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Washing method for insulin crystal or insulin analogue crystal

A technology of insulin analogs and washing methods, applied in the field of biomedicine, can solve the problems of unsuitability for large-scale industrial production, excessive acetic acid or residue on ignition, difficult control of crystallization mother liquor, etc., and achieve simple and easy process amplification and good washing effect , low cost effect

Active Publication Date: 2018-12-04
LUNAN PHARMA GROUP CORPORATION
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

CN105753966A discloses a multiple crystallization method, which reduces the risk of organic solvent residues, but the crystals are not washed, and the crystallization mother liquor residues are not easy to control, which can easily lead to excessive acetic acid or ignition residues, and the crystals are subjected to multiple sterile filter elements Filtration and transfer, low degree of automation, cumbersome operation
CN105585628A discloses a crystallization washing method of recombinant insulin glargine in which the crystals are collected by centrifugation and then washed with water. The material needs to be transferred by centrifugation for many times, the degree of automation is low, the risk of pollution is high, and the cost of process amplification is high, which is not suitable for large-scale industrial production
However, there is no literature report on the use of hollow fiber membranes for crystal washing.

Method used

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  • Washing method for insulin crystal or insulin analogue crystal
  • Washing method for insulin crystal or insulin analogue crystal
  • Washing method for insulin crystal or insulin analogue crystal

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] Embodiment 1 Escherichia coli expresses the washing of recombinant human insulin crystal (0.2 kilograms)

[0025] The hollow fiber membrane (made of polyethersulfone, the inner diameter of the fiber tube is 1mm, and the pore diameter of the filter membrane is 0.1μm) is first rinsed with water for injection to balance, and the water flow rate is adjusted so that the membrane pressure is 15bar and the permeation flux is 30LMH. Fully infiltrate the hollow fiber membrane with 3L of washing buffer (0.15mol / L hydrochloric acid adjusted to pH 5.5 with ammonia water), and 60L of crystallization solution containing 0.2 kg of Escherichia coli expressing recombinant human insulin (containing 17% acetonitrile, 1.1% isopropanol) Stir to form a suspension, pump into the hollow fiber membrane, so that the membrane pressure is 5bar, the permeation flux is 10LMH, and the crystallization suspension is concentrated to about 4L and stopped. Pump 20L of washing buffer solution (0.15mol / L hy...

Embodiment 2

[0032]Embodiment 2 Escherichia coli expresses the washing of recombinant human insulin crystal (1 kilogram)

[0033] The hollow fiber membrane (made of polysulfone, the inner diameter of the fiber tube is 1.75 mm, and the pore size of the filter membrane is 0.2 μm) is firstly rinsed with water for injection to balance, and the water flow rate is adjusted so that the membrane pressure is 15 bar and the permeation flux is 20 LMH. Fully infiltrate the hollow fiber membrane with 5 L of washing buffer (0.1 mol / L lactic acid adjusted to pH 5.0 with ammonia water), stir 300 L of recombinant human insulin crystal solution (containing 15% ethanol, 1.0% acetic acid) containing 1.0 kg of Escherichia coli to form The suspension is pumped into the hollow fiber system, so that the membrane pressure is 5 bar, the permeation flux is 10LMH, and the crystallization liquid suspension is concentrated to about 20L and stopped. Pump 200L of washing buffer solution (0.1mol / L lactic acid adjusted to ...

Embodiment 3

[0037] Embodiment 3 Escherichia coli expresses the washing of recombinant insulin glargine crystal (0.2 kilograms)

[0038] The hollow fiber membrane (made of regenerated cellulose, the inner diameter of the fiber tube is 1 mm, and the pore size of the filter membrane is 0.1 μm) is first rinsed with water for injection to balance, and the water flow rate is adjusted so that the membrane pressure is 15 bar and the permeation flux is 30 LMH. Fully infiltrate the hollow fiber membrane with 3L washing buffer (0.2mol / L citric acid adjusts pH7.0 with sodium hydroxide solution), and 50L containing 0.2 kg of Escherichia coli expressing recombinant insulin glargine crystal solution (containing 16.5% ethanol, 0.9% isopropanol) stirred to form a suspension, pumped into the hollow fiber system, so that the membrane pressure is 5bar, the permeation flux is 10LMH, and the crystallization liquid suspension is concentrated to about 5L and stops. Pump 30L of washing buffer (0.2mol / L citric aci...

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Abstract

The invention discloses a washing method for an insulin crystal or an insulin analogue crystal. The method adopts a hollow fiber membrane to process insulin crystal suspension or insulin analogue crystal suspension. The effective combination of crystal washing, liquid changing and crystal suspension condensation, washing effects can be strengthened, and produce solvent residues and residue on ignition are low; The method can realize continuously automatic operation; and the method is simple in process and easy in operation, technology stability and production efficiency can be enhanced, and therefore, the method is especially suitable for applications on large-scale industrial production.

Description

technical field [0001] The invention belongs to the field of biomedicine, and in particular relates to a method for washing insulin crystals or insulin analog crystals, in particular to a method for washing insulin crystals or insulin analog crystals by using a hollow fiber membrane. Background technique [0002] Insulin and its analogues are polypeptides produced by gene recombination technology and used effectively in the treatment of diabetes. In the process of using gene recombination technology to produce insulin and its analogues, a crystallization step is generally required to prepare insulin or insulin analogue raw materials with uniform structure, stable performance, and favorable preservation. [0003] In the crystallization process of insulin or insulin analogues, the mother liquor often contains organic solvents, which generally need to be removed during crystallization and subsequent crystal washing and freeze-drying. The residual organic solvent will bring risk...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K14/62C07K1/14
CPCC07K14/62
Inventor 张贵民柳常青于锋臣
Owner LUNAN PHARMA GROUP CORPORATION
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