title: Sustained activity and release of leuprolide acetate from an in situ forming polymeric implant.
abstract: The primary objective of this study was to evaluate the effect of drug loading on the release of leuprolide acetate from an injectable polymeric implant, formed in situ, and efficacy of the released drug in suppressing serum testosterone levels in dogs for at least 90 days. An additional objective was to compare the optimum implant formulation with a commercial microsphere product. Evaluated implant formulations contained 45% w/w 75/25 poly (DL-lactide-co-glycolide) polymer having an intrinsic viscosity of 0.20 dL/g, dissolved in N-methyl-2-pyrrolidone. Irradiated polymer solution was mixed with leuprolide at different drug loads (3%, 4.5%, and 6% w/w) prior to subcutaneous administration to dogs. Dog serum was analyzed for testosterone (RIA) and leuprolide (LC/MS/MS) levels and comparisons within the three implant formulation groups were made. Varying the drug load did not significantly affect the release of leuprolide or efficacy of the implant formulation. Thus, the 6% w/w formulation with the smaller injection volume was selected for comparison with the commercial LUPRON Depot product, which was administered intramuscularly at a similar dosage. These comparisons of serum testosterone and leuprolide levels showed no significant difference in the pharmacologic efficacy even though drug levels were different at a number of points. This was mainly due to associated high standard deviations. Based on these studies, the 6% w/w leuprolide implant formulation was considered to be a suitable candidate for further development. Additional benefits of this system include its simple manufacturing and lower costs.
authors.affiliation: Atrix Laboratories, Inc, 2579 Midpoint Drive, Fort Collins, CO 80525, USA. Hraviv@atrixlab.com
authors.forename: H B
authors.initials: HB
authors.lastname: Ravivarapu
authors.forename: K L
authors.initials: KL
authors.lastname: Moyer
authors.forename: R L
authors.initials: RL
authors.lastname: Dunn
mesh_terms: D000818:Animals; D003692:Delayed-Action Preparations / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D004285:Dogs; D004343:Drug Implants / Q000737:chemistry; D005300:Fertility Agents, Female / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D016729:Leuprolide / Q000097:blood / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D008297:Male; D008970:Molecular Weight; D011108:Polymers / Q000737:chemistry*; D019736:Prostheses and Implants; D013739:Testosterone / Q000097:blood
chemical_list: D003692:Delayed-Action Preparations; D004343:Drug Implants; D005300:Fertility Agents, Female; D011108:Polymers; D013739:Testosterone; D016729:Leuprolide