Design of an intravaginal ring for the controlled delivery of 17b-estradiol as its 3-acetate ester

Suitable ester prodrugs of 17b-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 17b-estradiol or an ester prodrug, the mix being activated with 0.5% w/w stannous octoate and cured at 808C 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 17b-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 17b-estradiol-3-acetate was the prodrug of choice for IVR delivery of ERT. In vivo, an IVR device releasing
100 mg/day of estradiol as its 3-acetate ester maintained over 84 days a circulating plasma concentration in the region of 300 pmol l , within the clinically desirable range for ERT.

Wasp-17b: An Ultra-Low Density Planet in a Probable Retrograde Orbit

We report the discovery of the transiting giant planet WASP-17b, the least-dense planet currently known. It is 1.6 Saturn masses, but 1.5-2 Jupiter radii, giving a density of 6%-14% that of Jupiter. WASP-17b is in a 3.7 day orbit around a sub-solar metallicity, V = 11.6, F6 star. Preliminary detection of the Rossiter-McLaughlin effect suggests that WASP-17b is in a retrograde orbit (? ˜ -150°), indicative of a violent history involving planet-planet or star-planet scattering. WASP-17b's bloated radius could be due to tidal heating resulting from recent or ongoing tidal circularization of an eccentric orbit, such as the highly eccentric orbits that typically result from scattering interactions. It will thus be important to determine more precisely the current orbital eccentricity by further high-precision radial velocity measurements or by timing the secondary eclipse, both to reduce the uncertainty on the planet's radius and to test tidal-heating models. Owing to its low surface gravity, WASP-17b's atmosphere has the largest scale height of any known planet, making it a good target for transmission spectroscopy.