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. 2000 Jul 19;1(4):4–16. doi: 10.1208/pt010427

Evaluation of orntide microspheres in a rat animal model and correlation to in vitro release profiles

Janusz W Kostanski 1, Bhas A Dani 1, George-Ann Reynolds 2, Cyril Y Bowers 2, Patrick P DeLuca 1,✉
PMCID: PMC2750451  PMID: 14727892

Abstract

Orntide acetate, a novel luteinizing hormone-releasing hormone (LHRH) antagonist, was prepared and evaluated in vivo in 30-day and 120-day sustained delivery formulations using a rat animal model. Orntide poly(d,l- lactide-co-glycolide) (PLGA) and poly(d,l- lactide) (PLA) microspheres were prepared by a dispersion method and administered subcutaneously in a liquid vehicle to rats at 2.2 mg Orntide/kg of body weight (30-day forms) or 8.8 mg Orntide/kg (120-day forms). Serum levels of Orntide and testosterone were monitored by radioimmunoassays, and a dose-response study at 4 closes (3, 2.25, 1.5, and 1.75 mg Orntide/kg) was conducted to determine the effective dose of Orntide. Microspheres with diameters between 3.9 and 14 μ were prepared. The onset and duration of testosterone suppression varied for different microsphere formulations and were influenced both by polymer properties and by microsphere characteristics. Microspheres prepared with 50∶50 and 75∶25 copolymers effectively sustained peptide release for 14 to 28 days, whereas an 85∶15 copolymer and the PLA microspheres extended the pharmacological response for more than 120 days. Increase in drug load generally accelerated peptide release from the microspheres, resulting in higher initial serum levels of Orntide and shorter duration of the release: In general, apparent release was faster in vivo than under in vitro conditions. Orntide microspheres effectively suppressed testosterone in rats, providing rapid onset of release and extended periods of chemical castration. Testosterone suppression occurred immediately after microsphere administration without the initial elevation seen with LHRH superagonists.

Key Words: LHRH antagonist, Orntide acetate, Peptide controlled delivery, PLGA microspheres, Prostate cancer

