(M1130-06-37) Revolutionizing Women’s Health by Enabling the Rational Development of Long-Acting Contraceptive Levonorgestrel Intrauterine Systems

Purpose: The past few years have witnessed a change in women’s contraceptive choices with an increasing number of women using hormonal intrauterine systems (IUSs) to provide long-term contraception. Levonorgestrel intrauterine systems (LNG-IUSs) are highly effective long-acting reversible contraceptives providing controlled drug release for 3-8 years. The LNG-IUSs offer additional therapeutic benefits, such as management of heavy menstrual bleeding. Despite the first levonorgestrel (LNG) IUS (Mirena^®) being approved in 2000, currently, there are only four LNG-IUS products approved by the U.S. Food and Drug Administration (FDA) and there are no LNG-IUS generic products. The complex nature of the excipients, the manufacturing challenges, and the complex release mechanisms are recognized as limiting factors in IUS development and have contributed to the paucity of IUS devices available in the market. The objective of the current research is to investigate the impact of the rate-controlling outer membrane on the performance of LNG-IUSs, with the goal of facilitating the development of generic IUS products. Development of more IUS products will lead to enhanced women's healthcare by expanding therapeutic options and providing more affordable LNG-IUSs.

Methods: IUSs with a drug loading of 52% w/w levonorgestrel (LNG) were prepared by mixing the drug and polydimethylsiloxane (PDMS) prepolymers (elastomer base and crosslinking agent) using a planetary mixer followed by subsequent processing via extrusion to form cylindrical implants. These implants were cured at elevated temperatures and underwent in situ polymer crosslinking to form the matrix. A similar procedure was used to prepare the rate controlling outer membrane without addition of LNG. Dimethyl PDMS (Pro-4238 PDMS, standard control, 20-40% w/w silica) outer membrane, along with other PDMS outer membranes with different chemical substitutions (Pro-4229 PDMS with 10% phenyl substitution), molecular weight (MW) (Pro-4227 PDMS, 100 kcP viscosity), silica filler content (Pro-4225 PDMS, containing 1/3^rd lower amount of silica), and curing conditions (Pro-4544 PDMS [condensation cure PDMS], Pro-4559 PDMS [addition cure PDMS, optimized for low API binding], and Pro-4521 PDMS [addition cure PDMS containing benzoyl peroxide catalyst]), were prepared. The thickness of the membranes was kept the same. The drug reservoirs were covered with the outer PDMS membranes to realize the final product (core-shell implant) (Fig. 1C). The in house LNG-IUS finished formulations with different outer membranes were evaluated alongside Mirena^® and Liletta^®, as well as an house LNG-IUS with pre-made DC Silastic outer membrane. The impact of these material attributes (polymer MW, chemical substitution, curing chemistry, and effect of additives) on the outer membrane performance and the overall LNG-IUSs performance was investigated. All formulations were characterized for microstructure, physicochemical properties, molecular composition, elemental composition, and dynamic mechanical properties. Scanning electron microscopy (SEM), scanning electron microscopy- energy dispersive x-ray (SEM-EDX) analysis, Fourier transform infrared (FTIR) spectroscopy and dynamic mechanical analysis (DMA) were utilized. Percentage of crosslinking was determined using a solvent extraction method. Real-time in vitro drug release testing was conducted (sample and separate method using water shaker bath at 37^ºC and 100 rpm, LNG concentrations were quantified using UPLC).

Results: All outer membranes showed >90% crosslinking except the PDMS optimized for low API binding (likely due to polymer surface group modifications) (Fig. 2F). FTIR analysis revealed structural similarities and differences. Microstructure analysis showed some differences in the different outer membranes (Fig. 2G). The SEM-EDX analysis and DMA studies showed differences in elemental composition and mechanical properties of the various PDMS outer membranes in comparison to Mirena^®, Liletta^® and the pre-made DC Silastic outer membranes (Fig. 3A and 3B). The differences in the outer membranes arise from variations in chemical composition, fillers, and the degree of crosslinking, which subsequently affected the release rate and overall performance of LNG-IUSs at various levels. The formulation with a high silica PDMS outer membrane showed decreased drug release compared to the low silica PDMS formulation, probably due to high silica content reducing polymer hydrophobicity and increasing API binding (Fig. 2A). The PDMS MW did not impact release rates (Fig. 2B). The formulation with condensation cured PDMS based membrane had a slightly higher release rate than the addition cured PDMS (Fig. 2C). This may be attributed to the slightly higher solubility of LNG in the condensation cured PDMS (contains the by-product alcohol). Polymer modification to achieve low API binding increased the drug release rates (Fig. 2C). The phenyl-substituted PDMS (non-polar) showed faster release than the dimethyl-substituted PDMS (polar) and the RLDs Mirena^® and Liletta^® (Fig. 2E).

