Pulmonary insulin crystals

• US 6,310,038 B1
• Filed: 03/20/1998
• Issued: 10/30/2001
• Est. Priority Date: 03/20/1997
• Status: Expired due to Term

• Current Assignee: Novo Nordisk A/S
• Original Assignee: Novo Nordisk A/S
• Inventors: Havelund, Svend
• Primary Examiner(s): Russel, Jeffrey E.
• Application Number:
  US09/045,038
• Time in Patent Office: 1,320 Days
• Field of Search: 530/303, 530/304, 530/305, 514/3.4
• 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
• CPC Class Codes: A61K 9/145 with organic compounds
• CPC Class Codes: C07K 14/62 Insulins

Abstract

The present invention relates to zinc free insulin crystals having a diameter below 10 μm and to therapeutic powder formulations suitable for pulmonary administration containing such insulin crystals. The crystals of the present invention exhibit a better stability profile than powders of essentially the same composition prepared by spray drying, freeze-drying, vacuum drying and open drying. The therapeutic powder formulations elucidate better flowing properties than corresponding amorphous powder formulations.

Claims

1. Zinc free insulin crystals having a diameter below 10 μ

m, wherein said insulin is selected from the group consisting of human insulin and Lys^B29(N-ε

-acylated) des(B30) human insulin.

2. Zinc free insulin crystals according to claim 1 having a crystal structure belonging to the cubic crystal system.

3. Zinc free insulin crystals according to claim 2 in the octadecahedral or dodecahedral crystal forms.

4. Zinc free insulin crystals according to claim 1 having a diameter in the range of 0.2 to 5 μ

m.

5. Zinc free insulin crystals according to claim 1 further comprising a stabilizing amount of a phenolic compound.

6. Zinc free insulin crystals according to claim 5 comprising m-cresol or phenol, or a mixture thereof.

7. A therapeutic powder formulation suitable for pulmonary administration comprising the zinc free insulin crystals according to claim 1.

8. The therapeutic powder formulation according to claim 7 which further comprises an enhancer which enhances the absorption of insulin in the lower respiratory tract.

9. The therapeutic powder formulation according to claim 8 wherein the enhancer is a surfactant.

10. The therapeutic powder formulation according to claim 9 wherein the surfactant is a salt of a fatty acid, a bile salt or a phospholipid.

11. The therapeutic powder formulation according to claim 10 wherein the surfactant is a salt of taurocholate.

12. The therapeutic powder formulation according to claim 7 which further comprises a carrier, selected from the group consisting of trehalose, raffinose, mannitol, sorbitol, xylitol, inositol, sucrose, sodium chloride and sodium citrate.

18. A method of treating diabetes mellitus comprising administering to a person in need of such treatment an effective amount of a therapeutic powder formulation according to claim 7.

13. A method for the preparation of zinc free insulin crystals having a diameter below 10 μ

m, comprising the steps of;

a) providing a first solution of insulin having a pH between 7.0 and 9.5;

b) mixing said first solution with a second solution of a salt of an alkali metal or an ammonium salt, wherein either or both of said first and second solutions comprises a water miscible organic solvent selected from the group consisting of ethanol, methanol, acetone and 2-propanol in an amount which provides a concentration of said organic solvent of 5 to 25% (v/v) in the solution obtained after mixing, and wherein the first and second solution are mixed within a period of less than 15 minutes; and

c) recovering the formed crystals.

14. The method according to claim 13, wherein the salt of an alkali metal or ammonium is selected from the group consisting of the hydrochloride or acetate of sodium, potassium, lithium or ammonia, and mixtures thereof.

15. The method according to claim 13, wherein the concentration of insulin after mixing is between 0.5% and 10% by weight.

16. The method according to claim 13, wherein the concentration of salt after mixing is between 0.2 M and 2 M.

17. The method according to claim 13, which further comprises a washing step, in which the crystals obtained are washed with a solution which comprises auxiliary substances and optionally comprises 5-25% of an alcohol, 5-50 mM of a preservative, and 0.1-2 M of a salt.