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Purification and ion control method of teriparatide acetate

A technology of teriparatide and control method, which is applied in the field of purification and ion control of teriparatide acetate, can solve the problem that the content of acetate group is not described, the content of impurities and ions is not clear, the content of single impurities is not specified, etc. question

Active Publication Date: 2018-08-07
NANJING HANXIN PHARMA TECH CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Chinese patent CN106167522A discloses dissolving the crude product in 30% acetonitrile aqueous solution, purifying with ammonium acetate buffer, controlling the pH to be 4.0~7.0, acetic acid / acetonitrile C18 column transfer salt, the method for preparing teriparatide acetate, although can obtain Teriparatide acetate acetate with a purity of more than 99%, but the impurity content is not indicated, and the acetate content in the final teriparatide acetate is not described
[0009] In order to solve the problem of unclear impurity and ion content in the prior art, and to obtain the teriparatide API that meets the quality requirements of USP 40, further research on purification and salt conversion methods is required

Method used

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  • Purification and ion control method of teriparatide acetate
  • Purification and ion control method of teriparatide acetate
  • Purification and ion control method of teriparatide acetate

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Embodiment 1

[0040] 1. Sample treatment: Dissolve each gram of crude teriparatide in 50ml of acetonitrile aqueous solution with volume ratio: acetonitrile: water = 5:95, sonicate until completely dissolved, filter through a 0.45 μm filter membrane, and collect the filtrate for later use.

[0041] 2. The first purification:

[0042] Purification conditions: Chromatographic column: DAC-20 dynamic axial pressurized column with octadecylsilane bonded silica gel as the stationary phase, column diameter and packing length: 20*25cm. Mobile phase A: ammonium bicarbonate aqueous solution with a molar concentration of 0.1 mol / L, adjust the pH to 8.0 with ammonia water; phase B: acetonitrile. Flow rate: 1200ml / min. Check wavelength 220nm. Gradient: B%: 10-30%, 45min, the injection volume is 80g.

[0043] Purification process: equilibrate the chromatographic column with mobile phase A and then load the sample, with a sample volume of 4L sample solution. The linear gradient was eluted for 45min, and ...

Embodiment 2

[0053] 1. Sample treatment: Dissolve each gram of crude teriparatide in 50ml of acetonitrile aqueous solution with volume ratio: acetonitrile: water = 5:95, sonicate until completely dissolved, filter through a 0.45 μm filter membrane, and collect the filtrate for later use.

[0054] 2. The first purification:

[0055] Purification conditions: Chromatographic column: DAC-20 dynamic axial pressurized column with octadecylsilane bonded silica gel as the stationary phase, column diameter and packing length: 20*25cm. Mobile phase A: ammonium bicarbonate aqueous solution with a molar concentration of 0.01mol / L, adjusted to pH 7.0 with acetic acid; phase B: acetonitrile. Flow rate: 1200ml / min. Check wavelength 220nm. Gradient: B%: 10% ~ 30%, 45min, the injection volume is 80g.

[0056] Purification process: equilibrate the chromatographic column with mobile phase A and then load the sample, with a sample volume of 4L sample solution. The linear gradient was eluted for 45min, and...

Embodiment 3

[0066] 1. Sample treatment: Dissolve each gram of crude teriparatide in 50ml of acetonitrile aqueous solution with volume ratio: acetonitrile: water = 5:95, sonicate until completely dissolved, filter through a 0.45 μm filter membrane, and collect the filtrate for later use.

[0067] 2. The first purification:

[0068] Purification conditions: Chromatographic column: DAC-20 dynamic axial pressurized column with octaalkylsilane bonded silica gel as stationary phase, column diameter and packing length: 20*25cm. Mobile phase A: ammonium bicarbonate aqueous solution with a molar concentration of 0.01 mol / L, adjust the pH to 7.5 with ammonia water; phase B: acetonitrile. Flow rate: 1200ml / min. Check wavelength 220nm. Gradient: B%: 10% ~ 30%, 45min, the injection volume is 80g.

[0069] Purification process: equilibrate the chromatographic column with mobile phase A and then load the sample, with a sample volume of 4L sample solution. The linear gradient was eluted for 45min, an...

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Abstract

The invention provides a purification and ion control method of teriparatide acetate. The method includes the steps of firstly, using the acetonitrile system of a ammonium bicarbonate aqueous solutionto perform first purification on a crude peptide solution; secondly, using the acetonitrile system of sodium sulfate / sulfuric acid to perform second purification on the collected eluent; thirdly, using the acetonitrile system of an ammonium acetate aqueous solution to elute the collected eluent, and then using the acetonitrile system of an acetic acid aqueous solution to elute the collected eluent to perform high performance liquid phase salt conversion; fourthly, performing vacuum concentration on the eluent after the salt conversion, and then adding hydrochloric acid. The method has the advantages that the hydrochloric acid is added after multiple times of purification and salt conversion to perform acetate plasma content control, different chromatographic systems are used, the purity of the teriparatide acetate prepared by the large-scale preparation is larger than 99%, methionine sulfoxide teriparatide impurity total sum is not larger than 0.05%, maximum unknown individual impurity is not larger than 0.10%, acetate ion content is not larger than 5%, chlorine ion content is not larger than 4%, trifluoroacetate content and sulfate content are not larger than 0.1%, and total yield is lager than 60%.

Description

technical field [0001] The invention relates to a polypeptide purification method, in particular to a purification and ion control method of teriparatide acetate meeting the quality requirements of USP 40. Background technique [0002] Teriparatide (PTH(1-34)), English name Teriparatide, is a long-chain polypeptide drug, and its peptide sequence is: [0003] H-Ser-Val-Ser-Glu-Ile-Gln-Leu-Met-His-Asn-Leu-Gly-Lys-His-Leu-Asn-Ser-Met-Glu-Arg-Val-Glu-Trp-Leu- Arg-Lys-Lys-Leu-Gln-Asp-Val-His-Asn-Phe-OH [0004] Teriparatide is a 1-34 amino acid fragment of human parathyroid hormone (PTH), which was developed by Eli Lilly Company of the United States through genetic recombination technology. It is made into a drug in the form of acetate and was approved by the FDA in 2002. . It is the first bone formation accelerator approved for the treatment of severe osteoporosis and has broad market prospects. [0005] At present, there are many documents and patents related to the synthes...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K14/635C07K1/20C07K1/14
CPCC07K14/635
Inventor 刘晓锐孟俊东刘彬丁伟伟汤传根徐勇刚陈松张昊宁
Owner NANJING HANXIN PHARMA TECH CO LTD
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