(T1030-09-52) Weekly Apixaban Transdermal Delivery System

Purpose: Eliquis® (apixaban), a direct factor Xa anticoagulant (blood thinner), is an approved oral medication for twice daily administration. Apixaban works by blocking the factor Xa enzyme, preventing the conversion of prothrombin to thrombin in the final common pathway of clot formation in blood vessels and heart. The oral drug product has two approved strengths: 2.5 mg and 5 mg as prescribed by doctors1 for different indications.2 Herein, a weekly apixaban transdermal delivery system is developed and reported.

Methods: Skin permeation rate, i.e., flux was assessed by in vitro human cadaver skin permeation studies using jacketed Franz diffusion cells. At each time point, the Franz cells were completely emptied of receiver solution and transferred into HPLC vials. Fresh receiver solution was supplied into each empty Franz cell. After the study, all sample solutions were tested by UPLC-UV to measure drug concentration over time and determine the corresponding permeation profiles.

Results: The lead formulation was developed and assessed with 6 different skin donors (42 replicates in total). The cumulative apixaban delivery profile and the skin flux profile are shown in Figure 1. The average 7-day flux rate is 7.5 µg/cm²/h, indicating < 40 cm² patch size. To understand the impact that lag time exhibits on the weekly patch change, the trough flux of the lead formulation was investigated from in vitro human cadaver skin permeation study, to mimic a patch change at day 7. Figure 2 shows theoretical 14-day flux profile with a patch change at day 7. The average trough flux is 4.2 µg/cm²/h from 6 skin donors (42 replicates in total) indicating that the C_min of 49.6 ng/ml plasma concentration from oral tablets should be achievable via the transdermal route of administration, and the lag time anticipated from the transdermal patch should not affect the therapeutic efficacy of apixaban following the patch change. A preliminary stability study was conducted in the lab, demonstrating that the drug content and drug release profiles are stable at ambient condition (Figure 3). A Primary Skin Irritation study was conducted on rabbits. The Primary Irritation Index (PII) is < 1, indicating negligible immune response from skin.

Conclusion: In summary, a weekly Apixaban transdermal delivery system was successfully developed. The patch size is < 40 cm² from in vitro human cadaver skin permeation studies and the lag time associated with transdermal apixaban delivery should not be expected to affect the efficacy following each patch change at seven days Compared with traditional oral tablets, there are advantages to using weekly apixaban transdermal patches. Firstly, transdermal delivery system allows for direct delivery of apixaban, a direct factor Xa anticoagulant, to the target blood circulatory system, where the pharmacological effect occurs. Secondly, oral Eliquis® tablets require twice daily dosing. A weekly transdermal patch is more convenient to the patients. Patients simply change the patch once a week to ensure compliance. Thirdly, oral apixaban pharmacokinetics demonstrate a highly variable blood concentration over twelve hours, while the transdermal apixaban system is intended for relatively steady-state blood concentration over seven days. Furthermore, transdermal delivery avoids common digestive side effects (e.g., nausea, or potential GI bleeding), bypassing the digestive tract. Transdermal delivery avoids the 1st pass hepatic metabolism, yielding higher bioavailability generally. In addition, transdermal delivery can be paused or stopped at any time via patch removal from skin, if any adverse event (AE) occurs.

References: 1. Byon, W.; Garonzik, S.; Boyd, R. A.; Frost, C. E.; Clin Pharmacokinet, 2019, 58, 1265.
2. Buckley, B. J.; Lane, D. A.; Calvert, P.; Zhang, J.; Gent, D.; Mullins, C. D.; Dorian, P.; Kohsaka, S.; Hohnloser, S. H.; Lip, G. Y.; J. Clin. Med. 2022, 11, 3788.

Figure 1: In vitro 7-day human cadaver skin permeation study results from 6 different skin donors; (left) cumulative Apixaban delivery profile and (right) Apixaban interval flux profile.

Figure 2: 14-day Apixaban interval flux profile with a patch change at day 7.

Figure 3: Apixaban release profiles from preliminary stability study.