Transdermal delivery of heparin and low-molecular weight heparin using low-frequency ultrasound

Purpose. Heparin and low-molecular weight heparin (LMWH) are the most commo nly used anticoagulants and are administered by intravenous or subcutaneous injections. However, injections of heparin have the potential risk of blee ding complications and the requirement of close monitoring in sonic cases. We hypothesized that transdermal delivery of heparin may provide an attract ive alternative to injections. However, the dose of transdermally delivered heparin is limited by low skin permeability, Methods. We increased skin permeability to heparin and LMWH using low-frequ ency (20 kHz) ultrasound. Biologic activity of transdermally delivered hepa rin was measured by using activated clotting time assays and by using anti- Xa (aXa) activity. Structural integrity of heparin was also assessed by usi ng gel electrophoresis, Results. Low-frequency ultrasound increased permeability of pigskin in vitr o and rat skin in vivo and allowed delivery of biologically active doses of heparin and low-molecular weight heparin transdermally. A prolonged contac t of transdermally delivered heparin with pigskin was found to reduce the b iologic activity of heparin, although no such deactivation was observed dur ing 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 elevation s of aXa level. Conclusions. Transdermal delivery of low-molecular weight heparin is a pote ntial alternative to injections.