Emerging for non-invasive heparin delivery systems: recent advances, barriers, solutions, and applicability
Abstract
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.
Introduction
Heparin, a highly sulfated polyanionic glycosaminoglycan drug with molecular weight (MW) ranging from 3000 to 30000 Da, was discovered by McLean and William H. Howell since 1916 in Toronto, Canada (Jamshidovich 2024). It is widely used for more than 80 years as an anticoagulant, anti-inflammatory and antithrombotic for the prevention and treatment of thrombotic events. The other indications for heparin may also include treatment of thrombosis-related pulmonary diseases, inhibition of metastases, atherosclerosis and angiogenesis of cancer, nephro- and neuro-tissue protection, as well as acting as antimicrobial agents against viruses and protozoa (Hogwood et al. 2023). It exerts its primary anticoagulant effect by inactivation of thrombin and stimulation for factor Xa via an antithrombin (AT)-dependent mechanism (Fig. 1). Heparin interacts with AT via a high-affinity pentasaccharide found on approximately one-third of heparin molecules. Heparin should bind to both the coagulation enzyme and AT in order to block thrombin, whereas the inhibition of factor Xa was not required for enzyme binding. Heparin molecules did not have enough chain length for bridging the gap between thrombin and AT, and so it was not be able to inhibit thrombin.
In contrast, relatively tiny heparin fragments with the pentasaccharide sequence can block factor Xa via AT pathway (Hogwood et al. 2023). Heparin not only blocks fibrin formation, but also it can prevent thrombin-induced activation of platelets as well as factors V and VIII. Heparin can be classified based on its molecular weight into two groups: (1) Unfractionated heparin (UFH, MW: 3000–30,000 Da), and (2) Fractionated low-molecular-weight heparins (LMWHs, MW: 2000–9000 Da). LMWHs have a lower frequency of toxicity, less protein binding, longer half-life periods, higher bioavailability, and greater anti-FXa activity than UFH (Arachchillage et al. 2024). This drug is usually administrated via parenteral routes since it has a high molecular weight and negative charge which display various limitations for effective pharmacotherapy of thrombosis. These include variation in pharmacokinetic and physiochemical properties, adverse events such as bleeding complications, and manufacturing restrictions (Shute 2023). For example, heparins have a strong affinity for plasma proteins which may lower their bioavailability and cause a variety of anticoagulant effects.
These proteins are histidine-rich glycoprotein, platelet factor 4, vitronectin, and von Willebrand factor. Besides, heparin has complex pharmacokinetics; for instance the clearance for this drug can be occurred through several pathways (Hirsh et al. 2001). These include fast and saturable clearance of heparin by the endothelial cells and macrophages. In the other hand, heparins are also cleared from the plasma by a slower and non-saturable renal mechanism. Consequently, the anticoagulant effect of heparin is not linearly related to dose in the therapeutic range. The biologic half-life of heparins fluctuates between 30 min (after a 25 U/kg IV bolus dose) and 150 min for 400 U/kg bolus dose (Hirsh et al. 2001; Zhang et al. 2025). In terms of safety, patients may produce IgG antibodies in response to heparin administration that can lead to target the heparin–platelet factor 4 complex. These antibodies activate platelets and increase the risk of subsequent arterial and venous thrombosis (Zhang et al. 2025). In contrast, various non-invasive routes of heparin (oral agents, rectal and vaginal, transdermal, pulmonary and nasal) could be used as the feasible, safe, and effective alternative options of injectable heparin (Motlekar and Youan, 2006; Zhang et al. 2025). For example, oral options have several advantages such as ease of administration, fast cellular recovery, high vascularization, non-invasive, and bypassing of the gastrointestinal system and liver clearance.
Additionally, the rectal and vaginal methods offer several benefits for local and systemic medication delivery such as increased the higher blood circulation and a large surface area for absorption. Transdermal drugs bypass first-pass metabolism and the gastrointestinal tract by delivering the drug through the skin. This approach effectively works for drugs that are strongly metabolised or poorly absorbed orally (Motlekar, and Youan, 2006; Zhai et al. 2021). Besides, the rapid clinical response, vast absorptive surface area, predictable absorption kinetics, and lower risk of systemic side effects make inhaled approaches such as nasal and pulmonary routes the beneficial alternative choices for delivering heparin (Zieliński et al. 2019). In accordance, nanovesicles have been shown to be beneficial in improving the permeability, absorption, bioavailability, and bioactivity of heparin (Pilipenko et al. 2019). As a result, this study aims to bridge the gaps in the existing research regarding the delivery barriers of injectable heparin, specifically the lack of non-invasive delivery methods. Therefore, this work may also open the discussion of future research requirements. To do that, this review divides the previous data that explored the heparin delivery systems into three categories: (1) Traditional parenteral and invasive methods for delivery of heparin; (2) The novel non-invasive heparin delivery systems; and (3) Heparin-based nanoparticles. The past and recent in vitro and in vivo studies as well as the clinical trials that were conducted for each delivery system were also organized and summarized in tables.
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Excipients mentioned in the paper beside others: labrasol, sulfonated surfactants, EDTA, saponins, chitosan derivatives, carbopol 934P
Albatsh, M. Emerging for non-invasive heparin delivery systems: recent advances, barriers, solutions, and applicability. Saudi Pharm. J. 33, 17 (2025). https://doi.org/10.1007/s44446-025-00022-6