Release-modulating factors strongly affecting steroid diffusion from silicone elastomer.

Investigations were undertaken to determine the cause of decreases over time in the release rate from levonorgestrel (LNG) implants consisting of silicone elastomer tubing filled with crystalline steroid. Emptying and refilling with the same steroid partially restored release rate. Surprisingly, a further increment in release rates was attained if the tubing was briefly irrigated with methanol before refill. Fractional crystallization showed that release-modulating factors could be concentrated in mother liquors and were initially present as impurities. Boiling LNG in ethanol or methanol produced a number of release-modulating factors of which the most prominent was also found in one production lot of LNG. It was identified as 6beta-hydroxy-levonorgestrel (6beta-OH-LNG). Added to LNG at the 2% level, 6beta-OH-LNG decreased the release rate by 27%.

Estradiol-progesterone interaction during the preparation of vaginal rings.

An unexpected enhanced release, in vitro, of estradiol (E2) was observed on the preparation of vaginal rings containing E2 and progesterone (P) in a silicone elastomer. The present work deals with exploring the reason(s) behind this enhanced E2 release. The effect of the ring design (i.e., putting P and E2 in the same compartment or in adjacent or separate compartments) was studied. The effects of the curing temperature as well as the curing time were also investigated. The possible interaction(s) between P and E2 on simple heating of their mixtures was investigated using infrared (IR), differential scanning calorimetry (DSC), and nuclear magnetic resonance (NMR) techniques. Also, the dissolution behavior of P, E2, and their mixture before and after heating was studied. The ring design, with respect to the position of the steroid layer(s), affected the release of P and E2 from the vaginal rings. Curing the rings at higher temperatures (>/=140 degrees C) for >/=30 min resulted in an enhanced release of the steroids, especially E2. The IR, DSC, phase diagram, and NMR results indicate that an interaction between P and E2, leading to the formation of a molecular complex, took place. It was concluded that putting P and E2 in the same compartment and curing by heating at a high temperature and for an extended time promoted this kind of interaction. The greater hydrophobicity of the interaction product, relative to that of E2, was considered the main reason behind the enhanced in vitro release of E2 from the vaginal rings.

Vaginal rings delivering progesterone and estradiol may be a new method of hormone replacement therapy.

OBJECTIVE: To determine whether a low dose of P delivered together with E(2) from a vaginal ring on a continuous schedule can prevent endometrial proliferation and yield a bleeding pattern dominated by amenorrhea. DESIGN: Longitudinal clinical study. SETTING: Three university hospitals. PATIENT(S): Fifty-five women 45 to 75 years of age, not hysterectomized, with E(2) levels of <20 pg/mL and hot-flash incidence of two or more per day in the past week. INTERVENTION(S): A vaginal ring delivering approximately 150 microg/d of 17beta-E(2) and approximately 5 mg/d or approximately 9 mg/d of P used continuously for 4 and 6 months. MAIN OUTCOME MEASURE(S): Endometrial thickness, bleeding pattern, and hot flash incidence. RESULT(S): Endometrial proliferation was prevented by both P doses. Bleeding incidence decreased. In months 4, 5, and 6, 8 of 12 women had no bleeding. Incidence of hot flashes and night sweats decreased quickly and significantly. CONCLUSION(S): A vaginal ring delivering E(2) and a low dose of P merits further study as a method for long-term hormone replacement therapy.