Use of GnRH agonists to support the luteal phase during infertility treatment

• US 7,671,027 B2
• Filed: 12/29/2003
• Issued: 03/02/2010
• Est. Priority Date: 12/27/2002
• Status: Expired due to Fees

• Current Assignee: PregLem SA (Chemical Works of Gedeon Richter Plc)
• Original Assignee: PregLem SA (Chemical Works of Gedeon Richter Plc)
• Inventors: Loumaye, Ernest
• Primary Examiner(s): Weber; Jon P
• Assistant Examiner(s): Mohamed; Abdel A
• Application Number:
  US10/540,228
• Publication Number:
  US 20060069031A1
• Time in Patent Office: 2,255 Days
• Field of Search: 514/15, 514/12, 530/313, 530/328, 530/398, 530/399, 424/559, 424/561, 424/562
• US Class Current: 514/1.1
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/138 Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine atenolol A61K31/165; pindolol A61K31/404; timolol A61K31/5377
• CPC Class Codes: A61K 31/381 having five-membered rings
• CPC Class Codes: A61K 31/4196 1,2,4-Triazoles
• CPC Class Codes: A61K 31/522 having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
• CPC Class Codes: A61K 31/566 having an oxo group in position 17, e.g. estrone
• CPC Class Codes: A61K 31/57 substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
• CPC Class Codes: A61K 38/09 Luteinising hormone-releasing hormone [LHRH] , i.e. Gonadotropin-releasing hormone [GnRH]; Related peptides
• CPC Class Codes: A61K 38/2093 Leukaemia inhibitory factor [LIF]
• CPC Class Codes: A61K 38/24 Follicle-stimulating hormone [FSH]; Chorionic gonadotropins, e.g. HCG; Luteinising hormone [LH]; Thyroid-stimulating hormone [TSH]
• CPC Class Codes: A61K 38/25 Growth hormone-releasing factor [GH-RF], i.e. somatoliberin
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 15/08 for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis

Abstract

The present invention concerns the use of an agonist of an hypothalamic hormone for the preparation of a pharmaceutical agent to support the luteal phase during infertility treatment of female mammals and more specifically of woman. According to this invention, the pharmaceutical agent is suitable to be used for supporting the luteal phase after a spontaneous ovulation or after stimulation of follicular growth, trigger of final follicular maturation and ovulation with one or several additional agents.

Claims

1. A method of treating infertility in a female mammal comprising administering a pharmaceutical agent comprising a gonadotrophin releasing hormone (GnRH) agonist in an amount and for a time sufficient to support the luteal phase, wherein the GnRH agonist is administered to the female mammal beginning within the first three days after ovulation in the female mammal and for at least 7 days thereafter either

i) after spontaneous ovulation in the female mammal, or

ii) after stimulation of follicular growth and triggering of final follicular maturation followed by an ovulation in the female mammal by administration of at least one additional agent,

such that infertility is treated in the female mammal.

2. The method according to claim 1, wherein the additional agent administered to trigger final follicular maturation and ovulation is a GnRH agonist different from the GnRH agonist administered to support the luteal phase.

3. The method according to claim 1, wherein the pharmaceutical agent which supports the luteal phase is administered after administration of a GnRH antagonist during the last days of follicular growth stimulation.

4. The method according to claim 1, wherein the pharmaceutical agent which supports the luteal phase is administered in combination with another luteal support agent selected from the group consisting of natural progesterone, a progestagen, human chorionic gonadotropin (hCG), luteinizing hormone (LH), one or more isoforms of LH or of hCG, a peptidomimetic of LH or of hCG, an LH or an hCG analog with a modified pharmacokinetic, a phosphodiesterase inhibitor, a non-peptidic modulator of cyclicAMP, and a combination of two or more of these agents.

5. The method according to claim 1, wherein the stimulation effected by the administration of the additional agent is followed, after ovulation trigger, with an intra-uterine insemination (IUI).

6. The method according to claim 1, wherein the GnRH agonist route of administration is selected from the group consisting of intra-nasal, oral, sub-cutaneous, intra-muscular, vaginal, rectal, transdermal, and pulmonary.

7. The method according to claim 1, wherein the additional agent triggering final follicular maturation and ovulation is selected from the group consisting of hCG, LH, one or more isoforms of hCG or LH, hCG and LH peptido-mimetics, hCG and LH analogs with a modified pharmacokinetic, phosphodiesterase inhibitors, and a combination of two or more of these agents.