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References

  • 1.Roeske RW, Chaturvedi NC, Hrinyo-Pavlina T, Kowalczuk M LHRH antagonist with low histamine releasing activity. In Vickery BH, Nestor JJ Jr.,LHRH and Its Analogs—Contraceptive and Therapeutic Applications (Part 2). MTP Press Limited; 1987:17–24.
  • 2.Weinbauer GF, Nieschlang E. LH-RH antagenists: state of the art and future perspectives. Recent Results Cancer Res. 1992;124:113–136. doi: 10.1007/978-88-470-2186-0_11. [DOI] [PubMed] [Google Scholar]
  • 3.Campen CA, Lai MT, Kraft P, Kirchner T, Phillips A, Hahn DW, Rivier J. Potent pituitary-gonadal axis suppression and extremely low anaphylactoid activity of a new gonadotropin releasing hormone (GnRH) receptor “azaline B”. Biochem Pharmacol. 1995;49(9):1312–1321. doi: 10.1016/0006-2952(95)00027-W. [DOI] [PubMed] [Google Scholar]
  • 4.Klingmuller D, Schepke M, Enzweiler C, Bidlingmaier F. Hormonal responses to the new potent GnRH antagonist Cetrorelix. Acta Endocrinol. 1993;128(1):15–18. doi: 10.1530/acta.0.1280015. [DOI] [PubMed] [Google Scholar]
  • 5.Chrisp P, Sorkin EM. Leuprorelin. A review of its pharmacology and therapeutic use in prostatic disorders. Drugs Aging. 1991;1(6):487–509. doi: 10.2165/00002512-199101060-00008. [DOI] [PubMed] [Google Scholar]
  • 6.Oesterling JE. LHRH agonists. A nonsurgical treatment for benign prostatic hyperplasia. J. Androl. 1991;12(6):381–388. [PubMed] [Google Scholar]
  • 7.Tunn UW, Bargelloni U, Cosciani S, Fiaccavento G, Guazzieri S, Pagano F. Comparison of LH-RH analogue 1-month depot and 3-month depot by their hormone levels and pharmacokinetic profile in patients, with advanced prostate cancer. Urol Int. 1998;60(Suppl.1):9–16. doi: 10.1159/000056540. [DOI] [PubMed] [Google Scholar]
  • 8.Garnick MB, Lipton A, Harvey A, Max DT, Smith JA, Glode LM. Trials with Leuprolide. In: Vickery BH, Nestor JJ Jr.LHRH and Its Analogs—Contraceptive and Therapeutic Applications (Part 1): MTP Press Limited, 1987:383–395.
  • 9.Kienle E., Lubben G. Efficacy and safety of leuprorelin acetate depot for prostate cancer: The German Leuprorelin Study Group. Urol Int. 1996;56(Suppl. 1):23–30. doi: 10.1159/000282865. [DOI] [PubMed] [Google Scholar]
  • 10.Thompson IM, Zeidman EJ, Rodriguez FR. Sudden death due to disease flare with luteinizing hormone-releasing homone ogonist therapy for carcinoma of the prostate. J Urol. 1990;144(6):1479–1480. doi: 10.1016/s0022-5347(17)39774-4. [DOI] [PubMed] [Google Scholar]
  • 11.Kostanski JW, Dani BA, Schrier B, DeLuca PP. Effect of the concurrent LHRH antagonist administration with a LHRH superagonist in rats. Pharm Res. 2000;17:445–450. doi: 10.1023/A:1007581004844. [DOI] [PubMed] [Google Scholar]
  • 12.Lanfrey P, Mottet N, Dagues F, Bennaoum K, Costa P, Louis JF, Navratil H. Hot flashes and hormonal treatment of prostate cancer. Prog Urol. 1996;6(1):17–22. [PubMed] [Google Scholar]
  • 13.Mahler C. Is disease flare a problem? Cancer. 1993;15(12 Suppl. 12):3799–3802. doi: 10.1002/1097-0142(19931215)72:12+<3799::AID-CNCR2820721707>3.0.CO;2-9. [DOI] [PubMed] [Google Scholar]
  • 14.Bruchovsky N, Goldenberg SL, Akakura K, Rennie PS. Luteinizing hornone-releasing hormone agonsts in prostate cancer. Elimination of flare reaction by pretreatment with cyproterone acetate and low-dose diethylstilbestrol. Cance r. 1993;72(5):1685–1691. doi: 10.1002/1097-0142(19930901)72:5<1685::aid-cncr2820720532>3.0.co;2-3. [DOI] [PubMed] [Google Scholar]
  • 15.Illions EH, Scott RT, Carey KD, Navot D. Evaluation of the impact of concurrent gonadotropin-releasing hormone (GnRH) antagonist administration on GnRH agonist-induced gonadotrope desensitization. Fertil Steri. 1995;64:848–854. doi: 10.1016/s0015-0282(16)57864-9. [DOI] [PubMed] [Google Scholar]
  • 16.Sharma OP, Weinbauer GF, Behre HM, Nieschlang E. The gonadotropin-releasing hormone (GnRH) agonist-induced initial rise of bioactive LH and testosterone can be blunted in a dose-dependent manner by GnRH antagonist in the non-human primate. Urol Res. 1992;20:317–321. doi: 10.1007/BF00922743. [DOI] [PubMed] [Google Scholar]
  • 17.Pinski J, Lamharzi N, Halmos G, et al. Chronic administration of the Luteinizing Hormone-Releasing Hormone (LHRH) antagonist Cetrorelix decreases gonadotrope responsiveness and pituitary LHRH receptor messenger ribonucleic acid levels in rats. Endocrimol. 1996;137:3430–3436. doi: 10.1210/en.137.8.3430. [DOI] [PubMed] [Google Scholar]
  • 18.Habenicht UF, Schneider MR, El Etreby MF. Effect of the new potent LH-RH antagonist, Antide. J. Steroid Biochem Mol Biol. 1990;37:937–942. doi: 10.1016/0960-0760(90)90447-S. [DOI] [PubMed] [Google Scholar]
