Emerging for non-invasive heparin delivery systems: recent advances, barriers, solutions, and applicability.

Nowadays, the use of unfractionated low molecular weight heparins through intravenous and subcutaneous routes has been limited by several delivery challenges. These include pharmacological activity fluctuations, bleeding issues, and numerous manufacturing restrictions. To address these issues, several efforts have been taken to find alternative routes for this medication. Unfortunately, the past and recent reviews were mainly explored the oral dosage forms of heparin and the other possible indications in practice. This review focuses on emerging efficient and non-invasive heparin options such as buccal, sublingual, oral, rectal and vaginal, transdermal, pulmonary and nasal. To do that, the past and recent studies were categorized into three main groups: (1) Conventional invasive heparin delivery methods; (2) Novel non-invasive heparin delivery systems; and (3) Heparin-based nanoparticles. The main challenges to use non-invasive heparin delivery systems were found to be negative charge and high molecular weight of heparin. Besides, the biological, biophysical, and pharmacological constraints could also limit the benefits of these alternatives. To overcome these issues, the following mechanisms have been used to enhance the delivery of heparin through several routes: (1) Improvement of cell-membrane penetration, (2) Changing of the tight-junctions, (3) Promoting the lipophilicity and (4) Preserving against acidic pH of the stomach. The applicability of alternative delivery options for heparin was mainly affected by overcoming the main penetration barriers. Nanoparticles were found to be effective in increasing the permeability, absorption, bioavailability and bioactivity of heparin.