Micronized insulin and micronized insulin analogues prepared under acidic conditions, and methods of manufacturing the same under acidic conditions

• US 10,258,573 B2
• Filed: 07/08/2015
• Issued: 04/16/2019
• Est. Priority Date: 07/08/2014
• Status: Active Grant

• Current Assignee: Amphastar Pharmaceuticals Incorporated
• Original Assignee: Amphastar Pharmaceuticals Incorporated
• Inventors: Ding, Jeffrey, Bo, Aili, Luo, Mary Ziping, Zhang, Jack Yongfeng
• Primary Examiner(s): Skowronek, Karlheinz R.
• Assistant Examiner(s): Fischer, Joseph
• Application Number:
  US14/794,766
• Publication Number:
  US 20160008287A1
• Time in Patent Office: 1,378 Days
• 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 9/008 comprising drug dissolved or suspended in liquid propellant for inhalation via a pressurized metered dose inhaler [MDI]
• CPC Class Codes: A61K 9/14 Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles microspheres A61K9/16; microcapsules A61K9/50; nanocapsules, nanoparticles of the matrix type A61K9/51
• CPC Class Codes: A61K 9/1617 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/1688 resulting in pure drug agglomerate optionally containing up to 5% of excipient
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

A method of preparing an inhalable insulin suitable for pulmonary delivery includes: dissolving an insulin raw material in an acidic solution to form a dissolved insulin solution; titrating the dissolved insulin solution with a buffer solution to form a suspension comprising micronized insulin particles; and stabilizing the micronized insulin particles.

Claims

1. A method of preparing an inhalable insulin suitable for pulmonary delivery, the method comprising:

dissolving an insulin raw material in an acidic solution to form a dissolved insulin solution;

titrating the dissolved insulin solution with a buffer solution to form a suspension comprising micronized insulin particles; and

stabilizing the micronized insulin particles after titrating the dissolved insulin solution,

wherein the stabilizing of the micronized insulin particles comprises adding a stabilizing agent to the suspension,

wherein the stabilizing agent is selected from the group consisting of an alcohol, a ketone, and a mixture thereof,

wherein the inhalable insulin suitable for pulmonary delivery comprises the micronized insulin particles, the micronized insulin particles are substantially spherical in shape, and the micronized insulin particles comprise up to 99 vol % particles having a particle size of less than 5 μ

m, based on the total volume of the micronized insulin particles, and

wherein the micronized insulin particles consist of insulin.

2. The method of claim 1, wherein the acidic solution comprises one selected from the group consisting of water, an organic solvent, and a mixture thereof.

3. The method of claim 2, wherein the acidic solution comprises the organic solvent in an amount of 10 to 90 vol %, based on the total volume of the acidic solution.

4. The method of claim 2, wherein the acidic solution comprises the organic solvent in an amount up to 90 vol %, based on the total volume of the acidic solution.

5. The method of claim 2, wherein the organic solvent comprises an alcohol.

6. The method of claim 5, wherein the alcohol is selected from the group consisting of methanol, ethanol, and a mixture thereof.

7. The method of claim 1, wherein the buffer solution has a pH of 3 to 7.

8. The method of claim 1, wherein the stabilizing agent has a neutral pH and is miscible with water.

9. The method of claim 1, wherein the stabilizing agent is a ketone that stabilizes the micronized insulin particles.

10. The method of claim 1, wherein the micronized insulin particles are micronized at a pH of 3 to 7.

11. The method of claim 1, wherein the micronized insulin particles are micronized at a pH of 4.5 to 6.9.

12. The method of claim 1, wherein the substantially spherical particles have a volume mean diameter of about 1.2 to 2 μ

m.

13. The method of claim 1, wherein the acidic solution has a pH of 1.0 to 3.0.

14. The method of claim 1, wherein the acidic solution has a pH of 1.8 to 2.2.

15. The method of claim 1, wherein the acidic solution has a pH of about 2 and comprises water and 10 vol % to 90 vol % of an organic solvent selected from the group consisting of methanol, ethanol, and a mixture thereof, based on the total volume of the acidic solution.

16. The method of claim 1, wherein the micronized insulin particles comprise an insulin selected from the group consisting of human insulin, an animal insulin, an insulin analogue, and a mixture thereof.

17. The method of claim 16, wherein the insulin analogue is selected from the group consisting of insulin aspart, insulin glargine, and a mixture thereof.

18. The method of claim 1, wherein one selected from the dissolving, the titrating, the stabilizing, and a combination thereof are performed at room temperature.

19. The method of claim 1, wherein the insulin raw material comprises a crystalline insulin selected from the group consisting of crystalline human insulin, a crystalline animal insulin, a crystalline insulin analogue, and a mixture thereof.

20. The method of claim 19, wherein the crystalline insulin analogue is selected from the group consisting of crystalline insulin aspart, crystalline insulin glargine, and a mixture thereof.