Meyer B R, Kreis W, Eschbach J, O'Mara V, Rosen S, Sibalis D
Department of Medicine, North Shore University Hospital, Manhasset, NY 11030.
Clin Pharmacol Ther. 1988 Dec;44(6):607-12. doi: 10.1038/clpt.1988.201.
The human stratum corneum constitutes a relatively impermeable barrier to the transdermal absorption of most substances, including polypeptides and proteins. This double-blind, randomized, crossover study in 13 normal men evaluated whether a low level of electrical current could induce changes in cutaneous permeability sufficient to produce absorption of a polypeptide. We compared cutaneous absorption of 5 mg of leuprolide (a 9 amino acid luteinizing hormone releasing hormone analogue) in transdermal patches containing 0.2 mA electrical current (active) and in patches containing no electrical current (passive). Serum luteinizing hormone (LH) concentration was measured 12 times during an 8-hour period as a measure of drug effect. Similar baseline LH levels were seen in each group: active = 11.3 +/- 3.1 mIU/ml and passive = 13.7 +/- 4.7 mIU/ml (p not significant). Significant elevations of LH were seen in active compared with passive patches (p = 0.0084). As predicted, passive patches produced no elevation of LH concentration (LH = 11.8 +/- 7.1 mIU/ml at 4 hours). However, active patches produced elevations comparable to those achieved with subcutaneous administration of the drug (LH = 56.4 +/- 49.6 mIU/ml at 4 hours and p = 0.003 compared with passive). The patches were well tolerated without significant cutaneous toxicity. It is concluded that the use of low levels of electrical current can induce changes in the permeability of the stratum corneum. These changes are sufficient to promote the transdermal absorption of therapeutically relevant amounts of a polypeptide. This has major importance for our understanding of skin permeability and for the development of new techniques for drug administration.
人类角质层对包括多肽和蛋白质在内的大多数物质的经皮吸收构成了相对不可渗透的屏障。这项针对13名正常男性的双盲、随机、交叉研究评估了低水平电流是否能诱导皮肤通透性发生变化，足以使多肽被吸收。我们比较了含0.2 mA电流的透皮贴剂（活性组）和不含电流的透皮贴剂（被动组）中5 mg亮丙瑞林（一种9氨基酸促黄体生成激素释放激素类似物）的皮肤吸收情况。在8小时内测量血清促黄体生成激素（LH）浓度12次，作为药物效果的指标。每组的基线LH水平相似：活性组 = 11.3±3.1 mIU/ml，被动组 = 13.7±4.7 mIU/ml（p无统计学意义）。与被动组相比，活性组的LH显著升高（p = 0.0084）。正如预期的那样，被动组的贴剂未使LH浓度升高（4小时时LH = 11.8±7.1 mIU/ml）。然而，活性组的贴剂使LH升高，与皮下给药达到的升高水平相当（4小时时LH = 56.4±49.6 mIU/ml，与被动组相比p = 0.003）。这些贴剂耐受性良好，无明显皮肤毒性。结论是，使用低水平电流可诱导角质层通透性发生变化。这些变化足以促进治疗相关量多肽的经皮吸收。这对于我们理解皮肤通透性以及开发新的药物给药技术具有重要意义。
