Stable concentrated insulin preparations for pulmonary delivery

• US 6,211,144 B1
• Filed: 10/15/1999
• Issued: 04/03/2001
• Est. Priority Date: 10/16/1998
• Status: Active Grant

• Current Assignee: Novo Nordisk A/S
• Sponsoring Entity: Novo Nordisk A/S
• Inventors: Havelund, Svend
• Primary Examiner(s): Reamer, James H.
• Time in USPTO: 536 Days
• Field of Search: 514/4
• US Class Current: 514/5.9
• CPC Class Codes: A61K 38/28 : Insulins
• CPC Class Codes: A61K 47/02 : Inorganic compounds
• CPC Class Codes: A61K 47/10 : AlcoholsPhenolsSalts thereof, e.g. glycerolPolyethylene glycols [PEG]PoloxamersPEG/POE alkyl ethers
• CPC Class Codes: A61K 47/18 : AminesAmidesUreasQuaternary ammonium compoundsAmino acidsOligopeptides having up to five amino acids
• CPC Class Codes: A61K 47/183 : Amino acids, e.g. glycine, EDTA or aspartame
• CPC Class Codes: A61K 47/26 : Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharidesDerivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
• CPC Class Codes: A61K 47/28 : Steroids, e.g. cholesterol, bile acids or glycyrrhetinic acid
• CPC Class Codes: A61K 9/0078 : for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions

Abstract

Concentrated aqueous insulin formulations of high physical and chemical stability are disclosed. The formulations are highly suitable for pulmonary delivery.

Claims

1. An aqueous insulin formulation comprising:

3 to 20 mM of dissolved human insulin or an analogue or a derivative thereof, less than 50 mM of chloride, less than 10 mM of any anions other than chloride and acetate, 2 to 5 Zn²⁺ ions per six molecules of insulin and at least 3 phenolic molecules per six molecules of insulin.

2. An insulin formulation according to claim 1 comprising 3 to 15 mM of human insulin or an analogue or a derivative thereof.

3. An insulin formulation according to claim 2 comprising 4 to 15 mM.

4. An insulin formulation according to claim 1 comprising up to 50 mM of phenolic molecules.

5. An insulin formulation according to claim 1 comprising less than 40 mM of chloride.

6. An insulin formulation according to claim 1 comprising up to 5 mM of phosphate.

7. An insulin formulation according to claim 1 comprising 2 to 4 Zn²⁺ ions per six molecules of insulin.

8. An insulin formulation according to claim 1, further comprising 5 to 150 mM of a zwitterionic amine.

9. An insulin formulation according to claim 1, further comprising 5 to 50 mM of trishydroxymethylaminomethan.

10. An insulin formulation according to claim 1 comprising sodium ions, potassium ions, or a mixture thereof, as cations.

11. An insulin formulation according to claim 1, further comprising between 0.001% by weight and 1% by weight of a non-ionic surfactant.

12. An insulin formulation according to claim 1, further comprising 1 mM to 10 mM of an anionic surfactant.

13. An insulin formulation according to claim 1 comprising human insulin.

14. An insulin preparation according to claim 1, comprising an analogue of human insulin wherein position B28 is Asp, Lys, Leu, Val or Ala and position B29 is Lys or Pro;

or des(B28-B30), des(B27) or des(B30) human insulin.

15. An insulin preparation according to claim 14, comprising an analogue of human insulin wherein position B28 is Asp or Lys, and position B29 is Lys or Pro, preferably Asp^B28 human insulin or Lys^B28Pro^B29 human insulin.

16. An insulin preparation according to claim 1, comprising a derivative of human insulin having one or more lipophilic substituents.

17. An insulin preparation according to claim 16, wherein the insulin derivative is selected from the group consisting of B29-N^ε

-myristoyl-des(B30) human insulin, B29-N^ε

-palmitoyl-des(B30) human insulin, B29-N^ε

-myristoyl human insulin, B29-N^ε

-palmitoyl human insulin, B28-N^ε

-myristoyl Lys^B28 Pro^B29 human insulin, B28-N^ε

-palmitoyl Lys^B28 Pro^B29 human insulin, B30-N^ε

-myristoyl-Thr^B29Lys^B30 human insulin, B30-N^ε

-palmitoyl-Thr^B29Lys^B30 human insulin, B29-N^ε

-(N-palmitoyl-γ

-glutamyl)-des(B30) human insulin, B29-N^ε

-(N-lithocholyl-γ

-glutamyl)-des(B30) human insulin, B29-N^ε

-(ω

-carboxyheptadecanoyl)-des(B30) human insulin and B29-N^ε

-(ω

-carboxyheptadecanoyl) human insulin.

18. An insulin preparation according to claim 17, wherein the insulin derivative is B29-N^ε

-myristoyl-des(B30) human insulin or B29-N^ε

-(N-lithocholyl-γ

-glutamyl)-des(B30) human insulin.

19. An insulin preparation according to claim 1, comprising an insulin analogue or human insulin as well as an insulin derivative.

20. An insulin preparation according to claim 1, wherein the phenolic molecules are selected from the group consisting of phenol, m-cresol, chloro-cresol, thymol, and any mixture of any of the foregoing.

21. An insulin preparation according to claim 1 having a pH value in the range of 7 to 8.5.

22. A method of treating type I or type II diabetes, comprising administering to a patient in need of such treatment an insulin formulation according to claim 1.

23. A method according to claim 22, wherein insulin is administered in connection with meals.

24. An insulin formulation according to claim 3 comprising 5 to 15 mM of human insulin or an analogue or a derivative thereof.

25. An insulin formulation according to claim 24 comprising 6 to 15 mM of human insulin or an analogue or a derivative thereof.

26. An insulin formulation according to claim 1 comprising 9 mM of human insulin or an analogue or a derivative thereof.

27. An insulin formulation according to claim 2 comprising 12 mM of human insulin or an analogue or a derivative thereof.

28. An insulin formulation according to claim 1 comprising 3 to 12 phenolic molecules per six molecules of insulin.

29. An insulin formulation according to claim 28 comprising 3 to 9 phenolic molecules per six molecules of insulin.

30. An insulin formulation according to claim 5 comprising less than 30 mM of chloride.

31. An insulin formulation according to claim 30 comprising 5 to 20 mM of chloride.

32. An insulin formulation according to claim 7 comprising 7 comprising 2.2 to 3.2 Zn²⁺ ions per six molecules of insulin.

33. An insulin formulation according to claim 8, wherein said zwitterionic amine is selected from the group consisting of glycylglycine and glycine.

34. An insulin formulation according to claim 11, wherein said non-ionic surfactant is selected from the group consisting of Tween-20™

(poly(oxyethylene)_n-sorbitan monolaurate) and Polox-188™

(OH(CH₂CH₂O)₇₅(CH(CH₃)CH₂O)₃₀(CH₂CH₂O)₇₅H).

35. An insulin formulation according to claim 12, wherein said anionic surfactant is sodium taurocholate.

36. An insulin formulation according to claim 1, wherein said insulin derivative is an acylated insulin derivative.

37. An insulin formulation according to claim 1, wherein said formulation has a pH between 7.4 and 7.9.