Parameters affecting the efficacy of a sustained release polymeric implant of leuprolide.
The objective of this study was to evaluate the formulation parameters critical to the efficacy of an injectable polymeric implant of leuprolide acetate, formed in situ, in suppressing and maintaining serum testosterone levels of animals in the range 0.5 ng/ml for over 90 days. The formulation evaluated contained 45% (w/w) 75/25 poly (DL-lactide-co-glycolide) polymer having an intrinsic viscosity of 0.20 dl/g, dissolved in 55% (w/w) N-methyl-2-pyrrolidone with 3% (w/w) leuprolide acetate added either as a homogeneous solution or a two-part suspension (A/B) system, in which the drug was dispersed within the polymer solution immediately prior to use. The formulation parameters evaluated in this study included polymer molecular weight, polymer concentration, and drug loading. Both rat and dog models were used to evaluate efficacy. Serum testosterone was assayed by radioimmunoassay to determine efficacy, and retrieved implants from the rats at the termination of the study were analyzed by HPLC for residual drug content to determine the extent of drug release. With the candidate formulation, testosterone levels in dogs diminished to the targeted levels of 0. 5 ng/ml by day 14 and remained suppressed up to day 91, reproducing the results seen in rats. Variations in polymer concentration (40-50%), and drug load (3-6% (w/w)) did not have a significant effect on the apparent level and duration of efficacy. However, employing lower molecular weight polymer decreased the duration of efficacy of the formulation.
Ravivarapu
H B
HB
Atrix Laboratories, Incorporated, 2579 Midpoint Drive, Fort Collins, CO 80525, USA. hraviv@atrixlab.com
Moyer
K L
KL
Dunn
R L
RL
D000818:Animals; D003692:Delayed-Action Preparations; D004285:Dogs; D004343:Drug Implants; D006801:Humans; D019344:Lactic Acid / Q000008:administration & dosage; D016729:Leuprolide / Q000008:administration & dosage* / Q000494:pharmacology; D008297:Male; D011100:Polyglycolic Acid / Q000008:administration & dosage; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011108:Polymers / Q000008:administration & dosage; D051381:Rats; D017207:Rats, Sprague-Dawley; D013535:Suspensions; D013739:Testosterone / Q000097:blood
D003692:Delayed-Action Preparations; D004343:Drug Implants; D011108:Polymers; D013535:Suspensions; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D013739:Testosterone; D016729:Leuprolide