Antagonistic peptides of GnRH having improved water solubility are disclosed. These peptides are capable of suppressing serum testosterone levels in vivo to chemical castration levels of ≦0.5 ng/ml. Stable, filter sterilizable, non-gelling solutions containing the GnRH antagonists at least at levels
Antagonistic peptides of GnRH having improved water solubility are disclosed. These peptides are capable of suppressing serum testosterone levels in vivo to chemical castration levels of ≦0.5 ng/ml. Stable, filter sterilizable, non-gelling solutions containing the GnRH antagonists at least at levels typically used in sustained release formulations also are disclosed, as is a method of increasing the solubility of GnRH antagonist in a polymer containing dispersed phase, which method comprises addition of an acid to the dispersed phase.
대표청구항▼
1. A gonadotropin releasing hormone antagonist having the formula: AcDNal1, DpCIPhe2, D3Pal3 Ser4, NicLys5, D(6ANic)Orn6, Pro9, DAla10NH2. 2. A gonadotropin releasing hormone antagonist having the formula: AcDNal1, DpCIPhe2, D3Pal3 Ser4, NicLys5, D(6ANic)Orn6, Leu7, IprLys8, Pro9, DAla10NH2. 3. A ph
1. A gonadotropin releasing hormone antagonist having the formula: AcDNal1, DpCIPhe2, D3Pal3 Ser4, NicLys5, D(6ANic)Orn6, Pro9, DAla10NH2. 2. A gonadotropin releasing hormone antagonist having the formula: AcDNal1, DpCIPhe2, D3Pal3 Ser4, NicLys5, D(6ANic)Orn6, Leu7, IprLys8, Pro9, DAla10NH2. 3. A pharmaceutical composition comprising the antagonist of claim 2 and a pharmaceutically acceptable carrier or diluent. 4. A method of suppressing testosterone levels in a mammal comprising administering to the mammal the antagonist or composition as in any of the preceding claims in an amount sufficient to achieve suppression of said levels in the mammal compared to an untreated mammal. 5. The method of claim 4, wherein the antagonist or composition is administered subcutaneously. 6. The method of claim 4, wherein the mammal is a human. 7. A method for antagonizing gonadotropin releasing hormone in a mammal suffering from said hormone related disorder comprising administering an effective amount of a composition comprising a GnRH antagonist to the mammal, wherein said antagonist is AcDNal1, DpCIPhe2, D3Pal3 Ser4, NicLys5, D(6ANic)Orn6, Leu7, IprLys8, Pro9, DAla10NH2. 8. The method of claim 7, wherein said disorder is a testosterone dependent disorder, benign prostate hypertrophy or prostate cancer. 9. The method of claim 7, wherein said composition is administered subcutaneously. 10. The method of claim 6, wherein said mammal is a human. 11. A method for reversible suppression of male fertility comprising treating a male with an effective amount of a composition comprising a GnRH antagonist to the mammal, wherein said antagonist is AcDNal1, DpCIPhe2, D3Pal3 Ser4, NicLys5, D(6ANic)Orn6, Leu7, IprLys8, Pro9, DAla10NH2, wherein male fertility is restored after cessation of treatment with said antagonist. 12. The method of claim 10, wherein the amount of antagonist in the composition is from about 0.09 to 2.5 mg per kilogram of body weight per day. 13. The method of claim 11, wherein the amount of antagonist in the composition is about 0.09 mg per kilogram of body weight per day. 14. A composition for a dispersed phase formulation comprising a gonadotropin releasing hormone (GnRH) antagonist having the formula: AcDNal1, DpCIPhe2, D3Pal3 Ser4, NicLys5, D(6ANic)Orn6, Leu7, IprLys8, Pro9, DAla10NH2, and an acid additive consisting of one or more acids having a pKa of 5.0 or lower. 15. The composition of claim 14, wherein the GnRH analog is a freeze-dried GnRH antagonist. 16. The composition of claim 14, wherein the acid additive is an organic or an inorganic acid additive or a combination thereof. 17. The composition of claim 16, wherein the organic or inorganic acid additive is one acid. 18. The composition of claim 17, wherein the organic acid additive is selected from the group consisting of: glacial acetic acid, lactic acid, glycolic acid, glyceric acid, benzoic acid, propanoic acid, methane sulfonic acid, and mesitylic acid or a combination of these acids. 19. The composition of claim 17, wherein the inorganic acid additive is HCl. 20. The composition of claim 14, wherein the composition further comprises a biocompatible and biodegradable polymer. 21. The dispersed phase formulation of claim 14, wherein the polymer is a homopolymer of lactic acid or a copolymer of lactic acid and glycolic acid.
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이 특허에 인용된 특허 (11)
Bowers Cyril Y. (New Orleans LA) Folkers Karl A. (Austin TX) Janecka Anna (Lodz PLX), Antagonists of LHRH.
Bowers Cyril Y. (New Orleans LA) Folkers Karl A. (Austin TX) Ljungqvist Anders (Austin TX) Feng Dong-Mei (Harleysville PA) Janceka Anna (Austin TX), Antagonists of LHRH.
Folkers Karl (Austin TX) Ljungqvist Anders (Austin TX) Feng Dong-Mei (Austin TX) Bowers Cyril Y. (New Orleans LA) Tang Pui-Fun L. (Kowloon HKX) Kubota Minoru (Yotsukaido JPX), Effective antagonists of the luteinizing hormone releasing hormone which release negligible histamine.
Rivier Jean E. F. (La Jolla CA) Porter John S. (Leucadia CA) Hoeger Carl A. (San Marcos CA) Jiang Guangcheng (La Jolla CA) Rivier Catherine L. (La Jolla CA), GNRH antagonists XIII.
Hoeger Carl A. (San Marcos CA) Rivier Jean E. F. (La Jolla CA) Theobald Paula G. (Oceanside CA) Porter John S. (Leucadia CA) Rivier Catherine L. (La Jolla CA) Vale ; Jr. Wylie W. (La Jolla CA), GnRH analogs.
DeLuca Patrick P. (Lexington KY) Kanke Motoko (Fukuyama JPX) Sato Toyomi (Tokyo CA JPX) Schroeder Hans G. (Encinitas CA), Porous microspheres for drug delivery and methods for making same.
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