Therapeutic preparation for inhalation

• US 5,747,445 A
• Filed: 01/04/1996
• Issued: 05/05/1998
• Est. Priority Date: 06/24/1993
• Status: Expired due to Term

• Current Assignee: Astra AB (Astrazeneca PLC)
• Original Assignee: Astra AB (Astrazeneca PLC)
• Inventors: Edman, Peter, Johansson, Ann Charlotte Birgit, Backstrom, Kjell Goran Erik, Dahlback, Carl Magnus Olof
• Primary Examiner(s): Tsang, Cecilia J.
• Assistant Examiner(s): HARLE, JENNIFER I
• Application Number:
  US08/583,205
• Time in Patent Office: 852 Days
• Field of Search: 514/3, 514/4
• US Class Current: 514/6.5
• CPC Class Codes: A61K 38/28 Insulins
• CPC Class Codes: A61K 47/12 Carboxylic acids; Salts or anhydrides thereof
• CPC Class Codes: A61K 9/0075 for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
• CPC Class Codes: A61K 9/145 with organic compounds

Abstract

A therapeutic preparation for inhalation which comprises insulin and a substance which enhances the absorption of insulin in the lower respiratory tract, is provided in the form of a powder preparation suitable for inhalation.

Claims

1. A therapeutic preparation the active ingredients of which consist of (A) insulin and (B) a bile salt which enhances the absorption of insulin in the lower respiratory tract, in the form of a dry powder suitable for inhalation from a dry powder inhaler, wherein at least 50% of the total mass of active ingredients consists of (a) particles having a diameter of up to 10 microns or (b) agglomerates of such particles.

2. The therapeutic preparation of claim 1, wherein the therapeutic preparation contains only said active ingredients.

3. The therapeutic preparation of claim 1, wherein the dry powder contains, in addition to said active ingredients, a pharmaceutically acceptable carrier.

4. The therapeutic preparation of claim 1, wherein said bile salt is a trihydroxy bile salt.

5. The therapeutic preparation of claim 1, wherein the bile salt is a salt of cholic acid, glycocholic acid or taurocholic acid.

6. The therapeutic preparation of claim 1, wherein the bile salt is sodium taurocholate.

7. The therapeutic preparation of claim 1, wherein the bile salt is potassium taurocholate.

8. The therapeutic preparation of claim 1, wherein the bile salt is a sodium or potassium salt of cholic acid.

9. The therapeutic preparation of claim 1, wherein the bile salt is a sodium or potassium salt of glycocholic acid.

10. The therapeutic preparation of claim 1, wherein the bile salt is a salt of chenodeoxycholic acid, glycochenodeoxycholic acid, taurochenodeoxycholic acid, deoxycholic acid, glycodeoxycholic acid, taurodeoxycholic acid, lithocholic acid, or ursodeoxycholic acid.

11. The therapeutic preparation of claim 1, in which at least 50% of the dry powder consists of (a) particles having a diameter of between 1 and 6 microns or (b) agglomerates of such particles.

12. The therapeutic preparation of claim 1, wherein the insulin is semisynthetic human insulin or a biosynthetic human insulin.

16. The therapeutic preparation of claim 1, wherein the ratio of (A) to (B) in said preparation is in the range of 9:

1 to 1;

1.

17. The therapeutic preparation of claim 6, wherein the ratio of (A) to (B) in said preparation is in the range of 9:

1 to 1;

1.

21. The therapeutic preparation of claim 3, wherein said carrier is selected from mono-, di-, and polysaccharides, sugar alcohols and other polyols.

22. The therapeutic preparation of claim 3, wherein said carrier is raffinose, melezitose, lactitol, maltitol, trehalose, sucrose, mannitol or starch.

13. A therapeutic preparation consisting essentially of active compounds (A) insulin and (B) sodium taurocholate, which preparation is in the form of a dry powder suitable for inhalation from a dry powder inhaler, in which at least 50% of the total mass of active compounds (A) and (B) consists of (a) primary particles having a diameter of less than 10 microns, or (b) agglomerates of such particles.

