Campaña-Seoane Maria, Peleteiro Aaron, Laguna Reyes, Otero-Espinar Francisco J
Department of Pharmacy and Pharmaceutical Technology, University of Santiago de Compostela, Campus Vida s/n, Santiago de Compostela 15782, Spain.
Department of Pharmacology, University of Santiago de Compostela, Campus Vida s/n, Santiago de Compostela 15782, Spain.
Int J Pharm. 2014 Dec 30;477(1-2):495-505. doi: 10.1016/j.ijpharm.2014.10.066. Epub 2014 Nov 1.
The aim of this study is to propose that mucoadhesive vaginal emulsions can be able to resist the clearance effect of vaginal fluid and to have an effective control release of progesterone. With this goal, silicon derivative, cyclomethicone pentamer, was selected as the bioadhesive and water resistant material. In order to obtain a system which is insensitive to the dilution of aqueous fluids, water in silicone (W/S) emulsions were prepared and different proportions of cyclomethicone as well as 8% or 15% w/w of progesterone were employed. The rheological, mechanical and mucoadhesive properties of emulsions were characterized and the drug release was measured for each formulation. Mucoadhesive behavior was determined and the influence of simulated vaginal fluid (SVF) at bioadhesion was assessed using three commercial mucoadhesive vaginal gels (Crinone(®), K-Y jelly(®) and Zidoval(®)) as the bioadhesive references. All assayed emulsions have good rheological and mechanical properties and their consistence and viscosity increase when the proportion of the internal phase increases. Related to mucoadhesion, in the absence of SVF, W/S emulsions showed similar bioadhesive levels like the commercial formulations. However, in the presence of SVF, W/S emulsions are able to keep their mucoadhesive properties while the marketed references drastically lose their consistency and adherence to the vaginal mucosa. Drug release profiles from W/S emulsion show that progesterone is released with pseudo-order zero kinetics and a constant release rate is maintained for at least two weeks. The results of the in vivo studies developed in rats show that after a single vaginal administration, bioadhesive W/S emulsions increase the uterine tissue progesterone levels in young and postmenopausal rats. Moreover in postmenopausal rats, they provide high uterine levels of progesterone compared to the bioadhesive-marketed gel used as a reference. Therefore, W/S emulsions have an interesting potential as bioadhesive vaginal delivery systems for drug administration.
本研究的目的是提出粘膜粘附性阴道乳剂能够抵抗阴道液的清除作用，并能有效控制孕酮的释放。为实现这一目标，选择硅衍生物环五聚二甲基硅氧烷作为生物粘附和防水性材料。为了获得对水性流体稀释不敏感的体系，制备了硅包水（W/S）乳剂，并采用了不同比例的环五聚二甲基硅氧烷以及8%或15% w/w的孕酮。对乳剂的流变学、力学和粘膜粘附性能进行了表征，并测定了每种制剂的药物释放情况。测定了粘膜粘附行为，并以三种市售粘膜粘附性阴道凝胶（Crinone®、K-Y jelly®和Zidoval®）作为生物粘附参考，评估了模拟阴道液（SVF）对生物粘附的影响。所有测定的乳剂都具有良好的流变学和力学性能，并且当内相比例增加时，它们的稠度和粘度会增加。关于粘膜粘附性，在没有SVF的情况下，W/S乳剂显示出与市售制剂相似的生物粘附水平。然而，在存在SVF的情况下，W/S乳剂能够保持其粘膜粘附性能，而市售参考制剂则大大失去其稠度和对阴道粘膜的粘附性。W/S乳剂的药物释放曲线表明，孕酮以伪零级动力学释放，并且至少两周内保持恒定的释放速率。在大鼠体内进行的研究结果表明，单次阴道给药后，生物粘附性W/S乳剂可提高年轻和绝经后大鼠子宫组织中的孕酮水平。此外，在绝经后大鼠中，与用作参考的市售生物粘附凝胶相比，它们能使子宫中的孕酮水平升高。因此，W/S乳剂作为药物给药的生物粘附性阴道给药系统具有有趣的潜力。
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