A one year controlled release implant for the luteinizing hormone releasing hormone superagonist RS-49947. I. Implant characterization and analysis of in vitro results

Abstract RS-49947 ([ d -Nal 6 ,aza-Gly 10 ]-luteinizing hormone releasing hormone)-silicone elastomer implants exhibit one year of therapeutic drug release in the target species, the canine [1]. Twentyone batches of these nonerodible porous matrix implants were studied by in vitro methodology to assess the effects of drug loading level, gamma irradiation dose, drug particle size and implant size on drug release. In vitro release data as a function of drug loading level are consistent with percolation theory [2–4], or modified percolation theory for small implant size [5]. The implants exhibit a percolation threshold [6–8] at ca. 30–35% of drug raw material. Simple geometric considerations are consistent with observed drug particle and implant size effects on in vitro release results. This model is consistent with an RS-49947 drug particle diameter in the implant of 100 μm. The drug raw material used to make these implants exhibits a unique morphology. Each drug powder particle is an agglomerate of sub-μm sized spheroidal primary particles. The sub-structure to each drug powder particle suggests that contacts between drug particles in the implant would occur on two size scales: (1) inter-particle contacts on a tens or hundreds of μm scale, and (2) intra-particle (primary particle) contacts on a sub-μm scale. Consistent in vitro release results are achieved without any control of overall gross drug particle size. Deagglomeration of RS-49947 drug raw material during the implant manufacturing process could explain the consistent implant performance.