Long-acting intrauterine systems: Recent advances, current challenges, and future opportunities.

Levonorgestrel intrauterine systems (LNG-IUSs) are complex drug-device combination products designed to release a hormonal contraceptive drug for up to 7 years. These drug delivery systems offers a great promise as a modern method of long-acting reversible contraceptives (LARCs) to improve women's health. Unfortunately, there are some scientific challenges associated with the development of these products which are among the major reasons contributing to the availability of relatively few IUS products on the market. This review summarizes the formulation considerations (drug and excipient attributes), manufacturing methods, advances in characterization and in vitro drug release testing of IUSs, as well as factors influencing drug release from IUSs. A critical discussion on the major challenges to IUS product development is presented. Specifically, insights on bioequivalence evaluation, in vitro-in vivo correlation (IVIVC) establishment, and regulatory challenges are detailed. Lastly, methodological tools to overcome some of these hurdles to product development are proposed. The knowledge furnished through this review will be helpful towards obtaining better product understanding. Such understanding will facilitate the development of these complex drug products, as well as their regulatory approval process.