Method for producing powder formulation comprising an insulin

• US 5,898,028 A
• Filed: 03/20/1998
• Issued: 04/27/1999
• Est. Priority Date: 03/20/1997
• Status: Expired due to Fees

• Current Assignee: Novo Nordisk A/S
• Original Assignee: Novo Nordisk A/S
• Inventors: Hansen, Philip, Jensen, Steen
• Primary Examiner(s): Russel, Jeffrey E.
• Application Number:
  US09/045,316
• Time in Patent Office: 403 Days
• Field of Search: 530/303, 530/304, 530/305, 514/3, 514/4
• US Class Current: 514/6.3
• CPC Class Codes: A61K 38/28 Insulins
• CPC Class Codes: A61K 9/0075 for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles

Abstract

A therapeutic powder formulation suitable for pulmonary administration comprising particles composed of human insulin or any analogue or derivative thereof and an enhancer which enhances the absorption of insulin in the lower respiratory tract, wherein at least 50% by weight of the particles are crystalline.

Claims

1. A therapeutic powder formulation suitable for pulmonary administration, comprising particles which comprise (i) human insulin, any analogue or derivative thereof, or combinations of the foregoing;

and (ii) an enhancer which enhances the absorption of insulin in the lower respiratory tract, wherein at least 50% by weight of said particles are crystalline and wherein the molar ratio of insulin to enhancer is between about 9;

1 and 1;

9.

2. A therapeutic powder formulation according to claim 1 wherein at least 75% by weight of said particles are crystalline.

3. A therapeutic powder formulation according to claim 1 wherein the enhancer is a surfactant.

4. A therapeutic powder formulation according to claim 3 wherein the surfactant is selected from the group consisting of a salt of a fatty acid, a bile salt, and a phospholipid.

5. A therapeutic powder formulation according to claim 4 wherein the surfactant is sodium taurocholate.

6. A therapeutic powder formulation according to claim 1 which further comprises zinc in an amount corresponding to a ratio of between 2 Zn atoms/insulin hexamer to 12 Zn atoms/insulin hexamer.

7. A therapeutic powder formulation according to claim 6 wherein said ratio is from 2 Zn atoms/insulin hexamer to 10 Zn atoms/insulin hexamer.

8. A therapeutic powder formulation according to claim 1 wherein the majority of the crystals have a diameter of 10 μ

m or less.

9. A therapeutic powder formulation according to claim 1 wherein the molar ratio of insulin to enhancer is between 3:

1 to 1;

3.

10. A therapeutic powder formulation according to claim 1 which further comprises a carrier selected from the group consisting of trehalose, raffinose, mannitol, sorbitol, xylitol, inositol, sucrose, sodium chloride and sodium citrate.

11. A therapeutic powder formulation according to claim 1 which further comprises a stabilizing amount of a phenolic compound.

12. A therapeutic powder formulation according to claim 11 which comprises at least 3 molecules of a phenolic compound/insulin hexamer.

13. A therapeutic powder formulation according to claim 11 which comprises m-cresol or phenol, or a mixture thereof.

14. A method of treating diabetes, comprising administering to a subject in need thereof a therapeutically effective amount of the powder formulation according to claim 1.

15. A method of treating diabetes according to claim 14, wherein said insulin analogue is Lys^B28 -Pro^B29 human insulin or Asp^B28 human insulin.

16. A therapeutic powder formulation suitable for pulmonary administration, comprising co-crystals of (i) human insulin, any analogue or derivative thereof, or combinations of the foregoing;

and (ii) an enhancer which enhances the absorption of insulin in the lower respiratory tract, wherein the molar ratio of insulin to enhancer in said crystals is between about 9;

1 and 1;

9.

17. A therapeutic powder formulation suitable for pulmonary administration comprising particles composed of (i) human insulin, any analogue or derivative thereof, or combinations of the foregoing;

and (ii) an enhancer which enhances the absorption of insulin in the lower respiratory tract, wherein at least 50% of said particles are crystalline and wherein said enhancer is sodium taurocholate.

18. A therapeutic powder formulation suitable for pulmonary administration comprising particles composed of (i) human insulin, any analogue or derivative thereof, or combinations of the foregoing;

(ii) an enhancer which enhances the absorption of insulin in the lower respiratory tract, and (iii) a stabilizing amount of a phenolic compound wherein at least 50% of said particles are crystalline.

19. A therapeutic powder formulation according to claim 18 which comprises at least 3 molecules of a phenolic compound/insulin hexamer.

20. A therapeutic powder formulation according to claim 18 which comprises m-cresol or phenol, or a mixture thereof.