High-purity inhalable particles of insulin and insulin analogues, and high-efficiency methods of manufacturing the same
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.
1. A high-purity inhalable insulin material for a pulmonary pharmaceutical product, 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;
(ii) the total amount of insulin-related impurities in the insulin particles being not more than 2% by weight;
(iii) 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; and
(iv) the total amount of nonsolvent-related impurities in the insulin particles being not more than 0.3% by weight, each of the foregoing % by weight being based on the total weight of the insulin particles,
wherein the insulin-related impurities comprise insulin dimer and the total amount of insulin dimer is less than or equal to 0.13% by weight on the dried basis.
2. The high-purity inhalable insulin material for a pulmonary pharmaceutical product of claim 1 , wherein the insulin particles comprises a crystalline insulin selected from the group consisting of crystalline human insulin, crystalline animal insulin, crystalline insulin analogue, and any mixture thereof.
3. The high-purity inhalable insulin material for a pulmonary pharmaceutical product of claim 2 , wherein the crystalline insulin analogue is selected from the group consisting of crystalline insulin aspart, crystalline insulin glargine, and any mixture thereof.
4. The high-purity inhalable insulin material for a pulmonary pharmaceutical product of claim 1 , wherein the insulin particles are substantially spherical in shape and have a particle size of less than 5 μm.
5. The high-purity inhalable insulin material for a pulmonary pharmaceutical product of claim 1 , wherein 99% by volume of the insulin particles comprise particles having a particle size of less than 5 μm, based on the total volume of the insulin particles.
6. The high-purity inhalable insulin material for a pulmonary pharmaceutical product of claim 1 , wherein the insulin particles comprise substantially spherical particles having a volume mean particle diameter of about 1 μm to 2 μm.
7. The high-purity inhalable insulin material for a pulmonary pharmaceutical product of claim 1 , wherein the insulin-related impurities comprise high molecular weight proteins.
8. The high-purity inhalable insulin material for a pulmonary pharmaceutical product of claim 1 , wherein the insulin-related impurities comprise A-21 desamido insulin.
9. The high-purity inhalable insulin material for a pulmonary pharmaceutical product of claim 8 , wherein the total amount of the A-21 desamido insulin is less than or equal to 0.63% by weight on the dried basis.