Development and characterization of low molecular weight heparin-triethanolamine cream: Skin permeability and antithrombotic efficacy

Abstract

Heparin’s coagulation factor inhibitory activity varies depending on its molecular size. Low-molecular-weight heparin (LMWH), which has fewer side effects, such as bleeding, compared to unfractionated heparin, has attracted attention. To develop a LMWH formulation with high skin permeability, a LMWH-TEA (LMWH-triethanolamine) cream formulation with improved liposolubility was developed by replacing the metal ion complex of LMWH into its TEA complex. A method for quantifying LMWH-TEA was established using high-performance liquid chromatography with fluorescence detection. The partition coefficient of LMWH-TEA increased with decreasing pH, indicating enhanced lipophilicity under acidic conditions. In the skin permeation study, LMWH-TEA showed higher skin permeability than LMWHNa for up to 48 h. In the carrageenan-induced rat tail thrombosis model, the group treated with 0.5 g of LMWH-TEA 0.3 % cream exhibited substantially greater antithrombotic efficacy compared to both the untreated control group and the group treated with LMWHNa 0.3 % cream. LMWH-TEA can serve as a novel transdermal formulation of LMWH and may be widely adopted in clinical practice.