  • 19.Reissmann T, Hilgard P, Harleman JH, Engel J, Comaru-Schally AM, Schally AV. Treatment of experimental DMBA induced mammary carcinoma with Cetrorelix (SB-75): a potent antagonist of luteinizing hormone—releasing hormone. J. Cancer Res Clin Oncol. 1992;118:44–49. doi: 10.1007/BF01192310. [DOI] [PubMed] [Google Scholar]
  • 20.Szende B, Sikalovic G, Groot K, Lapis K, Schally AV. Regtession of nitrosamide-induced pancreatic cancers in hamsters treated with luteinizing hormone-releasing hormone antagonists or agonists. Cancer Res. 1990;50:3716–3721. [PubMed] [Google Scholar]
  • 21.Szepeshazi K, Korkut E, Szende B, Lapis K, Schally AV. Histological changes in dunning prostate tumors and testes of rats treated with LH-RH antagonist SB-75. Prostate. 1991;18:255–270. doi: 10.1002/pros.2990180307. [DOI] [PubMed] [Google Scholar]
  • 22.Karten MJ, Rivier JE. Gonadotropin-releasing hormone analog design Structure- function studies toward the development of agonists and antagonists: rationale and perspective. Endocrinol Rev. 1986;7:44–66. doi: 10.1210/edrv-7-1-44. [DOI] [PubMed] [Google Scholar]
  • 23.Phillipa A, Hahn DW, McGiure JL, et al. Evaluation of the anaphylactoid activity of a new LHRH antagonist. Life Sci. 1988;43:883–888. doi: 10.1016/0024-3205(88)90263-9. [DOI] [PubMed] [Google Scholar]
  • 24.Rivier JE, Porter J, Rivier CL, et al. New effective gonadotropin releasing hormone antagonists with minimal potency for histamine releasein vitro. J Med Chem. 1986;29:1846–1851. doi: 10.1021/jm00160a008. [DOI] [PubMed] [Google Scholar]
  • 25.Folkers K, Bowers C, Xiao XSB, Tang PF, Kubota M. Increased potency of antagonists of the luteinizing hormone releasing hormone which have D-3-Pal in position 6. Bioche Biophy Res Commun. 1986;137:709–715. doi: 10.1016/0006-291X(86)91136-8. [DOI] [PubMed] [Google Scholar]
  • 26.Kostanski JW, Thanoo BC, DeLuca PP. Preparation, characterization and in vitro evaluation of I- and 4- month controlled release Orntide PLA and PLGA microspheres.Pharm Dev Tech. Vol. 5 No. 4, 2000. [DOI] [PubMed]
  • 27.Kostanski JW, DeLuca PP. A novel in vitro release technique for peptide-containing biodegradable microspheresPharmSciTech. 2000;1(1) Article 4 [DOI] [PMC free article] [PubMed]
  • 28.Okada H, Doken Y, Ogawa Y, Toguchi H. Preparation of three-month depot injectable microspheres of Leuprorelin acetate using biodegradable polymers. Pharm Res. 1994;11(8):1143–1147. doi: 10.1023/A:1018936815654. [DOI] [PubMed] [Google Scholar]
  • 29.Csernus VJ, Szende B, Schally AW. Release of peptides from sustained delivery (microcapsules and microparticles) in vivo. A histological and immunohistochemical study. Int J Peptide Protein Res. 1990;35:557–565. doi: 10.1111/j.1399-3011.1990.tb00262.x. [DOI] [PubMed] [Google Scholar]
  • 30.Blanco-Prieto MJ, Besseghir K, Orsolini P, et al. Importance of the test medium for the release kinetics of a somatostatin analogue from poly(D,L-lactide-co-glycolide) microspheres. Int J Pharm. 1999;184(2):243–250. doi: 10.1016/S0378-5173(99)00118-0. [DOI] [PubMed] [Google Scholar]
  • 31.Holland SJ, Tighe BJ, Gould PL. Polymers for biodegradable medical devices 1. The potential of polyesters as controlled macromolecular release systems. J Controlled Releas e. 1986;4:155–180. doi: 10.1016/0168-3659(86)90001-5. [DOI] [Google Scholar]
  • 32.Makino K, Arakawa M, Kondo T Preparation and in vitro degradation properties of polylactide microcapsules.Chem. Pharm Bull 33(3):1195–1201. [DOI] [PubMed]
  • 33.Mader K, Bittner B, Li Y, Wohlauf W, Kissel T. Monitoring microviscosity and microacidity of the albunm microenviroument inside degrading microparticles from poly(lactide-co-glycolide) (PLG) or ABA-triblock polymers containing hydrophobic poly(lactide-co-glycolide) A Blocks and hydrophilic poly(ethyleneoxide) B blocks. Pharm Res. 1998;15(6):787–793. doi: 10.1023/A:1011939607573. [DOI] [PubMed] [Google Scholar]
  • 34.Makino K, Ohshima H, Kondo T. Potential distribution across a plasma protein-coated poly(L-lactide) microcapsule surface. J Microencapsulation. 1990;7(2):199–208. doi: 10.3109/02652049009021833. [DOI] [PubMed] [Google Scholar]
  • 35.Makino K, Ohshima H, Kondo T. Effects of plasma proteins on degradation properties of poly(1- lactide) microcapsules. Pharm. Res. 1987;4(1):62–65. doi: 10.1023/A:1016438129284. [DOI] [PubMed] [Google Scholar]
  • 36.Kenley RA, Lee MO, Randolph Mahoney T. Sanders LM Poly(lactide-co-glycolide) decomposition kinetics in vivo and in vitro. Macromolecules. 1987;20(10):2398–2403. doi: 10.1021/ma00176a012. [DOI] [Google Scholar]

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