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. 2021 Nov 20;609:121192. doi: 10.1016/j.ijpharm.2021.121192. Epub 2021 Oct 16.
Polydimethylsiloxane (PDMS)-based levonorgestrel intrauterine systems (LNG-IUSs) such as Mirena® are long-acting drug-device combination products designed to release LNG for contraceptive purposes up to 6 years. LNG-IUSs consist of a hollow cylindrical drug-PDMS reservoir mounted with a polyethylene frame and covered by an outer PDMS membrane. PDMS is the release-controlling excipient present in both the matrix and the outer membrane. The degree of PDMS crosslinking is a key parameter in LNG-IUS manufacturing, dictating the elasticity and mechanical strength (which are critical parameters in molding and demolding of the cylindrical reservoirs). In addition, elasticity and mechanical strength are also important to prevent deformation during insertion into the uterine cavity. The objectives of this study were to investigate the impact of PDMS crosslinking on the physicochemical properties of LNG-IUSs and to develop appropriate testing methods for characterization of their mechanical strength. Formulations with different degrees of crosslinking were prepared by varying the ratio of the PDMS elastomer base and the crosslinking agent. A novel solvent swelling and extraction method was developed to determine the degree of PDMS crosslinking. The extent of crosslinking was also characterized via FTIR, Raman, H NMR, DSC, TGA and dynamic mechanical analysis. As expected, formulations with higher degrees of crosslinking showed lower crystallinity. Interestingly, the less crystalline formulations showed higher Tg values and storage moduli compared to the high crystalline formulations, implying that crosslinking is the predominant parameter governing the physicochemical and mechanical properties in LNG-IUSs. Correlations were established between PDMS crosslinking and the physicochemical properties of LNG-IUSs which will be useful for quality control purposes during formulation screening and development. A better understanding of the physicochemical characteristics of these complex products will facilitate drug product development.
基于聚二甲基硅氧烷（PDMS）的左炔诺孕酮宫内节育系统（LNG-IUS），如 Mirena®，是一种长效药物-器械组合产品，旨在为避孕目的释放 LNG，有效期长达 6 年。LNG-IUS 由一个带有聚乙烯框架的空心圆柱形药物 PDMS 储库组成，储库上覆盖有一个外部 PDMS 膜。PDMS 是存在于基质和外膜中的释放控制赋形剂。PDMS 的交联程度是 LNG-IUS 制造中的一个关键参数，决定了弹性和机械强度（这是圆柱形储库成型和脱模的关键参数）。此外，弹性和机械强度对于防止插入子宫腔时变形也很重要。本研究的目的是研究 PDMS 交联对 LNG-IUS 理化性质的影响，并开发适当的测试方法来表征其机械强度。通过改变 PDMS 弹性体基础和交联剂的比例，制备了不同交联程度的配方。开发了一种新的溶剂溶胀和提取方法来确定 PDMS 交联程度。还通过 FTIR、Raman、H NMR、DSC、TGA 和动态力学分析来表征交联程度。正如预期的那样，交联程度较高的配方表现出较低的结晶度。有趣的是，与高结晶度配方相比，结晶度较低的配方表现出更高的 Tg 值和储存模量，这表明交联是控制 LNG-IUS 理化和机械性能的主要参数。建立了 PDMS 交联与 LNG-IUS 理化性质之间的相关性，这将有助于在配方筛选和开发过程中的质量控制。更好地了解这些复杂产品的理化特性将有助于药物产品的开发。
