Release-modulating factors strongly affecting steroid diffusion from silicone elastomer
Nash,Harold A.; Robertson,Dale N.; Evans,Simone J.
Journal of Pharmaceutical Sciences 93(10): 2420-2430
Publication date: 2004
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 6-hydroxy-levonorgestrel (6-OH-LNG). Added to LNG at the 2% level, 6-OH-LNG decreased the release rate by 27%.