University of Connecticut, School of Pharmacy, Storrs, CT 06269, United States of America.
Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, FDA, Silver Spring, MD 20993, United States of America.
J Control Release. 2019 Dec 28;316:349-358. doi: 10.1016/j.jconrel.2019.11.015. Epub 2019 Nov 13.
Performance evaluation of polydimethylsiloxane (PDMS) based long-acting (e.g. 3-5 years) levonorgestrel (LNG) intrauterine systems (IUSs), such as Mirena®, is challenging due to their complex formulation, locally-acting feature, and extremely long duration of drug release. To achieve such long-term release, a large amount of drug (up to 52 mg in Mirena®) must be incorporated as a drug reservoir in the IUS. Consequently, dose dumping or unanticipated changes in the LNG-IUS in vivo release characteristics may give rise to adverse product safety and efficacy. Therefore, it is crucial to understand, and have appropriate control over, the physicochemical properties and in vitro release characteristics of these products. This requires an understanding of the LNG-IUSs drug release mechanism and the development of a sensitive yet robust in vitro release testing method. There have been no previous reports on in vitro drug release and the release mechanism from LNG-IUSs. This is probably a consequence of the extremely slow drug release rate of LNG-IUSs under real-time in-use conditions (e.g., 3-5 years) and therefore it is impractical to obtain complete release profiles (e.g. there is only 60% release in 5 years for Mirena®). Therefore, the development of appropriate accelerated in vitro release methods is imperative. Following preparation of LNG-IUSs, similar to Mirena®, real-time release was tested in (0.9% w/v NaCl) media in a water shaker bath at 37 °C for over 2 years. Addition of surfactant (sodium dodecyl sulfate (SDS)), elevation of temperature, addition of organic solvents (ethanol (EtOH), isopropanol (IPA), tert-butanol (TBA) and tetrahydrofuran (THF)) and a combination thereof were utilized as release media to accelerate drug release for LNG-IUSs. Complete drug release was achieved in 32 and 672 days in THF and TBA hydro-organic media, respectively. The release profile in THF was considered too fast as it may result in change of release mechanism, whereas the release profile in TBA was deemed suitable following model fitting. Model fitting was performed to understand the release characteristics as well as the release mechanisms. The release rate in the hydro-alcoholic media was linearly proportional to the swelling ratio of the PDMS in the corresponding organic solvents. Zero-order, first-order and two-phase models were utilized to fit the release profiles obtained under the different release conditions. The data analysis was comparable using the parameters from different models given the high R values. However, the two-phase model was better in terms of the release mechanism of the LNG-IUSs considering the full drug release profile. The present study will facilitate the process of granting of biowaivers through an in vitro approach, thus reducing the necessity for clinical studies. In addition, it will help reduce the regulatory burden without sacrificing product quality of LNG-IUS products.
聚二甲基硅氧烷（PDMS）长效（例如 3-5 年）左炔诺孕酮（LNG）宫内节育系统（IUS）的性能评估具有挑战性，因为它们的配方复杂，具有局部作用，并且药物释放时间极长。为了实现如此长的释放时间，必须将大量药物（Mirena®中高达 52mg）作为药物储库纳入 IUS。因此，LNG-IUS 体内释放特性的剂量倾倒或意外变化可能会导致产品安全性和疗效出现不良反应。因此，了解这些产品的理化性质和体外释放特性并进行适当控制至关重要。这需要了解 LNG-IUS 药物释放机制并开发灵敏且稳健的体外释放测试方法。以前没有关于 LNG-IUS 体外药物释放和释放机制的报道。这可能是由于 LNG-IUS 在实时使用条件下（例如 3-5 年）下的药物释放速度非常缓慢，因此无法获得完整的释放曲线（例如，Mirena®在 5 年内仅释放 60%）。因此，开发合适的加速体外释放方法势在必行。LNG-IUS 制备完成后，类似于 Mirena®，在 37°C 的水浴摇床中在（0.9%w/v NaCl）介质中实时测试释放超过 2 年。添加表面活性剂（十二烷基硫酸钠（SDS））、升高温度、添加有机溶剂（乙醇（EtOH）、异丙醇（IPA）、叔丁醇（TBA）和四氢呋喃（THF））及其组合被用作释放介质，以加速 LNG-IUS 的药物释放。在 THF 和 TBA 水-有机介质中分别在 32 和 672 天内实现了完全药物释放。THF 中的释放曲线被认为太快，因为它可能导致释放机制发生变化，而 TBA 中的释放曲线在模型拟合后被认为是合适的。进行模型拟合以了解释放特性和释放机制。水醇介质中的释放速率与相应有机溶剂中 PDMS 的溶胀率成正比。使用零级、一级和两相模型拟合在不同释放条件下获得的释放曲线。考虑到完整的药物释放曲线，使用不同模型的参数进行数据分析具有可比性。然而，两相模型在 LNG-IUS 的释放机制方面更好。本研究将通过体外方法简化生物豁免的审批过程，从而减少对临床研究的需求。此外，它将有助于降低监管负担，同时不会牺牲 LNG-IUS 产品的质量。
