Washing method of insulin detemir crystal

A technology of insulin detemir and washing method, which is applied to the preparation methods of insulin and peptides, chemical instruments and methods, etc., can solve the problems of fragile crystal protein, poor uniformity of crystal form, slow crystal sedimentation, etc., and achieves simple operation, The effect of large sample volume and maintaining integrity

Active Publication Date: 2017-09-01
SHANDONG EHUA BIOLOGICAL PHARMA +1
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  • Claims
  • Application Information

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Problems solved by technology

According to the nature of insulin products that are not easily soluble in water, and referring to the crystal washing process of Chinese patent CN 102219851 A, it is found that the crystal protein obtained by low-speed centrifugation and washing with water for injection is fragile, the crystal form uniformity is poor, and the crystal sedimentation is slow during the washing process , some crystals are easy to dissolve, and the yield is low

Method used

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  • Washing method of insulin detemir crystal
  • Washing method of insulin detemir crystal
  • Washing method of insulin detemir crystal

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0059] The washing method of embodiment 1 insulin detemir crystal

[0060] Insulin detemir crystals (prepared in the preliminary examples, the same below) are elongated columnar crystals with a length of 60-100 um. The crystallized solution contains about 0.5mol / L sodium salt, 7.2% acetonitrile (v / v), 0.07% phenol (w / v); with reference to Chinese Patent Application Publication No. CN 102219851A, the crystal is centrifuged at low speed to remove most of the supernatant, and then Wash with cold water for injection. The crystals were completely dissolved after washing.

[0061] The specific steps are:

[0062] (1) Low-speed centrifugation: Divide the crystals and supernatant into individual centrifuge bottles, centrifuge at 600g at 4°C for 15min.

[0063] (2) Washing with water for injection: remove the supernatant from the sample after low-speed centrifugation, and wash the crystal sample with 3.5 L of pre-cooled water for injection, and the crystal is completely dissolved af...

Embodiment 2

[0065] The washing method of embodiment 2 insulin detemir crystals

[0066] Insulin detemir crystals are elongated columnar crystals with a length of 60-100um. The solution of crystallization contains about 0.5mol / L sodium salt, 7.2% acetonitrile (v / v), 0.07% phenol (w / v); carry out crystal washing with reference to Chinese patent CN102219851B: use ammonium acetate of pH7.8 concentration 0.02mol / L Crystal washing was carried out, and the results showed that the crystals were mostly dissolved.

[0067] Concrete ammonium acetate washing step is:

[0068] About 3.4L of ammonium acetate solution (pH7.8, 0.02mol / L) was used to replace the crystallization solution in an equal volume. The ammonium acetate solution was mixed with the crystals and then stirred slightly. During the standing process, it was found that the crystals settled slowly and the crystals became less.

[0069] Stand still for 0.5-1 hour, take a small amount of crystal mirror to check the crystal state, the cryst...

Embodiment 3

[0070] The washing method of embodiment 3 insulin detemir crystals

[0071] Insulin detemir crystals are elongated columnar crystals with a length of 60-100um. The crystallization solution contains about 0.5mol / L sodium salt, 7.2% acetonitrile (v / v), 0.07% phenol (w / v); crystal washing solution: salt solution A is disodium hydrogen phosphate (0.02mol / L), lemon Ammonium citrate (0.015mol / L), pH3.5; Salt solution B is ammonium citrate (0.015mol / L), pH5.6, and the washing liquid for the third time to the fifth washing liquid is precooled water for injection (4 -8°C). All washing operations need to be carried out in a cold room at 4-8°C.

[0072] The specific steps are:

[0073] (1) One wash: Use 3.4 L of salt solution A to replace the crystallization solution in an equal volume, mix salt solution A with the crystals, stir slightly, and let stand for 3 hours.

[0074] (2) Second washing: Use 3.4 L of salt solution B to replace the first washing solution, mix salt solution B wi...

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Abstract

The invention discloses a washing method of an insulin detemir crystal. The method comprises the following steps: (1), removing a crystallization solution after crystallization reaction is accomplished, and adding a weak acid salt solution to wash the left insulin detemir crystal for the first time; (2), removing a washing liquid produced during the washing for the first time, and adding the weak acid salt solution to wash the left insulin detemir crystal for the second time; (3), removing a washing liquid produced during the washing for the second time, and adding water for injection to wash the left insulin detemir crystal for the third time; and (4), removing a washing liquid, and freezing the insulin detemir crystal. The method can efficiently wash the crystallized insulin detemir crystal, the washed insulin detemir crystal is completely kept, the sample yield is high, and the sample purity is not affected. The washing method is simple to operate, low in cost and suitable for industrial large scale production.

Description

technical field [0001] The invention relates to a washing method for insulin detemir crystals, belonging to the field of preparation of insulin detemir crystals. Background technique [0002] Diabetes has become the third chronic non-communicable disease that threatens human health after cardiovascular and cerebrovascular diseases and malignant tumors. The World Health Organization's 2016 annual global diabetes report pointed out that the prevalence of diabetes in China has exploded. The prevalence of diabetes in China reached 9.7% in 2010, and the number of diabetic patients in China exceeded 110 million in 2015. China invests more than 170 billion RMB in diabetes management every year; direct medical expenditure on diabetes accounts for 13% of China's total medical expenditure. The World Health Organization predicts that if actions are not taken as soon as possible, the number of diabetic patients in China will increase to 150 million by 2040, which will seriously affect...

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 刘海峰应欢周祥山黄菁许波马立平聂洪霞刘立岗史兆松
Owner SHANDONG EHUA BIOLOGICAL PHARMA
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