8. The method according to claim 1, wherein the female mammal is a woman.

9. The method according to claim 1, wherein the administration of the GnRH agonist sufficient to support the luteal phase is for a duration of 7 to 14 days.

10. The method according to claim 1, wherein the administration of the GnRH agonist sufficient to support the luteal phase is for a duration of up to 28 days in a female mammal that has conceived.

11. The method according to claim 1, wherein the pharmaceutical agent which supports the luteal phase is administered in combination with a cytokine involved in embryo implantation mechanisms.

12. The method according to claim 11, wherein the cytokine is selected from the group consisting of native Leukemia Inhibitory Factor (LIF), recombinant LIF, a peptidic or a non-peptidic agonist analog of LIF, and a combination thereof.

13. The method according to claim 1, wherein the additional agent administered to trigger final follicular maturation and ovulation is a GnRH agonist which is the same as the GnRH agonist administered to support the luteal phase.

14. The method according to claim 13, wherein the GnRH agonist is buserelin and is administered intra-nasally, at least once, at a dose of between 50 and 600 μ

g.

15. The method according to claim 14, wherein buserelin is administered intra-nasally at a dose of 200 μ

g.

16. The method according to claim 1, wherein the GnRH agonist is selected from the group consisting of a natural (native) GnRH, a recombinant GnRH, a synthetic peptide agonist of GnRH, a non-peptide GnRH agonist, and a molecular chimera of GnRH.

17. The method according to claim 16, wherein the synthetic peptide is selected from the group comprising buserelin(e), nafarelin(e), triptorelin(e), leuprorelin(e), goserelin(e), deslorelin(e) and histrelin(e), analogs thereof, and a combination of two or more of these agonists.

18. The method according to claim 17, wherein the GnRH agonist is buserelin.

19. The method according to claim 1, wherein the stimulation effected by the administration of the additional agent is followed, before ovulation, by an oocyte retrieval procedure, wherein at least one oocyte is obtained.

20. The method according to claim 19, wherein the oocyte undergoes an in vitro maturation.

21. The method according to claim 19, wherein the oocyte undergoes an in vitro fertilization.

22. The method according to claim 1, wherein the additional agent stimulating follicular growth is selected from the group comprising human menopausal gonadotrophins (hMG), urine-derived follicle stimulating hormone (FSH), recombinant FSH, one or several FSH isoforms, FSH mimetics, FSH analogs with a modified phamacokinetic, selective estrogen receptors modulators (SERM), aromatases inhibitors, phosphodiesterase inhibitors, and a combination of two or more of these agents.

23. The method according to claim 22, wherein the SERM is selected from the group consisting of clomiphen(e), tamoxifen(e), raloxifen(e), and a combination of two or more of these agents.

24. The method according to claim 22, wherein the aromatase inhibitor is selected from the group consisting of anastrozole, letrozole, exemestane, and a combination of two or more of these agents.

25. The method according to claim 22, wherein the phosphodiesterase inhibitor is theophyline.

26. A method of treating infertility in a female mammal comprising administering a pharmaceutical agent which comprises a GnRH agonist comprising buserelin, which supports luteal phase after stimulation of follicular growth and induction of final follicular maturation and ovulation with one or more additional agents, wherein said buserelin is administered intra-nasally within the first three days following ovulation trigger at a dose of between 50 and 400 μ

g and at a frequency between three times a day and once every three days for a duration of 7 to 14 days, such that infertility in the female mammal is treated.

27. The method according to claim 26, wherein buserelin is administered on the first day following ovulation trigger.

28. The method according to claim 26, wherein buserelin is administered at a dose of 100 μ

g.

29. The method according to claim 26, wherein buserelin is administered for a duration of 14 days.

30. A method of treating infertility in a female mammal comprising administering a pharmaceutical agent which comprises a GnRH agonist comprising buserelin, which supports luteal phase after stimulation of follicular growth and induction of final follicular maturation and ovulation with one or more additional agents, wherein said buserelin is administered intra-nasally within the first three days following ovulation trigger at a dose of between 50 and 400 μ

g and at a frequency between three times a day and once every three days for a duration of up to 28 days in a female mammal that has conceived, such that infertility in the female mammal is treated.