杨酸或双氯芬酸进行了体内经皮吸收研究。众所周知，去氧肾上腺素可通过血管收缩作用减少局部血流，将其局部应用以减少皮肤局部血流。测定了给药部位和对侧部位的活皮肤和肌肉中药物浓度以及皮肤局部血流，以评估局部血流对局部应用药物向肌肉层递送的影响。首先研究了去氧肾上腺素在0.4至10微摩尔范围内对安替比林作用的剂量依赖性。局部应用后2小时，安替比林在活皮肤和肌肉层中的分布显著增加，但去氧肾上腺素的作用在2微摩尔左右达到饱和，且两种组织的剂量依赖性曲线几乎重叠。另一方面，对侧部位的吸收分数剂量、血浆浓度以及活皮肤和肌肉层中的浓度呈下降趋势，且在2微摩尔左右作用达到饱和。为证实去氧肾上腺素对皮肤局部血流的影响，在局部应用2微摩尔去氧肾上腺素后2小时测量皮肤血流，发现血流显著减少。也对水杨酸和双氯芬酸进行了体内经皮吸收研究。尽管供体池中的总吸收呈下降趋势，但两种药物在活皮肤和肌肉层中的渗透均有显著增强。总之，减少皮肤局部血流可增强局部应用药物的直接渗透，这可能是改善局部应用药物局部递送的一种可行方法。
