Sustained-release preparations

• US 20060074027A1
• Filed: 02/09/2005
• Published: 04/06/2006
• Est. Priority Date: 02/10/2004
• Status: Active Grant

• Current Assignee: Takeda Pharmaceutical Company Limited
• Original Assignee: Takeda Pharmaceutical Company Limited
• Inventors: Saito, Kazuhiro, Futo, Tomomichi, Hoshino, Tetsuo
• Granted Patent: US 7,662,408 B2
• Time in Patent Office: Days
• US Class Current: 424/468
• CPC Class Codes: A61K 38/08 Peptides having 5 to 11 amino acids A61K38/043 - A61K38/046 take precedence
• 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 47/34 Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers A61K47/10 takes precedence
• CPC Class Codes: A61K 9/5031 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide)
• CPC Class Codes: A61K 9/5089 Processes
• CPC Class Codes: A61P 13/08 of the prostate
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 15/08 for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
• CPC Class Codes: A61P 15/18 Feminine contraceptives
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 5/02 of the hypothalamic hormones, e.g. TRH, GnRH, CRH, GRH, somatostatin

Abstract

A sustained release preparation comprising a combination of a microcapsule which gradually releases a GnRH agonist or a salt thereof for a long term, and a microcapsule which gradually releases a GnRH agonist or a salt thereof for a short term.

Claims

1-15. -15. (canceled)

16. A sustained release preparation comprising a combination of first microcapsules which gradually release a GnRH agonist or a salt thereof for a long term, and second microcapsules which gradually release a GnRH agonist or a salt thereof for a short term.

17. The preparation according to claim 16, wherein the GNRH agonist or a salt thereof is a peptide represented by the formula:

5-oxo-Pro-His-Trp-Ser-Tyr-Y-Leu-Arg-Pro-Z

wherein Y represents a residue selected from DLeu, DAla, DTrp, DSer (tBu), D2Nal and DHis (ImBzl), and Z represents NH—

C₂H₅ or Gly-NH₂

or a salt thereof.

18. The preparation according to claim 16, wherein the GnRH agonist or a salt thereof is an acetate of a peptide of the formula:

5-oxo-Pro-His-Trp-Ser-Tyr-Dleu-Leu-Arg-Pro-NH—

C₂H₅

19. The preparation according to claim 16, wherein the long term is 5 months or longer, and the short term is shorter than 5 months.

20. The preparation according to claim 16, wherein the long term is 5 months or longer and 8 months or shorter, and the short term is 1 week or longer and shorter than 5 months.

21. The preparation according to claim 16, wherein the microcapsules comprise a lactic acid polymer or a lactic acid-glycolic acid polymer.

22. The preparation according to claim 16, wherein the ratio of first microcapsules to second microcapsules is from 5:

1 to 20;

1 expressed as weight ratios of the GnRH agonist or a salt thereof.

23. The preparation according to claim 16, wherein:

(a) the first microcapsules comprise;

(i) a GNRH agonist or a salt thereof, and

(ii) a lactic acid polymer having a weight-average molecular weight of about 18,000 to about 30,000; and

(b) the second microcapsules comprise;

(i) a GnRH agonist or a salt thereof, and

(ii) a lactic acid-glycolic acid polymer (75/25 (mol %)) having a weight-average molecular weight of 3,000 to about 12,000, or a lactic acid polymer having a weight-average molecular weight of about 13,000 to about 18,000.

24. The preparation according to claim 16, wherein:

(a) the first microcapsules comprise;

(i) a GNRH agonist or a salt thereof, and

(ii) a lactic acid polymer having a weight-average molecular weight of about 15,000 to about 50,000 in which a content of a polymer having a weight-average molecular weight of 5,000 or less is about 5% or less by weight; and

(b) the second microcapsules;

(1) comprise (i) a GnRH agonist or a salt thereof, and (ii) a lactic acid-glycolic acid polymer in which a weight-average molecular weight (Mw) is about 8,000 to about 11,500, and a ratio of a weight-average molecular weight (Mw) to a number-average molecular weight (Mn) is greater than 1.9, and a compositional molar ratio of lactic acid to glycolic acid is 99.9/0.1 to 60/40, and which does not contain a drug retaining substance, or

(2) zero order-release a GNRH agonist or a salt thereof over 2 months, and are prepared by microencapsulating a W/O emulsion prepared from an inner aqueous phase solution containing a GNRH agonist or a salt thereof in about 20 to 70% by weight, and an oil phase solution containing, as a release controlling substance, a copolymer or a homopolymer in which a compositional ratio of lactic acid/glycolic acid is 80/20 to 100/0, and a weight-average molecular weight is about 7,000 to about 30,000.

25. The sustained-release preparation according to claim 16, which gradually releases a substantially constant amount of a GnRH agonist or a salt thereof for a long term.

26. The sustained-release preparation according to claim 25, wherein the long term is 5 months or longer.

27. A composition comprising:

(a) a pharmaceutically effective amount for preventing or treating prostate cancer, prostatomegaly, endometriosis, hysteromyoma, metrofibroma, precocious puberty, dysmenorrhea or breast cancer, or for contraception of the sustained-release preparation according to claim 16, and

(b) a pharmaceutically acceptable excipient.

28. A process for producing the sustained-release preparation according to claim 16, which comprises mixing the first and second microcapsules.

29. A method comprising administering an effective amount for preventing or treating prostate cancer, prostatomegaly, endometriosis, hysteromyoma, metrofibroma, precocious puberty, dysmenorrhea or breast cancer, or preventing conception of the sustained-release preparation according to claim 16 to a mammal in need thereof.