Dallal Bashi Yahya H, Murphy Diarmaid J, McCoy Clare F, Boyd Peter, Brown Leeanne, Kihara Matthew, Martin François, McMullen Nicole, Kleinbeck Kyle, Dangi Bindi, Spence Patrick, Hansraj Bashir, Devlin Brid, Malcolm R Karl
School of Pharmacy, Queen's University Belfast, Belfast BT9 7BL, UK.
Elkem Silicones, Two Tower Centre Boulevard, Suite 1802, East Brunswick, NJ 08816, USA.
Int J Pharm X. 2021 Jul 14;3:100091. doi: 10.1016/j.ijpx.2021.100091. eCollection 2021 Dec.
A dapivirine-releasing silicone elastomer vaginal ring for reducing women's risk of HIV acquisition has recently been approved. A next-generation multipurpose vaginal ring releasing dapivirine and levonorgestrel is currently in development, offering hormonal contraception and HIV prevention from a single device. Previously, we reported challenges with incorporating levonorgestrel into rings manufactured from addition-cure silicone elastomers due to an irreversible chemical reaction between the levonorgestrel molecule and the hydride-functionalised crosslinker component of the silicone elastomer formulation, leading to low drug content assay, cure inhibition, and reduced ring mechanical properties (which may account for the increased incidence of ring expulsion in vivo). Here, we report on the development and testing of various custom silicone elastomer materials specifically formulated to circumvent these issues. After extensive testing of the custom silicones and subsequent manufacture and testing (Shore M hardness, pot life, content assay, oscillatory rheology, mechanical testing) of rings containing both dapivirine and levonorgestrel, a lead candidate formulation was selected that was amenable to practical ring manufacture via injection molding, exhibited no substantial levonorgestrel binding, and offered suitable mechanical properties.
一种用于降低女性感染艾滋病毒风险的释放达匹韦林的硅橡胶阴道环最近已获批准。目前正在研发一种释放达匹韦林和左炔诺孕酮的下一代多功能阴道环，该单一装置可提供激素避孕和艾滋病毒预防功能。此前，我们报告了将左炔诺孕酮纳入由加成固化硅橡胶制成的环时所面临的挑战，这是由于左炔诺孕酮分子与硅橡胶配方中的氢化物官能化交联剂成分之间发生了不可逆的化学反应，导致药物含量测定值低、固化抑制以及环的机械性能降低（这可能是体内环排出发生率增加的原因）。在此，我们报告了专门为规避这些问题而配制的各种定制硅橡胶材料的研发和测试情况。在对定制硅橡胶进行广泛测试，并对含有达匹韦林和左炔诺孕酮的环进行后续制造和测试（邵氏M硬度、适用期、含量测定、振荡流变学、机械测试）后，选择了一种先导候选配方，该配方适合通过注塑进行实际的环制造，未表现出大量左炔诺孕酮结合，且具有合适的机械性能。
