title: Transdermal delivery of heparin and low-molecular weight heparin using low-frequency ultrasound.
abstract: 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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  Transdermal delivery of low-molecular weight heparin is a potential alternative to injections.
authors.affiliation: Department of Chemical Engineering, University of California, Santa Barbara 93106, USA. samir@engineering.ucsb.edu
authors.forename: S
authors.initials: S
authors.lastname: Mitragotri
authors.forename: J
authors.initials: J
authors.lastname: Kost
mesh_terms: D000279:Administration, Cutaneous; D000818:Animals; D000925:Anticoagulants / Q000008:administration & dosage* / Q000493:pharmacokinetics; D001777:Blood Coagulation / Q000187:drug effects; D004553:Electric Conductivity; D004591:Electrophoresis, Polyacrylamide Gel; D005260:Female; D006493:Heparin / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D006495:Heparin, Low-Molecular-Weight / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D066298:In Vitro Techniques; D007444:Inulin; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012869:Skin Absorption / Q000502:physiology*; D013552:Swine; D014465:Ultrasonics
chemical_list: D000925:Anticoagulants; D006495:Heparin, Low-Molecular-Weight; D006493:Heparin; D007444:Inulin