Date Published: January 17, 2013
Publisher: Hindawi Publishing Corporation
Author(s): Ying Zhang, Chun-Xiao Li, Mei-Ying Ning, Xue-Yan Duan, Ying Liu.
In the present study, we investigated the feasibility of the vaginal administration of drospirenone silicone IVR. The in vitro release characteristics of matrix-type and reservoir-type IVR were compared under sink conditions in 21 days. At the same time, API excipients compatibility and preformulation study was performed by HPLC, IR, and DSC methods. Biocompatibility of reservoir system was evaluated by tolerability on tissue level in rats. It was found that, under strong light exposure, high temperature, and high humidity conditions, drospirenone and excipients had no significant interactions. The daily release of reservoir-type IVR was about 0.5 mg/d sustaining 21 days, which significantly decreased the burst effect compared with the matrix system. When drospirenone was modified by the PVPk30 in the reservoir system formulation, the daily release rate increased to 1.0 mg/d sustaining 21 days. The cumulative release of reservoir-type IVR was fitted to zero release equation. In addition, biocompatibility of drospirenone IVR system in this dosage is safe. It is feasibility feasibile to further developed for safe, convenient, and effective contraceptive drug delivery with reduced dosing interval.
Drospirenone (6b,7b,15b,16b-dimethylene-3-oxo-17a-pregn-4-ene-21,17-carbolactone) is an analogue of the antimineralocorticoid spironolactone (Figure 1) that is synthesized from androstenolone. Unlike other progestogens, drospirenone, an analogue of spironolactone, has biochemical and pharmacologic profiles similar to endogenous progesterone, especially regarding antimineralocorticoid and antiandrogenic activities. Drospirenone counteracts the estrogen-induced stimulation of the renin-angiotensin-aldosterone system and blocks testosterone from binding to androgen receptors. Because of these characteristics, it has the potential to reduce body weight, blood pressure, and low-density lipoprotein levels and to enhance high-density lipoprotein levels. As a combination, oral contraceptive, drospirenone with ethinyl estradiol, is effective and has positive effects on weight and lipid levels .
Intravaginal ring (IVR) containing drospirenone is one kind of vaginal ring devices, and the drug-loaded core was obtained by using hot vulcanization method with silicone elastomer as the matrix polymer, which was encapsulated by the same kind of polymer membrane. A method for this preparation of drospirenone reservoir system was obtained by adding PVPk30 additives to increase drospirenone solubility. Drospirenone was used as the active pharmaceutical ingredient and silicone elastomer as matrix and controlled release membrane agent. PVPk30 was used as increasing drospirenone solubility and without resulting in the drospirenone degradation detected by HPLC gradient method. Under strong light, high temperature, and high humidity conditions, drospirenone raw materials and formulation excipients PVPk30 and silicon rubber had no significant interactions and indicate good compatibility. It is found that the drospirenone release rate was increasing with the PVPk30 amount at a constant range. Silicone elastomer was also employed as membrane for controlling membrane permeability. In vitro drug release testing was conducted in a dissolution apparatus, the release medium was 200 mL 0.3% SDS meeting with sink conditions, and release samples were determined by the UV-Vis spectrophotometry. The daily release of reservoir system of drospirenone IVR was about 0.5 mg, which sustained 21 days at this release rate and significantly decreased burst effect compared with matrix system. When the drug is modified by PVPk30 in the reservoir system formulation, the daily release quantity increased and sustained 21-days at the release rate of 1.0 mg/d. The cumulative release of reservoir of drospirenone IVR was fitted to zero release equation. In addition, drospirenone IVR system was evaluated by tolerability on tissue level in rat. Drospirenone IVR did not affect the morphology of vaginal tissues.