A one year controlled release implant for the luteinizing hormone releasing hormone superagonist RS-49947. II. Clinical performance results

Abstract

A small macroporous nonerodible matrix implant supplying therapeutic levels of the decapeptide drug RS-49947 ([ d-Nal(2) 6,aza-Gly 10]-luteinizing hormone releasing hormone) for one year is described and analyzed. The implant is indicated for estrus or male sexual behavior suppression (reversible chemical castration), or for the treatment of sex hormone dependent diseases in the canine or feline. These small (55 mg) slab devices are implanted below the ventral surface skin of the animal through a small incision, and can be removed or replaced at the end of one year of therapy. The optimal system contains 41% of water soluble drug raw material (33.6% theoretical of RS-49947 free base) dispersed in Silastic 382 silicone elastomer. Plasma levels of drug and clinical performance parameters in the canine are presented for the optimal formulation and for formulations containing higher (44% drug solubles) and lower (39% drug solubles) percentages of drug raw material. Formulations containing 39% or 41% of drug raw material release in vivo by an unanticipated apparent zero order release mechanism. Comparison of clinical and in vitro data suggests that in vivo itmechanisms may control drug release rates from these systems. In vitro data for these implants are consistent with current knowledge of macroporous implants, while the in vivo data show anomalous drug release durations and profile shapes. Hypotheses for the differences between in vitro and in vivo drug release are presented. The drug raw material used to manufacture these implants exhibits a unique morphology, which may further complicate understanding of the in vivo release results. In vitro data for these systems give some insight into in vivo release, although the mechanisms of in vitro and in vivo drug release apparently differ.