Woolfson A D, Elliott G R, Gilligan C A, Passmore C M
School of Pharmacy, The Queen's University of Belfast, Medical Biology Centre, 97 Lisburn Road, Belfast, UK.
J Control Release. 1999 Sep 20;61(3):319-28. doi: 10.1016/s0168-3659(99)00148-0.
Suitable ester prodrugs of 17beta-estradiol are identified, thus permitting effective sustained and controlled estrogen replacement therapy (ERT) from an elastomeric, silicone intravaginal ring (IVR). IVR devices of reservoir design were prepared by blending silicone elastomer base with n-propylorthosilicate (cross-linker) and 10% w/w of 17beta-estradiol or an ester prodrug, the mix being activated with 0.5% w/w stannous octoate and cured at 80 degrees C for 2 min. A rate-controlling membrane was similarly prepared, without the active agent. IVR devices were of cross-sectional diameter 9 mm, outer diameter 54 mm, with core cross-sectional diameter of 2 mm and core length varied as required. Sink conditions were evident for the 17beta-estradiol esters in 1.0% aqueous benzalkonium chloride solution. The low release rates into 0.9% w/v saline of the lipophilic valerate and benzoate esters were due to their intrinsically low aqueous solubilities. In vivo, these esters failed to raise plasma estradiol above baseline levels in postmenopausal human volunteers, despite good in vitro release characteristics under sink conditions. The best release rates under sink conditions, in combination with substantial aqueous solubilities as indicated by the release rates into saline, were observed for the acetate and propionate esters. A combination of drug release characteristics, short plasma half-life and a toxicologically acceptable hydrolysis product indicated that 17beta-estradiol-3-acetate was the prodrug of choice for IVR delivery of ERT. In vivo, an IVR device releasing 100 microg/day of estradiol as its 3-acetate ester maintained over 84 days a circulating plasma concentration in the region of 300 pmoll(-1), within the clinically desirable range for ERT.
已鉴定出17β-雌二醇合适的酯前药，从而能够通过弹性体硅酮阴道环（IVR）进行有效的持续和可控雌激素替代疗法（ERT）。通过将硅酮弹性体基质与原硅酸正丙酯（交联剂）以及10% w/w的17β-雌二醇或酯前药混合来制备储库设计的IVR装置，混合物用0.5% w/w的辛酸亚锡活化，并在80℃下固化2分钟。同样制备不含活性剂的控速膜。IVR装置的横截面直径为9毫米，外径为54毫米，芯部横截面直径为2毫米，芯部长度根据需要变化。在1.0%苯扎氯铵水溶液中，17β-雌二醇酯的漏槽条件明显。亲脂性戊酸酯和苯甲酸酯在0.9% w/v盐水中的低释放速率是由于其固有的低水溶性。在体内，尽管这些酯在漏槽条件下具有良好的体外释放特性，但在绝经后人类志愿者中，它们未能使血浆雌二醇水平升高至基线水平以上。在漏槽条件下，观察到乙酸酯和丙酸酯的释放速率最佳，同时从盐水中的释放速率表明它们具有较高的水溶性。药物释放特性、短血浆半衰期和毒理学上可接受的水解产物的综合结果表明，17β-雌二醇-3-乙酸酯是IVR递送ERT的首选前药。在体内，一个释放100微克/天雌二醇3-乙酸酯的IVR装置在超过84天的时间内将循环血浆浓度维持在300 pmol l⁻¹左右，处于ERT临床理想范围内。
