University of Connecticut, School of Pharmacy, Storrs, CT 06269, USA.
Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, FDA, Silver Spring, MD 20993, USA.
Int J Pharm. 2018 Oct 25;550(1-2):447-454. doi: 10.1016/j.ijpharm.2018.09.004. Epub 2018 Sep 5.
Mirena® is long-acting (5 years) contraceptive intrauterine device. It is composed of a hollow cylindrical drug reservoir (containing Levonorgestrel and polydimethylsiloxane), which is covered with a release rate controlling silicone membrane. This structure presents a manufacturing challenge and to date, there have been no literature reports on the manufacturing, product design and quality evaluation of these hollow cylindrical intrauterine devices. It is vital to develop a reproducible and robust manufacturing process for these long-acting intrauterine devices or systems to obtain an understanding the in vitro and in vivo performance of such drug-device combinations. In this study, a twin-syringe method with a customized mold was developed to manufacture hollow cylindrical polydimethylsiloxane (PDMS)-based levonorgestrel intrauterine systems (LNG-IUSs). Different mold materials, curing temperatures and times were screened to fabricate PDMS-drug reservoirs with good quality characteristics (easy demolding, good appearance and appropriate physicochemical characteristics). The prepared PDMS-drug reservoirs were covered with the release rate controlling membrane to fabricate the LNG-IUSs. Physicochemical characterization (drug content and content uniformity, powder X-Ray diffraction (PXRD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) and Fourier-transform infrared spectroscopy (FTIR) of the PDMS-drug reservoirs with different drug loadings (10%, 25% and 50% w/w) was conducted. Real-time in vitro drug release testing of LNG-IUSs with different drug loading was performed in normal saline (0.9% w/v NaCl) at 37 °C using a water bath shaker rotating at 100 rpm. The prepared PDMS-drug reservoirs demonstrated good and reproducible quality characteristics including appearance (smooth surfaces), targeted drug loading and good drug content uniformity in the PDMS matrix. The PXRD showed that the crystallinity of the API was maintained inside the PDMS matrix. DSC, TGA and FTIR confirmed the structure of the drug and the PDMS, indicating no interaction between the drug and the PDMS matrix in the prepared LNG-IUSs. Real-time in vitro drug release from the LNG-IUSs with different drug loadings showed zero-order release kinetics, and the drug release rate (based on daily release percentage) was inversely proportional to the drug loading.
Mirena® 是一种长效（5 年）宫内节育器。它由一个空心圆柱形药物储库（含有左炔诺孕酮和聚二甲基硅氧烷）组成，药物储库外面覆盖着一层控释硅橡胶膜。这种结构给制造带来了挑战，迄今为止，还没有关于这些空心圆柱形宫内节育器的制造、产品设计和质量评估的文献报道。开发一种可重复且稳健的制造工艺对于这些长效宫内节育器或系统至关重要，以便能够理解此类药物-器械组合的体外和体内性能。在这项研究中，开发了一种使用定制模具的双注射器法来制造空心圆柱形基于聚二甲基硅氧烷（PDMS）的左炔诺孕酮宫内节育系统（LNG-IUS）。筛选了不同的模具材料、固化温度和时间，以制造具有良好质量特性（易于脱模、外观良好和适当的理化特性）的 PDMS-药物储库。将制备好的 PDMS-药物储库覆盖控释膜，以制备 LNG-IUS。对不同载药量（10%、25%和 50%w/w）的 PDMS-药物储库进行了理化特性表征（药物含量和含量均匀度、粉末 X 射线衍射（PXRD）、差示扫描量热法（DSC）、热重分析（TGA）和傅里叶变换红外光谱（FTIR））。在 37°C 的水浴摇床中以 100rpm 的转速在生理盐水（0.9%w/v NaCl）中对不同载药量的 LNG-IUS 进行实时体外药物释放测试。制备的 PDMS-药物储库具有良好且可重现的质量特性，包括外观（表面光滑）、靶向载药量和 PDMS 基质中的良好药物含量均匀度。PXRD 表明 API 的结晶度在 PDMS 基质中得以保持。DSC、TGA 和 FTIR 证实了药物和 PDMS 的结构，表明在制备的 LNG-IUS 中药物与 PDMS 基质之间没有相互作用。不同载药量的 LNG-IUS 的实时体外药物释放显示出零级释放动力学，药物释放率（基于每日释放百分比）与载药量成反比。
