Search tips
Search criteria 


Logo of aapspharmspringer.comThis journalToc AlertsSubmit OnlineOpen Choice
AAPS PharmSciTech. 2000 March; 1(1): 1–8.
Published online 2015 February 19. doi:  10.1208/pt010101
PMCID: PMC2784829

Sustained activity and release of leuprolide acetate from an in situ forming polymeric implant


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 commercial microsphere product. Evaluated implant formulations contained 45% w/w 75/25 poly (DL-lactide-coglycolide) 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.

Keywords: Polymeric Implant, Leuprolide Acetate, Dog, Sustained Release, Testosterone Suppression

Full Text

The Full Text of this article is available as a PDF (157K).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
1. Plosker GL, Brodgen RN. Leuprorelin. A review of its pharmacology and therapeutic use in prostate cancer, endometriosis and other sex hormone-related disorders. Drugs. 1994;48(6):930–967. doi: 10.2165/00003495-199448060-00008. [PubMed] [Cross Ref]
2. Garnick MBfor the Leuprolide Study Group Leuprolide versus diethylstilbestrol for metastatic cancer. N Engl J Med. 1984;311:1281–1286. doi: 10.1056/NEJM198411153112004. [PubMed] [Cross Ref]
3. Okada H, Sakura Y, Kawaji T, Yashiki T, Mima H. Regression of rat mammary tumors by a potent leutinizing hormone-releasing hormone (Leuprolide) administered vaginally. Cancer Res. 1983;43:1869–1874. [PubMed]
4. Redding TW, Schally AV. Inhibition of prostate tumor growth in two rat models by chronic administration of D-Trp6 analogue of leutinizing hormone-releasing hormone. Proc Natl Acad Sci U S A. 1981;78:6509–6512. doi: 10.1073/pnas.78.10.6509. [PubMed] [Cross Ref]
5. Lemay A, Quesnel G. Potential new treatment of endometriosis: reversible inhibition of pituitary-ovarian function by chronic intranasal administration of a leutinizing hormone-releasing hormone (LHRH) agonist. Fertil. Steril. 1982;38:376–379. [PubMed]
6. Sharifi R, Soloway M. Clinical study of leuprolide depot formulation in the treatment of advanced prostate cancer. J Urol. 1990;143:68–71. [PubMed]
7. Okada H, Heya T, Ogawa Y, Toguchi H, Shimamoto T. Sustained pharmacological activities in rats following single and repeated administration of once-a-month injectable microspheres of leuprolide acetate. Pharm Res. 1991;8(5):584–587. doi: 10.1023/A:1015844421319. [PubMed] [Cross Ref]
8. Okada H, Toguchi H. Biodegradable microspheres in drug delivery. Crit Rev Ther Drug Svs. 1995;12(1):1–99. doi: 10.1615/CritRevTherDrugCarrierSyst.v12.i1.10. [PubMed] [Cross Ref]
9. Dunn RL, English JP, Cowsar DR, Vanderbilt DP, inventors; Atrix Laboratories, Inc., Fort Collins, CO assignee. Biodegradable in situ forming implants and methods of producing the same. US Patent No. 4938 763. July 3, 1990.
10. Dunn RL, Tipton AJ, Menardi EM. A Biodegradable In-Situ Forming Drug Delivery System. In: Jones A, Smith B, eds. Proceed. Intern. Symp. Control Rel. Bioact. Mater., 18 (1991) pp 222–235.
11. Lee KP, Chromey NC, Culik R, Barnes JR, Schneider PW. Toxicity of N-methyl-2-pyrrolidone (NMP): Teratogenic, subchronic, and two year inhalation studies. Fundam. Appl. Toxicol. 1987;9:222–235. doi: 10.1016/0272-0590(87)90045-5. [PubMed] [Cross Ref]
12. Ravivarapu HB, Moyer KL, Dunn RL. Sustained suppression on pituitary-gonodal axis with an injectable, in situ forming implant of leuprolide acetate. In press. [PubMed]
13. Ravivarapu HB, Moyer KL, Dunn RL. Parameters affecting the efficacy of a sustained release polymeric implant of leuprolide. In press. [PubMed]
14. Okada H, Inoue Y, Heya T, Ueno H, Ogawa Y, Toguchi H. Pharmacokinetics of once-a-month injectable microspheres of leuprolide acetate. Pharm. Res. 1991;8(6):787–791. doi: 10.1023/A:1015818504906. [PubMed] [Cross Ref]
15. Athanasiou KA, Niederauer GG, Agrawal CM. Sterilization toxicity, biocompatibility and clinical applications of polylactic acid/polyglycolic acid copolymers. Biomaterials. 1996;17:93–102. doi: 10.1016/0142-9612(96)85754-1. [PubMed] [Cross Ref]
16. Tunn UW, Bargelloni U, Cosciani S, Fiaccavento G, Pagano F. Comparison of LHRH analogue 1-month depot and 3-month depot by their hormonal levels and pharmacokinetic profile in patients with advanced prostate cancer. Urol Int. 1998;1:9–16. doi: 10.1159/000056540. [PubMed] [Cross Ref]
17. DeLuca PP, Mehta RC, Hausberger AG, Thanoo BC. Biodegradable Polyesters for Drug and Polypeptide Delivery. In: El-Nokaly MA, Piatt DM, Charpentier BA, editors. Polymeric Delivery Systems, Properties and Applications. Washington, DC: American Chemical Society; 1993. pp. 53–79.
18. Mehta RC, Thanoo BC, DeLuca PP. Peptide containing microspheres from low molecular weight and hydrophilic poly (dl-lactide-coglycolide) J Control Rel. 1996;41:249–257. doi: 10.1016/0168-3659(96)01332-6. [Cross Ref]
19. Ravivarapu HB, Lee H, DeLuca PP. Enhancing initial release of peptide from PLGA microspheres by addition of a porosigen and increasing drug load. Pharm Dev Tech. 2000;5(2):281–190. doi: 10.1081/PDT-100100543. [PubMed] [Cross Ref]

Articles from AAPS PharmSciTech are provided here courtesy of American Association of Pharmaceutical Scientists