Influence of chemical and structural features on skin penetration of low molecular weight heparins

Low molecular weight heparins (LMWHs) are potent anticoagulant and antithrombotic drugs obtained by chemical or enzymatic depolymerization of unfractionated heparin (UFH). With respect to their precursor, they exhibit a lower degree of binding for plasma proteins and therefore they have a more predictable effect, better pharmacokinetic and safety profiles. As consequence, LMWHs do not require strict monitoring and can be administered to outpatients. For this reason, their use has replaced that of UFH in clinical practice. Depending on the production method, each LMWH has its own structure and peculiar physical, chemical and biological properties. Subcutaneous administration of LMWHs is associated with pain and poor compliance, along with an increased risk of side effects. Then, there is a claim for a non-invasive route of administration. Transdermal delivery may represent an attractive alternative, although the diffusivity of LMWHs through the skin is limited by their large molecular weight, hydrophilicity and negative charge. To overcome this drawback, several physical and chemical strategies of skin penetration enhancement have been studied. However, the available data are in some extent contradictories and a systematic analysis of the impact of the structural and chemical features of different LMWHs on skin penetration is missing. The purpose of this work was to elucidate the impact of the structural features of LMWHs on their ability to diffuse through the human epidermis. With this aim the skin permeability of six commercially available compounds was determined in vitro. UFH was also included in the study to assess the permeation parameters of the precursor with complete polysaccharide chain and with the highest molecular weight.