Purpose: The development and testing of long-acting (e.g., 3-5 years) levonorgestrel (LNG) intrauterine systems (IUSs) like MIRENA® is challenging due to their complex formulation and extremely long duration of drug release. To achieve the long duration of drug release of the LNG-IUS, a large amount of LNG (up to 52 mg in Mirena®) is required to be incorporated in the drug reservoir. Consequently, dose dumping or unanticipated changes in the in vivo release characteristics of the LNG-IUS may lead to adverse product safety and efficacy. Therefore, to ensure product quality, it is crucial to establish a reproducible physicochemical testing method as well as a robust in vitro release testing method.
Methods: Polydimethylsiloxane (PDMS)-based cylindrical LNG-IUS drug reservoirs with 50% w/w LNG were prepared using a mold and were cured at 80°C for 20 hours. The drug reservoir was cut into 100 mg per unit and a rate controlling silicone rubber elastomer membrane was applied by first swelling the membrane in hexane, and then pulling it over the drug reservoir. Real-time drug release was tested at 37°C using 300 ml of 0.9% w/v NaCl and 0.25% w/v SDS in pH 7.4 PBS as the media. The in vitro release test was performed using either a water bath shaker with a rotation speed of 100 rpm or an USP apparatus 2 with an agitation speed of 100 rpm. The sampling plan was as follows: 1 ml samples were withdrawn on Days 3 and 7, and replenished with fresh media. Following the Day 7 sampling, all the media in the bottles were drained and replenished with fresh media. Thereafter samples were withdrawn weekly and all the media in the bottles were drained and replenished with fresh media following sampling.
Results: The manufacturing process of LNG-IUS showed good reproducibility in appearance and drug content. Drug release from the LNG-IUS showed zero-order release kinetics using both the USP apparatus 2 and water bath shaker methods. Higher daily drug release from the IUSs was obtained using the USP apparatus 2 method compared with the water bath shaker method in both release media (saline and 0.25% w/v SDS in pH 7.4 PBS). Daily drug release of the IUS in 0.25% w/v SDS in pH 7.4 PBS was higher than that in saline. The difference in the daily drug release from the two release media was the same using both methods. Due to the mechanical issues and the media evaporation when using the current USP apparatus 2 method, performing in vitro release testing for extended periods such as for long-acting IUSs is challenging. In contrast in vitro release testing using the water bath shaker method with screw-capped release bottles does not have these issues, showing superiority over the USP apparatus 2.
Conclusion: Drug release profiles obtained from both water bath shaker and USP apparatus 2 showed zero-order release kinetics. The two methods are comparable in terms of the reproducibility of the release data. However, the set-up of USP apparatus 2 had issues with media evaporation and mechanical issues that may need to be addressed for the in vitro release testing of the long-acting LNG-IUS.
Yuan Zou– Staff Fellow, United States Food and Drug Administration
Yan Wang– Staff Fellow, United States Food and Drug Administration
Stephanie Choi– Chemist, US Food and Drug Administration, Maryland
Darby Kozak– Chemist (Lead), Untied States Food and Drug Administration, White Oak, Maryland
Diane Burgess– Distinguished Professor of Pharmaceutics, University of Connecticut, Storrs, Connecticut