Sustained-release preparation

• US 6,087,324 A
• Filed: 04/22/1996
• Issued: 07/11/2000
• Est. Priority Date: 06/24/1993
• Status: Expired due to Fees

• Current Assignee: Takeda Pharmaceutical Company Limited
• Original Assignee: Takeda Chemical Industries, Ltd. (Takeda Pharmaceutical Company Limited)
• Inventors: Yamagata, Yutaka, Igari, Yasutaka
• Primary Examiner(s): O SULLIVAN, PETER G
• Application Number:
  US08/644,631
• Time in Patent Office: 1,541 Days
• Field of Search: 514/3, 514/2, 514/12, 424/499, 530/399
• US Class Current: 514/11.3
• CPC Class Codes: A61K 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61K 38/1816 Erythropoietin [EPO]
• CPC Class Codes: A61K 38/193 Colony stimulating factors [CSF]
• CPC Class Codes: A61K 38/212 IFN-alpha
• CPC Class Codes: A61K 38/27 Growth hormone [GH], i.e. somatotropin
• CPC Class Codes: A61K 38/28 Insulins
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• 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)

Abstract

According to a first embodiment, there is provided a sustained-release preparation comprising a water-insoluble or slightly water-soluble polyvalent metal salt of a water-soluble physiologically active substance which is not an endothelin antagonist, and a biodegradable polymer. The sustained-release preparation of the first embodiment is highly efficient in incorporating the water-soluble physiologically active substance and suppresses the initial burst of the water-soluble physiologically active substance. The sustained-release preparation of the present invention is capable of releasing the water-soluble physiologically active substance while retaining its bioactivity after administration in vivo. Furthermore, the water-soluble physiologically active substance in the sustained-release preparation is kept stable for a long period of time, with little loss of bioactivity.

According to a second embodiment, there is provided a sustained-release preparation comprising an anti-endothelin substance and a biodegradable polymer. The sustained-release preparation of the present invention sustainedly releases an anti-endothelin substance, serving well in the treatment of endothelin-associated diseases.

Claims

1. A sustained-release preparation comprising:

(a) a water-insoluble or slightly water-soluble polyvalent metal salt of a water soluble physiologically active substance comprising a growth hormone, said polyvalent metal salt being formed from a combination comprising a water-soluble physiologically active peptide, derivative or a water-soluble salt thereof and a water-soluble polyvalent metal salt, wherein the solubility of the water-insoluble or slightly water-soluble polyvalent metal salt in water is about 0 to about 0.01% (w/w) at 20°

C., and a biodegradable polymer.

2. A preparation of claim 1, wherein the polyvalent metal salt is a transition metal salt.

3. A preparation of claim 1, wherein the polyvalent metal salt is a zinc salt.

4. A preparation of claim 1, which contains about 0.1 to about 50% (w/w) of the polyvalent metal salt.

5. A preparation of claim 1, which contains about 1 to about 30% (w/w) of the polyvalent metal salt.

6. A preparation of claim 1, wherein the biodegradable polymer is an aliphatic polyester.

7. A preparation of claim 6, wherein the aliphatic polyester is a polymer of lactic acid and glycolic acid.

8. A preparation of claim 7, wherein the composition ratio of lactic acid and glycolic acid is 100/0 to about 40/60 (mole %).

9. A preparation of claim 8, wherein the composition ratio is about 90/10 to about 45/55 (mole %).

10. A preparation of claim 7, wherein the weight-average molecular weight of the polymer is about 3,000 to about 20,000.

11. A preparation of claim 7, wherein the weight-average molecular weight of the polymer is about 3,000 to about 14,000.

12. A preparation of claim 6, wherein the aliphatic polyester is a homopolymer of lactic acid.

13. A preparation of claim 12, wherein the weight-average molecular weight of the homopolymer is about 3,000 to about 20,000.

14. A preparation of claim 12, wherein the weight-average molecular weight of the homopolymer is about 3,000 to about 14,000.

15. A preparation of claim 1, wherein the preparation is a microcapsule.

16. A preparation of claim 15, wherein the microcapsule is for injection.

17. A preparation of claim 1, which is injectable.

20. A preparation according to claim 1, wherein said physiologically active substance has a molecular weight from 200 to 200,000.

21. A sustained release preparation according to claim 1, wherein said growth hormone comprises human growth hormone.

18. A method for the production of a sustained-release preparation comprising

admixing a water-insoluble or slightly water-soluble polyvalent metal salt of a physiologically active substance comprising a growth hormone and a biodegradable polymer, wherein the solubility of the water-insoluble or slightly water-soluble polyvalent metal salt in water is about 0 to about 0.01% (w/w) at 20°

C.

22. A method according to claim 18, wherein said growth hormone comprises human growth hormone.

19. A method of producing a sustained-release preparation comprising:

dispersing or dissolving a water-insoluble or slightly water-soluble polyvalent metal salt of a water-soluble physiologically active substance comprising a growth hormone in an oil phase comprising a biodegradable polymer to form a solid-in-oil emulsion, said polyvalent metal salt being formed from a combination comprising a water-soluble physiologically active peptide, derivative or a water-soluble salt thereof and a water-soluble polyvalent metal salt, wherein the solubility of the water-insoluble or slightly water soluble polyvalent metal salt in water is about 0 to about 0.01% (w/w) at 20°

C.,

adding the solid-in-oil emulsion to a water-phase to make a solid-in-oil emulsion, and

in-water drying the solid-in-oil-in-water emulsion.

23. A method according to claim 19, wherein said growth hormone comprises human growth hormone.