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Method for improving stability of polypeptide active pharmaceutical ingredients

A raw material drug and stability technology, which is applied in the field of polypeptide drug preparation, can solve problems such as unfavorable freeze-dried powder uniformity, and achieve effects that are beneficial to uniformity, water change, sublimation and volatilization

Active Publication Date: 2016-12-07
SINOPEP ALLSINO BIOPHARMACEUTICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] The Chinese published patent document CN 104877024 A introduces the preparation method of bivalirudin, which uses -45°C for pre-freezing, and the obtained ice crystals will present irregular large particles in the shape of snowflakes or rods, which is not conducive to the uniformity of the freeze-dried powder

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0022] Example 1, a method for improving the stability of a polypeptide raw material drug. After the polypeptide raw material drug is salted, a polypeptide solution containing a counterion ion is obtained, and then the target polypeptide product is prepared by an ultra-low temperature vacuum freeze-drying method.

[0023] The polypeptide raw materials are bivalirudin, octreotide acetate, lanreotide acetate, eptifibatide, cetrorelix acetate, ganirelix acetate, degarelix, liraglutide, oxytocin , thymosin α1, leuprolide acetate, goserelin acetate, terlipressin, or liralotide.

[0024] Salt-forming methods include, but are not limited to, reversed-phase high performance liquid chromatography, ion exchange chromatography, or nanofiltration. Said compensation ion is selected from acetic acid, trifluoroacetic acid or non-salt ion. The polypeptide solution is prepared to a suitable concentration by vacuum concentration method, nanofiltration method or dilution method.

[0025] When ...

Embodiment 2

[0026] Embodiment 2: the preparation of Bivalirudin (Bivalirudin)

[0027] (1) Salt conversion

[0028] Get purified bivalirudin solution 15.32 g, concentrate and remove acetonitrile, carry out salt conversion with reversed-phase high performance liquid chromatography, and the chromatographic conditions are as follows:

[0029] Chromatographic column: 50×250 mm, ODS column;

[0030] Loading volume: 3 g target peptide

[0031] Mobile phase A: 2% trifluoroacetic acid, adjust pH to 1.5~6.5 with ammonia water;

[0032] Mobile Phase B: Acetonitrile

[0033] Mobile phase C: 0.05% trifluoroacetic acid in water

[0034] Salt conversion process: inject bivalirudin solution into the chromatographic column, 5% mobile phase B / (B+A) for ion conversion, and then wash bivalirudin with 50% mobile phase B / (B+C) down.

[0035] Concentrate the desalted bivalirudin to 150 mg / ml and prepare for lyophilization.

[0036] The purity of bivalirudin determined by HPLC: 99.61%, the content of the...

Embodiment 3

[0044] Embodiment 3: Preparation of Degarelix Acetate

[0045] (1) Salt conversion

[0046] Get 12.34 g of degarelix acetate solution after purification, concentrate to remove acetonitrile, and carry out salt conversion with reversed-phase high-performance liquid chromatography, and the chromatographic conditions are as follows:

[0047] Chromatographic column: 50×250 mm, ODS column;

[0048] Loading volume: 3 g target peptide

[0049] Mobile phase A: 50 mM ammonium acetate;

[0050] Mobile Phase B: Acetonitrile

[0051] Mobile phase C: 0.05% acetic acid in water

[0052] Salt conversion process: inject degarelix solution into the chromatographic column, 5% mobile phase B / (B+A) for ion conversion, and then wash degarelix with 50% mobile phase B / (B+C) down.

[0053] Concentrate desalted degarelix to 50 mg / ml for lyophilization.

[0054] The purity of degarelix determined by HPLC: 99.33%, the content of the target substance was 11.39 g, and the yield was 92.3%.

[0055] ...

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Abstract

The invention discloses a method for improving the stability of polypeptide active pharmaceutical ingredients. The polypeptide active pharmaceutical ingredients comprise but are not limited to bivalirudin, octreotide acetate, lanreotide acetate, eptifibatide or cetrorelix acetate, ganirelix acetate, degarelix, liraglutide, oxytocin, thymosin alpha1, leuprolide acetate, goserelin acetate, terlipressin or linaclotide. The method comprises the steps that after polypeptide drugs are salified, a polypeptide solution containing compensation ions is obtained, and a target polypeptide product is prepared through an ultralow temperature vacuum freeze-drying method. According to the method for improving the stability of the polypeptide active pharmaceutical ingredients, the problem that the polypeptide active pharmaceutical ingredients are prone to degradation after being placed for a long time is solved, the uniformity of the product is improved, and the drug risk is reduced.

Description

technical field [0001] The invention relates to the technical field of preparation of polypeptide drugs, in particular to a method for improving the stability of polypeptide raw materials. Background technique [0002] There are a variety of polypeptides in the human body, which participate in the regulation of various physiological functions of the human body. Polypeptides are compounds linked by amino acids in the form of peptide bonds. It has been proved that they have strong physiological activity, low immunogenicity, A class of drugs with high curative effect and safe use. There are more than 70 kinds of peptide drugs in the world. In 2015, the peptide drug market reached 26 billion US dollars, and this number is growing at a rate of 15% to 20%. [0003] Peptide drugs have a short half-life in the human body, and the products are unstable and easily degraded. At present, most of them are injections. Methods to improve the stability of peptides include chemical modificat...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K1/20C07K1/18C07K1/34C07K1/14C07K7/08C07K7/06C07K7/23C07K14/605C07K7/16C07K14/575
CPCC07K1/14C07K1/18C07K1/20C07K1/34C07K7/06C07K7/08C07K7/16C07K7/23C07K14/57581C07K14/605
Inventor 刘标谷海涛王蔡典王小涛肖英陈守菊
Owner SINOPEP ALLSINO BIOPHARMACEUTICAL CO LTD
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