Conclusion: This research provides an enhanced understanding of the impact of the rate-controlling outer membrane composition on LNG-IUS product performance and may help guide rational selection of the LNG-IUS outer-membrane polymer. Ultimately, this will allow tailoring of drug release and overall performance to facilitate the development of new and generic IUSs to improve patient access and women’s health. Furthermore, insight obtained from the current study will be beneficial to the development of other PDMS-based controlled-release products.

References: 1. Abhang et al., Recent advancements and future applications of intrauterine drug delivery systems. Expert opinion on Drug Delivery, 2025: 1-16.
2. Fanse et. al., Long-acting intrauterine systems: recent advances, current challenges, and future opportunities. Advanced drug delivery reviews, 2022: 191, 114581.
3. Bao Q., et al., Drug release testing of long-acting intrauterine systems. Journal of Controlled Release, 2019: 316, 349-358.
4. Bao et al., Manufacturing and characterization of long-acting levonorgestrel intrauterine systems. International Journal of Pharmaceutics, 2018: 447-454.

Acknowledgements: Funding for this project was made possible by a U.S. Food and Drug Administration grant (1U01FD005443-01). This abstract reflects the views of the authors and should not be construed to represent FDA’s views or policies.


Fig. 1. A) Schematic of hormonal LNG-IUS; B) schematics of different curing chemistry/processes used in preparation of LNG-IUSs; and C) schematic of the lab-scale formulation process of LNG-IUSs.


Fig. 2. A) In vitro drug release profiles of formulations with rate-controlling outer membranes containing PDMS with varying amounts of silica (mean±SD, n=3); B) in vitro drug release profiles of formulations with rate-controlling outer membranes of different molecular weight PDMSs (mean±SD, n=3); C) in vitro drug release profiles of formulations with rate-controlling outer membranes containing PDMSs of different curing chemistry (mean±SD, n=3); D) in vitro drug release profiles of formulations with rate-controlling outer membranes containing PDMSs of different chemical substitutions (mean±SD, n=3); and E) in vitro drug release profiles of all formulations containing different PDMS rate-controlling outer membranes in comparison with RLD Mirena® and RLD Liletta® (dissolution conditions: real-time in vitro drug release testing of LNG-IUSs was performed in 300 mL of saline (0.9 % w/v sodium chloride) via a sample and separate method using a water shaker bath at 37ºC and 100 rpm); F) degree of crosslinking (%) of different PDMS rate-controlling outer membranes in comparison with the RLD Mirena®, Liletta®, and pre-made DC Silastic outer membranes; G) representative FTIR spectrum of different PDMS rate-controlling outer membranes in comparison with the RLD Mirena®, the RLD Liletta®, and the pre-made DC Silastic outer membranes; H) microstructural similarities and differences between different PDMS rate-controlling outer membranes in comparison with the RLD Mirena®, the RLD Liletta®, and the pre-made DC Silastic outer membranes (determined via SEM, 1000X magnification).


Fig. 3. A) Elemental composition differences between the different PDMS rate-controlling outer membranes in comparison with the RLD Mirena®, RLD Liletta®, and pre-made DC Silastic outer membranes (determined via SEM-EDX). B) The DMA studies showed dissimilarities in the mechanical properties of the various PDMS rate controlling outer membranes in comparison to the RLD Mirena®, RLD Liletta®, and pre-made DC Silastic outer membranes (determined via dynamic mechanical analyzer).