Category: Formulation and Quality
Purpose: Performance testing of long-acting (e.g., 3-5 years) levonorgestrel (LNG) intrauterine systems (IUSs) such as Mirena® is challenging due to their complex formulation and long duration of drug release. Currently all of the LNG-IUSs consist of a T-shaped polyethylene frame (T-body) with a steroid reservoir which is made of a mixture of LNG and polydimethylsiloxane (PDMS) and covered by a PDMS-based outer membrane (release rate-controlling membrane). It is critical to understand the physicochemical properties of the outer membrane and their impact on the drug release characteristics. In this part of the study, PDMS membranes from different sources were evaluated.
Methods: 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 cured drug reservoirs were cut to form pieces that weighed 100 mg. Five PDMS outer membranes (A, B, C, D, and E) with the same dimensions, but from different sources, were swollen in hexane, and then pulled over the drug reservoirs. Accelerated in vitro drug release testing of the prepared LNG-IUSs was performed at 45°C in a hydro-alcoholic media (containing 20% v/v tert-butanol (TBA), 80% v/v of pH 7.4 PBS and 0.25% w/v sodium dodecyl sulfate (SDS)). The in vitro release testing was performed using a water shaker bath with a rotation speed of 100 rpm. The sampling plan was as follows: 1-ml samples were withdrawn on days 1, 2, 3, 4 and 7, and replenished with fresh media. Following the initial seven-day testing period, 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 Thereafter samples were withdrawn weekly and all the media in the bottles were drained and replenished with fresh media following sampling. The five outer membranes were characterized using a texture analyzer, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and energy dispersive X-Ray spectroscopy (EDS).
Results: The LNG-IUSs prepared using different outer membranes showed the same release kinetics (zero-order), but different release rates with the following rank order: IUS-B >IUS-C >IUS-A≈IUS-D >IUS-E. The IUS prepared using the membrane from source B showed significantly higher release compared to the IUSs prepared using the membranes from other sources (p< 0.05). The IUS prepared using the membrane from source E showed significantly lower release rate compared with the IUS-C and IUS-B (p< 0.05), but not with IUS-A and IUS-D. Outer membranes from different sources also showed different physicochemical properties such as tensile strength, thermal behavior and elemental difference.
Conclusion: Using outer membrane from different sources did not affect the release mechanisms, but had an impact on the drug release rates from LNG-IUSs. The outer membranes from different sources had different physicochemical properties (mechanical and thermal behavior, as well as elemental analysis), which may be responsible for the differences in drug release rates of LNG-IUSs. Therefore, selection of outer membranes for the manufacturing of LNG-IUSs should be carefully considered.
Yuan Zou– Staff Fellow, United States Food and Drug Administration, Silver Spring, Maryland
Yan Wang– Staff Fellow, United States Food and Drug Administration, Silver Spring, Maryland
Stephanie Choi– Chemist, US Food and Drug Administration, Silver Spring, Maryland
Darby Kozak– Chemist (Lead), Untied States Food and Drug Administration, Silver Spring, Maryland
Diane Burgess– Distinguished Professor of Pharmaceutics, University of Connecticut, Storrs Mansfield, Connecticut