Anticoagulants have had an amazing development pathway since the discovery of heparin in 1916 by Jay McLean at John Hopkins University and their impact on patients’ lives has been nothing other than dramatic. Over the decades the development of these anti-clot medicines has evolved rapidly alongside expanding the clinical areas of usage accompanied by approved licensing.

Used for various medical conditions including treatment and prevention of deep vein thrombosis (DVT), treatment and prevention of pulmonary embolism (PE), myocardial infarction (MI), unstable angina, atrial fibrillation (AF), occlusive stroke, and hemo-filtration, their efficacy is undisputable and the morbidity and mortality of patients has massively improved over the past 50 years.

Historically all anticoagulants—apart from warfarin—have been delivered via subcutaneous injections until the arrival of the novel oral anticoagulants (NOACs) in the late 2000s. Both heparin and low-molecular-weight-heparins (LMWHs) are injectable subcutaneously, which will always create issues with regards to patient compliance and can carry the risk of hematoma and more seriously, heparin-induced thrombocytopenia (HIT). While warfarin is an oral alternative it takes time to achieve the required level of anticoagulation and also requires regular monitoring of INR (international normalized ratio). For these reasons warfarin isn’t used in acute management situations but for long-term anticoagulation.

The arrival of the NOACs—dabigatran, rivaroxaban, apixaban and edoxaban—has seen great efficacy in anticoagulation without the issues of delivery route, but they aren’t without their potential problems and the cost implications. NOACs have a rapid onset and a relatively short half-life and are therefore suitable to be used in the acute setting. However, they are costly and have no effective approved antidote other than for dabigatran. Given that, they require no monitoring unlike warfarin, which can often sway the finances in favor of the NOACs. However, whichever way you look at it, all the anticoagulant options are standardized dosing regimens and the lack of monitoring can lead to inadequate or overzealous activity. The delivery of anticoagulation can be anything but precise, but this may be about to change.

Considering that standard heparin has been available “cheap as chips” for years, if an effective delivery and “live” monitoring system could be created without the need for invasive drug delivery and additional monitoring, this has the potential to not only improve the anticoagulation control but also reduce the cost of medication compared to other newer agents. The risks associated with uncontrolled heparinization are hefty at either end of the scale. Too much and there is a risk of hemorrhage and too little and there is a risk of clotting. As with any disease management, tight control with minimum effort will always result in the best outcomes.

A group of researchers from North Carolina State University and the University of North Carolina at Chapel Hill have spent the past two years investigating the options for such an innovative self-controlling dosing and monitoring system for anticoagulation, and recently released preliminary results of their developments. After assessing alternatives the scientists have worked to develop a skin patch, which has the potential to not only deliver, but also monitor and modulate delivery of heparin.

The patch, which has been developed to incorporate microneedles consisting of hyaluronic acid (HA) and loaded with heparin, has been modified such that the HA is able to detect differing levels of thrombin. Thrombin is involved in the coagulation cascade by converting fibrinogen into fibrin, and increasing coagulative activity in the blood. Although naturally and physiologically involved in the clotting process, increased levels of thrombin are associated with pathological states and can be controlled by the anti-Xa activity of pharmacological agents such as heparin and LMWH, which are historically delivered subcutaneously.

When applied to the skin tissue the microneedles pierce the cutaneous layers and are able to detect alterations in the level of thrombin enzymes. Elevated levels of thrombin cause the HA to release increased amounts of heparin, and a reduction in the levels has the opposite effect, creating a closed loop system for delivery of the antithrombotic without additional monitoring of dose and maintaining thrombin levels within normal physiological limits.

In animal-based research studies the results have been impressive. Using a mouse model the animals were injected with what would potentially be a lethal dose of thrombin if left untreated. The first experiment involved giving either a heparin injection, applying the HA-heparin patch to the skin or no treatment 10 minutes prior to the injection of thrombin. Fifteen minutes after the thrombin injection all treated mice (heparin on HA-heparin patch) animals survived, whereas all untreated specimens died.

In a second experiment the thrombin injection was applied 6 hours following treatment and 80% of the heparin treated mice died whereas all the animals with the HA-heparin mice survived. The indications are that the HA-heparin patch has maintained anticoagulative activity for a prolonged period of time sustaining its efficacy.

Heparin is a widely used medicine, which has an important place in management of coagulation. If an effective delivery mechanism can be created to decrease the discomfort of injections and reduce the necessity for blood monitoring this will be a really progressive step.

If at the same time it can push the cost of medication in the right direction the use of heparin could be completely rejuvenated. Although only proven in animal models at the moment the research group is sourcing funding to take the “smart” patch into pre-clinical testing. There is the potential to be able to adapt dose, modify delivery period and personalize the medicine. We’re used to seeing patches for delivering HRT and nicotine, but being able to introduce a monitoring device at the same time would be a real bonus.

---

Adele Graham-King
Contributing Editor
Adele is a design consultant who works in product development for medical and healthcare applications. Her background is in pharma, and she has a degree in applied physiology.