18. The therapeutic preparation of claim 13, wherein the ratio of (A) to (B) in said preparation is in the range of 9:

1 to 1;

1.

14. A therapeutic preparation consisting essentially of insulin, sodium taurocholate, and a pharmaceutically acceptable carrier, which preparation is in the form of a dry powder suitable for inhalation from a dry powder inhaler, of which at least 50% by mass consists of (a) particles having a diameter of less than about 10 microns, or (b) agglomerates of said particles.

19. The therapeutic preparation of claim 14, wherein the ratio of (A) to (B) in said preparation is in the range of 9:

1 to 1;

1.

15. A therapeutic preparation consisting essentially of

active compounds (A) insulin and (B) sodium taurocholate, wherein at least 50% of the total mass of active compounds (A) and (B) consists of particles having a diameter of less than about 10 microns;

and

a pharmaceutically acceptable carrier,

which preparation is in the form of a dry powder suitable for inhalation from a dry powder inhaler, wherein an ordered mixture is formed between the active compounds and the pharmaceutically acceptable carrier.

20. The therapeutic preparation of claim 15, wherein the ratio of (A) to (B) in said preparation is in the range of 9:

1 to 1;

1.

23. A process for the manufacture of a therapeutic preparation of insulin, comprising

forming, in a solvent, a solution of insulin and a trihydroxy bile salt which enhances the absorption of insulin in the lower respiratory tract;

removing the solvent to obtain a solid comprising said insulin and said bile salt; and

processing said solid to obtain a powder of which at least 50% of the total mass consists of particles which have a diameter of up to 10 microns.

24. The process of claim 23, further comprising adding to said solution a pharmaceutically acceptable carrier.

25. The process of claim 23, wherein said bile salt is a salt of cholic acid, glycocholic acid, or taurocholic acid.

26. The process of claim 23, wherein said bile salt is a sodium or potassium salt of cholic acid, glycocholic acid, or taurocholic acid.

27. The process of claim 23, wherein said bile salt is potassium taurocholate.

28. The process of claim 23, wherein said processing step comprises micronising the solid.

31. The process of claim 27, further comprising dry-mixing a pharmaceutically acceptable carrier together with the insulin and bile salt, prior to said processing step.

32. The process of claim 27, wherein said bile salt is a salt of cholic acid, glycocholic acid, or taurocholic acid.

33. The process of claim 27, wherein said bile salt is a sodium or potassium salt of cholic acid, glycocholic acid, or taurocholic acid.

34. The process of claim 27, wherein said processing step comprises micronising the mixture.

29. A process for the manufacture of a therapeutic preparation of insulin, comprising

forming, in a solvent, a solution of insulin and a bile salt selected from the group consisting of salts of chenodeoxycholic acid, glycochenodeoxycholic acid, taurochenodeoxycholic acid, deoxycholic acid, glycodeoxycholic acid, taurodeoxycholic acid, lithocholic acid, and ursodeoxycholic acid;

removing the solvent to obtain a solid comprising said insulin and said bile salt; and

processing said solid to obtain a powder of which at least 50% of the total mass consists of particles which have a diameter of up to 10 microns.

30. A process for the manufacture of a therapeutic preparation of insulin, comprising dry-mixing insulin together with a trihydroxy bile salt which enhances the absorption of insulin in the lower respiratory tract, and processing said mixture to obtain a powder of which at least 50% consists of particles which have a diameter of up to 10 microns.

35. A process for the manufacture of a therapeutic preparation of insulin, comprising

dry-mixing insulin together with a bile salt selected from the group consisting of salts of chenodeoxycholic acid, glycochenodeoxycholic acid, taurochenodeoxycholic acid, deoxycholic acid, glycodeoxycholic acid, taurodeoxycholic acid, lithocholic acid, and ursodeoxycholic acid;

and

processing said mixture to obtain a powder of which at least 50% consists of particles which have a diameter of up to 10 microns.