Mitragotri S, Kost J
Department of Chemical Engineering, University of California, Santa Barbara 93106, USA.
Pharm Res. 2001 Aug;18(8):1151-6. doi: 10.1023/a:1010979010907.
PURPOSE. Heparin and low-molecular weight heparin (LMWH) are the most commonly used anticoagulants and are administered by intravenous or subcutaneous injections. However, injections of heparin have the potential risk of bleeding complications and the requirement of close monitoring in some cases. We hypothesized that transdermal delivery of heparin may provide an attractive alternative to injections. However, the dose of transdermally delivered heparin is limited by low skin permeability.
We increased skin permeability to heparin and LMWH using low-frequency (20 kHz) ultrasound. Biologic activity of transdermally delivered heparin was measured by using activated clotting time assays and by using anti-Xa (aXa) activity. Structural integrity of heparin was also assessed by using gel electrophoresis.
Low-frequency ultrasound increased permeability of pigskin in vitro and rat skin in vivo and allowed delivery of biologically active doses of heparin and low-molecular weight heparin transdermally. A prolonged contact of transdermally delivered heparin with pigskin was found to reduce the biologic activity of heparin, although no such deactivation was observed during short exposures. Transdermally delivered LMWH resulted in sustained aXa levels in the blood. This result was in strong contrast to subcutaneous or intravenous injections of LMWH, which resulted in only temporary elevations of aXa level.
Transdermal delivery of low-molecular weight heparin is a potential alternative to injections.
目的。肝素和低分子量肝素（LMWH）是最常用的抗凝剂，通过静脉或皮下注射给药。然而，肝素注射存在出血并发症的潜在风险，且在某些情况下需要密切监测。我们推测肝素的透皮给药可能是注射给药的一种有吸引力的替代方法。然而，肝素透皮给药的剂量受到皮肤低渗透性的限制。
我们使用低频（20千赫兹）超声提高皮肤对肝素和低分子量肝素的渗透性。通过活化凝血时间测定和抗Xa（aXa）活性测定来测量透皮给药肝素的生物活性。还通过凝胶电泳评估肝素的结构完整性。
低频超声在体外增加了猪皮的渗透性，在体内增加了大鼠皮肤的渗透性，并允许透皮递送生物活性剂量的肝素和低分子量肝素。发现透皮给药的肝素与猪皮长时间接触会降低肝素的生物活性，尽管在短时间暴露期间未观察到这种失活现象。透皮给药的低分子量肝素导致血液中aXa水平持续升高。这一结果与皮下或静脉注射低分子量肝素形成强烈对比，后者仅导致aXa水平暂时升高。
低分子量肝素的透皮给药是注射给药的一种潜在替代方法。
