High-purity inhalable particles of insulin and insulin analogues, and high-efficiency methods of manufacturing the same

• US 10,322,168 B2
• Filed: 01/07/2016
• Issued: 06/18/2019
• Est. Priority Date: 01/07/2016
• 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): Bredefeld, Rachael E
• Assistant Examiner(s): Yang, Kaipeen E
• Application Number:
  US14/990,787
• Publication Number:
  US 20170196941A1
• Time in Patent Office: 1,258 Days
• CPC Class Codes: A61K 38/28 Insulins
• CPC Class Codes: A61K 9/0073 Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy; nasal sprays A61K9/0043; inhalation of vapours of volatile or heated drugs, e.g. essential oils or nicotine, A61K9/007; devices A61M
• 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 9/143 with inorganic compounds
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: C07K 14/62 Insulins

Abstract

A high-purity inhalable insulin material, used for preparing a pulmonary pharmaceutical product, includes insulin particles having a particle size at the micrometer level and having the following characteristics: (i) the purity of insulin is not less than 96% on the dried basis; (ii) the total amount of insulin-related impurities is not more than 2%; (iii) the total amount of solvent impurities, which is not a co-solvent formulation component for a pulmonary product, is not more than 0.03%; and (iv) the total amount of non-solvent impurities is not more than 0.3%. Up to 99% by volume of the insulin particles in the inhalable insulin have a particle size of less than 5 μm, based on the total volume of the insulin particles. A high-efficiency method prepares high-purity inhalable insulin material. The yield rate for the high-efficiency method is 75 to 85% or more.

Claims

1. A high-purity inhalable insulin material for a pulmonary pharmaceutical product to be delivered by metered dose inhaler, comprising:

insulin particles having a particle size at the micrometer level, and having the following characteristics;

(i) the purity of the insulin particles being not less than 96% by weight on the dried basis;

(ii) the amount of zinc in the insulin particles being not more than 1% by weight, and not less than 0.3% by weight, on the dried basis;

(iii) the total amount of insulin-related impurities consisting of insulin dimer, high molecular weight proteins, and A-21 desamido insulin in the insulin particles being not more than 2% by weight on the dried basis, wherein, of the total amount of insulin-related impurities, the total amount of A-21 desamido insulin is less than or equal to 0.63%, and/or the total amount of insulin dimer is less than or equal to 0.13%, by weight on the dried basis;

(iv) the total amount of solvent-related impurities in the insulin particles, which solvent-related impurities do not include a co-solvent formulation component in the pulmonary product, being not more than 0.03% by weight on the dried basis; and

(v) the total amount of nonsolvent-related impurities other than insulin-related impurities in the insulin particles being not more than 0.3% by weight on the dried basis.

2. The insulin material 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 any mixture thereof.

3. The insulin material of claim 2, wherein the insulin analogue is selected from the group consisting of insulin aspart, insulin glargine, and any mixture thereof.

4. The insulin material of claim 1, wherein the insulin particles are substantially spherical in shape and have a particle size of less than 5 μ

m.

5. The insulin material of claim 1, wherein 99% by volume of the insulin particles comprise particles having a particle size of less than 5 μ

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

6. The insulin material of claim 1, wherein the insulin particles comprise substantially spherical particles having a volume mean particle diameter of about 1 μ

m to 2 μ

m.

7. A high-purity inhalable insulin material for a pulmonary pharmaceutical product to be delivered by metered dose inhaler, consisting of:

unencapsulated insulin particles having a particle size at the micrometer level, and having the following characteristics;

(i) the purity of the unencapsulated insulin particles being not less than 96% by weight on the dried basis;

(ii) the amount of zinc in the unencapsulated insulin particles being not more than 1% by weight, and not less than 0.3% by weight, on the dried basis;

(iii) the total amount of insulin-related impurities consisting of insulin dimer, high molecular weight proteins, and A-21 desamido insulin in the unencapsulated insulin particles being not more than 2% by weight on the dried basis, wherein, of the total amount of insulin-related impurities, the total amount of A-21 desamido insulin is less than or equal to 0.63%, and/or the total amount of insulin dimer is less than or equal to 0.13%, by weight on the dried basis;

(iv) the total amount of solvent-related impurities in the unencapsulated insulin particles, which solvent-related impurities do not include a co-solvent formulation component in the pulmonary product, being not more than 0.03% by weight on the dried basis; and

(v) the total amount of nonsolvent-related impurities other than insulin-related impurities in the unencapsulated insulin particles being not more than 0.3% by weight on the dried basis.

8. A metered dose inhaler comprising the high-purity inhalable insulin material of claim 7.