Heparin: The Journey from Parenteral Agent to Nasal Delivery

Abstract

Although the worldwide usage of direct oral anticoagulants has continuously increased over the past decade, heparin remains an important weapon in the current arsenal of anticoagulant drugs. Parenteral heparin administration (i.e., either intravenously or subcutaneously) has represented for decades the only possible route for generating a significant anticoagulant effect, although being notoriously associated with some important drawbacks such as discomfort and risk of low compliance, thus paving the way to searching for more amenable means of administration. We provide here an updated analysis of animal and human studies that have explored the feasibility, suitability, and efficiency of heparin administration through the unconventional nasal route, as a possible alternative to the more traditional parenteral injection. The major hurdles that contribute to impair intranasal absorption and systemic delivery of heparin are represented by its relatively high molecular weight and negative charge. Therefore, although pure drug administration would not be associated with efficient nasal adsorption, or by systemic biological activity (i.e., anticoagulant effect), the combination of low molecular weight heparins and absorption enhancers such as surfactants, mucoadhesive, cyclodextrins, polyethylenimines and encapsulation into (nano)carriers seems effective to at least partially improve drug transport through the nasal route and allow systemic delivery in animals. Besides generating anticoagulant effects, intranasal heparin administration can also produce local pleiotropic effects, mostly related to anti-inflammatory properties, such as attenuating airway allergic inflammation or inhibiting the binding of the spike protein of some coronaviruses (including severe acute respiratory syndrome coronavirus 2) to their host cell receptors. This preliminary evidence represents a valuable premise for planning future studies in humans aimed at establishing the pharmacokinetics and biological activity of locally and systemically delivered intranasal heparin formulations.

Improving Nasal Protection for Preventing SARS-CoV-2 Infection

“…Recent evidence has been provided that the anticoagulant drug heparin displays pleiotropic antiviral properties, mostly by binding to the spike protein of SARS-CoV-2 and thus inhibiting host cell infection [ 56 ]. It is hence not surprising that its administration through the unconventional nasal route has been conceived as a prophylactic treatment against SARS-CoV-2 infection [ 57 ]. To this end, Eder et al, carried out a single-center, open-label intervention study aimed at exploring the effect of low molecular weight heparin (LMWH) inhalation for preventing SARS-CoV-2 infection [ 58 ].…”

How often are parenteral anticoagulants administered by parents?

“…There are a variety of anticoagulant drugs that are administered parenterally, although heparin reflects the most common of these agents. Heparin can be administered as either unfractionated heparin, which may be administered by injection or infusion, or one of the low molecular weight heparins (LMWH), which are usually administered by injection, although studies on nasal delivery are also under way 1 . Other well‐known parenterally administered anticoagulant agents include lepirudin, argatroban, and bivalirudin.…”

To Clot or Not to Clot: Is That the Question?

“…To help prevent thrombosis in moderate-to-severe COVID-19, it is recommended that patients be given anticoagulant therapy, and potentially antiplatelet agents. The most common anticoagulant given is heparin [ 3 ], and the most common antiplatelet agent potentially applied is aspirin [ 4 ]. Heparin is a common anticoagulant given to treat or prevent venous thrombosis, and anti-platelet agents such as aspirin are commonly administered to help prevent arterial thrombosis.…”

“…Heparin is usually given parenterally (i.e., injected subcutaneously or intravenously). However, there is increasing evidence that heparin has additional benefits beyond that of anticoagulation, and for example, a local anti-inflammatory effect and potential to reduce SARS-CoV-2 binding (and thus subsequent infection) is evident when heparin is applied intra-nasally [ 3 ].…”