Design of an intravaginal ring for the controlled delivery of 17 beta-estradiol as its 3-acetate ester.
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.
Woolfson
A D
AD
School of Pharmacy, The Queen's University of Belfast, Medical Biology Centre, 97 Lisburn Road, Belfast, UK. d.woolfson@qub.ac.uk
Elliott
G R
GR
Gilligan
C A
CA
Passmore
C M
CM
D000282:Administration, Intravaginal; D003692:Delayed-Action Preparations; D016503:Drug Delivery Systems; D004355:Drug Stability; D004952:Esters / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry; D004958:Estradiol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000737:chemistry; D005260:Female; D006207:Half-Life; D006801:Humans; D006868:Hydrolysis; D011355:Prodrugs / Q000008:administration & dosage* / Q000737:chemistry
D003692:Delayed-Action Preparations; D004952:Esters; D011355:Prodrugs; C074283:estradiol 3-benzoate; D004958:Estradiol