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Preparation method of insulin crystals and products thereof

A technology of insulin and insulin aspart, applied in the field of protein crystals, can solve the problems of hexahedral crystallization of insulin, etc., and achieve the effects of wide crystallization temperature range, easy industrial production, and shortening of freeze-drying time.

Pending Publication Date: 2022-01-07
HEFEI TIANMAI BIOTECH DEV
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0007] However, follow-up researchers pointed out that applying the preparation method in CN106117345B could not make insulin form hexahedral crystals, and still existed in the form of amorphous precipitates

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  • Preparation method of insulin crystals and products thereof
  • Preparation method of insulin crystals and products thereof
  • Preparation method of insulin crystals and products thereof

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preparation example Construction

[0107] The preparation method of insulin crystals of the present invention may comprise the following steps: 1) mixing insulin, citric acid, phenolic substances, zinc substances, water and optional organic solvents to obtain a crystallization solution; 2) adjusting the pH using a pH regulator 1) The pH value of the crystallization solution in the medium, crystallization, and insulin crystallization.

[0108] In the preparation method of the present invention, insulin, citric acid, phenolic substances and zinc substances in the crystallization solution may have a certain dosage ratio relationship.

[0109] In one embodiment, the molar ratio among insulin, citric acid, phenolic substance and zinc substance may be 1:(127.3-1272.9):(3.1-123.0):(4.3-85.6).

[0110] In a preferred embodiment, the molar ratio among insulin, citric acid, phenolic substance and zinc substance may be 1:(127.3-1272.9):(3.1-123.0):(10.0-85.6).

[0111] In a preferred embodiment, the molar ratio among ins...

Embodiment 1

[0264] Embodiment 1 (comparative example)

[0265] The crystallization of insulin aspart is prepared with reference to the crystallization method of recombinant insulin glargine in CN106117345B.

[0266] The 250mL crystallization liquid contains about 2.53g / L recombinant insulin aspart, about 0.5g / 100mL citric acid, about 0.05g / 100mL zinc chloride and about 0.1g / 100mL solid phenol, pH=5.0, wherein: The molar ratio between insulin aspart, citric acid, phenol, and zinc chloride is about 1:60.3:24.5:8.6. The specific operation is as follows: Weigh 0.63g of recombinant insulin aspart and dissolve it in 125mL of water to make recombinant aspart Insulin solution; 0.249g of phenol, 0.126g of zinc chloride and 1.25g of citric acid were added thereto, and the volume was adjusted to 250mL by adding water to prepare a crystallization solution. The crystallization solution was stirred at room temperature at a low speed, the pH value was adjusted to 5.0 with sodium hydroxide, and stirred ...

Embodiment 2

[0269] Experiment A:

[0270] The 40mL crystallization solution contains about 0.2M citric acid, about 5g / L recombinant insulin aspart, about 0.2g / 100mL solid phenol, about the same weight of recombinant aspart zinc chloride, about 0.1v / v% ethanol, pH=6.0, wherein: the molar ratio among recombinant insulin aspart, citric acid, phenol and zinc chloride is about 1:255.0:24.6:42.8.

[0271] Experiment B:

[0272] The crystallization solution contains about 5v / v% ethanol, and the other components are the same as in Experiment A.

[0273] The specific operation is as follows: dissolve recombinant insulin aspart in water to prepare a 10g / L recombinant insulin aspart solution, and dissolve solid phenol in water to prepare a 30g / L phenol solution for use; take two 50mL triangular flasks, each Add 20mL of recombinant insulin aspart solution to each flask, then add 1.68g of citric acid, 2.65mL of phenol solution and 200mg of zinc chloride to each flask, and then add 40μL and 2mL to th...

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Abstract

The invention belongs to the technical field of protein crystals, and relates to a preparation method of insulin crystals and a products thereof. Specifically, the method comprises the following steps: 1) mixing insulin, citric acid, phenols, zinc substances, water and an optional organic solvent to obtain crystalline liquid; 2) adjusting the pH value of the crystalline liquid by using a pH regulator, and crystallizing to obtain insulin crystals. The molar ratio among insulin, citric acid, phenols and zinc substances is 1: (127.3-1272.9): (3.1-123.0): (4.3-85.6). The method has the advantages of easiness in crystal formation, mild crystallization conditions, large crystallization temperature range, and short crystallization time. The insulin hexahedral crystals obtained by the method have the advantages of small sedimentation volume, uniformity, stability, high production efficiency, and easiness in industrial production.

Description

technical field [0001] The invention belongs to the technical field of protein crystals, and relates to a method for preparing insulin crystals and insulin crystals obtained by the preparation method. Background technique [0002] Diabetes mellitus is a metabolic disorder characterized by hyperglycemia resulting from defective insulin secretion or action. According to statistics, there are 445 million adults with diabetes in the world, and China accounts for 114 million, which means that more than 1 / 4 of the world's sugar lovers are in China, and the number of diabetics accounts for the first in the world. Diabetes has become an increasingly serious global problem. In recent years, the global prevalence of diabetes has continued to increase. In 2019, the number of people with diabetes aged 20-79 has reached 463 million, and it is predicted that by 2045 it will reach 629 million. [0003] The danger of diabetes is second only to cardiovascular and cerebrovascular diseases an...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K14/62C07K1/30
CPCC07K14/62C07K1/306
Inventor 朱珠方美姑王长凤亓振国张飞周伟路江杰熊爱军
Owner HEFEI TIANMAI BIOTECH DEV
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